ASEAN Federation of Endocrine Societies ASEAN Federation of Endocrine Societies

Indexed in Now Indexed in
PubMed
Central
Journal of the
ASEAN
Journal of Federation
the of
Endocrine
ASEAN Societies
Federation of
Endocrine Societies
Vol. 35 No. 2 November 2020 | ISSN 0857-1074 (Print)| eISSN 2308-118x (Online)
REVIEW ARTICLE
COVID-19 and Thyroid Diseases: How the Pandemic Situation Affects Thyroid Disease Patients
ORIGINAL ARTICLES
Clinical Characteristics, Residual Beta-Cell Function and Pancreatic Auto-Antibodies in Thai people
with Long-Standing Type 1 Diabetes Mellitus
Prevalence of Vitamin B12 Deficiency and its Associated Factors among Patients with Type 2 Diabetes
Mellitus on Metformin from a District in Malaysia
The Association between Maternal Serum Vitamin D Levels and Gestational Diabetes Mellitus among
Filipino Patients: A Cross-Sectional Study
Prevalence and Risk Factors for Hypovitaminosis D among Healthy Adolescents in Kota Bharu, Kelantan
Efficacy of Repetitive Transcranial Magnetic Stimulation (rTMS) in Inducing Weight Loss among Obese
Filipino Patients: A Randomized Controlled Trial
Relationship between Plasma Adiponectin Level and Corrected QT Interval in Smoker and Non-smoker
mber 2017 | ISSNAdult Male
0857-1074 Subjects
| eISSN 2308-118x
CASE REPORTS
Triple Synchronous Tumors Presenting as Right Nasolabial Basal Cell Carcinoma, Papillary Thyroid
Carcinoma and Prolactinoma: A Rare Case Report
Who were those MEN hiding behind the Ulcers?: A Case Report
Primary Partial Empty Sella

ess, peer-reviewed, English language, medical and health science journal
ties (AFES). Its editorial policies are aligned with the policies of the
presenting with Prepubertal Hypogonadotropic Hypogonadism: A Case
Report
Bilateral Genu Valgum in an

e form of original articles, review articles, case reports, feature articles
eviews, et cetera), editorials, letters to the Editor, brief communications
Adolescent with Primary Hyperparathyroidism: A Case Report and Review
FES. of Literature
CASE SERIES
hor Form consisting of: (1) Authorship Certification, that the manuscript
ave been met by each author; (2) the Author Declaration, that the article
Agoitrous
en published or accepted for publication Graves’ Hyperthyroidism
elsewhere; (3) the Statement of with Markedly Elevated Thyroid Stimulating Immunoglobulin Titre
displaying Rapid Response to Carbimazole with Discordant Thyroid Function
FES and are licensed with an Attribution-Share Alike-Non-Commercial
purposes as long as they are properly cited]; and the ICMJE form for
red to submit a scanned copy of the Ethics Review Approval of their
mation about patients.Legions of Presentations of Myxedema Coma: A Case Series from a Tertiary Hospital in India
or(s) and should not be construed to reflect the opinions of the Editors or
Dome-Shaped
authors. It likewise does Pituitary
not ask for subscription fees Enlargement
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Journal of the
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Journal of Federation
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Endocrine
ASEAN Societies
Federation of
Endocrine Societies
Vol. 32 No. 2 November 2017 | ISSN 0857-1074 | eISSN 2308-118x
Vol. 35 No. 2 November 2020 | ISSN 0857-1074 (Print)| eISSN 2308-118x (Online)
The Journal of the ASEAN Federation of Endocrine Societies (JAFES) is an open-access, peer-reviewed, English language, medical and
health science journal that is published two times a year by the ASEAN Federation of Endocrine Societies (AFES). Its editorial policies
are aligned with the policies of the International Committee of Medical Journal Editors (www.icmje.org), and resolves ethical issues
using recommendations and guidelines of the Committee on Publication Ethics (COPE). It is a member of the World Association of
Medical Editors (WAME) and CrossRef, and indexed in PubMed Central, Scopus, Web of Science (WoS), ASEAN Citation Index (ACI),
Directory of Open Access Journals (DOAJ), Western Pacific Index Medicus (WPRIM) and APAMED Central.
The Journal of the ASEAN Federation of Endocrine Societies (JAFES) is an open-access, peer-reviewed, English language, medical and health science journal
that is JAFES welcomes
published manuscripts
two times a year by on
theallASEAN
aspectsFederation
of endocrinology and metabolism
of Endocrine in the Its
Societies (AFES). form of original
editorial articles,
policies reviewwith
are aligned articles, case reports,
the policies of the
featureCommitttee
International articles (clinical practice
of Medical guidelines,
Journal clinical case seminars, clinical practice guidelines, book reviews, et cetera), editorials, letters
Editors (www.icmje.org).
to the Editor, brief communications and special announcements. Authors may include members and non-members of the AFES.
JAFES welcomes manuscripts on all aspects of endocrinology and metabolism in the form of original articles, review articles, case reports, feature articles
Authors are required to accomplish, sign and submit scanned copies of the JAFES Author Form consisting of: (1) Authorship
(clinicalCertification, that
practice guidelines,the
clinical case seminars,
authors contributedclinical practice guidelines,
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to the work; reviews,
the etmanuscript
cetera), editorials,
has been letters
readto and
the Editor, brief by
approved communications
all authors,
and special
and announcements. Authors for
that the requirements mayauthorship
include members
have and
beennon-members
met by eachof author;
the AFES.
(2) the Author Declaration, that the article represents original
material that is not being considered for publication or has not been published or accepted for publication elsewhere; that the article
Authorsdoes not infringe
are required or violatesign
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Form no references
consisting have been Certification,
of: (1) Authorship made to predatory/suspected
that the manuscript
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read and(3) the Author
approved Contribution
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the requirements forlists the specific
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research. Consent forms,
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otherpublished
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the JAFES of the the
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of should not be construed
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EDITORIAL
EDITORIAL CONTACTCONTACT INFORMATION:
INFORMATION: Journal
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the ASEAN ASEAN Federation
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Copyright © 2017 by the Journal of the ASEAN Federation of Endocrine Societies
www://asean-endocrinejournal.org
www.asean-endocrinejournal.org
ELIZABETH PAZ-PACHECO EDITORIAL
Editor-in-Chief Better Normal, A Silver Lining in 2020: JAFES is Accepted for Indexing in PubMed Central 151
Elizabeth Paz-Pacheco
CECILIA A. JIMENO
REVIEW ARTICLE
Vice Editor-in-Chief COVID-19 and Thyroid Diseases: How the Pandemic Situation Affects Thyroid Disease 155
Patients
GABRIEL V. JASUL JR. Laurentius Aswin Pramono
MADE RATNA SARASWATI
WAN NAZAIMOON WAN MOHAMUD ORIGINAL ARTICLES
KYU KYU MAUNG Clinical Characteristics, Residual Beta-Cell Function and Pancreatic Auto-Antibodies 158
LIM SU-CHI in Thai people with Long-Standing Type 1 Diabetes Mellitus
CHAICHARN DEEROCHANAWONG Yotsapon Thewjitcharoen, Sirinate Krittiyawong, Somboon Vongterapak, Soontaree
NGUYEN THY KHUE Nakasatien, Suphab Aroonparkmongkol, Ishant Khurana, Assam El-Osta, Thep
Associate Editors Himathongkam
MARY ANN R. ABACAN Prevalence of Vitamin B12 Deficiency and its Associated Factors among Patients with 163
LORNA R. ABAD Type 2 Diabetes Mellitus on Metformin from a District in Malaysia
Gayathri Devi Krishnan, Miza Hiryanti Zakaria, Norhayati Yahaya
MARISSA M. ALEJANDRIA
PIA D. BAGAMASBAD The Association between Maternal Serum Vitamin D Levels and Gestational Diabetes 169
YUPIN BENJASURATWONG Mellitus among Filipino Patients: A Cross-Sectional Study
CHNG CHIAW LING Carmen Carina Cabrera, Oliver Allan Dampil, Albert Macaire Ong-Lopez
NOR AZMI KAMARUDDIN
TINT SWE LATT Prevalence and Risk Factors for Hypovitaminosis D among Healthy Adolescents in Kota 176
KHOO CHIN MENG Bharu, Kelantan
NORLAILA MUSTAFA Suhaimi Hussain and Maged Elnajeh
NURAIN MOHD NOOR
NATHANIEL S. ORILLAZA JR. Efficacy of Repetitive Transcranial Magnetic Stimulation (rTMS) in Inducing Weight 181
PAUL MATTHEW D. PASCO Loss among Obese Filipino Patients: A Randomized Controlled Trial
AGUNG PRANOTO Margaret Encarnacion, Oliver Allan Dampil, Ludwig Damian, Maria Leila Doquenia,
Divina Cristy Redondo-Samin, Mary Karen Woolbright
CATHERINE LYNN T. SILAO
ROGELIO V. TANGCO Relationship between Plasma Adiponectin Level and Corrected QT Interval in Smoker 190
NGUYEN VAN TUAN and Non-smoker Adult Male Subjects
MYO WIN Yin Thu Theint, Ei Ei Khin, Ohnmar Myint Thein, Mya Thanda Sein
Editorial Board
CASE REPORTS
MARIA LUISA PATRICIA B. GATBONTON Triple Synchronous Tumors Presenting as Right Nasolabial Basal Cell Carcinoma, 200
Chief Manuscript Editor Papillary Thyroid Carcinoma and Prolactinoma: A Rare Case Report
Mateo Te III, Donnah Bless Lumanlan-Mosqueda, Kenny Jun Demegillo
AIMEE A. ANDAG-SILVA
MA. CECILLE S. AÑONUEVO-CRUZ Who were those MEN hiding behind the Ulcers?: A Case Report 210
ELAINE C. CUNANAN Shazatul Reza Binti Mohd Redzuan and Yong Sy Liang
Manuscript Editors
Primary Partial Empty Sella presenting with Prepubertal Hypogonadotropic 215
Hypogonadism: A Case Report
ROBERTO C. MIRASOL Maria Angela Matabang and Buena Sapang
Business Manager
Bilateral Genu Valgum in an Adolescent with Primary Hyperparathyroidism: A Case 220
CATHERINE JESSICA MERCADO-LAZARO Report and Review of Literature
Radiology Editor Siow Ping Lee, Shu Teng Chai, Leh Teng Loh, Norhaliza Mohd Ali
JERICO B. GUTIERREZ CASE SERIES

Creative Editor Agoitrous Graves’ Hyperthyroidism with Markedly Elevated Thyroid Stimulating 224
Immunoglobulin Titre displaying Rapid Response to Carbimazole with Discordant
MARITA V.T. REYES Thyroid Function
JOSE MA. C. AVILA Yin Chian Kon, Brenda Su Ping Lim, Yingshan Lee, Swee Eng Aw, Yoko Kin Yoke Wong
BENITO M. PACHECO
Legions of Presentations of Myxedema Coma: A Case Series from a Tertiary Hospital 233
Editorial Board Advisers in India
Nirmalya Roy, Anirban Majumder, Debmalya Sanyal, Soumyabrata Roy Chaudhuri,
AMADO O. TANDOC III Suman Sarkar, Ankan Pathak
Editorial Coordinator
Dome-Shaped Pituitary Enlargement in Primary Hypothyroidism: Avoiding Neurosurgical 238
MELISSA O. TANDOC Interventions
Secretary/Website Administrator Satyam Chakraborty, Mona Tiwari, Rajan Palui, Kajari Bhattacharya, Kalyan Kumar
Gangopadhyay
JOHANN FABRIAN Q. BOLINAO
KIM L. COCHON Instructions to Authors 244
ETHEL M. ESTANISLAO Authorship Form 248
AL JOSEPH R. MOLINA ICMJE Form for Disclosure of Potential Conflicts of Interest 251
Patient Consent Form 254
JESUS N. SAROL JR.
Peer Reviewers 255
Statisticians
Emerging Sources Citation Index

Editorial JAFES
Better Normal, A Silver Lining in 2020:

JAFES is Accepted for Indexing in PubMed Central
COVID-19 continues to redefine the way we live and the way we work. We have no
recourse but to embrace a different way of life: wearing masks and face shields in public,
establishing physical and social distancing, and practicing hand hygiene at all times.
As medical practitioners, educators, and researchers, we adapt our profession and practice
in the context of this public health threat.
We have realized that there are novel and innovative ways to take care of our patients,
confer and meet with our colleagues, teach our students, and mentor our Residents and
Fellows. When it concerns our researches for purposes of understanding a disease and
improving a policy, data gathering among patients in clinics and hospitals remains limited;
yet different research designs and strategies still enable meaningful studies.
For us at the JAFES, the new normal meant getting together virtually for the bi-annual
editorial board meeting. To our pleasant surprise, the virtual meetings allowed for near
complete attendance by the Philippine team as well as the ASEAN editors. With live
interactive discussions, even if remote, the outputs became more profound and prolific.
(Figure 1). Why didn’t we think of virtual meeting before the pandemic? Technology
allowed us to see each other beyond the usual written correspondences. Despite the
challenges of bandwidth and connectivity, we had in-depth discussions on concerns with
publication ethics and operational issues.
Figure 1. JAFES Editorial Board members from the ASEAN countries hold a productive
virtual editorial board meeting to finalize its second issue.
The May JAFES issue headlined diabetes, its impact on one’s susceptibility to COVID-19
and likelihood of having a more stormy course. This time, the November issue banners a
review article on COVID-19 and thyroid disorders, underscoring the need for re-assessing
how we take care of endocrine disorders during these challenging times. Recognizing some
delays in the patients’ trips to the hospital or clinic for non-urgent elective care, periodic
follow-ups of these conditions can still be successfully carried out through tele consults
with electronic prescriptions. Patient education continues through the electronic sharing of
materials and videos. When necessary, we have designated smaller teams with safe hospital
set-ups and technologies to carry out the task, all for the best interests of our patients to
proceed with diagnostic work-ups, elective surgeries, and other treatment options. The
internet has become a more powerful tool; and, as most everyone is engaged in its use,
guidance for its more responsible use should become available.
Vol. 35 No. 2 November 2020 www.asean-endocrinejournal.org 151

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/).
152 Editorial
Amid the uncertainties and challenges brought on by the COVID-19 pandemic, we celebrate
another major milestone in the continuing journey of the JAFES. We formally announce
here our acceptance to PubMed Central, (Figure 2), after being included in Scopus and
Clarivate Analytics Emerging Sources Citation Index in the last 2 years. Launched in 2000,
PubMed Central is a free archive of full-text biomedical and life sciences journal articles,
serving as a digital counterpart to the print journal collection of the US National Library
of Medicine. As a participating journal, JAFES shall be depositing full text articles starting
from 2017 and these shall be available 100% open access and searchable also in MedLine.
US National Library of Medicine

National Institutes of Health
Figure 2. JAFES passed the scientific quality and technical review by NML for PMC.
The pandemic shook us out of our comfort zones, obliged us a new look at doing things, and
led us to improve our ways and the effects on the people that we serve. We all look toward
a better normal.
We wish everyone a safe and healthy end of 2020 and hope for a better New Year 2021!
Elizabeth Paz-Pacheco
Editor-in-Chief
________________________________________
https://doi.org/10.15605/jafes.035.02.15
www.asean-endocrinejournal.org Vol. 35 No. 2 November 2020

Journal of the
ASEAN Federation of
Endocrine Societies
We are pleased to announce that the

Journal of the ASEAN Federation of Endocrine Societies
(JAFES) has been accepted for indexing in PubMed
Central (PMC) after undergoing in-depth review of editorial
content and policies, including a rigorous technical
assessment.
This achievement is a significant addition to the JAFES’ list of

credentials. JAFES is currently indexed in Scopus®, Emerging
Sources Citation Index™ (ESCI) under Clarivate™ Analytics,
PubMed Central is a
ASEAN Citation Index (ACI), the Directory of Open Access
Journals (DOAJ), and the Western Pacific Region Index free archive of full-text
Medicus (WPRIM). biomedical and
life sciences journal
All articles published in JAFES from 2017 to present shall now
be indexed and made available 100% Open Access through
articles, serving as a
PubMed Central, and searchable through PubMed. This is digital counterpart to
part of our commitment to authors to ensure wide reach of the print journal
their scientific findings, and to our readers to assure you of the collection of the
quality of our content.
US National Library
Follow us in: of Medicine.
Review Article
Journal of the
ASEAN Federation of
Endocrine Societies
COVID-19 and Thyroid Diseases:

How the Pandemic Situation Affects Thyroid Disease Patients
Laurentius Aswin Pramono
Department of Public Health and Nutrition, School of Medicine and Health Sciences, Atma Jaya Catholic University of Indonesia, Jakarta, Indonesia
Department of Internal Medicine, Saint Carolus Hospital, Jakarta, Indonesia
Abstract
Patients with thyroid diseases need special attention during this COVID-19 pandemic. There is a paucity of publications
that review the effect of coronavirus infection on thyroid disease patients, such as those with hyperthyroidism,
hypothyroidism, thyroid nodules and cancer. This article aims to collect reviews and statements about how the
COVID-19 pandemic has affected the management of thyroid disease patients.
Key words: COVID-19, thyroid disease, hyperthyroidism, hypothyroidism, thyroid cancer
INTRODUCTION Autopsy findings in patients with SARS showed destruction

of follicular and parafollicular thyroid cells which led
The World Health Organization (WHO) announced to low T3 and T4.7 Viral infections can affect thyroid
the global pandemic situation caused by severe acute hormone synthesis causing low T4 and T3, a common
respiratory syndrome coronavirus 2 (SARS-CoV-2) as phenomenon known as non-thyroidal illness syndrome.
coronavirus disease 2019 (COVID-19) in March 2020.1 The
disease has spread widely all over the world, including Chronic viral infections can later lead to autoimmune
Southeast Asian countries.1 The pandemic is a great burden disease, including thyroid diseases, such as Graves’ disease
to all communities and populations. Older citizens and and Hashimoto’s thyroiditis. Viral infections account for
people with chronic and degenerative diseases are prone major environmental factors in subacute and chronic auto-
to severe illness if infected by the virus.2 Furthermore, immune thyroiditis.8 Coxsackie virus, echovirus, Epstein-
morbidity and mortality caused by COVID-19 are higher in Barr virus, herpes simplex virus, mumps and parvovirus
patients with chronic, metabolic and degenerative diseases are thought to cause autoimmune thyroiditis. Presently,
such as diabetes, hypertension, cardiovascular disease, there are no published studies on the effect of COVID-19
cancer, stroke and autoimmune diseases.3 and the risk for later autoimmune thyroid disease.
As COVID-19 is a new illness, its effects on patients Statements from thyroid societies
with thyroid disease are not yet known.4 Because of the
prevalence of thyroid disease—1 to 2% for spontaneous Various thyroid interest groups, including the American
hypothyroidism, 0.5 to 2% for hyperthyroidism in women Thyroid Association (ATA), the European Thyroid
(10 times more common than in men), and 1% and 5% Association (ETA), the British Thyroid Foundation (BTF)
for clinically detectable thyroid nodules in men and and the American Association for Clinical Endocrinologists
women, respectively—it may be surmised that patients (AACE), have released statements in their respective
with the disease may be affected directly and indirectly official websites for the guidance of thyroid patients during
by the pandemic situation.5 This review aims to collect the COVID-19 pandemic.4,9-11 The statements provide
publications which discuss consequences of COVID-19 in information for physicians and patients on how to deal
thyroid disease patients. with specific thyroid concerns during the pandemic.
Pathobiology Thyroid disorders may be generally divided to three major

conditions, namely, hyperthyroidism, hypothyroidism,
There are a limited number of publications on the effect of and thyroid nodules and cancer. Hyperthyroidism
viral infections on thyroid pathology. A study on severe encompasses conditions caused by overactive thyroid
acute respiratory syndrome (SARS) patients during the function, resulting in elevated levels of thyroid hormones
outbreak in 2003 found that triiodothyronine (T3) and (free T4 and free T3) and low levels of thyroid stimulating
thyroxine (T4) levels were lower in SARS patients compared hormone (TSH). This includes Graves’ disease, toxic
to controls, during the acute and convalescent phases.6 multinodular goiter (Plummer’s disease) and toxic nodular
________________________________________
ISSN 0857-1074 (Print) | eISSN 2308-118x (Online) Corresponding author: Laurentius Aswin Pramono, MD, MSc (Epidemiology)
Printed in the Philippines Academic Staff, Department of Public Health and Nutrition
Copyright © 2020 by Pramono. School of Medicine and Health Sciences
Received: May 25, 2020. Accepted: July 13, 2020. Atma Jaya Catholic University of Indonesia
Published online first: July 30, 2020. Jalan Pluit Raya 2, North Jakarta, Indonesia
https://doi.org/10.15605/jafes.035.02.01 E-mail: [email protected], [email protected]
ORCiD: https://orcid.org/0000-0001-7271-7594

156 Laurentius Aswin Pramono How the COVID-19 Pandemic Situation Affects Thyroid Disease Patients
goiter (toxic adenoma). Hypothyroidism is a condition be prescribed for 3 or 4 months to limit clinic visits. Calcium
of low free T4 and free T3 levels, and high TSH, as seen and vitamin D must also be continued with the same dose.
in csongenital hypothyroidism, endemic goiter (iodine
deficiency disorder), and chronic autoimmune thyroid Thyroid nodule and cancer
disease (Hashimoto’s thyroiditis). Thyroid nodules and
cancer are in the same category of neoplasia. The treatment The urgency to perform fine needle aspiration (FNA) biopsy
of thyroid cancer includes surgery (thyroidectomy), or thyroid cyst aspiration is determined by the patient’s
radioactive iodine therapy (radioablation), and TSH risk factors, the characteristics of the nodule and clinical
suppression therapy with levothyroxine. judgment.9 Generally, it is safe to perform FNA biopsy
or cytology if standard personal protective equipment
Hyperthyroidism (PPE) are worn.13 If the nodule is highly suspicious for
malignancy, has indicators of thyrotoxicosis, or with
The ATA, BTF and AACE have stated that autoimmune concomitant compression signs and symptoms, prompt
thyroid disease which resulted to hyperthyroidism (Graves’ referral to a head and neck, thyroid or oncologic surgeon
disease, multinodular toxic goiter or toxic adenoma) does to prepare for thyroidectomy is recommended. If the
not increase the risk for COVID-19 infection, morbidity or nodule is deemed moderately to highly suspicious and
mortality.9-11 Patients maintained on anti-thyroid drugs or would be aided by preoperative cytology, FNA biopsy
levothyroxine also do not have a higher risk for COVID-19 may be performed with a moderate level of PPE. If the
infection. It is important to continue thyroid medications nodule has very low to low suspicion of malignancy,
since being untreated or suboptimally controlled may biopsy may be postponed and the nodule may be observed
increase the risk of viral infection or complications.4,11 by repeating thyroid ultrasonography at 3 to 6 months.
Treatment with anti-thyroid drugs (ATD) like Thyroid cancer patients generally do not have a higher
propylthiouracil, carbimazole, methimazole may cause risk for COVID-19 infection. Majority of thyroid cancers
agranulocytosis, a very rare adverse reaction with are well-differentiated, specifically papillary and follicular
symptoms resembling COVID-19. These include fever, thyroid cancer.4,9,10 Both types are slow growing, rarely
sore throat and muscle pain.9,11 Physician assessment must aggressive, and infrequently metastasize to distant organs.
be done promptly to ascertain the cause of the symptoms. Some well-differentiated cancers with aggressive character
and higher stages from vascular invasion, lymph node
ATDs must be continued with the same dose and titration, metastases and distant spread pose a higher risk for viral
as was done prior to the pandemic. The medications may infection including COVID-19. Morbidity and mortality
be prescribed for two to three months to minimize the need can also increase, especially in those with lung metastases.11
for frequent clinic visits.9-11 Maintaining euthyroidism as
long as possible can prevent more severe conditions such Poorly-differentiated thyroid cancers, specifically medullary
as thyroid storm, an unexpected severe complication of and anaplastic types, have a higher risk for morbidity and
viral infections in uncontrolled hyperthyroid patients.12 mortality from COVID-19 infection. These patients, and
also those with aggressive variants of well-differentiated
In Graves’ orbitopathy or other forms of thyroid-related thyroid cancer, sometimes receive tyrosine kinase
eye disease, the use of high dose (500 mg) intravenous inhibitors (sorafenib, vandetanib or lenvatinib) after total
glucocorticoid (methylprednisolone) weekly for six weeks thyroidectomy or radioactive iodine therapy. These agents
may suppress the immune system and increase the risk suppress the immune system and may confer a higher risk
for infection, including COVID-19; or worsen blood of severe pneumonia in outbreak situations.4,9-11 Patients
glucose control which can lead to prolonged length of who have previously received external beam radiotherapy
stay in the hospital.11 The decision to give this therapy to the neck also have a higher risk for severe illness
has to be made after having fully discussed the risks from COVID-19.4 All high risk thyroid cancer patients
and benefits with the patient. The patient should be well must then be advised to self-isolate and stay at home
advised to observe and maintain physical hygiene and during the pandemic.
distancing while on high dose corticosteroid therapy.
The decision to proceed with thyroid surgery during
Hypothyroidism the pandemic is based on consideration of the surgeon,
the patient’s condition, the hospital (i.e., availability of
The various etiologies of hypothyroidism such as operating room), the availability of personal protective
Hashimoto’s thyroiditis, post-thyroidectomy for thyroid equipment (PPE) and adequate screening prior to surgery.
nodule or thyroid cancer, post-radioactive iodine therapy Hospitals in Jakarta, such as the Saint Carolus Hospital,
or congenital hypothyroidism, are all treated with perform examinations including chest X-ray, chest
levothyroxine to maintain normal thyroid hormone levels. computerized tomography scan, complete blood count,
Hashimoto’s thyroiditis is a chronic autoimmune condition C-reactive protein, lactate dehydrogenase, rapid antibody
that may present with other autoimmune conditions. The test for IgM/IgG SARS-CoV2, real time-polymerase chain
BTF reassures patients that the condition does not increase reaction for SARS-CoV2 of nose and throat specimens,
the risk of COVID-19 infection, morbidity or mortality.4 and adequate preoperative consultation and screening
with an internal medicine specialist or pulmonologist
Levothyroxine must be continued with the same dose as and an anesthesiologist.14 With the application of a complete
before the pandemic.4,9-11 Once the patient has attained general preoperative assessment including specific
euthyroidism (normal free T4 and TSH levels) with a screening to prevent the spread of COVID-19, thyroid
known total dose in a day or a week, the medication may surgical procedures can be performed safely.

How the COVID-19 Pandemic Situation Affects Thyroid Disease Patients Laurentius Aswin Pramono 157
Table 1. Conditions that warrant urgent (<4 weeks) thyroid surgery

1. Thyroid cancer which is life-threatening (large size), with local invasion to the trachea or recurrent laryngeal nerve, with aggressive features (rapid growing,
adherent to nearby organs, with distant metastases)
2. Graves’ disease or toxic adenoma with severe or life-threatening symptoms, which cannot be controlled by anti-thyroid medications
3. Goiter or enlargement of the thyroid gland with respiratory or gastrointestinal tract compressive symptoms
4. Open core-biopsy (and removal, total or near-total thyroidectomy) for nodules highly suspicious for thyroid cancer, such as medullary thyroid cancer
(high calcitonin and with highly suspicious ultrasonographic characteristics), anaplastic thyroid cancer or thyroid lymphoma if other diagnostic modalities
are equivocal or inconclusive
5. Pregnant patient with thyrotoxic and compressive symptoms presenting a life-threatening condition for the mother and fetus and cannot be controlled
with anti-thyroid medications
Adapted from the American Thyroid Association. Novel coronavirus (COVID-19) and the thyroid. https://www.thyroid.org.9
Other issue is about radioactive iodine therapy during Funding Source

the COVID-19 pandemic. The ATA clearly states that None.
radioactive iodine (RAI) therapy for patients with possible
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Graves’ hyperthyroidism or toxic multinodular goiter, anti- org/10.1016/j.jinf.2020.03.005.
3. Yang J, Zheng Y, Gou X, et al. Prevalence of comorbidities and its
thyroid medications may be preferred, as these provide effects in patients infected with SARS-CoV-2: A systematic review
an easier and simpler means of achieving euthyroidism. and meta-analysis. Int J Infect Dis. 2020;94:91-5. PMID: 32173574.
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4. British Thyroid Foundation. Thyroid disease and coronavirus
Conclusion (COVID-19). 4 May 2020. https://www.btf-thyroid.org/news/thyroid-
disease-and-coronavirus-covid-19.
During this time of the COVID-19 pandemic, thyroid 5. Vanderpump MPJ. Epidemiology of thyroid disorders. In: Luster
M, Duntas L, Wartofsky L, eds. The Thyroid and Its Diseases:
disease patients must receive optimal therapy for each A Comprehensive Guide for the Clinician. Cham, Switzerland:
of their conditions, such as hyperthyroidism, thyroid Springer, 2019.
eye disease, hypothyroidism, thyroid nodules and 6. Pal R, Banerjee M. COVID-19 and the endocrine system: Exploring the
unexplored. J Endocrinol Invest. 2020;43(7):1027-31. PMID: 32361826.
thyroid cancer. Statements from the American Thyroid PMCID: PMC7195612. https://doi.org/10.1007/s40618-020-01276-8.
Association, the European Thyroid Association, the British 7. Wei L, Sun S, Xu C, et al. Pathology of the thyroid in severe acute
Thyroid Foundation and the American Association for respiratory syndrome. Hum Pathol. 2007;38(1):95-102. PMID: 16996569.
PMCID: PMC7112059. https://doi.org/10.1016/j.humpath.2006.06.011.
Clinical Endocrinologists (AACE) can guide clinicians, 8. Desailloud R, Hober D. Viruses and thyroiditis: An update. Virol J.
physicians, endocrinologists and thyroid surgeons in 2009;6(5). https://doi.org/10.1186/1743-422X-6-5.
their therapeutic decisions. 9. American Thyroid Association. Novel coronavirus (COVID-19) and
the thyroid: Resources. https://www.thyroid.org/covid-19/.
10. European Thyroid Association. COVID-19: Information and
Acknowledgments recommendations for patients with thyroid diseases. ETA Public
The author expresses his gratitude to the Department of Public Health Board Statement. https://www.eurothyroid.com/news/covid-
Health and Nutrition, School of Medicine and Health Sciences, 19-thyroid-diseases.html.
Atma Jaya Catholic University of Indonesia; the Department of 11. American Association of Clinical Endocrinologists. AACE position
statement: Coronavirus (COVID-19) and people with thyroid disease.
Internal Medicine, Saint Carolus Hospital; and the Saint Carolus
https://www.aace.com/recent-news-and-updates/aace-position-
COVID-19 Outbreak Team for supporting the faculty in their statement-coronavirus-covid-19-and-people-thyroid-disease.
teaching and academic activities, in clinical work, and in their 12. Baharoon SA. H1N1 infection-induced thyroid storm. Ann Thorac
endeavors in writing studies and reviews during the time of Med. 2010;5(2):110-2. PMID: 20582177. PMCID: PMC2883193.
the COVID-19 pandemic. https://doi.org/10.4103/1817-1737.62475.
13. Vigliar E, Iaccarino A, Bruzzese D, et al. Cytology in the time of
coronavirus disease (COVID-19): An Italian perspective. J Clin Pathol.
Statement of Authorship
2020; jclinpath-2020-206614. PMID: 32312717. PMCID: PMC7211103.
The author certifies fulfillment of ICMJE authorship criteria. https://doi.org/10.1136/jclinpath-2020-206614.
14. Hardi F, Shinto R, Putra AC, Fahmi M, Wiyono WH, Pramono LA, et
Author Disclosure al. Coronavirus disease (Covid-19) service in Saint Carolus Hospital.
The author declared no conflicts of interest. Updated 29 April 2020. Saint Carolus Hospital, Jakarta, Indonesia.
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Vol. 35 No. 2 November 2020 www.asean-endocrinejournal.org

Original Article
Journal of the
ASEAN Federation of
Endocrine Societies
Clinical Characteristics, Residual Beta-Cell Function

and Pancreatic Auto-Antibodies in Thai people
with Long-Standing Type 1 Diabetes Mellitus
Yotsapon Thewjitcharoen,1 Sirinate Krittiyawong,1 Somboon Vongterapak,1 Soontaree Nakasatien,1
Suphab Aroonparkmongkol,2 Ishant Khurana,3 Assam El-Osta,3 Thep Himathongkam1
1
Diabetes and Thyroid Center, Theptarin Hospital, Bangkok, Thailand
2
Division of Pediatric Endocrinology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
3
Epigenetics in Human Health and Disease Laboratory, Department of Diabetes, Central Clinical School,
Faculty of Medicine Nursing and Health Sciences, Monash University, Melbourne, Australia
Abstract
Objectives. To describe the characteristics of long-standing T1DM in Thai patients and assess residual beta-cell
function with status of pancreatic autoantibodies.
Methodology. This is a cross-sectional study of Thai subjects with T1DM and disease duration ≥ 25 years seen at
the Theptarin Hospital. Random plasma C-peptide and pancreatic auto-antibodies (Anti-GAD, Anti-IA2, and Anti-ZnT8)
were measured. Patients who developed complications were compared with those who remained free of complications.
Results. A total of 20 patients (males 65%, mean age 49.4±12.0 years, BMI 22.5±3.1 kg/m2, A1C 7.9±1.6%) with
diabetes duration of 31.9±5.1 years were studied. Half of the participants remained free from any diabetic complications
while the proportions reporting retinopathy, nephropathy, and neuropathy were 40%, 30%, and 15%, respectively. HDL
cholesterol was significantly higher and triglyceride concentration significantly lower in patients who were free from
diabetic nephropathy but not in those who were free from other complications. The prevalence rates of anti-GAD, anti-
IA2, and anti-ZnT8 were 65%, 20%, and 10%, respectively. None of the patients who tested negative for both anti-GAD
and anti-IA2 was positive for anti-ZnT8. Residual beta-cell function based on detectable random plasma C-peptide
(≥ 0.1 ng/mL) and MMTT was found in only 3 patients (15%). There was no relationship between residual beta-cell
function and protective effects of diabetic complications.
Conclusion. Endogenous insulin secretion persists in some patients with long-standing T1DM and half of long-
standing T1DM in Thai patients showed no diabetic complications. HDL cholesterol was significantly higher and
triglyceride concentration significantly lower in patients who were free from diabetic nephropathy.
Key words: type 1 diabetes mellitus, long-standing, residual beta-cell function, pancreatic autoantibodies, Thai people
INTRODUCTION clinical endpoint in clinical trials. However, the clinical

significance of long-duration T1DM in Asian populations
Emerging evidence in Caucasian populations suggests remained poorly understood. A recent study of 95
that endogenous insulin secretion persists in long-standing Chinese people with T1DM duration of ≥30 years revealed
type 1 diabetes mellitus (T1DM). This is protective against that almost 70% of the participants remained free from
severe hypoglycemia and is implicated in the reduced diabetic complications.4 Interestingly, residual beta-cell
incidence of microvascular complications.1-3 Following function assessed by plasma C-peptide ≥0.075 nmol/L
onset of diabetes, patients with T1DM exhibit diverse was observed in 15% of study participants but pancreatic
amounts of residual c-peptide, indicating varying auto-antibodies had been detected in less than 20% of
levels of endogenous insulin production and beta cell patients. Furthermore, favorable lipid profiles were
function. Persistence of residual c-peptide is associated observed in these participants and closely corresponded
with improved glycemic control and reduced risk of with the Golden Years Cohort from United Kingdom and
complications and its preservation has been used as a the Joslin 50-Year Medalist cohort from United States.
________________________________________
ISSN 0857-1074 (Print) | eISSN 2308-118x (Online) Corresponding author: Yotsapon Thewjitcharoen, MD
Printed in the Philippines Diabetes and Thyroid Center, Theptarin Hospital
Copyright © 2020 by Thewjitcharoen et al. 3858 Rama IV Rd., Long Toey, Bangkok 10110, Thailand
Received: May 25, 2020. Accepted: July 28, 2020. Tel. No.: +66-02-3487000
Published online first: August 3, 2020. Fax No.: +66-02-2498774
https://doi.org/10.15605/jafes.035.02.02 E-mail: [email protected]
158 www.asean-endocrinejournal.org Vol. 35 No. 2 November 2020

Clinical and Pathological Characteristics in Long-Standing Type 1 DM in Thai People Yotsapon Thewjitcharoen, et al 159
Objectives 3-6 months apart. Neuropathy was detected based on

annual monofilament test and/or vibration perception
To better understand the clinical features of long- threshold testing. Macrovascular complications including
standing T1DM in Thai people, we evaluated the coronary artery disease, stroke, and peripheral vascular
clinical characteristics of long-standing T1DM (duration disease were noted.
of diabetes ≥25 years) in Thai patients and assessed
residual beta-cell function together with the status of Plasma C-peptide was measured by chemiluminescent
pancreatic autoantibodies. immunometric assay (IMMULITE®, Siemens) with an inter-
assay coefficient of variation 3.3% at plasma C-peptide
Methodology 0.2 nmol/L. Mixed meal tolerance test (MMTT) was
measured if random plasma C-peptide was ≥ 0.03 nmol/L.
A cross-sectional study of Thai participants with T1DM MMTT was done by ingestion of 6 mL/kg of Ensure®
registered at Theptarin Hospital, a tertiary diabetes up to 360 mL (1 calorie/mL; 65% carbohydrates, 21%
center in Bangkok was performed from January 2019 protein and 14% fat) after overnight fasting (at least 8 h)
to June 2019. T1DM was defined based on the clinical and withholding of insulin injection or oral agents (at
presentations of abrupt onset of symptoms including least 12 h). Plasma C-peptide and plasma glucose were
polyuria, polydipsia or unexplained weight loss, diabetic obtained at 0 and 90 min after the ingestion. Pancreatic
ketoacidosis (DKA) and insulin requirement from the auto-antibodies (Anti-GAD, Anti-IA2, and Anti-ZnT8)
time of diagnosis for control of hyperglycemia. Plasma were assessed by ELISA method (RSR ®, UK). All the
C-peptide was measured in all T1DM cases and potential cut-off values for positivity of pancreatic auto-antibodies
cases of misdiagnosis of T1DM were excluded if fasting were based on the manufacturer label. Cut-off point for
C-peptide is ≥0.2 nmol/L after several years of onset anti-GAD positivity is 5 U/mL with a specificity of 98%
of DM.5 If pancreatic autoantibodies were negative or and sensitivity of 92%. Cut-off point for anti-IA2 positivity
unknown, then insulin must have been started at or is 7.5 U/mL with a specificity of 100% and sensitivity of
shortly after diagnosis and used continually thereafter. 68%. Cut-off value for ZnT8A positivity is 15 U/ml with a
Other types of diabetes including latent autoimmune specificity of 97% and sensitivity of 76%. Participants who
diabetes in adults (LADA) and Maturity Onset Diabetes developed complications were compared with those that
of the Young (MODY) were excluded. None of the T1DM remained free of diabetic complications. All participants
patients in our cohort underwent islet cell transplantation provided informed consent and the Ethics Committee
or pancreatic transplantation. No HLA haplotype was of Theptarin Hospital approved the study (EC 09/2018).
done in our routine care of patients with T1DM. Long-
standing T1DM was defined as disease duration ≥25 years. Statistical analyses
Demographic data, mean glycated hemoglobin (HbA1c) in Continuous variables were presented as mean (SD) and
the previous 12 months, lipid profiles, serum creatinine, categorical variables were presented as proportions.
history of acute diabetic complications including severe Comparisons between T1DM without any complication
hypoglycemia in the previous 12 months, chronic diabetic and T1DM with complication were done using unpaired
complications, and other co-morbidities during the study Student’s t-test for continuous data and Chi-square
period were noted. Retinopathy was detected with the test for categorical data. P-value ≤0.05 was considered
regular dilated eye examinations by ophthalmologists statistically significant. All statistical analyses were
annually. Nephropathy was defined as persistent conducted using the Statistical Package for the Social
microalbuminuria greater than 30 mg of albumin per Sciences (version 17.0; SPSS, Chicago, IL, USA).
g of creatinine from spot urine on at least 2 occasions,
Table 1. Clinical characteristics and laboratory data of Thai people with long-standing type 1 diabetes mellitus
All patients Free of any complication With DM complications
p-value
(n=20) (n=10) (n=10)
Age (yrs) 49.4±12.0 47.3±11.9 51.4±12.3 0.459
Male/Female 13/7 8/2 5/5 0.160
Age at diagnosis (yrs) 17.5±9.4 16.4±9.2 18.5±10.0 0.632
Pre-pubertal onset (%) 35% 50% 25% 0.160
Initial presentation with DKA (%) 70% 60% 80% 0.235
Duration of DM (yrs) 31.9±5.1 30.9±5.1 32.9±5.1 0.392
Current Smoking (%) 10% 10% 10% 0.763
BMI (kg/m2) 22.5±3.1 22.0±2.5 23.0±3.7 0.501
Daily insulin usage (unit/kg) 40.7±14.9 38.6±8.9 42.8±19.5 0.547
HbA1c (mmol/mol) 63±2 57±1 68±2 0.176
HbA1c (%) 7.9±1.6 7.4±1.1 8.4±1.9 0.176
SBP (mmHg) 120±14 118±12 121±16 0.577
DBP (mmHg) 69±9 70±10 67±8 0.459
Total Cholesterol (mmol/l) 4.6±0.8 4.9±1.0 4.2±0.4 0.088
Triglyceride (mmol/l) 0.8±0.4 0.8±0.4 0.9±0.4 0.370
HDL (mmol/l) 1.9±0.5 2.1±0.5 1.7±0.5 0.097
LDL (mmol/l) 2.7±0.8 2.9±0.9 2.5±0.5 0.237
Detectable random plasma C-peptide (%) 15% 10% 20% 0.435

160 Yotsapon Thewjitcharoen, et al Clinical and Pathological Characteristics in Long-Standing Type 1 DM in Thai People
Table 2. Comparisons between T1DM patients with residual beta-cell function and patents without residual
beta-cell function
T1DM with residual T1DM without residual
p-value
beta-cell function (n=3) beta-cell function (n=17)
Age (yrs) 41.7±8.5 50.7±12.1 0.238
Male/Female 1/2 12/5 0.234
Age at diagnosis (yrs) 11.7±5.8 18.5±9.7 0.261
Pre-pubertal onset (%) 33.3% 35.3% 0.345
Duration of DM (yrs) 30.0±3.0 32.2±5.3 0.496
BMI (kg/m2) 23.6±4.8 22.3±2.9 0.496
Daily insulin usage (unit/kg) 36.7±15.0 41.4±15.3 0.625
HbA1c (mmol/mol) 61±1 63±1 0.862
HbA1c (%) 7.7±2.1 7.9±1.5 0.862
Free from DM complications (%) 33.3% 52.9% 0.556
Episodes of severe hypoglycemia in the past 12 months (%) 33.3% 35.3% 0.745
Results
From a total of 89 T1DM cases in our hospital, 20

long-standing T1DM participants were identified and
studied. Baseline clinical data (males 65%, mean age
49.4±12.0 years, BMI 22.5±3.1 kg/m2, HbA1c 63±2 mmol/
mol, 7.9±1.6%) with duration of diabetes 31.9±5.1 years
were shown in Table 1. DKA was the initial presentation
in 14 patients from the cohort of 20 T1DM patients
(70%) with long-standing duration of diabetes. Severe
hypoglycemia in the previous 12 months was found in
35% of all patients. Half of the participants remained free
from any diabetic complications while the proportions
reporting retinopathy, nephropathy, and neuropathy
were 40%, 30%, and 15%, respectively. Even though
HDL cholesterol tended to be higher in participants
Figure 1. The distribution of pancreatic auto-antibodies
who were free from any diabetic complications, it did
in our T1DM patients with long-standing duration (N =
not reach statistical significance (2.1 mmol/L vs. 1.7
20 cases).
mmol/L, p-value = 0.097). However, HDL cholesterol was
significantly higher (2.1 mmol/L vs. 1.5 mmol/L, p-value =
0.011) and triglyceride concentrations were significantly Discussion
lower (1.7 mmol/L vs. 2.5 mmol/L, p-value = 0.036) in
participants who were free from diabetic nephropathy T1DM is a heterogeneous disease and the recent
but not in those who were free from other complications. description of the ‘endotype’ has been supported using
histological assessments from different ages at the onset
The prevalence rates of anti-GAD, anti-IA2, and anti-ZnT8 of disease.6 The extent of insulitis and aberrant sub-
were 65%, 20%, and 10%, respectively. No participant cellular distribution of proinsulin and mature insulin in
who tested negative both anti-GAD and anti-IA2 was the residual beta cells presented differently depending on
positive for anti-ZnT8. The distribution of pancreatic a younger (<7 years old) or older age of onset. However,
autoantibodies in our T1DM patients with long-standing the study has been conducted exclusively in childhood-
duration is shown in Figure 1. Residual beta-cell function onset T1DM. The clinical profiles and immunologic
based on detectable random plasma C-peptide (≥0.03 studies in non-Caucasians are rarely reported. In this
nmol/L) and MMTT were found in only 3 participants clinical study in Thai people with T1DM, our observations
(15%). The mean random plasma C-peptide was 0.07 suggest that endogenous insulin secretion persists in
nmol/L in these patients and the mean peak C-peptide some people with long-standing T1DM. In contrast to a
from stimulated MMTT was 0.29 nmol/L. No relationship previous study from China,4 pancreatic auto-antibodies
was observed for residual beta-cell function and the have been detected in up to 65% of the Thai participants
protective effects of diabetic complications as revealed with long-standing T1DM with anti-GAD antibodies as
in Table 2. Two of 3 participants with residual beta- the most detected pancreatic auto-antibodies. Therefore,
cell function had proliferative diabetic retinopathy and it remains unclear whether anti-ZnT8 is a useful marker
diabetic nephropathy. Persistent secretion of C-peptide for long-duration T1DM.7
was not associated with self-reported episodes of severe
hypoglycemia in the last 12-month period. The presence Consistent with other studies,1,4,7-9 almost half of our long-
of any pancreatic autoantibodies was 66.7% in participants standing T1DM cohort showed no diabetic complication.
with residual beta-cell function compared with 70.6% in The summarized comparison of results of our current study
participants without residual beta-cell function. There with other previous cohorts is shown in Table 3. Access
was no association between pancreatic autoantibody to comprehensive diabetes services and specialists with
positivity and residual beta-cell function (p-value = 0.270). expertise in T1DM poses several challenges in Thailand and

Clinical and Pathological Characteristics in Long-Standing Type 1 DM in Thai People Yotsapon Thewjitcharoen, et al 161
Table 3. Comparisons between our present study in Thai people with long-standing T1DM with other
published series
Country DM duration (yrs) Complications Persistent C-peptide
Joslin 50-year Medalist Study 56.2±5.8 PDR 55% Minimal C-peptide
(United States, N=411)1 MAU 13% (0.1-0.6 ng/mL) = 64.4%
DN 61% Sustained C-peptide
CVD 48% (≥ 0.6 ng/mL) = 2.6%
Diabetes UK The Golden Years cohort 55.8±5.4 PRP 43% N/A
(United Kingdom, N=400)8 DKD 36%
Chinese Study 37.3±6.8 DR 68% C-peptide ≥ 0.2 ng/mL = 14.7%
(China, N=95)4 DKD 34%
DN 61%
CVD 14%
Japanese Study 55.4±3.9 PDR 59% C-peptide > 0.4 ng/mL = 6.9%
(Japan, N=29)9 DKD 46%
CVD 25%
Theptarin cohort 31.9±5.1 DR 40% C-peptide ≥ 0.1 ng/mL = 15.0%
(Thailand, N=20) DKD 30%
DN 10%
CVD 0%
Abbreviations: CVD – Cardiovascular Disease; DKD – Diabetic Kidney Disease; DN – Diabetic Neuropathy; DR – Diabetic Retinopathy;
MAU – Microalbuminuria; PDR- Proliferative Diabetic Retinopathy; PRP – Panretinal Photocoagulation
other countries in Southeast Asia; however, T1DM patients determinants associated with long-term survival in this
could have long life expectancy similar to the general unique population.
population if they adhere to self-diabetes management
and have good support system. A recent mechanistic Acknowledgments
study among long-standing T1DM in the United States The authors wish to thank Dr. Tinapa Himathongkam for
showed that elevated medium-sized HDL particles and the excellent language editing and the staff at the Diabetes
elevated levels of HDL-associated paraoxonase 1 (PON1) and Thyroid Center, Theptarin Hospital for taking care of all
the patients.
which is an atheroprotective enzyme might contribute to
vascular protection in this group of people.10 Statement of Authorship
All authors certified fulfillment of ICMJE authorship criteria.
The limitations of the study should be acknowledged. First,
this was a cross-sectional study from a tertiary diabetes Author Disclosure
care center in Bangkok. Our institute has an advantage The authors declared no conflict of interest.
as a comprehensive diabetes center in Thailand for over
three decades. Therefore, to be generalizable, our findings Funding Source
should be confirmed in more heterogeneous healthcare This work was supported by the grant for promoting research
services across Southeast Asia. Second, the mean HbA1c in Theptarin Hospital (Grant No. 1/2561).
values were obtained in the past 12 months. The long-
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8. Bain SC, Gill DV, Dyer PH, et al. Characteristics of type 1 diabetes
of genetic and epigenetic indices should be considered in of over 50 years duration (the golden years cohort). Diabet
these individuals with long-standing T1DM. These studies Med. 2003;20(10):808-11. PMID:14510860. https://doi.org/10.1046/
will provide a better understanding of the contributing j.1464-5491.2003.01029.x.

162 Yotsapon Thewjitcharoen, et al Clinical and Pathological Characteristics in Long-Standing Type 1 DM in Thai People
9. Otani T, Kasahara T, Miura J, Uchigata Y, Babazono T. Clinical 10. Vaisar T, Kanter JE, Wimberger J, et al. High concentration of medium-
background of Japanese patients with type 1 diabetes mellitus sized HDL particles and enrichment in HDL paraoxonase 1 associated
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Original Article
Journal of the
ASEAN Federation of
Endocrine Societies
Prevalence of Vitamin B12 Deficiency and its Associated Factors

among Patients with Type 2 Diabetes Mellitus on Metformin
from a District in Malaysia
Gayathri Devi Krishnan,1 Miza Hiryanti Zakaria,2 Norhayati Yahaya1
1
Hospital Raja Perempuan Zainab II, Kota Bharu, Kelantan, Malaysia
2
Hospital Tengku Ampuan Afzan, Kuantan, Pahang, Malaysia
Abstract
Introduction. Vitamin B12 deficiency is more common among metformin-treated subjects although the prevalence is
variable. Many factors have been associated with this. The aim of this study is to determine the prevalence of vitamin
B12 deficiency and its associated factors among patients with type 2 diabetes mellitus (DM) who are on metformin.
Methodology. A total of 205 patients who fit eligibility criteria were included in the study. A questionnaire was completed,
and blood was drawn to study vitamin B12 levels. Vitamin B12 deficiency was defined as serum B12 level of ≤300 pg/
mL (221 pmol/L).
Results. The prevalence of vitamin B12 deficiency among metformin-treated patients with type 2 DM patients was
28.3% (n=58). The median vitamin B12 level was 419 (±257) pg/mL. The non-Malay population was at a higher
risk for metformin-associated vitamin B12 deficiency [adjusted odds ratio (OR) 3.86, 95% CI: 1.836 to 8.104, p<0.001].
Duration of metformin use of more than five years showed increased risk for metformin-associated vitamin B12
deficiency (adjusted OR 2.06, 95% CI: 1.003 to 4.227, p=0.049).
Conclusion. Our study suggests that the prevalence of vitamin B12 deficiency among patients with type 2 diabetes
mellitus on metformin in our population is substantial. This is more frequent among the non-Malay population and
those who have been on metformin for more than five years.
Key words: Vitamin B12, metformin, deficiency, type 2 diabetes mellitus, type 2 DM
INTRODUCTION early detection and treatment are clinically important in

patients with diabetes who are on metformin.9
Type 2 diabetes mellitus is a major non-communicable
disease in Malaysia for which metformin is one of the The first large scale study among Asians designed to
most commonly prescribed first line medications. Multiple investigate the prevalence and risk factors associated with
cross-sectional studies have reported a wide range in vitamin B12 deficiency was conducted among Koreans
prevalence of biochemical vitamin B12 deficiency with in 2014. It reported vitamin B12 deficiency in 9.5% of the
metformin exposure, ranging from 5.8% to as high as patients who were on metformin.9 Interestingly, another
30%.1-5 Vitamin B12 deficiency associated with metformin study among the South African population demonstrated
use is thought to occur due to vitamin B12 malabsorption that subjects of black South African descent on metformin
at the terminal ileum.5-7 had a lower prevalence of B12 deficiency, suggesting that
different ethnic origins may influence the prevalence
Vitamin B12 deficiency is clinically important as it is of metformin-associated vitamin B12 deficiency.10
a reversible cause of bone marrow failure and nerve This study is the first of its kind that investigated the
damage.8 Neurological damage as a result of metformin- association between ethnicity and vitamin B12 deficiency
induced vitamin B12 deficiency can present as peripheral among metformin-treated type 2 DM patients.
neuropathy and may be mistaken for diabetic neuropathy.8
Because vitamin B12 deficiency and its associated Duration of use and dose of metformin have also been
complications are treatable and potentially reversible, shown to influence vitamin B12 levels. A meta-analysis
of six randomized controlled trials showed a significant
________________________________________
ISSN 0857-1074 (Print) | eISSN 2308-118x (Online) Corresponding author: Gayathri Devi Krishnan, MRCP (UK)
Printed in the Philippines Clinical Specialist and Fellow in Endocrinology
Copyright © 2020 by Krishnan et al. Ministry of Health, Malaysia
Received: April 4, 2020. Accepted: August 7, 2020. Hospital Raja Perempuan Zainab II, 15586 Kota Bharu, Kelantan, Malaysia
Published online first: August 25, 2020. Tel. No.: 09-745 2000
https://doi.org/10.15605/jafes.035.02.03 Fax No.: 09-748 6951
E-mail: [email protected]
* This study was presented as a poster at the ASEAN Federation of Endocrine Societies (AFES) Congress in 2019 at Manila, Philippines.

164 Gayathri Devi Krishnan, et al Vitamin B12 Deficiency in Type 2 DM Patients on Metformin
reduction in vitamin B12 levels induced by metformin 0.05, the required sample size was 178.16 Sample size was
and suggested that this may be dose dependent.11 In augmented by 15% to take into account missing data. The
another large study published in the same year, Korean final sample size was determined to be 205.
patients on higher doses (metformin >1 g daily) and with
longer treatment duration (>4 years) were more likely to Statistical Analysis
be deficient in vitamin B12.9 Descriptive analyses of all the demographic and outcome
variables were performed. Results of the continuous
Some studies have found lower serum levels of vitamin variables are described with mean and standard deviation
B12 in smokers, but the exact mechanism for this is still or median and interquartile range and results of categorical
poorly understood.12 It is thought that smokers generally variables are described with frequency and percentage.
have poor dietary intake. The second National Health Test of normality was used to determine the distribution
and Nutrition Survey (NHANES II) found that smokers of the outcome variables. Independent sample t-test
have a lower intake of most vitamins and were less likely was used for normally distributed variables, and Mann-
to have consumed fruit, vegetables, vitamins and mineral Whitney U-test or Fisher Exact test for variables with a
supplements. Proton pump inhibitors (PPI) and histamine skewed distribution. Pearson Chi-Square test was used
2 receptor antagonists (H2RA) may lead to malabsorption to determine association between categorical predictors
of vitamin B12 due to inhibition of gastric acid secretion variables and outcome variables. The vari ables with
and reduced production of the intrinsic factor.13 Excessive p-value <0.2 in the univariate analysis were included in the
alcohol intake is also linked to vitamin B12 deficiency. multivariate analysis. Multiple logistic regression analysis
This has been attributed to intestinal malabsorption was performed to assess the independent predictive effect
due to altered binding of intrinsic factor and alcohol- of the variables on the risk for vitamin B12 deficiency.
induced ileal damage.10,14 All statistical analyses were performed using Statistical
Package for Social Science (SPSS) Version 22.0. A p-value of
The primary objective of this study is to determine the less than 0.05 was considered significant.
prevalence of vitamin B12 deficiency among patients
with type 2 DM who are on metformin in Malaysia. Our Results
secondary objective is to determine the associated factors
contributing to vitamin B12 deficiency in this cohort. Two hundred fifty-two patients with type 2 DM were
screened from two study centers. Forty-six patients
Methodology were subsequently excluded. A total of 205 patients
from two study centers were finally included in the
Study Population study (Figure 1). Majority (51.7%, n=106) were recruited
This was a cross-sectional prevalence study. A total from a tertiary hospital while 48.3% (n=99) were from a
of 252 patients with type 2 DM were screened from health clinic.
two study centers in the district of Kuantan, Pahang in
Malaysia. Patients who turned up for their scheduled Table 1 shows the baseline demographic data of our study
clinic appointment at the type 2 diabetes clinic in the population. A total of 79 (38.5%) males and 126 (61.5%)
two centers were seen screened and recruited during females were enrolled. Majority of the patients were of
their routine clinic visit between September 2018 and Malay race (78%) while the remaining were non-Malay
February 2019. Patients aged 18 years old and above with (15.6% Chinese and 6.3% Indian). The median age of the
a diagnosis of type 2 DM who were on metformin for at
least 6 preceding months were screened. Participants were
recruited based on eligibility and willingness to participate. Screened for eligibility and met inclusion criteria
Forty-six patients were excluded based on the exclusion (n=252)
criteria, while one declined to join. Patients who had
pernicious anaemia; prior bariatric surgery, gastrectomy,
colectomy or inflammatory bowel disease; ongoing critical
illnesses; malignancy; liver cirrhosis or renal impairment Met exclusion criteria (n=47)
(creatinine ≥265 µmol/L) were excluded. Subjects who • Liver cirrhosis (n=3)
were vegetarians, recipients of vitamin B12 injections • Malignancy (n=1)
or supplements within the past 3 months, pregnant or • Vegetarian (n=1)
lactating were excluded as well. Once informed consent • On Vitamin B12 supplements (n=41)
was obtained, all participants were interviewed based on a • Declined to participate (n=1)
standardized questionnaire (Appendix 1). Blood extraction
for serum vitamin B12 levels was done. Vitamin B12
deficiency was defined as serum B12 level ≤300 pg/mL (221 Enrolled in the study
pmol/L). This encompasses vitamin B12 levels defined as (n=205)
low and borderline low.3,9,15 Serum vitamin B12 level was
measured by chemiluminescent microparticle Intrinsic
Factor assay using the 7K61 ARCHITECT B12 Reagent Kit.
Vitamin B12 ≤300 pg/mL Vitamin B12 >300 pg/mL
Sample size was calculated based on the 9.5% prevalence
(n=58) (n=147)
of B12 deficiency among type 2 diabetes patients
on metformin.9 Using the sample size calculator for Figure 1. Study design summarizing sample recruitment.
estimations with type I error probability and precision of

Vitamin B12 Deficiency in Type 2 DM Patients on Metformin Gayathri Devi Krishnan, et al 165
Table 1. Baseline demographics according to Vitamin B12 levela

Characteristic Total (n=205) Deficient in Vitamin B12 (n=58) Normal Vitamin B12 (n=147) p-value
Age, yr (±SD) 56 (15.0) 59 (13.7) 55 (14.0) 0.039b
Gender (%) 0.599c
Men 79 (38.5) 24 (41.3) 55 (37.4)
Women 126 (61.5) 34 (58.6) 92 (62.6)
Race (%) <0.001c
Malay 160 (78.1) 33 (56.9) 127 (86.4)
Non-Malay 45 (21.9) 25 (43.1) 20 (13.6)
Duration of diabetes, month (±SD) 72 (84.0) 90 (123.0) 60 (96.0) 0.045b
Current smoker (%) 17 (8.3) 8 (13.8) 9 (6.1) 0.092d
Alcohol intake (%) 2 (0.9) 0 (0) 2 (1.4) 1.000d
BMIe (kg/m2) 28.9 (6.3) 28.8 (6.2) 28.0 (6.3) 0.626b
Duration of metformin use (%) 0.010c
≤5 years 100 (48.8) 20 (34.5) 80 (54.4)
>5 years 105 (51.2) 38 (65.5) 67 (45.6)
Daily dose of metformin (%) 0.324c
≤1000 mg 33 (16.1) 7 (12.1) 26 (17.7)
>1000 mg 172 (83.9) 51 (87.9) 121 (82.3)
HbA1cf 0.067c
≤7% 31 (15.1) 13 (22.4) 18 (12.2)
>7% 174 (84.9) 45 (77.6) 129 (87.8)
Concomitant medication (%)
Sulfonylurea 88 (42.9) 25 (43.1) 63 (42.9) 0.974c
DPP-4g inhibitor 16 (7.8) 4 (6.9) 12 (8.16) 1.000d
Alpha-glucosidase inhibitor 2 (1.0) 0 (0) 2 (1.36) 1.000d
SGLT2h inhibitor 3 (1.5) 1 (1.7) 2 (1.36) 1.000d
GLP-1i receptor agonist 1 (0.5) 1 (1.7) 0 (0) 0.283d
Insulin 113 (55.1) 26 (44.8) 87 (59.2) 0.063c
Statin 166 (81.0) 47 (81.0) 119 (80.9) 0.989c
H2RA j 3 (1.5) 1 (1.7) 2 (1.4) 1.000d
PPIk 2 (1) 1 (1.7) 1 (0.7) 0.487d
a
Values were expressed as mean (SD) for normally distributed continuous variables, median (interquartile range) for not normally distributed continuous
variables and n (%) for categorical variables.
b
Mann Whitney test
c
Chi square test
d
Fisher exact test
e
BMI, body mass index
f
HbA1c, glycosylated hemoglobin
g
DPP-4, dipeptidyl peptidase-4
h
SGLT2, sodium glucose cotransporter-2
i
GLP-1, glucagon-like peptide-1
j
H2RA, H2 receptor antagonist
k
PPI, proton pump inhibitor
patients was 56 years. The median duration of diabetes was to 9.70, p<0.01). Duration of metformin use of more than
72 months with only 15.1% of patients achieving HbA1c five years was associated with more than a two-fold
≤7%. HbA1c value was not available for 10 participants. risk for vitamin B12 deficiency (OR 2.27, 95% CI: 1.21 to
The median body mass index (BMI) was 29 kg/m2. We 4.27, p=0.01). The other studied factors did not reveal a
were unable to obtain the BMI for one participant whose significant association with vitamin B12 deficiency in our
height was not measured as he was unable to stand. Most study population (Table 2).
patients (51.2%) were treated with metformin for more than
5 years. Majority of the included patients (83.9%) were on In the multivariate analysis, after adjusting for age,
a metformin dose of more than 1 gram daily. Concomitant smoking status, duration of diabetes and HbA1c, the
medications were largely sulfonylureas (42.9%), insulin non-Malay population remained at a significantly higher
(55.1%) and statins (81%). A small proportion of patients risk for metformin-associated vitamin B12 deficiency
were on H2 receptor antagonists (1.5%) and proton pump (adjusted OR 3.86, 95% CI: 1.836 to 8.104, p<0.001)
inhibitors (1%). There were a few smokers (8.3%) and (Table 3). Metformin use for a duration of more than five
alcoholic beverage consumers (0.9%). years showed an increased risk for metformin-associated
vitamin B12 deficiency (adjusted OR 2.06, 95% CI: 1.003 to
Vitamin B12 deficiency was defined as serum B12 level 4.227, p=0.049).
≤300 pg/mL (221 pmol/L). The prevalence of vitamin B12
deficiency among metformin-treated type 2 DM patients Discussion
was 28.3% (n=58). The median vitamin B12 level was 419
(±257) pg/mL. Among the population deficient in vitamin Vitamin B12 deficiency has been long known to adversely
B12, 56.9% were of Malay race while 43.1% were non- affect health, causing anaemia and neuropathy among
Malays. In the normal vitamin B12 category, 86.4% were other complications. Metformin, a widely used anti-
of Malay race. diabetes drug, has been reported as a risk factor for vitamin
B12 deficiency. To the best of our knowledge, this is the
Univariate analysis showed that participants of non- first study in Southeast Asia designed to investigate the
Malay race had a significantly higher risk for metformin- prevalence vitamin B12 deficiency among metformin-
associated vitamin B12 deficiency (OR 4.81, 95% CI: 2.39 treated patients with type 2 diabetes mellitus.

Table 2. Univariate logistic regression analysis was a significant protective factor for vitamin B12 deficiency
OR a
95% CI p-value among metformin-treated patients.21 This was the first
Gender 1.18 0.63 - 2.20 0.60 study to report ethnic differences in vitamin B12 levels
Male 1 among metformin-exposed type 2 DM patients. Higher
Female levels of the vitamin binding proteins transcobalamin II
Race 2.39 - 9.70 <0.01
Non-Malay 4.81
and haptocorrin in black individuals have been described in
Malay 1 South African settings, explaining their relatively elevated
Daily metformin dose (g/day) 0.64 - 3.84 0.33 vitamin B12 levels.21 The difference in prevalence of vitamin
>1000 mg 1.57 B12 deficiency among different ethnic groups in Asia has
≤1000 mg 1
not been studied. The currently utilized cut-off points and
Metformin treatment duration 1.21 - 4.27 0.01
>5 years 2.27
definitions of vitamin B12 deficiency do not consider the
≤5 years 1 possible effects of ethnicity.21 Further research is needed to
HbA1c b 0.94 - 4.56 0.07 determine why Malay ethnicity seemed protective against
≤7% 2.07 metformin-associated vitamin B12 deficiency.
>7% 1
Age, yr 1.03 1.00 - 1.06 0.06
Duration of metformin use of more than five years conferred
BMIc, kg/m2 1.02 0.98 - 1.07 0.33
Diabetes duration, month 1.00 1.00 - 1.01 0.03
a greater than two-fold increased risk for vitamin B12
Smoking 2.45 0.90 - 6.70 0.08 deficiency (p=0.049) in our population. Several studies have
Sulfonylurea 1.01 0.55 - 1.87 0.97 shown a significant positive association between duration
DPP-4d inhibitor 0.83 0.26 - 2.70 0.76 of metformin use and vitamin B12 deficiency.3,9,17,22 In a
SGLT-2e inhibitor 1.27 0.11 - 14.30 0.85 large-scale study among Koreans (n=799), daily metformin
PPIf 2.56 0.16 - 41.65 0.51 dosage and treatment duration were the most consistent
H2RA g 1.27 0.11 - 14.30 0.85 risk factors for vitamin B12 deficiency.9 Secondary analysis
a
OR, odds ratio from the Diabetes Prevention Program Outcomes Study
b
(DPPOS) showed that 13 years after randomization, there
c
BMI, body mass index
d
DPP-4, dipeptidyl peptidase-4 was a 13% increased risk for vitamin B12 deficiency per
e
SGLT2, sodium glucose cotransporter-2 year of total metformin use.17 The results of our study
f
PPI, proton pump inhibitor echo these findings of increased risk for vitamin B12
g
H2RA, H2 receptor antagonist
deficiency with longer duration of metformin use.
The prevalence of vitamin B12 deficiency in our study Age, sex, body mass index, smoking, duration of
population is 28.3%, which falls at the upper end of diabetes and HbA1c levels did not show a statistically
global prevalence. The worldwide prevalence of vitamin significant association with vitamin B12 deficiency in
B12 deficiency among metformin users ranges between our population. There was no significant association
4.3 to 30%.1,9,17,18 Vitamin B12 deficiency associated with between vitamin B12 deficiency and the use of other anti-
metformin use is thought to occur due to vitamin B12 diabetes medications (Table 2).
malabsorption. It is postulated that metformin interferes
with the calcium-dependent membrane action responsible Previous studies have linked vitamin B12 deficiency
for vitamin B12-intrinsic factor absorption in the terminal with the use of PPI and H2RA among metformin-
ileum.6,7,19,20 The substantial prevalence of vitamin B12 treated patients. These observations were supported by
deficiency in our population should prompt consideration the concept that gastric acidity is vital for vitamin B12
for routine screening of this deficiency among metformin- absorption, and that PPI and H2RA result in reduction
treated type 2 DM patients. in acid discharge by gastric parietal cells.20,23,24 However,
this finding was controversial.1,11 Our study did not find
Our study demonstrated that race and duration of a significant association between use of PPI or H2RA and
metformin use were the most consistent associated factors vitamin B12 deficiency. This could be attributed to the very
with vitamin B12 deficiency among metformin users. small number of patients in our study who were on PPI
This association remained evident after adjusting for or H2RA (n=5).
potential confounding factors by multivariate analysis.
Vitamin B12 deficiency is clinically important as it can
The most significant association was race. Non-Malay race cause anemia, bone marrow failure, peripheral neuropathy
was associated with an approximately four-fold increased and cognitive impairment.8,9,25 Neuropathy secondary
risk for metformin-associated vitamin B12 deficiency even to metformin-associated vitamin B12 deficiency may
after adjusting for potential confounders (p<0.001). A study be mistaken for peripheral neuropathy secondary to
conducted in Africa found that Black South African descent diabetes-associated microvascular complications, as
Table 3. Multiple logistic regression analysis

Adjusted ORa 95% CI P Cov and Snell R square Nagelkerke R square
Non-Malay race 3.86 1.836 - 8.104 <0.001 0.13 0.19
Duration of metformin use >5 years 2.06 1.003 - 4.227 0.049
Non-smoker 0.36 0.120 - 1.059 0.063
HbA1cb ≤ 7% 2.32 0.934 - 5.751 0.070
Constant 3.24 0.056
a
OR, odds ratio
b

Vitamin B12 Deficiency in Type 2 DM Patients on Metformin Gayathri Devi Krishnan, et al 167
both diseases can result in reduced vibration sense and Statement of Authorship
diminished proprioception.8,26 There is no definitive All authors certified fulfillment of ICMJE authorship criteria.
clinical or electrophysiological test that can differentiate
diabetic peripheral neuropathy from vitamin B12- Author Disclosure
The authors declared no conflicts of interest.
associated neuropathy.8 This may lead to inappropriate
use of tricyclic antidepressants and anticonvulsants Funding Source
to manage symptoms.8,27,28 The Malaysian Endocrine and Metabolic Society (MEMS) funded
this research.
Recognition of metformin-associated vitamin B12
deficiency is imperative as it is potentially treatable and References
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their gratitude to Dr. Wan Hasmawati Binti Wan Ismail, family org/10.3122/jabfm.2009.05.090044.
medicine physician, and the staff of Klinik Kesihatan Paya Besar, 19. Berchtold P, Dahlqvist A, Gustafson A, Asp NG. Effects of a biguanide
(metformin) on vitamin B12 and folic acid absorption and intestinal
for accommodating their research.

enzyme activities. Scand J Gastroenterol. 1971;6(8):751-4. PMID: 26. Lindenbaum J, Healton EB, Savage DG, et al. Neuropsychiatric
5139118. https://doi.org/10.3109/00365527109179948. disorders caused by cobalamin deficiency in the absence of anemia
20. Bauman WA, Shaw S, Jayatilleke E, Spungen AM, Herbert V. Increased or macrocytosis. N Engl J Med. 1988; 318(26):1720-8. PMID: 3374544.
intake of calcium reverses vitamin B12 malabsorption induced by https://doi.org/10.1056/NEJM198806303182604.
metformin. Diabetes Care. 2000;23(9):1227-31. PMID: 10977010. https:// 27. Naha K, Dasari S, Vivek G, Prabhu M. Vitamin B12 deficiency: An
doi.org/10.2337/diacare.23.9.1227. unusual cause for recurrent generalised seizures with pancytopaenia.
21. Fernandes-Costa F, Metz J. A comparison of serum transcobalamin BMJ Case Reports. 2012;10.1136/bcr-2012-006632. PMID: 22948998.
levels in white and black subjects. Am J Clin Nutr. 1982;35(1):83-6. PMCID: PMC4543758. https://doi.org/10.1136/bcr-2012-006632.
PMID: 7064880. https://doi.org/10.1093/ajcn/35.1.83. 28. Durand C, Mary S, Brazo P, Dollfus S. Psychiatric manifestations of
22. Ahmed MA, Muntingh G, Rheeder P. Vitamin B12 deficiency in vitamin B12 deficiency: A case report. Encephale. 2003;29(6):560-5.
metformin-treated type 2 diabetes patients, prevalence and association PMID: 15029091.
with peripheral neuropathy. BMC Pharmacol Toxicol. 2016;17:44. 29. McKay DL, Perrone G, Rasmussen H, Dallal G, Blumberg JB.
PMID: 27716423. PMCID: PMC5054613. https://doi.org/10.1186/ Multivitamin/mineral supplementation improves plasma B-vitamin
s40360-016-0088-3. status and homocysteine concentration in healthy older adults
23. Valuck RJ, Ruscin JM. A case-control study on adverse effects: consuming a folate-fortified diet. J Nutr. 2000;130(12):3090-6. PMID:
H2 blocker or proton pump inhibitor use and risk of vitamin B12 11110875. https://doi.org/10.1093/jn/130.12.3090.
deficiency in older adults. J Clin Epidemiol. 2004;57(4):422-8. PMID: 30. Wolters M, Hermann S, Hahn A. Effect of multivitamin supplementation
15135846. https://doi.org/10.1016/j.jclinepi.2003.08.015. on the homocysteine and methylmalonic acid blood concentrations in
24. Ruscin JM, Page RL 2nd, Valuck RJ. Vitamin B(12) deficiency associated women over the age of 60 years. Eur J Nutr. 2005;44(3):183-92. PMID:
with histamine(2)-receptor antagonists and a proton-pump inhibitor. 15309436. https://doi.org/10.1007/s00394-004-0510-2.
Ann Pharmacother. 2002;36(5):812-6. PMID: 11978157. https://doi. 31. Institute for Public Health 2020. National Health and Morbidity Survey
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25. Hin H, Clarke R, Sherliker P, et al. Clinical relevance of low serum health literacy—Key Findings. http://iku.moh.gov.my/images/IKU/
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study. Age Ageing. 2006;35(4):416-22. PMID: 16709605. https://doi. English.pdf.
org/10.1093/ageing/afl033.
Appendix 1. Association of Vitamin B12 deficiency and Metformin in Type 2 Diabetes Mellitus
Data Collection Sheet

Date Centre
Name of Investigator
Subject Information
Subject Initials Subject ID (IC number)
Gender M/F Race Malay / Chinese / Indian / Others
Age (years) Others (please specify):____________
Height (cm) Weight (kg) BMI (kg/m2)
Current Smoker Yes / No Alcohol consumption (units/week or units/month-
see appendix)
Duration of diabetes mellitus (since diagnosis)
Current metformin dose (daily dose)
Total duration of metformin use (in years/months)
Medications: (tick relevant box)
Sulphonylurea Proton pump inhibitor (PPI)
DPP-IV antagonist H2 antagonist
GLP-1 agonist Statin
SGLT-2 inhibitor ACEi/ARB
Alpha glucosidase inhibitor Aspirin
Thiazolidinediones Insulin
Others (please specify)
Lab Investigations
Test Value Date
Vitamin B12 level (pg/mL)
Fasting Blood Sugar (mmol/L)
HbA1c (%) *(latest available value)

Original Article
Journal of the
ASEAN Federation of
Endocrine Societies
The Association between Maternal Serum Vitamin D Levels

and Gestational Diabetes Mellitus among Filipino Patients:
A Cross-Sectional Study
Carmen Carina Cabrera,1 Oliver Allan Dampil,1 Albert Macaire Ong-Lopez2
1
Section of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, St. Luke’s Medical Center, Quezon City, Philippines
2
Department of Medicine, St. Luke’s Medical Center, Quezon City, Philippines
Abstract
Objectives. To determine the association between low maternal serum vitamin D and gestational diabetes mellitus
(GDM) among Filipino women in St. Luke’s Medical Center, Quezon City.
Methodology. A cross-sectional study involving pregnant women at outpatient clinics in a tertiary hospital in the
Philippines. Simultaneous testing for fasting blood sugar, 75g oral glucose tolerance test and serum vitamin D was
done. Participants were classified as GDM versus non-GDM, and normal versus low serum vitamin D. Univariate and
multivariate statistics were done to determine relationship between vitamin D and GDM.
Results. Of 211 included women, 198 (93.8%) had low vitamin D levels, and 56 (26.5%) had GDM. Vitamin D was
significantly higher in the GDM group (21.0±8.1 vs 18.8±5.3 ng/mL, p=0.0189). The proportion of women with low vitamin
D levels was significantly higher among those without GDM (96.1% vs 87.5%, OR=0.28, p=0.029]. After adjusting
for age, parity, history of GDM and pre-pregnancy BMI, no significant association was observed (adjusted OR=0.66,
p=0.522). No correlation was seen between vitamin D and FBS (r=0.28, p=0.095), 1-hour post-75 g OGTT (r=0.26,
p=0.643), and 2-hour post-75 g OGTT (r=0.28, p=0.113).
Conclusion. There was an association found between maternal serum vitamin D level and GDM in the univariate
analysis, but none was evident after adjusting for possible confounders. The unanticipated high prevalence of low
vitamin D levels among pregnant Filipinos needs to be verified in future studies.
Key words: gestational diabetes mellitus, gestational diabetes, vitamin D deficiency
Introduction history of abnormal glucose metabolism and polycystic

ovarian syndrome. Parity per se was not found to have
Gestational Diabetes Mellitus (GDM) any direct link to GDM appearance.5 Recently, vitamin D
GDM is defined by the American Diabetes Association was identified as a potential contributor to its occurrence.
(ADA) as diabetes diagnosed in the second or third
trimester of pregnancy that is not clearly either type 1 Vitamin D and its Extra-skeletal Effects
or type 2 diabetes.1 Its occurrence, like type 2 diabetes There is gaining interest in the role of vitamin D in diabetes
mellitus, is increasing reaching a global prevalence of 15% mellitus. Studies found that its function extends beyond
to 20%,2 while locally in the Philippines, it was reported calcium and bone metabolism. It was demonstrated in
to be at 14%.3 It carries the risk of adverse maternal, fetal animal models to improve pancreatic exocrine function
and neonatal outcomes including increased birth weight and insulin sensitivity.6 Calcitriol or 1,25(OH)2D, the form
above the 90th percentile, as well as a higher incidence of of vitamin D produced in the kidneys, was shown in animal
neonatal hypoglycemia and primary cesarean section models to have effects on the synthesis, secretion, and
demonstrated in the large-scale multinational cohort actions of insulin.7,8 It enhances insulin-dependent glucose
study called The Hyperglycemia and Adverse Pregnancy transport by inducing insulin receptor expression.
Outcome (HAPO) study.4 Other reported risks increased
by GDM are the development of preeclampsia and Pregnancy and Vitamin D
dystocia, and the predisposition of both the mother and Physiologic changes in vitamin D metabolism during
offspring to develop obesity, type 2 diabetes mellitus and pregnancy are still incompletely understood. Studies
the metabolic syndrome. Recognized risk factors in the showed an increase in vitamin D binding proteins by
development of GDM include advanced maternal age, 7% to 152% 9,10,11,12 as well as serum 1,25(OH)2D by 104%
obesity, ethnicity, family history of diabetes, and a previous to 134% with minimal effect on serum 25(OH)D.13,14
________________________________________
ISSN 0857-1074 (Print) | eISSN 2308-118x (Online) Corresponding author: Carmen Carina G. Cabrera, MD
Printed in the Philippines Fellow-in-training, Section of Endocrinology, Diabetes and Metabolism
Copyright © 2020 by Cabrera et al. St. Luke’s Medical Center, Quezon City
Received: May 20, 2020. Accepted: August 16, 2020. 279 E Rodriguez Sr. Ave. Quezon City, 1112, Philippines
Published online first: September 1, 2020. Tel. No.: +638-723-0101

170 Carmen Carina Cabrera, et al Maternal Serum Vitamin D Levels and GDM among Filipino Patients
Serum 1,25(OH)2D levels are expected to return to pre- D levels were associated with GDM [pooled odds ratio
pregnancy levels by weeks 8 to 10 postpartum. Both forms (OR)=1.49, (1.18-1.89)] with no evidence of heterogeneity
of vitamin D cross the placenta to the growing fetus, the (I2=0%).24 Participants in this meta-analysis, however,
latter theorized to be the predominant metabolite.15 included Americans, Asians, Europeans, Canadians and
Middle Easterners. There was no representative study
There is still a lack of consensus on the definition of normal for Southeast Asians.
vitamin D levels among pregnant women. Based on the
systematic review by the Institute of Medicine (IOM), serum A recently published article by Hu et al., (2018) pooled
25(OH)D levels below 20 ng/mL (50 nmol/L) are considered data from 29 observational studies which included 28982
insufficient.16 The Endocrine Society Clinical Practice participants, with more than half being Asian of Chinese
Guidelines define vitamin D insufficiency as 25(OH)D levels and Korean descent, 4634 of whom were diagnosed with
of >20 ng/mL (50 nmol/L) and <30 ng/mL (75 nmol/L), and GDM. It was demonstrated that low levels of vitamin D
vitamin D deficiency as levels ≤20 ng/mL.17 The National significantly increased the risk for GDM by 39% (pooled
Institute for Health and Clinical Excellence guidelines, on OR=1.39, [1.20, 1.60]) albeit with moderate heterogeneity
the other hand, define vitamin D insufficiency as 25(OH) (I2=50.2%, p=0.001). Vitamin D levels were significantly
D levels less than 10 ng/mL (25 nmol/L).18 However, these lower among patients with GDM compared with controls
cutoff values are based on optimal levels in maintaining with a pooled effect of -4.79 (-6.43, -3.15) nmol/L and
skeletal health in the general population. There remains the significant heterogeneity (I2=65.0%, p<0.001).2
need to establish a normal range among pregnant women.
Several limitations of these meta-analyses may hinder the
GDM and Vitamin D applicability of results in the Filipino population. These
In gestational diabetes mellitus, vitamin D acts as a include the observational nature of included studies, as
potential immunosuppressant that downregulates the well as the diversity of study populations in terms of
expression of pro-inflammatory marker such as TNF-α and ethnicity with inadequate representation of Southeast
IL-2.19 Many observational studies found an association Asians. Other confounders that were not considered were
between low maternal levels of serum vitamin D and adiposity and laboratory techniques in the measurement
GDM. A case-control study done in Istanbul by Parildar et of serum 25(OH)D. In this light, local data is needed to
al., (2013) among 44 pregnant women with GDM and 78 assess its applicability in the Filipino community.
non-GDM pregnant women showed a lower mean serum
vitamin D level among GDM patients (14.3±8.2 ng/ml) The current guidelines of the American College of
versus that of controls (23.2±8.3 ng/ml, p=0.001). Vitamin D Obstetrics and Gynecology (ACOG)25 and World Health
deficiency (defined as vitamin D of ≤20 ng/mL) prevalence Organization26 do not recommend routine screening for
was 56.8% among GDM patients and 35.8% among non- vitamin D deficiency among pregnant women, except
GDM patients.20 Another nested case-control study by Wen those who are considered high risk – only then would
et al.,(2017) which included 4718 pregnant women from screening and treatment be initiated. Current knowledge
China, 1280 of whom were diagnosed with GDM, found points toward a possible link between GDM and low
that maternal serum 25(OH)D were significantly lower maternal vitamin D levels, but the challenge lies in its
in women with GDM [42.4 (34.5, 54.0) nmol/L] compared translation to clinical recommendation whether achieving
to controls [44.4 (36.0, 58.8) nmol/L, p<0.001]. Seventy optimal levels of vitamin D can actually prevent GDM
percent of women with GDM had vitamin D <50 nmol/L and its associated sequelae. Establishing an association
compared to 60.5% in the control group.21 between the two conditions among Filipinos can pave the
way for future local studies on causality and benefit of
There were other studies, however, that found no vitamin D screening and correction in pregnant patients
significant link between the two conditions. Makgoba to prevent GDM, in the hope of ultimately improving
et al., (2011) conducted a case-control study in Europe maternal and fetal outcomes in the country.
involving 248 women in the first trimester of pregnancy,
90 of whom developed GDM. They found no correlation This study aimed to determine the association of low
between mean vitamin D levels among those with GDM levels of maternal serum vitamin D levels and GDM
(18.9±10.7 ng/ml) versus those without GDM (19.0±10.7, among Filipino patients in St. Luke’s Medical Center,
p=0.874), even after adjustment for possible confounders Quezon City.
(p=0.784).22 A case-control study by Pleskacova et al.,
(2015) among 47 pregnant women with GDM and 29 METHODOLOGY
healthy controls measured mid-gestational and early
postpartum vitamin D levels. They found a high prevalence This was a single-center study. Target population included
of vitamin D deficiency in both groups (95.7% in women both social service and private outpatients in St. Luke’s
with GDM, 93.1% in controls), but mean levels were not Medical Center, Quezon City, a private tertiary hospital
significantly different [28.5 (21.0, 34.0) nmol/L in women in the Philippines, from April 2019 to January 2020.
with GDM, 31.7 (24.0, 40.0) in controls; p>0.05].23 Table 1 enumerates the inclusion and exclusion criteria
of participants.
Meta-analyses and systematic reviews aimed to absolve
these conflicting data. One done by Aghajafari (2013) on Description of Study Procedure
the role of vitamin D in pregnancy included 31 studies This was a cross-sectional study involving pregnant
published between 1980 and 2012, 10 studies of which had women seen at both private and social service outpatient
gestational diabetes as the outcome, with a total of 687 clinics at St. Luke’s Medical Center, Quezon City from
cases and 3425 controls. They reported that low vitamin April 2019 to January 2020.

Maternal Serum Vitamin D Levels and GDM among Filipino Patients Carmen Carina Cabrera, et al 171
Table 1. Eligibility criteria of 92 mg/dl; 1-hour post-OGTT of 180 mg/dl; or 2-hour

Inclusion criteria post-OGTT of 153 mg/dl.
• Pregnant Filipino women above 18 years old
Exclusion criteria Since there is still a lack of consensus on definitions of
• Pregnant women who fulfill diagnostic criteria for diabetes mellitus vitamin D deficiency and insufficiency among pregnant
before 24 weeks age of gestation women, the Endocrine Society Clinical Practice Guideline17
• Pregnant women with:
o History of type 1 or type 2 diabetes mellitus prior to pregnancy definition was applied. Patients were classified as having
o Multifetal pregnancy low levels of vitamin D when serum level of total vitamin
o Use of artificial reproductive technology
o Fetal abnormalities
D was ≤30 ng/ml. Those with low vitamin D levels were
o Chronic liver or renal failure further classified as vitamin D insufficient when levels were
o Parathyroid or bone metabolism abnormalities 21-30 ng/ml, and vitamin D deficient at levels ≤20 ng/ml.
o Malignancy
Outcome Measures
The primary outcome of this study was the prevalence
Consent was obtained from obstetricians and of low maternal levels of vitamin D among patients with
endocrinologists to screen their patients for inclusion in GDM. The secondary outcomes were the prevalence of
this study. All pregnant women who were in their second vitamin D insufficiency and vitamin D deficiency among
or third trimester scheduled to undergo FBS and 75 g patients with GDM, the mean vitamin D level among
OGTT as standard of care, who met eligibility criteria were patients with GDM, and the correlation between FBS and
included in the study. Informed consent was obtained 75g OGTT levels with maternal serum vitamin D levels.
by the study investigator or designated representative
during their clinic visit. The study investigator or Sample Size Estimation
designated representative gathered demographic Based on a level of significance of 5% and a power of 90%,
information which included age, pre-pregnancy BMI, a minimum of 190 patients were required for this study.
personal history of abnormal glucose metabolism This was derived from preliminary data from an article
(prediabetes, impaired glucose tolerance, impaired fasting by Parildar et al., (2013)20 which reported a prevalence of
glucose), previous GDM, history of poor obstetric outcome 56.8% of vitamin D deficiency among pregnant women
(including but not limited to macrosomia, fetal demise, with GDM and 35.8% in pregnant women without GDM.
spontaneous abortion), and family history of diabetes. Controlling for 2 more variables in the analysis (age,
parity), with an additional 10% for each control variable,
During their scheduled blood draw for FBS and final sample size required was 228. The computed
OGTT, blood samples were likewise taken through sample size assumes that the proportion of patients to be
venipuncture by the medical technologist to measure assigned to the two groups is equal.
serum vitamin D levels. These tests were done at the St.
Luke’s Medical Center laboratory. Patients were then Data Processing and Analysis
classified as to having GDM and no GDM, as well as to Data was processed and encoded using Microsoft Excel.
having low and normal vitamin D levels (Figure 1). Statistical analysis was done using STATA version 14.
Determination of the relationship between maternal
Description of Test Procedures serum vitamin D levels and GDM was analyzed using
The measurement of total vitamin D was done at St. univariate and multivariate statistics. Chi-square test and
Luke’s Medical Center, Quezon City serology laboratory logistic regression were done in the univariate analysis
using an in vitro diagnostic electrochemiluminescent of qualitative and quantitative independent variables,
process according to the manufacturer’s instructions. respectively. Multiple logistic regression was utilized in
Reported deviations are as follows: for concentrations the multivariate analysis. Crude and adjusted OR and the
up to 15ng/ml, deviation is ≤1.5 ng/ml; for concentrations 95% confidence interval were also calculated. Pearson’s r
>15 ng/ml, deviation is ≤10%. was calculated to determine the correlation of vitamin D
and parameters of OGTT. Level of significance was set at
Diagnosis α = 0.05.
The diagnosis of GDM was based on the ADA criteria,1
and was made when any of the following plasma glucose Ethical Considerations
values were met or exceeded with a 75 g OGTT during the The clinical protocol and all relevant documents were
second or third trimester of pregnancy: fasting blood sugar reviewed and approved by the SLMC Institutional Ethics
Pregnant women included in the study
GDM No GDM
Total vitamin D Total vitamin D
Low vitamin D Normal vitamin D Low vitamin D Normal vitamin D
Figure 1. Schematic diagram of study design from time of inclusion of participants.

Table 2. Baseline characteristics

GDM No GDM
p value
(n=56, 26.5%) (n=155, 73.5%)
Age (yrs) 33.2±5.6 28.7±5.2 0
Pre-pregnancy BMI (kg/m2) 23.0±3.6 22.1±3.6 0.12
Parity n (%)
Nulliparous 13 (23.2) 71 (45.8)
1-2 previous deliveries 40 (71.4) 74 (47.7) 0.008
≥3 previous deliveries 3 (5.4) 10 (6.5)
Previous history of GDM n (%) 14 (25.0) 15 (9.7) 0.004
History of poor obstetric outcome n (%) 4 (7.1) 19 (12.3) 0.292
History of abnormal glucose metabolism n (%) 1 (1.8) 1 (0.6) 0.461
History of polycystic ovarian syndrome n (%) 8 (14.3) 12 (7.7) 0.183
Family history of diabetes n (%) 21 (37.5) 73 (47.1) 0.272
Fasting blood glucose (mg/dL) 93.6±21.3 76.8±7.4 0
75g oral glucose tolerance (mg/dL)
1st hour (mg/dL) 192.1±34.7 133.6±26.2 0
2nd hour (mg/dL) 162.2±29.0 110.9±21.0 0
Vitamin D level (ng/mL) 21.0±8.1 18.7±5.3 0.0189
Review Committee. As respect to patient confidentiality, Low vitamin D levels were seen in 198 of the participants,
anonymity of patient records was ensured by assigning a accounting for 93.8% of the entire group. Vitamin D level
unique code to each patient. The principal investigators was significantly higher in the GDM group (21.0±8.1 vs
were responsible for the integrity of the data that was 18.7±5.3 ng/mL, p=0.0189). The proportion of patients
recorded. The protection of confidentiality of the data with low vitamin D levels was significantly higher among
was guaranteed by the manner of dissemination of those without GDM [GDM 49 (87.5%) vs no GDM 149
study results. Written and signed informed consent were (96.1%)]. Calculating for the odds ratio (OR), having
obtained and data collection forms were compiled and low vitamin D levels was significantly associated with a
stored in an envelope. Data was tabulated in Microsoft lower likelihood for GDM (OR=0.28, p=0.029). However,
Excel format and saved in a CD. These will be kept and after adjusting for age, parity, history of GDM, and pre-
filed in the Diabetes, Thyroid and Endocrine Center pregnancy BMI no significant association was observed
under the Section of Endocrinology for 5 years before they (OR=0.66, p=0.522). The same trend was demonstrated on
are shredded. subgroup analysis of those with vitamin D insufficiency
(OR=0.32, p=0.069; adjusted OR=0.55, p=0.433) and
RESULTS vitamin D deficiency (OR=0.27, p=0.025; adjusted OR=0.65,
p=0.511). These are summarized in Table 3. No correlation
Two hundred eighty-nine pregnant women were was found between Vitamin D and FBS (Figure 2, r=0.28,
screened and gave their consent to be included in this p=0.095), 1-hour post 75 g OGTT (Figure 3, r=0.26, p=0.643),
study. However, only 211 complied with the required and 2-hour post 75 g OGTT (Figure 4, r=0.28, p=0.113).
test procedures and were subsequently included in the
analysis. Fifty-six of these women (26.5%) were diagnosed DISCUSSION
with GDM by ADA criteria, and 155 (73.5%) without GDM.
Women with GDM had a significantly higher average Vitamin D acts as a potential immunosuppressant that
age compared to those without GDM (p<0.001). Both downregulates the expression of pro-inflammatory
groups likewise differed significantly in terms of parity. markers which are associated with the development of
Majority of those with GDM had 1-2 previous deliveries, GDM.19 It is also known to influence insulin secretion
while most of those without GDM were nulliparous or thereby affecting circulating glucose levels.27 Hence, low
had 1-2 previous deliveries (p=0.008). The proportion of concentrations of vitamin D is a potential risk factor for
women with a previous history of GDM was significantly developing GDM. GDM, on the other hand, is associated
higher among those with GDM (p=0.004) There was no with several adverse maternal and fetal outcomes including
significant difference between the two groups in terms increased birthweight, neonatal hypoglycemia, increased
of pre-pregnancy BMI, history of poor obstetric outcome, incidence for primary cesarean section, preeclampsia
abnormal glucose metabolism, PCOS or family history and dystocia, and the predisposition of both the mother
of diabetes. The summary of baseline characteristics is and offspring to develop obesity, type 2 diabetes mellitus
seen in Table 2. and the metabolic syndrome.
Table 3. Vitamin D levels among patients with GDM

GDM No GDM Unadjusted OR Adjusted OR
p value p value p value*
(n=56, 26.5%) (n=155, 73.5%) (95% CI) *(95% CI)
Normal Vitamin D (n=13) 7 (12.5) 6 (3.9) Reference – Reference –
0.021
Low Vitamin D (n=198) 49 (87.5) 149 (96.1) 0.28 (0.09-0.88) 0.029 0.66 (0.18-2.36) 0.522
Vitamin D insufficiency (n=59) 16 (69.6) 43 (87.8) 0.061 0.32 (0.09-1.09) 0.069 0.55 (0.12-2.48) 0.433
Vitamin D deficiency (n=139) 33 (82.5) 106 (94.6) 0.018 0.27 (0.08-0.85) 0.025 0.65 (0.18-2.38) 0.511
*adjusted for pre-pregnancy BMI, age, parity and history of GDM

an overall prevalence of 94.7%.23 Other studies, however,

reported lower rates. An incidence rate of vitamin D
deficiency (<50 nmol/L) among 98 pregnant Chinese
women was reported at 20.4%.19 A larger cohort of 4718
Chinese women were found to have a higher prevalence
rate of 63.1%21 with a median 25(OH)D concentration
of 43.7 nmol/L. Another study in Nepal involving 79
pregnant women revealed an even higher rate of 81%.28
Local data on the prevalence of vitamin D among

pregnant Filipino women are still lacking. For the general
population, however, the overall prevalence of combined
Figure 2. Scatter plot of FBS against total vitamin D.
vitamin D deficiency and insufficiency was 48.7%. In
the same report, low vitamin D levels were highest in
people residing in NCR (54.1%), with a higher prevalence
in females (62.5%), in the age group of 20-39 years old
(55.5%)29– all factors of which were similar to the profile
of the women included in this study which could explain
the relatively increased rates observed. Avoidance of sun
exposure, whether intentional (i.e., to maintain fair skin for
aesthetic reasons, to prevent sunburns) or unintentional
(i.e., occupation setting mostly indoors) likely contributes
to the low vitamin D levels in this population. It is unclear
if pregnancy per se contributes to this decrease.
Figure 3. Scatter plot of 1-hour post 75 g oral glucose
Important to note as well, although not quantified, is that
tolerance against total vitamin D.
women who were included in this study were already
on vitamin D supplementation as part of standard of
prenatal care. Yet, there remained a high prevalence of
low vitamin D levels. A study by Lau et al., found that
among 147 pregnant Australian women on daily vitamin
D supplementation of 400 IU or 500 IU, 41% remained
vitamin D deficient.30 This might imply that the amount
of supplementation given as standard of care is not
enough to augment already low vitamin D levels.
Vitamin D levels were significantly higher among patients

with GDM (GDM 21.0±8.1 ng/mL vs no GDM 18.7±5.3 ng/
mL, p=0.0189). However, the absolute difference between
Figure 4. Scatter plot of 2-hour post 75 g oral glucose both groups may be small clinically. Pregnant women with
tolerance against total vitamin D. low vitamin D levels were found to have lower odds of
having GDM (OR=0.28, p=0.029). These findings contradict
In this study, pregnant women diagnosed with GDM had the initial hypothesis of this study. To our knowledge,
a significantly higher mean age and history of previous there have been no studies reporting an association
GDM, both of which are established risk factors for GDM. between high vitamin D levels and the occurrence of GDM.
Other risk factors for GDM such as BMI, a history of We attribute this finding to random chance or a type I
abnormal glucose metabolism, PCOS, family history for error, as the initial calculated sample size of 228 was not
diabetes, were not found to have any direct link to GDM reached. Furthermore, after adjusting for, age, parity,
appearance in the participants. Increased parity was also history of GDM, and pre-pregnancy BMI, no significant
seen in the GDM group, although parity per se has not association was observed (adjusted OR=0.66, p=0.522). The
been shown to be a risk factor for its development.5 same finding was true when stratified according to vitamin
D insufficient (adjusted OR=0.55, p=0.433) and deficient
There is still no established cutoff to define normal vitamin individuals (adjusted OR=0.65, p=0.511). Similar findings
D levels among pregnant women. Several ranges have been of non-association were reported by previous studies.
used to define vitamin D sufficiency,16,17,18 but these were A study on 76 pregnant Czech women by Pleskacova et
set on the basis of optimal levels to maintain skeletal health al., found a prevalence of vitamin D deficiency of 95.7%
in the general population. There remains the prerequisite among those with GDM and 93.1% among controls
to determine the normal range for pregnant women. (p=NS)23. Makgoba et al., studied 248 women and found a
Employing the cutoffs recommended by the Endocrine rate of 57% among those with GDM versus 62.2% among
Society Clinical practice guidelines to define vitamin D those without GDM (p=0.502)22. However, the results
insufficiency (>20 to <30 ng/mL, or >50 to 75 nmol/L) and of this current study are in contrast with many other
deficiency (≤20 ng/mL, or ≤50 nmol/L),17 there was a high studies including meta-analyses by Aghajafari and Lu. In
overall prevalence of 93.8% for low vitamin D levels among the former, 10 studies were included in the analysis and
pregnant women included in this study. This is similar it was found that GDM was associated with insufficient
to a study on 74 pregnant Czech women which found vitamin D levels compared with controls (pooled OR=1.49

using random effects model, I2 = 0%).24 In the latter which Author Disclosure
analyzed 20 observational studies that contained a total of The author declared no conflicts of interest.
16,515 pregnant women, maternal vitamin D insufficiency
was found to be associated with greater risk for GDM Funding Source
This work was supported by the 2019 Philippine Society of
(RR=1.45, p<0.0001).31
Endocrinology, Diabetes and Metabolism (PSEDM) Philippine
Research Initiative in Diabetes and Endocrinology (PRIDE)
The lack of association between GDM and low maternal research grant, as well as the St. Luke’s Medical Center
serum vitamin D levels in this study may be due to the high Research and Biotechnology Division.
overall prevalence of low vitamin D levels. Hence, vitamin
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JAFES
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Original Article
Journal of the
ASEAN Federation of
Endocrine Societies
Prevalence and Risk Factors for Hypovitaminosis D

among Healthy Adolescents in Kota Bharu, Kelantan
Suhaimi Hussain and Maged Elnajeh
Hospital University Science Malaysia
Abstract
Objective. We aim to study the prevalence and risk factors of hypovitaminosis D among healthy adolescents in Kota
Bharu, Kelantan based on the most recent Paediatric Consensus guideline.
Methodology. Ten public schools were selected from Kota Bharu, Kelantan. We analysed their demography (age, gender,
ethnicity, income), measured their anthropometry (height, weight, BMI) and finally analysed their vitamin D and intact-
Parathyroid hormone levels.
Results. The prevalence of hypovitaminosis D was 16.9% among healthy teenagers with mean age of 15.9±1.39 years.
Multivariate analysis showed female gender (adjusted OR, 95% CI): 23.7 (5.64, 100.3) and Chinese 0.24 (0.07, 0.84)
were the significant predictors for hypovitaminosis D.
Conclusion. The prevalence of healthy adolescents with hypovitaminosis D in Kota Bharu, Kelantan was 16.9% using
the most recent cut off value of 30 nmol/L from the global consensus 2016. Female and Malay were the significant risk
factors associated with hypovitaminosis D. Higher cut off value would result in overestimation of prevalence rate of
hypovitaminosis D.
Key words: hypovitaminosis D, adolescents, nutritional rickets
INTRODUCTION of vitamin D deficiency was 33% among adolescents with

mean age of 15 years old from Selangor, Perak and the
Hypovitaminosis D or vitamin D deficiency is a cause capital of Malaysia, Kuala Lumpur. However, the definition
of nutritional rickets. Rickets is due to defective bone was based on higher cut off or adult value of 50 nmol/L.13
mineralization in growing children. Vitamin D plays
a major role in calcium regulation and as calcium is Eighty percent of the source of vitamin D is from skin
the main mineral in the bones, deficiency of vitamin D synthesis following exposure to sun light. UVB from the
would lead to failure to absorb calcium and therefore it sunlight would convert 7-dehydrocholesterol in the skin
results in poor bone mineralization or rickets.1-4 Vitamin to cholecalciferol which will later be hydroxylated to
D deficiency during teenage years compromise bone inactive vitamin D in the liver then active vitamin D in the
mass and put teenagers at risk of adverse consequences kidney. Any factors that may interfere with skin synthesis
of skeletal health; and there is also increase in likelihood related to sociodemographic factors would lead to vitamin
of other medical problems in the future such as diabetes, D deficiency.14-16 Any diseases that would affect liver,
hypertension, metabolic syndrome and certain cancers kidney and gut would also impair synthesis of vitamin
such as colorectal cancer.5-7 The prevalence of vitamin D D since liver and kidney are involved in the steps for
deficiency worldwide varies widely depending on the hydroxylation of vitamin D while gut is the site at which
definition used in the trials. It can be as low as 0.4% in active vitamin D and parathyroid hormone act to increase
China and as high as 86% in Middle East if it is based on calcium and oral vitamin D absorption from the food.
the definition of vitamin D level <30 nmol/L. With higher Known risk factors associated with vitamin D deficiency
cut off used, the reported prevalence ranged from 5-99%.8-10 are poor sunlight exposure, sunscreen usage, darker skin,
Global consensus 2016 recommendations on prevention poor diet, older age, clothing, obesity, female gender and
and management of nutritional rickets has defined vitamin geographical location away from equator.17-33 The purpose
D deficiency using <30 nmol/L as the critical cut off below of this trial was to investigate the prevalence of vitamin D
which nutritional rickets is more likely to occur.11 This deficiency using the most recent definition from the 2016
definition is consistent with that of The Institute of Medicine Global consensus in Kelantan which is one of the poorest
(IOM).12 Malaysian Health and Adolescents Longitudinal states in Malaysia, and to study factors associated with
Research Team Study (MyHeARTs) reported the prevalence vitamin D deficiency. Healthy adolescents were selected
________________________________________
ISSN 0857-1074 (Print) | eISSN 2308-118x (Online) Corresponding author: Suhaimi Hussain, MD
Printed in the Philippines Consultant Paediatric Endocrinologist
Copyright © 2020 by Hussain et al. Paediatric Department, Hospital University Science Malaysia
Received: June 18, 2020. Accepted: August 23, 2020. Jln Raja Perempuan Zainab 2, 16150, Kota Bharu, Kelantan, Malaysia
Published online first: September 17, 2020. Tel. No.: +6097676536
https://doi.org/10.15605/jafes.035.02.05 Fax No.: +6097673370

Hypovitaminosis D among Healthy Adolescents in Kota Bharu, Kelantan Suhaimi Hussain, et al 177
as teenage years is marked by the highest bone mineral analysis of factors associated with hypovitaminosis D in
accrual and if they do not have the optimal storage of the binary logistic regression with hypovitaminosis D as
vitamin D, they are more likely to face all detrimental the dependent variable or outcome. From the results of
effects of hypovitaminosis D as an adult.34 simple logistic regression, selected variables / independent
variables that have p value <0.25 were included in the
METHODOLOGY multiple logistic regression. As for the multiple logistic
regression analysis, we used forward and backward LR
Sampling design initially and it was decided to use the output of backward
There were 45 public secondary schools in Kota Bharu LR for the presentation of the final results.
based on the list provided by the Kelantan State Education.
It was decided that ten schools were sufficient in order to Ethical Approval
recruit the required sample size. Participants were selected The study was approved by the University Ethical Board
via nonprobability sampling. Specifically, students were with its reference USM/PPP/Ethics Com. /2012(60)
recruited via purposive sampling. With the assistance
and supervision of the teachers in charge, an invitation RESULTS
to participate were given to students in class who met the
inclusion criteria. The students who expressed their interest A total of 361 healthy adolescents with the mean age
were invited for a briefing by the primary research team. (SD);15.9±1.39 years, age range (13-18 years) were recruited
from 10 public schools in Kota Bharu, Kelantan. The
Research tool predominant race was Malay, 307 (85%) while 54 (15%)
Subjects who gave consent, were asked to fill in the were Chinese students. Female subjects outnumbered
questionnaire to explore about sociodemographic factors. male with 227 (62.9%) vs 134 (37.1%). The mean vitamin
Height and weight were measured using standardized D level was 19.62 ng/mL, 95% CI (18.77, 20.47) with
instruments and methods. Blood for 25-(OH)Vit D, interval estimates 19.62±0.8466. The average vitamin D
intact-PTH were taken in EDTA tubes, centrifuged and level lies between 18.7 and 20.46 ng/mL. The prevalence
stored at -80 degree centigrade. Vitamin D was analysed of hypovitaminosis D / vitamin D deficiency based on the
using Elecsys Vitamin D Cobas that utilised Electro definition of <30 nmol/L or 12 ng/mL was 16.3%. The mean
Chemiluminescent Immunoassay for the quantitative weight and height (SD) were 53.0±16.8 kg, 156.2±19.2 cm.
measurement of total vitamin D. The Elecsys Vitamin D The mean (SD) of vitamin D level and intact-PTH were
demonstrated good overall performance with a precision 19.6±8.2 ng/mL and 33.4±18.0 pmol/L respectively (Table 1).
testing that showed within-run coefficient of variations
(CVs) of <7%, within-laboratory CVs of 9.5%, between- Table 1. Demographics of participants
laboratory precision CVs of <10.1% and a functional Variable Results
sensitivity below 9.8 nmol/L (at CV 12.9%). Age (years)# 15.9±1.39
Gender*
Inclusion and exclusion Male 134 (37.1)
Female 227 (62.9)
Healthy adolescents with age from 13-18 years old, without
Weight (kg)# 53.0±16.8
major medical problems such as kidney, liver and gut Height (cm)# 156.2±19.2
diseases were included. The information with regard to Vitamin D (ng/mL)# 19.6±8.2
the health status and intake of vitamin D supplements i-PTH (pmol/L)# 33.4±18.0
were answered by parents in the questionnaire. Those Race*
who were on vitamin D supplements and had incomplete Malay 307 (85)
data entry were excluded. Chinese 54 (15)
BMI*
Obese 27 (7.5)
Statistical analysis Normal 292 (80.9)
Data analysis was performed using SPSS (IBM) version 22. Underweight 40 (11.1)
Numerical data (age, weight, height, vitamin D, I-PTH) * n (%)
#
mean±SD
were expressed as mean and standard deviation while
categorical data (gender, race, BMI) were presented as
number and percentage. Simple and multiple logistic Significant factors associated with vitamin D deficiency
regression were applied to study the factors that affect after univariate analysis were older age, crude OR (95%
vitamin D deficiency. CI); 0.87 (0.72, 1.06), female gender; 22.1 (5.30, 92.3), Malay;
3.79 (1.14, 12.59), family income <RM 2000; 4.32 (1.12, 16.59)
The prevalence of vitamin D deficiency was determined and obesity; 2.74 (1.16, 6.49) (Table 2).
using a single proportion formula at confidence level/z
=95% or 1.96, margin of error at 5%/ standard value of However, multivariate analysis revealed only Chinese race;
0.05 and an estimated prevalence from Perez-Lopez et adjusted OR (95% CI); 0.24 (0.07, 0.84) and female gender;
al., Jan 2010= 28%. By using the formula, a sample of 310 23.7 (5.64, 100.3) were significant prognostic factors for
subjects was required to obtain a 95% confidence interval hypovitaminosis D (Table 3).
of 5% around a prevalence estimate of 20% and in order
to allow for an expected 20% drop out rate (62), a total DISCUSSION
of 372 students were needed. Sample size for calculating
factors associated with hypovitaminosis D was calculated The prevalence of healthy adolescents with vitamin D
with Pocock’s formula for comparing two proportions. deficiency in Kota Bharu, Kelantan was 16.3% if it is
Both numerical and categorical data were selected for the based on the paediatric cut off <30 nmol/L. In MyHeARTs

178 Suhaimi Hussain, et al Hypovitaminosis D among Healthy Adolescents in Kota Bharu, Kelantan
Table 2. Univariate analysis for factors affecting vitamin benefit beyond the recommended levels.12 Based on inverse
D level relationship between PTH and vitamin D, the level of
Variable Crude OR (95% CI) P value* vitamin D at which PTH is plateauing with increasing
Age 0.87 (0.72, 1.06) 0.191 level of vitamin D is defined as the cut off for vitamin
Gender D deficiency.37 The effect of high PTH with vitamin D
Male 1.00 0.0001 deficiency would result in an increase in bone resorption
Female 22.1 (5.30, 92.3)
or skeletal effects but which level of vitamin D that is
Race
Chinese 1.00 0.029 associated with other non-skeletal effects is still unknown
Malay 3.79 (1.14, 12.59) and controversial and this might contribute to different
Socio-economy cut-off values of vitamin D used in many other trials.6
<RM 2000 1.00 0.033
>RM 2000 4.32 (1.12, 16.59)
BMI
Based on univariate analysis, significant factors associated
Normal 1.00 with increased odds to have hypovitaminosis D among
Obesity 2.74 (1.16,6.49) 0.022 healthy teenagers were older age, female gender, Malay
Underweight 0.61 (020, 1.79) 0.37 race, poor socioeconomic status and obesity; OR (95%
i-PTH 1.00 (0.99, 1.02) 0.249
CI): 0.87 (0.72,1.06), 22.1 (5.30, 92.3), 3.79 (1.14, 12.59),
* Simple logistic regression
4.32 (1.12,16.59), 2.74 (1.16, 6.49). From multivariate
analysis, there were only two significant predictors for
Table 3. Multivariate analysis for factors associated with hypovitaminosis D which were female gender and race.
vitamin D deficiency We found that female gender had 22.1 times increased
Wald odds than male gender to have hypovitaminosis D while
Crude ORa Adjusted ORb
Variable
(95% CI) (95% CI)
statistic P valueb Chinese had 74% reduced odds to have hypovitaminosis
(df) D compared to Malay. The risk factors associated with
Race
Malay 1.00
hypovitaminosis D are similar to data found in most of the
Chinese 0.26 (0.07, 0.87) 0.24 (0.07, 0.84) 4.99 (1) 0.025 other vitamin D studies.17-31 From MyHeARTs study, the
Gender factors that were identified were female gender, obesity,
Male 1.00 wearing long sleeves, Malay and Indian ethnicity. Female;
Female 22.1 (5.30, 92.3) 23.7 (5.64, 100.3) 18.6 (1) 0.0001
5.5 (3.4-7.5), Malay; 3.2 (1.3-8.0), Indians; 4.3 (1.6-12.0)
a
Simple logistic regression
b
Multiple logistic regression, the model reasonably fits well. Model
and wearing long sleeves; 2.4 (1.1, 5.4) were the factors
assumptions are met. There are no interaction & multicollinearity associated with increased odds to have hypovitaminosis
problems. D after multivariate analysis.13 A cross sectional study of
Variance Inflation Factor <10
402 healthy school children aged 7-12 years old in Kuala
Correlation is weak that indicates no multicollinearity
Hosmer-Lemeshow goodness-of-fit p-value=0.966, not significant and Lumpur found that 35.3% of the children had serum
therefore the model fits 25(OH)D <37.5 nmol/L. The subjects were younger and it
Overall correct classification=83.8% was found that the high prevalence was higher in obese
Area under the curve=0.762 (95% CI=0.706, 0.818)
boys with chi square=5.958; p=0.016. As expected when a
higher value for cut off was chosen, the prevalence would
(Malaysian Health and Adolescents Longitudinal Research be higher.38 Compared to other South East Asia countries
Team Study) the prevalence of vitamin D deficiency was from SEANUTS survey conducted in 2010/2011 in
33% among healthy adolescents from 15 schools in Selangor, Indonesia, Malaysia, Thailand and Vietnam, the prevalence
Perak and Kuala Lumpur which are located in states with of vitamin D deficiency among children with age range 0.5-
higher revenue than Kelantan but the definition of vitamin 12 years old were 4.1% in Malaysia, 2% in Thailand, and
D deficiency used was 50 nmol/L that was higher than our 11.1% in Vietnam. The subjects were younger than our
definition of 30 nmol/L.13As a higher cut off value was used cohort and the cut off value to define vitamin D deficiency
to define hypovitaminosis D, therefore their prevalence was similar to our definition. Our prevalence is higher
rate was higher. Their prevalence might be similar to us if most probably since our subjects are older. Older age/
only a lower cut off was used to define hypovitaminosis D adolescents have higher metabolic demands for vitamin D,
since higher value would result in over diagnosing vitamin owing to the rapid growth of the skeleton during puberty
D deficiency and furthermore the cut off of 50 nmol/L is and are therefore at higher risk of vitamin D deficiency.39
mostly used in adult trials. This current definition was based Among risk factors associated with vitamin D deficiency
on strong evidence supported by the increased incidence of from SEANUTS were older age, girls, wearing head scarf
nutritional rickets with 25(OH)D concentration <30 nmol/L or long trousers and darker skins in certain ethnicity
based on the latest global consensus recommendations especially Indian. In Malaysia (SEANUTS), significant
on prevention and management of nutritional rickets.11 It differences were noted between races in which Indians had
is also consistent with the latest recommendation by The lower value of vitamin D; 45.6±2.9) compared to Malays;
Institute of Medicine (IOM).12 There are many studies with 53.7±1.2, and Chinese; 56.2±1.7 nmol/L. Older age; 1.4 (1.2,
different cut off level to diagnose Vitamin D deficiency, 1.5), female gender; 1.8 (1.0, 3.1) had increased odds to
insufficiency and sufficiency but with higher cut off have hypovitaminosis D. In Thailand (SEANUTS), older
values used would likely to overestimate the burden of age; 1.1 (1.0,1,2) female gender; 2.2 (1.3,3.7) were associated
vitamin D deficiency across all age groups and this might with increased odds of hypovitaminosis D. In Vietnam
also lead to unnecessary treatment with vitamin D.35,36 (SEANUTS), significant factors that were associated with
IOM (2010) committee has based its recommendation as increased odds for hypovitaminosis D were older age; 1.1
deficiency <30 nmol/L, insufficiency 30-50 nmol/L and (0.9, 14) and female gender 1.0 (06,1.7) and the same were
sufficiency 50-75 nmol/L on the indicators of bone health as also seen in Indonesia (SEANUTS), with values for older
review of many literature did not suggest any additional age at 1.1 (1.0, 1.2) and for female gender at 2.7 (1.3, 5.5).40

Hypovitaminosis D among Healthy Adolescents in Kota Bharu, Kelantan Suhaimi Hussain, et al 179
Solar radiation (UVB band of 290-315 nm) stimulates CONCLUSION

synthesis of pre-vitamin D in the skin from
7-dehydrocholesterol to cholecalciferol, an inactive The prevalence of hypovitaminosis D among healthy
metabolite of vitamin D.32 The sun exposure is affected by adolescents in Kota Bharu, Kelantan was 16.9% based
many factors such as latitude, altitude, season, time of the on the most recent cut off value of 30 nmol/L. Female
day, cloud cover, air quality and personal factors which are gender and Malay race were the significant risk factors
life style, clothing, time spent outdoor and use of sunscreen. associated with hypovitaminosis D. Higher cut off limit
The dose-response of circulating 25(OH)D to cutaneous used to diagnose vitamin D deficiency would result in
UVB exposure is dependent on skin pigmentation, age, overestimation of the prevalence rate.
body composition, genetic factors and baseline 25(OH)D.17
Kota Bharu is the capital of Kelantan and it is located at Both authors certified fulfillment of ICMJE authorship criteria.
6.133 N 102.23 E. Abundant sunlight is received throughout
the year as Malaysia is located close to the equator. Most Author Disclosure
Both authors declared no conflict of interest.
of the Malays have darker skin compared to Chinese and
this contributed to higher proportion of Malay teenagers
Funding Source
with vitamin D deficiency since sunlight is the main The University Science Malaysia provided short term grant
source of endogenous vitamin D synthesis. The mean funding for the study with reference number 304/PPSP/613-10055.
vitamin D (Malay vs Chinese) was 19.0 vs 23.0 ng/mL;
(p=0.001). Males have higher level of vitamin D compared References
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Original Article
Journal of the
ASEAN Federation of
Endocrine Societies
Efficacy of Repetitive Transcranial Magnetic Stimulation (rTMS)

in Inducing Weight Loss among Obese Filipino Patients:
A Randomized Controlled Trial
Margaret Encarnacion,1 Oliver Allan Dampil,1 Ludwig Damian,2 Maria Leila Doquenia,2
Divina Cristy Redondo-Samin,3 Mary Karen Woolbright3
1
Department of Internal Medicine, Section of Endocrinology, Diabetes and Metabolism, St. Luke’s Medical Center, Quezon City, Philippines
2
Department of Neurology, St. Luke’s Medical Center, Quezon City, Philippines
3
Department of Clinical Nutrition, St. Luke’s Medical Center, Quezon City, Philippines
Abstract
Objective. To determine the efficacy of rTMS in decreasing body mass index (BMI) versus sham stimulation among
obese Filipino patients.
Methodology. This was a single-center, randomized, sham-controlled, single-blind, parallel group trial. Participants
were 15-65 years old with BMI ≥30 kg/m2 and weight stable for 6 weeks. Participants were randomized to receive real
rTMS or sham stimulation. Each underwent 4 sessions of stimulation over 2 weeks. Anthropometrics, total caloric intake
(TCI), and VAS score for appetite were taken at baseline, 2, 4, 6, and 12 weeks.
Results. A total of 31 patients were randomized with 15 to the treatment and 14 to sham stimulation completing treatment,
with 2 lost to follow-up. A significant decrease in BMI was noted after 4 weeks from the start of rTMS in the treatment
group, (0.6±0.6, p-value=0.001), with weight change of -1.3±1.3 kg (p-value=0.009), but was no longer observed at 6
weeks onwards. No severe adverse effects were noted.
Conclusion. rTMS to the DLPFC effectively decreased BMI (0.6±0.6) and weight (-1.3±1.3 kg) from baseline to 4 weeks.
At 6-12 weeks after rTMS however, there was no longer a significant difference, indicating that 4 sessions of rTMS
may not be enough to produce a prolonged effect on weight loss.
Key words: obese, repetitive transcranial magnetic stimulation, weight loss
BACKGROUND to increased food cravings.6 Furthermore, stimulation

of this area also reduced the neural activity in more
Obesity is characterized by excessive fat accumulation, remote areas like the orbitofrontal and anterior cingulate
causing adverse effects on health and well-being.1,2 cortex,7 and this further reduces food cravings. With less
According to the Asia-Pacific guidelines, obesity is defined cravings, it is speculated that there will be decreased food
as a body mass index (BMI) of more than 25 kg/m2. It is consumption and overall weight loss.
considered as a fast-growing epidemic which occurs in
about 500 million adults, with its prevalence increasing rTMS is a non-invasive neuromodulation procedure that
in adolescents and children.3 Obesity is linked to several involves delivering magnetic waves at a high frequency.
disease entities that are leading causes of morbidity Research from animal studies have shown that activity in
and mortality worldwide. These include type 2 diabetes the prelimbic region (the homologous prefrontal cortex
mellitus, cardiovascular disease, cancer, and metabolic in rodents) is decreased by chronic cocaine use, and
syndrome.4 stimulation of the prelimbic cortex decreases compulsive
cocaine seeking which is similar to addictive behavior
Previously, non-pharmacologic treatment such as lifestyle in humans. Therefore, when the dorsolateral prefrontal
modification was the first line of treatment in obesity. cortex is stimulated by rTMS, it may decrease cortical
However, recent studies have shown that the success activity and improve cognitive control. These studies
rate of lifestyle modification alone is low.5 were then applied to human behavior.8
Several studies have explored the link between food rTMS delivered to the left DLPFC has been associated
cravings and incidence of obesity. In patients who were with reduction in cravings and subjective urge to smoke,
obese, there is a lack of stimulation of the dorsolateral both of which are associated with addictive behavior.9 It
prefrontal cortex (DLPFC) in response to food, leading is also currently accepted as a treatment option for several
________________________________________
ISSN 0857-1074 (Print) | eISSN 2308-118x (Online) Corresponding author: Margaret C. Encarnacion, MD
Printed in the Philippines Section of Endocrinology, Diabetes and Metabolism
Copyright © 2020 by Encarnacion et al. Department of Medicine, St. Luke’s Medical Center, Quezon City
Received: June 7, 2020. Accepted: September 10, 2020. 279 E. Rodriguez Sr. Avenue, Quezon City, Philippines 1112
Published online first: October 6, 2020. Telefax: +632-7230101 local 5210
ORCiD: https://orcid.org/ 0000-0003-4029-7032

182 Margaret Encarnacion, et al Efficacy of rTMS in Inducing Weight Loss among Obese Filipino Patients
neuropsychiatric disease conditions like depression, bipolar stimulation over a period of 12 weeks: change in body mass
disorder, Alzheimer’s disease and Parkinson’s disease.2 index, change in appetite and food cravings and change in
actual total caloric intake (TCI) 2) To describe the safety of
TMS is generally well tolerated and has been used for rTMS, including serious adverse effects like seizures.
several years. Reported mild adverse effects of rTMS
occur in about 5% of 1270 sessions among 113 patients METHODOLOGY
who underwent rTMS according to a study by Maizey et
al., in 2012.10 Among these patients, 37% of reported mild Trial Design
adverse effects were related to anxieties and expectations This was a single-center, randomized, sham-controlled,
regarding TMS.10 These mild adverse effects included mild single-blind, parallel group trial. Only the participants, and
headache, stinging skin sensation, and nausea. not the study staff, were blinded to the treatment given.
According to the Safety Guidelines on TMS published by Participants

Rossi et al., in 2009, the risk of rTMS to induce seizures is Participants included social service and private Filipino
very low, at less than 1% of the population. In a review outpatients SLMC QC who were 15-65 years old with BMI
of accidental seizure events during TMS, 3 or 4 instances ≥30 kg/m2 who remained weight stable (±5%) for 6 weeks.
of seizures that occurred and have temporal relationship Exclusion criteria were: history of prior rTMS, history
with receipt of TMS, 6 of 8 instances occurred in patients of head injury or epilepsy/ seizure disorder, pacemaker,
taking epileptogenic medications or have seizures already body metallic implants and other contraindications to MRI
occurring as part of their disease, and 3 of 8 cases may or rTMS, use of weight loss drugs within the past year or
represent non-epileptic events such as anxiety or syncope.11 very low calorie diet, pregnancy or breastfeeding, eating
disorder or substance dependence, current psychiatric
Local pain and headache are also described and may occur illness or use of psychotropic medications, unstable
in 28% and 39% respectively. The percentage of those who cardiovascular disease (recent MI or stroke within 1 year,
discontinued treatment due to pain is <2%, and was often heart failure, acute limb ischemia, severe peripheral
relieved by oral pain relievers like NSAIDS.11 arterial occlusive disease), neurologic deficits based
on initial physical exam, presence of other underlying
On review of existing literature, most studies explored causes of obesity (hypothyroidism, Cushing’s syndrome,
the effect of rTMS on reducing food cravings after only 1 hypogonadism, insulinoma) noted on history or physical
session of treatment. The assessment of impact on food examination, and current use of cochlear implants.
cravings and appetite came immediately after the rTMS.
These showed that rTMS did reduce food cravings, Randomization/Allocation
however this did not result in immediate reduction in food Participants were randomized to receive either real rTMS
intake. One of the reasons cited was that the evaluation plus standard of care non-pharmacologic therapy or sham
of treatment came after only one session, and thus its stimulation plus standard of care non-pharmacologic
longer-term benefits were not explored.9 therapy through sealed randomization envelopes, in a
1:1 ratio.
A study conducted by Se-Hong Kim in 20184 is a randomized,
single-blind, sham-controlled trial conducted in Korea The primary investigator and the staff who performed
which enrolled 60 participants, divided equally and received rTMS were aware of the treatment allocation whereas
either rTMS to the left DLPFC or sham stimulation over 2 participants were blinded.
weeks. Results showed that at the 4th week, participants
who received rTMS showed a significant weight loss from Intervention
baseline after 4 sessions (-1.35±2.31 kg vs 0.45±1.28 kg), Baseline assessment included anthropometrics, laboratory
reduction in BMI, fat mass and visceral adipose tissue results, Visual Analog Scale (VAS) score for appetite and
compared to sham stimulation. These participants also average total daily caloric intake.
had lesser appetite and consumed less kilocalories per day.
This study is more beneficial to current clinical setting as it Anthropometric measurements included weight, height
has significant influence in the management of obesity. and body mass index. The height of each participant was
measured up to the nearest 0.1 centimeter. The weight
One of the limitations cited in the study was that the effect was measured using the same standing weight scale in
of rTMS was only studied up to 2 weeks after the last the SLMC QC Weight Management Center, up to the
session. The long-term or permanent effect of rTMS even nearest 0.1 kilogram. Body mass index was determined by
after the intervention has been discontinued has not yet dividing the weight of the participant in kilograms from
been fully explored. Likewise, a similar study has not yet the square of the height in meters. Waist circumference was
been conducted in the Filipino population. measured to the nearest centimeter at the end of the normal
expiration in a horizontal plane immediately superior to
Objectives the left iliac crest (using the National Health and Nutrition
Examination Survey protocols). Blood pressure was
The general objective of the study was to compare the measured using an aneroid sphygmomanometer, and heart
efficacy of rTMS in decreasing BMI versus sham stimulation rate was obtained through palpation of radial pulse over
among obese patients at St. Luke’s Medical Center, 1 minute.
Quezon City (SLMC QC). Specific objectives were: 1) To
describe and compare the following parameters among Each participant also underwent the following laboratory
obese Filipino patients who received rTMS versus sham tests prior to initiation of the study: Thyroid stimulating

Efficacy of rTMS in Inducing Weight Loss among Obese Filipino Patients Margaret Encarnacion, et al 183
hormone, fasting blood sugar, glycohemoglobin, total

Patients who fit the inclusion criteria and
cholesterol, triglycerides, high density lipoprotein, low
have none of the exclusion criteria
density lipoprotein, 12-lead ECG, serum creatinine and
complete blood count.
Randomization to real rTMS group
Appetite was measured using 10 cm visual analog scales or placebo stimulation group
measuring “urge to eat”, “hunger,” and “prospective
food consumption.” These were obtained at the start of
the study, immediately after rTMS (week 2), 2 weeks after WEEK 0
rTMS (week 4), 4 weeks after rTMS (week 6), and 10 weeks Real rTMS for 2 Placebo stimulation
after rTMS (week 12). These scales are 10cm line scales with weeks + weight for 2 weeks + weight
each end labeled with opposite attributes e.g., for hunger management management program
– “not hungry at all” and on the other end “extremely program for 6 weeks for 6 weeks
hungry,” with different attributes of increasing intensity
of hunger placed at 1 cm intervals. The participants
were asked to encircle the category which best described WEEK 2
his/her hunger state. Posttest 1 (after the intervention)
WEEK 4
TCI was measured through a 3-day food diary, taken
at baseline, at 2 weeks, at 4 weeks, at 6 weeks, and at 12 Posttest 2 (at 2 weeks after intervention)
weeks of intervention. Food and beverage intake were
WEEK 6
recorded over 3 nonconsecutive days, including one
weekend day. Average daily TCI was monitored and Posttest 3 (at 4 weeks after intervention)
calculated by a nutritionist. WEEK 12
Study participants underwent either rTMS or sham Posttest 4 (at 10 weeks after intervention)
stimulation according to the group to which they were
randomized. There was a total of 4 rTMS sessions done Figure 1. Schematic diagram of study design.
at St. Luke’s Medical Center Global City Institute of
Neurosciences, provided over 2 non-consecutive days Outcomes
a week for 2 weeks. The TAMAS CR Technology device Primary outcome measure was a change in BMI from
with either real or sham butterfly magnetic coil was used baseline to 4, 6, and 12 weeks. Secondary outcome measures
to administer rTMS. After mapping the abductor pollicis were: weight change from baseline, change in average total
brevis site in the left motor cortex, the motor threshold for daily caloric intake and change in VAS score for appetite.
each participant was obtained as the minimum stimulus These were obtained at baseline, after the last session of
needed to induce contraction of the right thumb.4 transcranial stimulation, at week 4, week 6 and at week 12.
For the treatment group, the site for stimulation of the left Sample Size
DLPFC was 5 cm anterior to and in the same parasagittal The sample size was calculated based on the comparison
plane as the site of maximal abductor pollicis brevis of change in BMI, the primary outcome of choice, before
stimulation. Twenty trains of 5 seconds with 55-second and after treatment for the TMS group versus sham group.
intertrain intervals were given at a frequency of 10 Hz Assuming that the change in BMI for the TMS group is
and intensity of 110% of the participant’s motor threshold, -0.43±0.79 SD, and for the sham, 0.18±0.49, (Se-Hong Kim,
providing a total of 1000 pulses over 20 minutes.4 et al., 2018), with an alpha error of 5% and power of 80%,
and a 1-tailed alternative hypothesis, sample size deduced
In the sham group, the sham-coil was placed over the was 15 per group, for a total of 30 patients for 2 groups.
interhemispheric fissure at the vertex, and stimulation is
at low intensity (10% of resting motor threshold), enough Statistical Methods
to produce similar skin sensations as real rTMS.4 Blinding Descriptive statistics were used to summarize the clinical
was achieved in this way: both arms received a form of characteristics of the patients. Frequency and proportion
stimulation but the area and intensity are different. The were used for nominal variables, median and range for
staff and investigators were aware of their allocation but ordinal variables, and mean and SD for interval/ratio
did not disclose such to the participants. variables. Per-protocol analysis was done. In this analysis,
only those who completed the treatment allocation and
As part of standard of care, each participant in both follow-up were included in the study. The results were
treatment and sham groups was enrolled in a 6-week expressed as the mean ± standard deviation (SD).
standard weight management clinic, which included
nutrition counseling, 18 sessions of consultation (3-4 times Between-group differences on outcome variables measured
a week), and guided exercise/use of gym. Prior to entry at baseline and at weeks 2, 4, 6, and 12 respectively were
in the weight management program, each participant analyzed using ANCOVA with treatment group as
underwent cardiac clearance. The same physician also factor and baseline values as covariates. Effect sizes were
evaluated the patient at the end of the program. The rTMS calculated for statistical differences between-group. Mixed
sessions were done during the first 2 weeks of the 6-week linear model was used for within group differences for
weight management intervention. Figure 1 represents a those that were measured at baseline, at week 2, at week 4,
schematic diagram of the study design. week 6, and at week 12.

For subjective appetite scores using VAS, the 2-way and the sham group (p-value=0.0017). Patients in the
repeated measures ANOVA and multiple comparisons rTMS group had a mean 0.6±0.6 decrease in BMI while
with Bonferroni corrections were used. A two-tailed p-value the sham group had a mean 0.1±0.6 increase in BMI.
of <0.05 was considered statistically significant. Data Furthermore, large effect sizes were observed in change
were analyzed using the Statistical Package for the Social in body weight (0.786 to 0.996) and BMI (0.742 to 0.990)
Sciences version 21.4 indicating a strong relationship between rTMS and these
outcomes. At 6 weeks however, there was a plateau in
Ethical Consideration BMI from baseline but the p-value was not significant.
This clinical protocol and all relevant documents were The plateau in BMI at 6 weeks posttest coincides with the
reviewed and approved by the SLMC Institutional Ethics weight plateau and may have accounted for this difference.
Review Committee. To ensure confidentiality, each At 12 weeks, there was likewise no significant BMI change
patient was assigned a data generated code. The primary between the two groups.
investigator was responsible for the integrity of the data.
The manner of disseminating and communicating the There was a continuous decrease in waist circumference
study results guaranteed the protection of the patient’s with a difference of -5.3±7.3 cm at 6 weeks, however this
confidentiality. was not statistically significant as there was also a slight
decrease in the sham group (p-value=0.14). By 12 weeks,
RESULTS there was a slight regain/ increase in waist circumference
when compared to that at 6 weeks, but these were not
Recruitment period was from July to August 2019 and statistically significant.
all follow-up sessions were completed by February 2020.
A total of 31 patients were randomized with 15 to the There was a significant difference, from baseline to 2 weeks,
treatment and 14 to sham stimulation completing treatment, in the change in TCI after intervention between the rTMS
with 2 lost to follow-up. Figure 2 shows the participant group and the sham group (p-value=0.0292). Patients in
flow of the study. the rTMS group had a mean 281.8±41.0 kcal/day decrease
while the sham group had a mean 75.6±228.2 kcal/day
Table 1 summarizes the baseline characteristics of the study increase in total energy intake. However, from 4 weeks up
population. The two groups did not differ significantly to 12 weeks of the study, this effect is no longer observed.
at the start of the study. They were similar in terms of
BMI, VAS scores, total daily caloric intake, and comorbid VAS scores did not change significantly throughout the
conditions like hypertension and diabetes. Baseline study in three aspects of appetite- hunger, desire to eat,
laboratory values were also similar, as seen in Table 2.
Table 1. Baseline characteristics of the participants
From baseline to 4 weeks after the start of intervention, Placebo / Sham
there was a significant decrease in weight compared to rTMS group
stimulation group
(n=15)
baseline. There was significant difference in the change in (n=14)
weight at week 4 between the rTMS group and the sham Age (yrs) 41.3±10.4 41.2±7.6
group (p-value=0.0094). Patients in the rTMS group had a Sex
Male 7 (46.7%) 2 (14.3%)
mean 1.3±1.3 kg decrease in weight while the sham group Female 8 (53.3%) 12 (85.7%)
had a mean 0.1±1.5 kg increase in weight. Although there Waist circumference (cm) 110.6±9.9 107.4±10.8
was a decrease in weight in the treatment group at weeks Weight 89.9±12.0 85.9±15.3
6 and 12, this was not statistically significant as there was Height 157.2±5.6 154.6±6.0
also some weight loss observed in the sham group. BMI 36.0±4.3 35.9±6.5
VAS for subjective appetite
There was a significant difference in the change in BMI Hunger 4.1±2.7 3.6±2.4
compared to baseline at week 4 between the rTMS group Desire to eat 4.4±2.2 4.0±2.2
Food consumption 4.4±2.4 4.2±2.5
Total daily caloric intake 1851.3±605.5 1621.1±428.6
Hypertension 4 (26.7%) 3 (21.4%)
Fulfilled inclusion criteria and randomized (n=30)
Diabetes Mellitus 4 (26.7%) 5 (35.7%)
ALLOCATION
Real rTMS + Sham + Table 2. Baseline biochemical parameters of the
weight management weight management participants
n=15 n=15 Placebo / Sham
rTMS group
stimulation group
(n=16)
(n=15)
FOLLOW-UP
Fasting blood sugar (mg/dl) 98.6±34.6 115.8±46.9
15 Completed 14 Completed 12 week follow-up Glycohemoglobin (%) 6.0±1.2 6.5±1.7
12 week follow-up 1 Lost to follow-up at 4 weeks Thyroid Stimulating Hormone 1.9±0.5 1.9±1.0
Total Cholesterol (mg/dl) 184.3±31.5 182.1±34.6
ANALYSIS Triglycerides (mg/dl) 149.4±63.4 147.8±77.2
15 patients included 14 patients included High density lipoprotein (mg/dl) 43.1±7.2 44.3±8.6
in analysis in analysis Low density lipoprotein (mg/dl) 109.2±34.6 105.9±38.5
Serum creatinine (mg/dl) 0.84±0.34 0.77±0.15
Figure 2. Participant flow of the study.

Table 3. Within-group differences in study outcomes assessed using mixed linear regression
rTMS group Placebo/Sham Stimulation group
(n=15) (n=14)
Within Group Differences Within Group Differences
Coefficient Standard Error P-value Coefficient Standard Error P-value
Weight
After 2weeks -0.66 1.33 0.623 0.09 0.48 0.847
After 4 weeks -1.33 1.33 0.315 0.11 0.48 0.824
After 6 weeks -1.36 1.33 0.305 -0.15 0.48 0.756
After 12 weeks -2.87 1.33 0.030 -0.31 0.48 0.515
BMI
After 2weeks -1.16 0.65 0.076 0.09 0.23 0.682
After 4 weeks -0.60 0.65 0.359 0.08 0.23 0.746
After 6 weeks -0.56 0.65 0.387 -0.03 0.23 0.891
After 12 weeks -1.21 0.65 0.064 -0.21 0.23 0.377
Waist Circumference
After 2weeks -1.8 1.45 0.216 -2.3 1.14 0.042
After 4 weeks -3.7 1.45 0.011 -2.5 1.14 0.027
After 6 weeks -5.3 1.45 0.000 -3.2 1.14 0.005
After 12 weeks -4.1 1.45 0.005 -3.0 1.14 0.008
TCI
After 2weeks -281.1 124.3 0.024 75.6 87.3 0.387
After 4 weeks -282.4 124.3 0.023 10 87.3 0.909
After 6 weeks -236.8 124.3 0.057 -81.1 87.3 0.353
After 12 weeks -153.8 124.3 0.216 -114.6 87.3 0.189
VAS Hunger
After 2weeks 0.5 0.67 0.428 -0.9 0.61 0.129
After 4 weeks -0.6 0.67 0.361 -0.4 0.61 0.498
After 6 weeks -0.6 0.67 0.340 -0.4 0.61 0.476
After 12 weeks -1.1 0.67 0.088 0.0 0.61 1.000
VAS Desire to Eat
After 2weeks -0.3 0.50 0.523 -1.1 0.55 0.046
After 4 weeks -1.1 0.50 0.032 -0.9 0.55 0.090
After 6 weeks -1.4 0.50 0.004 -0.9 0.55 0.118
After 12 weeks -1.0 0.50 0.039 -0.4 0.55 0.482
VAS Food consumption
After 2weeks -0.4 0.56 0.511 -1.0 0.62 0.089
After 4 weeks -1.2 0.56 0.039 -1.1 0.62 0.069
After 6 weeks -1.1 0.56 0.045 -1.0 0.62 0.093
After 12 weeks -1.4 0.56 0.012 -0.7 0.62 0.325
and prospective food consumption. There was a significant Table 4. Correlation of change in VAS scores from
difference in hunger scores after intervention between baseline to 12 weeks with change in total caloric intake
the rTMS group and the sham group (p-value=0.023) at from baseline to 12 weeks
2 weeks. Patients in the rTMS group had a mean 0.5±2.9 Coefficient P-value
increase while the sham group had a mean 0.9±2.2 increase VAS Hunger 0.13 0.3441
in hunger scores. At 4 up to 12 weeks however, there VAS Desire to Eat -0.01 0.9398
was no longer an observed difference between the two VAS Food Consumption -0.03 0.8356
groups. There was no significant difference in desire to
eat and prospective food consumption between the two
groups from baseline up to 12 weeks of the study. Table 5. Correlation of change in weight, BMI, Waist
Circumference from baseline to 12 weeks with change in
Within-group differences were analyzed through mixed total caloric intake from baseline to 12 weeks
linear regression model. These showed that within the Coefficient P-value
rTMS group, there was a significant decrease in weight, Weight -0.17 0.3704
waist circumference and VAS score for prospective food BMI -0.17 0.3740
consumption when baseline values are compared to 12 Waist Circumference -0.27 0.1501
weeks. However, when compared to the sham group
(between-group difference) based on ANCOVA results
reported above, the changes were not significant. DISCUSSION
Safety Efficacy of rTMS in Decreasing BMI

rTMS was well-tolerated by the participants. 2 patients The weight loss in this study is comparable to that of
in the treatment group reported transient mild headache the study by Kim et al., in 20184 which also showed a
(graded 3/10 post 1st session of rTMS for 1 patient, and significant decrease in weight and BMI at 4 weeks after
graded 4/10 post 3rd and 4th session of rTMS for 1 patient). the rTMS. The weight loss in this study was -1.3±1.3 kg in
These occurred immediately after rTMS and were resolved the treatment group versus -1.35±2.31 kg in the study by
within 24 hours. No other adverse event was reported Kim et al. Since Week 2 anthropometric values were not
and no participant dropped out of the study because of measured in their study, the researchers are unable to
headache. No adverse effect was reported in the sham compare the 2-week data to that of other studies.
stimulation group.

These results are also supported by 2 other studies There was no longer a significant change observed at weeks
conducted in 2019 (both published after our study protocol 6 and 12, however, indicating that although rTMS may be
has been completed and subject recruitment was already effective in decreasing body weight, the effects may not
ongoing). In the study by Kim et al., in 2019, 8 sessions be permanent. The studies done by Kim and Alvarado-
of rTMS over 4 weeks were done and resulted in more Reynoso employed assessment of weight immediately
weight loss of 2.75±2.3 kg.12 Alvarado-Reynoso and Tututi’s after the last session, and therefore were not able to explore
study employed a longer treatment period, with 5 rTMS the long-term effects of rTMS even if this intervention
sessions every week for 2 weeks, then once a week on weeks is no longer present. This current study may imply that
3, 4, 6, 8, 12, 20 and 28 coupled with a low -carbohydrate regular sessions of rTMS may need to be given in order to
diet. They also found a continuous decline in weight up to maintain weight loss.
the last session at 28 weeks.13
As to waist circumference, although there was a continuous
The proposed explanation is that targeting the DLPFC decrease with a difference of -5.3+7.3 cm at 6 weeks, this
helps decrease deranged eating behaviors and excessive was not statistically significant when compared to that
food cravings. Decreased food cravings, in turn, decreases of the sham group. It is possible that a steady decline in
food intake and aids in weight loss.4,12 The researchers did waist circumference may be observed if the study is further
a correlation analysis and found that change in caloric extended, or that there was inter-observer variability in
intake was not significantly associated with change in measuring the waist circumference at each follow-up.
BMI, waist circumference and weight. Although it is
accepted in studies that less food intake leads to weight It is important to note that one of the subjects in the rTMS
loss, several factors may have affected the results of this group displayed a significantly higher decrease in weight
study. One may be that the sample size was not adequate and BMI compared to the other subjects in both groups, and
for the correlation analysis done. Food intake through this may be a possible outlier in the study.
3-day food diary may also be inaccurately collected by the
subjects, thus a significant decrease in intake in relation to Effect of rTMS on TCI
weight loss was also not observed. In the first 2 weeks, the TCI was significantly lower in the
treatment group. However, for the succeeding 2 weeks
90 112
Waist Circumference (cm)
89 88.9
88 88.3 88.3 110
87.6
Weight (kg)
87
108
86 85.9 86 86 86 86.1
85.6
85 106
84
83 104
82
102
81
80 100
Baseline Week 2 Week 4 Week 6 Week 12 Baseline Week 2 Week 4 Week 6 Week 12
rTMS group (n=15) sham group (n=14) rTMS group (n=15) sham group (n=14)
Figure 3. Comparison of weight from baseline between Figure 5. Comparison of waist circumference from baseline
rTMS vs sham group. between rTMS vs sham group.
36.2 1900
Total Caloric Intake (kcal/day)
36 1800
Body Mass Index (BMI)
35.8 1700
35.6
1600
35.4
1500
35.2
1400
35
1300
34.8
34.6 1200
34.4 1100
34.2 1000
Baseline Week 2 Week 4 Week 6 Week 12 Baseline Week 2 Week 4 Week 6 Week 12
rTMS group (n=15) sham group (n=14) rTMS group (n=15) sham group (n=14)
Figure 4. Comparison of BMI from baseline between Figure 6. Change in total daily caloric intake from baseline
rTMS vs sham group. between rTMS vs sham group.

onwards, there was no significant difference anymore 5

between the two groups. This initial decrease coincided 4.5
with the duration of rTMS procedure indicating that TCI 4
may be decreased by rTMS but the effect is not permanent.
3.5
VAS Score
This may be reflective of the short-term impact of rTMS 3
in decreasing appetite and food cravings. Thus, when the 2.5

rTMS was no longer continued, there was a corresponding 2
increase in intake in the treatment group. The permanency 1.5
or reversibility of effects of rTMS on weight loss and food 1
cravings in obese patients has not yet been studied, yet it
0.5
is an area that needs to be explored. In a study by Mally et
al., long-term effect of rTMS was studied in patients with 0
Baseline Week 2 Week 4 Week 6 Week 12
Parkinson’s disease. rTMS was given 2 times a day for 7
days (1 Hz, 100 stimuli per day) and was repeated at least rTMS group (n=15) sham group (n=14)
twice a year for 3 years. There was significant decrease
in progression of Parkinson’s disease with the repeated Figure 7. Change in hunger scores from baseline between
stimulation over 3 years. They proposed that prolonged rTMS vs sham group.
stimulation produced prolonged inhibition in intracortical
5
connections which delayed progression of the disease.14
Therefore, increasing the total number of rTMS to the 4.5
DLPFC may potentially induce longer lasting effects on 4
weight loss and caloric intake as well. 3.5
VAS Score
3
The result of this study is in contrast to the study by Kim 2.5
et al., where there was a continued decrease in total caloric 2
intake at Week 4.4 However, since there was no Week 2
1.5
assessment in their study, a comparison of intake between
1
Week 2 and Week 4, and therefore a possibility that there
was lesser caloric intake at Week 2 than at Week 4, was 0.5
not determined. 0
Baseline Week 2 Week 4 Week 6 Week 12
Change in VAS scores for appetite and change in total rTMS group (n=15) sham group (n=14)
caloric intake showed no significant association when
correlation analysis was done. A meta-analysis by Lowe et Figure 8. Change in desire to eat from baseline between
al., in 2017 supported this study’s result, where they found rTMS vs sham group.
that food cravings decreased after multiple stimulation
however actual food consumption after both single and 4.5
multiple sessions for rTMS was found to be inconsistent 4
among different studies.2 A study by Uher et al., showed
that a decrease in subjective food craving did not necessarily 3.5
translate to less food consumption between the two 3

VAS Score
groups.6 Differences in methodology i.e., specific brand of

2.5
stimulation device, frequency and intensity of stimulation
and higher BMI cutoffs in this study may account for 2
the incongruent results.2,6,12 It is also possible that the 1.5
sample size in this study was not powered to observe a
correlation between food cravings and food intake, as this 1
study used change in BMI in computing for the sample size. 0.5
0
Another is the possible discrepancy in the method of Baseline Week 2 Week 4 Week 6 Week 12
collecting data for total caloric intake through the use
of food diaries. Since it is subjective and based on recall, rTMS group (n=15) sham group (n=14)
factors such as inaccurate recording of intake, writing
down only of days with the least amount of oral intake, or Figure 9. Change in prospective food consumption from
inability to recall all food taken may have played a role in baseline between rTMS vs sham group.
the inability to show significant results at week 4 onwards.
reduction in prospective food consumption as mentioned
Effect of rTMS on appetite in the former study.4 In their 2019 study, however there was
Results showed that there was no significant difference no significant difference in prospective food consumption,
in appetite between the treatment and sham groups from but there was a significant reduction in hunger and desire
baseline to 12 weeks. This is comparable to the study by to eat.12
Kim et al., where there was no significant difference in the
sham and treatment groups in terms of hunger and desire There can be several reasons why there are contradicting
to eat; however, this study failed to show a significant results in the VAS scores for appetite. One reason may

be the differences in fasting time prior to taking the VAS CONCLUSION

scores. In the 2018 study by Kim et al., it was taken after 4
hours of fasting while in their 2019 study, it was after only 2 rTMS to the DLPFC effectively decreases BMI and weight
hours.4,12 In this study, the fasting hours prior to testing were from baseline to 4 weeks in the treatment group compared
consistent for each participant, but was not uniform across to the sham group, with a decrease in weight by -1.3±1.3
all subjects, and these ranged from 2-5 hours of fasting (i.e., kg and decrease in BMI by 0.6±0.6. At 6-12 weeks after
participant 1 fasted for 2 hours prior to each assessment, rTMS however, there was no longer a significant difference,
participant 2 fasted for 4 hours prior to assessment). indicating that 4 sessions of rTMS are not enough to
produce a permanent effect on weight loss. Although
Another reason may be that caloric intake during the there was an initial significant decrease in total caloric
study was not standardized. Only the specific timing of intake in the first 2 weeks by about 200 kilocalories a day,
last meal was consistent for each participant, however the it failed to show a consistent decline in total caloric intake
actual intake/ meal prior to each assessment of appetite was after 2 weeks from the last session of rTMS. Furthermore,
not the same for all participants and therefore these may subjective scoring showed no difference as to hunger,
have affected their subjective scores. desire to eat and prospective food consumption in the
treatment group versus the sham group.
Another reason is the possible placebo effect on the control
group. Most of the patients in the sham group believed Recommendations
themselves to be in the treatment group and therefore The researchers recommend a more controlled food intake
these may have given lower ratings on perceived appetite. and fasting time prior to testing for subjective appetite
in order to have a better estimate of appetite/ hunger
Lastly, the differences in technique of rTMS application that is not related to quantity of food consumed prior to
may also account for the different results in weight and the testing. Body fat analysis may also help to determine
appetite/ food cravings. In our study, we used 20 trains of if visceral adipose tissue decreases with rTMS, as this
5 seconds at a frequency of 10 Hz and intensity of 110% is an important risk factor for cardiovascular disease in
of the participant’s motor threshold. In the study by Kim obese patients. To eliminate bias and placebo effect,
et al., in 2019, 40 trains of 5 seconds with frequency of 10 the researchers recommend exploring the usefulness
Hz and intensity of 110% motor threshold was used.12 of measuring neuroendocrine hormones like leptin,
Alvarado-Reynoso in 2019 used 10 trains of 100 pulses B-endorphins, cortisol and norepinephrine as objective
given at 10 Hz and 90% of motor threshold, with more markers of appetite in order to supplement the much more
sessions employed compared to the two studies.13 While subjective food diaries and VAS scoring to measure hunger
all these produced weight loss, the degree of weight loss and appetite of the participants.
and reduction in food cravings were different among the
3 studies. Acknowledgments
The authors sincerely thank the active consultants and trainees of
Neuroendocrine effects of rTMS on food cravings have been SLMC QC for helping in enrolling participants in this study. They
studied. Ferrulli et al., in 2018, reported that orexigenic would also like to thank the SLMC QC Research and Biotechnology
group, statistician, and the participants who volunteered to take
pathways have been altered as a result of TMS, producing
part in the research.
an increase in norepinephrine and B-endorphins, while
salivary cortisol is decreased. This suggests a potential Statement of Authorship
role of TMS in inducing dopaminergic activation and All authors certified fulfillment of ICMJE authorship criteria.
modulation of the food-reward system.15 With the advent
of these biochemical tests that provide objective and Author Disclosure
measurable assessment of appetite, evaluation of food The authors declared no conflicts of interest.
cravings no longer need to be purely subjective, thus
increasing the accuracy of results. It still needs to be Funding Source
established, however, if alteration of the neuroendocrine Funding for rTMS, weight management program, and the
laboratory tests done came from the SLMC-QC Research and
pathways translates into actual reduction in food intake.
Biotechnology Division and the PSEDM-Abbott Nutrition Year
2019 research grant.
Limitations
There were only 4 sessions of rTMS done due to cost and References
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Original Article
Journal of the
ASEAN Federation of
Endocrine Societies
Relationship between Plasma Adiponectin Level and

Corrected QT Interval in Smoker and Non-smoker Adult Male Subjects
Yin Thu Theint, Ei Ei Khin, Ohnmar Myint Thein, Mya Thanda Sein
Department of Physiology, University of Medicine 2, Yangon, Republic of the Union of Myanmar
Abstract
Objective. This study determined the relationship between plasma adiponectin level and corrected QT interval (QTc) in
smokers and non-smokers.
Methodology.This cross-sectional analytical study was undertaken in 30 smokers and 30 non-smokers. Plasma
adiponectin level was determined by enzyme-linked immunosorbent assay (ELISA). The QT interval was measured by
routine 12-lead ECG with Lead II rhythm and QTc was calculated.
Results. Mean plasma adiponectin level was significantly lower in smokers (27.89±15 µg/ml) than that of non-smokers
(52.13±21.57µg/ml) (p<0.001). Mean QTc interval was significantly longer in smokers than that of non-smokers
(415.37±29.9 versus 395.63±26.13 ms, p<0.01). Higher risk of low adiponectin level (odds ratio [OR],8.1; 95% confidence
interval [CI],1.61-40.77) and QTc interval prolongation (OR,6; 95%CI,1.17-30.73) were observed in smokers. There
was weak significant negative correlation between plasma adiponectin level and QTc interval in the study population
(n=60, r=-0.407, p=0.001). Moreover, low plasma adiponectin level was significantly associated with prolonged QTc
interval in the study population (n=60, Fisher's exact p value<0.05). Risk of QTc interval prolongation was 4.3 times
higher in subjects with low plasma adiponectin level (OR,4.27; 95% CI,1.05-17.46).
Conclusion. Smokers have greater risk for low plasma adiponectin level and prolonged QTc interval. There is a relationship
between plasma adiponectin level and QTc interval.
Key words: smoker, adiponectin, QTc
INTRODUCTION QTc means corrected QT interval with heart rate because

normal QT interval decreases as heart rate increases. QTc
Adiponectin is a 247 amino-acid protein secreted from interval was calculated using Bazett’s formula as follows:
adipocytes1 and exerts beneficial effects on the cardio- QTc=QT/√RR.9QTc interval of more than 440ms in men
vascular system by directly acting on vascular smooth and 460ms in women is considered prolonged.10 So, it can
muscle cells, endothelial cells and cardiac myocytes.2,3,4 be assumed that adiponectin might be associated with
It can mediate anti-atherosclerotic, anti-fibrotic, anti- QT interval. Only a few studies are available focusing
apoptotic and anti-inflammatory effects.3,4,5 Thus, low on the role of adiponectin in QTc interval in humans.
plasma adiponectin level is associated with increased In a study done in Japan, it was shown that QTc interval
prevalence of cardiovascular diseases (CVD). had inverse correlation with adiponectin in healthy
male subjects.11 Further studies are needed to explore the
Animal study reported that adiponectin plays a role in association between adiponectin and QTc interval.
expression of transient outward potassium channel (Ito)
and duration of action potential in rat ventricular muscles.6 According to previous studies,12-15 the circulating
A loss of Ito channel protein expression and function was adiponectin level was significantly decreased in smokers
associated with action potential prolongation7 which was compared to non-smokers. Present study selected the
reflected by QT prolongation.8 The QT interval represents smokers as participants to determine the association
the time from onset of ventricular depolarization to between plasma adiponectin level and QTc interval.
completion of repolarization. When QT interval is Thus, present study investigated the relationship between
prolonged, repolarization is irregular with increased plasma adiponectin level and corrected QT interval in male
incidence of ventricular arrhythmias and sudden death.8 adult smokers and non-smokers.
________________________________________
ISSN 0857-1074 (Print) | eISSN 2308-118x (Online) Corresponding author: Prof. Mya Thanda Sein, MBBS, MMedSc (Physiology), PhD,
Printed in the Philippines Dip Med Edu, DCME
Copyright © 2020 by Theint et al. Department of Physiology, University of Medicine 2
Received: June 7, 2020. Accepted: October 2, 2020. Yangon, Republic of the Union of Myanmar 11031
Published online first: October 19, 2020. Tel. No.: 95-95109450
https://doi.org/10.15605/jafes.035.02.09 Fax No.: 95-1-9690265
* This research work was presented in the 20th AFES Congress 2019, Philippines and was awarded best poster presentation.

Plasma Adiponectin Level and QTc in Adult Male Subjects Yin Thu Theint, et al 191
METHODOLOGY According to the adiponectin level derived from Fan et al.17

This cross-sectional analytical study was undertaken in X̄ 1 = mean plasma adiponectin level of smoker = 2.49 µg/ml
apparently healthy male subjects 18-40 years old, residing X̄ 2 = mean plasma adiponectin level of non-smoker
in Hlaingtharyar Township,Yangon, Myanmar from April = 3.23 µg/ml
2018 to December 2018. The present study used the non- σ1 = standard deviation of smoker = 0.35
probability convenience sampling method. No (8) Quarter σ2= standard deviation of non-smoker = 0.37
was selected from 22 Quarters in Hlaingtharyar Township sample size n1= 9
since that quarter has high population density. We asked
for approval from the local administrator for recruitment According to the QTc value derived from Sharma et al.18
of apparently healthy male subjects between 18-40 years
old. Voluntary written informed consent was obtained after X̄ 1 = mean QTc interval of smoker = 413.9 ms
thorough explanation of research purpose and procedures. X̄ 2 = mean QTc interval of non-smoker = 377.9 ms
σ1 = standard deviation of smoker = 34.17
All participants underwent history taking and physical σ2= standard deviation of non-smoker = 20.88
examination. Subjects with no acute illness and no known sample size n2= 23
history of hypertension, diabetes, ischemic heart disease,
cerebrovascular accident, arrhythmia, peripheral arterial A total of 60 male adult subjects (30 smokers and 30 non-
disease, renal disease and bronchial asthma were regarded smokers) were recruited in the present study.
as apparently healthy subjects. Individuals with the
following characteristics were excluded from the study: The study was conducted in the morning between 7 to
those who consumed heavy alcohol (more than 3 units 9 am in the fasting state. At the beginning, fasting blood
of alcohol per day) that decreased adiponectin levels as a sugar level was determined by pricking the fingertip using
result of increased tumor necrosis factor-α; individuals a glucose meter. Subjects having fasting blood sugar (FBS)
who chewed betel quid with tobacco containing nicotine levels >110 mg/dl were excluded from the study. Routine
that affects both adiponectin and QT interval; individuals 12 lead ECG was performed using ECG machine (CM 100,
who are currently taking drugs that altered adiponectin Shenzhen Comen Medical Instruments Co., Ltd, China)
concentration like omega 3 fish oil, niacin and statin; after the subjects were allowed to lie down comfortably on
individuals who are currently using antimicrobial agents the bed with attachment of limb electrodes for 15 minutes.
such as fluoroquinolones, erythromycin, antidepressant Paper speed was 25 mm/s and manual calibration was
agents such as amitriptyline that prolonged QT interval. carefully adjusted at 10 mm/mV before recording. Lead
II rhythm strip was also taken for 10 seconds. QT interval
Each participant was interviewed by using a questionnaire was measured from the start of Q-wave to the end of
to collect history of cigarette smoking including average T-wave in a normal beat. Heart rate was calculated from
number of cigarettes smoked per day and duration of average R-R intervals of the beat within 10 seconds. QT
cigarette smoking. Those who currently smoke a minimum intervals and R-R intervals were measured using vernier
of 10 cigarettes per day for at least 5 years were selected as caliper. Then, QTc interval was calculated by using Bazett’s
smokers and those who have never smoked any form of formula (QTc=QT/√RR).9 Then, 3 milliliters of fasting
tobacco in their life and with no history of smoking in their venous blood was drawn from the antecubital vein under
family members were defined as non-smokers. aseptic condition using a disposable syringe and needle
for each subject. Blood samples were collected into a tube
Subjects with normal body mass index (BMI) (18.5-24.9 containing EDTA disodium anticoagulant and carried
kg/m2) were selected. Resting arterial blood pressure to the common research laboratory of the University of
was measured in lying position using a mercury Medicine 2. On arrival, plasma separation was done by
sphygmomanometer and a stethoscope by an indirect centrifuging at 2000 rpm at 4°C for 10 minutes and stored
method. The average of three measurements taken over at -20°C until sample analysis. Plasma adiponectin level
a one-minute interval was used. Subjects having systolic was determined by Adiponectin ELISA Kit (ab99968,
blood pressure (SBP) >120 mmHg and diastolic blood Abcam, UK).
pressure (DBP) >80 mmHg were excluded according to
American Health Association guideline 2017. Data entry and analysis were done by SPSS software
(version 22, SPSS Inc., Chicago, IL, USA). Data were
Sample size was calculated by using Rosner's formula.16 described by mean ± SD. Independent "t" test was used to
compare the plasma adiponectin level and QTc interval
between smokers and non-smokers. Correlation studies
were computed by Pearson’s correlation. Chi-square
n = number of subjects for each group test was used to determine whether there are significant
δ = X̄ 2 – X̄ 1 associations between smoking, plasma adiponectin
σ12 = variance of X1 level and QTc interval. Values of p<0.05 were accepted as
σ22 = variance of X2 statistically significant. This study was approved by Ethics
Z1-α = the Z value from normal distribution associated with Review Committee, University of Medicine 2, Yangon.
a probability of 1-α
Z1-β = the Z value from normal distribution associated with RESULTS
a probability of 1-β
If α = 0.05, Z1-α= 1.96 The general characteristics of the study population are
If β = 0.01, Z1-β = 2.326 shown in Table 1. Mean age, BMI, SBP, DBP and FBS of two

192 Yin Thu Theint, et al Plasma Adiponectin Level and QTc in Adult Male Subjects
groups showed no significant differences indicating that as low adiponectin level in the present study and it was
both groups were comparable to each other. Heart rate of observed in 11 out of 30 (36.7%) smokers and 2 out of
the two groups showed significant difference. 30 (6.7%) non-smokers. Therefore, risk of lower plasma
adiponectin level was 8.1 times higher in smokers than non-
Table 1. Baseline characteristics of the subjects smokers (odds ratio (OR), 8.1; 95% confidence interval (CI),
Non-smokers Smokers 1.61-40.77). Also, smokers had higher proportion of low
Parameters (Mean±SD) (Mean±SD) p value adiponectin level compared to non-smokers (z value=2.84,
(n=30) (n=30)
p=0.005).
Age (years) 25.43±3.52 26.47±4.1 0.29
BMI (kg/m2) 20.95±2.1 21.67±1.66 0.15
In the present study, 9 out of 30 (30%) smokers and 2 out
SBP (mmHg) 112±7.14 113.3±7.58 0.49
DBP (mmHg) 70.3±7.18 72±7.14 0.37
of 30 (6.7%) non-smokers had prolonged QTc interval
FBS (mg/dl) 103±10.8 107.2±3.98 0.06 (>440 ms). Therefore, risk of prolonged QTc interval was
HR 72.13±9.45 81.53±11.89 0.001 6 times higher in smokers than non-smokers (OR, 6.0;
95% CI=1.17-30.73). Smokers also had a higher proportion
of prolonged QTc interval compared to non-smokers
Figure 1 shows the comparison of plasma adiponectin (z value=2.33, p=0.02).
level between smokers and non-smokers. There was a
significantly lower mean plasma adiponectin level in It was also noted that 5 out of 13 (38.5%) subjects with
smokers compared with non-smokers (27.89±15 versus low plasma adiponectin level had prolonged QTc interval
52.13±21.57 µg/ml) (p<0.001). Mean QTc intervals were and 6 out of 47 (12.8%) subjects with normal plasma
415.37±29.9 and 395.63±26.13 ms for smoker and non- adiponectin level had prolonged QTc interval (>440 ms).
smoker groups respectively. Mean QTc interval of smokers Therefore, risk of prolonged QTc interval was 4.3 times
was significantly higher than that of non-smokers (p<0.01) higher in subjects with low plasma adiponectin level than
(Figure 2). subjects with normal plasma adiponectin level (OR, 4.27;
95%CI, 1.05-17.46). Table 2 showed that there is a significant
Correlation between plasma adiponectin level and QTc association between low plasma adiponectin level and
interval in the study population is illustrated in Figure 3. prolonged QTc interval in the whole population (n=60,
There was a weak negative correlation between plasma Fisher's exact p value <0.05).
adiponectin level and QTc interval in the whole study
population (r=-0.407, p=0.001, n=60) (Figure 3A). This was Table 2. The association between low plasma
statistically significant. When the study population was adiponectin level and prolonged QTc interval in total
subdivided into smokers and non-smokers, significant population (n=60)
weak negative correlation was only observed in smokers Variable
QTc interval n (%)
Prolonged Normal *p value
(n=30) (r=- 0.434, p=0.017) (Figure 3B) but not in non-
Subjects with <0.05
smokers (n=30) (r= - 0.175, p=0.35) (Figure 3C). According
Low adiponectin 5(38.5%) 8 (61.5%)
to Fumeron et al.,19 plasma adiponectin level of healthy Normal adiponectin 6(12.8%) 41 (87.2%)
individuals presented in a wide range from 20 to 45 µg/ml. *Fisher's Exact test
Thus, adiponectin value under 20 µg/ml was considered
*Indicates significant difference (p<0.001) *Indicates significant difference (p<0.01)

Comparison was done by independent "t" test Comparison was done by independent "t" test
Figure 1. Plasma adiponectin level in smokers and non- Figure 2. QTc interval in smokers and non-smokers.
smokers.

r, Pearson correlation coefficient; n, total number of subjects r, Pearson correlation coefficient; n, total number of subjects
Figure 3A. Correlation between plasma adiponectin level Figure 3B. Correlation between plasma adiponectin level
and QTc interval in study population. and QTc interval in smokers (n=30).
by determining carotid intima media thickness,21 lipid

profiles22 and ECG23 and have shown that CVD risk is
increased in smokers. Constituents of cigarette smoke
are mainly nicotine, carbon monoxide, and free radical
mediated oxidant gases which not only potentially
contribute to cardiovascular diseases24 but also inhibit the
adiponectin gene expression.12 Thus, the present study
recruited smokers to investigate the role of adiponectin
on QTc interval.
In the present study, among the smokers, the mean

number of cigarettes smoked per day was 12.5±4.8 and
mean cigarette smoking duration was 7.8±2.9 years.
The present study showed that significant decrease of
mean plasma adiponectin level was observed in smokers
compared with non-smokers. The findings agree with the
reports of previous studies.12-15 In addition, risk of lower
plasma adiponectin level was 8.1 times greater in smokers
than non-smokers (OR,8.1; 95% CI, 1.61-40.77). Thus, the
present study can conclude that smokers have greater risk
r, Pearson correlation coefficient; n, total number of subjects
for low plasma adiponectin level.
Figure 3C. Correlation between plasma adiponectin level
and QTc interval in non-smokers (n=30). Several explanations have been proposed for the
mechanisms by which smoking reduces adiponectin
concentration. In previous in vitro and in vivo studies,
DISCUSSION nicotine itself induces lipolysis through local nicotinic
cholinergic (nAchR) and catecholaminergic receptors
An animal study has shown that adiponectin affects in adipose tissue25 and inhibits the expression of the
channel proteins (Ito) in rat ventricular myocyte and adiponectin gene in cultured mouse 3T3-L1 adipocytes.12
hypoadiponectinaemia may be involved in prolongation Moreover, nicotine also has direct actions on the
of QT interval.6 Komatsu et al.,11 reported that there was differentiation of adipocytes by increasing peroxisome
inverse relationship between adiponectin and QTc interval proliferator-activated receptor-γ (PPAR-γ), which is
in healthy men. Contrary to this study, Wu et al.,20 recently essential for inducing differentiation from preadipocytes
reported that there was positive association between to mature adipocytes. Supraphysiological activation
adiponectin level and QTc in patients with stable angina. of PPARγ caused adipogenesis disturbances which
As there is limited information regarding the association may cause enhanced lipolysis and dysfunction of
between adiponectin and QT interval, further studies are adipokine secretion.26 Smoking provokes oxidative stress
needed to clarify the role of adiponectin on QT interval. and inflammatory cytokines that reduce adiponectin
concentration. Oxidative stress disrupts activation of a
Cigarette smoking is a major cause of cardiovascular key molecule, phosphatidylinositol 3-kinase (PI3K) for the
diseases. Many studies investigated CVD risk in smokers secretion of adiponectin in adipocytes.27,28 Inflammatory

194 Yin Thu Theint, et al Plasma Adiponectin Level and QTc in Adult Male Subjects
cytokines such as TNF and IL-6 had been found to have Corrected QT interval was significantly prolonged in
negative interaction with adiponectin secretion in in-vivo smokers compared to non-smokers.Thus, 8.1 times greater
and in-vitro studies.29,30 Another reason for low adiponectin risk of low plasma adiponectin and 6 times greater risk
concentration in smokers might be due to impaired vessel of QTc interval prolongation were observed in smokers
wall. Adiponectin accumulates in the injured vascular walls compared with non-smokers.
increasing consumption of circulating adiponectin.31,32
In addition, risk of prolonged QTc interval was 4.3 times
Mean QTc interval of smokers was 415.37±29.9 ms and higher in subjects with low plasma adiponectin level
significantly longer than non-smokers (395.63±26.13 ms) than subjects with normal plasma adiponectin level. A
(p<0.01) in the present study. The finding of the present significant weak negative correlation as well as a significant
study agreed with previous studies.18, 33,34 Contrary to association between plasma adiponectin level and QTc
the present study, Devi et al.,23 showed that there was no interval was observed in the whole study population. Thus,
significant difference in QT interval between smokers it can be concluded that relationship exists between plasma
and non-smokers. In the present study, 9 out of 30 (30%) adiponectin level and QTc interval.
smokers and 2 out of 30 (6.7%) non-smokers had prolonged
QTc interval (>440 ms). Therefore, risk of prolonged QTc Limitation of the study
interval was 6 times greater in smokers than non-smokers As a cross sectional analytical study, it cannot clearly
(OR,6; 95% CI,1.17-30.73). Based on the findings in the establish the causative effect of adiponectin level on QTc
present study, we can conclude that smokers have greater interval. This study is not powered as an interventional
risk for QTc interval prolongation. Possible mechanism of study which provides specific conclusions to clarify the
prolonged QTc interval might be due to constituents of link between adiponectin and QTc interval. Moreover, due
cigarette smoke such as nicotine, carbon monoxide and to relatively small sample size, the confidence intervals of
oxidant gas. These constituents induce fibrosis at different the odds ratios are very wide e.g., smoking and QTc: OR
cardiac sites which in turn lead to altered cardiac conduction 6 (1.17–30.73). The possibility of second hand smoke was
and repolarization abnormalities.35 Additionally, nicotine not accounted for in both groups, especially for the non-
interacts directly with channel protein in ventricular smokers in the present study.
myocytes and blocks cardiac K+ currents (including
delayed rectifier current and inward rectifier current) with Acknowledgments
preferential inhibition of Ito. Thus, it decreased repolarizing The authors thank all the participants of the Hlaingtharyar
current and prolonged action potential, which is reflected Township who willingly gave consent to this study. The authors
as prolongation of the QT interval.36,37 Moreover, smoking also wish to acknowledge the External Grant Committee,
Department of Medical Research, Lower Myanmar, Republic
induced inflammatory marker, TNF-α decreases Itowhich
of Myanmar for the financial support and the Ethics Review
prolongs action potential duration in rat ventricular Committee, University of Medicine 2, Yangon, Republic of
myocytes.38 In the present study, 5 out of 13 (38.5%) Myanmar for providing ethical clearance.
subjects with low plasma adiponectin level had prolonged
QTc interval and 6 out of 47 (12.8%) subjects with normal Statement of Authorship
adiponectin level had prolonged QTc interval (>440 ms). All authors certified fulfillment of ICMJE authorship criteria.
Therefore, risk of prolonged QTc interval was 4.3 times
greater in subjects with low plasma adiponectin level Author Disclosure
than subjects with normal adiponectin level (OR,4.27; 95% The authors declared no conflicts of interest.
CI, 1.05-17.46). It indicated that occurrence of prolonged
Funding Source
QTc interval was increased with low plasma adiponectin
The study was financially supported by the External Grant
level. Moreover, significant weak negative correlation was Committee of the Department of Medical Research, Lower
found between plasma adiponectin level and QTc interval Myanmar, Republic of Myanmar.
in this study population (r=-0.407, p=0.001, n=60). This
finding was similar to previous study done by Komatsu References
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JCDR/2013/5180.2950.

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Case Report
Journal of the
ASEAN Federation of
Endocrine Societies
Triple Synchronous Tumors Presenting as

Right Nasolabial Basal Cell Carcinoma, Papillary Thyroid Carcinoma
and Prolactinoma: A Rare Case Report
Mateo Te III, Donnah Bless Lumanlan-Mosqueda, Kenny Jun Demegillo
Department of Internal Medicine, Southern Philippines Medical Center, Davao City, Philippines
Abstract
Multiple primary tumors are rare, with a published meta-analysis that shows the frequency of second primary tumor
at 3-5%, and a third tumor at 0.5%. A 57-year-old female sought consultation due to a persistently bleeding right
nasolabial mass. On further history and examination, she also presented with a right anterior neck mass, repeated
abortions, secondary amenorrhea, and loss of libido years prior. Serum prolactin was significantly elevated and an
incidental finding of a pituitary mass on head and neck CT scan was appreciated. Metastasis and syndromic familial
disorder were ruled out. Bromocriptine was given and she underwent total thyroidectomy and wide excision of the right
nasolabial mass which turned out to be papillary thyroid carcinoma (PTC) and basal cell carcinoma (BCC) respectively
on histopathologic report. On follow up, repeat serum prolactin decreased to normal levels. After extensive literature
review, this is the first documented case of triple synchronous tumors with a combination of BCC of the right nasolabial
area, PTC and prolactinoma in local, national and international studies. With comprehensive work up and literature
search, the diagnosis was established and ultimately the patient benefited from a multidisciplinary management.
Key words: multiple primary, synchronous tumors
INTRODUCTION origins and locations. The manifestation of each tumor

has different timeline of appearance however all three
A reported meta-analysis of multiple primary tumors tumors were already manifested by the patient and were
show the frequency of second primary tumor as 3-5%, diagnosed within 6 months during the work up hence
a third tumor as 0.5% and a fourth tumor as 0.3%.1,2 This considered synchronous.
is a rare case of triple synchronous tumors consisting of
basal cell carcinoma of the right nasolabial area, papillary CASE
thyroid carcinoma and prolactinoma in a 57-year-old
female who presented with infertility, amenorrhea, and A 57-year-old, female, sought consultation due to a
loss of sexual desire in the absence of galactorrhea. The persistently bleeding right nasolabial mass.
incidence of the individual tumor presented is relatively
common however this case report highlights that the Five years prior to admission (PTA), a small dark mole
combination of three common tumors in a single patient is was noted by the patient on her right nasolabial area
a rare occurrence. which progressively grew in size to 3x4 cm over five years.
The mass ruptured, ulcerated and bled out. Persistent
Approaching different tumors involving multiple bleeding prompted the consultation.
endocrine organs is challenging. Hence this case report
features the diagnostic approach to classifying the nature Past medical history revealed 15 years PTA, a 1x1 cm
of multiple tumors whether primary, metastatic or smooth, non-tender mass was appreciated over the
syndromic. anterior right side of the neck that moved with deglutition.
Increase in size, prompted consultation at a local hospital.
The need to utilize an objective and standardized Fine needle aspiration biopsy (FNAB) was done however
classification and diagnosis of multiple primary tumors is she was lost to follow up.
important. Thus, the definition given by the International
Association of Cancer Registries (IACR) was utilized. Heredo-familial diseases in the family only revealed
A 6-month rule interval to diagnosing synchronous a maternal aunt with thyroid cancer of unknown
from metachronous tumors arising from different histopathology (Appendix A). She is a street vegetable
sites regardless of the time of onset is observed.3 The peddler. She is a non-smoker and non-alcoholic beverage
patient had three primary tumors of different germline drinker.
________________________________________
ISSN 0857-1074 (Print) | eISSN 2308-118x (Online) Corresponding author: Mateo C. Te III, MD
Printed in the Philippines Senior Resident, Department of Internal Medicine
Copyright © 2020 by Te III et al. Southern Philippines Medical Center
Received: July 26, 2020. Accepted: September 30, 2020. JP Laurel Avenue, Bajada, Davao City, 8000, Davao del Sur
Published online first: October 20, 2020. Tel. No.: 082 227-2731

Triple Synchronous Tumors Mateo Te III, et al 201
Her perinatal history was unremarkable. Her developmental After her miscarriages (Figure 1), she had amenorrhea
milestones were at par with her peers. She developed at the age of 26 which was associated with loss of sexual
secondary sexual characteristics and growth spurt almost desire. There were no headache, dizziness, visual
at the same rate as her female peers. abnormalities, and galactorrhea.
Her menarche was at the age of 12 years old, with She was examined awake with normal vital signs, and
unremarkable menstrual pattern. The patient’s obstetric with a body mass index of 29.3 kg/m2 (obese 1 for Asians).
profile is G4P0. As depicted on Figure 2, pertinent physical findings
revealed a pedunculated mass with rolled up edges and
Table 1. Obstetric Profile central ulceration on the right nasolabial area. A nodular,
G1 1981 Spontaneous abortion at 8 weeks non-tender mass was palpated over the right anterior
G2 1982 Spontaneous abortion at 8 weeks neck that moved with deglutition. There were no cervical
G3 1984 Spontaneous abortion at 8 weeks
lymphadenopathies and neck vein distension. Breast
G4 1996 Spontaneous abortion at 16 weeks and underwent
dilatation and curettage with minimal blood loss and female genitalia examination were unremarkable
(Tanner V).
1982 2003-2013 2018

– 4 consecutive spontaneous abortions
– Progressive growth of thyroid mass – Ulcerating and persistently
– Secondary amenorrhea at the age of 26
– FNAB done - unrecalled result bleeding mass over the
– Loss of libido
– Lost to follow up right nasolabial area
– (–) Galactorrhea and visual symptoms
2003 2013
– 1x1 cm marble-sized thyroid mass – Progressively growing
– Moves with swallowing dark mass with rolled
– Non-tender, immobile up borders over right
– irregular contour nasolabial area
– No consult done – Non-ulcerating
Figure 1. History timeline.
A B
Figure 2. (A) 3x4 cm pedunculated mass with rolled up borders and central ulceration (right nasolabial area); (B) 6x5 cm
nodular mass (right anterior neck).

202 Mateo Te III, et al Triple Synchronous Tumors
Visual acuity was 20/20 and peripheral vision was intact. As summarized in Table 2, serum prolactin was markedly
The rest of the neurologic physical examination was elevated. At this point hyperprolactinaemia from pro-
unremarkable. lactinoma secondary to pituitary macroadenoma
was considered. Hence patient was started on
She was admitted with a working impression of right bromocriptine 2.5 mg/tab; ½ tablet twice a day. Serum LH,
nasolabial mass to consider basal cell carcinoma; and FSH, and cortisol were low. Intact parathyroid hormone
anterior neck mass secondary to nodular nontoxic goiter; was slightly elevated on a background of normal serum
to consider malignancy. calcium.
Basic laboratory examination showed an elevated fasting Table 2. Hormonal and blood chemistry panel
blood sugar and glycosylated haemoglobin (HbA1c) at Hormone Result Reference Interval
7.4 mmol/L and 7%; respectively. The ECG and chest Prolactin 9,368 6.0-29. ng/mL 9
X-ray were unremarkable. Wedge biopsy of the right TSH 2.27 0.38-5.33 µIU/mL
nasolabial mass and an FNAB of the thyroid mass revealed LH 2.26 Postmenopause: 7.7-58.5 mIU/mL
basal cell carcinoma and papillary thyroid carcinoma, FSH 13.10 Postmenopause: 26-135 mIU/mL
respectively. ACTH (8AM) 20.50 <50 pg/mL
FT4 8.63 7.90-14.40 pmol/L
IGF-1 70.50 36.00-200.00 ng/mL
Head and neck CT scan with contrast revealed an
Cortisol (at 8AM) 7.32 AM: 8.7-22.4 / PM: <10.0 µg/dL
ulcerating mass over the right nasolabial area, a mass over
iPTH 80.67 10.0-65.0pg/mL
the right thyroid lobe, and an incidental finding of a mass Calcium 2.36 2.23-2.58 mmol/L
over the left parasellar area (Figure 3). Sodium 141.90 136-144 mmol/L
FBS 7.41 4.10-6.60 mmol/L
In view of an incidental finding of a sellar mass, a cranial Abbreviations: TSH – Thyroid Stimulating Hormone, LH – Luteinizing
Magnetic Resonance Imaging (MRI) was performed, Hormone, FSH – Follicle Stimulating Hormone, ACTH – Adrenocortico-
tropic Hormone, FT4 – Free Thyroxine (T4), IGF-1 – Insulin-like Growth
revealing a poorly defined complex mass in the sella as
Factor-1, iPTH – intact Parathyroid Hormone, FBS – Fasting Blood Sugar.
shown in Figure 4.
R L R L
A B
R L R L
C D
Figure 3. CT Scan with contrast of the head and neck. (A) Ulcerating mass (right nasolabial area); (B) 6.5x5.0x4.8 cm
enhancing mass with peripheral calcifications (right thyroid lobe). Incidental left parasellar 2.3x2.9x3.6 cm enhancing mass
with erosion of posterior wall of the sphenoid sinus and petrous apex in a (C) Cross-sectional view and in (D) Coronal view.

A B
C D
Figure 4. Cranial Magnetic Resonance Imaging (MRI). A 2.2x3.1x3.1 cm poorly defined complex mass predominantly
solid in the sella with extension to left parasellar region. (A) T1 Weighted Image (T1WI) – Isointense (B) T1 contrast image –
Isointense (C) T2 Weighted Image (T2WI) – Mixed Signals (D) Fluid Attenuation Inversion Recovery (FLAIR) post gadolinium
study - homogenous contrast enhancement. Noted encasement of the cavernous portion of the left carotid artery and bony
destruction of the left petrous apex bone.
Ophthalmologic evaluation was normal except for a left For Philippines, in 2015, the predicted number of new cases
quadrantanopsia on perimetry studies (Appendix B). of cancer was about 109,280 and death from cancer was
about 66,151 cases.5
The patient underwent wide excision of the right nasolabial
mass with frozen section biopsy for margins and total The three tumors presented by the patient have relatively
thyroidectomy. She was then started with synthetic thyroid common prevalence. Basal Cell Carcinoma (BCC) is the
hormone replacement. Final histopathologic report of most common skin malignancy with prevalence estimated
the right nasolabial mass and thyroid mass revealed to be 2.0%, 1.4%, and 0.7%, for Australia, Europe, and the
basal cell carcinoma and papillary thyroid carcinoma US, respectively.6,7 In Philippines, more than 60% of all skin
respectively as shown in Figures 5 and 6. The patient’s cancers are of BCC.8 Papillary thyroid carcinoma (PTC) is
final diagnosis was triple synchronous tumors with a the most common thyroid malignancy constituting 50% to
combination of right nasolabial basal cell carcinoma, 90% of well-differentiated thyroid carcinoma worldwide.9
papillary thyroid carcinoma and prolactinoma. Thyroid cancer was estimated to be the 8th most common
malignancy among Filipinos with an incidence of 2%.5
While on bromocriptine, repeat serum prolactin after A local study conducted in the Philippine General
6 weeks revealed an exponential decrease from a Hospital – Otorhinolaryngology Department reported
baseline of 9,368 ng/mL to a normal level at 16.17 ng/mL. that 82.9% of thyroid malignancies admitted were PTC.10
Dose of bromocriptine was decreased and the patient Prolactinoma is the most common pituitary adenoma that
was advised to follow up for the surveillance tests. A accounts for up to 45% of pituitary tumors.11-13 Each tumor
postoperative radioactive iodine adjuvant therapy was the presented has a common prevalence but when all three are
next plan for the patient. combined in a single patient, it becomes a rare occurrence.
DISCUSSION The Disease and its International, National and Local

Epidemiology
Overall, it is estimated that there were 14.1 million new cases Albeit extensive literature reviews, there are no existing
and 8.2 million deaths attributed to cancer worldwide.4 official registry that accounted triple primary tumors

A B
Figure 5. Histopathology report of nasolabial mass. (A) Nests & sheets of atypical basaloid cells (H&E, x40); (B) Atypical
cells with palisading pattern at the periphery (H&E, x100).
A B
Figure 6. Histopathology report of thyroid mass. (A) Complex branching and randomly oriented papillae with fibro-
vascular core associated with follicles lined by atypical cells (H&E, x40); (B) Atypical Cell with Orphan-Annie Nuclei and
nuclear longitudinal grooves (H&E, x400).
internationally, nationally and locally. A reported meta- of Obstetrics and Gynecology documented triple primary
analysis shows the frequency of second primary tumor as tumors consisting of an ovarian cancer, an endometrial
3-5%, a third tumor as 0.5% and a fourth tumor as 0.3%.1,2 cancer and a uterine sarcoma in a 56-year-old single,
In one study, the most common site of multiple primary nulligravid.14 For multiple malignancies of head and
tumors was head and neck, followed by gynecological neck, there are no documented and reported cases among
cancers, breast cancer, lung cancer, and other cancers.2 national medical publications and even in our institution,
Appendix C summarized documented case reports of triple making our patient as the first ever documented individual
primary tumors specific only to the head and neck reported presenting with triple synchronous tumors of the head
in international published journals. Common in all these and neck with a rare combination of right nasolabial BCC,
cases is the involvement of tumors from the skin, thyroid PTC, and prolactinoma.
gland, and aerodigestive tract of the head and neck that were
managed with surgical removal, adjuvant or neoadjuvant Clinical Manifestations and Clinical Correlation
chemotherapy or radiotherapy. This case presented with The diagnostic approach of multiple tumors in a single
right nasolabial BCC, PTC, and a prolactinoma which individual is challenging as it obviates the need to look
arose intracranially presenting with endocrinologic signs into the possibility of metastases as one might be arising
and symptoms. The rare combination of the three tumors from the other. The occurrence of distant metastasis in BCC
was never reported and documented in a single patient and PTC is very rare having a rate varying from 0.0028% to
among published international medical journals. 0.55% and 1-7%, respectively. The two most common sites
of distant metastasis in both BCC and PTC are the lungs and
To date, there is no official case reports of triple primary bones.14-15 This case did not present with signs and symptoms
malignancies in a single individual in the Philippines. of pulmonary and osseous metastases. Pituitary metastases
However, a published case report in the Philippine Journal occur in ~3% of cancer patients. Blood borne metastasis are

found almost exclusively in the posterior pituitary gland of prolactin is >200 ug/L (>200 ng/mL) and is almost
and about 50% of pituitary metastases originate from breast invariably indicative of a prolactin secreting pituitary
cancer. The patient has a normal breast examination and adenoma.23,24 A “stalk effect” secondary to a large sellar mass
presented an anterior pituitary gland tumor, ruling out the as in this case may also increase serum prolactin levels
possibility of a metastatic process.16 due to obstruction of inhibitory dopamine flow from the
hypothalamus. The elevation would usually fall between
Having two tumors originating from different endocrine 96-200ng/mL and would not be too elevated, thus this
organs, it is very crucial not to miss multiple endocrine was ruled out.24 All other causes for hyperprolactinemia
neoplasia (MEN) syndrome; most likely the MEN type 1 were ruled out in this case. Evaluation of the hormones
(MEN-1). MEN-1 or Wermer’s syndrome has a clinical involved in the hypothalamus-pituitary-endocrine gland
triad of tumors arising from the anterior pituitary gland, axis is imperative (Table 2). The low LH and FSH levels in
parathyroid gland, and pancreatic islets.17 No one in the this case can be attributed to the suppressive effects of high
family of the patient clinically presented with the endocrine serum prolactin to the release of gonadotropin releasing
tumors implicated in MEN-1. Appendix D summarized the hormone (GnRH).19 Growth hormone and ACTH synthesis
program of tests and schedule for suspected MEN-1.17,18 and release are not affected by hyperprolactinemia.
Intact parathyroid hormone was slightly elevated on a This explains why IGF-1 and ACTH are within normal
background of normal serum calcium and the fasting blood levels.25 However, a low cortisol level on a background
sugar was elevated. This ruled out hyperparathyroidism of low or normal ACTH seen in this case may point to a
secondary to parathyroid adenoma, and pancreatic central adrenal insufficiency. It is prudent to include a
islet tumors which are the other components of MEN-1. dynamic study using synthetic ACTH (short synacthen
Following the consensus on the schedule of tests, other test) to accurately diagnose adrenal insufficiency in the
recommended work up were not clinically indicated. next follow up.26 Clinically the patient did not present
The nature, origin and presentation of the three tumors with lethargy, hypotension, and hyponatremia hence the
did not fit a syndromic differential diagnosis. urgency for cortisol replacement was not warranted. Lastly
an ophthalmologic evaluation and perimetry studies are
The International Association of Cancer Registries and salient in pituitary macroadenoma, as the involvement of
International Agency for Research on Cancer (IACR/IARC) the optic chiasm is crucial in the management.27
utilize the 6-month rule interval to diagnosing synchronous
from metachronous tumors arising from different sites Molecular Mechanisms and Genomics
regardless of the time of onset of each tumor.3 The patient The concept of “field cancerization” in oncology has
had three tumors of different germline origins and locations. explained the occurrence of multiple tumors arising
The manifestation of each tumor has different timeline from the head and neck. It presumes that, after repeated
of appearance however all three tumors were already carcinogenic exposures, the entire superficial epithelium
manifested by the patient and were diagnosed within 6 of the upper aerodigestive tract has an increased risk of
months during the work up hence considered synchronous. developing multifocal malignant lesions with tendency
of locoregional recurrence.28,29 This theory can be applied
The patient’s significant exposure to sun for a prolonged to the development of right nasolabial BCC and PTC as
period as a vegetable street peddler was considered the well as all the reported cases of triple primary tumors
most significant risk factor for BCC.14 A neck mass that (Appendix C). There are number of genetic mutations
moves with deglutition is consistent with a thyroid origin. identified in genomic studies involving tumors arising from
It has a very straight forward clinical approach. A normal the head and neck but these are not found in the somatic
TSH as initial hormone assay will lead to the utilization mutation of prolactinoma which involves pituitary tumor
of thyroid imaging (thyroid ultrasound) before doing transforming gene (PTTG) and fibroblast growth factor 4
biopsy.16 This was not done since a CT scan of head and (FGF4).30 This raises the question whether the prolactinoma
neck was already performed. has a different tumorogenesis coincidental to the other two
tumors or are the three tumors associated with each other
Large sellar and suprasellar mass may impede the genetically since we have ruled out MEN in the case. Thus,
decussating fibers of the optic pathway and may present with this case report highly recommends a genetic analysis
bitemporal hemianopsia as its classic finding. Galactorrhea to be done in the patient to characterize the pattern or
occurs in 80% of women with hyperprolactinemia. It association of genetic mutations on her next follow up.
also presents with secondary amenorrhea, infertility and
loss of libido due to elevated prolactin that suppresses Management
the pulsatile release of gonadotropin releasing hormone The gold standard management for BCC and PTC is
(GnRH) causing hypogonadotropic hypogonadism which surgery with a goal of a zero border resection. Mohs
were all seen in the patient.19 Surprisingly, the patient did micrographic surgery offers superior histologic analysis of
not present with galactorrhea but it is worth noting that tumor margins while permitting maximal conservation of
many premenopausal women with hyperprolactinemia tissue compared with standard excisional surgery for BCC
do not have galactorrhea, and many with galactorrhea however this was not performed to the patient wherein a
do not have hyperprolactinemia. This is because wide excision was done.14 For PTC, total thyroidectomy is
galactorrhea requires estrogenic or progesterone priming the surgery of choice which was done to the patient. It is
of the breast. Thus, galactorrhea is also very uncommon in followed with post-operative radioactive iodine adjuvant
postmenopausal women.20-22 therapy which will be the next plan for the patient. A
postoperative serum thyroglobulin and thyroglobulin
As a rule of thumb, the diagnosis of endocrine diseases is antibody as well as an ultrasound of the thyroid bed will
clinical and biochemical or hormonal. Significant elevation be monitored on top of the basic thyroid function tests to

detect recurrence and evaluate surgical adequacy on the Funding Source

next follow up.31 None.
The cornerstone management for prolactinoma is References

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The authors declared no conflicts of interest. prolactinemia: The importance of sequential pituitary imaging.

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JAFES
Unique, interesting, enlightening.
Your case report and the JAFES.

APPENDICES
Appendix A. Family Pedigree
Appendix B. Octopus Perimetry Study Report
This perimetry study reports normal visual field of the right eye and a finding of a left Quadrantanopsia. However this
perimetry study was taken with poor validity having a positive catch of 67% and a negative catch of 21%. A repeat study
is recommended.

Appendix C. Case reports of triple primary tumors specific only to the head & neck33-38
Author Features Age Management

Case #1 — 1. Wide local excision + left supra-omohyoid neck dissection +
1. Carcinoma left buccal Mucosa radiation
2. Carcinoma left upper alveolus and hard palate 2. Subtotal maxillectomy with free flap reconstruction + re-irradiation
3. Carcinoma right side base of tongue with concurrent chemotherapy
3. Near total glossectomy + right modified radical neck dissection +
re-irradiation
Case #2 — 1. Radiation with concurrent chemotherapy
1. Carcinoma left tonsil 2. Wide local excision + ipsilateral radical neck dissection
Shah, M. et al 2. Carcinoma left lateral tongue 3. Neoadjuvant chemotherapy followed by re-irradiation and
India 3. Carcinoma cervical esophagus concurrent chemotherapy
(2017)33
Case #3 — 1. Radiation
1. Carcinoma vallecular 2. Re-irradiation with concurrent chemotherapy
2. Carcinoma-in-situ middle esophagus 3. Neoadjuvant chemotherapy followed by re-irradiation
3. Carcinoma post cricoid
Case #4 — 1. Wide local excision + supraomohyoid neck dissection + adjuvant
1. Carcinoma right buccal mucosa radiation
2. Carcinoma right lateral tongue 2. Hemiglossectomy + re-irradiation with concurrent chemotherapy
3. Carcinoma glottis 3. Palliative Chemotherapy
1. Squamous cell carcinoma of larynx 71 yo 1. Total laryngectomy with
Singh, N. et al
2. Papillary thyroid carcinoma 2. Total thyroidectomy and bilateral selective neck dissection +
India
3. Non-Hodgkin’s Lymphoma adjuvant radiation followed by radioactive iodine ablation
(2015)34
3. Chemotherapy (Cyclophoshamide and Dexamethasone)
Yalavarthi, S. et al
1. Hodgkin’s lymphoma 21 yo 1. Chemotherapy
India 2. Mucoepidermoid carcinoma of the salivary gland 2. Not mentioned
(2014)35 3. Follicular variant of papillary thyroid carcinoma 3. Left hemithyroidectomy
1. Adenoid cystic carcinoma of left parapharyngeal 63 yo 1. Transparotid-trancervical excision + supraomohyoid neck
mass dissection + adjuvant chemotherapy
Umeshappa, H. et al
2. Follicular thyroid carcinoma 2. Left thyroid lobectomy with frozen section with concurrent
India
3. Basal cell carcinoma of the right upper lip completion thyroidectomy with central neck compartment
(2014)36
dissection + radioactive iodine
3. Wide local excision
1. Hypopaharyngeal cancer 37 yo 1. Hypopaharyngealectomy and cervical lymphadenectomy +
Nishikawa, K et al
2. Esophageal cancer adjuvant Radiotherapy
Japan
3. Tongue cancer 2. Esophagectomy
(2014)37
3. Partial and subtotal resection of tongue
1. Papillary thyroid carcinoma 43 yo 1. Subtotal thyroidectomy
Clarke DR. et al
2. Squamous cell carcinoma of the left vocal cord 2. Laryngectomy and left radical neck dissection
UK
3. Squamous cell carcinoma and lymphoma of the 3. Chemotherapy
(1986)38
left posterior mandible
Appendix D. Program of tests, and schedule for suspected MEN-1
Tumor Age Biochemical Test (Annual) Imaging

Parathyroid Adenoma 8 Calcium, PTH None
Gastrinoma 20 Gastrin None
Insulinoma 5 FBS, Insulin MRI
Anterior Pituitary Tumor 5 Prolactin, IGF-1 MRI
Foregut Carcinoid 20 None CT-Scan
*Adapted from the Consensus Guidelines for MEN-1 and MEN-219,20

Case Report
Journal of the
ASEAN Federation of
Endocrine Societies
Who were those MEN hiding behind the Ulcers?: A Case Report
Shazatul Reza Binti Mohd Redzuan and Yong Sy Liang
Endocrine Unit, Medical Department, Hospital Tengku Ampuan Rahimah, Selangor, Malaysia
Abstract
Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant disease caused by a mutation in the
MEN1 gene. We present a 65-year-old man with MEN1 who has primary hyperparathyroidism, microprolactinoma,
meningioma and gastrinoma. He had undergone parathyroidectomy followed by tumour excision of meningioma. The
duodenal gastrinoma lesion was inoperable as it was close to the superior mesenteric artery with high surgery risk.
Medical therapy with octreotide LAR had been initiated and showed good biochemical response as well as disease
progression control. Chemoembolization was proposed if the duodenum lesion reduces in size on maintenance
treatment with octreotide LAR. This case highlights the challenges in managing this rare condition and octreotide LAR
has shown to be effective in controlling the disease progression in MEN1 with inoperable gastrinoma.
Key words: MEN1, gastrinoma, octreotide LAR, meningioma
INTRODUCTION mmol/L) and intact parathyroid hormone (iPTH) of 22.13

pmol/L and a diagnosis of primary hyperparathyroidism
MEN 1 is an autosomal dominant disorder that is due to was confirmed. Otherwise, he had no clinical symptoms
mutations in the tumor suppressor gene MEN1 which of hypercalcaemia such as bodily ache, constipation,
encodes a 610 amino acid protein, menin. MEN1 is osteoporotic fracture or renal stone. Others relevant blood
characterized by the occurrence of parathyroid, pancreatic tests are shown in Table 1. The patient underwent left
islet and anterior pituitary tumours. Patients with MEN1 superior and inferior parathyroidectomy. Histopathology
have decreased life expectancy and the outcomes of analysis of the parathyroid glands revealed left inferior and
current treatment are not as successful because of multiple superior parathyroid adenoma (Figure 1). His calcium level
tumors, which are larger, more aggressive and resistant to remained normal after the removal of the glands.
treatment and concurrence of metastases. The prognosis
for MEN1 patients might be improved by presymptomatic Table 1. Initial blood investigations
tumor detection and treatment specific for MEN1 tumors. Initial blood test Reference value
Corrected Ca 2.88 mmo/L 2.20-2.65 mmol/L
Case Phosphate 0.68 mmol/L 0.81-1.45 mmol/L
iPTH 22.13 pmol/L 1.3-9.3 pmol/L
We describe a 65-year-old male who was referred to the Prolactin 7235 mU/L <500 mU/L
FT4 15.03 pmol/L 11-22 pmol/L
endocrine service initially for poorly controlled diabetes. TSH 1.2 mU/L 0.3-5.6 mU/L
Review of his history revealed a Zollinger-Ellison Testosterone 13.9 nmol/L 8.0- 31.3 nmol/L
syndrome that had initially presented with persistent GH 0.82 μg/L <3 μg/L
diarrhea, abdominal pain and vomiting when the patient IGF-1 272 μg/L 30-210 μg/L
was in his late forties. Gastroduodenoscopy revealed 24 Hour catecholamine
Norepinephrine 22.7 μg/day 12.1-85.5
multiple duodenal ulcers and esophagitis. Elevated fasting
Epinephrine 10.0 μg/day 1.7-22.4
serum gastrin without proton pump inhibitor (PPI) at 405.8 Dopamine 16.1 μg/day <498.1
ng/L (Reference value [RV]: 44-104 ng/L), confirmed the Gastrin 405.8 ng/L 44-104 ng/L
diagnosis. CT scan of the abdomen showed a well defined
intensely enhancing nodule at the third part of duodenum
(2 cm from the gastroduodenal junction) suggestive of Pituitary MRI was done to screen for pituitary lesion show-
gastrinoma. However, he defaulted follow up for many ing right parietal lobe extraaxial tumour or meningioma
years prior to his presentation to us. with suprasellar lesion (Figures 2 and 3). Prolactin level
was elevated at 7235 mU/L (RV: 86-324). Otherwise, he
During our evaluation, he was worked up for MEN had no headache, vision problem or hypogonadism
associated tumors in view of the history of Zollinger-Ellison symptoms. He has since been on cabergoline 0.5 mg twice
syndrome. Further work up revealed high calcium level of weekly. Surgery of right parietal tumour was offered at
2.88 mmol/L, phosphate level of 0.68 mmol/L (RV: 0.81-1.45 that time but the patient refused.
________________________________________
ISSN 0857-1074 (Print) | eISSN 2308-118x (Online) Corresponding author: Shazatul Reza Binti Mohd Redzuan, MD
Printed in the Philippines Endocrine Fellow, Hospital Tengku Ampuan Rahimah
Copyright © 2020 by Redzuan et al. Jalan Langat, 41200 Klang, Selangor, Malaysia
Received: March 31, 2020. Accepted: October 2, 2020. E-mail: [email protected]
Published online first: October 30, 2020. ORCiD: https://orcid.org/0000-0002-1658-1538
https://doi.org/10.15605/jafes.035.02.10

Who were those MEN hiding behind the Ulcers?: A Case Report Shazatul Reza Binti Mohd Redzuan, et al 211
Figure 1. HPE of the parathyroid showing tumor cell with Figure 2. MRI of the brain showing a well-defined extra
clear cytoplasm, arranged in sheets and cords traversed axial soft tissue mass in the right parietal lobe with cystic
by delicate blood vessels (H&E, 100x). areas noted within the tumor.
A B
Figure 3. MRI of the pituitary showing small well-defined hypo to isointense nodules within the suprasellar region
measuring 0.2x0.4x0.4 cm. (A) coronal view and (B) sagittal view.
Reassessment of the duodenal lesion with CT scan having family history of MEN1 or MEN1 associated
abdomen showed increasing size of the duodenal lesion at tumors. Genetic test was not performed for him due to
13.0x8.1x5.1 cm (Figure 4). Repeated gastroduodenoscopy unavailability of the test at that time. His 3 children were
demonstrated prominent gastric fold and duodenitis. advised to go for health and genetic screening. One of
Endoscopic ultrasound was scheduled but he was not his children tested positive for menin gene; the other 2
keen. He had symptoms of hypergastrinemia with peak children’s status are still unknown.
gastrin levels 2013 pmol/L and symptoms improved with
proton pump inhibitor (PPI). During follow-up, the patient was taking cabergoline 0.5
mg twice/week, alphacalcidol 0.25 mcg bd, esomeprazole
He was suspected to have MEN1 due to presence of three 40 mg daily and basal bolus insulin. He was monitored
primary MEN1 tumours which are gastrinoma, primary clinically and CT scan abdomen was arranged in to monitor
hyperparathyroidism and microprolactinoma. He denied the size of the duodenal lesion.

212 Shazatul Reza Binti Mohd Redzuan, et al Who were those MEN hiding behind the Ulcers?: A Case Report
right craniotomy and tumor excision for the right

parasagittal mass. The histopathology examination of the
tumor revealed right parietal lobe fibrous meningioma
WHO grade 1. The surgery was complicated by massive
upper gastrointestinal bleeding with hypovolemic shock.
Ga-68 Dotatate PET-CT was performed to look for

metastatic lesions and showed increased uptake at the
duodenum, stomach and abdominal nodes (Figure 5).
There are multilobulated masses (5x12.5x9.4 cm) at the
3rd part of the duodenum (SUVmax 88.3), two foci at
stomach wall at cardia (SUVmax 132), paracaval node at
L1/L2 vertebral level (SUVmax 86.6) and aortocaval node at
L1L2 vertebral level (SUVmax 69.7) measuring 0.9x1.2 cm
and 1.5x1.2 cm respectively. The two foci in the stomach
wall at cardia could be ulcer rather than metastasis to
the stomach after discussion with nuclear medicine team.
Figure 4. CT scan of the abdomen showing large well-
The patient was started on intramuscular octreotide LAR 30
defined multinodular and multilobulated, heterogenously
mg monthly after a multidisciplinary discussion involving
enhancing mass lesion with irregular cystic component,
his surgeon, nuclear medicine physician, interventional
arising from the wall of the 3rd part of the duodenum to
radiologist, oncologist and endocrine service to shrink the
proximal jejunum [13.0x8.1x5.1 cm (AP)].
tumor and subsequently plan for chemo-embolization.
However, patient was only keen for octreotide LAR
Unfortunately, four years later, the patient developed until now. He reported improvement in symptoms
insidious onset left sided body weakness and MRI brain especially gastric pain after treatment with proton pump
showed right fronto-parietal extra axial enhancing mass inhibitor and octreotide LAR with better quality of life. His
with edema, mass effect with midline shift. He underwent pituitary lesion, prolactin and calcium level remain stable.
A B
Figure 5. Ga-68 DOTATATE PET-CT showing uptake at 3rd part of duodenum (SUVmax 88.3), stomach (SUVmax 132)
and abdominal nodes (SUVmax 69.7).

Who were those MEN hiding behind the Ulcers?: A Case Report Shazatul Reza Binti Mohd Redzuan, et al 213
Table 2. Serial Investigation after octreotide LAR treatment

Baseline Before treatment After octreotide LAR
Date 2000 June 2017 September 2017 August 2018 February 2020
Gastrin (RV: 6-55 pmol/L ) 405.8 2013 NA 630 680
Chromogranin A (RV: 27.0-94.0 ng/ml ) NA 14256 6564 >770 2500
NA: not available
as well as limited genetic tests available during that time.

He denied having family history of MEN 1 or MEN
associated tumor. One of his three children tested positive
for menin gene.
Primary hyperparathyroidism is the most common feature

of MEN 1 and occurs in approximately 95% of MEN1
patients.5 Pancreatic neuroendocrine tumors (NET), consist
of gastrinomas, insulinomas, glucagonomas, vasoactive
intestinal polypeptidomas (VIPomas) and nonfunctioning
pancreatic NETs occur in approximately 40-70% of
MEN1 patients.6 Anterior pituitary tumors consisting of
prolactinomas, somatotrophinomas, corticotrophinomas
and nonfunctioning adenomas occur in approximately
30-40% of patients.7
In the absence of treatment, these tumors are associated

with an earlier mortality. Untreated patients with MEN1
Figure 6. Repeated CT scan of the abdomen after octreotide have decreased life expectancy with 50% probability of
LAR. Image showed similar size of duodenal lesion. death by the age of 50 and the cause of death in 50-70% is
usually due to a malignant tumor process or sequelae of
the disease.8 In particular, malignant pancreatic NET and
His serum gastrin and chromogranin A had reduced thymic carcinoid tumor were associated with a marked
markedly after octreotide LAR (30 mg monthly) treatment increase in the risk of death.
(Table 2). PPI was discontinued prior obtaining the
serum gastrin level. He has been maintained on this Subtotal parathyroidectomy has resulted in persistent or
dose (Octerotide LAR 30 mg monthly) to date. Repeated recurrent hypercalcaemia within 10-12 years after surgery
CT scan abdomen after 5 months of octreotide LAR in 40-60% of patients. For this case, patient had undergone
treatment revealed no significant change in the gastric, parathyroidectomy and his calcium level was stable after 6
mesenteric and pancreatic lesion (Figure 6). years of surgery. However, close monitoring of his calcium
level together with regular assessment for symptom onset
Currently he is being monitored closely for disease and complications are important, noting that patients
progression and symptoms of gastrinoma with yearly with MEN1 have an increased risk of persistent or
CT scan abdomen, Ga-68 Dotatate PET CT scan and recurrent hyperparathyroidism due to tendency towards
biochemical investigations specifically fasting gastrin as multiglandular disease.9
well as chromogranin A.
Gastrinoma is the most frequent functioning pancreato-
Discussion duoedenal NET that causes gastric acid hypersecretion
with the manifestation of the Zollinger-Ellison syndrome
MEN1 is a rare autosomal dominant disease caused by a (ZES). The hypergastrinemia has a trophic effect on
mutation in the MEN1 gen (chromosome 11) encoding gastric mucosa and gastric enterochromaffin cell. It is
the tumor suppressor protein menin.1 MEN 1 is suspected diagnosed in at least 50% of MEN1 patients at the age of
when two or more of the most common neuroendocrine 50 and with higher prevalence in men.8 ZES is associated
tumors are found such as parathyroid tumor, pancreatic with recurrent peptic ulcerations. These ulcers frequently
islet cell tumor and pituitary tumor. Approximately 80- appear small, less than 5 mms in diameter, with multiple
90% of patients diagnosed with MEN1 show a MEN1 nodular lesions arising deep in the mucosa. Gastrinomas
gene mutation.2 The diagnosis of MEN1 can be made usually grow slowly but frequently metastasize to
clinically on the basis of family history or genetic testing peripancreatic lymph nodes and rarely to the liver.
for a MEN1 gene mutation.3 Our patient had gastrinoma/
Zollinger-Ellison disease in his late forties, and then a few The ideal treatment for a non-metastatic gastrinoma
years later had primary hyperparathyroidism and micro- of the pancreas is surgical excision because the disease
prolactinoma. This patient also had meningioma which is related survival in-patient with tumors that are more than
a rare tumor in MEN1. Meningiomas have been reported 2 cm has improved after surgery.10 In most patients with
in about 8% of MEN1 patients and typically present later in MEN1, gastrinomas are multiple and occur within the
life.4 This case is a rare condition of meningioma in MEN1. duodenum and surgical cure may be difficult. Most centers
do not offer Whipple resection for the majority of MEN1
Genetic evaluation to confirm MEN1 gene mutation was patients because fewer operations are associated with
not performed in this patient due to financial constraints excellent survival.11 Therefore, the surgical procedure needs

214 Shazatul Reza Binti Mohd Redzuan, et al Who were those MEN hiding behind the Ulcers?: A Case Report
to be individualized according to preoperative findings Statement of Authorship

and the patient’s preference. Both authors certified fulfillment of ICMJE authorship criteria.
For this case, he was not a suitable candidate for Whipple Author Disclosure
Both authors declared no conflicts of interest.
surgery as the duodenal tumor is close to the superior
mesenteric artery and is a high risk surgery. In our patient, Funding Source
multidisciplinary discussion involving a hepatobiliary None.
surgeon, oncology and interventional radiologist had
decided to start the patient on octreotide LAR for longer References
duration and then proceed with chemoembolization of 1. Christopoulos C, Papavassiliou E. Gastric neuroendocrine tumors:
Biology and management. Ann Gastroenterol. 2005;18(2):127–40.
the duodenal tumor.
2. Falchetti A. Genetic screening for multiple endocrine neoplasia
syndrome type 1 (MEN-1): When and how. F1000 Med Rep. 2010;2:14.
Somatostatin analogue (SSA) has been demonstrated to PMID: 20948872. PMCID: PMC2948394. https://doi.org/10.3410/M2-14.
control the growth of gastro-entero-pancreatic NETs but no 3. Thakker RV, Newey PJ, Walls GV, et al. Clinical practice
guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin
data are available regarding their effects on the growth of Endocrinol Metab. 2012;97(9):2990-3011. PMID: 22723327. https://doi.
MEN1 associated gastrinoma.12 Only case reports or small org/10.1210/jc.2012-1230.
series support the use of SSA in advanced gastrinoma, 4. Asgharian B, Chen YJ, Patronas NJ, et al. Meningiomas may
be a component tumor of multiple endocrine neoplasia type1.
therefore it is difficult to quantify their ability to control Clin Cancer Res. 2004;10(3);869-80. PMID: 14871962. https://doi.
tumor growth and disease progression. Tomassetti et al., org/10.1158/1078-0432.ccr-0938-3.
had shown reduction in number and size of carcinoid 5. Brandi ML, Gagel RF, Angeli A, et al. Guidelines for diagnosis
tumors after 6 months of therapy and gross resolution of and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab.
2001;86(12):5658-71. PMID: 11739416. https://doi.org/10.1210/jcem.
disease in 1 year. All the patients in the study had small 86.12.8070.
tumors <1 cm in size, suggesting that LAR SSA maybe 6. Thomas-Marques et al. Prospective endoscopic ultrasonographic
beneficial in controlling smaller disease burden.13 evaluation of the frequency of nonfunctioning pancreaticoduodenal
endocrine tumor in patients with MEN1. Am J Gatroenterol.
2006;101(2):266-73. PMID: 16454829. https://doi.org/10.1111/j.1572-
After 5 months of the somatostatin analogue treatment, 0241.2006.00367.x.
our patient had reduction in the chromogranin A and 7. Trouillas J, Labat-Moleur F, Sturm N, et al. Pitutary tumor and
hyperplasia in MEN 1: A case control study in a series of 77 patient
gastrin level but not the size of duodenal tumor. Otherwise,
versus 2509 non-MEN1 patient. Am J Surg Pathol. 2008;32(4):534-43.
clinically, the patient was feeling much better with PMID: 18300794. https://doi.org/10.1097/PAS.0b013e31815ade45.
less gastric discomfort and a better quality of life after 8. Ito T, Igarashi H, Uehara H, Berna MJ, Jensen RT. Causes of death
somatostatin analogue treatment. In our patient, with a and prognostic factors in multiple endocrine neoplasia type 1:
A prospective study: comparison of 106 MEN1/Zollinger-Ellison
huge duodenal gastrinoma, long acting SSA appeared syndrome patients with 1613 literature MEN1 patients with or without
contributory in controlling disease progression. pancreatic endocrine tumors. Medicine (Baltimore). 2013;92(3):135-
81. PMID: 23645327. PMCID: PMC3727638. https://doi.org/10.1097/
MD.0b013e3182954af1.
Conclusion 9. Doherty GM, Lairmore TC, DeBenedetti MK. Multiple endocrine
neoplasia type 1 parathyroid adenoma development over time. World
We report a rare case of MEN1 with huge duodenal J Surg. 2004;28(11):1139-42. PMID: 15490065. https://doi.org/10.1007/
s00268-004-7560-8.
gastrinoma, primary hyperparathyroidism and micro- 10. Norton JA, Jensen RT. Role of surgery in Zollinger-Ellison
prolactinoma. The growth of gastrinoma tumor in MEN1 syndrome. J Am Coll Surg. 2007;205(4 Suppl):S34-7. PMID: 17916516.
remained unchanged with octreotide LAR and symptoms https://doi.org/10.1016/j.jamcollsurg.2007.06.320.
were controlled with both the octreotide LAR and PPI. This 11. Norton JA. Surgical treatment and prognosis of gastrinoma. Best
Pract Res Clin Gastroenterol. 2005;19(5):799-805. PMID: 16253901.
case highlights that octreotide LAR has a potential role to https://doi.org/10.1016/j.bpg.2005.05.003.
control disease progression as well as improve quality of 12. Berardi R, Morgese F, Torniai M, et al. Medical treatment for gastro-
life and possibly increase survival rates in a patient with entero-pancreatic neuroendocrine tumors. World J Gastrointest Oncol.
MEN1 with an inoperable, huge duodenal gastrinoma. org/10.4251/wjgo.v8.i4.389.
13. Tomassetti P, Migliori M, Caletti GC, Fusaroli P, Corinaldesi
Ethical Considerations R, Gullo L. Treatment of type II gastric carcinoid tumors with
Patient consent was obtained before submission of the manuscript. somatostatin analogues. N Engl J Med. 2000;343(8):551-4. PMID:
10954763. https://doi.org/10.1056/NEJM200008243430805.

Case Report
Journal of the
ASEAN Federation of
Endocrine Societies
Primary Partial Empty Sella presenting with Prepubertal

Hypogonadotropic Hypogonadism: A Case Report
Maria Angela Matabang1 and Buena Sapang2
1
Department of Internal Medicine, Ospital ng Makati, Makati City, Philippines
2
Department of Endocrinology, Cardinal Santos Medical Center, San Juan City, Philippines
Abstract
Primary partial empty sella occurs when less than 50% of an enlarged or deformed sella turcica is filled with cerebro-
spinal fluid in the setting of unidentified etiologic pathological conditions. Prepubertal hypogonadotropic hypogonadism
presenting as its main manifestation is rare since its peak incidence commonly occurs late at 30 to 40 years of age and
has a sexual predilection for female. We described a case of 20-year-old male who presented with micropenis and absent
secondary sex characteristics. Work up showed cranial MRI finding of partial empty sella, low testosterone, LH, FSH,
Estradiol and Beta HCG levels. Sex hormone replacement may not improve fertility for this case but may help produce
and maintain virilization and prevent future complications of hypogonadotropic hypogonadism.
Key words: PES, hypogonadotropic, hypogonadism, micropenis
INTRODUCTION vaginal delivery to a 35-year-old G3P3 mother, with no

perinatal complications. However, there was intake of
an abortifacient (4 tablets of misoprostol) on the 5th week of
Empty sella is a radiologic finding pertaining to an enlarged pregnancy. At birth, there was noted “monggo seed” sized
or deformed sella turcica which can be partially (<50%) penis and “paper-thin” scrotum. His mother was advised
or completely (>50%) filled with cerebrospinal fluid.1 Its by the local health center physician to seek consult with a
diagnosis is confirmed with magnetic resonance (MR) study surgeon however due to financial difficulties, there were
of sellar and suprasellar regions or computed tomography no tests nor consult with a specialist done. His childhood
(CT) for those with absolute contraindication/s to MR.2 and pre-puberty years were unremarkable. There were
no symptoms of palpitations, heat or cold intolerance,
Based on etiology, empty sella can be classified as polyuria, polydipsia, polyphagia. There were no episodes
primary or secondary. Compared to secondary empty of frequent urinary tract infection, dysuria, or abdominal
sella which is caused by pituitary pathological conditions pain. There were no instances of elevated blood pressure,
like previous surgical, pharmacological or radiotherapy headache, change in vision. There were no significant health
treatment, the pathogenesis behind primary empty sella problems during his childhood except for appendicitis
(PES) is unclear.2 Some of the identified mechanisms for which he underwent an emergency appendectomy in
include incomplete formation of sellar diaphragm and the July 28, 2008 at Ospital ng Makati.
influence of suprasellar or pituitary promoting factors.1
Its incidence is not that high, ranging from 5.5%-12% as However, at around 14 to 16 years of age, there was
accidental finding in autopsy to 8%-35% in clinical practice. persistence of high pitched voice, scant pubic and axillary
Majority of the prevalence of PES is among women – those hair and fat deposition on waist and bilateral breasts. There
with history of at least one completed pregnancy in their was minimal growth in penile size at approximately 2-3
physiological history. Moreover, its occurrence in children centimeters (cm) and a bilateral palpable scrotal sac.
is also less frequent compared to adults, and it is more or
less associated with hypothalamic–pituitary dysfunction, On physical examination, he was ambulatory with stable
genetic disorders or perinatal complication.2 vital signs. He is overweight with BMI of 29.09 kg/m2 and
weight of 74.5 kilograms. His waist to hip ratio is 0.89
CASE with his waist circumference spanning 86 cm and hip
circumference at 96.5 cm. He presented with eunuchoid
RC, a 20-year-old male, sought consult in our institution proportion (Figure 1) with a height of 162 cm and arm span
for small penile size. He was born full-term via normal of 171 cms. His mother stands 151 cm while his father at 169
________________________________________
ISSN 0857-1074 (Print) | eISSN 2308-118x (Online) Corresponding author: Maria Angela M. Matabang, MD
Printed in the Philippines Medical Resident, Ospital ng Makati
Copyright © 2020 by Matabang et al. Sampaguita corner Gumamela Streets, Pembo
Received: July 31, 2020. Accepted: October 19, 2020. Makati City, Philippines 1218
Published online first: November 4, 2020. Tel. No.: +632-88826316 to 36
* The abstract was accepted for poster presentation in the SICEM 2019 at the Grand Walkerhill, Seoul Korea in April 18-21, 2019.

216 Maria Angela Matabang, et al Primary Partial Empty Sella presenting as Hypogonadism
A B
Figure 1. Eunuchoid proportion (A) height of 162 centimeters; (B) arm span Figure 2. Bilateral gynecomastia, mode-
of 171 centimeters. rately enlarged without skin excess in an
overweight 20-year-old male.
A B C
Figure 3. Tanner stage 1 (A) flaccid penile length; (B) stretched penile length; (C) penile width and scrotum.
cm with computed mid parental height for boys of 166.5 Micropenis is defined by Schonfeld and Beebe as Stretched
cm. Thyroid gland was not palpable. He has gynecomastia Penile Length (SPL) 2.5 SD less than the mean for age
without galactorrhea (Figure 2). Genital and pubic hair without the presence of any other penile anomalies and
development was graded as Tanner Stage 1 (Figure 3). presence of internal and external genital organs compatible
He has a flaccid and stretched penile lengths of 2.5 and with a 46 XY karyotype.3 For an average adult patient,
3 cm respectively with width of 4 cm. He has palpable mean stretched penile length is 13.3 cm with 9.3 cm as the
small, firm left testis while non palpable on the right. calculated 2.5 standard deviation less than the mean for
Neurologic examination was normal except for bilateral age. The patient has a stretched penile length of 3 cm falling
anosmia. Evaluation was done by Otorhinolaryngology more than 2.5 SD below the mean for adult.
service which showed recurrent rhinosinusitis. CT scan
of paranasal sinuses showed pansinusitis with opacified To satisfy the criteria for micropenis, pelvic and inguino-
and widened ostiomeatal units. A trial of steroid scrotal ultrasound was done to confirm the presence of
therapy was recommended which provided slight relief internal genital organs, which revealed small left testicle
of anosmia. measuring 0.9x0.5x0.7 cm with chronic parenchymal

Primary Partial Empty Sella presenting as Hypogonadism Maria Angela Matabang, et al 217
A B C
Figure 4. Cranial MRI (A) T2 sagittal view; (B) T2 axial view; (C) T2 coronal view. The arrows point to fluid-filled sella.
A B C
Figure 5. X-ray of left hand comparing (A) patient’s bone age, (B) normal 16-year-old male and (C) normal 18-year-old male.
changes and a non visualized right testicle. The prostate hypogonadism, where the growth plates are not yet fused
gland measures 2.2x1.6x1.7 cm (~3 grams). A whole and there is lack of sex steroids, growth plates of the
abdominal CT scan was done with noted left inguinal extremities continue to grow past the usual age of cessation.
hernia and ovoid soft tissue density in right inguinal As a result, there is decreased upper to lower ratio and
region possibly representing the right testis. Other findings an increased arm span for height leading to eunuchoid
include hepatic steatosis and nephrocalcinosis on the proportion like in the patient.
left. Lastly, to satisfy the criteria, chromosome analysis
was done revealing a karyotype with no numerical Aside from this, determination of skeletal development
and structural aberrations and an XY sex chromosome by x-ray of left hand and wrist is also a useful way of
complement in all 50 cells examined. Hence the patient has establishing the stage of physiological development which
a male karyotype of 46,XY. in some cases may not be parallel with chronological age.
The patient has a delayed bone age (compatible to 16 and
However, the patient did not just present with isolated 5/12 to 14 and 5/12 year old male) by the Greulich-Pyle
micropenis. Alongside, he has gynecomastia, persistently method (Figure 4). Estradiol is a product of aromatization
high pitched voice and underdeveloped adult sexual of testosterone and it mediates additional effects of
characteristics. Most authorities accept the definition testosterone on bone resorption, epiphyseal closure,
of delayed puberty as the absence of secondary sexual sexual desire, and fat deposition. From the physical
development at an age 2 SD above the mean age of onset examination and the patient’s bone x-ray, this low estradiol
of puberty. This is the age at which 95% of normal children might have contributed to the unfused ossification
have already entered puberty. Based on etiology, pubertal centers and eunuchoid proportion. Related to this is that
delay can be classified into constitutional growth delay androstenedione is converted to testosterone by 17-beta
or hypogonadism. The latter can be further classified into hydroxysteroid dehydrogenase before it gets aromatized
hypogonadotropic or hypergonadotropic hypogonadism.3 to estradiol. However, androstenedione itself can be
aromatized to estrogen which might have contributed to
Though stature is the most obvious change in growth, gynecomastia and fat deposition.
the ratio of the upper and lower segment also changes
significantly. Sex steroids are necessary for increase in The patient’s cranial MRI showed a shallow sella with
growth hormone secretion and they directly stimulate apparent flattening of pituitary gland at its floor (Figure 5).
epiphyseal plate’s growth and fusion. In prepubertal The results of baseline endocrine tests are summarized in

218 Maria Angela Matabang, et al Primary Partial Empty Sella presenting as Hypogonadism
Table 1. Serologic and immunologic test results Table 2. Biochemical test results
Test Result Normal Values Test Result Normal Values
Estradiol (ECLIA) <5.00 pg/mL Male: 25.8-60.7 pg/mL AST/SGOT 34 5-35 U/L
Beta HCG with Dilution <0.100 mIU/mL 0.0-2.0 mIU/mL ALT/SGPT 34 0-55 U/L
FSH (ECLIA) 0.43 mIU/mL Male: 1.5-12.40 mIU/mL BUN 3.5 3.2-7.4 mmol/L
LH (ECLIA) 0.22 mIU/mL Male: 1.7-8.60 mIU/mL Creatinine 46 64-104 umol/L
Testosterone (ECLIA) 0.16 ng/mL Male: 2.8-8.00 ng/mL Sodium 138 136-145 mmol/L
IGF-1 59.35 ng/mL 115-350 mg/mL Potassium 4.1 3.5-5.1 mmol/L
Serum Cortisol 160.5 nmol/L (8:31 AM) 6-10 AM: 172-49 nmol/L Chloride 102 101-110 mmol/L
ACTH 27.41 pg/mL (8:31 AM) 7-10 AM: 7.2-63.30 pg/mL Phosphorous 1.11 0.74-1.52 mmol/L
Prolactin 125.30 mIU/L 86-324 mIU/L Magnesium 0.91 0.70-0.91 mmol/L
FT3 2.95 pg/mL 1.71-3.71 pg/mL HDL 1.20 up to 1.04 mmol/L
FT4 0.77 ng/mL 0.70-1.48 ng/mL VLDL 0.77 ng/mL
Thyroid Stimulating Hormone 1.0363 mIU/L 0.35-4.94 uIU/mL Triglyceride 0.54 up to 1.70 mmol/L
LDL 2.90 up to 2.59 mmol/L
Cholesterol 3.61 up to 5.18 mmol/L
FBS 4.78 3.89-5.49 mmol/L
Table 1 showing hypogonadotropic hypogonadism (low is 5:1 with peak incidence occurring at 30 to 40 years,
testosterone, FSH and LH). Other biochemical results are occasionally earlier in women. It occurs less frequently in
summarized in Table 2 which showed normal fasting blood children and is associated with hypothalamic–pituitary
sugar, serum sodium, potassium, AST and ALT. While, dysfunction, genetic disorders or perinatal complications.
lipid profile showed normal levels of total cholesterol and
triglyceride but elevated LDL. The etiology of PES is unclear but some of the etiopathogenic
hypotheses identified include: 1. incomplete formation
With these findings, the patient was diagnosed with Primary of sellar diaphragm 2. upper sellar factors (persistent
Empty Sella (PES) (Partial) which is probably congenital or intermittent intracranial idiopathic hypertension,
based on history of abortifacient use on first trimester of CSF pulsatility, obesity, systemic hypertension) or 3.
pregnancy, findings of prepubertal hypogonadotropic pituitary factors (conditions associated with variation of
hypogonadism and MRI showing a partially empty sella. pituitary volume like pregnancy, lactation, menopause,
hypophysitis, compensatory pituitary hypertrophy to
He was referred to Endocrinology and Urology services. primary hormonal deficit).2
Sex hormone replacement was recommended. He was
offered testosterone therapy however this was not yet Patients with PES have varied symptoms, and endocrine
started due to lack of funds. Steroid was not initiated since dysfunction is one the least common presenting
serum cortisol is just borderline low and patient is also manifestations. In a study done by De Marinis et al.,
asymptomatic. Orchiectomy as prophylaxis for develop- only 19% (n=40, N=213) had documented endocrine
ment of malignancy is not warranted but orchidopexy abnormalities in which only 22% (n=9, N=40) are male.4
may be offered to monitor tumor development. This marginal number of male patients with PES presenting
with endocrine problem was also seen in a study done
Counseling was offered regarding possible psychosocial by Maira et al., where in only 12% was documented.5
impact of the physical changes brought about by the
endocrine problem. Since he has a partner it was also The prevalent endocrine problem varies in different studies.
suggested in order to help them regarding possible plans In a study done by Radha Rani et al., hypocortisolemia
to have children. However, they refused the offer since was most common (62.5%, n=10, N=16). In the same study,
they’ve already decided to adopt a child in the future. The hypogonadism was observed in minority (18.75%, n=3)
patient verbalized that currently, the psychical changes which presented as amenorrhea and erectile dysfunction.6
has no derogatory impact on his personal and social life. On the other hand, in a study done by Ghatnatti et al.,
hyperprolactinemia was the most common dysfunction
For continuation of care and surveillance of the possible (20.8% n=5, N=12) and isolated hypogonadotropic
impact of the hormonal deficiencies on other organ hypogonadism was only observed in 2 patients.7
systems, the patient was endorsed to the succeeding
endocrinology rotator and outpatient resident. He was last One study on PES showed hypogonadotropic hypo-
seen on December 2019 and repeat blood chemistries were gonadism as the most common endocrine problem (19%,
requested; however, he was lost to follow up thereafter. n=5; N= 21) which presents as oligomenorrhoea in females
and decreased sexual function in male.8 Micropenis and
DISCUSSION lack of secondary sex characteristics are rare presentations
since PES is seldom seen during prepubertal years. Its peak
Data on epidemiology of PES varies based on means incidence is notable at postpubertal years hence the usual
of diagnosis. It is usually an incidental finding in 5.5%- clinical manifestations of decrease in sexual function
12% of autopsy cases. However, using neuroimaging, or erectile dysfunction are observed. One event was
its overall incidence has been estimated at 12%, while documented in 1973 which is almost similar with our case.
approximately 9-35% if based on clinical findings as A 24-year-old, 46XY patient was admitted for evaluation
reported in various case series. Its female-to-male ratio of infertility and lack of development of secondary sex

Primary Partial Empty Sella presenting as Hypogonadism Maria Angela Matabang, et al 219
characteristics. He is obese with eunuchoid proportion Author Disclosure

given the height and arm span. He has gynecomastia, Both authors declared no conflicts of interest.
bilateral undescended testes, normal prostate and
decreased male body hair, however data on micropenis was Funding Source
None.
not mentioned.9
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also uncommon, mostly seen late at 30 to 40 years of age J Endocrinol Metabol. 2013;17(Suppl 1):S125-6. PMID: 24251130.
and majority in females. Prompt recognition of prepubertal PMCID: PMC3830276. https://doi.org/10.4103/2230-8210.119527.
7. Ghatnatti V, Sarma D, Saikia U. Empty sella syndrome - beyond
hypogonadotropic hypogonadism at an early age can being an incidental finding. Indian J Endocrinol Metab. 2012;16(Suppl
maximize both surgical and medical management in these 2):S321-3. PMID: 23565413. PMCID: PMC3603061. https://doi.
patients. However, since the patient in this case sought org/10.4103/2230-8210.104075.
8. Stelmachowska-Banaś M, Czajka-Oraniec I, Zgliczyński, W. Clinical
consult late, it is also important to reiterate at this point and hormonal assessment of patients with empty sella on MRI. Postępy
alternative options if there are future plans for reproduction Nauk Medycznych. 2014;23(12):814-8. http://www.pnmedycznych.pl/
as well as methods to prevent future complications of these wp-content/uploads/2015/01/pnm_2014_814-818.pdf
hormonal imbalances. 9. Thomas Jr HM, Lufkin EG, Ellis 3rd GJ, Hartman CR, Hofeldt FD,
Herman RH. Hypogonadotropism and "empty sella": Improvement
in 2 cases with clomiphene citrate. Fertil Steril. 1973;24(4):252-9.
Ethical Considerations PMID: 4694501. https://doi.org/10.1016/s0015-0282(16)39609-1.
Patient consent was obtained before submission of the manuscript. 10. Petak SM, Nankin HR, Spark RF, et al. American Association of
Clinical Endocrinologists Medical Guidelines for clinical practice
Statement of Authorship for the evaluation and treatment of hypogonadism in adult male
patients--2002 update. Endocr Pract. 2002;8(6):440-56. PMID: 15260010.
Both authors certified fulfillment of ICMJE authorship criteria.
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Case Report
Journal of the
ASEAN Federation of
Endocrine Societies
Bilateral Genu Valgum in an Adolescent

with Primary Hyperparathyroidism:
A Case Report and Review of Literature
Siow Ping Lee,1 Shu Teng Chai,1 Leh Teng Loh,2 Norhaliza Mohd Ali1
1
Department of Medicine, Hospital Sultanah Aminah, Johor, Malaysia
2
Gleneagles Medini, Johor, Malaysia
Abstract
Primary hyperparathyroidism in children and adolescents is rare and often symptomatic at presentation. A 15-year-old boy
presented with bilateral genu valgum for two years. Biochemical results were consistent with primary hyperparathyroidism.
Calcium levels normalized two months after removal of a left inferior parathyroid adenoma.
Key words: primary hyperparathyroidism, adolescent, genu valgum, parathyroid neoplasms
INTRODUCTION Physical examination revealed short stature (below 5th

percentile) and bilateral genu valgum (Figure 1). There were
Primary hyperparathyroidism (PHPT) is a disorder of bone no bony deformities including those typical of rickets. He had
and mineral metabolism caused by autonomous secretion no polydactyly, joint laxity or lumbar kyphosis to suggest
of parathyroid hormone (PTH). It is mainly seen in adults skeletal dysplasia. The knee joints were not swollen, tender
between 50 and 60 years of age, with an annual incidence or warm. Laboratory evaluation showed hypophosphatemia
of 30 per 100,000 and a lifetime prevalence of one per and elevated levels of calcium, alkaline phosphatase and
1,000. The female to male ratio is approximately 3:1.1 On intact parathyroid hormone (iPTH), consistent with the
the other hand, PHPT in children and adolescents is rare, diagnosis of primary hyperparathyroidism (Table 1). Neck
with a prevalence of two to five cases per 100,000 and no ultrasonography revealed a well-defined hypoechoic
apparent sex predilection.1,2 In contrast to adults who are lesion measuring 1.2x1.5x2.7 cm at the inferior pole of left
often asymptomatic and commonly recognized during thyroid lobe. Kidney and liver function tests were normal.
routine biochemical screening, children and adolescents Unfortunately, serum vitamin D, urinary calcium, kidney
with PHPT are mostly clinically symptomatic with end- ultrasonography and bone mineral density scan were not
organ damage. These include skeletal abnormalities and/or performed in this case.
nephrolithiasis at presentation.2
He subsequently underwent left inferior parathyroid-
Genu valgum is an unusual manifestation of PHPT in ectomy in December 2018. Histopathologic examination
children and adolescents. To date, there is a limited number of the resected parathyroid gland confirmed a parathyroid
of published reports describing such presentation. We adenoma. His immediate postoperative serum calcium
report a young patient who had bilateral genu valgum as a was 1.9 mmol/L, for which he received oral calcium and
result of a parathyroid adenoma. calcitriol for a month. His calcium levels normalized two
months after surgery (Table 1). Meanwhile, corrective
Case osteotomy is currently being contemplated by the pediatric
orthopedic surgery team.
A 15-year-old boy presented in October 2018 with bilateral
knock-knee for two years. He had an uneventful antenatal Discussion
history and normal developmental milestones. He did not
have any knee pain, swelling or stiffness. He had no history Our adolescent patient presented with bilateral genu
of injury, fracture or infection to his knees or legs. None valgum as a result of excessive parathyroid hormone
of his family members had disorders related to multiple secretion from a parathyroid adenoma. His age at
endocrine neoplasia type 1 (MEN 1) or type 2A (MEN 2A), presentation corresponds to those with a similar deformity
hyperparathyroidism-jaw tumor (HPT-JT) syndrome or described in literature (Table 2). Majority of reported cases
familial isolated hyperparathyroidism (FIHPT). presented during the adolescent period—between 11 to 17
________________________________________
ISSN 0857-1074 (Print) | eISSN 2308-118x (Online) Corresponding author: Siow Ping Lee, MD
Printed in the Philippines Physician and Endocrine Fellow
Copyright © 2020 by Lee et al. Endocrine Unit, Department of Medicine
Received: July 20, 2020. Accepted: September 21, 2020. Hospital Sultanah Aminah, Jalan Persiaran Abu Bakar Sultan
Published online first: November 29, 2020. 80100 Johor Bahru, Johor, Malaysia
https://doi.org/10.15605/jafes.035.02.07 Tel. No.: +6072257000
Fax No.: +6072242694

Bilateral Genu Valgum in an Adolescent with Primary Hyperparathyroidism Siow Ping Lee, et al 221
Table 1. Preoperative and postoperative biochemical profile

Two months Six months
Preoperation Reference
Parameters post-operation post-operation
(October 2018) range
(February 2019) (June 2019)
Corrrected calcium, mmol/L 2.97 2.14 2.13 2.10-2.55
Phosphate, mmol/L 1.03 1.64 1.3 1.45-2.10
Alkaline phosphatase, U/L 1354 560 377 116-468
Intact PTHa, pmol/L 154 – – 1.5-7.6
Creatinine, µmol/L 33 55 – 50-77
a
PTH, parathyroid hormone
Table 2. Primary hyperparathyroidism presenting as genu valgum: A summary of case reports and case series from
published literature
Publication Year Age, yr Gender End-organ damage Etiology Outcome after parathyroidectomy
McClure RD et al6 1945 14 Female Skeletal abnormalities Left inferior parathyroid adenoma Biochemical normalization and
spontaneous correction of genu valgum
Balch HE et al3 1953 21 Female Skeletal abnormalities Left inferior parathyroid adenoma Hungry bone syndrome in immediate
post-operative period, followed
by biochemical normalization and
recalcification of demineralized bones
Lloyd HM et al7 1965 14 Male Skeletal abnormalities Left inferior parathyroid adenoma Biochemical normalization and skeletal
improvement
Rapaport D et al4 1986 15 Female Skeletal abnormalities, Right inferior parathyroid adenoma Clinical and biochemical resolution
nephrolithiasis
15 Male Skeletal abnormalities, Right inferior parathyroid adenoma Clinical and biochemical resolution
nephrolithiasis
Kauffmann C et al8 1993 13 Female Skeletal abnormalities Left inferior parathyroid adenoma Biochemical normalization and
resolution of bone demineralization
Menon PS et al9 1994 14 Female Skeletal abnormalities, Left superior parathyroid adenoma Normalization of calcium and phosphate
nephrolithiasis
Harman CR et al10 1999 14 Female Skeletal abnormalities – –
Walczyk A et al11 2011 15 Male Skeletal abnormalities Right inferior parathyroid adenoma Biochemical resolution and improvement
of BMDa
Dutta D et al21 2013 12 Female Skeletal abnormalities Right inferior parathyroid adenoma Clinical and biochemical resolution
Ratnasingam J et al12 2013 15 Female Skeletal abnormalities Right parathyroid adenoma Biochemical resolution
Ramkumar S et al13 2014 16 Male Skeletal abnormalities Left inferior parathyroid adenoma Biochemical resolution
13 Male Skeletal abnormalities Right inferior parathyroid adenoma Biochemical resolution
Sharma S et al14 2016 15 Female Skeletal abnormalities Left inferior parathyroid adenoma Biochemical resolution
Zil-E-Ali A et al15 2016 14 Female Skeletal abnormalities Right inferior parathyroid adenoma Biochemical resolution
Arambewela MH et al16 2017 12 Female Skeletal abnormalities Right inferior parathyroid adenoma Resolution of primary
hyperparathyroidism
Kamath SP et al17 2018 11 Female Skeletal abnormalities Left superior parathyroid adenoma Normalization of iPTHb
12 Male Skeletal abnormalities, Left superior parathyroid adenoma Normalization of iPTHb
nephrolithiasis
Khan KA et al22 2019 17 Male Skeletal abnormalities Left inferior parathyroid adenoma Biochemical resolution
Paruk IM et al18 2019 17 Male Skeletal abnormalities Left inferior parathyroid adenoma Clinical and biochemical resolution
13 Male Skeletal abnormalities Right superior parathyroid adenoma Clinical and biochemical resolution
Rao KS et al19 2019 12 Female Skeletal abnormalities, Right inferior parathyroid adenoma Hungry bone syndrome in immediate
nephrolithiasis post-operative period, long term
outcome not reported
Yanrismet Y et al20 2019 13 Male Skeletal abnormalities Right inferior parathyroid adenoma Hungry bone syndrome in immediate
post-operative period, long term
outcome not reported
a
BMD, bone mineral density
b
iPTH, intact parathyroid hormone
years old— except for one who came for medical attention HPT-JT and FIHPT. Our patient most likely has sporadic
at the age of 21.3 Out of these 23 patients with PHPT who PHPT due to the absence of a family history of the
manifested either unilateral or bilateral genu valgum, 13 aforementioned disorders. Moreover, additional screening
were females. The underlying reason for the occurrence revealed a normal prolactin level and a normal pituitary
of such deformity in this particular age group remains gland on magnetic resonance imaging. Solitary parathyroid
unclear. It has been postulated that the direct effect of adenoma appears to be the etiology in all the reported cases,
elevated parathyroid hormone on the epiphyseal plate and including our patient (Table 2).
bone remodeling during the pubertal growth spurt could
be the main contributing factor.4 Our patient presented with isolated bilateral genu valgum
with no other symptoms attributable to hypercalcemia.
Primary hyperparathyroidism in children and adolescents This piece of information has to be taken with a pinch of
is caused by either parathyroid adenoma (solitary or salt because it is well-known that children and adolescents
multiple) or hyperplasia, which may be sporadic or with PHPT may have vague and non-specific symptoms
familial. Parathyroid carcinoma in this age group is rarely involving the gastrointestinal, renal, musculoskeletal and
reported.2 Familial causes encompass MEN 1 or MEN 2A, neurological systems.1,2 These non-specific complaints

222 Siow Ping Lee, et al Bilateral Genu Valgum in an Adolescent with Primary Hyperparathyroidism
may potentially be dismissed as trivial and hence fail to around specific joints, brown tumors, salt-and-pepper
raise the alarm unless a calcium level, which is often not radiologic appearance of the skull and osteopenia. It is
part of routine blood tests in children, is checked. As a noteworthy that three patients were initially treated as
consequence, delayed diagnosis of PHPT and end-organ vitamin D deficiency rickets before the final diagnosis of
damage at presentation are common in this age group. PHPT was made.20-22 In fact, genu valgum is one of the
known clinical features of nutritional rickets.23 In these
Interestingly, the lack of routine biochemical screening patients, the lack of clinical improvement and new onset
in children and adolescents may not exclusively justify of hypercalcemia coupled with persistent elevation of
the more severe presentations of PHPT in this juvenile parathyroid hormone following vitamin D repletion
population compared to their adult counterparts. This is eventually unveiled the diagnosis of PHPT. On a different
because symptomatic PHPT remains uncommon at the note, concomitant nephrolithiasis seems infrequent, as only
fourth and fifth decades of life, as it is detected mainly four out of twenty-three total cases in literature exhibited
by routine biochemical tests.1 The question of whether the said complication.4,9,17
juvenile PHPT and adult PHPT represent two separate
entities remains unanswered. A meta-analysis of 16 Parathyroidectomy is the mainstay of treatment in children
studies that included 268 juvenile and 2,405 adult patients with PHPT.1 Treatment goals include immediate and
with PHPT demonstrated that the former had greater permanent cure of excessive calcium and parathyroid
hypercalcemia and hypercalciuria, despite similar serum hormone secretion, mitigation of symptoms as well
iPTH levels. Decreased parathyroid adenoma sensitivity to as reversal of end-organ damage.2 All reported cases
negative feedback by calcium and increased target tissue including ours underwent successful parathyroidectomy.
responsiveness to the effects of parathyroid hormone in Hungry bone syndrome during the immediate post-
juvenile PHPT were suggested to be the key differences operative period, which constituted a significant risk in this
between these two age groups, providing the basis for age group due to the greater disease severity, was reported
future research.5 in a handful of cases.3,19,20 Long-term outcomes post-
parathyroidectomy are favorable as evidenced by clinical
In addition to genu valgum, most patients reported in and/or biochemical resolution in majority of patients. Our
literature also manifested with other radiologic changes patient’s calcium levels remained within normal range
typical of primary hyperparathyroidism.3,6-20 These six months after surgery without any calcium or vitamin
include subperiosteal bone resorption especially over D supplement (Table 1). However, he will still require
the phalanges, acro-osteolysis, subchondral resorption osteotomy to correct his bilateral genu valgum.
A B
Figure 1. Clinical (A) and radiologic (B) evidence of bilateral genu valgum.

Bilateral Genu Valgum in an Adolescent with Primary Hyperparathyroidism Siow Ping Lee, et al 223
In conclusion, primary hyperparathyroidism in children 9. Menon PS, Madhavi N, Mukhopadhyaya S, Padhy AK, Bal CS, Sharma
LK. Primary hyperparathyroidism in a 14 year old girl presenting
and adolescents is rare and often diagnosed late, with genu
with bone deformities. J Paediatr Child Health. 1994;30(5):441-3.
valgum being an unusual manifestation of this disorder. PMID: 7833084. https://doi.org/10.1111/j.1440-1754.1994.tb00698.x.
Nevertheless, a high index of suspicion is warranted, as 10. Harman CR, van Heerden JA, Farley DR, Grant CS, Thompson GB,
prompt parathyroidectomy may lead to cure and reversal Curlee K. Sporadic primary hyperparathyroidism in young patients:
A separate entity? Arch Surg. 1999;134(6): 651-5. PMID: 10367876.
of debilitating complications. https://doi.org/10.1001/archsurg.134.6.651.
11. Walczyk A, Szalecki M, Kowalska A. Primary hyperparathyroidism:
Acknowledgment A rare endocrinopathy in children. Two case reports. Endokrynol
The authors would like to thank the Director General of Health Pol. 2011;62(4):346-50. PMID: 21879476.
Malaysia for the permission to publish this case report. 12. Ratnasingam J, Tan ATB, Vethakkan SR, et al. Primary
hyperparathyroidism: A rare cause of genu valgus in adolescence.
J Clin Endocrinol Metab. 2013;98(3):869-70. PMID: 23337722.
Ethical Consideration https://doi.org/10.1210/jc.2012-3839.
Patient consent was obtained before submission of the manuscript. 13. Ramkumar S, Kandasamy D, Vijay MK, Tripathi M, Jyotsna VP. Genu
valgum and primary hyperparathyroidism in children. Int J Case
Statement of Authorship Rep Images. 2014;5(6):401-7. https://doi:10.5348/ijcri-201455-CS-10041.
14. Sharma S, Kumar S. Bilateral genu valgum: An unusual presentation
All authors certified fulfillment of ICMJE authorship criteria.
of juvenile primary hyperparathyroidism. Oxf Med Case Reports.
Author Disclosure org/10.1093/omcr/omw023.
All authors declared no conflicts of interest. 15. Zil-E-Ali A, Latif A, Rashid A, Malik A, Khan HA. Presentation of
parathyroid adenoma with genu valgum and thoracic deformities.
Funding Source J Pak Med Assoc. 2016;66(1):101-3. PMID: 26712192.
16. Arambewela MH, Liyanarachchi KD, Somasundaram NP, Pallewatte
None.
AS, Punchihewa GL. Case report: Rare skeletal manifestations in
a child with primary hyperparathyroidism. BMC Endocr Disord.
References 2017;17(1):45. PMID: 28732535. PMCID: PMC5521059. https://doi.
1. Roizen J, Levine MA. Primary hyperparathyroidism in children and org/10.1186/s12902-017-0197-z.
adolescents. J Chin Med Assoc. 2012;75(9):425-34. PMID: 22989537. 17. Kamath SP, Shenoy J, Kini KP, Shetty KB, Pai KA. Primary
PMCID: PMC3710287. https://doi.org/10.1016/j.jcma.2012.06.012. hyperparathyroidism presenting as bilateral genu valgum. Int J Health
2. Alagaratnam S, Kurzawinski TR. Aetiology, diagnosis and surgical Allied Sci. 2018;7(2):114-6. https://doi.org/10.4103/ijhas.IJHAS_69_1.
treatment of primary hyperparathyroidism in children: New 18. Paruk IM, Pirie FJ, Motala AA. Rickets mimicker: A report of two cases
trends. Horm Res Paediatr. 2015. PMID: 25966652. https://doi.org/ of primary hyperparathyroidism in adolescence. J Endocrinol Metab
10.1159/000381622. Diabetes S Afr. 2019; 24(1):23-7. https://doi.org/10.1080/16089677.
3. Balch HE, Spiegel EH, Upton AL, Kinsell LW. Hyperparathyroidism: 2018.1546365.
Report of 2 cases with some relatively unusual manifestations. J Clin 19. Rao KS, Agarwal P, Reddy J. Parathyroid adenoma presenting as genu
Endocrinol Metab. 1953;13(6):733-8. PMID: 13061594. https://doi.org/ valgum in a child: A rare case report. Int J Surg Case Rep. 2019;59:27-
10.1210/jcem-13-6-733. 30. PMID: 31102836. PMCID: PMC6525286. https://doi.org/10.1016/
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hyperparathyroidism in children. J Pediatr Surg. 1986;21(5):395-7. 20. Yanrismet Y, Tridjaja B. Genu valgum as a rare clinical manifestation
PMID: 3712190. https://doi.org/10.1016/s0022-3468(86)80505-x. in child with primary hyperparathyroidism: A case report. Arch Dis
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of primary hyperparathyroidism in youths to the biochemistry of 2019-epa.646.
primary hyperparathyroidism in adults. J Clin Endocrinol Metab. 21. Dutta D, Kumar M, Das RN, et al. Primary hyperparathyroidism
2014;99(12):4555-64. PMID: 25181388. PMCID: PMC4255125. https:// masquerading as rickets: Diagnostic challenge and treatment
doi.org/10.1210/jc.2014-2268. outcomes. J Clin Res Pediatr Endocrinol. 2013;5(4):266-9. PMID:
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7. Lloyd HM, Aitken RE, Ferrier TM. Primary hyperparathyroidism 23. Misra M, Pacaud D, Petryk A, Collett-Solberg PF, Kappy M, Drug and
resembling rickets of late onset. Brit Med J. 1965;2(5466):853-6. PMID: Therapeutics Committee of the Lawson Wilkins Pediatric Endocrine
5827800. PMCID: PMC1846345. https://doi.org/10.1136/bmj.2.5466.853. Society. Vitamin D deficiency in children and its management:
8. Kauffmann C, Leroy B, Sinnassamy P, Carlioz H, Gruner M, Review of current knowledge and recommendations. Pediatrics.
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[Article in French]. PMID: 8060206.

Case Series
Journal of the
ASEAN Federation of
Endocrine Societies
Agoitrous Graves’ Hyperthyroidism with Markedly Elevated Thyroid

Stimulating Immunoglobulin Titre displaying Rapid Response
to Carbimazole with Discordant Thyroid Function
Yin Chian Kon,1 Brenda Su Ping Lim,1 Yingshan Lee,1 Swee Eng Aw,2 Yoko Kin Yoke Wong3
1
Department of Endocrinology, Tan Tock Seng Hospital, Singapore
2
Department of Nuclear Medicine and Molecular Imaging, Singapore General Hospital, Singapore
3
Department of Epidemiology, Singapore Clinical Research Institute, Singapore
Abstract
We characterize the clinical and laboratory characteristics of 5 patients with Graves’ thyrotoxicosis whose serum free
thyroxine (fT4) concentration decreased unexpectedly to low levels on conventional doses of carbimazole (CMZ)
therapy. The initial fT4 mean was 40.0 pM, range 25-69 pM. Thyroid volume by ultrasound measured as mean 11 ml,
range 9.0-15.6 ml. Initial TSI levels measured 1487% to >4444%. Serum fT4 fell to low-normal or hypothyroid levels
within 3.6 to 9.3 weeks of initiating CMZ 5 to 15 mg daily, and subsequently modulated by fine dosage adjustments.
In one patient, serum fT4 fluctuated in a “yo-yo” pattern. There also emerged a pattern of low normal/low serum fT4
levels associated with discordant low/mid normal serum TSH levels respectively, at normal serum fT3 levels. The long-
term daily-averaged CMZ maintenance dose ranged from 0.7 mg to 3.2 mg. Patients with newly diagnosed Graves'
hyperthyroidism who have small thyroid glands and markedly elevated TSI titres appear to be “ATD dose sensitive.” Their
TFT on ATD therapy may display a “central hypothyroid” pattern. We suggest finer CMZ dose titration at closer follow-up
intervals to achieve biochemical euthyroidism.
Key words: Graves' disease, Thyroid Stimulating Immunoglobulin, responsiveness, carbimazole
INTRODUCTION elevated TRAb titre. Intriguingly, he also demonstrated a

discordant profile of suppressed serum TSH level despite
In patients with newly diagnosed Graves’ hyperthyroidism concomitantly low serum fT4 and low to normal serum fT3
started on anti-thyroid drugs (ATDs), various factors concentrations during the course of ATD treatment.3 A low
affect the rate of decrease of serum free thyroxine (fT4) serum fT4 may prompt the clinician to stop ATD therapy,
concentrations. Current guidelines recommend the initial which leads to rebound thyrotoxicosis. We report the
starting dose of ATD to be based on a number of factors, biochemical and clinical features of a further 5 patients with
such as initial serum fT4 concentration, thyroid gland rapid response to ATD. Early recognition of this phenotype
size and triiodothyronine (T3) levels.1 In a retrospective can help to avoid swings between hypothyroidism and
multivariate analysis by Choi et al., of 99 patients with hyperthyroidism upon commencing and after adjusting
new onset Graves’ disease, high level of fT4, high thyroid ATD therapy.
stimulating hormone receptor antibody (TRAb) titre and
absence of goiter were associated with rapid responsiveness CASES
to methimazole treatment.2 In their entire cohort, most
patients showed normalization of free thyroxine within Patients
about 2 months, regardless of the initial free thyroxine level. We describe 5 patients referred for management of Graves’
hyperthyroidism from July 2008 to March 2017 at the
Dalan et al., had previously reported on a male patient Department of Endocrinology, Tan Tock Seng Hospital,
with newly diagnosed agoitrous Graves’ hyperthyroidism Singapore, who developed hypothyroxinemia after
who unexpectedly developed severe hypothyroxinemia starting oral carbimazole (CMZ). This case series has been
within 3 weeks of starting anti-thyroid treatment, and approved for publication by our institutional review board
rapidly rebounded back to hyperthyroidism within one (DSRB Ref 2014/00896). Serum TRAb, thyroid stimulating
week of ATD discontinuation.3 He demonstrated a highly immunoglobulin (TSI), TSH, fT4 and fT3 concentrations,
________________________________________
ISSN 0857-1074 (Print) | eISSN 2308-118x (Online) Corresponding author: Yin Chian Kon, BSc (London), MBBS (London), MRCP
Printed in the Philippines (UK), FAMS (Endocrinology)
Copyright © 2020 by Kon et al. Senior Consultant, Department of Endocrinology, Tan Tock Seng Hospital
Received: September 24, 2020. Accepted: November 12, 2020. 11 Jalan Tan Tock Seng, Singapore, 308433
Published online first: November 19, 2020. Tel. No.: 65-81263173
https://doi.org/10.15605/jafes.035.02.13 Fax No.: 65-63573087
* This paper had previously been presented at 37th Annual Meeting of the Endocrine Society of Taiwan, Taipei, Taiwan, on 20 March 2016 and in the 12th Asia and
Oceania Thyroid Association (AOTA) Congress, Busan, Korea, on 17 March 2017.

Agoitrous Graves’ Hyperthyroidism responsiveness to Carbimazole Yin Chian Kon, et al 225
random spot urine iodine-creatinine ratio and thyroid spectrometry (Elan Dynamic Reaction Cell II; Perkin
size by ultrasound imaging, performed by our hospital Elmer) in standard mode using tellurium (Te) as an
radiology service, were measured. The volume of the internal standard. Urine (60 µL) was first diluted 1:25 in
thyroid gland was calculated as the sum of right and left diluent (50 mcg/L Te and 10 mcg/L Rh in 1 % tetramethyl-
thyroid lobes using ellipsoid formula 0.479 x length x ammonium hydroxide) and then quantified using an
depth x width. Low echogenicity in the thyroid gland was aqueous acidic calibration. The analytical measuring range
classified into 4 categories as previously described: Grade was 10-40,000 mcg/L. Urine creatinine was measured
0, diffuse high-amplitude echoes throughout the whole using Roche assay, based on the enzymatic conversion
thyroid lobe; Grade 1, low-amplitude non-uniform echoes of creatinine by creatininase, creatinase, and sarcosine
in the whole or several regions of the thyroid; Grade 2, oxidase to glycine, formaldehyde and hydrogen peroxide.
several sonolucent regions in the thyroid; and Grade 3, no Catalyzed by peroxidase, the liberated hydrogen peroxide
apparent echoes or very low amplitude echoes throughout reacts with 4‑aminophenazone and HTIBa to form a
the whole thyroid.4 quinone imine chromogen. The colour intensity of the
quinone imine chromogen formed is directly proportional
Laboratory analysis to the creatinine concentration in the reaction mixture,
utilizing inductively coupled plasma mass spectrometry
Free thyroid hormones and TSH (ICP-MS) for iodine quantification in urine. This was
Serum free T4 and free T3 were measured by Access® normalized to urine creatinine, performed by enzymatic
Thyroid kit in a 2-step competitive immunoassay on a colorimetric assay (Roche).
Beckman CoulterTM automated platform. Serum TSH
was measured by Access® HYPERsensitive (3rd generation) Descriptive analysis
chemiluminescent sandwich immunoassay on a Beckman The baseline clinical characteristics and initial thyroid
Coulter automated platform. function response from all 5 patients are tabulated together
with the reference range of each test. When a serum result
TRAb Assay was expressed as greater or less than a numerical limit,
TRAb was measured using a third generation M22-biotin that value of limit was utilized. For each patient, thyroid
based ELISA commercial kit (Euroimmun TRAb Fast function (fT4, fT3, TSH), TRAb, TSI, anti-TPO Ab titre,
ELISA IgG) on the Triturus Analyser. Measurements were and CMZ dose were summarised graphically across the
performed according to the manufacturer's instructions. follow-up calendar time.
TBII is detected by inhibiting the binding of M22 to
immobilized recombinant human TSHR. The calibration RESULTS
is standardized against WHO 1995 Standard 90/672
(NIBSC 90/672). Patients presented with typical symptoms such as weight
loss, increased appetite, palpitations, heat intolerance,
Thyroid Stimulating Immunoglobulin (TSI) diarrhoea and tremors. Patients 1 and 4 presented with
The thyroid stimulating activity of TSH receptor antibodies complications of atrial fibrillation and thyrocardiac failure.
is measured by their ability to stimulate susceptible Baseline demographics, thyroid function, thyroid volume
cells to make thyroid adenylate cyclase (cAMP). The and echogenicity, starting CMZ dose and initial thyroid
immunoglobulin (Ig) fraction of patients’ sera is precipitated function response are shown in Table 1. In all 5 patients,
with a 20 % solution of polyethylene glycol (PEG). 120 CMZ was started at doses equivalent to, or below, the
µl of the reconstituted Ig fraction is then incubated with methimazole (MMI)-equivalent starting dose (CMZ 10
cloned JP-26 cells in a 96-well microtiter culture plate for mg equivalent to MMI 6 mg) suggested for the degree of
two hours at 37 oC in 5 % CO2/95 % air atmosphere, using fT4 elevation by the 2016 American Thyroid Association
hypotonic buffer. The supernatants are then collected Guidelines.1 The initial free thyroxine mean was 41.5 pM,
and assayed for cAMP contents in a radioimmunoassay. range 25-69 pM. The mean thyroid volume measured by
Results are expressed as percent increase in patient cAMP ultrasound was 11.2 ml, range 9.0-15.6 ml. All patients
production as compared to normal human serum (NHS) remained clinically agoitrous throughout the course of
cAMP production. The calculation formula for TSI results follow-up. The range of initial TSI was 1487 % to >4444
are expressed as %: (Patient’s cAMP / NHS’s cAMP) x 100 %. Serum fT4 plunged to low-normal or hypothyroid
% (Reference range of TSI=50 % to 179 %; >179 % indicate levels within 3.6 to 9.3 weeks of initiating oral CMZ 5 to
stimulating). Each sample is performed in duplicate and 15 mg daily and were subsequently modulated by fine
the results averaged. The estimated inter-assay coefficient adjustments in CMZ dosage.
of variation (CV) of the TSI assay is 10 % to 20 %.
Our 5 patients’ follow-up ranged from 14.7 months to 121.7
Thyroid Peroxidase Antibody months (mean of 66.27 months, SD of 39.3 months). Their
TPO Ab was measured using the commercial kit long-term biochemical course in response to CMZ treatment
(ORGENTEC Diagnostika GmbH ELISA IgG) on the Triturus are shown in Figures 1-5. In all instances, the date of the
Analyser. Measurements were performed according to the dispensation of CMZ was verified to be the same as the date
manufacturer's instructions. The calibration is standardized of prescription, suggesting patient compliance to therapy.
against the international reference preparation WHO In patients #1 and #2, whilst on ATD treatment, serum TSH
MRC66/387 for anti-TPO antibodies as 1000 IU/ml. was seen to remain inappropriately suppressed despite fT4
decreasing to and remaining at low normal concentrations,
Urine Iodine-Creatinine Ratio (UICR) whilst fT3 levels remained normal (Figures 1-2). In patient
Specimens were sent to Mayo Laboratories. Urine iodine #2, TSH was seen to be restored to within the lower half
was analysed using inductively coupled plasma mass of reference range (its suppression was overcome) at

226 Yin Chian Kon, et al Agoitrous Graves’ Hyperthyroidism responsiveness to Carbimazole
Table 1. Baseline Clinical Characteristics and Initial Thyroid Function Response After Starting Oral Carbimazole (CMZ)
Time from Random
USS Hypoecho- Initial
Ethnicity, Initial Initial Initial Initial Starting Next Next Urine
Patient Thyroid genicity CMZ Next TSH
Age/Gender fT4 TSH TRabT TSI CMZ to fT4 fT3 Iodine/
volume Gradea dose
Next TFT Cr Ratio
(yrs) (cm3) (pM) (mIU/L) (IU/L) (%) (mg/d) (weeks) (pM) (pM) (mIU/L) (mcg/g)
1 Chinese / 56 / F 14.3 1 69 0.03 5.4 1487 15 9.3 6 3.7 0.02 167
2 Chinese / 81 / F 9.1 1 28 <0.01 >40.0 >4444 5 9.0 8 3.7 0.01 192
3 Chinese / 55 / F 7.2 1 49 0.02 >30.0 >4444 15 4.0 5 3.8 0.02 -
4 Chinese / 72 / M 15.6 1 25 0.06 34.3 >4000 10 3.6 6 4.6 0.06 145
5 Chinese / 82 / M 9.0 0 29 0.05 31.2 3160 10 5.3 6 3.8 0.18 108
Expected range < 15 8-21 0.34-5.64 <0.4 80-179 8-21 3.5-6.0 0.34-5.64 26-705
a
Grade 0, diffuse high-amplitude echoes throughout the whole thyroid lobe; Grade 1, low-amplitude non-uniform echoes in the whole or several regions of
the thyroid; Grade 2, several sonolucent regions in the thyroid; and Grade 3, no apparent echoes or very low amplitude echoes throughout the whole thyroid.
Figure 1. Patient 1 clinical course (A) thyroid function; (B) serum TSH receptor antibody (TRAb) and thyroid stimulating
immunoglobulin (TSI) levels; (C) carbimazole (CMZ) therapy-average daily dose. From 22.3.12-25.5.12 (9.4 weeks), serum
TSH remained inappropriately suppressed or inappropriately normal in the presence of low serum fT4.

immunoglobulin (TSI) levels; (C) carbimazole (CMZ) therapy-average daily dose. Between 24.10.08 and 8.10.09, fT4
showed a “yo-yo” pattern with small dose adjustments of CMZ. Between 25.11.10 and 30.06.15, TFT showed “central
hypothyroid” pattern.
concomitant fT4 values that were below normal (Figure 2). All our patients preferred and were maintained on
These patterns resembled “central hypothyroid” patterns. prolonged low dose CMZ, in averaged daily doses ranging
As all patients were non-pregnant, dose of CMZ was from 0.7 mg to 3.2 mg. Remarkably, in the long-term,
adjusted to keep serum fT3 mid-normal as the first priority. patient #2 required the lowest dose of only CMZ 2.5 mg

immunoglobulin (TSI) levels; (C) carbimazole (CMZ) therapy-average daily dose. Patient received block and replace, followed
by CMZ only therapy. Although TRAb levels demonstrated a downtrend, paired TSI activity remained discordantly elevated.
twice per week (averaged to 0.7 mg daily) to maintain DISCUSSION

euthyroidism, despite having persistently elevated TSI
levels at 24 times above upper limit of normal (Figure 2). We present 5 patients with newly diagnosed Graves' hyper-
thyroidism whose serum fT4 plunged to unexpectedly

Figure 4. Patient 4 clinical course (A) thyroid function, serum TSH receptor antibody (TRAb) and thyroid stimulating
immunoglobulin (TSI) levels; (B) carbimazole (CMZ) therapy-average daily dose. On 7 weeks of CMZ 10 mg od, patient
became primary hypothyroid. CMZ was stopped for 1 week, then resumed on 2.5 mg daily to avoid rebound thyrotoxicosis.
Figure 5. Patient 5 thyroid function course in response to carbimazole (CMZ) therapy. On CMZ 10 mg od for 3.6 weeks,
patient became hypothyroxinemic; CMZ was not stopped but decreased to 2.5 mg daily, to avoid rebound thyrotoxicosis.
low levels after commencing CMZ at doses equivalent to, elevated TRAb and TSI levels around the time of diagnosis.
or below, that suggested for the degree of fT4 elevation by In a retrospective multivariate analysis by Choi et al.,
the 2016 American Thyroid Association Guidelines.1 All 5 of 99 patients with new onset Graves’ disease, high level
patients demonstrated absence of goiter with remarkably of fT4, high titre of TRAb and absence of goiter were

associated with rapid responsiveness to methimazole serum T4 and low-normal serum T3 levels. Remarkably,
treatment.2 Their study, together with our case series, 2 of these patients had non-elevated serum TSH levels.
suggest that Graves’ patients presenting with normal-sized
thyroid glands and markedly elevated TSI levels predict ATD may reversibly or irreversibly inhibit thyroid
a “rapid responder” phenotype to conventional doses of peroxidase (TPO) catalyzed iodination, depending on
ATD. Moreover, we observed the perplexing profile of the relative intra-thyroidal concentrations of iodine and
prolonged suppressed, or inappropriately normal, TSH ATD.11-13 At low intrathyroidal iodine level, iodination
despite concomitantly low-normal or low serum fT4 during inhibition by ATD is irreversible, but an increase in iodine
the course of ATD treatment, when serum fT3 was low concentration competitively overcomes the inhibition. It
to normal. is considered that rapid responders with small thyroid
volume and thus small intrathyroidal iodine pool
Dalan et al., reported on an agoitrous Graves’ patient require a markedly elevated TSI level and a fast iodine
with markedly elevated TRAb who rapidly became turnover rate to maintain elevated thyroid hormone
hypothyroxinemic 2 weeks after being treated with a levels. The high iodine turnover in turn, contributes to the
conventional dose of CMZ (Appendix A, reproduced with small iodine pool.
permission).3 Presence of thyroid stimulating blocking
antibody (TSBAb) was excluded. After CMZ therapy When relatively high doses of ATD are started, the intra-
was discontinued for a week, a thyroid uptake scan thyroidal ATD to iodide concentration ratio is increased,
demonstrated 63% uptake at 4 hours, and 42% uptake at almost complete blockage of iodide organification ensues,
24 hours, with 24-hr minus 4-hr delta RAIU of -21%, or leading to a rapid decrease in serum fT4 relative to serum
remarkably high iodine turnover. fT3. Intriguingly, Taurog observed from his animal
experiments, that "the change from reversible to irreversible
Similarly, Gemma et al., reported that the difference inhibition of iodination with both propylthiouracil and
between 3-hour and 24-hour RAIU predicted rapidity methimazole occurred with seemingly slight elevations
of response to MMI therapy in Graves’ patients.5 They in the concentrations of these drugs."12 Perhaps this
found that 24-hr minus 3-hr delta RAIU was significantly relates clinically to the marked swing in fT4 levels with
lower in rapid responders (TFT was normal or low within slight changes in ATD dose, seen initially for example, in
1 month) than gradual responders. Delta RAIU was patient 2 (Figure 2).
negatively correlated with the reduction in serum fT4 level
at two weeks after MMI initiation and positively correlated Azizi reported that Graves’ hyperthyroidism responds
with the biological half-life of intrathyroidal iodine. more rapidly to MMI in an iodine-deficient area (Teheran)
compared with in an iodine-sufficient area (Boston), where
TSH and TSI drive thyroidal iodine turnover. In 1944, urinary iodine/creatinine ratio above 50 g/g represented
Astwood and Bissell demonstrated that when normal rats iodine-sufficiency.14 In a subsequent study he reported
were administered blocking doses of propylthiouracil that less than the usual recommended doses of MMI or
(PTU) that rendered them hypothyroid, severe thyroidal PTU caused a rapid decline of thyroid hormone indices
iodine depletion occurred within days despite adequate in patients residing in Teheran.15 In opposite contrast,
iodine intake.6 Upon discontinuing ATD, the thyroid patients with type 1 amiodarone-induced thyrotoxicosis
gland’s ability to re-accumulate iodine after it had been may require higher than usual doses of ATD, because of
depleted was suppressed by thyroxine treatment or the drug-derived iodine load.
hypophysectomy, presumably by preventing rise of TSH.
When hypophesectomy was performed before PTU was All four of our patients in whom we performed random
given, or if thyroxine was concomitantly administered urine iodine/creatine ratio had values above 100 µg/g
with PTU, thyroidal iodine loss was prevented or amelio- (Mayo Lab lower reference value 70 µg/g), suggesting
rated in a graded manner.6 It is now well established that that the rapid-responder phenotype may also occur in the
elevated serum TSH or TSI increases thyroidal iodide presence of adequate iodine intake, when small thyroid
uptake, increases T3 formation relative to that of T4, and and markedly elevated TSI titre are concomitantly present.
leads to increased iodine turnover via its return to the
circulation as thyroid hormone, with relatively more T3 Besides driving high thyroidal iodine turnover, it is
than T4 secreted compared to normal.7-9 Hence a high speculated that a high TRAb level may downregulate
serum TSI level may be regarded as a marker for increased pituitary TSH secretion by an ultra-short negative
iodine turnover. feedback loop by acting on the pituitary TSH receptor
(TSHR).16,17 The pituitary TSHR, expressed in the human
The intra-thyroidal iodine pool seen in untreated and anterior pituitary on folliculo-stellate cells, lies outside
treated Graves’ thyroids are lower than those of normal the blood-brain barrier and is therefore accessible to these
thyroids.10,11 In 1975, Larsen compared the thyroidal autoantibodies.18 As the pituitary TSHR is also recognized
iodine content of 13 patients with Graves’ disease who by TSI, this interaction plausibly explains the prolonged
had undergone thyroidectomy to that of 11 normal human serum TSH suppression seen in patients with Graves’
thyroid glands.10 He found that the mean thyroidal iodine subclinical hyperthyroidism.19
content of 2 patients who had received only propranolol
(450 µg/g wet weight of thyroid tissue) was lower than In the course of follow-up, our patients demonstrated
normal (630±60 µg/g), but those who had received specific a discordant pattern of prolonged suppressed or low-
ATD treatment prior to surgery had the lowest levels. normal TSH with corresponding low-normal or low fT4
In particular, 3 of these patients were found to have levels. The concomitant fT3 levels were normal, hence
very low thyroidal iodine (100±26 µg/g) and markedly low the inappropriately low TSH is not due to T3-toxicosis.

Thus, persistent highly elevated serum TRAb levels References

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receptor antibody titres, and absence of goiter were associated
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8. Lauberg P, Vestergaard H, Nielsen S, et al. Sources of circulating
Our small case series together with Dalan’s case report 3,5,3’- triiodothyronine in hyperthyroidism estimated after blocking
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equivalent), they may become hypothyroxinemic in 4-6 Comparison of the acute changes during therapy with antithyroid
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PMC301541. https://doi.org/10.1172/JCI107744.
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serum fT4 are at hypothyroid levels, the period of ATD iodine content. J Clin Endocrinol Metab. 1975;41(06):1098-104. PMID:
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1-methyl-2-mercaptoimidazole in vitro and in vivo. Endocrinology.
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to accumulate experience and evidence. methimazole in patients with diffuse toxic goiter. J Clin Endocrinol
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jcem-61-2-374.
CONCLUSION 15. Azizi F. Medical treatment of toxic goiter in an area of iodine deficiency.
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16. Prummel MF, Brokken LJS, Wiersinga WM. Ultra-short-loop feedback
Patients with newly diagnosed Graves' hyperthyroidism
of thyrotropin secretion. Thyroid. 2004;14(10): 825-9. PMID: 15588378.
who have small thyroid glands and markedly elevated TSI https://doi.org/10.1089/thy.2004.14.825.
titres appear to be “ATD dose sensitive.” Free T4 may swing 17. Brokken LJ, Scheenhart JW, Wiersinga WM, Prummel MF. Suppression
markedly with small dose adjustments of ATD, or a “central of serum TSH by Graves’ Ig: Evidence for a functional pituitary
TSH receptor. J Clin Endocrinol Metab. 2001;86(10): 4814-7. PMID:
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finer ATD dose titration at closer follow-up intervals to 18. Prummel MF, Brokken LJ, Meduri G, Misrahi M, Bakker O, Wiersinga
achieve biochemical euthyroidism, guided by monitoring WM. Expression of the thyroid-stimulating hormone receptor in the
folliculo-stellate cells of the human anterior pituitary. J Clin Endocrinol
TFT, fT3 and TRAb or TSI. Metab. 2000;85(11):4347-53. PMID:11095478. https://doi.org/10.1210/
jcem.85.11.6991.
Ethical Considerations 19. Brokken LJS, Wiersinga WM, Prummel MF. Thyrotropin receptor
Ethics approval was obtained by the authors. autoantibodies are associated with continued thyrotropin suppression
in treated euthyroid Graves’ disease patients. J Clin Endocrinol
Metab. 2003;88:4135-8. https://doi.org/10.1210/jc.2003-030430.
20. Vagenakis AG, Braverman LE, Azizi F, Portnay GI, Ingbar SH. Recovery
All authors certified fulfillment of ICMJE authorship criteria. of pituitary thyrotrophic function after withdrawal of prolonged
thyroid-suppression therapy. N Engl J Med. 1975;293(14):681-4.
Author Disclosure PMID: 808728. https://doi.org/10.1056/NEJM197510022931402.
All authors declared no conflicts of interest. 21. Lauberg P. Remission of Graves’ disease during anti-thyroid drug
therapy. Time to reconsider the mechanism? Eur J Endocrinol.
2006;155(6):783-6. PMID: 17132745. https://doi.org/10.1530/eje.1.02295.
Funding Source
None.

APPENDICES
Appendix A. High-iodine-turnover Graves’ patient displaying (1) rapid response to low dose CMZ; (2) rapid rebound
thyrotoxicosis after stopping CMZ; (3) “central hypothyroid” TFT pattern.
Appendix B. Proposed Schematic of Small Thyroid-High TSI Rapid-Responder Graves’ Pathophysiology.

Case Series
Journal of the
ASEAN Federation of
Endocrine Societies
Legions of Presentations of Myxedema Coma:

A Case Series from a Tertiary Hospital in India
Nirmalya Roy,1 Anirban Majumder,2 Debmalya Sanyal,2 Soumyabrata Roy Chaudhuri,2
Suman Sarkar,1 Ankan Pathak1
1
Department of Internal Medicine, KPC Medical College and Hospital, West Bengal University of Health Sciences, Kolkata, India
2
Department of Endocrinology, KPC Medical College and Hospital, West Bengal University of Health Sciences, Kolkata, India
Abstract
Myxedema coma is associated with decreased mental status and hyponatremia among patients with diagnosed or
undiagnosed hypothyroidism. The diagnosis is challenging in the absence of universally accepted diagnostic criteria, but
should be considered as a differential even in cases with competing established diagnoses. All patients should receive
intensive care level treatment. Even with optimal treatment, mortality is very high.
Key words: myxedema coma, presentations, outcomes, case reports
INTRODUCTION Case 2
A 70-year-old male with a long-standing history of
Myxedema coma is a rare and potentially fatal condition. hypothyroidism following radio-iodine treatment for
Even with the best possible treatment, mortality remains Graves' disease was brought to the emergency room
very high.1 Untreated hypothyroidism due to any cause with progressively increasing sleepiness and altered
including autoimmune disease, iodine deficiency, sensorium. He did not reveal the history of radio-iodine
congenital abnormalities, drugs affecting thyroid function therapy. Investigations showed community acquired
or secondary hypothyroidism can result in myxedema pneumonia which was treated accordingly. Hyponatremia
coma. The crisis is usually triggered by stressful events, and subnormal thyroid function were detected later
the most common of which is infections. The incidence once the history of radio-iodine therapy was obtained.
of myxedema coma in India is not known, but several He recovered with thyroid hormone replacement and
case reports and case series have been published in recent conventional care.
years.2-6 In developing countries recognition of this entity
is made difficult by its slow onset, lack of awareness Case 3
among both patients and physicians, and absence of A 75-year-old female with known hypothyroidism, type
diagnostic facilities in remote areas. Due to its rarity, 2 diabetes, and hypertension presented in the emergency
physicians often fail to identify or keep it as a remote room with breathing difficulty and altered sensorium.
possibility while treating critically ill patients. This case She had hyponatremia and subnormal thyroid function.
series documents the myriad presentations of myxedema Investigations revealed the presence of heart failure with
coma encountered in tertiary practice and encourages reduced ejection fraction. She was treated with standard
physicians to keep it in mind as a possibility while treating care and with mechanical ventilatory support but
patients with altered sensorium. succumbed after a few days.
Cases Case 4
A 72-year-old female with known hypothyroidism
Case 1 presented in the emergency room with a history of bilateral
A 75-year-old female with a history of recurrent lower limb swelling, facial puffiness and progressive
hospitalization for atrial fibrillation, heart failure, and unresponsiveness for four days. History from her
sepsis was brought to the emergency room with circulatory attendants suggested that she had a very irregular intake of
collapse. She had been on amiodarone therapy for a her thyroid medication. She was presumptively diagnosed
long period of time, and was never diagnosed as having as a case of myxedema coma and was treated with standard
hypothyroidism. Investigation revealed hyponatremia care before laboratory reports were made available. She
and subnormal thyroid function. She was treated with eventually succumbed on the next day.
conventional care including thyroid hormone and
mechanical ventilation support but succumbed after a
few days.
________________________________________
ISSN 0857-1074 (Print) | eISSN 2308-118x (Online) Corresponding author: Prof. Anirban Majumder, MBBS
Printed in the Philippines KPC Medical College and Hospital, West Bengal University of Health Sciences
Copyright © 2020 by Roy et al. 1F Raja S.C. Mullick Road, Jadavpur, Kolkata, India 700032
Received: June 22, 2020. Accepted: October 15, 2020. Tel. No.: 033-6621 1700
Published online first: November 29, 2020. Fax No.: 033-6621 1768
ORCiD: https://orcid.org//0000-001-6937-8675

234 Nirmalya Roy, et al Legions of Presentations of Myxedema Coma
Case 5 permanent pacemaker, was admitted with massive fluid

A 68-year-old male, chronic alcoholic but not known to overload. After the fourth session of sustained low-
be hypothyroid, presented in the emergency room with a efficiency dialysis (SLED), he became confused, agitated,
history of swelling of lower limbs and altered sensorium and stuporous. Investigations revealed hyponatremia,
for two days. He was presumptively diagnosed as a case subnormal thyroid function, and bilateral pleural effusion.
of hepatic encephalopathy and was treated accordingly. He was treated with standard myxedema crisis care and
Investigations revealed hyponatremia and subnormal with bi-level positive airway pressure support in the
thyroid function. Myxoedema coma management intensive care unit (ICU) and recovered in five days.
was started three days after his hospitalization but he
succumbed after a few days. Case 10
A 66-year-old female with no current levothyroxine
Case 6 treatment was admitted to the ICU for myocardial
An 83-year-old female, known hypertensive and infarction along with coma and bradycardia. Her core
hypothyroid, with a fractured femur operated one week body temperature was documented at 88°F. She had severe
earlier, became progressively drowsy over the past three hyponatremia and urosepsis. She required mechanical
days. Herpes zoster -related blisters on the left side of the ventilation but did not survive.
neck was noted. Investigations revealed hyponatremia
with subnormal thyroid function. She developed multi- Case 11
organ failure and did not survive despite standard care and A 71-year-old female not known to be hypothyroid was
mechanical ventilatory support. admitted to the ICU for myocardial infarction along
with stupor and bradycardia. The core temperature was
Case 7 documented to be 90°F. Aside from severe hyponatremia,
A 50-year-old male, known hypothyroid and chronic she was also found to have urosepsis. She required
alcoholic, was brought to the emergency room with mechanical ventilation but did not survive.
inappropriate behavior. He was observed to be aggressive
and impulsive. He was presumptively diagnosed and The case records of 11 patients with the diagnosis of
treated as a case of alcohol intoxication but did not improve. myxedema coma between 1st January 2015 and 31st
Investigations on the next day revealed hyponatremia, December 2019 admitted to our tertiary care hospital
subnormal thyroid function, pericardial effusion and were reviewed (Table 1). Patients with poor clinical and/
community acquired pneumonia. He recovered with or biochemical documentation were excluded from our
conventional care. study population. There are review articles and scoring
systems to aid diagnosis, but these have limited sensitivity.7
Case 8 Myxedema coma is best recognized by the clinician when
An 80-year-old female with known hypothyroidism, there is a high index of suspicion. The diagnosis in the case
diabetes, and hypertension presented in the emergency series was done clinically by the treating physicians. Data
room with abnormal mentation. She had a pale puffy regarding age, sex, date of hospitalization, precipitating
face with very slow mentation. Investigations revealed events, clinical presentation (central nervous system
hyponatremia, anemia, subnormal thyroid function with symptoms, heart rate, blood pressure, temperature),
mildly elevated TSH and a huge pericardial effusion. biochemical findings at presentation [free thyroxine (FT4),
She recovered with standard care for myxedema coma. thyroid-stimulating hormone (TSH), random serum
cortisol, serum sodium], management strategy (use of
Case 9 mechanical ventilation or noninvasive ventilation) and
A 92-year-old male, known to have hypertension, outcomes were retrieved from the documentation in the
hypothyroidism, chronic kidney disease and with a archival department of the hospital (Table 2).
Table 1. Presentations of myxedema coma cases

Identifier Age, yr Sex Season Background Precipitating event CNSa symptoms HRb BPc Temperature (°F)
Case 1 75 F December Not known hypothyroid Amiodarone Coma 118 90/60 98.4
Case 2 70 M October Known hypothyroid Pneumonia Yes 58 100/60 98.7
Case 3 70 F November Known hypothyroid, T2DMd and HTNe Heart failure Yes 58 140/80 97.2
Case 4 72 F November Known hypothyroid Stopped LT4f Yes 60 100/60 96.7
Case 5 68 M December Not known hypothyroid and known Hepatic Coma 95 110/60 95.9
alcoholic encephalopathy
Case 6 83 F September Known hypothyroid Herpes zoster Coma 56 100/60 96
Case 7 50 M December Known hypothyroid and alcoholic Pneumonia Yes 50 110/70 97.4
Case 8 80 F August Known hypothyroid, T2DMd and HTNe Anaemia Yes 56 150/90 97
Case 9 92 M November Known hypothyroid, T2DMd and HTNe SLEDg Yes 78 160/80 97
Case 10 66 F November Known hypothyroid and stopped LT4f MIh Coma 58 90/60 88
Case 11 71 F October Not known hypothyroid Urosepsis Yes 52 80/58 90
a
CNS, central nervous system
b
HR, heart rate
c
BP, blood pressure
d
T2DM, type 2 diabetes mellitus
e
HTN, hypertension
f
LT4, levothyroxine
g
SLED, sustained low-efficiency dialysis
h
MI, myocardial infarction

Legions of Presentations of Myxedema Coma Nirmalya Roy, et al 235
Table 2. Laboratory findings and outcome of myxedema coma cases

FT4a, TSHb, Random serum Serum Nad, Use of mechanical Use of non-invasive
Identifier Outcome
ng/dL mIU/L cortisolc, µg/dL mEq/L ventilation ventilation
Case 1 0.7 77.3 Not done 122 Yes No Expired
Case 2 0.56 37.7 12.7 117 No No Recovered
Case 3 0.7 77.32 Not done 133 Yes No Expired
Case 4 0.26 >100 Not done 116 No No Expired
Case 5 0.26 >150 12 124 No No Expired
Case 6 0.46 113 14 124 Yes No Expired
Case 9 0.24 31.22 17 122 No Yes Recovered
a
FT4, free thyroxine; reference range 0.8-1.8 ng/dL
b
TSH, thyroid stimulating hormone; reference range 0.5-5.0 mIU/L
c
Random serum cortisol reference range 10-20 µg/dL
d
Serum Na reference range 135-145 mEq/L
Most of our patients were women (7 out of 11) and elderly Discussion
(all above age 65 years except Case 7). Myxedema coma
mostly develops in the winter months in patients with a The diagnosis of myxedema coma is based on history
history of thyroid disorders and a precipitating illness.1 (especially with an identified precipitating event),
Although Eastern India is not very cold during winter physical findings (specifically hypothermia, hypotension,
(average temperature of 12 to 26°C), most of our patients bradycardia, and hypoventilation), deteriorating mental
presented early in the season (between September to status and laboratory abnormalities.8 No single diagnostic
December) and surprisingly not during the peak month test can confirm or exclude the diagnosis. In suspected
(January). The presentation in India may be more common cases, a random blood sample should be drawn prior to
in winter months but can also occur at other times of the treatment for the measurement of TSH, FT4 and serum
year.1 All but three (Cases 1, 5 and 11) had no previous cortisol. Laboratory results showed low FT4 and elevated
history of thyroid disorders, posing a diagnostic challenge TSH in all the cases. The TSH value was not significantly
for the treating physicians. A significant number of high in one case (Case 8), and the low FT4 value raises
patients with myxedema coma may not have had a the possibility of secondary hypothyroidism.
previous history of thyroid disorders.1,2 Patients tend to
forget their history of treatment for thyroid disorders Myxedema coma is the final stage of severe long-standing
(radio-iodine therapy or surgery) carried out many years hypothyroidism, associated with marked impairment
earlier. This can lead to a delay in diagnosis and loss of of central nervous system function, cardiovascular
precious time as illustrated in Case 2. All but one (Case decompensation and high mortality rate, mostly seen in
4) had a precipitating event. Sepsis or infection was the the elderly during the winter months.9 Clinically there
most common precipitating factor in our cohort as shown is subnormal temperature as low as 23°C, bradycardia,
in other studies.2 Myxedema crisis may also be caused by hypotension, delay in deep tendon reflexes, seizures and
discontinuation of thyroid supplementation as observed in coma. In the background of untreated hypothyroidism,
Cases 4 and 10.1 The term myxedema coma is a misnomer myxedema coma is induced by exposure to cold
as many patients present without coma.8 However, 4 out environments, surgery, trauma, cerebrovascular accidents,
of 11 patients were hospitalized in comatose condition in gastrointestinal bleeding, heart failure, infections like
our series, while the rest had altered mentation. As all the pneumonia or urosepsis, but the usual signs of infection
patients were elderly, dysglycemia, neurologic causes and (fever, diaphoresis, tachycardia) are generally absent.1,9-11
sedative exposure were the primary considerations in those Medications like anesthetics, sedatives, narcotics,
who presented with decreased sensorium. Appropriate lithium, amiodarone, sunitinib and phenytoin can
history, laboratory and radiologic evaluation were done precipitate myxedema coma.1 Thyroid hormone activates
to rule out these common causes. It is noteworthy that not mitochondrial metabolism, stimulates nuclear receptors
all patients presented with classic features of hypothermia, through cell membrane Na+, K+-ATPase and increases
bradycardia and hypotension.8 The most common oxygen consumption leading to a characteristic increase
findings were a combination of altered mental status and in basal metabolic rate.9 Severe hypothermia (core
hyponatremia. Hypothermia (temperature below 97°F) temperature less than 90°F or 32.2°C), hyponatremia,
was observed only in five patients and seen only with decreased cerebral blood flow, hypoxemia and sepsis
rectal temperature measurement. The incidence of severe can lead to altered mental status with lowering of seizure
hypothermia is expected to be low in India.1 Considering threshold in myxedema.1,10 Altered respiratory sensitivity
the variety of presentations, physicians must have a high to hypoxia and hypercapnia, reduction in respiratory drive,
index of suspicion in all cases presenting with altered pneumonia, along with respiratory muscle dysfunction, can
mentation. Even in patients with competing established lead to hypoventilation.1,11,12 In addition, myxedematous
diagnoses, such as encephalopathy from alcoholic chronic swelling of the upper airway with macroglossia, pleural
liver disease, the possibility of myxedema crisis should still effusion and obstructive sleep apnea can further aggravate
be considered, as found in Case 5 of our cohort. hypoxia and carbon dioxide retention.11

236 Nirmalya Roy, et al Legions of Presentations of Myxedema Coma
Figure 1. Pathophysiology of myxoedema coma.
Negative inotropic and chronotropic alterations in Dose, preparation and route of administration of
hypothyroidism, manifested as decreased stroke volume, levothyroxine (LT4) have always been a matter of debate.
bradycardia and decreased cardiac output, precipitate In some institutions, intravenous thyroxine (T4) or a
cardiogenic shock.1,10,13 Increase in α-adrenergic responsive- combination of triiodothyronine (T3) and T4 are used.
ness in hypothyroidism causes peripheral vasoconstriction, While oral T3 is not available in India, oral T4 is easily
which shunts blood away from skin and muscle to available. However, administration of T4 through Ryles
maintain core body temperature and presents with the tube is equally effective as intravenous T4, with the
characteristic finding of cool and pale skin. In addition, advantage of easier interpretation of serum T4.1,5 Despite
accumulation of mucopolysaccharides and water can result following a standard protocol for myxedema management
in pericardial effusion obscuring ischemic findings but may (empiric antibiotic, dextrose-saline infusion, thyroxine
also result in cardiac tamponade physiology.14 In response sodium 300 to 500 µg through Ryles tube, intravenous
to vasoconstriction, there is a reduction in blood volume hydrocortisone 100 mg every 8 hours, warming blanket
by as much as 20%, while a reduction in erythropoietin to prevent heat loss and ventilatory support if required),
levels lead to a decline in red cell production and fall in seven out of 11 expired in our institute. No adverse event,
hematocrit by approximately 30%. Hyponatremia occurs especially cardiac, was documented with such a high dose
due to diminished capacity to clear free water load as a of thyroxine sodium. Patients with hypoventilation (six
consequence of the combined effects of lower renal perfusion out of 11) required ventilatory support; most of them (five
and inappropriately elevated antidiuretic hormone levels out of 6) expired. Predicting the outcome of the patients
despite low serum osmolality.10,11,15 Increased insulin with myxedema coma is difficult. However, hypotension
sensitivity, poor appetite and potential simultaneous and bradycardia at presentation, need for mechanical
adrenal insufficiency impairing gluconeogenesis, all ventilation, unresponsive hypothermia, presence of sepsis,
contribute to hypoglycemia in severe hypothyroidism.1,15 intake of sedative drugs, low Glasgow Coma Scale and
Reduced intestinal motility in severe hypothyroidism high APACHE II score are proposed as possible predictors
may reduce absorptive efficiency contributing to paralytic for mortality.5
ileus with abdominal distention.10 Further sluggish
circulation and severe hypometabolism impair absorption Our study has several limitations. First, recorded
of therapeutic agents from the gut or from subcutaneous diagnoses in retrospective real-world studies are less
or intramuscular sites. As such, medications should be well-validated than those in well-planned randomized
administered intravenously if possible. controlled trials. Hence, the generalizability of our results
may be limited. Second, our results were mainly based

Legions of Presentations of Myxedema Coma Nirmalya Roy, et al 237
on enteral administration of levothyroxine; intravenous 3. Mylliemngap B, Swain S, Vyas S, Kumar P. Myxedema coma,
pancytopenia, and hypocoagulopathy: A rare presentation of
thyroxine remains as the standard therapy for patients
Sheehan's syndrome. Indian J Endocrinol Metab. 2019;23(2):268-9.
with myxedema coma. Third, post-discharge mortality PMID: 31161117. PMCID: PMC6540897. https://doi.org/10.4103/ijem.
information is not available to us. Lastly, we could not IJEM_120_19.
perform multivariate logistic regression analysis of all 4. Baduni N, Sinha SK, Sanwal MK. Perioperative management of a
patient with myxedema coma and septicemic shock. Indian J Crit
potential risk factors for myxedema coma mortality because Care Med. 2012;16(4):228-30. PMID: 23559735. PMCID: PMC3610460.
of the small sample size. https://doi.org/10.4103/0972-5229.106510.
5. Dutta P, Bhansali A, Masoodi SR, Bhadada S, Sharma N, Rajput R.
Predictors of outcome in myxoedema coma: A study from a tertiary
Conclusion care centre. Crit Care. 2008;12(1):R1. PMID: 18173846. PMCID:
PMC2374608. https://doi.org/10.1186/cc6211.
In the absence of a definitive diagnostic tool, myxedema 6. Ono Y, Ono S, Yasunaga H, Matsui H, Fushimi K, Tanaka Y. Clinical
characteristics and outcomes of myxedema coma: Analysis of a
coma is largely a clinical diagnosis. In view of the myriad national inpatient database in Japan. J Epidemiol. 2017;27(3):117-22.
of presentations and absence of classic features in many PMID: 28142035. PMCID: PMC5350620. https://doi.org/10.1016/j.je.
situations, a high index of suspicion is required for a timely 2016.04.002.
diagnosis. In elderly people presenting with hyponatremia 7. Popoveniuc G, Chandra T, Sud A, et al. A diagnostic scoring system
for myxedema coma. Endocr Pract. 2014;20(8):808-17. PMID: 24518183.
and decreased sensorium, myxedema coma should be https://doi.org/10.4158/EP13460.OR.
considered as a differential diagnosis. Despite standard 8. Wall CR. Myxedema coma: Diagnosis and treatment. Am Fam
treatment after detection, myxedema coma is associated Physician. 2000;62(11):2485-90. PMID: 11130234.
9. Nicoloff JT, LoPresti JS. Myxedema coma. A form of decompensated
with poor outcomes. hypothyroidism. Endocrinol Metab Clin North Am. 1993;22(2):279-90.
PMID: 8325287.
Ethical Consideration 10. Rodrigo C, Gamakaranage CS, Epa DS, Gnanathasan A, Rajapakse
Patients' consent were obtained before submission of the S. Hypothyroidism causing paralytic ileus and acute kidney injury
manuscript. - case report. Thyroid Res. 2011;4(1):7. PMID: 21303532. PMCID:
PMC3041782. https://doi.org/10.1186/1756-6614-4-7.
11. Abuzaid AS, Birch N. The controversies of hyponatraemia in
Statement of Authorship hypothyroidism: Weighing the evidence. Sultan Qaboos Univ Med
All authors certified fulfillment of ICMJE authorship criteria. J. 2015;15(2):e207-12. PMID: 26052453. PMCID: PMC4450783.
12. Zwillich CW, Pierson DJ, Hofeldt FD, Lufkin EG, Weil JV.
Author Disclosure Ventilatory control in myxedema and hypothyroidism. N Engl J
All authors declared no conflicts of interest. Med. 1975;292(13):662-5. PMID: 1113761. https://doi.org/10.1056/
NEJM197503272921302.
13. Silva EI, Landsberg L. “Catecholamines and the sympathoadrenal
Funding Source system in hypothyroidism.” In: The Thyroid. LE Braverman, RD
None. Utiger, eds. Philadelphia: J.B. Lippincott Co., 1992.
14. Schenck JB, Rizvi AA, Lin T. Severe primary hypothyroidism
References manifesting with torsades de pointes. Am J Med Sci. 2006;331(3):154-
1. Mathew V, Misgar RA, Ghosh S, et al. Myxedema coma: A new look 6. PMID: 16538077. https://doi.org/10.1097/00000441-200603000-00008.
into an old crisis. J Thyroid Res. 2011;2011:493462. PMID: 21941682. 15. Iwasaki Y, Oiso Y, Yamauchi K, et al. Osmoregulation of plasma
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Case Series
Journal of the
ASEAN Federation of
Endocrine Societies
Dome-Shaped Pituitary Enlargement in Primary Hypothyroidism:

Avoiding Neurosurgical Interventions
Satyam Chakraborty,1 Mona Tiwari,2 Rajan Palui,3 Kajari Bhattacharya,1 Kalyan Kumar Gangopadhyay1
Department of Endocrinology, Institute of Neurosciences, Fortis Hospital, Kolkata, West Bengal, India
1
2
Department of Radiology, Institute of Neurosciences, Kolkata, West Bengal, India
3
Mission Hospital, Durgapur, West Bengal, India
Abstract
We describe three cases of primary hypothyroidism which presented initially to neurosurgery department with pituitary
hyperplasia. We have found a novel pattern of ‘dome-shaped’ enlargement of pituitary in MRI of these patients. Out
of these 3 patients, in two of them, the planned surgery was deferred when endocrinologists were consulted and the
pituitary hyperplasia completely resolved with levothyroxine treatment. In the third case, pituitary surgery was already
performed before endocrinology consultation and histopathology revealed thyrotroph hyperplasia.
The hyperplastic lesions described typically have a homogenous symmetrical ‘dome’ shaped architecture unlike the
non-functioning pituitary adenoma (NFPA), which usually might often be of varying shapes and homogeneity. Analysis
of pituitary images from similar case reports published in literature, also showed this typical ‘dome’ shaped pituitary
enlargement. This imaging characteristic can be a clue to look for underlying hormone deficiency, especially in primary
hypothyroidism. Therefore, a thorough endocrine evaluation especially looking for primary hypothyroidism in such dome-
shaped pituitary lesions are mandatory to prevent unwarranted neuro-surgical intervention as treatment of primary
hypothyroidism may result in resolution of the abnormal enlargement.
Key words: pituitary adenomas, pituitary hyperplasia, dome-shaped enlargement, case report
INTRODUCTION life long treatment. We report three such cases of pituitary

lesions arising secondarily because of untreated primary
Pituitary adenomas constitute around 2.7% of supratentorial hypothyroidism, which simulated an adenoma with a
tumours in childhood and 3.5%-6% of surgically resected common uniqueness in imaging. This however, resolved
tumours.1 Craniopharyngiomas constitute 80%-90% of the spontaneously after levothyroxine supplementation.
neoplasms arising from pituitary origin.1 The neoplasms
present with visual disturbances but at times with CASE 1
growth failure, delayed puberty, secondary adrenal and
thyroid insufficiency.1 Non-specific headache might also A 16-year-old female patient was referred to our institute
accompany in certain cases.1 Imaging usually clinches for consideration of pituitary surgery as the magnetic
the diagnosis and surgery is the treatment of choice in resonance imaging (MRI) revealed a pituitary tumour.
craniopharyngiomas and many selected cases of non- The MRI was done at a peripheral clinic because of a
functional pituitary adenomas. However, pituitary history of primary amenorrhea and short stature. She
hyperplasia is also seen in end organ insufficiency complained of a minor headache and some eye pain but
from primary gonadal insufficiency, primary adrenal no visual disturbance. There was no history to suggest any
insufficiency, and primary hypothyroidism.2 Pituitary malabsorption. She was the only child of her parents.
hyperplasia in untreated overt primary hypothyroidism
is more common than previously thought.2 Until 2019, Her height was 124 cm (less than 3rd percentile for her
there are 105 cases of pituitary hyperplasia in untreated age) and a body mass index (BMI) of 21.4 kg/m2. Sexual
hypothyroidism that have been reported.2 Such hyperplasia maturity rating revealed that she was in stage 3 for breast
may take the shape of a dome-shaped elevation and development and stage 2 for pubic hair as per Tanner
might compress the optic chiasma necessitating neuro- scale. Physical examination was otherwise unremarkable.
surgical opinion which may result in unnecessary pituitary Laboratory investigation showed haemoglobin 12 g/dL,
surgery as was carried out in one of our cases below.2 serum TSH 119.20 μIU/mL, free T4 4.14 pmol/L, prolactin
of 36 μgm/L. Further hormonal testing was refused by
Unwarranted surgical excision especially in children the parents because of cost issues. The cranial Magnetic
and adolescent females may result in life-long risk of Resonance Imaging (MRI) showed pituitary space
multiple pituitary hormone deficiency and the need for occupying lesion (SOL) with a size of 15x10x22 mm
________________________________________
ISSN 0857-1074 (Print) | eISSN 2308-118x (Online) Corresponding author: Satyam Chakraborty, MD (Medicine), DM (Endocrinology)
Printed in the Philippines Consultant Endocrinologist,
Copyright © 2020 by Chakraborty et al. Institute of Neurosciences, Fortis Hospital
Received: August 19, 2020. Accepted: November 13, 2020. 703, Anandapur, EM Bypass Road,
Published online first: November 29, 2020. Kolkata, West Bengal, India 700107

Dome-Shaped Pituitary Enlargement in Primary Hypothyroidism Satyam Chakraborty, et al 239
abutting the optic chiasma with minimal para-sellar short stature and a possible pituitary tumour on the basis
extension into the cavernous sinus inferiorly (Figure 1A). of a MRI performed at the centre suggesting a pituitary
Visual field on confrontation was unremarkable. In view of macroadenoma. The patient had attained menarche at the
the grossly raised TSH, it was thought that it could merely age of 13 years but had oligomenorrhea with less than 5 cycles
be a thyrotroph secreting pituitary hyperplasia rather than per year. The patient did not have any overt symptoms of
a true adenoma. The patient was treated with levothyroxine hypothyroidism other than easy fatigability. She, however,
supplementation at a dose of 75 μgm. The patient attained was a 6th standard drop-out. There were no symptoms
a height of 131 cm in 6 months. The corresponding suggestive of malabsorption. Physical examination revealed
thyroid profile was serum TSH 3.36 μIU/mL, free T4 12.4 a Tanner stage 4 for breast and pubic hair and had a height
pmol/L. Follow-up MRI after 6 months revealed complete of 140 cm which was just less than 3rd centile for her age.
resolution of the hyperplastic pituitary (Figure 1B). Physical examination was otherwise non- contributory.
Laboratory investigation showed haemoglobin 11.5 g/dL,
CASE 2 TSH >100 μIU/mL, free T4 5.8 pmol/L, prolactin 57.78 µg/L.
The MRI (Figure 2) was similar to patient 1 with a dome-
As in the 1st case, a 15-year-old female patient was referred shaped superior protrusion of the pituitary gland almost
from primary health care to a neurosurgeon because of abutting the optic chiasma.
A B
Figure 1. (A) Coronal post contrast T1-weighted image showing pituitary enlargement with dome-shaped convexity.
(B) Coronal post contrast T1-weighted image showing lesion disappearing 6 months after levothyroxine supplementation.
A B
Figure 2. (A) Coronal post contrast T1-weighted image showing dome-shaped superior convexity of the pituitary prior
to starting levothyroxine therapy. (B) Post coronal T1-weighted image showing post-levothyroxine therapy depicting total
resolution of the thyrotroph hyperplasia and obliteration of the “dome.”

240 Satyam Chakraborty, et al Dome-Shaped Pituitary Enlargement in Primary Hypothyroidism
Treatment with 75 µgm of levothyroxine was initiated and homogenous symmetric architecture. Visual field
and at the end of 6 months, her TSH was 2.3 µIU/ml and on perimetry testing was marred by poor comprehension
prolactin was 8 µgm/L. The patient had a height of 143 cms of the patient.
and had 4 regular cycles in the preceding 4 months prior
to follow-up. A repeat MRI at 6 months revealed complete She was seen by an endocrinologist on the first post-
resolution of the hyperplastic pituitary, previously operative day for diabetes insipidus as she had a urine
presumed to be a tumour. output of 3500 ml/24 hrs. Her sodium was 154 mmol/L.
On evaluation of the pre-operative hormonal profile it
CASE 3 was found that she had a TSH of >100 micro IU/ml. The
diabetes insipidus was managed by increase in free fluid
In the aforementioned two cases, an unnecessary intake and it subsided by day 5, when she had a sodium
Neuro-Surgical intervention was averted not only by of 136 mmol/L. She was started on a dose of levothyroxine
Endocrine evaluation but also by the Neuro-Radiologist’s 100 µg post-operatively. The young female fortunately did
insistence of a symmetric, homogenous “Dome-Shaped” not have any Post-operative Neuro-hormonal deficits and
pituitary enlargement which was common to both cases her regular cycles resumed from the third month post-
which suggested a hyperplasia rather than a tumorous operative. Post-operative hormonal evaluation performed
growth. Our third case supplements our 1st two cases at 6 weeks revealed a free T4 level of 13.8 pmol/L, 8 am
where a similar thyrotroph hyperplasia with high S. cortisol of 9.8 µg/dl, FSH- 5.38 mIU/ml, LH-6.4 mIU/ml
TSH levels and a typical “Dome-Shaped,” symmetric, and IGF-1 – 213 ng/ml which was normal for her age.
homogenous pituitary enlargement was missed due to
lack of pre-operative endocrinological intervention and DISCUSSION
radiological supervision.
The above case reports reveal few unique areas in
A 24-year-old female was referred for endocrine consultation patients with long-standing hypothyroidism that are of
but this time it was on the first post-operative day after particular clinical relevance. Untreated long-standing
pituitary surgery. She was referred in the post-operative hypothyroidism in adolescent females might present
period for diabetes insipidus; however, initially sent to with certain symptoms like short stature, amenorrhea
the neurosurgical team for a pituitary macroadenoma (primary or secondary), delayed or precocious puberty,
(Figure 3). She had a history of irregular menstrual cycles non-specific headache and visual disturbances usually due
for a year followed by secondary amenorrhea for 6 months to benign intra-cranial hypertension, which may closely
duration and intermittent headache and a one-month simulate the features of pituitary adenoma.3 Untreated
history of blurry vision. The MRI revealed a pituitary long standing hypothyroidism results in thyrotroph
macroadenoma with a dome-shaped protrusion towards hyperplasia not only because of lack of feedback inhibition
the optic chiasma of size 13x10x21 cm. This is similar to of thyroid hormones on pituitary thyrotrophs but also due
the above two cases, which we believe is also thyrotroph to unopposed stimulation by high levels of Thyrotrophin
hyperplasia as evidenced by the typical “Dome sign” Releasing Hormone (TRH).4 Sellar imaging may reveal
adenoma which may lead to surgical management. Neuro-
surgical initiatives in these cases are not only unnecessary
but may also expose the patients to developing multiple
pituitary hormonal deficits which require life-long
supplementation, and may result in problems with fertility,
which fortunately our third patient did not have. A pre-
operative endocrine and neuro-radiological evaluation is
therefore mandatory in all cases of pituitary adenomas,
to avoid unnecessary neurosurgical intervention.
In our series, we also found that there were certain

similarities in the imaging characteristics of all three
patients. All their lesions had an almost symmetrical
dome-shaped architecture i.e., diffuse enlargement of the
gland with an upward protrusion. A detailed review of
the previous case-reports did show similar architecture.
Ahmed et al., put forward the nipple sign based upon CT
findings of 5 cases in 1989.5 In our series of 3 cases, the
MRI revealed enlargement of the pituitary with superior
convex margins and extension in suprasellar region with
a symmetrical dome shape. This typical morphology with
homogeneous signal intensity and contrast enhancement
and lack of necrosis/ cystic change/ haemorrhage
indicates hyperplasia.
Sarlis et al., demonstrated similar configuration as ours

which completely regressed after levothyroxine therapy
Figure 3. Preoperative coronal T1-weighted image within 1 month (Figure 4).6 Passeri et al., and Franceschi
depicting similar pituitary enlargement as in Figures 1 and 2. et al., in 2011 reported similar cases with characteristic

or neurosurgeons to ask for full endocrine evaluation

before any surgical intervention is planned.10
Our cases reveal few aspects of the common problem of

untreated hypothyroidism. Firstly, the initial symptoms
and signs of hypothyroidism might be subtle enough
to remain unnoticed and undetected for a significant
time period. Thyrotroph hyperplasia is the usual result.
Secondly, the symptoms, particularly in adolescents with
short stature, headaches and menstrual disturbances in
females, might simulate the features of an NFPA. This
often results in imaging studies by primary care physicians
or gynaecologists, with or without hormonal evaluation,
because in a real world scenario, most cases will consult
them initially and not with an endocrinologist.
As soon as an imaging suggestive of pituitary enlargement

is found, a Neurosurgical evaluation should follow, which
at times may complicate the entire picture as what happened
in Case 3. In this context, Du et al., reported two cases of
primary hypothyroidism in which pituitary surgery was
performed before normalisation of thyroid function (TSH
and thyroid hormones) although levothyroxine therapy
Figure 4. Coronal post contrast T1-weighted image was started before surgery.11 It is worth mentioning that
depicting pituitary enlargement with characteristic dome none of the cases had any obvious neurologic deficit before
shape (arrows) (used with permission).6 or after treatment. Thirdly, an expert neuro-radiological
evaluation of the MR images depicting the “dome” sign,
together with hormonal evaluation will lead to the correct
similarity as our cases which regressed even within 1 week diagnosis, that of primary hypothyroidiism, and prevent
of levothyroxine therapy (Figure 5 and 6).7,8 The MRI of unnecessary neuro-surgical intervention.
Cao et al., reported in 2018 also did bear the characteristic
similarity of the dome-shaped convex homogenous Conclusions
architecture (Figure 7).9
Untreated hypothyroidism leading to the development of
Finally, in 2019 Shukla et al., in their detailed review thyrotroph hyperplasia is still a common entity, not only in
also reported similar findings.2 The anatomical location developing but also in the developed world. Neuro-surgical
of the thyrotrophs in the midline has been depicted by initiatives in these cases is not only unnecessary, but also
Ben-Shlomo et al., (Figure 8) which makes it imperative can cause patients to have multiple pituitary hormonal
that any hyperplasia in the aforementioned region will deficits which require life-long supplementation, lead to
cause similar “dome-shaped” imaging characteristic problems with fertility and finally, loss of bone mineral
which can alert primary care physicians, gynaecologists density which adds on to the morbidity.
A B
Figure 5. (A) Coronal T1 image showing pituitary enlargement which (B) regressed
subsequently on Levothyroxine supplementation (used with permission).7

242 Satyam Chakraborty, et al Dome-Shaped Pituitary Enlargement in Primary Hypothyroidism
A B C
Figure 6. Coronal (A) pre and (B) post contrast T1 image showing characteristic dome-shaped pituitary which shows
(C) resolution on follow up image (used with permission).8
Figure 7. Coronal post contrast T1-weighted image Figure 8. Anatomical location of the thyrotrophs (adapted).10
showing homogeneously enhancing pituitary gland
with superior convexity reaching up to optic chiasm
(used with permission).9
The hyperplastic lesions described typically have a Statement of Authorship

homogenous symmetrical ‘dome’ shaped architecture All authors certified fulfillment of ICMJE authorship criteria.
unlike an NFPA which is usually of varying shapes and
homogeneity. Analysis of pituitary images from similar Author Disclosure
All authors declared no conflicts of interest.
case reports published in literature, also showed this
typical ‘dome’ shaped pituitary enlargement. This imaging Funding Source
characteristic can be a clue to look for underlying hormone None.
deficiency, especially in primary hypothyroidism.
References
Our discussion not only adds to the already established 1. Fleseriu M, Karavitaki N. Non-functioning pituitary adenomas,
not all the same and certainly not boring! Pituitary. 2018;21:109-10.
necessity of endocrine evaluation prior to all pituitary
https://doi.org/10.1007/s11102-018-0875-5.
surgeries, but also recommends that the presence of a 2. Shukla P, Bulsara KR, Luthra P. Pituitary hyperplasia in severe
“DOME sign” on MRI of the pituitary along with an primary hypothyroidism: A case report and review of the literature.
elevated TSH, suggests thyrotroph hyperplasia due to Case Rep Endocrinol. 2019;2019:2012546. PMID: 31341683. PMCID:
PMC6614958. https://doi.org/10.1155/2019/2012546.
primary hypothyroidism rather than a true pituitary 3. Beck-Peccoz P, Brucker-Davis F, Persani L, Smallridge RC, Weintraub
adenoma and therefore, patients can be treated medically BD. Thyrotropin-secreting pituitary tumors. Endocr Rev. 1996;
by levothyroxine supplementation with the expectation of 17(6):610-38. PMID: 8969971. https://doi.org/10.1210/edrv-17-6-610.
4. Dutta D, Maisnam I, Ghosh S, Mukhopadhyay P, Mukhopadhyay
complete regression of the hyperplastic growth. S, Chowdhury S. Panhypopituitarism with empty sella a sequel of
pituitary hyperplasia due to chronic primary hypothyroidism. Indian
Ethical Considerations J Endocrinol Metab. 2012;16 (Suppl 2): S282–4. PMID: 23565400.
Patients’ consent were obtained before submission of the PMCID: PMC3603048. https://doi.org/10.4103/ 2230-8210.104060.
manuscript.

5. Ahmed M, Banna M, Sakati N, Woodhouse N. Pituitary gland 9. Cao J, Lei T, Chen F, Zhang C, Ma C, Huang H. Primary hypothyroidism
enlargement in primary hypothyroidism: A report of 5 cases with in a child leads to pituitary hyperplasia: A case report and literature
follow-up data. Horm Res 1989;32(5-6):188-92. PMID: 2634612. review. Medicine (Baltimore). 2018;97(42):e12703. PMID: 30334955.
https://doi.org/10.1159/000181287. PMCID: PMC6211862. https://doi.org/10.1097/MD.0000000000012703.
6. Sarlis NJ, Brucker-Davis F, Doppman JL, Skarulis MC. MRI- 10. Ben-Shlomo A, Melmed S. Hypothalamic regulation of anterior
demonstrable regression of a pituitary mass in a case of primary pituitary function. In the Pituitary, 4th ed.; 2017. https://doi.
hypothyroidism after a week of acute thyroid hormone therapy. org/10.1016/B978-0-12-804169-7.00002-7.
J Clin Endocrinol Metab. 1997;82(3):808-11. PMID: 9062487. 11. Du J, Ji H, Jin J, Gao S, Yan X, Hu S. Pituitary adenoma secondary
https://doi.org/10.1210/jcem.82.3.3796. to primary hypothyroidism: Two case reports. Medicine (Baltimore).
7. Passeri E, Tufano A, Locatelli M, Lania AG, Ambrosi B, Corbetta S. 2020;99(8):e19222. PMID: 32080117. PMCID: PMC7034716. https://
Large pituitary hyperplasia in severe primary hypothyroidism. J Clin doi.org/10.1097/MD.0000000000019222.
Endocrinol Metab 2011;96(1):22-3. https://doi.org/10.1210/jc.2010-2011.
8. Franceschi R, Rozzanigo U, Failo R, Bellizzi M, Di Palma A. Pituitary
hyperplasia secondary to acquired hypothyroidism: Case report.
Ital J Pediatr 2011;37:15. PMID: 21473748. PMCID: PMC3079613.
https://doi.org/10.1186/1824-7288-37-15.
JAFES
Clinical controversies and disease updates are also
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www.ASEAN-endocrinejournal.org.

Journal of the
ASEAN Federation of
Endocrine Societies Instructions to Authors
The Journal of the ASEAN Federation of Endocrine Societies
(JAFES) is an open-access, peer-reviewed, English language, 4. PRISMA (2009) Checklist for Reporting Systematic Reviews
medical and health science journal that is published two times and Meta-Analyses
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ADHERENCE TO EQUATOR NETWORK GUIDELINES 2. The manuscript should be arranged in sequence as follows:
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3. COREQ (2007) Checklist for Reporting Qualitative Research promptly returned for correction and resubmission.

Instructions to Authors 245
Title Page 6. The style/punctuation approved by JAFES conforms to that

1. The title should be as concise as possible. recommended by the International Committee of Medical
2. Only the full names of the authors directly affiliated with Journal Editors (ICMJE) available at http://www.icmje.org.
the work should be included (First name, Middle initial Follow the format of the examples shown below:
and Last name). There are 4 criteria for authorship (ICMJE
recommendations): Journal Article
2.1. Substantial contributions to the conception or design of Padua FR, Paspe MG. Antinuclear antibody in the rheumatic
the work; or the acquisition, analysis, or interpretation and non-rheumatic diseases among Filipinos. Acta Med
of data for the work; AND Philippina. 1990; 26(2):81-85.
2.2. Drafting the work or revising it critically for important
intellectual content; AND One to Six Authors (Commentary, Online)
2.3. Final approval of the version to be published; AND Krause RM. The origin of plagues: old and new. Science.
2.4. Agreement to be accountable for all aspects of the work 1992;257:1073-1078.
in ensuring that questions related to the accuracy or
integrity of any part of the work are appropriately Barry JM. The site of origin of the 1918 influenza pandemic and
investigated and resolved. its public health implications. [Commentary]. JTranslational
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should be included as an attachment whenever appropriate medicine.com/content/2/1/3. Accessed November 18, 2005.
4. Name and location of no more than one (1) institutional
affiliation per author may be included. Mokdad AH, Bowman BA, Ford ES, Vinicor F, Marks JS,
5. If the paper has been presented in a scientific forum or Koplan JP. The continuing epidemics of obesity and diabetes
convention, a note should be provided indicating the in the US. JAMA. 2001;286(10):1195-1200.
name, location and date of its presentation.
More than Six Authors
Abstract McGlynn EA, M.Asch S, Adams J, et al. The quality of health
For original articles, the abstract should contain no more than care delivered to adults in the United States.N Engl J Med.
200 words with a structured format consisting of the objective/s, June 26, 2003;348(26):2635-2645.
methodology, results and conclusion. For feature articles, case
reports, interhospital grand rounds, and brief communications, Authors Representing a Group
the abstract should be from 50 to 75 words and need not be Moher D, Schulz KF, Altman D; for the CONSORT Group.
structured. The CONSORT statement: revised recommendations
for improving the quality of reports of parallel-group
Keywords randomized trials. JAMA. 2001;285(15):1987-1991.
At least 3 keywords but no more than 6, preferably using terms
from the Medical Subject Headings (MeSH) list of Index Medicus, Book
should be listed horizontally under the abstract for cross- Byrne, DW. Publishing your medical research paper: What
indexing of the article. they don’t teach in medical school. Baltimore: Williams &
Wilkins, 1998.
Text
1. Generally, the text should be organized consecutively as World Wide Web
follows: Introduction, Methodology, Results and Discussion, The key and critical objectives of JAMA. http://jama.ama-
and Conclusion (IMRAD format). assn.org/misc/aboutjama.dtl. Accessed April 4, 2007.
2. All references, tables, figures and illustrations should be
cited in the text, in numerical order. Tables
3. All abbreviations should be spelled out once (the first time 1. Cite all tables consecutively in the text and number them
they are mentioned in the text) followed by the abbreviation accordingly.
enclosed in parentheses. The same abbreviation may then 2. Create tables preferably using Microsoft Excel with one table
be used subsequently instead of the long names. per worksheet.
4. All measurements and weights should preferably be in 3. Tables should not be saved as image files.
System International (SI) units. 4. The content of tables should include a table number (Arabic)
5. If appropriate, information should be provided on and title in capital letters above the table, and explanatory
institutional review board/ethics committee approval. notes and legends as well as definitions of abbreviations
6. Acknowledgments to individuals/groups of persons, or used below.
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before the references. Grants and subsidies from government 6. Each table must be self-explanatory, being a supplement
or private institutions should also be acknowledged. rather than a duplicate of information in the text.
5. Up to a maximum of five (5) tables are allowed.
References
1. References in the text should be identified by Arabic Figures and Graphs
Numerals in superscript on the same line as the preceding 1. Figures or graphs should be identified by Arabic Numeral/s
sentence. with titles and explanations underneath.
2. References should be typed double-spaced on a separate 2. The numbers should correspond to the order in which the
sheet. They should be numbered consecutively in the order figures/graphs occur in the text. It is recommended that
by which they are mentioned in the text. They should not figures/graphs also be submitted as image files (preferably as
be alphabetized. .jpeg or .png files) of high resolution.
3. All references should provide inclusive page numbers. 3. Provide a title and brief caption for each figure or graph.
4. Journal abbreviations should conform to those used Caption should not be longer than 15-20 words.
in PubMed. 4. All identifying data of the subject/s or patient/s under study
5. A maximum of six authors per article can be cited; beyond such as name or case numbers, should be removed.
that, name the first three and add “et al.” 5. Up to a maximum of five (5) figures and graphs are allowed.

246 Instructions to Authors
Illustrations and Photographs PROCESS

1. Where appropriate, all illustrations/photographic images 1. Upon receipt of the manuscript, the Editor shall review
should be at least 800 x 600 dpi and submitted as image files the submission, check if it has met aforementioned criteria
(preferably as .jpeg or .png files). and consult with members of the Editorial Board to decide
2. For photomicrographs, the stain used (e.g., H&E) and whether it shall be considered for publication or not.
magnification (e.g., X400) should be included in the 2. Within one (1) week of submission, authors shall be notified
description. through e-mail that their manuscript either (a) has been
3. Computer-generated illustrations which are not suited sent to referees for peer-review or (b) has been declined
for reproduction should be professionally redrawn or without review.
printed on good quality laser printers. Photocopies are 3. The JAFES implements a strict double blind peer review
not acceptable. policy. For manuscripts that are reviewed, authors can
4. All letterings for illustration should be done professionally expect an initial decision within forty five (45) days after
and should be of adequate size to retain even after submission. There may be instances when decisions can take
size reduction. longer than 45 days, in such cases, the editorial assistant
5. Figure legends should be numbered sequentially, typed shall inform the authors. The editorial decision for such
double-spaced on a separate sheet of paper. Give the manuscripts shall be one of the following: (a) acceptance
meaning of all symbols and abbreviations used in the figure. without further revision, (b) acceptance with minor
6. Up to a maximum of five (5) illustrations/photographs revisions, or (c) major manuscript revision and resubmission.
are allowed. 4. Accepted manuscripts are subject to editorial modifications
to bring them in conformity with the style of the journal.
N.B.: For tables, figures, graphs, illustrations and photographs
that have been previously published in another journal or book, EDITORIAL OFFICE CONTACT INFORMATION:
a note must be placed under the specific item stating that such Journal of the ASEAN Federation of Endocrine Societies
has been adapted or lifted from the original publication. This Unit 2005, 20th Floor, Medical Plaza Ortigas, San Miguel Avenue,
should also be referenced in the References portion. Ortigas Center, Pasig City, Philippines 1605
Editorial Assistant: Amado O. Tandoc III, MD, FPSP
Telefax number: (+632) 8637-3162
E-mail: [email protected]; [email protected]
Website: http://www.asean-endocrinejournal.org
ARTICLE TYPES
Original Articles
The abstract should contain no more than 200 words with a structured format consisting of the objective/s, methodology, results and conclusion.
A manuscript for original articles should not exceed 25 typewritten pages (including tables, figures, illustrations and references) or 6000 words.
Reviews
Review articles provide information on the “state of the art.” JAFES encourages that reviews not only summarize current understanding of a particular
topic but also describe significant gaps in the research, and current debates. The abstract should be from 50 to 75 words and should not be structured.
A manuscript for reviews should not exceed 15 typewritten pages (including tables, figures, illustrations and references) or 4000 words.
Case Reports / Case Series

The abstract should be from 50 to 75 words and should not be structured. A manuscript for case reports or case series should not exceed 10
typewritten pages (including tables, figures, illustrations and references) or 3000 words.
Feature Articles
JAFES may feature articles, either as part of an issue theme, such as Summary Clinical Practice Guidelines on endocrinology from each AFES
country society, or a special topic on endocrinology by an international expert or authority. The abstract should be from 50 to 75 words and should
not be structured. A manuscript for feature articles should not exceed 25 typewritten pages (including tables, figures, illustrations and references)
or 6000 words.
Endocrine Perspectives
JAFES may invite topic experts to publish viewpoints, opinions, and commentaries on relevant topics. A manuscript for endocrine perspectives
should not exceed 10 typewritten pages (including tables, figures, illustrations and references) or 3000 words. *Not peer reviewed.
Interhospital Grand Rounds

JAFES encourages submission of special articles that summarize and document the proceedings of endocrinology grand rounds, which includes
presentation of medical problems of a particular patient, evaluation and work-up, treatment and clinical course, discussion of key diagnostic and
management points, and commentaries by specialty experts. JAFES recognizes the importance of this type of article as an educational tool for
physicians and health practitioners. The abstract should be from 50 to 75 words and should not be structured. A manuscript for grand rounds
should not exceed 25 typewritten pages (including tables, figures, illustrations and references) or 6000 words.
Brief Communications
Brief Communications are short reports intended to either extend or expound on previously published research OR present new and significant
findings which may have a major impact in current practice. If the former, authors must acknowledge and cite the research which they are building
upon. The abstract should be from 50 to 75 words and should not be structured. A manuscript for brief communications should not exceed
5 typewritten pages (including tables, figures, illustrations and references) or 1500 words.
Editorials
Articles that represent the scientific opinion and views of an author. Every issue of JAFES includes an Editorial by the Editor-in-Chief and may
include one or two additional editorials from experts from the scientific community commenting on a particular field or issue on endocrinology.
No abstract or keywords necessary.
Letters to the Editor

JAFES welcomes feedback and comments on previously published articles in the form of Letters to the Editor. No abstract or keywords necessary.
A Letter to the Editor must not exceed 2 typewritten pages or 500 words.
Special Announcements
Special announcements may include upcoming conventions, seminars or conferences relevant to endocrinology and metabolism. The Editors shall
deliberate and decide on acceptance and publication of special announcements. Please coordinate with the Editorial Coordinator for any request
for special announcements.

Instructions to Authors 247
Checklist Guide for Submission of Manuscripts to JAFES

Instructions
to Authors  Review manuscript submission guidelines
 Include cover letter as an attachment

 Indicate in the letter the title of the work
Cover Letter  Indicate all the authors (complete names, affiliations, ORCID iD, specific role/s in writing
the manuscript and email address)
 Indicate in the letter the Corresponding author: and provide complete contact information
(post address, telephone, fax number, e-mail address)
EQUATOR
Network  Review manuscript if compliant with appropriate EQUATOR Network Guidelines and
Guidelines submit checklist (e.g., CONSORT for clinical trials, CARE for case reports)
 Ensure all authors have read and agreed to the following: (1) the Authorship Certification,
Author Form (2) the Author Declarations, (3) the Author Contribution Disclosure, and (4) the Author
Publishing Agreement
 Submit a scanned copy of the fully accomplished form
ICMJE Form for
Disclosure of  Ensure all authors have read and agreed to disclose potential Conflicts of Interest
Potential Conflicts  Submit the PDF copy of the fully accomplished form
of Interest *The form is also downloadable at: http://www.icmje.org/conflicts-of-interest/
Ethics Review  For Original articles, submit a scanned copy of the Ethics Review Approval of research
Approval  For manuscripts reporting data from studies involving animals, submit a scanned copy of
the Institutional Animal Care and Use Committee approval
Patient  For Case Reports, Images in Endocrinology and Clinical Case Seminars, submit a
Consent Form scanned copy of the fully accomplished form; otherwise, obtain appropriate ethical
(if applicable) clearance from the institutional review board.
 Full names of the authors directly affiliated with the work (First name and Last name),
highest educational attainment
Title Page  Name and location of 1 institutional affiliation per author
 If presented in a scientific forum or conference, provide a footnote should be provided
indicating the name, location and date of presentation
 Provide an abstract conforming with the format
Abstract  Structured for Original Articles: Objective/s, Methodology, Results, Conclusion
 Unstructured for Case Reports and Feature Articles
Keywords  Provide 3-5 keywords (listed in MeSH)
 Provide text/content in IMRAD format (Introduction, Methodology, Results and Discussion,

Conclusion)
 Make sure all abbreviations are spelled out once (the first time they are mentioned in the
text) followed by the abbreviation enclosed in parentheses; the same abbreviation may
then be used subsequently
Content  Make sure all measurements and weights are in SI units
 If appropriate, provide information on institutional review board/ethics review committee
approval
 Acknowledgments to individuals/groups of persons, or institution/s should be included at
the end of the text just before the references; grants and subsidies from government or
private institutions should also be acknowledged
References  All references should be cited in the text, in numerical order. Use Arabic numerals
 Ensure all references follow the prescribed format
 All tables, figures, illustrations and photographs should be cited in the text, in numerical
order per type
Tables, Figures,  Provide separate files for tables, figures and illustrations
Illustrations and  Provide a title and legend (if appropriate) for each table
Photographs  Provide a title, legend (if appropriate), and caption for each figure and illustration
(caption should be no longer than 15-20 words)
 If table, figure, or illustration is adapted, state so and include the reference.

Journal of the
ASEAN Federation of
Endocrine Societies Author Form
JAFES AUTHOR FORMS (2019)
COMPLETE TITLE OF MANUSCRIPT
4. AUTHOR PUBLISHING AGREEMENT

The undersigned author(s) shall retain the copyright for the Article. No rights in patent, trademark,
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order to agreed
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all authors; JAFES
an website.
additional sheet if necessary)
The undersigned Author Nameauthor(s) is/are entitled to use the published manuscript
Institutional Affiliation in subsequent
compilations of the undersigned
[Last name/First name] author(s) works, to use excerpts or portions of the published
manuscript in other works, including dissertations or books/book chapters, for both commercial
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________________________________________________ (supplementary information) in print, electronic,
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and all other media (including future platforms developed), throughout the world, for the full term
4. ________________________________________________ ____________________________________________________________
of copyright.
5. The
________________________________________________
undersigned author(s) recognizes that the ____________________________________________________________
JAFES is an OPEN-ACCESS publication which allows
third
*NOTE: partywith
Indicate users to share,
an asterisk markcopy and redistribute
the corresponding author. the published manuscript in any medium or
format, adapt, remix, transform, and build upon the published manuscript, for non-commercial
purposes through
1. AUTHORSHIP its Creative Commons Attribution-Non Commercial user license (CC BY-NC 4.0).
CERTIFICATION
BasedThis agreementCommittee
on International shall alsoofgive JAFES
Medical exclusive
Journal rights to
Editors (ICMJE) license
Criteria others to do the same as above
for Authorship.
through the user license, and to enforce these rights against third parties.
In consideration of our submission to the Journal of the ASEAN Federation of Endocrine Societies
The undersigned author(s) understand and agree that all rights granted under this agreement
(JAFES), the undersigned author(s) of the manuscript hereby certify, that all of us have actively and
shall revert to the undersigned author(s) should the submitted manuscript be withdrawn or
sufficiently participated in:
rejected, or the published manuscript be retracted.
(1) the conception or design of the work, the acquisition, analysis and interpretation of data for
the work; AND
(2) drafting the work, revising it critically for important intellectual content; AND
SIGNED:*(3) that we are all responsible for the final approval of the version to be published; AND
Authorto
(4) we all agree Name
be accountable for all aspects ofSignaturethe work in ensuring that questions Date related
[Last name/First name] [MM/DD/YY]
to the accuracy or integrity of any part of the work are appropriately investigated and
resolved.
1. ________________________________________________ ________________________ ___________________________
2. 2.AUTHOR DECLARATIONS
________________________________________________ ________________________ ___________________________
3. The undersigned author(s) of the manuscript________________________

________________________________________________ hereby certify, that the___________________________
submitted manuscript
represents original, exclusive and unpublished material. It is not under simultaneous consideration
4. ________________________________________________ ________________________ ___________________________
for publication elsewhere. Furthermore, it will not be submitted for publication in another journal,
until a decision is conveyed regarding its acceptability
5. ________________________________________________ for publication in the
________________________ JAFES.
___________________________
The undersigned author(s) hereby certify that the submitted manuscript and supplemental
materials do not infringe any copyright, violate any other intellectual property, data privacy rights
*NOTE: Indicate with an asterisk mark the corresponding author.
of any person or entity, and have obtained written permissions from copyright or intellectual
property right owners for all copyrighted/patented works that are included in the manuscript.
The undersigned author(s) hereby certify, that the study on which the manuscript is based had
conformed to ethical standards and/or had been reviewed by the appropriate ethics
committee, and that no references or citations have been made to predatory/suspected
predatory journals.
The undersigned author(s) likewise hereby certify, that the article had written/informed consent
for publication from involved subjects (for Case Report/series, Images in Endocrinology, Clinical
Case Seminars).*
*NOTE: In case the involved subject/s can no longer be contacted (i.e., retrospective studies, no contact information, et cetera) to
obtain consent, the author must seek ethical clearance from the institutional board to publish the information about the subject/s.
For submissions to the JAFES to be accepted, all authors must read and accomplish the JAFES Author Forms consisting
of: (1) the Authorship Certification, (2) the Author Declarations, (3) the Author Contribution Disclosure, and (4) the Author
Publishing Agreement. The completely accomplished JAFES Author Forms shall be scanned and submitted along with
the manuscript. No manuscript shall be received without the completely accomplished JAFES Author Forms.

Author Form 249
3. AUTHOR CONTRIBUTION DISCLOSURE (Place an “x” mark where an author made the contribution)
Adapted from Contributor Roles Taxonomy [CRediT] developed by the Consortia for Advancing Standards in Research Administration
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AUTHOR PUBLISHING AGREEMENT
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Conceptualization
manuscript are based) are transferred to the Journal.
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aims. The undersigned author(s) is/are entitled to proper attribution and credit for the published
manuscript, and to share the published manuscript in the same manner permitted to third parties
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the CrossRef DOI link to the version of record in the JAFES website.
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compilations
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development; author(s) works, to use excerpts or portions of the published
designing computer
programs; implementation of the computer code and supporting
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algorithms; testing of existing code components
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formalThe undersigned
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stages
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250 Author Form
4. AUTHOR PUBLISHING AGREEMENT

manuscript
4. AUTHOR are based)
PUBLISHING AGREEMENTare transferred to the Journal.
The undersigned author(s)
The undersigned author(s) shall is/are entitled
retain to proper
the copyright attribution
for the andrights
Article. No credit for thetrademark,
in patent, published
manuscript, and to share the published manuscript in the same
and other intellectual property rights (to include all research data on which the published manner permitted to third parties
under the JAFES Creative Commons BY-NC
manuscript are based) are transferred to the Journal. 4.0 user license, so long as the shared version contains
the CrossRef
The DOI link
undersigned to the version
author(s) is/are of record to
entitled in the JAFESattribution
proper website. and credit for the published
The undersigned author(s) is/are entitled
manuscript, and to share the published manuscript in the same to use the published
manner manuscript
permitted in subsequent
to third parties
under the JAFES Creative Commons BY-NC 4.0 user license, so long as the shared versionpublished
compilations of the undersigned author(s) works, to use excerpts or portions of the contains
manuscript
the CrossRefinDOIotherlink works, including
to the version dissertations
of record in the orJAFESbooks/book
website. chapters, for both commercial
and non-commercial purposes.
The undersigned author(s) is/are entitled to use the published manuscript in subsequent
The undersigned
compilations of theauthor(s) understands
undersigned and agrees
author(s) works, to to use
grantexcerpts
JAFES exclusive
or portions rightsof to publish
the and
published
distribute the manuscript detailed in this form and any tables,
manuscript in other works, including dissertations or books/book chapters, for both commercial figures, illustrations, and other
materials
and submitted as
non-commercial part of the manuscript (supplementary information) in print, electronic,
purposes.
and all other media (including
The undersigned author(s) understands future platforms
and agreesdeveloped),
to grant throughout the world,
JAFES exclusive rightsforto the full term
publish and
of copyright.
The undersigned
materials submitted author(s)
as partrecognizes that the JAFES
of the manuscript is an OPEN-ACCESS
(supplementary publication
information) in print,which allows
electronic,
third party users to share, copy and redistribute the published manuscript
and all other media (including future platforms developed), throughout the world, for the full term in any medium or
format, adapt,
of copyright. remix, transform, and build upon the published manuscript, for non-commercial
purposes throughauthor(s)
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recognizes thatAttribution-Non
the JAFES is anCommercial
OPEN-ACCESS userpublication
license (CCwhich BY-NC 4.0).
allows
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third party users to share, copy and redistribute the published manuscript in any medium or others to do the same as above
through adapt,
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SAVE
ICMJE Form for Disclosure of Potential Conflicts of Interest
Instructions
The purpose of this form is to provide readers of your manuscript with information about your other interests that could
influence how they receive and understand your work. The form is designed to be completed electronically and stored
electronically. It contains programming that allows appropriate data display. Each author should submit a separate
form and is responsible for the accuracy and completeness of the submitted information. The form is in six parts.
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This section asks for information about the work that you have submitted for publication. The time frame for this reporting is that of the
work itself, from the initial conception and planning to the present. The requested information is about resources that you received,
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without receiving any financial support from any third party -- that is, the work was supported by funds from the same institution that
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This section asks about your financial relationships with entities in the bio-medical arena that could be perceived to influence, or that
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that could be considered broadly relevant to the work. For example, if your article is about testing an epidermal growth factor receptor
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For grants you have received for work outside the submitted work, you should disclose support ONLY from entities that could be
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4. Intellectual Property.
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5. Relationships not covered above.

Use this section to report other relationships or activities that readers could perceive to have influenced, or that give the appearance of
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Definitions.
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academic institution, etc. Pending: The patent has been filed but not issued
Grant: A grant from an entity, generally [but not always] paid to your Issued: The patent has been issued by the agency
organization Licensed: The patent has been licensed to an en�ty, whether
Personal Fees: Monies paid to you for services rendered, generally earning royal�es or not
honoraria, royalties, or fees for consulting , lectures, speakers bureaus, Royalties: Funds are coming in to you or your institution due to
expert testimony, employment, or other affiliations your patent
Non-Financial Support: Examples include drugs/equipment
supplied by the entity, travel paid by the entity, writing assistance,
administrative support, etc.

252 ICMJE Form for Disclosure of Potential Conflicts of Interest
SAVE
Section 1. Identifying Information
1. Given Name (First Name) 2. Surname (Last Name) 3. Date
4. Are you the corresponding author? Yes No
5. Manuscript Title
6. Manuscript Identifying Number (if you know it)
Section 2. The Work Under Consideration for Publication

Did you or your institution at any time receive payment or services from a third party (government, commercial, private foundation, etc.) for
any aspect of the submitted work (including but not limited to grants, data monitoring board, study design, manuscript preparation,
statistical analysis, etc.)?
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Section 3. Relevant financial activities outside the submitted work.
Place a check in the appropriate boxes in the table to indicate whether you have financial relationships (regardless of amount
of compensation) with entities as described in the instructions. Use one line for each entity; add as many lines as you need by
clicking the "Add +" box. You should report relationships that were present during the 36 months prior to publication.
Are there any relevant conflicts of interest? Yes No
ADD
Section 4. Intellectual Property -- Patents & Copyrights
Do you have any patents, whether planned, pending or issued, broadly relevant to the work? Yes No

ICMJE Form for Disclosure of Potential Conflicts of Interest 253
SAVE
Section 5. Relationships not covered above

Are there other relationships or activities that readers could perceive to have influenced, or that give the appearance of
potentially influencing, what you wrote in the submitted work?
Yes, the following relationships/conditions/circumstances are present (explain below):

No other relationships/conditions/circumstances that present a potential conflict of interest
At the time of manuscript acceptance, journals will ask authors to confirm and, if necessary, update their disclosure statements.
On occasion, journals may ask authors to disclose further information about reported relationships.
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Journal of the
Patient Consent Form ASEAN Federation of

Endocrine Societies
PATIENT CONSENT FORM
PATIENT
For a patient’s CONSENT
consent to publication FORM
of information about them in the
Journal of the ASEAN Federation of Endocrine Societies (JAFES).
For a patient’s consent to publication of information about them in the
Journal of the ASEAN Federation of Endocrine Societies (JAFES).
Name of person described in article or shown in photograph:__________________________
Subject matter of photograph or article:___________________________________________
Name of person described in article or shown in photograph:__________________________
__________________________________________________________________________
Subject matter of photograph or article:___________________________________________
___________________________________________________________________________
__________________________________________________________________________
(The Subject matter of the photograph or article is hereafter termed as the “INFORMATION.”)
JAFES manuscript number:____________________________________________________
___________________________________________________________________________
Title of Subject
(The article:_______________________________________________________________
matter of the photograph or article is hereafter termed as the “INFORMATION.”)
JAFES manuscript number:____________________________________________________
__________________________________________________________________________
Title of article:_______________________________________________________________
__________________________________________________________________________
__________________________________________________________________________
Corresponding author:________________________________________________________
__________________________________________________________________________
Corresponding author:________________________________________________________
I, _________________________________________ , give my consent for this information
[please insert your full name]
I, _________________________________________
about MYSELF/MY CHILD OR WARD/MY RELATIVE , give my consentto for
relating thethis information
subject matter
[please encircle
[please insertcorrect description]
your full name]
about
above MYSELF/MY
to appear in theCHILD
JournalOR WARD/MY
of the RELATIVEofrelating
ASEAN Federation to the
Endocrine subject(JAFES)
Societies matter
[please encircle correct description]
above
subjecttoto appear in the Journal
its publication policiesof
andtheethical
ASEAN Federation of Endocrine Societies (JAFES)
standards.
Isubject
have seento itsand
publication
read the policies
material and
to beethical standards.
submitted to the JAFES and thoroughly understand the
following:
I •have
The Information will be
seen and read thepublished
materialin to
thebe
JAFES withouttomythe
submitted name.
JAFESIt is the
andobligation of theunderstand
thoroughly JAFES to make
the
all attempts,
following: within its reasonable jurisdiction and authority, to ensure my anonymity.
••The Information
The Information may also
will be be placedinon
published thethe JAFES’
JAFES website.
without my name. It is the obligation of the JAFES to make
• The JAFES shall not allow the Information to be
all attempts, within its reasonable jurisdiction and authority, ensure my or
used fortoadvertising packaging or to be used out of
anonymity.
•context (i.e., used to accompany an entirely different
The Information may also be placed on the JAFES’ website. article or topic).
••I canJAFES
The withdraw mynot
shall consent
allowatthe
anyInformation
time beforetopublication,
be used for butadvertising
once the Information hasoralready
or packaging to be been
used sent to
out of
press, it is my understanding that it will not be possible to revoke
context (i.e., used to accompany an entirely different article or topic). the consent.
• I can withdraw my consent at any time before publication, but once the Information has already been sent to
press, it is my understanding that it will not be possible to revoke the consent.
Signed:__________________________________ Date:______________________
[signature over complete name]
Signed:__________________________________ Date:______________________
[signature over complete name]
Witness:
Signed:__________________________________ Date:______________________
Witness: [signature over complete name]
Signed:__________________________________JAFES Office Date:______________________
2005, 25thover
Unit [signature complete
Floor, name]
Medical Plaza
Ortigas, Ortigas Center, Pasig City 1605
E-mail address: [email protected],
JAFES Office [email protected]
th Telefax: (+632) 86373162
Unit 2005, 25 Floor, Medical Plaza Ortigas, Ortigas Center, Pasig City 1605
E-mail address: [email protected], [email protected]
Telefax: (+632) 86373162

Peer Reviewers JAFES
Prof. Samir Naim Assaad, MD, MRCP(UK), FRCP (Edin) Prof. Ko Ko, MBBS, MMedSc (Int Med), MRCP, FRCP
University of Alexandria, Egypt (Edin), Dr Med Sc, Dip Med Ed
University of Medicine (2), Yangon, Myanmar
Prof. Aye Aye Aung, MBBS, MMed Sc (Int Med), MRCP
(UK), FRCP (Edin), DTM&H (London), Dr Med Sc Rebecca Lim Alba, MD, FPCP, FPSEDM
(Gen Med), Dip Med Ed Chinese General Hospital, Manila, Philippines
University of Medicine, Mandalay, Myanmar
Tom Edward N. Lo, MD, FPCP, FPSEDM
Prof. Moe Wint Aung, MBBS, MMed Sc (Int Med), Philippine General Hospital-University of the Philippines
MRCP (UK), FRCP (Edin), FRCP (London), Dr Med S Manila
(Gen Med), Dip Med Ed
University of Medicine (1), Yangon, Myanmar Dr. Dinesh Carl Junis Mahendran, MBBS (Hons),
FRACP
Prof. Than Than Aye, MBBS, MMed Sc (Int Med), Khoo Teck Puat Hospital, Singapore
MRCP (UK), FRCP (Edin), FRCP (London), DTM&H
(London), Dr Med Sc (Gen Med) Prof. Kyu Kyu Maung, MBBS, PhD (Kumamoto),
Professor Emeritus, University of Medicine (2), Dip Med Ed
Yangon, Myanmar University of Medicine (1), Yangon, Myanmar
Pia D. Bagamasbad, PhD Timothy Joseph S. Orillaza, MD, FPCR, FPSVIR,

National Institute of Molecular Biology and Biotechnology FCTMRI
University of the Philippines, Diliman The Medical City, Pasig City, Philippines
Hartanto Bayuaji, MD, PhD Paul Matthew D. Pasco, MD, FPNA

Universitas Padjadjaran, Bandung, Indonesia College of Medicine, University of the Philippines Manila
Winston Kon Yin Chian, FRCPE, FAMS (Endocrinology), Amanda Lam Yun Rui, MBBS, MRCP (UK), MMed
FACE Singapore General Hospital
Tan Tock Seng Hospital
Jalan Tan Tock Seng, Singapore Chee Keong See MD (UPM), MRCP (UK), MRCPS
(Glasgow), Fellowship Endocrinology and Diabetes (Mal)
Mary Anne D. Chiong, MD, MSc, FPPS Hospital Sultan Haji Ahmad Shah, Pahang, Malaysia
Philippine General Hospital–University of the Philippines
Manila Thiti Snabboon, MD
Chulalongkorn University, Bangkok,Thailand
Prof. David S. Cooper, MD, FACE
The Johns Hopkins University School of Medicine, Edison So, MD, DPCP, DPSEDM
Baltimore, Maryland, USA St. Luke's Medical Center, Global City, Taguig, Philippines
Raymond E. dela Rosa, MD Seng Kiong Tan, MBBS (Singapore), MMed

Millennium Physician Group (Int Medicine), MRCP (UK)
Englewood, Florida, USA Khoo Teck Puat Hospital, Singapore
Prof. Rohanna Abdul Ghani, MMed (UKM) Prof. Khin Saw Than, MBBS, MMed Sc (Int Med), MRCP
Universiti Teknologi MARA (UiTM), Malaysia (UK), FRCP (Edin), DTM & H (London), Dr Med Sc
(Gen Med), Dip Med Sc (Medical Education)
Maria Antonia E. Habana, MD, MSc, FPOGS, FPSRM, Grand Hanthar International Hospital, Yangon, Myanmar
FPSGE
College of Medicine, University of the Philippines Manila Beatrice J. Tiangco, MD
The Medical City, Pasig City, Philippines
Tien-Shang Huang, MD
National Taiwan University & Cathay General Catherine Anne Pangilinan Vazquez, MD, DPPS, FPSPME
Hospital, Taipei, Taiwan Manila Doctors Hospital, Philippines
Prof. Dr Muhammad Yazid Jalaludin, MD Assoc. Prof. Wan Mohd Izani Wan Mohamed
University of Malaya Universiti Sains Malaysia
Kuala Lumpur, Malaysia
Marc Gregory Yu, MD, FPCP, FPSEDM
Alvin M. Jorge, MD, FPCS Joslin Diabetes Center, Boston, USA
Cosmedics A Dermaster Clinic, Bonifacio Global City,
Taguig, Philippines

The Philippine Society of Endocrinology,
Diabetes and Metabolism, Inc.
and
The Philippine Specialty Board of Endocrinology,
Diabetes and Metabolism
wish to announce the dates for the
Written and Oral Examination for
Diplomate in Endocrinology, Diabetes and Metabolism
JANUARY 22, 2021 (Friday)

WRITTEN EXAMINATION
JANUARY 24, 2021 (Sunday)

ORAL EXAMINATION
For further details, please contact:
THE PSEDM SECRETARIAT

Units 2005-2006, 20/F, Medical Plaza Ortigas,
San Miguel Avenue, Ortigas Center, Pasig City, Philippines
Tel. No.: 632-8633-6420 Fax No: 632-8637-3162
Email: [email protected]
Website: www.endo-society.org.ph

11
MEMS ANNUAL CONGRESS
2021
Pre-Congress: Congress:
29th July 2021 30th July to 1st August 2021
Hilton & Le Méridien Kuala Lumpur, Malaysia
UNRAVELLING THE INTRICACIES IN ENDOCRINOLOGY
MASTERCLASS IN
THYROID CARCINOMA
29th July 2021 l Clarke Ballroom, Level 6, Le Meridien Kuala Lumpur
OBJECTIVE WHO SHOULD ATTEND

To provide the latest updates & Surgeons / Endocrinologists /
discussions on the investigations Oncologists / Nuclear Medicine
and multimodal treatment Physicians / Radiologists /
options for Thyroid Carcinoma Pathologists / General
Physicians / Paediatricians /
Medical Officers / Trainees
CALL FOR ABSTRACTS!

Stand a chance to present your work in the upcoming MEMS Annual Congress MAC 11, for the year 2021.
In addition, all accepted abstract will be published in the Journal of the ASEAN Federation of Endocrine Societies
(JAFES), or in a Supplementary copy.
Submission Deadline:
Abstracts submitted & accepted for Oral
Presentation by first author/presenter Young 31st May 2021
who are 40 years old or younger in 2021
will stand a chance to compete for
Investigator Acceptance Notice:
the prestigious Award 30th June 2021
Find out more details & submit your abstract online: www.memsmac.org/callForAbstracts.php
Find out more about registration at www.memsmac.org


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Indexed in Now Indexed in

Primary Partial Empty Sella

Bilateral Genu Valgum in an

N Federation of Endocrine Societies

20TH INTERNATIONAL CONGRESS OF ENDOCRINOLOGY

Held in Supported by Managed by

* This Advertisement is a complimentary service of the JAFES for member societies/organizations.

Copyright © 2017 by the Journal of the ASEAN Federation of Endocrine Societies

JERICO B. GUTIERREZ CASE SERIES

Emerging Sources Citation Index

Better Normal, A Silver Lining in 2020:

Vol. 35 No. 2 November 2020 www.asean-endocrinejournal.org 151

US National Library of Medicine

www.asean-endocrinejournal.org Vol. 35 No. 2 November 2020

We are pleased to announce that the

This achievement is a significant addition to the JAFES’ list of

COVID-19 and Thyroid Diseases:

Key words: COVID-19, thyroid disease, hyperthyroidism, hypothyroidism, thyroid cancer

INTRODUCTION Autopsy findings in patients with SARS showed destruction

Pathobiology Thyroid disorders may be generally divided to three major

Vol. 35 No. 2 November 2020 www.asean-endocrinejournal.org 155

www.asean-endocrinejournal.org Vol. 35 No. 2 November 2020

Table 1. Conditions that warrant urgent (<4 weeks) thyroid surgery

Other issue is about radioactive iodine therapy during Funding Source

Vol. 35 No. 2 November 2020 www.asean-endocrinejournal.org

Clinical Characteristics, Residual Beta-Cell Function

INTRODUCTION clinical endpoint in clinical trials. However, the clinical

158 www.asean-endocrinejournal.org Vol. 35 No. 2 November 2020

Objectives 3-6 months apart. Neuropathy was detected based on

Vol. 35 No. 2 November 2020 www.asean-endocrinejournal.org

From a total of 89 T1DM cases in our hospital, 20

www.asean-endocrinejournal.org Vol. 35 No. 2 November 2020

Vol. 35 No. 2 November 2020 www.asean-endocrinejournal.org

www.asean-endocrinejournal.org Vol. 35 No. 2 November 2020

Prevalence of Vitamin B12 Deficiency and its Associated Factors

INTRODUCTION early detection and treatment are clinically important in

Vol. 35 No. 2 November 2020 www.asean-endocrinejournal.org 163

www.asean-endocrinejournal.org Vol. 35 No. 2 November 2020

Table 1. Baseline demographics according to Vitamin B12 levela

Vol. 35 No. 2 November 2020 www.asean-endocrinejournal.org

Table 3. Multiple logistic regression analysis

www.asean-endocrinejournal.org Vol. 35 No. 2 November 2020

Vol. 35 No. 2 November 2020 www.asean-endocrinejournal.org

Data Collection Sheet

www.asean-endocrinejournal.org Vol. 35 No. 2 November 2020

The Association between Maternal Serum Vitamin D Levels

Key words: gestational diabetes mellitus, gestational diabetes, vitamin D deficiency

Introduction history of abnormal glucose metabolism and polycystic

Vol. 35 No. 2 November 2020 www.asean-endocrinejournal.org 169

www.asean-endocrinejournal.org Vol. 35 No. 2 November 2020

Table 1. Eligibility criteria of 92 mg/dl; 1-hour post-OGTT of 180 mg/dl; or 2-hour

Pregnant women included in the study

Total vitamin D Total vitamin D

Low vitamin D Normal vitamin D Low vitamin D Normal vitamin D

Figure 1. Schematic diagram of study design from time of inclusion of participants.

Vol. 35 No. 2 November 2020 www.asean-endocrinejournal.org

Table 2. Baseline characteristics

Table 3. Vitamin D levels among patients with GDM

www.asean-endocrinejournal.org Vol. 35 No. 2 November 2020

Indicates significant difference (p<0.001) Indicates significant difference (p<0.01)