journal of the society of endocrinology and … · 2019-05-09 · sevim güllü, md...

JOURNAL OF THE SOCIETY OF ENDOCRINOLOGY AND METABOLISM OF TURKEY

OWNER ON BEHALF OF THE SOCIETY OF ENDOCRINOLOGY AND METABOLISM OF TURKEYSevim Güllü, MD

MANAGING CLERICAL DIRECTORNilgün Başkal, MD

ADRESS FOR MANAGEMENTThe Society of Endocrinology and Metabolism of TurkeyMeşrutiyet Caddesi No: 29/12 Kızılay, Ankara, TURKEYPhone: +90 312 425 20 72Fax: +90 312 425 20 98web: www.turkjem.orgE-mail: [email protected]

Publication Type and PeriodsTurkish Journal of Endocrinology and Metabolism is published 4 (March, June, September and December) times a year.

Local perid publication.

The Turkish Journal of Endocrinology and Metabolism is indexed in Emerging Sources of Citation Index (ESCI),British Library, CINAHL, Directory of Open Access Journals (DOAJ), EBSCO, EMBASE, SCOPUS,Tübitak / Ulakbim TR Index, TürkMedline, Türkiye Citation Index.

For requests concerning subscription information and advertising, please contact the Publisher:

Publishing House: Türkiye KlinikleriAddress: Nasuh Akar Mah. Türkocağı Cad. No:30 Balgat - Ankara TurkeyTelephone: +90 312 286 56 56Fax: +90 312 220 04 70E-mail: [email protected] page: www.turkiyeklinikleri.com

The services of “Article Tracking (Automation)”, “Layout”, “Web Site Design-Operation” and “e-Mailing” are provided

by Türkiye Klinikleri.

Publication Date: 11.04.2018

ISSN: 1301-2193E-ISSN: 1308-9846

Owner on Behalf of the Society ofEndocrinology and Metabolism of TurkeySevim Güllü, Ankara, Turkey

Editor-In-ChiefNilgün Başkal, Ankara, Turkey

Deputy EditorMurat Faik Erdoğan, Ankara, Turkey

Associate EditorsHasan Ali Altunbaş, Antalya, TurkeyDilek Gogas Yavuz, İstanbul, TurkeySerkan Yener, İzmir, Turkey

Statistical ConsultantAtilla Halil Elhan, Ankara, TurkeyLevent Dönmez, Antalya, TurkeyDerya Öztuna, Ankara, TurkeyCan Ateş, Van, Turkey

Language EditorJennifer Gabriel, California, USA

Honorary BoardSema Akalın, İstanbul, TurkeyMetin Arslan, Ankara, TurkeyGürbüz Erdoğan, Ankara, TurkeyOlcay Gedik, Ankara, TurkeySadi Güngoğdu, İstanbul, TurkeyHüsrev Hatemi, İstanbul, TurkeyŞazi İmamoğlu, Bursa, TurkeyTaylan Kabalak, İzmir, TurkeySenay Molvalılar, İstanbul, TurkeyCandeğer Yılmaz, İzmir, Turkey

Editorial BoardErsin Akarsu, Gaziantep, TurkeyMüjde Aktürk, Ankara, Turkeyİnan Anaforoğlu, İstanbul, TurkeyAyşegül Atmaca, Samsun, TurkeyMustafa Kemal Balcı, Antalya, TurkeyNeslihan Başçıl Tütüncü, Ankara, TurkeyDavid Baylink, California, UsaFahri Bayram, Kayseri, TurkeyMehtap Çakır, İzmir, TurkeyAbdurrahman Çömlekci, İzmir, TurkeySelçuk Dağdelen, Ankara, TurkeyLeslie J. Degroot, Kingston, UsaTomris Erbaş, Ankara, TurkeyMehmet Erdoğan, İzmir, TurkeyEda Ertörer, Adana, TurkeyJohn W. Funder, Victoria, AustraliaHossein Gharib, Minnesota, UsaNilgün Güvener, İstanbul, TurkeySerdar Güler, Ankara, TurkeyAlptekin Gürsoy, Ankara, TurkeyZeliha Hekimsoy, Manisa, TurkeyLarry Jameson, Philadelphia, Usa

Pınar Kadıoğlu, İstanbul, TurkeyPierre J. Lefebvre, Liege, BelgiumMesut Özkaya, Gaziantep, Turkeyİlhan Satman, İstanbul, TurkeyFüsun Saygılı, İzmir, TurkeyAlper Sönmez, Ankara, Turkeyİbrahim Şahin, Malatya, TurkeyMustafa Şahin, Ankara, TurkeyKubilay Ukinç, Çanakkale, TurkeyBetül Uğur Altun, İstanbul, TurkeyKürşad Ünlühızarcı, Kayseri, TurkeyAyşe Kubat Üzüm, İstanbul, TurkeyAnthony Weetman, Sheffield, UKBülent Okan Yıldız, Ankara, Turkey

Advisory BoardFaruk Alagöl, İstanbul, TurkeyYalçın Aral, Ankara, TurkeyGöksun Ayvaz, Ankara, TurkeyÖmer Azal, Ankara, TurkeyErol Bolu, İstanbul, TurkeyBerrin Çetinarslan, Kocaeli, TurkeyAhmet Çorakçı, Ankara, TurkeyHatice Sebila Dökmetaş, İstanbul, TurkeyBelgin Efe, Eskişehir, TurkeySevinç Eraslan, İzmir, TurkeySait Gönen, İstanbul, TurkeyAhmet Kaya, Konya, TurkeyFahrettin Keleştimur, Kayseri, TurkeyMustafa Kutlu, Ankara, TurkeyTümay Sözen, Ankara, TurkeyRefik Tanakol, İstanbul, TurkeyAli Rıza Uysal, Ankara, TurkeySema Yarman, İstanbul, Turkey

JOURNAL OF THE SOCIETY OF ENDOCRINOLOGY AND METABOLISM OF TURKEYJOURNAL OF THE SOCIETY OF ENDOCRINOLOGY AND METABOLISM OF TURKEY


AIMS AND SCOPE

The Turkish Journal of Endocrinology and Metabolism isthe peer-reviewed periodical on clinical and experimen-tal endocrinology and metabolism diseases and relatedfields. It is the official journal of the Society of Endocri-nology and Metabolism of Turkey and is published quar-terly (March, June, September and December) ashardcopy and an electronic journal at www.turkjem.org.The manuscripts are published in English language.The journal publishes original research papers, reviewsand case reports which primarily focus on clinical endoc-rinology. The journal's aim is to be the essential readingfor both endocrinologists and clinical practitioners.

Open Access PolicyThe Turkish Journal of Endocrinology and Metabolism isan open access journal. This journal provides immediateopen access to its content on the principle that makingresearch freely available to the public supports a greaterglobal exchange of knowledge.Open Access Policy is based on rules of Budapest Open Ac-cess Initiative (BOAI) http://www.budapestopenaccessini-tiative.org/.Instructions for online manuscript submission, current is-sues and archives of the journal can be found atwww.turkjem.org. Please do not send manuscripts to theeditorial office. For other related issues you may contactthe editorial office:

Subscription informationThe Turkish Journal of Endocrinology and Metabolism isdistributed free of charge to all endocrinology academici-ans and instructors serving in our country. Access to full-text articles of all issues of the journal is free at thejournal's website www.turkjem.org

Instructions for authorsInstructions for authors are published in the journal pagesand can be accessed at the web site of the journalwww.turkjem.org

Material DisclaimerStatements or opinions expressed in the manuscriptspublished in the Turkish Journal of Endocrinology and Me-tabolism reflect the views of the author(s) and are notthe opinions of the editors, the editorial board and thepublisher. The editors, editorial board and the publisherdisclaim any responsibility or liability for such materials.

The journal is printed on acid-free paper.

All rights are reserved. Rights to the use and reproduction, including in the electronic media, of all communications, papers, photographs and illustrations appea-ring in this journal belong to the Turkish Journal of Endocrinology and Metabolism. Reproduction without prior written permission of part or all of any material isforbidden. The journal complies with the Professional Principles of the Press.

The paper used the print this journal conforms to ISO 9706: 1994 standard (Requirements for Permanence). The National Library of medicine suggests that bio-medical publications be printed on acid free paper (alkaline paper).

Reviewing the articles’ conformity to the publishing standards of the Journal, typesetting, reviewing and editing and editing the manuscripts and abstracts in En-glish and publishing process are realized by Türkiye Klinikleri.


INSTRUCTIONS FOR AUTHORSTurkish Journal of Endocrinology and Metabolism issues papers on all as-pects of endocrinology. The journal is the scientific publishing organ of theSociety of Endocrinology and Metabolism of Turkey and has been publishedquarterly (March, June, September and December) since 1997.In additionto original articles, case reports, review articles, letters to the editor, edu-cational articles, sections of question and answers, abstracts from litera-ture and announcements of congresses/meetings are also published.Turkish Language Institution dictionary and orthography guide should betaken as basic for literary. The idioms used should be checked.The scien-tific and ethical liability of the manuscripts belongs to the authors and thecopyright of the manuscripts belongs to the Turkish Journal of Endocrinol-ogy and Metabolism. The authors should submit the signed copyright trans-fer form together with their manuscripts. Authors are responsible for thecontents of the manuscript and accuracy of the references.The authorsshould guarantee that their manuscripts has not been published and/or isnot under consideration for publication in any other periodical. This re-quirement does not apply to papers presented in scientific meetings andwhose summaries, not exceeding 250 words, are published. In this case,however, the name, date and place of the meeting in which the paper waspresented should be stated. The signed statement of scientific contribu-tions and responsibilities of all authors is required.The Turkish Journal of Endocrinology and Metabolism does not charge anyarticle submission or processing charges.

Peer-reviewEditorial policies of the journal are conducted according to the rules ad-vised by Council of Science Editors and reflected in the Uniform Require-ments for Manuscripts Submitted to Biomedical Journals: Writing andEditing for Biomedical Publication (http://www.icmje.org/).Submitted manuscripts are subjected for double-blind peer-review. Thescientific board guiding the selection of the papers to be published in theJournal consists of elected experts of the Journal and if necessary, selectedfrom national and international experts in the relevant field of research.All manuscripts are reviewed by the editor, section associate editors and atleast three internal and external expert referees. All research articles un-dergo review by statistical editor as well.Submitted manuscripts are also subjected for the evaluation of plagiarism, du-plicate publication by automatic software. Authors are obliged to acknowledgeif they published study results in full or in part in form of abstracts.The authors of the accepted manuscripts should be in consent that the ed-itor and associate editors could make corrections without changing themain text of the paper.Manuscript format should be in accordance with Uni-form Requirements for Manuscripts Submitted to Biomedical Journals:Writing and Editing for Biomedical Publication (http://www.icmje.org/).

General GuidelinesManuscripts can only be submitted electronically through the web site(http://www.turkjem.org) after creating an account. This system allowsonline submission and peer-review.The manuscripts are archived accord-ing to ICMJE-www.icmje.org, Index Medicus (Medline/PubMed) and Ulak-bim-Turkish Medicine Index Rules. Rejected manuscripts, except artworkare not returned.For the experimental, clinical and drug human studies, approval byethical committee and statement on the adherence of the study protocolto the international agreements (Helsinki Declaration revised 2013(www.wma.net/en/30publications/10policies/b3/) are required. In exper-imental animal studies, the authors should indicate that the proceduresfollowed were in accordance with animal rights (Guide for the care anduse of laboratory animals, www.nap.edu.catalog/5140.html) and

they should obtain animal ethic committee approval. The Ethic Committeeapproval document should be submitted to the Turkish Journal of En-docrinology and Metabolism together with the manuscript.The approval of the ethic committee, statement on the adherence to interna-tional guidelines mentioned above and that the patients` informed consent isobtained should be indicated in the `Material and Method` section and is re-quired for case reports whenever data/media used could reveal identity of thepatient. The declaration of the conflict of interest between authors, institu-tions, acknowledgement of any financial or material support, aid is mandatoryfor authors submitting manuscript and the statement should appear at theend of manuscript. Reviewers are required to report if any potential conflict ofinterest exists between reviewer and authors, institutions.

Original ArticlesClinical research should comprise clinical observation, new techniques orlaboratory studies. Provided that these manuscripts are written with lower-case letters, they should include the title in Turkish/English, the back-ground and the key words in Turkish/English, introduction, materials andmethods, results (findings), discussion, references, tables, charts, picturesand they should be written in accordance with Journal Agent rules. Theyshould not exceed sixteen (A4) pages.It is recommended to present research articles and meta-analysis/systematicreviews article according to the guidelines on specific design of the study: ran-domized studies (CONSORT), observational studies (STROBE), studies on di-agnostic accuracy (STARD), meta- analysis and systematic review (PRISMA,MOOSE) and other study designs (www.equator-network.org).

Author InformationThe name and the surname of the authors should be written without ab-breviation. The academic titles, the affiliations and the addresses of theseaffiliations should be clearly declared. Furthermore, the contact informationof the corresponding author should be entered to the system. Since e-mailwill be used primarily for the contact with the authors, the e-mail of thecorresponding author should be indicated. In addition the phone and thefax numbers should be also indicated.

Title PageThis page should include the titles of the manuscript, key words and runningtitles. In Turkish manuscripts the title in English should also take place.Likely, Turkish title should be mentioned for articles in foreign language. Ifthe content of the paper has been previously presented or its abstract hasbeen published, an explanation should be made in this page about this issue.If there are any grants and other financial supports by any institutions orfirms for the study, information must be provided by the authors.

AbstractTurkish and English summaries of the manuscript should take place in amanner that it will not exceed 250 words. The keywords should be writtenat the end of the summary. The references should not be cited in the sum-mary section. As far as possible, use of abbreviations is to be avoided. Ifany abbreviations are used, they must be taken into consideration inde-pendently of the abbreviations used in the text. The summary should bewritten with four running titles.Purpose: The goal of the study should be clearly stated.Material and Method: The study should be defined, the standard crite-ria; it should be also indicated whether the study is randomized or not,whether it is retrospective or prospective, the statistical method, if any,should be indicated.Results (Findings): The detailed result of the study should be given andthe statistical significance level should be indicated.


INSTRUCTIONS FOR AUTHORSDiscussion: It should reflect the results of the study, the favorable and un-favorable aspects should be declared.Key words: At least three and maximum eight key words. (in English and inTurkish) Do not use abbreviations in the key words. Turkish key words will beprovided by the editorial office for the authors who are not Turkish speakers.If you are not a native Turkish speaker, please re-enter your English keywordsto the area provided for the Turkish keywords. English key words should beprovided from Medical Subject Headings (http://www.nlm.nih.gov/mesh/)while Turkish key words should be provided from http://www.bilimterim-leri.com.Original researches should have the following sections;IntroductionBrief explanation about the topic should be done, the objective of the studyshould be indicated and these should be supported by the literature infor-mation.Materials and MethodsThe study design should be described, it should be indicated whetherit is interventional randomized or observational, whether it is retrospec-tive or prospective, the number of trials, the characteristics, studied vari-ables and specific methods, the used statistical methods should be indicated.If any, it should be indicated that the results should be scrutinized.Results (Findings)The results should be given, the tables and the pictures should be given innumerical order and, the results should be indicated as % and/or p-values.DiscussionThe obtained values should be discussed with its favorable and unfavorableaspects and, they should be compared with literature.Study Limitations: Study Limitations and strengths, and directions forfurther research or implication must be discussed.Conclusion: The conclusion of the study should be highlighted.Authors contributions, Declaration of conflict of interest and Acknowledge-ments should appear at the end of the main text of manuscript.ReferencesAccuracy of reference data is the author’s responsibility. Referencesshould be numbered according to the consecutive citation in the text.References should be indicated by parenthesis in the text. If thereis Turkish Reference, attention should be paid to indicate this. Journaltitles should be abbreviated according to the style used in the IndexMedicus. All the references, books, papers and similar articles shouldbe cited as references should be written according to the rules of theInternational Committee of Medical Journal Editors Uniform Require-ments for Manuscripts Submitted to Biomedical Journals(http://www.nlm.nih.gov/bsd/uniform_requirements.html).Journal: The surnames of the authors and the initial of authors’ names,the title of the paper, the title of the journal (the original abbreviationstated in the journal), year, volume and the page numbers.Example: Collin JR, Rathbun JE. Involutional entropion: a review withevaluation of a procedure. Arch Ophthalmol. 1978;96:1058-1064.Book with a Single Author: The surname and the initial of the author,the title, chapter and section, the name of the editor, title of the book, placeof publication, name of the printing house, year of print, page numbers.Example: Herbert L. Conjunctivitis, keratitis and infections of periorbitalstructures. In: Armstrong D, Cohen J, eds. The Infectious Diseases (1sted). Philadelphia; Mosby Harcourt; 1999;11;1-8.

Book Chapter: The surname and the initial of the author, chapter and sec-tion, name of the editor, title of the book, place of publication, name of theprinting house, year of print, page numbers.Example: O’Brien TP, Green WR. Periocular Infections. In: Feigin RD,Cherry JD, eds. Textbook of Pediatric Infectious Diseases (4th ed). Philadel-phia; W.B. Saunders Company;1998:1273-1278.Visual Materials (Tables, Graphics, Figures, and Pictures): All tables,graphics or figures should be enumerated according to the sequence withinthe text and a brief descriptive caption should be written. The abbreviationsused should be definitely explained in the figure’s legend. Especially, thetext of tables should be easily understandable and should not repeat thedata of the main text. Illustrations that already published are acceptable ifsupplied by permission of authors for publication. The details of the pic-tures should be distinguishable and they should be recorded in JPEG for-mat and in 500 pixels per inch at least.Case ReportsIt should consist of the title, summary, key words, summary in English,keywords, introduction, case report, discussion and references, thecase or the cases should be worth to be presented, it should contribute toliterature, and all of them should not exceed 5 papers in (A4) sizes.ReviewIt should include new topics, the own experiences of the author, if possi-ble, and the references also. It should consist of the title in Turkish, thesummary, the keywords, the title in English, the summary in English andthe keywords in English.Letters to the EditorThey should be assays in the “review” manner in various topics or the as-says concerning the articles published in the Turkish Journal of En-docrinology and Metabolism with the contributive content or contents asquestions that do not exceed 200 words.Scientific LettersThe manuscripts should be error-free in the summaries compiled from thearticles in other journals, the author names (surname, name) should bewritten, the journal title should be written with its original abbreviation, itsyear should be indicated and, the name and he surname of the translatorshould be indicated under the manuscript.Open Access PolicyThis journal provides immediate open access to its content on the princi-ple that making research freely available to the public supports a greaterglobal exchange of knowledge.

CorrespondenceAll correspondences can be done to the following postal address or to thefollowing e-mail address, where the journal editorial resides:Address: Ankara University Faculty of Medicine, Department of En-docrinology and Metabolism, Ankara, TurkeyPhone: +90 312 508 21 00Fax: +90 312 309 45 05E-mail: [email protected]

“This journal licenced under the terms of the Creative Commons 4.0 In-ternational Licence (CC BY 4.0)”

CONTENTS

Original Articles1 Serum Heart Type Fatty Acid Binding Protein Levels in Primary Hyperparathyroidism

Primer Hiperparatiroidizmde Serum Kalp Tipi Yağ Asidi Bağlayıcı Protein DüzeyleriBekir Uçan, Mustafa Şahin, Mustafa Özbek, Mustafa Çalışkan, Muhammed Kızılgül,Gülfer Öztürk, Mehmet Akif Öztürk, Erman Çakal

7 Clinical Value of Histogram Analysis Using Gray-Scale Ultrasound Images in ThyroiditisTiroiditlerde Gri Skala Ultrason Görüntülerinin Histogram Analizinin Klinik DeğeriHatice Ayça Ata Korkmaz, Mustafa Köse

16 Cytologic Comparison Between Growing and Non-growing Benign Thyroid Nodules Evaluated UsingTwo Different Growth Criteriaİki Farklı Büyüme Kriterine Göre Büyüyen ve Büyümeyen Benign Nodüllerin Sitolojik KarşılaştırmasıMehmet Muhittin Yalçın, Sena Yeşil, Barış Akıncı, Fırat Bayraktar, Abdurrahman Çömlekçi,Sinan Ünal, Aytaç Gülcü, Sevinç Eraslan, Tülay Canda

21 Ratio of Thyrotropin to Thyroglobulin as a Novel Marker for Differentiating BetweenBenign and Malignant Thyroid Nodules within Different Bethesda CategoriesBenign ve Malign Tiroid Nodüllerinin Ayrımında ve Farklı Bethesda KategorilerindeYeni Bir Belirteç Olarak Tirotropin Tiroglobulin OranıAbbas Ali Tam, Didem Özdemir, Cevdet Aydın, Muhammet Cüneyt Bilginer,Mustafa Ömer Yazıcıoğlu, Nuran Süngü, Reyhan Ersoy, Bekir Çakır

Review Article32 Implication of Findings from International Studies on Hypoglycemia for Management of Diabetes

in Insulin-treated Patients in TurkeyHipoglisemi ile İlgili Uluslararası Çalışmalardaki BulgularınTürkiye’de İnsülin Tedavisi Gören Hastalarda Diyabet Yönetimine EtkileriRıfat Emral, Ramazan Sarı, Serdar Güler

March 2018 Volume: 22 Issue: 1


Case Reports41 A Different Cause of Malignant Hypercalcemia in a Breast Carcinoma with Bone Metastasis

Kemik Metastazı Olan Meme Kanserli Bir Hastada Malign Hiperkalseminin Farklı Bir NedeniBünyamin Aydın, Sevim Süreyya Çerçi, Murat Koçer, Banu Kale, Pınar Talip Bülbül,Fatih Çolak, Mustafa Yıldız, Celal Çerçi

45 Two Siblings with Triple-A Syndrome: Endocrinologic and Neurologic FeaturesTriple A Sendromlu İki Kardeş: Endokrinolojik ve Nörolojik ÖzelliklerNilüfer Özdemir Kutbay, Fatma Keklik, Banu Sarer Yürekli, Gökçe Kavasoğlu, Nevin Oruç,Mehmet Erdoğan, Şevki Çetinkalp, Gökhan Özgen, Füsun Saygılı

50 Pregnancy-Associated Osteoporosis: Long-term Follow-up of a Patient with Two PregnanciesGebelikle İlişkili Osteoporoz: İki Gebeliği Boyunca Hastanın Uzun Dönem TakibiAslıhan Taraktaş, Feyza Ünlü Özkan, Özge Gülsüm İlleez, Duygu Geler Külcü, İlknur Aktaş

Invited Review54 Review of Clinical Recommendations on Prolactinoma and Pregnancy

Prolaktinoma ve Gebeliğe Dair Klinik Önerilerin Gözden GeçirilmesiGülşah Yenidünya Yalın, Sema Çiftçi Doğanşen, Sema Yarman


EDITORIAL

DDeeaarr eesstteeeemmeedd rreeaaddeerrss ooff TTuurrkkJJEEMM FFaammiillyy,,

Industrialization and mass production globally is believed to be causing climate change with drastic temperature changesin the northern hemisphere; while very cold weather in Germany and UK but mild winter in Balkans. In this letter a focus inan area which endocrinology and metabolism discipline’s importance from a very different perspective. Study conductedin UK by Amanda Hughes and Meena Kumariand focuses on the unemployment, underweight, and obesity interaction.Statistically significant results for elevated morbidity and mortality among jobseekers may be partly explained by adipos-ity. Research done in 2016 asks the question whether unemployment is associated with being overweight and obesity.They used unemployment and body mass index (BMI) data for different groups to justify their hypothesis. In short theyconcluded that unemployment is associated with underweight and in nonsmokers, obesity. Unemployment was positivelyassociated with underweight and negatively associated with overweight, with effects more apparent for longer-term job-seekers, men, and jobseekers from lower-income households.

In a world of want where 1.4 billion people are struggling to survive on $1.25 a day, Hedwig Lee asks the question howpoverty leads to obesity and life-long problem. All these findings show that we are in vicious circle of poverty triggeringobesity, and obesity and overweight positively associated by unemployment which further deteriorates the income level.Treatment of obesity and related metabolic diseases has direct affects as well as social and economic consequences wherea holistic as well as differentiated approach is lacking. Global academia’s focus on humanity and its wellbeing should andwill focus on these primary, secondary and tertiary relations in time.

With such focus in mind for this issue of TJEM we have the following researches as contributions: “Serum Heart Type FattyAcid Binding Protein Levels in Primary Hyperparathyroidism”, “Clinical Value of Histogram Analysis Using Gray-Scale Ul-trasound Images in Thyroiditis”, “Cytologic Comparison Between Growing and Non-growing Benign Thyroid Nodules Eval-uated Using Two Different Growth Criteria”, “Ratio of Thyrotropin to Thyroglobulin as a Novel Marker for DifferentiatingBetween Benign and Malignant Thyroid Nodules within Different Bethesda Categories”, “Implication of Findings from In-ternational Studies on Hypoglycemia for Management of Diabetes in Insulin-treated Patients in Turkey”, “A Different Causeof Malignant Hypercalcemia in a Breast Carcinoma with Bone Metastasis”, “Two Siblings with Triple-A Syndrome: En-docrinologic and Neurologic Features”, “Pregnancy-Associated Osteoporosis: Long-term Follow-up of a Patient with TwoPregnancies” and “Review of Clinical Recommendations on Prolactinoma and Pregnancy”.

Spring is not too far; let’s keep our hopes for more rigorous research for overcoming obesity, diabetes and metabolic dis-eases. I wish you all a happy new season and a good reading.

WWiitthh mmyy bbeesstt rreeggaarrddss,,

NNiillggüünn BBaaşşkkaall MMDDEEddiittoorr--iinn--CChhiieeff


Original ArticleTurk J Endocrinol Metab 2018;22:1-6

Serum Heart Type Fatty Acid BindingProtein Levels in Primary Hyperparathyroidism

Primer HiperparatiroidizmdeSerum Kalp Tipi Yağ Asidi Bağlayıcı Protein Düzeyleri

University of Health Sciences, Dışkapı Yıldırım Beyazıt Training and Research Hospital, Clinic of Endocrinology and Metabolism, Ankara, Turkey*Ankara University Faculty of Medicine, Department of Endocrinology and Metabolism, Ankara, Turkey

**University of Health Sciences, Dışkapı Yıldırım Beyazıt Training and Research Hospital, Clinic of Biochemistry, Ankara, Turkey***Gazi University Faculty of Medicine, Department of Rheumatology, Ankara, Turkey

DO

I:10

.251

79/t

jem

.201

7-57

329

Purpose: Recent studies indicate that plasma heart-typefatty acid binding-protein (H-FABP) concentration can beused as an early biochemical marker for macrovascular di-seases. Patients with primary hyperparathyroidism (PHT)reportedly display an increase in cardiovascular (CV) riskfactors. Our aim was to evaluate plasma H-FABP concen-tration in these subjects with primary hyperparathyroidism,by comparing them with healthy controls.Material and Method: Anthropometric parameters, serumH-FABP, serum lipid, serum calcium, phosphorus, parathor-mone (PTH), insulin resistance (HOMA-IR), high sensitiveC-reactive protein (h-CRP), 24-hour urine microalbuminexcretion and carotid intima-media thickness (CIMT) wereevaluated among primary hyperparathyroidism patients (8males, 80 females) and 87 healthy subjects (12 males, 75females).Results: No significant difference was seen in the levels ofH-FABP between patients [1086.07 (298-3744)] and con-trols [1113.36 (263.27-3510)]. The average values of PTH,HOMA-IR, total cholesterol, LDL cholesterol, triglyceridesand calcium and mean CIMT were found to be significantlyhigher in patients with primary hyperparathyroidism(p<0.05). H-FABP was positively correlated with age, fas-ting blood glucose, BMI, and HsCRP.Discussion: H-FABP levels correlated with some of the CVrisk factors like age, fasting blood glucose, BMI, and h-CRP,moreover no difference in H-FABP levels was seen amongpatients of primary hyperparathyroidism having no cardiacdisease.

Keywords: Hyperparathyroidism; H-FABP;cardiovascular risk

Amaç: Son dönem yapılan çalışmalar, plazma kalp tipi yağasidi bağlayıcı protein (H-FABP) konsantrasyonunun mak-rovasküler hastalıklar için erken biyokimyasal bir belirteçolarak kullanılabileceğini göstermektedir. Primer hiper-paratiroidizmli hastalarda kardiyovasküler risk faktör-lerinin arttığı bildirilmektedir. Bu çalışmada amacımız pri-mer hiperparatiroidizmli hastalarda plazma H-FABP dü-zeylerini sağlıklı kontrollerle karşılaştırarak değerlendir-mektir.Gereç ve Yöntemler: Primer hiperparatiroidizmli 88 (8erkek, 80 kadın) hasta ve 87 sağlıklı olguda (12 erkek, 75kadın) antropometrik parametreler, serum H-FABP, serumlipid, serum kalsiyum, fosfor, parathormon, insulin direnci(HOMA-IR), yüksek-hassasiyetli CRP (hs-CRP), 24 saatlik id-rarda mikroalbumin atılımı, karotis intima-media kalınlığı(KIMK) ölçümü yapıldı.Bulgular: Hasta [1086.07 (298–3744)] ve kontrol gru-bunda [1113.36 (263.27–3510)] H-FABP düzeyleri arasındaanlamlı farklılık bulunmamıştır. Primer hiperparatiroidizmlihastalarda PTH, HOMA-IR, total kolesterol, LDL kolesterol,trigliserid ve kalsiyum ve ortalama KİMK düzeyleri anlamlıolarak yüksek bulunmuştur (p<0.05). H-FABP ile yaş, açlıkkan glukozu, vücut kitle indeksi (VKİ) ve Hs-CRP arasındaanlamlı pozitif korelasyon bulunmuştur.Tartışma: H-FABP düzeyleri yaş, açlık kan glukozu, VKİ vehs-CRP gibi bazı kardiyovasküler risk faktörleriyle korele ol-makla birlikte kardiyak hastalığı olmayan primer hiperpara-tiroidizmli hastalarda sağlıklı olgulara kıyasla anlamlı farklılıkgörülmemiştir.

Anahtar kelimeler: Hiperparatiroidizm; H-FABP;kardiyovasküler risk

Address for Correspondence: Bekir Uçan, University of Health Sciences, Dışkapı Yıldırım Beyazıt Training andResearch Hospital, Department of Endocrinology and Metabolism, Ankara, Turkey

Phone: +90 533 940 4676 E-mail: [email protected] Received: 19/07/2017 Accepted: 06/02/2018

®Copyright 2018 by Turkish Journal of Endocrinology and Metabolism AssociationTurkish Journal of Endocrinology and Metabolism published by Türkiye Klinikleri

1

https://orcid.org/0000-0003-4455-7276

https://orcid.org/000-0001-7203-3934

https://orcid.org/0000-0003-1190-4761

https://orcid.org/0000-0002-8468-9196

https://orcid.org/0000-0003-0342-571X

https://orcid.org/0000-0003-1125-3823

https://orcid.org/0000-0002-4718-0083

https://orcid.org/0000-0002-0810-5224

IntroductionPrimary hyperparathyroidism (PHT) is one of themost common endocrine disorders, resultingmost commonly from parathyroid adenomas.Multiple observational studies indicate that pri-mary hyperparathyroidism might be associatedwith cardiovascular diseases (1). Hypertension iscommonly reported among patients with mildPHT (2–4), while other observational studies alsosuggest a correlation between left ventricular hy-pertrophy/diastolic dysfunction and PHT (5,6).The mean carotid intima-media thickness (CIMT)is significantly higher in patients with PHPT andsignificantly higher levels of parathormone (PTH)are associated with the thickness of aortic andcarotid artery (7,8). These results suggested thatarteriosclerosis might be associated with theseverity of hyperparathyroidism.Heart-type fatty acid binding-protein (H-FABP) isa low molecular weight, cytoplasmic and non-en-zymatic protein that provides the transport oflong-chain fatty acids to cardiomyocytes (9).We have previously demonstrated the presenceof elevated levels of H-FABP in various en-docrinological and metabolic disorders includingacromegaly, prediabetes and metabolic syn-drome (10–12). However, these levels were notaffected in hyperprolactinemia and hyperthy-roidism (13,14).The kinetics and release of this protein are simi-lar to that of myoglobin, but unlike the latter, it isavailable at a higher concentration in the heartthan the skeletal muscle. Thus making H-FABPmore specific than myoglobin for heart tissue(15). Various studies have indicated that H-FABPis closely related to the cardiovascular risk fac-tors, and is an independent risk factor for cardio-vascular mortality (16,17). H-FABP is anexcellent early marker for cardiac injury in acutecoronary syndromes, providing early diagnosis ofminor myocardial injury in heart failure and un-stable angina (18–20). Moreover, elevated levelsof serum H-FABP is also seen in myocardial in-juries such as heart failure, hypertrophic and di-lated cardiomyopathy, and pulmonary embolism(21–23).Carotid intima-media thickness is an importantmarker of early changes in the atheroscleroticprocess and an indicator for the development ofcardiovascular events. The most critical changesseen during the early, subclinical stage of ather-osclerotic disease are endothelial dysfunction inthe entire arterial system and increased intima-media thickness (IMC). The carotid intima-media

thickness is frequently used as a strong predictorof cardiovascular events (myocardial infarction,stroke, and transient ischemic attack) (24).The purpose of this study is to determine thelevel of H-FABP in primary hyperparathyroidismand also to evaluate the possible relationship ofplasma H-FABP levels with CIMT, serum lipid,HOMA-IR, HsCRP, and microalbuminuria.

Material and MethodsAbout 88 patients with primary hyperparathy-roidism and 87 control subjects in the study wereenrolled in this study. Ethical committee approvaland written informed consent of participants wereobtained before the commencement of the study.After overnight fasting, blood samples were col-lected from all of the subjects to check the levelsof parathormone (PTH), glucose, insulin, free T4,thyroid-stimulating hormone (TSH), low-densitylipoprotein (LDL), high-density lipoprotein (HDL),triglyceride, total cholesterol, high sensitive C-re-active protein (h-CRP), and H-FABP. Excretion of24-hour urine microalbumin was assessed in thepatient and control group. Weight, height, andwaist and hip circumference were measured andthe BMI and homeostasis model assessment ofinsulin resistance (HOMA-IR) were also calculatedfor both the groups. Additionally, all the patientsunderwent high-resolution B-mode ultrasonogra-phy to measure the carotid artery intima-mediathickness (CIMT), wherein the same investigatorcarried out all the scans and image measure-ments. Furthermore, all the study participantswere interviewed using a standard questionnairethat included information about their demo-graphic characteristics, concomitant disease, useof medications that could affect H-FABP levels andsmoking history. Afterward, the patients under-went a physical examination, and those with ahistory of the acute coronary syndrome (ACS),pulmonary embolism, stroke and heart failure orwith immunological or renal diseases were ex-cluded from the study. A control group, compris-ing of volunteers who had no history of ACS,heart failure, cardiomyopathy, pulmonary em-bolism, renal diseases, immunological diseasesand diabetes mellitus, was also used in this study.

Heart-type fatty acid-binding protein

The H-FABP measurements were performed withthe Epoch micro-volume spectrophotometer sys-tem (BioTek, Inc., Winooski, VT, USA) using acommercially available enzyme-linked im-munosorbent assay ELISA kit (Hycult Biotech,

2

Uçan et al. Turk J Endocrinol MetabHFABP in Primary Hyperparathyroidism 2018;22:1-6

2

Uden, The Netherlands). The assay range of theH-FABP ELISA kit was 102 to 25000 pg/mL andthe measurements were calculated simultane-ously during the same experiment.The ready-to-use solid-phase human H-FABPELISA is based on the sandwich principle. Sam-ples and standards were incubated together witha peroxidase-conjugated secondary antibody inmicrotiter wells coated with a primary antibodythat recognizes human H-FABP. During incubation,the solid bound primary antibody captures thehuman H-FABP and the secondary antibody thenbinds to the captured human H-FABP, followingwhich, the peroxidase-conjugated antibody reactswith the substrate tetramethylbenzidine (TMB;this reaction was stopped by the addition of oxalicacid). The absorbance at 450 nm was measuredwith a spectrophotometer.

Statistical Analysis

The statistical analysis was performed usingSPSS 11.5 (SPSS, Inc) software. The presenta-tion of the variables that were normally distrib-

uted was as mean ±standard deviation (SD) andof those that were non normally distributed wasas median (min-max). Categorical variables arepresented as case number and percentage (%).Student’s t-test was used to analyze normallydistributed continuous variables. The significanceof the difference between medians was comparedby the Mann-Whitney U test and categorical vari-ables were compared using the Pearson’s chi-square or Fisher‘s exact test. Correlations wereanalyzed using Pearson‘s and Spearman’s corre-lation and a p-value of <0.05 was considered tobe statistically Significant for all analyses.

ResultsMean age (49.01±13.08 to 46.06±10.93, p=0.111),sex distribution and BMI were found to be simi-lar between groups (Table 1). The prevalence ofhypertension (HT) was significantly higher in thepatients as compared to healthy individuals (18%to 0%, p=0.004), but the frequency of smokingwas significantly lower in the patients (11% to20%, p<0.0001). Additionally, no significant dif-

3

Turk J Endocrinol Metab Uçan et al.2018;22:1-6 HFABP in Primary Hyperparathyroidism

3

* Values are median (minimum-maximum).Abbreviations: BMI: Body mass index; TSH: Thyroid-stimulating hormone; HOMA-IR: Homeostasis model assessment of insulin re-sistance; LDL: Low-density lipoprotein; HDL: High-density lipoprotein; H-FABP: Heart-type fatty acid-binding protein; CIMT: Caro-tid intima-media thickness, HsCRP: High sensitive C-reactive protein.

Patients (n=89) Control (n=87) p

Male/Female 8/81 12/75 0.315

*Age (years) 50.5 (18-73) 46 (23-68) 0.099

*BMI (kg/m2) 28.39 (19.40-42.91) 27 (20.1-42) 0.065

*Waist/hip ratio 0.90 (0.76-1.20) 0.91 (0.81-1.05) 0.213

*Parathormone (pg/mL) 212 (92-896) 57 (26-133) <0.001*

*Free T4 (ng/dL) 0.99 (0.52-1.46) 0.97 (0.64-1.40) 0.211

*TSH (µIU/mL) 1.5 (0.52-4.34) 1.63 (0.46-4.1) 0.534

*Fasting blood glucose (mg/dL) 88 (66-138) 86 (71-104) 0.878

*HOMA-IR 2.62 (0.49-11.6) 1.94 (0.27-5) 0.017

*Total cholesterol (mg/dL) 201 (127-382) 186 (17-293) 0.121

*LDL cholesterol (mg/dL) 114 (63.5-225.8) 109 (30.7-160) 0.025

*HDL cholesterol (mg/dL) 49 (26.8-99) 47 (24-83) 0.880

*Triglycerides (mg/dL) 117 (48-1585) 106 (40-290) 0.019

*Microalbuminuria (mg/g) 4.3 (0.1-79) 3.8 (2.7-21.3) 0.723

*HsCRP (mg/L) 2 (0.3-18) 2 (0.68-8) 0.706

*H-FABP (pg/mL) 1086.07 (298-3744) 1113.36 (263.27-3510) 0.374

*Mean CIMT (mm) 0.53 (0.33-0.695) 0.48 (0.4-0.595) 0.018

*Calcium (mg/dL) 10.7 (9.1-13.8) 9.4 (8.6-10.1) <0.0001

*Vitamin D 12 (4-118) 12 (4-59) 0.537

*Creatinine 0.8 (0.4-1.12) 0.7 (0.6-1) 0.182

Table 1. Demographic characteristics and biochemical data for the patients with primary hyperparathyroidismand the control subjects.

ference was observed between the patients andcontrols with respect to the prevalence of dia-betes mellitus (DM) (4% to 0%, p=0.351). Coro-nary artery disease (CAD) was not seen in thepatients enrolled in the study and there was nosignificant difference in average H-FABP value be-tween the patients with or without HT ((1126(819) to 1059 (956), p=0.218). The average val-ues of PTH, HOMA-IR, total cholesterol, LDL cho-lesterol, triglycerides, and calcium levels andmean CIMT were significantly higher in patientswith primary hyperparathyroidism (p<0.05)(Table 1). Some patients from the control grouphad secondary hyperparathyroidism due to vita-min D deficiency. No significant change was iden-tified between these two groups with respect toother values (Table 1) and no significant differ-ence was found in H-FABP levels between pa-tients [1078.13 (298-3744)] and controls[1049.91 (263.27-4403.02)] (Figure 1).There was a positive correlation between age,fasting blood glucose, BMI, HsCRP levels and H-FABP levels (Table 2).

DiscussionHyperparathyroidism is known to be associatedwith cardiovascular mortality and morbidity andwith cardiomyopathy, arrhythmia, myocardial hy-pertrophy, as well as atherosclerosis, and valveand cardiac calcification (8,25,26). In vivo stud-ies have demonstrated the vascular remodelingand vascular calcification effects of the parathor-mone through atherogenesis, as well as its pro-sclerotic effects on the vascular smooth musclecells (27). In addition to these direct effects, hy-perparathyroidism has indirect effects on the car-diovascular disease because of its assumedpositive correlation to hypertension (28-30). H-FABP is a protein present in the cytosol of car-diomyocytes that is rapidly released intocirculation during the event of myocardial tissuedamage. H-FABP has been indicated as a moreaccurate and early marker in the identification ofacute myocardial damage (31,32). Several stud-ies have indicated a positive correlation betweenH-FABP and cardiometabolic risk factors (2–8)Therefore, we investigated whether H-FABP levelis increased in patients with PHT. We demon-strated that H-FABP levels did not differ betweenpatients and controls. We further investigated H-FABP levels with various CV risk factors.Age of the individual also appears to contribute tothe development of CVD. In a cohort of morethan 3.6 million individuals, aged 40 years or

older, who underwent self-referred screening forcardiovascular disease (ankle-brachial index,carotid duplex ultrasound, and abdominal ultra-sound), the prevalence of any type of vasculardisease increased significantly with each decadeof life (33). In addition, h-CRP measurement isalso considered to be a useful and independentmarker for cardiovascular risk assessment (34).In our study, H-FABP levels showed a positivecorrelation with age, fasting blood glucose, BMI,and h-CRP.American Heart Association has identified obesityas an independent risk factor (35). In a meta-analysis of studies assessing the impact of bodyweight on CHD, there was a 29 percent increasein CHD for every five-unit increase in body massindex (BMI) (36). Similarly, we also found a pos-itive correlation between H-FABP levels and BMIin our study.In one study with a large group of volunteers,serum H-FABP levels were found to be affectedby age, gender, obesity, renal function, and ECGabnormality (37). Another study demonstratedthat concentrations of H-FABP and h-CRP corre-

4


4

Figure 1: H-FABP levels in patients and control group.

4000

3500

3000

2500

2000

1500

1000

500

0

HFA

BP

Control PHPTGROUP

R P

Age (Years) 0.507 <0.001

Fasting blood glucose (mg/dL) 0.352 0.002

BMI (kg/m2) 0.312 0.007

HsCRP (mg/L) 0.311 0.028

Table 2. Correlation analyses between H-FABP anddemographics, metabolic parameters, andcardiovascular risk factors in patients with primaryhyperparathyroidism.

lated positively (38). Taken together these stud-ies suggest that H-FABP levels could be influ-enced by some CV risk factors and/or markers,such as age, HsCRP, and BMI.The design of our study excluded patients withovert cardiovascular or cerebrovascular disorder,although, there was an evidence of subclinicalatherosclerosis in our patient group. Early ath-erosclerosis can be detected by CIMT and meas-ured easily in a non-invasive manner. From theultrasonographic point of view, CIMT measure-ments represent a good correlation with histol-ogy (40) where increased CIMT is associatedwith vascular risk factors and the presence ofsevere atherosclerosis (35–38), thus makingCIMT level a widely accepted sign of early ath-erosclerosis. In our study, CIMT levels in patientgroup were higher than controls, suggestingthat the patients with PHPT are at a higher riskfor CV diseases. However, probably because ofthe exclusion of patients with overt CV, no cor-relation was found between the levels of CIMTand H-FABP.To the best of our knowledge, this is the firststudy that evaluates the importance of H-FABP inpatients with primary hyperparathyroidism in theliterature. The findings of our study reinstate thatcardiovascular risk factors such as hyperlipidemiaand CIMT are higher in patients with primary hy-perparathyroidism. In addition, we found a posi-tive correlation between H-FABP and age, fastingblood glucose, BMI and h-CRP and similar H-FABPlevels between groups, which necessitates com-prehensive studies including larger populations toenlighten the relationship between H-FABP andprimary hyperparathyroidism.The limitations of this study are its relativelysmall sample size and it being a single centerstudy.

ConclusionIn the present study, H-FABP levels were seen tocorrelate with some CV risk factors such as age,fasting blood glucose, BMI and h-CRP; however,these levels did not differ in primary hyper-parathyroidism patients who had no cardiac dis-ease.Source of Finance: During this study, no finan-cial or spiritual support was received neither fromany pharmaceutical company that has a directconnection with the research subject, nor from acompany that provides or produces medical in-struments and materials which may negativelyaffect the evaluation process of this study.

Conflict of Interest: No conflicts of interest be-tween the authors and/or family members of thescientific and medical committee members ormembers of the potential conflicts of interest,counseling, expertise, working conditions, shareholding and similar situations in any firm.

Author ContributionsIdea/Concept: Bekir Uçan, Mustafa Şahin, Mus-tafa Özbek; Design: Bekir Uçan, Mustafa Şahin,Mustafa Özbek; Control/Supervision: Bekir Uçan,Mustafa Çalışkan, Muhammed Kızılgül; DataCollection and/or Processing: Bekir Uçan, Mus-tafa Çalışkan; Analysis and/or Interpretation:Bekir Uçan, Muhammed Kızılgül; LiteratureReview: Bekir Uçan, Muhammed Kızılgül; WritingThe Article: Bekir Uçan, Mustafa Şahin, Güler Öz-türk, Mehmet Akif Öztürk; Critical Review: BekirUçan, Mehmet Akif Öztürk, Erman Çakal; Refe-rences and Fundings: Bekir Uçan, MuhammedKızılgül, Mehmet Akif Öztürk, Erman Çakal; Ma-terials: Bekir Uçan, Güler Öztürk, Mehmet AkifÖztürk, Erman Çakal.

References1. Andersson P, Rydberg E, Willenheimer R. Primary hyper-

parathyroidism and heart disease--a review. Eur Heart J.2004;25:1776-1787.

2. Lind L, Hvarfner A, Palmér M, Grimelius L, Akerström G,Ljunghall S. Hypertension in primary hyperparathyroi-dism in relation to histopathology. Eur J Surg.1991;157:457-459.

3. Lind L, Ljunghall S. Pre-operative evaluation of risk fac-tors for complications in patients with primary hyperpa-rathyroidism. Eur J Clin Invest. 1995;25:955-958.

4. Lind L, Jacobsson S, Palmér M, Lithell H, Wengle B,Ljunghall S. Cardiovascular risk factors in primary hyper-parathyroidism: a 15-year follow-up of operated andunoperated cases. J Intern Med. 1991;230:29-35.

5. Stefenelli T, Abela C, Frank H, Koller-Strametz J, GlobitsS, Bergler-Klein J, Niederle B. Cardiac abnormalities inpatients with primary hyperparathyroidism: implicationsfor follow-up. J Clin Endocrinol Metab. 1997;82:106-112.

6. Näppi S, Saha H, Virtanen V, Limnell V, Sand J, Salmi J,Pasternack A. Left ventricular structure and function inprimary hyperparathyroidism before and after parathy-roidectomy. Cardiology. 2000;93:229-233.

7. Rubin MR, Maurer MS, McMahon DJ, Bilezikian JP, Silver-berg SJ. Arterial stiffness in mild primary hyperparathy-roidism. J Clin Endocrinol Metab. 2005;90:3326-3330.

8. Walker MD, Fleischer J, Rundek T, McMahon DJ, HommaS, Sacco R, Silverberg SJ. Carotid vascular abnormalitiesin primary hyperparathyroidism. J Clin Endocrinol Metab.2009;94:3849- 3856.

9. Glatz JF, van Bilsen M, Paulussen RJ, Veerkamp JH, vander Vusse GJ, Reneman RS. Release of fatty acid-bindingprotein from isolated rat heart subjected to ischemia andreperfusion or to the calcium paradox. Biochim BiophysActa. 1988;961:148-152.

10. Ozbek M, Erdogan M, Dogan M, Akbal E, Ozturk MA, Ure-ten K. Serum heart-type fatty acid binding protein (H-FABP) levels in acromegaly patients. J Endocrinol Invest.2011;34:576-579.

5

Turk J Endocrinol Metab Uçan et al.2018;22:1-6 HFABP in Primary Hyperparathyroidism

5

11. Akbal E, Özbek M, Güneş F, Akyürek Ö, Ureten K, Deli-başı T. Serum heart type fatty acid binding protein levelsin metabolic syndrome. Endocrine. 2009;36:433-437.

12. Karbek B, Özbek M, Bozkurt NC, Ginis Z, Güngünes A,Ünsal IÖ, Cakal E, Delibası T. Heart-type fatty acid bin-ding protein (H-FABP): relationship with arterial intima-media thickness and role as diagnostic marker foratherosclerosis in patients with impaired glucose meta-bolism. Cardiovasc Diabetol. 2011;10: 37.

13. Arslan MS, Topaloglu O, Sahin M, Tutal E, Gungunes A,Cakir E, Ozturk IU, Karbek B, Ucan B, Ginis Z, Cakal E,Ozbek M, Delibasi T. Preclinical atherosclerosis in pati-ents with prolactinoma. Endocr Pract. 2014;20:447-451.

14. Ozbek M, Gungunes A, Sahin M, Ginis Z, Ucan B, SaykiM, Tutal E, Cakal E, Kuşkonmaz SM, Öztürk MA, DelibasiT. Serum heart type fatty acid binding protein levels arenot changed in hyperthyroidism. Minerva Endocrinol.2016;41:298-301.

15. Bilezikian JP, Silverberg SJ, Shane E, Parisien M, Demps-ter DW. Characterization and evaluation of asymptoma-tic primary hyperparathyroidism. J Bone Miner Res.1991;6:S85-89.

16. Tso AW, Xu A, Sham PC, Wat NM, Wang Y, Fong CH,Cheung BM, Janus ED, Lam KS. Serum adipocyte fattyacid binding protein as a new biomarker predicting thedevelopment of type 2 diabetes: a 10-year prospectivestudy in a Chinese cohort. Diabetes Care. 2007;30:2667-2672.

17. Xu A, Tso AW, Cheung BM, Wang Y, Wat NM, Fong CH,Yeung DC, Janus ED, Sham PC, Lam KS. Circulating adi-pocyte-fatty acid binding protein levels predict the de-velopment of the metabolic syndrome: a 5-yearprospective study. Circulation. 2007;115:1537-1543.

18. Pelsers MM, Hermens WT, Glatz JF. Fatty acid-bindingproteins as plasma markers of tissue injury. Clin ChimActa. 2005;352:15-35.

19. Figiel Ł, Wraga M, Bednarkiewicz Z, Lipiec P, Smigielski J,Krzemińska-Pakuła M, Kasprzak JD. Direct comparison ofthe diagnostic value of point-of-care tests detectingheart-type fatty acid binding protein or glycogen phosp-horylase isoenzyme BB in patients with acute coronarysyndromes with persistent ST-segment elevation. Kar-diol Pol. 2011;69:1-6.

20. Boscheri A, Wunderlich C, Langer M, Schoen S, Wiede-mann B, Stolte D, Elmer G, Barthel P, Strasser RH. Cor-relation of heart-type fatty acid-binding protein withmortality and echocardiographic data in patients withpulmonary embolism at intermediate risk. Am Heart J.2010;160:294-300.

21. Arimoto T, Takeishi Y, Niizeki T, Nozaki N, Hirono O, Wa-tanabe T, Nitobe J, Tsunoda Y, Suzuki S, Koyama Y, Kita-hara T, Okada A, Takahashi K, Kubota I. Cardiacsympathetic denervation and ongoing myocardial da-mage for prognosis in early stages of heart failure. J CardFail. 2007;13:34-41.

22. Komamura K, Sasaki T, Hanatani A, Kim J, Hashimura K,Ishida Y, Ohkaru Y, Asayama K, Tanaka T, Ogai A, Naka-tani T, Kitamura S, Kangawa K, Miyatake K, Kitakaze M.Heart-type fatty acid binding protein is a novel prognos-tic marker in patients with non-ischaemic dilated cardi-omyopathy. Heart. 2006;92:615-618.

23. Renaud B, Ngako A. Heart-type fatty acid-binding prote-ins (H-FABP): a reliable tool for initial risk stratification ofpulmonary embolism? Eur Heart J. 2007;28:146-147.

24. Delibasi T, Emral R, Erdogan MF, Kamel N. Effects of alen-dronate sodium therapy on carotid intima media thick-ness in postmenopausal women with osteoporosis. AdvTher. 2007;24:319-325.

25. Walker MD, Silverberg SJ. Cardiovascular aspects of pri-mary hyperparathyroidism. J Endocrinol Invest. 2008;31:925-931.

26. Saleh FN, Schirmer H, Sundsfjord J, Jorde R. Parathyroidhormone and left ventricular hypertrophy. Eur Heart J.2003;24:2054-2060.

27. Rashid G, Bernheim J, Green J, Benchetrit S. Parathyroidhormone stimulates endothelial expression of atherosc-lerotic parameters through protein kinase pathways. AmJ Physiol Renal Physiol. 2007;292:F1215-F1218.

28. Jorde R, Svartberg J, Sundsfjord J. Serum parathyroidhormone as a predictor of increase in systolic blood pres-sure in men. J Hypertens. 2005;23:1639-1644.

29. Snijder MB, Lips P, Seidell JC, Visser M, Deeg DJ, DekkerJM, van Dam RM. Vitamin D status and parathyroid hor-mone levels in relation to blood pressure: a population-based study in older men and women. J Intern Med.2007;261:558-565.

30. Taylor EN, Curhan GC, Forman JP. Parathyroid hormoneand the risk of incident hypertension. J Hypertens.2008;26:1390-1394.

31. Ozdemir L, Elonu OH, Gocmen AY. Heart type fatty acidbinding protein is more sensitive than troponin I andcreatine kinase myocardial band at early stage in deter-mining myocardial injury caused by percutaneous coro-nary intervention. Int Heart J. 2011;52:143-145.

32. McMahon CG, Lamont JV, Curtin E, McConnell RI, Croc-kard M, Kurth MJ, Crean P, Fitzgerald SP. Diagnostic ac-curacy of heart-type fatty acid-binding protein for theearly diagnosis of acute myocardial infarction. Am JEmerg Med. 2012;30: 267-274.

33. Savji N, Rockman CB, Skolnick AH, Guo Y, Adelman MA,Riles T, Berger JS. Association between advanced ageand vascular disease in different arterial territories: a po-pulation database of over 3.6 million subjects. J Am CollCardiol. 2013;61:1736-1743.

34. Pearson TA, Mensah GA, Alexander RW, Anderson JL,Cannon RO 3rd, Criqui M, Fadl YY, Fortmann SP, Hong Y,Myers GL, Rifai N, Smith SC Jr, Taubert K, Tracy RP, Vini-cor F; Centers for Disease Control and Prevention, Ame-rican Heart Association. Markers of inflammation andcardiovascular disease: application to clinical and publichealth practice: a statement for healthcare professionalsfrom the Centers for Disease Control and Prevention andthe American Heart Association. Circulation. 2003;107:499-511.

35. Eckel RH. Obesity and heart disease: a statement for he-althcare professionals from the Nutrition Committee,American Heart Association. Circulation. 1997;96:3248-3250.

36. Bogers RP, Bemelmans WJ, Hoogenveen RT, BoshuizenHC, Woodward M, Knekt P, van Dam RM, Hu FB, VisscherTL, Menotti A, Thorpe RJ Jr, Jamrozik K, Calling S, StrandBH, Shipley MJ; for the BMI-CHD Collaboration Investi-gators. Association of overweight with increased risk ofcoronary heart disease partly independent of blood pres-sure and cholesterol levels: a meta-analysis of 21 cohortstudies including more than 300 000 persons. Arch In-tern Med. 2007;167:1720-1728.

37. Niizeki T, Takeishi Y, Takabatake N, Shibata Y, Konta T,Kato T, Kawata S, Kubota I. Circulating levels of heart-type fatty acid-binding protein in a general Japanese po-pulation: effects of age, gender, and physiologiccharacteristics. Circ J. 2007;71:1452-1457.

38. Jeong JH, Seo YH, Ahn JY, Kim KH, Seo JY, Kim MJ, LeeHT, Park PW. The prognostic value of serum levels ofheart-type fatty acid binding protein and high sensitivityC-reactive protein in patients with increased levels ofamino-terminal pro-b type natriuretic peptide. Ann LabMed. 2016;36(5):420-426.

39. Pignoli P, Tremoli E, Poli A, Oreste P, Paoletti R. Intimalplus medial thickness of the arterial wall: a direct mea-surement with ultrasound imaging. Circulation. 1986;74:1399-1406.

6


6

Address for Correspondence: Hatice Ayça Ata Korkmaz, Health Science University, Kanuni Research and Education Hospital,Clinic of Radiology, Trabzon, Turkey

Phone: +90 462 341 56 56 E-mail: [email protected] Received: 21/11/2017 Accepted: 10/01/2018


Clinical Value of Histogram Analysis UsingGray-Scale Ultrasound Images in Thyroiditis

Tiroiditlerde Gri Skala Ultrason GörüntülerininHistogram Analizinin Klinik Değeri

Health Science University, Kanuni Research and Education Hospital, Clinic of Radiology, Trabzon, Turkey* Health Science University, Kanuni Research and Education Hospital, Clinic of Endocrinology and Metabolism, Trabzon, Turkey


IntroductionDiffuse thyroid diseases include hyperthyroidism,chronic autoimmune hyperthyroidism (Hashimoto’s

thyroidism [HT]), subacute thyroiditis (SAT), andGraves’ disease (GD). The imaging features of thy-roid parenchyma echogenicity are used in B-mode

DO

I:10

.251

79/t

jem

.201

7-58

942

Objective: The main purpose of this study was to investi-gate the histogram analysis (HA) in terms of the differentialdiagnosis of thyroiditis.Material and Methods: A total of 137 cases with a defini-tive diagnosis of thyroiditis confirmed with clinical and la-boratory findings were evaluated in the study. Out of these,23 cases were diagnosed as Graves’ disease (GD), 94 asHashimoto’s thyroiditis (HT), and 20 as subacute thyroiditis(SAT), and 34 healthy volunteers were included in this studyas a control group. The thyroid and sternocleidomastoidmuscle’s (SCM) HA and thyroid-to-SCM echogenicity ratio(TRSCMR) were evaluated.Results: The HA values of thyroid parenchyma and SCM(mean±SD) of patients with GD, HT, SAT, and CG were83.49±27.91, 71.25±20.93, 70.83±13.94, and 80.95±20.88, and 52.74±24.11, 58.17±18.67, 67.20±14.71,and 69.32±18.94, respectively. The HAs of thyroid pa-renchyma of GD, HT, and SAT were not statistically signifi-cant. The TRSCMR (mean±SD) of patients with GD, HT, SAT,and CG were 1.85±0.86, 1.29±0.41, 1.09±0.26, and1.25±0.5, respectively. Compared with the control group,the GD TRSCMRs were higher than the CG TRSCMRs(p<0.0001). Compared with SAT, GD TRSCMRs were higherthan SAT TRSCMRs, and these results were statistically sig-nificant (p<0.001).Conclusion: This study demonstrated that HA may help indifferentiating SAT from GD that show similar appearanceon routine ultrasonography.

Keywords: Histogram analysis; subacute thyroiditis;Hashimoto’s thyroiditis; Graves' disease;thyroid ultrasonography

Amaç: Bu çalışmanın temel amacı tiroiditlerin ayırıcı tanı-sında histogram analizinin (HA) yerini araştırmaktır.Gereç ve Yöntemler: Klinik ve laboratuar bulgularıyla ti-roidit tanısı kesinleşmiş 137 olgu çalışmaya dahil edildi. Ol-guların 23’ü Graves Hastalığı (GH), 94 hasta Hashimototiroiditi (HT), 20’si ise Subakut Tiroidit (SAT) tanısı almıştı.Sağlıklı 34 gönüllü ise kontrol grubu (KG) olarak çalışmayadahil edildi. Tiroid ve sternocleidomastoid kası (SCM) his-togram analizleri ile tiroid parankim ekosunun SCM ekosunaoranı (TRSCM) değerlendirildi.Bulgular: GH, HT, SAT, KG olgularının tiroid parankimi veSCM HA (ortalama± SD) değerleri sırasıyla 83.49 ±27.91,71.25±20.93, 70.83±13,94, 80.95±20.88 ve 52.74±24.11,58.17±18.67, 67.20±14.71, 69.32±18.94 şeklindedir. GH,HT ve SAT tiroid parankim HA değerleri arasında istatistik-sel olarak anlamlı fark yoktu. GH, HT, SAT ve KG’nunTRSCMR (ortalama ± SD) değerleri sırasıyla 1.85±0.86,1.29±0.41, 1.09±0.26 and 1.25±0.5’dir. Kontrol grubu ilekarşılaştırıldığında GH TRSCMR değerleri KG TRSCMR de-ğerlerinden yüksek, SAT grubunun TRSCMR değerleri ise KGgrubunun TRSCMR değerlerinden düşük olup, istatistikselolarak anlamlıydı (p<0.05). SAT ve GH tiroiditlerininTRSCMR değerleri karşılaştırıldığında, GH TRSCMR değerleriSAT TRSCM değerlerinden yüksek olup, istatistiksel olarakanlamlıydı (p=0.001).Sonuç: Çalışmamız, ultrasonografide benzer görüntülemeözelliklerine sahip SAT ve GH’ nin ayırıcı tanısının yapılma-sında histogram analizinin faydalı olabileceğini göstermiştir.

Anahtar kelimeler: Histogram analizi; subakut tiroidit;Hashimoto tiroiditi; Graves hastalığı;tiroid ultrasonografisi

7

https://orcid.org/0000-0001-5713-7348

https://orcid.org/0000-0001-9987-3351

imaging in the differential diagnosis of thyroiditis.However, this differentiation is subjective and de-pends on the examiner. The differentiation of GDand SAT in gray-scale sonograms is difficult be-cause of their similar appearances. Although theyshare similar clinical, biochemical, and sonographicproperties, they have different etiopathogenesisand require different treatments. Therefore, a cor-rect diagnosis of these types of thyroiditis by ultra-sonography is critical. Ultrasound assessment haslimited value in terms of the differential diagnosis ofthyroiditis. Therefore, radiological imaging tech-niques may have to be developed to provide crucialinformation to clinicians for planning treatment al-gorithms.With the developing technology, computer pro-grams may be able to diagnose diseases similarto a radiologist in the near future. Therefore, thequantitative B-mode evaluation methods shouldbe developed. In this study, we aimed to investi-gate the use of histograms in diagnosing thy-roiditis.Palpation has long been used for the examinationof the thyroid. Sonoelastography (USE), firstused by Ophir et al., has replaced palpation in theexamination of thyroid (1). The current literaturereported the use of USE in thyroiditis by a shearwave and strain elastography (1-6). However,elastography is a new developing technology thatis not currently available in several ultrasonic de-vices, and the contribution of the differential di-agnosis of thyroiditis remains unclear.In addition, gray-scale ultrasound imaging is auniversal and easily accessible technology world-wide. Thus, new evaluation techniques should bedeveloped for accurate diagnosis and treatment.Histogram analysis (HA) is based on the record-ings of images obtained in the ultrasonographicgray-scale mode, and these images are analyzedwith a special medical software program afterthey are transferred to a workstation.The HA of gray-scale ultrasound images has beeninvestigated in various organs for the differenti-ation of transudate from exudative ascites,breast tumor differentiation, perfusion defects ofkidney disease, characterization of parathyroidgland injury after head-and-neck radiotherapy,differentiation of asymptomatic diffuse thyroiddisease from normal thyroid, and investigation ofthe chronic thyroiditis appearance (7-15).Despite the benefits of HA in chronic thyroiditis,data regarding the use of HA in SAT, HT, and GDare limited (12-15). The capability of differential di-agnosis by HA and thyroid-to-sternocleidomastoid

muscle echogenicity ratio (TRSCMR) in thyroiditis isyet to be investigated. In this study, we aimed toinvestigate the applicability of HA and TRSCMR indifferent types of thyroiditis.

Graves’ Disease

GD is an autoimmune condition that presentswith thyrotoxicosis induced by circulating thyroid-stimulating hormone receptor autoantibodies(TRAbs) with thyroid-stimulating activity. In ad-dition, thyrotoxicosis is the result of differenttypes of painless thyroiditis. To identify the exactcause of thyrotoxicosis, radioactive iodine uptakemeasurement is still the gold standard of clinicalapplication. By contrast, nuclear medicine tech-niques are unavailable in several health facilities,though radioactive substances are contraindi-cated for lactating and pregnant women.The prevalence of GD is 5 to 10 times more com-mon in females than in males. The maximum in-cidences of the disease were observed during thethird to sixth decades. Tremor, heat intolerance,nervousness, weight loss, goiter, fatigue, tachy-cardia, and exophthalmos are the most usualclinical symptoms of GD. The evaluation of TRAblevels in the blood is advantageous for differenti-ating GD from HT and SAT. However, TRAb analy-ses are not accessible in general hospitals andclinics.Ultrasonography is a non-invasive and cost-ef-fective imaging technique for the examination ofthe thyroid parenchyma. GD is identified using B-mode ultrasonography through the developmentof diffuse thyroid enlargement with the loss ofechogenicity. In addition, it is associated with theincreased intraparenchymal thyroidal flow oncolor flow Doppler sonography (16).The increased thyroid vascularity is crucial evi-dence for GD, which is beneficial for differentiat-ing GD from SAT and HT (17).In theory, the differential diagnosis of GD fromSAT and HT by HA is possible because of the dif-ferent histopathologic characteristics and typesof thyroid gland vascularities for each condition.To date, no study has compared the TRSCMRsamong patients with GD and other types of thy-roiditis.

Subacute Thyroiditis

SAT is an unusual, self-limiting condition thatgenerally occurs after an upper tract viral infec-tion, which is the result of an autoimmune re-sponse (18). Clinically, this situation is associatedwith severe anterior neck pain and may radiate

8

Ata Korkmaz et al. Turk J Endocrinol MetabDifferantial Diagnose of Thyroiditis by Histogram Analysis 2018;22:7-15

8

up to the mandible, ear, and occipital fossa. Atthe beginning of this condition, SAT usuallycauses low-grade fever with thyrotoxicosis (19).The laboratory findings of SAT have decreasedthyrotropin levels, increased thyroid hormones(FT4 and FT3), and increased C-reactive protein(20).In general, the gray-scale and Doppler sono-graphic findings of SAT are thyroid enlargementand ill-defined focal hypoechoic areas with hypo-vascularity (19). After treatment, these findingsusually disappear (19).

Hashimoto’s Thyroiditis

HT is the most usual inflammatory process ofthe thyroid gland, and it is the main cause of au-toimmune hypothyroidism. This condition devel-ops 15 times more in women than in men. Themaximum incidences of HT were observed dur-ing the third to fifth decades (21). The preva-lence of HT is approximately 5% to 15% inwomen. HT is commonly associated with the de-velopment of circulating anti-thyroid autoanti-bodies, which are the cause of cytological injuryand thyroid malfunction. The detection of thy-roglobulin antibody and/or thyroid peroxidaseantibody in blood tests is used for the diagnosisof HT. Ultrasonography shows the loss ofechogenicity, increased heterogeneity, and de-creased normal vascularity with the develop-ment of septa and hypoechoic micronodules inthe patients with HT (22).The degree of thyroid fibrosis is associated withdecreased echogenicity in HT. The applicability ofHT for the evaluation of thyroid HA was first de-scribed by Schiemann et al. in 2003 (14).

Material and Methods

Study Population

Most of the patients were sampled from the pa-tient population treated in the Department of En-docrinology at Trabzon Kanuni Research andEducation Hospital, between November 2015 andJanuary 2017. The patients with a suspected di-agnosis of thyroiditis were identified. The patientsunder 18 years and above 90 years of age orwithout available images (B-mode ultrasonogra-phy) and laboratory tests were excluded. In ad-dition, the patients who were diagnosed withthyroiditis were excluded.The study was approved by the local institutionalreview board and all participants provided writteninformed consent. This prospective, single-insti-

tution study was conducted in compliance withthe Helsinki Declaration and good clinical practiceguidelines of the Ministry of Health of Turkey. Thestudy was approved by the local ethics commit-tee of Kanuni Research and Education Hospital,Turkey.An Aplio 500 ultrasound machine (Toshiba MedicalSystems, Co. Ltd., Otawara, Japan) with linear 4.8to 11 MHz transducers and elastography softwarewas used. All the examinations were performed byone radiologist with an experience of more than15 years in thyroid imaging. The radiologist wasblinded to the clinical findings, laboratory results,early clinical suspected differential diagnosis ofthyroiditis, and the final diagnosis of the patients.A total of 250 individuals examined in our radiol-ogy department from October 2015 to March2016 were screened. Out of these individuals, 52patients were having thyroid nodules in additionto thyroiditis, which were detected incidentally.High-quality images were not obtained from 17patients because of retrosternal thyroid enlarge-ment or short neck anatomical structure. A totalof 69 patients were excluded from the study. Fi-nally, 171 cases were included in the study. Outof these cases, 23 were diagnosed as GD (8 men,15 women; 33±12 years), 94 were diagnosed asHT (8 men, 86 women; 40±13 years), and 20were diagnosed as SAT (8 men, 12 women; 42±9years). All cases were confirmed by clinical ex-amination and laboratory findings. The controlgroup (CG) consisted of 34 healthy volunteers (5men, 29 women; 40±10 years) whose ultrasoundimaging and thyroid laboratory results were nor-mal (Table 1).

Ultrasound Imaging

The ultrasound examination started with gray-scale imaging. The patient was supine with aslightly hyperextended position over a specialwheeled bed, which was built for thyroid imag-ing. The B-mode ultrasonographic evaluation ofthyroid glands was performed with standardtransverse and longitudinal planes. In addition,thyroid dimensions and parenchymal echogenic-ity were evaluated. The echogenicity of the thy-roid parenchyma was defined as markedhypoechogenicity, isoechogenicity, and hypere-chogenicity.Thyroid echogenicity was evaluated by compar-ing neighboring neck muscles (23). During thegray-scale ultrasound, all thyroid regions sus-pected for thyroiditis were identified in a longitu-dinal scanning position.

9

Turk J Endocrinol Metab Ata Korkmaz et al.2018;22:7-15 Differantial Diagnose of Thyroiditis by Histogram Analysis

9

10


10

Before saving the image in the JPEG format in ul-trasound database, we checked that the selectedB-mode image does not contain any thyroid nod-ules and lymph nodes. If necessary, patientswere requested to hold their breath to preventgray-scale artifacts.To improve and standardize the imaging quality,we selected gray-scale time-gain compensationvalues between -30 and 30 dB and gain levelsbetween 0 and 60. Finally, the focus-level inter-val was from 0 to 4, and we used focus level 2.We obtained three sonographic images for eachof the thyroid gland and sternocleidomastoidmuscle (SCM). After the examination, we se-lected the technically perfect image from the col-lected data for HA. This selected JPEG wasconsidered valid.

Histogram Image Analysis

Electronically recorded sonographic data in theJPEG format were transferred to a high-resolu-

tion computer system, and ImageJ software (ver-sion 1.4.3.67, National Institutes of Health) wasused for gray-scale HA. The echogenicity of theimages was measured as gray-scale pixels rang-ing from 0 to 255 (0=black, 255=white) throughHA.A region of interest (ROI) for HA was identified.The ROI included maximum possible thyroidlobes that were affected from thyroiditis to in-vestigate a maximal amount of the thyroidparenchyma (Figure 1). The first ROI was ac-cepted as the target region. We then selected an-other ROI as a reference. The ipsilateral SCM wasselected for comparing the affected thyroiditisarea to depict color pixels (Figure 2). Both ROIsincluded maximum possible thyroid tissue andSCM. In addition, we ensured that both ROIswere placed at the same vertical axis to thetransducer and in the central region of the image.The TRSCMR was obtained from the collecteddata.

CG: Control group; HT: Hashimoto's thyroiditis; SAT: Subacute thyroiditis; GD: Graves' disease; ns: Nonsignificant.

Number of cases

CG n (%) HT n (%) SAT n (%) GD n (%)

Variable 34 (19,9) 94 (55,0) 20 (11,7) 23 (13,5) P value

Female 29 (20,4) 86 (60,6) 12 (8,5) 15 (10,5) 0.001

Male 5 (17,2) 8 (27,6) 8 (27,6) 8 (27,6) 0.001

Age 40.3±10.2 40.1±13.0 42.2±9.2 33.3±12.1 0.457

Table 1. The analysis of the study population.

Figure 1, 2: Grayscale evolution method for the Histogram Analysis of thyroidal parenchyma. Two ROIs for compari-son were delineated to calculate the SR. The big rectangle (target) A is the local ROI on the thyroid tissue, the smallrectangle (reference) B is the local ROI on the sternocleidomastoid in front of the ipsilateral thyroid.


Continuous variables were expressed asmean±standard deviation (SD), and categoricalvariables were expressed in percentages. The nor-mality of the continuous variables was analyzedusing the Kolmogorov-Smirnov test. The categor-ical variables between the groups were comparedusing the chi-square test. The numerical variablesbetween independent groups were compared. Ifthe normal distribution requirement was provided,then analysis of variance was performed. If thenormal distribution requirement was not provided,then Kruskal-Wallis variance analysis was used.The Mann-Whitney U test was performed to de-termine whether the distribution of thyroid andSCM HA and TRSCMR is different among CG, SAT,GD, and HT. In addition, the Mann-Whitney U testwas used to compare the HAs and TRSCMRs ofthe groups.The receiver operating characteristic curve wasused to determine the cut-off point of the HA andTRSCMR of normal and experimental subjects. Thep-values lower than 0.05 were considered statisti-cally significant. In the presence of a significantthreshold, sensitivity, and specificity values werecalculated. To evaluate the area under the curve(AUC), the diagnostic value of the test was ac-cepted as statistically significant when type 1 errorwas less than 5%. The statistical analysis was per-formed using SPSS 22.0 statistical software (24).

ResultsThe clinical and demographic characteristics ofpatients are shown in Table 1.The HA values of thyroid parenchyma (mean±SD) of patients with GD, HT, SAT, and CG were83.49±27.91, 71.25±20.93, 70.83±13.94,80.95±20.88, and 52.74±24.11, respectively. Bycontrast, the HA values of SCM (mean±SD) ofpatients with GD, HT, SAT, and CG were52.74±24.11, 58.17±18.67, 67.20±14.71, and69.32±18.94, respectively (Table 2).The thyroid parenchyma HAs of GD, HT, and SATwere not statistically significant, whereas SCM HAvalues of HT and GD were statistically significant(p=0.009).The TRSCMR (mean±SD) of patients with GD, HT,SAT, and CG were 1.85±0.86, 1.29±0.41,1.09±0.26, and 1.25±0.5, respectively (Table 3and Figures 3–5).Compared with the CG, patients with GD had sta-tistically significant TRSCMRs (p=0.001).TRSCMRs presented the following ascending order:SAT<CG<HT<GD. The boxplot of the TRSCMR val-ues to each group is shown in Figure 6. Patientswith GD had statistically different TRSCMRs(p=0.001) compared with patients with SAT. Thisresult is noteworthy because SAT and GD sharesimilar imaging properties in gray-scale sonography.The cut-off points of the TRSCMR of patients withGD, HT, and SAT to the CG were 1.32 (sensitivity

11


11

CG: Control group; HT: Hashimoto's thyroiditis; SAT: Subacute thyroiditis; GD: Graves' disease.

Group Number of cases n (%) Mean±SD (TP) Mean±SD (SCM)

CG 34 (19,88) 80,95 (20,88) 69,32 (18,94)

HT 94 (54,98) 71,25 (20,93) 58,17 (18,67)

SAT 20 (11,69) 70,83 ( 13,94) 67,20 ( 14,71)

GD 23 (13,45) 83,49 (27,91) 52,74 (24,11)

TOTAL 171 (100.0)

Table 2. The distributions of HA results of thyroidal parenchyma (TP) and SCM.

CG: Control group; HT: Hashimoto's thyroiditis; SAT: Subacute thyroiditis; GD: Graves' disease.

TRSCMRs

Group Number of cases n (%) Range Median Mean ±SD

CG 34 (19,88) 0,64–2,22 1,17 1,25 ±0.5

HT 94 (54,98) 0,61–2,65 1,22 1,29 ±0,41

SAT 20 (11,69) 0,69–1,25 1,02 1,09 ±0,26

GD 23 (13,45) 1,48–2,23 1,61 1,85 ±0,86

Total 171 (100.0)

Table 3. Thyroid and sternocleidomastoideus muscle ratio (TRSCMR) ranges of different groups.

74%, specificity 66%, AUC 0.711), 1.74 (sensi-tivity 96%, specificity 77%, AUC 0.500), and1.74 (sensitivity 100%, specificity 84%, AUC0.354), respectively. To determine a cut-off pointfor differentiation, the two most interferinggroups in B-mode imaging were SAT and GD. HTand CG were excluded. The cut-off point of theTRSCMR of patients with GD to the SAT was 3.34(sensitivity 87%, specificity 100%, AUC 0.791;Table 4 and Figure 7).

DiscussionIn this study, we performed the B-mode HA ofthyroid parenchyma using sonography and eval-uated its applicability to differentiate thyroiditisfrom healthy thyroid and the subtypes of thy-roiditis from one another.We found statistically significant values inTRSCMRs in GD compared with other types ofthyroiditis, indicating that TRSCMRs can be usedas a supplementary sonographic parameter.Compared with the CG, the GD TRSCMR valueswere higher than the CG TRSCMR values and theTRSCMR values of the SAT group were lower thanthe TRSCMR values of the CG group, which wasstatistically significant (p<0.0001).GD is an autoimmune condition that presentswith thyrotoxicosis, which can also be the resultof different types of thyroiditis. To identify theexact cause of thyrotoxicosis, the radioactive io-dine uptake measurement is still the gold stan-dard of clinical application. GD shows radioactiveiodine uptake even when SAT does not. By con-trast, nuclear medicine techniques are not easilyaccessible at several health centers, and radioac-tive materials are harmful to lactating and preg-nant women. GD’s gray-scale sonographicfeatures are thyroid enlargement with the loss ofparenchymal echogenicity.SAT is an unusual, self-limiting condition thatgenerally develops after an upper tract infectioncaused by a viral infection, which is the result of

an autoimmune response (18). Initially, SAT usu-ally causes low-grade fever with thyrotoxicosis(19).In general, the gray-scale sonographic findings ofSAT are thyroid enlargement and ill-defined focalhypoechoic areas (19).The gray-scale ultrasound findings of SAT and GDare highly similar. Our study results revealed thatthe gray-scale sonographic imaging findings ofSAT and GD showed no statistically significantdifferences (p=0.215).The treatment of SAT and GD depends on theiretiopathogenesis and is completely different.Non-steroidal anti-inflammatory drugs and corti-costeroids are used in SAT treatment, whereasanti-thyroid-acting propylthiouracil and thiama-zole are used in GD treatment. Discriminant di-agnosis must be performed correctly, as theyhave different treatments.

12


12

CG: Control group; HT: Hashimoto's thyroiditis; SAT: Subacute thyroiditis; GD: Graves' disease; TRSCMR: Thyroid and sternoclei-domastoideus muscle ratio; AUC; Area under the curve; CI: Confidence limits.

Group 95% CI Std. Error AUC p values

GD-CG 0,589–0,833 0,062 0.711 0,0001

SAT-CG 0,250–0,459 0,053 0,354 0,667

HT-CG 0,411–0,590 0,045 0,500 0,975

GD-SAT 0,651–0,932 0,072 0,791 0,001

Table 4. TRSCMR’s for differential diagnosis of thyroiditis and CG for different groups with the standard errorsand 95% Confidence limits for the AUC.

Figure 3: The receiver operating characteristic curve ofTRSCMRs for differential diagnosis of the group of GDand the control group.The diagonal segment is produced by ties.

In theory, the differential diagnosis of GD fromSAT and HT by HA is possible because of the dif-ferent histopathologic characteristics and typesof thyroid gland vascularities for each condition.To date, no study has compared the TRSCMRsamong patients with GD and other types of thy-roiditis.

In this study, GD TRSCMR values were higherthan SAT TRSCM values. TRSCMRs could statisti-cally significantly differentiate GD from SAT; how-ever, it could not differentiate SAT from HT andCG. This result was particularly remarkable be-cause SAT and GD have similar imaging proper-ties to gray-scale sonography.The applicability of HA for the evaluation ofchronic thyroiditis was first described by Schie-mann et al. in 2003 (14). The current studies fo-cused on ultrasound gray-scale HA in chronicthyroiditis (12-15,25). These studies are basedon thyroid parenchymal HA rather than TRSCMR.Conversely, conventional ultrasound is a world-wide, easily accessible, inexpensive, and innocu-ous diagnostic method. However, ultrasound is auser-dependent imaging modality, which is themost crucial disadvantage for technique stan-dardization. Kim et al. showed that even if expe-rienced radiologists identify the presence ofchronic thyroiditis based on the specific similarsonographic features of HT, their evaluations areinconsistent (25).SAT is a painful and inflammatory condition (26).Pain may be bilateral or unilateral and spread tothe mandible, occipital fossa, and ear. Re-searchers must realize that patients may chooseto avoid neck movements to prevent pain, andthis option may lead to an increase in muscleechogenicity. In this study, statistically significantTRSCMR differentiating SAT from GD was a resultof increased muscle echogenicity in SAT, whichwas secondary to immobilization and decreasedmuscle echogenicity in GD because of the in-creased vascularity.This study had some limitations. First, the genderof enrolled patients was not equal because of thenature of thyroiditis. Second, cytological findingsfor each of the thyroiditis groups and long-termfollow-up HA values after treatment were not in-cluded.Further studies in the recovery phase of thyroidi-tis are required to enrich the findings of thisstudy.

ConclusionThe HA of sonographic imaging is applicable fordifferentiating patients with thyroiditis fromhealthy individuals; however, its differentiatingvalue for different types of thyroiditis, such asSAT and HT, is limited. TRSCMR is valuable fordifferentiating patients with thyroiditis fromhealthy individuals; however, it has limited valuein differentiating SAT-HT from GD-HT. Our study

13


13

Figure 4: Receiver operating characteristic curve ofTRSCMRs for differential diagnosis of the group of Has-himoto’s thyroiditis and the control group.The diagonal segment is produced by ties.

Figure 5: Receiver operating characteristic curve ofTRSCMRs for differential diagnosis of the group of SATand the control group.The diagonal segment is produced by ties.

results revealed that TRSCMR was the only use-ful method for differentiating GD from SAT.TRSCMR is a useful method for the differential di-agnosis of GD from a healthy population or fromSAT.HA would be useful in differentiating GD fromother causes of hyperthyroidism to avoidovertreating SAT and provide a prognosis. Nu-clear medicine studies may confirm this role;however, they involve radiation and are not al-ways available. In addition, laboratory tests areuseful but not always available.HA combined with conventional ultrasonographyis an excellent tool for the discrimination of GDfrom SAT.Source of Finance: During this study, no finan-cial or spiritual support was received neither fromany pharmaceutical company that has a directconnection with the research subject, nor from acompany that provides or produces medical in-struments and materials which may negativelyaffect the evaluation process of this study.Conflict of Interest: No conflicts of interest be-tween the authors and / or family members ofthe scientific and medical committee members ormembers of the potential conflicts of interest,counseling, expertise, working conditions, shareholding and similar situations in any firm.

Authorship ContributionsIdea/Concept: Hatica Ayça Ata Korkmaz; Design:Hatica Ayça Ata Korkmaz; Control/Supervision:Mustafa Köse; Data Collection And/Or Process-ing: Mustafa Köse; Analysis and/or Interpreta-

14


14

Figure 6: Boxplot of strain ratios in different groups.GH TRSCMR values were higher than SAT TRSCM values and these results were statistically significant (p<0.001).

Figure 7: Receiver operating characteristic curve ofTRSCMRs for differential diagnosis of the group of GDand SAT.The diagonal segment is produced by ties.

tion: Hatica Ayça Ata Korkmaz; Literature Re-view: Hatica Ayça Ata Korkmaz; Writing the Arti-cle: Hatica Ayça Ata Korkmaz; Critical Review:Mustafa Köse; Materials: Mustafa Köse, HaticaAyça Ata Korkmaz.

References1. Ophir J, Céspedes I, Ponnekanti H, Yazdi Y, Li X.

Elastography: a quantitative method for imagingthe elasticity of biological tissues. Ultrason Imaging.1991;13:111-134.

2. Ruchala M, Szczepanek-Parulska E, Zybek A,Moczko J, Czarnywojtek A, Kaminski G, Sowinski J.The role of sonoelastography in acute, subacute andchronic thyroiditis: a novel application of themethod. Eur J Endocrinol. 2012;166:425-432.

3. Menzilcioglu MS, Duymus M, Gungor G, Citil S,Sahin T, Boysan SN, Sarica A. The value of real-timeultrasound elastography in chronic autoimmunethyroiditis. Br J Radiol. 2014;87:20140604.

4. Kim I, Kim EK, Yoon JH, Han KH, Son EJ, Moon HJ,Kwak JY. Diagnostic role of conventional ultra-sonography and shearwave elastography in asymp-tomatic patients with diffuse thyroid disease: initialexperience with 57 patients. Yonsei Med J.2014;55:247-253.

5. Ruchała M, Szmyt K, Sławek S, Zybek A,Szczepanek-Parulska E. Ultrasound sonoelastogra-phy in the evaluation of thyroiditis and autoimmunethyroid disease. Endokrynol Polska. 2014;65:520-531.

6. Yang Z, Zhang H, Wang K, Cui G, Fu F. Assessmentof diffuse thyroid disease by strain ratio in ultra-sound elastography. Ultrasound Med Biol.2015;41:2884-2889.

7. Çekiç B, Toslak IE, Şahintürk Y, Cekin AH, KokselYK, Koroglu M, Demos TC. Differentiating transuda-tive from exudative ascites using quantitative B-mode gray-scale ultrasound histogram. AJR Am JRoentgenol. 2017;209:313-319.

8. Erol B, Kara T, Gürses C, Karakoyun R, Köroğlu M,Süren D, Bülbüller N. Gray scale histogram analysisof solid breast lesions with ultrasonography: can le-sion echogenicity ratio be used to differentiate themalignancy? Clin Imaging. 2013;37:871-875.

9. Rossi C, Artunc F, Martirosian P, Schlemmer HP,Schick F, Boss A. Histogram analysis of renal arte-rial spin labeling perfusion data reveals differencesbetween volunteers and patients with mild chronickidney disease. Invest Radiol. 2012;47:490-496.

10.Yang X, Tridandapani S, Beitler JJ, Yu DS, YoshidaEJ, Curran WJ, Liu T. Ultrasound histogram assess-ment of parotid gland injury following head-and-neck radiotherapy: a feasibility study. UltrasoundMed Biol. 2012;38:1514-1521.

11.Kim DW, Eun CK, In HS, Kim MH, Jung SJ, Bae SK.Sonographic differentiation of asymptomatic diffusethyroid disease from normal thyroid: a prospectivestudy. AJNR Am J Neuroradiol. 2010;31:1956-1960.

12.Mazziotti G, Sorvillo F, Iorio S, Carbone A, RomeoA, Piscopo M, Capuano S, Capuano E, Amato G,Carella C. Grey‐scale analysis allows a quantitative

evaluation of thyroid echogenicity in the patientswith Hashimoto's thyroiditis. Clin Endocrinol (Oxf).2003;59:223-229.

13.Acharya UR, Vinitha Sree S, Mookiah MR, Yantri R,Molinari F, Zieleźnik W, Małyszek-Tumidajewicz J,Stępień B, Bardales RH, Witkowska A, Suri JS. Di-agnosis of Hashimoto's thyroiditis in ultrasoundusing tissue characterization and pixelclassification.Proc Inst Mech Eng H. 2013;227:788-798.

14.Schiemann U, Avenhaus W, Konturek JW, Gellner R,Hengst K, Gross M. Relationship of clinical featuresand laboratory parameters to thyroid echogenicitymeasured by standardized grey scale ultrasonogra-phy in patients with Hashimoto's thyroiditis. Med SciMonit. 2003;9:MT13-17.

15.Loy M, Cianchetti ME, Cardia F, Melis A, Boi F, Mar-iotti S. Correlation of computerized gray‐scale sono-graphic findings with thyroid function and thyroidautoimmune activity in patients with Hashimoto'sthyroiditis. J Clin Ultrasound. 2004;32:136-140.

16.Cappelli C, Pirola I, De Martino E, Agosti B, DelbarbaA, Castellano M, Rosei EA. The role of imaging inGraves’ disease: a cost-effectiveness analysis. Eur JRadiol. 2008;65:99-103.

17.Bogazzi F, Bartalena L, Brogioni S, Burelli A, ManettiL, Tanda ML, Gasperi M, Martino E. Thyroid vascu-larity and blood flow are not dependent on serumthyroid hormone levels: studies in vivo by color flowdoppler sonography. Eur J Endocrinol. 1999;140:452-456.

18.Omori N, Omori K, Takano K. Association of the ul-trasonographic findings of subacute thyroiditis withthyroid pain and laboratory findings. Endocr J.2008;55:583-588.

19.Park SY, Kim EK, Kim MJ, Kim BM, Oh KK, Hong SW,Park CS. Ultrasonographic characteristics of suba-cute granulomatous thyroiditis. Korean J Radiol.2006;7:229-234.

20.Benker G, Olbricht T, Windeck R, Wagner R, AlbersH, Lederbogen S, Hoff HG, Reinwein D. The sono-graphical and functional sequelae of de Quervain'ssubacute thyroiditis: long-term follow-up. Acta En-docrinol (Copenh). 1988;117:435-441.

21.Pearce EN, Farwell AP, Braverman LE. Thyroiditis. NEngl J Med. 2003;348:2646-2655.

22.Anderson L, Middleton WD, Teefey SA, Reading CC,Langer JE, Desser T, Szabunio MM, Mandel SJ,Hildebolt CF, Cronan JJ. Hashimoto thyroiditis: Part2, sonographic analysis of benign and malignantnodules in patients with diffuse Hashimoto thyroidi-tis. AJR Am J Roentgenol. 2010;195:216-222.

23.El Jai A. Les cancers différenciés de la thyroïde apropos de 35 cas. 2009.

24.Released I. IBM SPSS Statistics for Windows. 20.Armonk, NY: IBM Corp; 2013.

25.Kim GR, Kim EK, Kim SJ, Ha EJ, Yoo J, Lee HS, HongJH, Yoon JH, Moon HJ, Kwak JY. Evaluation of un-derlying lymphocytic thyroiditis with histogramanalysis using grayscale ultrasound images. J Ultra-sound Med. 2016;35:519-526.

26.Engkakul P, Mahachoklertwattana P, Poomthavorn P.Eponym: de Quervain thyroiditis. Eur J Pediatr.2011;170:427-431.

15


15


16

16

Address for Correspondence: Mehmet Muhittin Yalçın, Dr. Ersin Arslan Training and Research Hospital,Clinic of Endocrinology and Metabolism, Gaziantep, Turkey



Cytologic Comparison Between Growingand Non-growing Benign Thyroid Nodules

Evaluated Using Two Different Growth Criteriaİki Farklı Büyüme Kriterine Göre Büyüyen ve Büyümeyen

Benign Nodüllerin Sitolojik Karşılaştırması

Dr. Ersin Arslan Training and Research Hospital, Clinic of Endocrinology and Metabolism, Gazinatep, Turkey*Dokuz Eylül University Faculty of Medicine, Department of Endocrinology and Metabolism, İzmir, Turkey

**Karşıyaka State Hospital, İzmir, Turkey***Dokuz Eylül University Faculty of Medicine, Department of Radiology, İzmir, Turkey

****Dokuz Eylül University Faculty of Medicine, Department of Pathology, İzmir, Turkey

DO

I:10

.251

79/t

jem

.201

7-58

819

Objective: Thyroid nodules are frequent in the adult popu-lation. Thyroid fine-needle aspiration biopsy is performedfor diagnosing cancerous nodules. It is suggested that bi-opsy-proven benign thyroid nodules should be followed upclinically, and if they grow, rebiopsy should be performed.However, certain growth criteria have not yet been defined.Material and Methods: We retrospectively reviewed thyroidfine-needle aspiration records of all patients at Dokuz EylülUniversity Hospital between January 2006 and June 2009.The nodules that underwent second biopsies were evaluatedusing two different growth criteria: at least 50% increase inthe nodule maximal diameter and 20% increase in at leasttwo nodule dimensions with a minimal increase of 2 mm.Results: From a total of 4217 thyroid nodules, we evalua-ted the cytological results of 117 benign thyroid nodules,which underwent follow-up biopsies. No significant diffe-rence was observed in the cytological results of the growinggroup (n:21), which had at least 50% increase in the ma-ximal nodule diameter, and the non-growing group (n:96)(p=0.999). In addition, using the growth criteria of 20% in-crease in at least two nodule dimensions with a minimal in-crease of 2 mm, no significant difference was observed inthe cytological results of the growing (n:47) and non-gro-wing (n:70) benign thyroid nodules (p=0.700).Conclusion: According to two different growth criteria, thegrowth of a benign nodule is not an additional risk factor forcancer.

Keywords: Thyroid nodule; nodule growth;thyroid fine-needle aspiration biopsy

Amaç: Tiroid nodülü erişkinlerde sık görülür. Tiroid inceiğne aspirasyon biyopsisi tiroid nodülünde kanser varlığınıaraştırmak amaçlı kullanılır. Biyopsi ile benign olduklarısaptanan nodüllerin klinik olarak izlenmesi, büyüme tespitedildiğinde yeniden biyopsi alınması önerilmektedir. Fakatnet bir büyüme kriteri belirlenmemiştir.Gereç ve Yöntemler: Dokuz Eylül Üniversitesi Hastane-si’nde Ocak 2006-Haziran 2009 tarihleri arasında uygula-nan TİİAB kayıtları geriye dönük olarak incelendi. İkincibir TİİAB yapılmış olan benign nodüllerin izlemdeki büyü-meleri iki farklı büyüme kriteri kullanılarak (en büyüknodül çapında %50 ve ya üzerinde artış, nodülün en az ikiçapında -2 mm’den az olmamak üzere- %20 veya üze-rinde artış) değerlendirildi.Bulgular: İnce iğne aspirasyon biyopsisi yapılan 4217 ti-roid nodülden izlem biyopsileri olan benign nodüller ince-lemeye alındı. İzlemde maximum çapta %50 ve üzerindeartışa göre büyüyenle (n: 21), bu kritere göre büyümeyen(n:96) benign nodüller incelendiğinde aralarında anlamlısitolojik fark saptanmadı (p=0.999). Benzer şekilde no-dülün en az iki çapında –iki mm’den az olmamak üzere%20 ve üzerinde boyut artışı saptanan nodüllerle (n:47),bu kritere göre büyümeyenler (n:70) arasında anlamlı si-tolojik fark saptanmadı (p=0.700).Sonuç: Çalışmada kullanılan iki farklı büyüme kriterinegöre benign nodüllerin izlemde büyümesi kanser varlığıiçin ek risk oluşturmamıştır.

Anahtar kelimeler: Tiroid nodülü; nodül büyümesi;tiroid ince iğne aspirasyon biyopsisi

https://orcid.org/0000-0002-2560-5001

https://orcid.org/0000-0001-6608-4508

https://orcid.org/0000-0002-3135-2127

https://orcid.org/0000-0002-8634-4845

https://orcid.org/0000-0002-1041-6881

IntroductionA thyroid nodule is a frequently observed healthproblem. Thyroid nodules can be detected in 4%of the population by palpation and in up to 67%by ultrasonography (1). Thyroid nodules are clin-ically crucial, as they have 5% to 10% probabil-ity of thyroid cancer (2). A clinical approach tothyroid nodules aims at detecting cancerous nod-ules. The simplest and safest method to screenthyroid cancer is thyroid fine-needle aspirationbiopsy (TFNAB; 3).It is recommended that benign nodules diag-nosed by TFNAB should be followed up with phys-ical examination and thyroid ultrasonography (3).One of the most crucial criteria to be assessedduring follow-up is the nodule growth. Rebiopsyis recommended for a growing nodule, which wasinitially benign (3). However, studies have shownthat benign nodules can also grow in their natu-ral course (4–6). There is no consensus about the“growth” criteria of thyroid nodules. Several cri-teria were used to establish the nodule “growth”(>50% increase in the maximal dimension of thenodule, >15% increase in the nodule volume,>30% increase in the nodule volume, etc. (7).American Thyroid Association (ATA) has defined a20% increase in at least two nodule dimensionswith a minimal increase of 2 mm as an accept-able growth criterion (3). However, till date, noevidence exists that cancer risk increases in be-nign nodules growing at follow-up.This study aimed to compare the TFNAB resultsof the growing nodules, which had initially benigncytology, with non-growing nodules. We used twodifferent growth criteria (i.e., at least 50% in-crease in the nodule maximal diameter and 20%increase in at least two nodule dimensions with aminimal increase of 2 mm) to detect whether thecancer risk of nodules growing at follow-up in-creases compared with the ones that do notgrow.

Material and MethodsWe retrospectively reviewed all results of ultra-sonography-guided fine-needle aspiration biop-sies performed at Dokuz Eylül University Hospitalbetween January 2006 and June 2009. Werecorded nodules that had repeated biopsies.Age, sex, radiation history to the neck, additionalmalignancy history, thyroid surgery history, fa-milial history, and thyrotrophin stimulating hor-mone (TSH) level of the patient and thedimensions of the nodules were recorded. Thenodules which had repeated biopsies were classi-

fied as growing and non-growing. Growth classi-fication and evaluation have been performed sep-arately according to two different criteria (at least50% increase in the nodule maximal diameterand 20% increase in at least two nodule dimen-sions with a minimal increase of 2 mm), as noconsensus exists about the exact growth criteriaof thyroid nodules.The biopsy results were classified as benign, in-termediate, or malign. Nodules that are Thy 2-3-4 according to Bethesda classification wereclassified as intermediate. The existence of sur-gical intervention toward the nodule after thesecond fine-needle aspiration biopsy was ascer-tained. If there was any surgical intervention, werecorded the pathological diagnosis of the nod-ule.The study protocol was approved by the localethics committee.Statistical analysis was performed using SPSSV15.0, SPSS Inc., Chicago. Nominal data wereevaluated using chi-square test; continuous vari-ables were assessed using independent sample‘st-test or Mann-Whitney U test. Logistic regres-sion analysis was performed for assessing the in-dependent impact of a specific variable on otherparameters.

ResultsWe retrospectively analyzed 4217 thyroid nodulebiopsies from 3202 patients at Dokuz Eylül Uni-versity Hospital between January 2006 and June2009 (Figure 1). The general characteristics ofthe nodules are summarized in Table 1.Out of the initial benign nodules (3509), 117 nod-ules that had repeated biopsy were included inthe statistical analysis. There were 47 growingand 70 non-growing nodules using the growthcriteria of 20% increase in at least two nodule di-mensions with a minimal increase of 2 mm(Group 1); and there were 21 growing and 96non-growing nodules using the growth criteria ofat least 50% increase in the nodule maximal di-ameter (Group 2).

Group 1

No difference was observed in terms of age, TSH,and the initial maximal diameter of the nodulebetween growing and non-growing groups (Table2). Follow-up time was longer in the growinggroup than the non-growing group (2.76 ±1.30years vs. 2.13 ±1.33 years, p = 0.050). In ad-dition, no difference was observed in the cyto-logical results of rebiopsies between the two

17

Turk J Endocrinol Metab Yalçın et al.2018;22:16-20 Comparison Between Growing and Non-growing Benign Thyroid Nodules

17

18

Yalçın et al. Turk J Endocrinol MetabComparison Between Growing and Non-growing Benign Thyroid Nodules 2018;22:16-20

18

groups (p=0.70). Two nodules with non-benigncytology in the growing group were operated;both nodules were defined as papillary thyroidcancer (PTC). A total of 5 nodules out of 45 nod-ules with benign cytology in the growing groupwere operated; 3 of these nodules were definedas PTC. There were five nodules with intermedi-ate cytology in the non-growing group; three ofthese nodules were operated, and two PTC andone benign nodule were established (Table 3). Allof the five nodules with benign cytology in thenon-growing group had benign pathology aftersurgery.In the linear regression model including age, sex,TSH level, and follow-up period, the follow-up pe-riod was 1.5 times high in the growing nodules(Table 4).

Group 2

No difference in terms of age and TSH levels wasobserved between the growing and non-growinggroups. The non-growing group had higher initialdiameter than the growing group (Table 2). Inaddition, no difference was observed in terms ofcytological results between the growing and non-growing groups (p=0.999). In both groups, ma-lign cytology result was not found. After the

surgical excision of the nodule with intermediatecytology in the growing group, PTC was found.Out of the 20 growing nodules, which had benigncytology, three were operated and all of themhad benign pathology. Furthermore, four noduleswith intermediate cytology were excised surgi-cally in the non-growing group, although PTC wasdetected in three of them (Table 3). In addition,seven of the non-growing nodules with benigncytology were operated, although three of themhad PTC.When the data were evaluated with linear re-gression analysis, age, sex, initial TSH level, andfollow-up period were not associated with nod-ules, which grow according to Group 2 criteria(Table 5).A total of seven malign and eight benign pathol-ogy results were found. The growth rate of be-nign nodules was 1.81 [-2, 35-12, 42] mm/year,and the growth rate of malign nodules was 1.21[-1, 12-4, 44] mm/year.

DiscussionIn this study, we retrospectively examined the re-biopsies of thyroid nodules. Considering the twodifferent growth criteria, we did not find an in-creased rate of malignancy in growing, initiallybenign nodules.The natural course of benign thyroid nodules isnot completely understood. Although the growthof the benign nodule can be attributed to its nat-ural course, most guidelines recommended re-biopsy to exclude malignancy in growing nodules(3). There were different growth criteria used fordefining the nodule “growth.” The rate of nodulegrowth differed when different growth criteriawere used. Erdogan et al. reported the rates ofnodule growth for different criteria (32% for≥15% change in the nodule volume, 24.1% for≥30% change in the nodule volume, and 4.1%

Total number of nodules 4217

Number of females (%) 3463 (80.0%)

Age (years) mean±SD 53.62±13.16

Nodule maximal diameter before 16.90±9.01

initial biopsy (mm) mean±SD

Serum TSH level before initial biopsy 0.85

(µu/mL) median [minimum-maximum] [<0.001-353]

Table 1. Characteristics of the nodules that underwentthyroid fine needle aspiration biopsy between January2006–June 2009.

Group 1: 20% increase in at least two nodule dimensions with a minimal increase of 2 mm.Group 2: At least 50% increase in nodule maximal diameter.

Group 1 Group 2

Growing Non-growing Growing Non-growing

(n=47) (n=70) P (n=21) (n=96) P

Age (year) 52.94±11.73 55.64±12.05 0.231 54.81±11.99 54.5±11.99 0.943

Maximal Diameter of the Nodule (mm) 15.38±6.39 17.60±6.25 0.065 12.00±5.05 17.74±6.18 0.013

TSH (µU/mL) 1.23±1.70 1.38±1.42 0.625 1.71±2.36 1.23±1.28 0.495

Follow up Time (year) 2.76 ±1.30 2.13 ±1.33 0.050 2.31 ±1.15 2.40 ±1.39 0.969

Growth Speed (mm/year) 3.2 ±2.87 0.37 ±3.5 0.009 5.83 ±4.88 0.59 ±2.42 0.011

Table 2. Nodule characteristics.

for ≥50% change in the maximal diameter of thenodule; 7). Lim et al. reported that 11.8% and9.4% of benign nodules grew using ≥50% in-crease in volume and ≥20% increase in at leasttwo nodule dimensions with a minimal increaseof 2 mm as a cut-off value, respectively (8).ATA recommended the rebiopsy of initially be-nign nodules if ≥20% increase was observed inat least two nodule dimensions with a minimal

increase of 2 mm (3). Durante et al. reportedthat 15.4% (n=153) of the benign nodules grewusing the ATA criteria (9). Only two malignan-cies were detected from these nodules after sec-ond TFNAB. Rosario et al. reported the rebiopsyresults of the initial benign nodules (10). Out of86 growing nodules (using ATA criteria), onlythree malignancies (3.5%) were detected afterthe second biopsy. In addition, Kim et al. re-ported a growth rate of 21.1% considering thecriteria of 50% change in the nodule volume(11). Moreover, they found only one malignancyamong 172 growing nodules. The results of allthese studies suggested that a proportion of be-nign nodules grow over time and the malignancyrate of these growing nodules in follow-up isvery low.In a recent study, malign nodules were foundmore likely to grow more than 2 mm/year com-pared with benign nodules (12). As a limitednumber of patients had final pathology in ourstudy, no difference was observed between be-nign and malign nodules in terms of nodulegrowth speed. In addition, the follow-up time forgrowing nodules was longer than that for non-growing nodules in Group 1. No data exist in theliterature comparing the follow-up time andgrowth; therefore, additional studies are requiredto interpret this finding.We have found intermediate cytological results ingrowing and non-growing nodules during follow-up. The reason for changing the cytological char-acteristics of the nodules may be the falsenegative rate of the initial TFNAB rather than thatthe growth in follow-up increases the malignancyrisk. As in a study in which growth has not beenused as a criterion and the rebiopsies of benignnodules during follow-up have been examined,rebiopsies in 13.2% of benign nodules showed in-termediate or malign cytology (13). Similarly, inanother study including the rebiopsies of benignnodules with suspicious ultrasonographic fea-tures, in 17.4% of them, suspicious cytology wasfound (14). Therefore, in some studies, TFNAB isrecommended for benign thyroid nodules in fol-low-up (15).We faced various limitations during our study.First, a retrospective approach weakens thestrength of the study. In this study, we used thebiopsies from non-growing nodules as a controlgroup. However, data were not available indicat-ing the reason for taking a biopsy from the non-growing nodules during follow-up. Repeatedbiopsy may have been taken from a group with

19

Turk J Endocrinol Metab Yalçın et al.2018;22:16-20 Comparison Between Growing and Non-growing Benign Thyroid Nodules

19

Cytology (n) Pathology (n)

Group 1 Growing (N= 47) Benign: 45 Benign: 2

PTC: 3

Intermediate: 2 Benign: 0

PTC:2

Group 1 Nongrowing (N=70) Benign: 65 Benign: 5

PTC: 0

Intermediate: 5 Benign:1

PTC: 2

Group 2 Growing (N=21) Benign:20 Benign:3

PTC:0


PTC:1

Group 2 Nongrowing (N=96) Benign: 90 Benign:4

PTC:3


PTC:3

Table 3. Characteristics of cytology and pathology ofgrowing and nongrowing nodules.

Group 1: 20% increase in at least two nodule dimensions with a mi-nimal increase of 2 mm.Group 2: At least 50% increase in nodule maximal diameter.PTC: Papillary thyroid cancer.

*p<0.05.

ODDS ratio 95% CI p-value

Age 0.967 0.93-1.01 0.100

Sex 1.240 0.38-4.10 0.724

Follow-up period 1.537 1.07-2.20 0.023*

TSH 0.921 0.68-1.24 0.588

Table 4. Factors predicting “20% increase in at leasttwo nodule dimensions with a minimal increase of 2mm”.

ODDS ratio 95% CI p-value

Age 0.99 0.95-1.04 0.810

Sex 0.554 0.11-2.83 0.478

Follow-up period 1.023 0.66-1.60 0.920

TSH 1.157 0.86-1.56 0.333

Table 5. Factors predicting at least 50% increase innodule maximal diameter.

high clinical cancer suspicion even there was nodimensional growth. Therefore, the control groupmay be a group with high risk. Intermediate riskcategory is a very heterogeneous group, andpossible discordance between the cytologists isanother limitation.

Conclusions and RecommendationsThe most outstanding clinical importance of thy-roid nodule is a cancer risk. In this study, two dif-ferent growth criteria were used, and it wasobserved that the cancer risk of growing benignnodules was not higher than the non-growingones. It is necessary that these findings are sup-ported by broad and prospective studies.Source of Finance: During this study, no fi-nancial or spiritual support was received neitherfrom any pharmaceutical company that has adirect connection with the research subject,nor from a company that provides or producesmedical instruments and materials which maynegatively affect the evaluation process of thisstudy.Conflict of Interest: No conflicts of interest be-tween the authors and / or family members ofthe scientific and medical committee members ormembers of the potential conflicts of interest,counseling, expertise, working conditions, shareholding and similar situations in any firm.

Authorship ContributionsIdea/Concept: Mehmet Muhittin Yalçın, SenaYeşil, Barış Akıncı; Design: Mehmet MuhittinYalçın, Barış Akıncı, Abdurrahman Çömlekci, FıratBayraktar; Control/Supervision: AbdurrahmanÇömlekci, Fırat Bayraktar, Sevinç Eraslan, AytaçGülcü, Tülay Canda; Data Collection and/or Pro-cessing: Mehmet Muhittin Yalçın, Sinan Ünal;Analysis and/or Interpretation: Mehmet MuhittinYalçın, Barış Akıncı, Sena Yeşi; Literature Review:Mehmet Muhittin Yalçın, Barış Akıncı, Sena Yeşil;Writing the Article: Mehmet Muhittin Yalçın, BarışAkıncı; Critical Review: Abdurrahman Çömlekci,Fırat Bayraktar, Sevinç Eraslan, Aytaç Gülcü,Tülay Canda; References and Fundings: Abdur-rahman Çömlekci, Fırat Bayraktar, SevinçEraslan.

References1. Ezzat S, Sarti DA, Cain DR, Braunstein GD. Thyroid

incidentalomas. Prevalence by palpation and ultra-sonography. Arch Intern Med. 1994;154:1838-1840.

2. Hegedüs L. Clinical practice. The thyroid nodule. NEngl J Med. 2004;351:1764-1771.

3. Haugen BR, Alexander EK, Bible KC, Doherty GM,Mandel SJ, Nikiforov YE, Pacini F, Randolph GW,Sawka AM, Schlumberger M, Schuff KG, ShermanSI, Sosa JA, Steward DL, Tuttle RM, Wartofsky L.2015 American Thyroid Association ManagementGuidelines for Adult Patients with Thyroid Nodulesand Differentiated Thyroid Cancer: the AmericanThyroid Association Guidelines Task Force on Thy-roid Nodules and Differentiated Thyroid Cancer.Thyroid. 2016;26:1-133.

4. Alexander EK, Hurwitz S, Heering JP, Benson CB,Frates MC, Doubilet PM, Cibas ES, Larsen PR, Mar-qusee E. Natural history of benign solid and cysticthyroid nodules. Ann Intern Med. 2003;138:315-318.

5. Kuma K, Matsuzuka F, Kobayashi A, Hirai K, MoritaS, Miyauchi A, Katayama S, Sugawara M. Outcomeof long standing solitary thyroid nodules. World JSurg. 1992;16:583-587.

6. Papini E, Petrucci L, Guglielmi R, Panunzi C, RinaldiR, Bacci V, Crescenzi A, Nardi F, Fabbrini R, PacellaCM. Long-term changes in nodular goiter: a 5-yearprospective randomized trial of levothyroxine sup-pressive therapy for benign cold thyroid nodules. JClin Endocrinol Metab. 1998;83:780-783.

7. Erdogan MF, Gursoy A, Erdogan G. Natural course ofbenign thyroid nodules in a moderately iodine-defi-cient area. Clin Endocrinol (Oxf). 2006;65:767-771.

8. Lim DJ, Kim JY, Baek KH, Kim MK, Park WC, Lee JM,Kang MI, Cha BY. Natural course of cytologically be-nign thyroid nodules: observation of ultrasono-graphic changes. Endocrinol Metab (Seoul).2013;28:110-118.

9. Durante C, Costante G, Lucisano G, Bruno R,Meringolo D, Paciaroni A, Puxeddu E, Torlontano M,Tumino S, Attard M, Lamartina L, Nicolucci A, FilettiS. The natural history of benign thyroid nodules.JAMA. 2015;313:926-935.

10.Rosário PW, Calsolari MR. What is the best criterionfor repetition of fine-needle aspiration in thyroidnodules with initially benign cytology? Thyroid.2015;25:1115-1120.

11.Kim SY, Han KH, Moon HJ, Kwak JY, Chung WY, KimEK. Thyroid nodules with benign findings at cyto-logic examination: results of long-term follow-upwith US. Radiology. 2014;271:272-281.

12.Angell TE, Vyas CM, Medici M, Wang Z, Barletta JA,Benson CB, Cibas ES, Cho NL, Doherty GM, DoubiletPM, Frates MC, Gawande AA, Heller HT, Kim MI,Krane JF, Marqusee E, Moore FD Jr, Nehs MA,Zavacki AM, Larsen PR, Alexander EK. Differantialgrowth rates of benign vs. malign thyroid nodules.J Clin Endocrinol Metab. 2017;102:4642-4647.

13.Chehade JM, Silverberg AB, Kim J, Case C, Moora-dian AD. Role of repeated fine-needle aspiration ofthyroid nodules with benign cytologic features. En-docr Pract. 2001;7:237-243.

14.Rosário PW, Purisch S. Ultrasonographic character-istics as a criterion for repeat cytology in benignthyroid nodules. Arq Bras Endocrinol Metabol.2010;54:52-55.

15.Chernyavsky VS, Shanker BA, Davidov T, Crystal JS,Eng O, Ibrahim K, Kwong J, Trooskin SZ. Is one be-nign fine needle aspiration enough? Ann SurgOncol. 2012;19:1472-1476.

20

Yalçın et al. Turk J Endocrinol MetabComparison Between Growing and Non-growing Benign Thyroid Nodules 2018;22:16-20

20

Address for Correspondence: Abbas Ali Tam, Ankara Yıldırım Beyazıt University Faculty of Medicine,Department of Endocrinology and Metabolism, Ankara, Turkey



Ratio of Thyrotropin to Thyroglobulin as aNovel Marker for Differentiating Between

Benign and Malignant Thyroid Nodules withinDifferent Bethesda Categories

Benign ve Malign Tiroid Nodüllerinin Ayrımında veFarklı Bethesda Kategorilerinde Yeni bir Belirteç Olarak

Tirotropin Tiroglobulin Oranı

Ankara Yıldırım Beyazıt University Faculty of Medicine, Department of Endocrinology and Metabolism, Ankara, Turkey*Ankara Ataturk Education and Research Hospital, Clinic of General Surgery, Ankara, Turkey

**Ankara Yıldırım Beyazıt University Faculty of Medicine, Department of Pathology, Ankara, Turkey


DO

I:10

.251

79/t

jem

.201

7-58

803

Objective: We aimed to determine whether the ratio of thyrot-ropin (TSH) to thyroglobulin (Tg) (TSH/Tg) would be able to as-sist in predicting malignancy in thyroid nodules.Material and Methods: Euthyroid patients operated betweenthe year 2007 and 2014 were retrospectively reviewed. Patientswho previously had thyroid disease or surgery and those with in-creased levels of anti-thyroglobulin antibodies were excludedfrom this study. Clinicopathological features, as well as serumTSH, Tg, and TSH/Tg were compared between histopathologi-cally benign and malignant groups.Results: Data related to 370 (60.3%) benign and 244 (39.7%)malignant patients were analyzed. The malignant patients exhibi-ted significantly higher TSH, TSH/Tg, and total thyroid volume, anda lower Tg compared to the benign patients (p<0.001 for each).There were 924 (74.2%) benign and 321 (25.8%) malignant no-dules. Cytological distribution of the nodules was observed to beas follows: 343 (27.6%) nondiagnostic, 637 (51.2%) benign, 121(9.7%) atypia of undetermined significance/follicular lesion of un-determined significance (AUS/FLUS), 39 (3.1%) follicular neo-plasm/suspicious for follicular neoplasm (FN/SFN), 64 (5.1%)suspicious for malignancy (SM), and 41 (3.3%) malignant. TSH,Tg, and TSH/Tg were significantly different in different Bethesdacategories (p<0.001 for each). Median TSH/Tg was the lowest inbenign (0.013), and highest in SM (0.054) and malignant (0.086)cytologies. TSH/Tg was significantly higher in the malignant no-dules compared to benign nodules, in AUS/FLUS, FN/SFN, and SMcategories (p=0.001, p<0.001, and p=0.003, respectively). In theregression analysis, TSH/Tg demonstrated higher diagnostic per-formance compared to TSH and Tg (p<0.001).Discussion: Preoperative TSH/Tg could be used as a novel mar-ker for differentiating between benign and malignant thyroid no-dules. It could also assist in the prediction of risk of malignancyand management decisions when the cytology is indeterminate.

Keywords: Thyrotropin; thyroglobulin; thyroid malignancy;TSH/Tg; Bethesda

Amaç: Malign ve benign tiroid nodüllerinin ayırımında yeni birprediktif markır olarak tirotropin (TSH) tiroglobulin (Tg) oranınıaraştırmayı amaçladık.Gereç ve Yöntemler: 2007 ve 2014 arasında opere edilenötiroid hastalar retrospektif olarak değerlendirildi. Tiroid has-talığı veya cerrahi öyküsü olanlar ve artmış anti-tiroglobulinantikorları olanlar dışlandı.Histopatolojik olarak benign ve ma-lign gruplar klinikopatolojik özellikler ve serum TSH, Tg,TSH/Tg oranı açısından karşılaştırıldı.Bulgular: 370 (%60.3) benign ve 244 (%39.7) malignhasta vardı.Benign hastalara göre malign hastalarda anlamlıolarak yüksek TSH, TSH/Tg ve total tiroid hacmi ve düşük Tgvardı (her biri için, p<0.001). (%74.2) benign ve 321 (%25.8)malign nodül vardı. Sitopatalojik dağılım şöyleydi; 343(%27.6) nondiagnostik, 637 (%51.2) benign, 121 (%9.7)önemi belirlenemeyen atipi/önemi belirlenemeyen follikü-ler lezyon (ÖBA/ÖBFL), 39 (%3.1) folliküler neoplazi/follikülerneoplazi şüphesi (FN/FNŞ), 64 (%5.1) malignite şüphesi(MŞ) ve 41 (%3.3) malign. TSH, Tg ve TSH/Tg Bethesdakategorilerinde anlamlı olarak farklıydı (her biri için p<0.001).Median TSH/Tg benignde (0.013) en düşük ve MŞ (0.054)ve malign sitolojilerde (0.086) en yüksekti. ÖBA/ÖBFL,FN/FNŞ ve MŞ kategorilerinde, TSH/Tg oranı malign nodül-lerde benign nodüllere göre yüksek bulundu (sırasıyla,p=0.001, p<0.001 ve p=0.003). Regresyon analizindeTSH/Tg; TSH ve Tg'ye göre daha yüksek tanısal performansasahipti (p<0.001).Tartışma: TSH/Tg ameliyat öncesinde benign ve maligntiroid nodüllerinin ayırımında yeni bir marker olarak kulla-nılabilir. Ayrıca indetermine sitolojisi olan nodüllerde malig-nite riskinin belirlenmesine ve yönetimine yardımcı olabi-lir.

Anahtar kelimeler: Tirotropin; tiroglobulin; tiroid malignitesi;TSH/Tg; Bethesda

21

https://orcid.org/0000-0001-7826-9059

https://orcid.org/0000-0002-7652-7648

https://orcid.org/0000-0003-4552-1603

https://orcid.org/0000-0001-6150-0226

https://orcid.org/0000-0002-7437-1176

https://orcid.org/0000-0001-5187-2616

https://orcid.org/0000-0003-1552-706X

https://orcid.org/0000-0001-7526-8827

IntroductionNodular thyroid disease is the most common thy-roid pathology observed in clinical practice. Morethan 50% of the population has at least one thy-roid nodule under ultrasonography examination(1). Although nodule prevalence is very high,only 5-10% of the nodules are malignant and re-quire surgical and/or medical management (2).The major concern is to discriminate the malig-nant lesions from the benign ones, preopera-tively. Fine-needle aspiration biopsy (FNAB) forthyroid is the gold standard test used for this pur-pose. Although it is a rapid, cost-effective, safe,and reliable procedure, the nondiagnostic resultsrequiring re-biopsy and the indeterminate cytol-ogy defined as the “gray zone” are the limitationsof this method (3, 4). Atypia of undeterminedsignificance or follicular lesion of undeterminedsignificance (AUS/FLUS), follicular neoplasm orsuspicious for follicular neoplasm (FN/SFN), andsuspicious of malignancy (SM) categories in theBethesda classification may be considered inde-terminate cytologies. These groups are repre-sentative of morphologically abnormal findingsthat are related to an increased risk of malig-nancy, though not enough to confirm a malignantlesion (5). Majority of the nodules with indeter-minate cytology are surgically excised due totheir malignancy potential, which confronts thepatients with risks of morbidity and complicationsrelated to unnecessary surgeries (6). Therefore,it is comprehensible that in addition to cytology,certain other parameters are required to predictmalignancy preoperatively. Gender, age, nodulediameter, exposure to radiation, and certain ul-trasonography (US) features have been demon-strated to be associated with the risk ofmalignancy in previous reports (3, 7). Preopera-tive high serum thyrotropin (TSH) has also beendemonstrated to increase the risk of malignancyin various studies. Boelaert et al. (8) evaluatedserum TSH in patients with nodular or diffuse goi-ter, and observed that even though within nor-mal ranges, high serum TSH was associated withthyroid malignancy.Thyroglobulin (Tg) is a glycoprotein producedspecifically in the thyroid follicular cells, regard-less of whether they are of malignant or benignnature (9). It is a well-known marker for persist-ent or recurrent differentiated thyroid cancer(10). Although the role of Tg in the postoperativeperiod has been clearly defined, its use as a pre-dictive marker in the preoperative period is de-batable (9, 11, 12). Routine Tg measurement is

not recommended as an initial laboratory inves-tigation for thyroid nodules. It is not sensitive orspecific for thyroid cancer as it exhibits increasedlevels in several other thyroid diseases (13).In the present study, our aim was to evaluate therole of the ratio of TSH to Tg (TSH/Tg) as a novelmarker for the prediction of malignant nodules inpatients with the euthyroid nodular disease. Wealso attempted to investigate whether this ratiocould be used to predict malignancy in differentBethesda categories and thus, assist in deter-mining the optimal management in case of inde-terminate cytology.

Material and MethodsA retrospective analysis of 2,900 patients oper-ated in our center between January 2007 and De-cember 2014 was performed. Since the highanti-thyroglobulin (anti-Tg) levels could cause aconfounding effect on absolute Tg, patients withhigh anti-Tg and the patients without simultane-ous measurement of serum anti-Tg were ex-cluded from this analysis. Patients withundetectable preoperative Tg levels (<1 ng/mL)were also excluded from the analysis becausethis was suggestive of occult antibody interfer-ence. Clinical or subclinical hypothyroidism or hy-perthyroidism, radiation to head and neck,history of thyroid surgery, and previous or cur-rent use of antithyroid or thyroid hormone re-placement therapy were the other exclusioncriteria.Age, sex, preoperative thyroid functions, anti-thyroid autoantibodies, US features (thyroid vol-ume, the presence of nodule/nodules, and nodulesize and number), and FNAB results were evalu-ated.Serum TSH, free triiodothyronine (fT3), free thy-roxine (fT4), anti-thyroid peroxidase (anti-TPO),and anti-Tg levels were measured using chemilu-minescence methods (Immulite 2000, Diagnos-tic Products Corp., Los Angeles, CA, USA; UniCelDxl 800, Beckman Coulter, Brea, CA). The nor-mal levels for TSH, fT3, and fT4 were 0.4-4µIU/mL, 1.57-4.71 pg/mL, and 0.85-1.78 ng/dL,respectively. Anti-TPO levels higher than 35IU/mL, and anti-Tg levels higher than 40 IU/mLwere considered positive. The normal range forTg was 0-78 ng/mL.The three diameters obtained from thyroid ultra-sonography (maximal length × width × depth)were multiplied with π/6 to calculate the volumeof each lobe, and the sum of volumes of the twolobes was defined as the thyroid volume. US (GE

22

Tam et al. Turk J Endocrinol MetabTSH/Tg Ratio and Thyroid Nodules 2018;22:21-31

22

23

Turk J Endocrinol Metab Tam et al.2018;22:21-31 TSH/Tg Ratio and Thyroid Nodules

23

Logiq 200 Pro with a 7.5 MHz probe, Kyunggi-do,Korea) guided FNAB was performed in nodules>1 cm in size. Also, cytological evaluation wasperformed when suspicious US features (hypoe-chogenicity, taller-than-wide shape, microcalcifi-cation, infiltrative margins, increased nodularvascularization, and absence of peripheral halo)were observed in a subcentimeter nodule.Cytological diagnosis was classified according toBethesda system, which has the following cate-gories: nondiagnostic (ND), benign, AUS/FLUS,FN/SFN, SM, and malignant.Patients and nodules were grouped as benign andmalignant based on their histopathological re-sults. Demographical and clinicopathological fea-tures, serum TSH, Tg, TSH/Tg, and Tg/TSH werecompared between these two groups. Hashimotothyroiditis was determined histopathologically.TSH and Tg levels in the patient were consideredas the values of the nodule. In case of more thanone nodule in a patient, values for each nodulewere recorded. The local ethical committee ap-proved the study protocol.


Statistical analysis was performed using Statisti-cal Package for Social Sciences (SPSS) for Win-dows 20 (IBM SPSS Inc., Chicago, USA) andMedCalc 11.4.2 (MedCalc Software, Mariakerke,Belgium). Shapiro-Wilk test was used to deter-mine whether the variables were normally dis-tributed. Normally distributed variables wereexpressed as a mean ±standard deviation, andthe non-normally distributed variables were ex-pressed as median (min-max). Numbers and per-centages of categorical variables were calculated.Student’s T-test and Mann-Whitney U test wereused to compare the numerical values in malig-nant and benign patients. Categorical variableswere compared using Chi-square and Fisher’sexact tests. Numerical values in the Bethestagroups were compared using ANOVA (post-hoc:Bonferroni) and Kruskal-Wallis H test (post-hoc:Dunn’s test). Significant prognostic factors formalignancy determined in the univariate analy-sis were included in the stepwise backward elim-ination multivariate logistic regression model,and independent predictors were identified. ROCanalysis was performed and area under the curvewas used to identify the diagnostic discriminationamong independent predictors. Youden’s indexmethod was used in order to determine the pre-diction point of TSH/Tg ratio and Tg/TSH ratio formalignancy. In the statistical analysis, p<0.05

was considered to be significant and the ORswere presented with their respective 95% confi-dence interval.

ResultsData related to 614 euthyroid patients with nodu-lar thyroid disease were analyzed. Histopatho-logical diagnosis was benign in 370 (60.3%) andmalignant in 244 (39.7%) patients. Malignancywas an incidental finding in 67 (27.5%) of themalignant patients. Age, sex, mean age, nodulenumber, mean fT3, mean fT4, and anti-TPO pos-itivity were similar in benign and malignant pa-tients (p>0.05 for each) (Table 1). Malignantpatients exhibited a higher rate of histopatholog-ically confirmed Hashimoto thyroiditis comparedto benign patients (24.6% vs. 15.9%; p=0.008).Median total thyroid volume obtained was 31.4mL in malignant, and 20.9 mL in benign patients(p<0.001). Malignant patients exhibited signifi-cantly higher median TSH (1.4 µIU/mL vs. 1.1µIU/mL; p<0.001), and lower median Tg (34.1ng/mL vs. 59 ng/mL; p<0.001) compared to be-nign patients. Median TSH/Tg was higher (0.04µIU/ng vs. 0.02 µIU/ng; p<0.001), and medianTg/TSH was lower (23.8 ng/µIU vs. 53.1 ng/µIU;p<0.001) in malignant patients, compared to be-nign patients (Table 1).Preoperative cytological evaluation was per-formed in 1245 nodules of 614 patients; the cy-tological diagnosis was benign in 637 (51.2%),nondiagnostic in 343 (27.6%), AUS/FLUS in 121(9.7%), FN/SFN in 39 (3.1%), SM in 64 (5.1%),and malignant in 41 (3.3%) nodules. Histopatho-logically, 924 nodules (72.4%) were benign and321 (25.8%) were malignant. Mean fT4 was sim-ilar in all categories of Bethesda; whereas, meanfT3 was higher in FN/SFN category compared tothe other Bethesda categories (p=0.033) (Table2). Median TSH was similar in nondiagnostic andbenign nodules, and lower than that in the othercategories. AUS/FLUS and FN/SFN categoriespresented similar median TSH, which were lowerthan those observed in SM and malignant cate-gories (p<0.001). There was no significant dif-ference in median Tg between nondiagnostic,benign, AUS/FLUS, and FN/SFN cytology; how-ever, these categories exhibited significantlyhigher Tg compared to the SM and malignant cat-egories (p<0.001). Median TSH/Tg was lower innondiagnostic, benign, and AUS/FLUS categoriescompared to the FN/SFN category; it was higherin the SM category compared to the FN/SFN cat-egory, and in the malignant category compared

to the SM category (p<0.001). Median Tg/TSHwas highest in nondiagnostic, benign, andAUS/FLUS categories; whereas, it was signifi-cantly lower in the FN/SFN category compared tothese categories. SM category exhibited signifi-cantly lower Tg/TSH compared to FN/SFN cate-gory, and malignant category exhibitedsignificantly lower Tg/TSH compared to SM cate-gory (p<0.001 for each) (Table 2).Bethesda categories were analyzed separately,and histopathologically confirmed malignancywas observed in 80 (23.3%) of the nondiagnos-tic, 99 (15.5%) of the benign, 37 (30.5%) of theAUS/FLUS, 11 (28.2%) of the FN/SFN, 53

(82.8%) of the SM, and 41 (100%) of the malig-nant cytology (Table 3). In all Bethesda cate-gories, mean fT3 was similar inhistopathologically benign and malignant nod-ules. In the nodules with preoperative nondiag-nostic and AUS/FLUS cytology, mean fT4 washigher in malignant nodules compared to benignnodules (p=0.017 and p=0.019, respectively).Benign and malignant nodules presented similarmedian TSH when the Bethesda categories wereconsidered separately, except in the nondiagnos-tic category where malignant nodules demon-strated higher median TSH compared to thebenign ones (1.2 µIU/mL vs. 1.0 µIU/mL;p=0.012). Median Tg was significantly higher inhistopathologically benign nodules compared tomalignant nodules in AUS/FLUS, FN/SFN, and SMcytology (p=0.001, p<0.001, and p=0.002, re-spectively). Median TSH/Tg was significantlylower in benign nodules compared to malignantnodules in AUS/FLUS, FN/SFN, and SM categories(p=0.001, p<0.001, and p=0.003, respectively).Benign and malignant nodules demonstratedsimilar TSH/Tg in the nondiagnostic and benignBethesda categories (p=0.347 and p=0.580, re-spectively). These significant and nonsignificantresults for each Bethesda category were alsovalid for Tg/TSH, however, with inverse relations(Table 3).Variables associated with malignancy were ex-amined by multiple logistic regression analysismodel (Table 4). In Model I, the presence ofHashimoto thyroiditis, total thyroid volume, TSH,and Tg were included as variables. In addition tothe variables of Model I, TSH/Tg and Tg/TSH wereincluded in Model II and III, respectively. Totalthyroid volume (OR=1.045; p<0.001) and serumTSH (OR=1.260; p=0.043) were identified as in-dependent predictors for malignancy in Model I.Every 1 mL increase in the volume and every 1µIU/mL increase in TSH was associated with1.045 and 1.260 times increased risk of malig-nancy, respectively. In Model II, total thyroid vol-ume (OR=1.035; p<0.001) and TSH/Tg (x100)(OR=1.162; p<0.001) were identified as inde-pendent predictors for malignancy. Malignancyrisk increased by 1.162 times for every 1% in-crease in TSH/Tg. In Model III, total thyroid vol-ume (OR=1.035; p<0.001) and Tg/TSH (x100)(OR=0.993; p<0.001) were identified as inde-pendent predictors for malignancy, and a 1% de-crease in Tg/TSH was associated with 1.007(1/0.993) times increased risk of malignancy.Model II and III demonstrated higher model per-

Benign Malignant

(n=370) (n=244) p

Sex

Male 84 (22.7%) 60 (24.6%) 0.589

Female 286 (77.3%) 184 (75.4%)

Hashimoto thyroiditis

Absent 311 (84.1%) 184 (75.4%) 0.008

Present 59 (15.9%) 60 (24.6%)

Nodule number

Solitary 52 (14.1%) 41 (16.8%) 0.352

Multinodular 318 (85.9%) 20 (83.2%)

Table 1a. Clinicopathological features of patients withbenign and malignant histopathology (categoricalvariables).

Categorical variables are shown as numbers (%).

Benign Malignant

(n=370) (n=244) p

Age (years) 47.9±10.8 48.6 ±2.5 0.429

Total thyroid volume 20.9 31.4 <0.001

(mL) (5.6-150.1) (5.9-256.8)

Anti TPO positivity 36 (9.7%) 21 (8.6%) 0.639

fT3 (pg/mL) 3.26 ±0.5 3.24 ±0.5 0.700

fT4 (ng/dL) 1.20 ±1.18 1.19 ±0.18 0.898

TSH (µIU/mL) 1.1 (0.4-3.8) 1.4 (0.4-4.0) <0.001

Tg (ng/mL) 59.0 34.1 <0.001

(1.8-2175.0) (1.3-1000)

TSH/Tg (µIU/ng) 0.02 0.04 <0.001

(0.001-1.09) (0.001-2.24)

Tg/TSH (ng/µIU) 53.1 23.8 <0.001

(0.92-1587.3) (0.45-2137.5)

Table 1b. Clinicopathological features of patients withbenign and malignant histopathology (numericalvariables).

Numerical variables are shown as mean ±standard deviation or median(min-max).Anti-TPO: Anti-thyroid peroxidase; fT4: Free thyroxine; fT3: Free triio-dothyronine; TSH: Thyrotropin; Tg: Thyroglobulin.

24 Tam et al. Turk J Endocrinol MetabTSH/Tg Ratio and Thyroid Nodules 2018;22:21-31

24

The

anal

ysis

was

mad

ew

ith12

45no

dule

s.N

umer

ical

variab

les

are

show

nas

mea

n±

stan

dard

devi

atio

nor

med

ian

(min

-max

).fT

4:Fr

eeth

yrox

ine;

fT3:

Free

triio

doth

yron

ine;

TSH

:Th

yrot

ropi

n;Tg

:Th

yrog

lobu

lin;

ND

:N

ondi

agno

stic

;AU

S/F

LUS:

Atyp

iaof

unde

term

ined

sign

ifica

nce/

folli

cula

rle

sion

ofun

dete

rmi-

ned

sign

ifica

nce;

FN/S

FN:

Folli

cula

rne

opla

sm/s

uspi

ciou

sfo

rfo

llicu

lar

neop

lasm

;SM

:Sus

pici

ous

for

mal

igna

ncy.

a p<

0.05

vs.

ND

,b p

<0.

05vs

.Ben

ign,

c p<

0.05

vsAU

S/F

LUS,

d p<

0.05

vs.

FN/S

FN,

e p<

0.05

vsSM

,f p

<0.

05vs

.M

alig

nant

.

Beth

esd

a

cate

go

ries

nfT

4p

fT3

pTS

Hp

Tg

pTS

H/

Tg

pTg

/TS

Hp

ND

343

1.19

±0.

170.

990

3.25

±0.

46d,

e,f

0.03

31.

066

.80.

016

64

(0.4

-3.4

)c,d

,e,f

<0.

001

(1.8

-100

0)e,

f<

0.00

1(0

.001

-1.0

65)d

,e,f

<0.

001

(0.9

4-21

37.5

)d,

e,f

<0.

001

Ben

ign

637

1.20

±0.

173.

27±

0.46

d,e,

f0.

980

.30.

013

77.8

6

(0.4

-3.7

)c,d

,e,f

(1.8

-217

5)e,

f(0

.001

-1.0

88)d

,e,f

(0.9

2-21

37.5

)d,e

,f

AU

S/F

LUS

121

1.20

±0.

163.

29±

0.49

d,e,

f1.

379

.60.

017

58.8

0

(0.4

-4.0

)a,b

,e,f

(4-1

000)

e,f

(0.0

02-0

.431

)d,e

,f(2

.32-

531.

9)d,

e,f

FN/S

FN39

1.19

±0.

213.

44±

0.53

a,b,

c,e,

f1.

259

.00.

037

27.0

0

(0.5

-3.7

)a,b

,e,f

(8.8

-894

)e,f

(0.0

01-0

.291

)a,b

,c,e

,f(3

.43-

802.

86)a

,b,c

,e,f

SM

641.

19±

0.19

3.16

±0.

50a,

b,c,

d1.

622

.30.

054

18.5

9

(0.4

-3.3

)a,b

,c,d

(1.3

-100

0)a,

b,c,

d(0

.001

-2.2

40)a

,b,c

,d,f

(0.4

5-71

9.42

)a,b

,c,d

,f

Mal

igna

nt41

1.21

±0.

203.

14±

0.41

a,b,

c,d

1.6

23.9

0.08

611

.6

(0.5

-3.8

)a,b

,c,d

(2.1

-439

)a,b

,c,d

(0.0

03-0

.408

)a,b

,c,d

,e(2

.45-

300.

68)a

,b,c

,d,e

Tabl

e2.

Com

pariso

nof

fT3,

fT4,

TSH

,Tg

,TS

H/T

gan

dTg

/TSH

leve

lsin

differ

ent

Bet

hesd

aca

tego

ries

.

25Turk J Endocrinol Metab Tam et al.2018;22:21-31 TSH/Tg Ratio and Thyroid Nodules

25

formance compared to Model I. (Nagelk-erke’s R2 for Model III: 0.308, Model II:0.310, Model I: 0.203; p<0.001).The diagnostic performance of total thyroidvolume, TSH, Tg, TSH/Tg, and Tg/TSH forthe prediction of malignancy was evaluatedusing ROC curve analysis. TSH/Tg andTg/TSH demonstrated similar diagnosticperformance, which was higher than that oftotal thyroid volume, TSH, and Tg(p<0.001). In addition, the diagnostic per-formance of total thyroid volume was higherthan that of TSH and Tg (p<0.001) (Figure1).A cut-off value of >0.03 for TSH/Tg couldpredict malignancy with 61.9% sensitivityand 74.1% specificity. A Tg/TSH value of≤25.85 also demonstrated 61.1% sensitiv-ity and 76.8% specificity in predicting ma-lignancy.

DiscussionClinical follow-up is sufficient for most of thethyroid nodules after the clinical or cytolog-ical exclusion of malignancy. The major con-cern is to identify malignant lesionspreoperatively. Detecting the minority ofthyroid cancer patients is a great challengefor the clinician (14). Various risk factorsthat might assist in predicting malignancyin thyroid nodules have been investigatedto date. High serum TSH is one of those riskfactors. TSH plays an important role in theregulation of thyroid differentiation genes,growth factors, and receptors (15). Mito-genic effect of TSH on thyroid carcinomacells has been well described previously(16, 17). Varying levels of TSH-receptormRNA are expressed in nearly all papillaryand follicular carcinomas (18).Increasing serum TSH levels, althoughwithin normal limits, have been reported tobe associated with a higher risk of malig-nancy in patients with thyroid nodules (8,19). Shi et al. (14) demonstrated that theprevalence of differentiated thyroid cancer(DTC) increased significantly as the serumTSH levels increased. A serum TSH level of1.9-4.8 mIU/L and a serum TSH level >4.8mIU/L were observed to be associated with1.57 (95% CI: 1.03-2.40; p=0.038) timesand 5.71 (95% CI: 2.31-14.14; p=0.0002)times of the likelihood of malignancy, re-spectively, compared to a serum TSH level

The

anal

ysis

was

mad

ew

ith12

45no

dule

sN

umer

ical

variab

les

are

show

nas

mea

n±

stan

dard

devi

atio

nor

med

ian

(min

-max

)fT

4:Fr

eeth

yrox

ine;

fT3:

Free

triio

doth

yron

ine;

TSH

:Th

yrot

ropi

n;Tg

:Th

yrog

lobu

lin;

ND

:N

ondi

agno

stic

;AU

S/F

LUS:

Atyp

iaof

unde

term

ined

sign

ifica

nce/

folli

cula

rle

sion

ofun

dete

rmi-

ned

sign

ifica

nce;

FN/S

FN:

Folli

cula

rne

opla

sm/s

uspi

ciou

sfo

rfo

llicu

lar

neop

lasm

;SM

:Sus

pici

ous

for

mal

igna

ncy.

Beth

esd

a

cate

go

ries

nfT

4p

fT3

pTS

Hp

Tg

pTS

H/

Tg

pTg

/TS

Hp

Non

diag

nost

icB

263

1.18

±0.

170.

017

3.23

±0.

470.

147

1.0

0.01

267

.40.

825

0.01

60.

347

64.0

0.34

7

(0.4

-3.4

)(1

.8-1

000)

(0.0

01-0

.414

)(2

.41-

1587

.3)

M80

1.23

±0.

163.

31±

0.41

1.2

57.6

0.01

760

.54

(0.4

-3.1

)(2

.2-1

000)

(0.0

01-1

.065

)(0

.94-

2137

.5)

Ben

ign

B53

81.

20±

0.17

0.40

63.

26±

0.45

0.19

20.

90.

330

80.1

0.64

30.

013

0.58

078

.13

0.58

0

(0.4

-3.7

)(1

.8-2

175)

(0.0

01-1

.088

)(0

.92-

1587

.3)

M99

1.18

±0.

183.

33±

0.51

1.1

90.4

0.01

661

.43

(0.4

-3.3

)(5

.4-1

000)

(0.0

01-0

.380

)(2

.63-

2137

.5)

AU

S/F

LUS

B84

1.17

±0.

160.

019

3.24

±0.

460.

060

1.3

0.92

210

4.2

0.00

10.

014

0.00

170

.60.

001

(0.4

-4.0

)(4

.4-1

000)

(0.0

02-0

.230

)(4

.3-5

31.9

)

M37

1.25

±0.

163.

42±

0.53

1.4

41.9

0.04

323

.23

(0.4

-3.8

)(3

.9-5

91)

(0.0

03-0

.431

)(2

.32-

291.

25)

FN/S

FNB

281.

20±

0.21

0.63

83.

37±

0.50

0.25

51.

10.

233

81.4

<0.

001

0.01

7<

0.00

159

.70

<0.

001

(0.5

-3.7

)(1

1.1-

894)

(0.0

01-0

.091

)(1

0.99

-802

.86)

M11

1.16

±0.

223.

59±

0.60

1.4

22.0

0.05

518

.33

(0.6

-2.7

)(8

.8-5

6.9)

(0.0

37-0

.291

)(3

.44-

27.0

)

SM

B11

1.16

±0.

180.

594

3.09

±0.

460.

584

1.4

0.71

586

.60.

002

0.02

70.

003

37.7

30.

003

(0.6

-3.3

)(1

3.3-

1000

)(0

.001

-0.0

86)

(11.

63-7

19.4

2)

M53

1.20

±0.

193.

18±

0.51

1.5

17.5

0.07

713

.00

(0.4

-3.5

)(1

.3-5

00)

(0.0

02-2

.240

)(0

.45-

476.

19)

Mal

igna

ntM

411.

21±

0.20

-3.

14±

0.41

-1.

6-

23.9

-0.

086

-11

.6-

(0.5

-3.8

)(2

.1-4

39)

(0.0

03-0

.408

)(2

.45-

300.

68)

Tabl

e3.

Com

pariso

nof

fT3,

fT4,

TSH

,Tg

,TS

H/T

gan

dTg

/TSH

leve

lsin

hist

opat

holo

gica

llybe

nign

and

mal

igna

ntno

dule

sw

ithdi

ffer

ent

Bet

hesd

aca

tego

ries

.

26 Tam et al. Turk J Endocrinol MetabTSH/Tg Ratio and Thyroid Nodules 2018;22:21-31

26

TSH: Thyrotropin; Tg: Thyroglobulin.Model I: Hashimoto thyroiditis, total thyroid volume, TSH, and Tg were included.Model II: Hashimoto thyroiditis, total thyroid volume, TSH, Tg and TSH/Tg were included.Model III: Hashimoto thyroiditis, total thyroid volume, TSH, Tg and Tg/TSH were included.OR: Odds ratio, CI: Confidence interval.

95% CI

Variables β±SE OR lower upper p

Model I

Total thyroid volume 0.044±0.006 1.045 1.014 1.033 <0.001

TSH 0.231±0.114 1.260 1.007 1.576 0.043

Nagelkerke R2=0.203; p<0.001*

Model II


TSH/Tg 0.150±0.020 1.162 1.117 1.209 <0.001


Model III


Tg/TSH -0.008±0.001 0.993 0.990 0.996 <0.001


Table 4. The predictive variables of malignancy.

Figure 1: Diagnostic performance of risk factors for the prediction of malignancy.

27Turk J Endocrinol Metab Tam et al.2018;22:21-31 TSH/Tg Ratio and Thyroid Nodules

27

of 1.0-1.9 mIU/L. Higher TSH has also been ob-served to be associated with an increased risk oflymph node metastasis and an advanced diseasestage (14). Another study suggested an associ-

ation between higher serum TSH and signifi-cantly increased risk of DTC. The risk of malig-nancy increased by 25% when the TSH levelswere in the range of 0.40-1.39 mIU/L, while the

increase was 35% when the TSH levels were inthe range of 1.40-4.99 mIU/L (p=0.002) (20).Similar to these findings, we also observedhigher serum TSH (within normal ranges) inhistopathologically malignant patients comparedto benign patients. In contrast to these findings,Kim et al. (21) reported similar serum TSH lev-els in both papillary thyroid cancer (PTC) and be-nign nodules. There are also additional studiesthat reported lack of association between TSHand malignancy (6, 22).Tg is closely associated with the synthesis anddeposition of thyroid hormones, and smallamounts of physiological Tg are released into pe-ripheral circulation in healthy people. Detectionof Tg in serum after total thyroidectomy in pa-tients with DTC is suggestive of recurrent or per-sistent disease (23). Unlike the setting ofpostoperative cancer follow-up, the use of Tg inthe preoperative assessment of thyroid nodulesis debatable (12). Guarino et al. (24) did not findany diagnostic or prognostic value of preopera-tive Tg measurement in thyroid nodules. Anotherstudy examining the role of preoperative Tg, inaddition to the US features, in predicting malig-nancy in thyroid nodules demonstrated that itcould not be used for differentiating malignantnodules from the benign ones. The authors con-cluded that the only predictive factors for malig-nancy were suspicious US features (25). On thecontrary, there exist studies which suggest a pos-sible role of Tg in the preoperative diagnosis ofmalignancy (26, 27). However, Tg measurementis not yet a recommended laboratory examina-tion during the preoperative assessment of thy-roid nodules (13).In the present study, we observed that both TSHand Tg were risk factors for malignancy in euthy-roid patients with thyroid nodules. The other riskfactors determined were as follows: the presenceof Hashimoto thyroiditis, increased total thyroidvolume, increased TSH/Tg and decreasedTg/TSH. However, the diagnostic value of totalthyroid volume was higher than that of serumTSH and Tg. In the regression analysis, total thy-roid volume, TSH, TSH/Tg, and Tg/TSH wereidentified as independent predictors of malig-nancy. ROC curve analysis demonstrated thatboth TSH/Tg and Tg/TSH were better predictorscompared to the other risk factors. As confirmedin the present study, TSH/Tg appears to be one ofthe promising thyroid malignancy markers underinvestigation. Wang et al. (28)evaluated TSH/Tg

in 158 benign and 242 malignant nodules, andsuggested that a high preoperative serumTSH/Tg was a risk factor for thyroid cancer andthat TSH/Tg correlated with malignancy betterthan serum TSH. Sensitivity and specificity ofTSH/Tg for prediction of malignancy were 74.3%and 61.5%, respectively, in patients with normalanti-Tg levels. In the mentioned study, however,patients with positive anti-Tg and patients with Tgnon-producing and TSH unresponsive tumors,such as medullary and anaplastic cancer, werenot excluded from the analysis. In another studyincluding 134 benign and 68 malignant patients,preoperative TSH and Tg were not useful in de-tecting thyroid cancer, and although TSH/Tg wasobtained as a predictor for malignancy in the uni-variate analysis, it did not remain statistically sig-nificant in the multivariate analysis. Patients onantithyroid or thyroid hormone replacement ther-apy, along with one patient with thyroid metas-tasis from renal cell carcinoma, were alsoincluded in the mentioned study (29). In com-parison with the previous two studies, the sam-ple size was higher and the study population wasmore uniform in our study. Similar to the reportby Wang et al. (28), both TSH and TSH/Tg wereobtained as predictors for malignancy in thepresent study, and TSH/Tg was observed to besuperior to TSH.The risk of malignancy and recommended clinicalmanagement have been described for each cate-gory in The Bethesda System for Reporting Thy-roid Cytopathology (TBSRTC) (30). A benigncytology accurately predicts a benign nodule thatcan be followed-up, while a malignant cytologycarries a 97-99% risk of cancer, requiring thy-roidectomy. AUS/FLUS, FN/SFN, and SM cate-gories are cytologically indeterminate groups thatpresent a 5-15%, 15-30%, and 60-75% risk ofmalignancy, respectively. In these categories, thesamples are adequate for cytological evaluationand abnormal morphological findings are also ob-served, which are, however, not enough to con-firm malignancy (31). Clinical risk factors, USfeatures, and molecular testing results ought tobe considered during the management of noduleswith SM and FN/SFN cytologies. In the noduleswith AUS/FLUS cytology, repeat FNAB or molec-ular tests may be performed, according to theirclinical and US features (13). Thyroidectomy issuggested in this category in case of nondiag-nostic or persistent AUS/FLUS cytology, or in caseof a cytological result associated with greater

28


28

malignancy potential obtained in repeated FNAB.If repeated FNAB is benign, clinical follow-up isadequate (32). When cytology is indeterminate,both the patient and the physician stand at acrossroad and require reliable markers to choosethe right path. We tried to evaluate whether wecould use TSH/Tg to decide the management ofnodules with different Bethesda categories, par-ticularly the indeterminate ones. We demon-strated that TSH/Tg was markedly higher inmalignant nodules compared to the benign onesin the AUS/FLUS, FN/SFN, and SM categories. Inaddition, it was increasing in the malignant nod-ules as the cytology moved from the Bethesdacategory with lower to higher risk of malignancy.A similar situation was noted for Tg/TSH. In theAUS/FLUS, FN/SFN, and SM categories, Tg/TSHwas lower in histopathologically malignant nod-ules compared to benign nodules, and it de-creased as the cytology moved from theBethesda category with lower to higher risk ofmalignancy.There were certain limitations in our study. Weattempted to conduct a uniform group study,however, while doing that, a selection bias mighthave occurred inherently. The ratio of histopatho-logically confirmed malignant nodules was higherthan expected in all the Bethesda categories. Ourcenter is one of the biggest tertiary referral cen-ters in our country, and a considerable numberof patients with high suspicion of malignancy arereferred from other centers. Another limitationwas that the number of nodules was low in cer-tain Bethesda categories. We are aware that pa-tients with multiple nodules might havedominated the findings, particularly TSH/Tg andTg/TSH, in the module-based analysis. In suchpatients, the nodule exhibiting highest malig-nancy potential in the cytological examinationmight have been chosen instead of including eachnodule separately in the analysis. However, thisapproach would lead to consideration of only thenodule with the highest risk of malignancy andthe other nodules would not be represented. Ingeneral practice, when cytology is benign, thy-roidectomy is suggested as an option only in caseof large lesions or indeterminate results such asfollicular neoplasm. This might partly explain thehigher Tg levels in the histopathologically benigngroup. Lastly, we included only euthyroid patientsin our study. This may also be considered astrong aspect of our study. However, from an-

other perspective, patients with normal TSH, fT3,and fT4 displaying hot nodules in scintigraphymight exhibit lower TSH than the patients dis-playing warm or cold nodules. We could not ex-clude this possibility as we did not performthyroid scintigraphy.

ConclusionHigh serum TSH, even within normal ranges, wasobserved to be associated with an increased riskof thyroid malignancy. However, TSH/Tg provedto be a better predictor of malignancy comparedto TSH or the other risk factors identified in thisstudy. TSH/Tg could serve as a novel, cost-effec-tive, practical, and applicable index for risk strat-ification of thyroid nodules, and when combinedwith other factors, it could assist clinicians informing important decisions regarding the man-agement of nodules. Further prospective andlarge-scale research are required to supportthese findings.Ethics: Ethics Committee Approval and InformedConsent: Ethical review board of Yıldırım BeyazıtUniversity Ataturk Training and Research Hospitalapproved the study protocol.Source of Finance: During this study, no finan-cial or spiritual support was received neither fromany pharmaceutical company that has a directconnection with the research subject, nor from acompany that provides or produces medical in-struments and materials which may negativelyaffect the evaluation process of this study.Conflict of Interest: No conflicts of interest be-tween the authors and / or family members ofthe scientific and medical committee members ormembers of the potential conflicts of interest,counseling, expertise, working conditions, shareholding and similar situations in any firm.

Authorship ContributionsSurgical and Medical Practices: Abbas Ali Tam,Nuran Sungu, Mustafa Ömer Yazıcıoğlu; Concept:Abbas Ali Tam, Didem Özdemir, Bekir Çakır; De-sign: Abbas Ali Tam, Didem Özdemir, CevdetAydın, Muhammet Cüneyt Bilginer; Data collec-tion and Processing: Abbas Ali Tam, DidemÖzdemir; Analysis or Interpretetion: Abbas AliTam, Didem Özdemir, Reyhan Ersoy, Bekir Çakır,Cevdet Aydın, Muhammet Cüneyt Bilginer; Liter-ature Search: Abbas Ali Tam, Didem Özdemir,Nuran Sungu, Mustafa Ömer Yazıcıoğlu Writing:Abbas Ali Tam, Didem Özdemir.

29


29

References1. Ali SZ. Thyroid cytopathology: Bethesda and be-

yond. Acta Cytol. 2011;55:4-12.2. Arul P, Akshatha C, Masilamani S. A study of malig-

nancy rates in different diagnostic categories of theBethesda system for reporting thyroid cytopathol-ogy: an institutional experience. Biomed J. 2015;38:517-522.

3. Dorange A, Triau S, Mucci-Hennekinne S, Bizon A,Laboureau-Soares S, Illouz F, Rodien P, Rohmer V.An elevated level of TSH might be predictive of dif-ferentiated thyroid cancer. Ann Endocrinol (Paris).2011;72:513-521.

4. Bongiovanni M, Spitale A, Faquin WC, MazzucchelliL, Baloch ZW. The Bethesda system for reportingthyroid cytopathology: a meta-analysis. Acta Cytol.2012;56:333-339.

5. Liu X, Medici M, Kwong N, Angell TE, Marqusee E,Kim MI, Larsen PR, Cho NL, Nehs MA, Ruan DT,Gawande A, Moore F Jr, Barletta J, Krane JF, CibasES, Yang T, Alexander EK. Bethesda categorizationof thyroid nodule cytology and prediction of thyroidcancer type and prognosis. Thyroid. 2016;26:256-261.

6. Castro MR, Espiritu RP, Bahn RS, Henry MR, GharibH, Caraballo PJ, Morris JC. Predictors of malignancyin patients with cytologically suspicious thyroid nod-ules. Thyroid. 2011;21:1191-1198.

7. Jin J, Machekano R, McHenry CR. The utility of pre-operative serum thyroid-stimulating hormone levelfor predicting malignant nodular thyroid disease.Am J Surg. 2010;199:294-297.

8. Boelaert K, Horacek J, Holder RL, Watkinson JC,Sheppard MC, Franklyn JA. Serum thyrotropin con-centration as a novel predictor of malignancy in thy-roid nodules investigated by fine-needle aspiration.J Clin Endocrinol Metab. 2006;91:4295-4301.

9. Oltmann SC, Leverson G, Lin SH, Schneider DF,Chen H, Sippel RS. Markedly elevated thyroglobulinlevels in the preoperative thyroidectomy patientcorrelates with metastatic burden. J Surg Res.2014;187:1-5.

10.Zubair Hussain S, Zaman MU, Malik S, Ram N, As-ghar A, Rabbani U, Aftab N, Islam N. Preablationstimulated thyroglobulin/TSH ratio as a predictor ofsuccessful I (131)remnant ablation in patients withdifferentiated thyroid cancer following total thy-roidectomy. J Thyroid Res. 2014;2014:610273.

11.Petric R, Besic H, Besic N. Preoperative serum thy-roglobulin concentration as a predictive factor ofmalignancy in small follicular and Hürthle cell neo-plasms of the thyroid gland. World J Surg Oncol.2014;12:282.

12.Suh I, Vriens MR, Guerrero MA, Griffin A, Shen WT,Duh QY, Clark OH, Kebebew E. Serum thyroglobulinis a poor diagnostic biomarker of malignancy in fol-licular and Hürthle-cell neoplasms of the thyroid.Am J Surg. 2010;200:41-46.

13.Haugen BR, Alexander EK, Bible KC, Doherty GM,Mandel SJ, Nikiforov YE, Pacini F, Randolph GW,Sawka AM, Schlumberger M, Schuff KG, ShermanSI, Sosa JA, Steward DL, Tuttle RM, Wartofsky L.2015 American Thyroid Association ManagementGuidelines for Adult Patients with Thyroid Nodules

and Differentiated Thyroid Cancer: the AmericanThyroid Association Guidelines Task Force on Thy-roid Nodules and Differentiated Thyroid Cancer.Thyroid. 2016;2016:1-133.

14.Shi L, Li Y, Guan H, Li C, Shi L, Shan Z, Teng W. Use-fulness of serum thyrotropin for risk prediction ofdifferentiated thyroid cancers does not apply tomicrocarcinomas: results of 1,870 Chinese patientswith thyroid nodules. Endocr J. 2012;59:973-980.

15.Moon SS, Lee YS, Lee IK, Kim JG. Serum thy-rotropin as a risk factor for thyroid malignancy ineuthyroid subjects with thyroid micronodule. HeadNeck. 2012;34:949-952.

16.He H, Li W, Liyanarachchi S, Jendrzejewski J, Srini-vas M, Davuluri RV, Nagy R, de la Chapelle A. Ge-netic predisposition to papillary thyroid carcinoma:involvement of FOXE1, TSHR, and a novel lincRNAgene, PTCSC2. J Clin Endocrinol Metab. 2015;100:E164-172.

17.Hoelting T, Tezelman S, Siperstein AE, Duh QY, ClarkOH. Thyrotropin stimulates invasion and growth offollicular thyroid cancer cells via PKC- rather thanPKA-activation. Biochem Biophys Res Commun.1993;195:1230-1236.

18.Brabant G, Maenhaut C, Köhrle J, Scheumann G,Dralle H, Hoang-Vu C, Hesch RD, von zur MühlenA, Vassart G, Dumont JE. Human thyrotropin re-ceptor gene: expression in thyroid tumors and cor-relation to markers of thyroid differentiation anddedifferentiation. Mol Cell Endocrinol. 1991;82:R7-12.

19.Jonklaas J, Nsouli-Maktabi H, Soldin SJ. Endoge-nous thyrotropin and triiodothyronine concentra-tions in individuals with thyroid cancer. Thyroid.2008;18:943-952.

20.Haymart MR, Repplinger DJ, Leverson GE, Elson DF,Sippel RS, Jaume JC, Chen H. Higher serum thyroidstimulating hormone level in thyroid nodule patientsis associated with greater risks of differentiated thy-roid cancer and advanced tumor stage. J Clin En-docrinol Metab. 2008;93:809-814.

21.Kim KW, Park YJ, Kim EH, Park SY, Park DJ, Ahn SH,Park DJ, Jang HC, Cho BY. Elevated risk of papillarythyroid cancer in Korean patients with Hashimoto’sthyroiditis. Head Neck. 2011;33:691-695.

22.Negro R, Valcavi R, Riganti F, Toulis KA, Colosimo E,Bongiovanni M, Grassi P, Giovanella L, Gardini G,Piana S. Thyrotropin values in patients with mi-cropapillary thyroid cancer versus benign nodulardisease. Endocr Pract. 2013;19:651-655.

23.Lin YS, Li TJ, Liang J, Li X, Qiu L, Wang S, Chen Y,Kang Z, Li F. Predictive value of preablation stimu-lated thyroglobulin and thyroglobulin/thyroid-stim-ulating hormone ratio in differentiated thyroidcancer. Clin Nucl Med. 2011;36:1102-1105.

24.Guarino E, Tarantini B, Pilli T, Checchi S, Brilli L,Ciuoli C, Di Cairano G, Mazzucato P, Pacini F. Presur-gical serum thyroglobulin has no prognostic valuein papillary thyroid cancer. Thyroid. 2005;15:1041-1045.

25.Youn I, Sung JM, Kim EK, Kwak JY. Serum thy-roglobulin adds no additional value to ultrasono-graphic features in a thyroid malignancy. UltrasoundQ. 2014;30:287-290.

30


30

26.Lee EK, Chung KW, Min HS, Kim TS, Kim TH, RyuJS, Jung YS, Kim SK, Lee YJ. Preoperative serumthyroglobulin as a useful predictive marker to dif-ferentiate follicular thyroid cancer from benign nod-ules in indeterminate nodules. J Korean Med Sci.2012;27:1014-1018.

27.Sands NB, Karls S, Rivera J, Tamilia M, Hier MP,Black MJ, Gologan O, Payne RJ. Preoperativeserum thyroglobulin as an adjunct to fine-needleaspiration in predicting well-differentiated thyroidcancer. J Otolaryngol Head Neck Surg. 2010;39:669-673.

28.Wang L, Li H, Yang Z, Guo Z, Zhang Q. Preoperativeserum thyrotropin to thyroglobulin ratio is effectivefor thyroid nodule evaluation in euthyroid patients.Otolaryngol Head Neck Surg. 2015;153:15-19.

29.Yazici P, Mihmanli M, Bozkurt E, Ozturk FY, UludagM. Which is the best predictor of thyroid cancer:

thyrotropin, thyroglobulin or their ratio? Hormones(Athens). 2016;15:256-263.

30.Cibas ES, Ali SZ. The Bethesda system for reportingthyroid cytopathology. Am J Clin Pathol. 2009;132:658-665.

31.Liu X, Medici M, Kwong N, Angell TE, Marqusee E,Kim MI, Larsen PR, Cho NL, Nehs MA, Ruan DT,Gawande A, Moore F Jr, Barletta J, Krane JF, CibasES, Yang T, Alexander EK. Bethesda categorizationof thyroid nodule cytology and prediction of thyroidcancer type and prognosis. Thyroid. 2016;26:256-261.

32.Chen JC, Pace SC, Chen BA, Khiyami A, McHenryCR. Yield of repeat fine-needle aspiration biopsy andrate of malignancy in patients with atypia or follic-ular lesion of undetermined significance: the impactof the Bethesda System for Reporting Thyroid Cy-topathology. Surgery. 2012;152:1037-1044.

31


31

ReviewTurk J Endocrinol Metab 2018;22:32-40

32

32

Address for Correspondence: Rıfat Emral, Ankara University Faculty of Medicine,Department of Endocrinology and Metabolic Diseases, Ankara, Turkey



Implication of Findings fromInternational Studies on Hypoglycemia for

Management of Diabetesin Insulin-treated Patients in Turkey

Hipoglisemi ile İlgili Uluslararası Çalışmalardaki BulgularınTürkiye'de Insülin Tedavisi Gören Hastalarda

Diyabet Yönetimine Etkileri

Ankara University Faculty of Medicine, Department of Endocrinology and Metabolic Diseases, Ankara, Turkey*Akdeniz University Faculty od Medicine, Department of Endocrinology and Metabolism, Antalya, Turkey

**Ankara Numune Training Research Hospital, Clinic of Endocrinology, Ankara, Turkey***Hitit University Faculty of Medicine, Çorum, Turkey

DO

I:10

.251

79/t

jem

.201

7-57

369

Recent estimates indicate that diabetes occurs in 16.5% ofthe Turkish population, which is in keeping with the increa-sing global prevalence of diabetes. Following rapid economicgrowth, increase in life expectancy and changes in lifestyleover the past decade have resulted in the placement of atremendous cost burden on the Turkish economy by diabe-tes and associated co-morbidities, representing 20% of ove-rall spending on healthcare.Maintaining good glycemic control is vital for effective dia-betes management. Long-term studies have demonstratedthe ability of intensive glucose-lowering strategies to pre-vent or delay co-morbidities associated with diabetes. Ho-wever, insulin intensification is commonly associated withhypoglycemia, which is regarded as the most significantbarrier to attaining and maintaining good glycemic control.Patients are often unaware of the potential negative impactof hypoglycemia on their long-term health, as well as ondaily functions. In addition, hypoglycemia and its associatedsymptoms or co-morbidities greatly influence adherenceand dosing behavior, patients’ quality of life (QoL), and sig-nificantly affect economic productivity.The aim of this study is to review the impact of hypoglyce-mia in patients with diabetes, focusing on the implicationsof findings from international and Turkish studies for themanagement of hypoglycemia in Turkish patients.

Keywords: Hypoglycemia; nocturnal hypoglycemia;Turkish diabetic patients; insulin analog;pre-mixed insulin; co-morbidity; quality of life;glucose monitoring

Son yapılan çalışmalar, Türkiye nüfusunun %16,5'inde di-yabet olduğunu göstermektedir ki bu diyabetin artan kü-resel prevalansı ile uyumludur. Hızlı ekonomik büyümeninardından, geçtiğimiz on yılda yaşam beklentisinin artmasıve yaşam tarzındaki değişiklikler, diyabet ve buna eşlikeden komorbiditelerin Türkiye ekonomisine muazzam birmaliyet yükü getirmesiyle ve toplam sağlık harcamaları-nın %20'sini oluşturmasıyla sonuçlanmıştır.İyi glisemik kontrol etkili diyabet yönetimi için hayati önemesahiptir. Uzun süreli çalışmalar, yoğun glukoz düşürücü stra-tejilerin diyabetle ilişkili komorbiditelerin önlenmesi veya ge-ciktirilmesinde etkin olduğunu göstermiştir. Bununla birlikte,yoğun insülin tedavisi genellikle hipoglisemi ile ilişkilidir vebu durum iyi glisemik kontrol elde etmenin ve sürdürmeninönündeki en önemli engel olarak görülmektedir. Hastalar ge-nellikle hipogliseminin günlük faaliyetlerinin ve uzun vadedesağlıklarının üzerindeki potansiyel olumsuz etkilerinin far-kında değildirler. Ayrıca, hipoglisemi ve bununla ilişkilisemptomlar veya komorbiditeler tedaviye uyumu, dozlamadavranışını, hastaların yaşam kalitesini (QoL) ve ekonomikverimliliğini önemli ölçüde etkiler. Bu çalışmanın amacı, hi-poglisemi yönetimine dair uluslararası ve Türk çalışmalarınbulgularının Türk hastalardaki etkilerine odaklanılarak,diyabetli hastalarda hipogliseminin etkisini değerlendirmek-tir.

Anahtar kelimeler: Hipoglisemi; gece hipoglisemisi;Türk diyabetik hastalar; insülin analoğu;premiks insülin; komorbidite;yaşam kalitesi; glukoz takibi

https://orcid.org/0000-0002-5732-2284

IntroductionThe prevalence of diabetes is increasing world-wide and according to recent global estimates,there will be approximately 642 million adultswith diabetes by 2040 (1). The age-standardizedprevalence of diabetes in Turkey ranges from13.7% to 17.0%, with diabetes being more com-mon among women than men (17.2% vs.16.0%, p=0.008) (2). Recent figures indicatethat over 6.5 million adults in Turkey have beendiagnosed with diabetes, which represents an in-crease of 90% over the past 12 years (2). TheInternational Diabetes Federation predicts thatthe prevalence will rise to nearly 12 million by2035 (3).Following rapid economic growth in the pastdecade, the increase in the life expectancy andchanges in lifestyle (2) has resulted in diabetesplacing an enormous cost burden on the Turkisheconomy, accounting for ~1% of the nationalgross domestic product and approximately 20%of the overall spending on healthcare (4). There-fore, maintenance of good glycemic control bykeeping glycosylated hemoglobin levels and pre-and post-prandial blood glucose levels within rec-ommended limits are vital in the management ofdiabetes (5, 6). However, the management of di-abetes cannot follow a ‘one size fits all’ approach.Rather, treatment customization by balancing thebenefits of glycemic control with its potentialrisks such as the adverse effects of glucose-low-ering medications (particularly hypoglycemia), aswell as the patient’s age and health status amongother concerns, is a more viable option (6).Long-term studies have demonstrated that in-tensive glucose-lowering strategies (e.g., insulin-based treatment regimens) can prevent or delayco-morbidities such as long-term vascular com-plications which are commonly associated withdiabetes (7-10). However, the most common ad-verse condition associated with insulin therapyfor the management of type 1 and type 2 dia-betes mellitus (T1DM or T2DM) is hypoglycemia(11), which is regarded as the most significantbarrier preventing patients from attaining andmaintaining good glycemic control (12).Hypoglycemic episodes are usually defined as ei-ther asymptomatic, wherein patients are un-aware of a current episode, or symptomatic,wherein the hypoglycemia ranges from mild tomoderate (non-severe) which patients can self-treat, to severe episodes requiring third-party as-sistance and which can potentially belife-threatening (13). The aim of this article is to

review the impact of hypoglycemia in patientswith diabetes, focusing on the implications ofdata from international and Turkish studies forthe management of hypoglycemia in Turkish pa-tients.

Incidence of Hypoglycemia

The development of hypoglycemia, althoughsometimes asymptomatic, is often initiated by acombination of neurogenic or autonomous (in-cluding palpitations, sweating, shaking, hunger)and neurological symptoms (behavioral changes,inability to concentrate, confusion, seizures)(13). The patterns of symptoms vary with indi-viduals and patients can learn to recognize theirown pattern of hypoglycemic symptoms (13).Discussing these patterns with a healthcare pro-fessional can help in prediction or early recogni-tion of hypoglycemic episodes before theybecome severe. However, patients often do notreport non-severe hypoglycemia, which leads tolack of practical data on the incidence of hypo-glycemia and its impact on the management ofdiabetes in Europe in general, and specifically inTurkey, the Middle East, and North African re-gions.The difficulty in estimating the incidence of hy-poglycemia is complicated by a high proportionof patients with unrecognized mild to moderatehypoglycemic episodes. Several studies have as-sessed the incidence of hypoglycemia, includingthe PREDICTIVE study (14), two European onlinesurveys (15, 16), and two Danish surveys (17,18). The baseline data from the PREDICTIVEstudy, which was a large, prospective, interna-tional observational study of >19,000 adults withuncontrolled T1DM or T2DM on current treatmentand initiating basal insulin, showed an overall in-cidence of 47.5 episodes and 9.2 episodes of hy-poglycemia per patient-year among patients withT1DM and T2DM, respectively. The incidencerates for severe hypoglycemia and nocturnal hy-poglycemia were reported as 3.0 and 13.8episodes, respectively, in patients with T1DM,and 0.8 and 3.4, respectively, in patients withT2DM (14). The baseline frequency of hypo-glycemia in insulin-treated patients in the PRE-DICTIVE study increased with the duration ofdiabetes, a number of daily injections, and vari-ation in fasting glucose. A similar trend was ob-served in the Turkish cohort of the study, whichincluded 613 patients with T1DM and 2092 pa-tients with T2DM (14). Another survey recentlyassessed the self-reported, non-severe hypo-

33

Turk J Endocrinol Metab Emral et al.2018;22:32-40 Hypoglycemia in the Turkish Population

33

glycemic episodes in Europe, by recruiting pa-tients via consumer panels, nurses, telephone re-cruitment, and family referrals to complete fouronline questionnaires. This survey reported anannual hypoglycemic incidence of 94 episodesper year in T1DM and 21 to 36 episodes per year(depending on regimen) in insulin-treated pa-tients with T2DM (15). A single-center, cross-sec-tional survey in Denmark, which had recruitedsuccessive patients with T2DM with a previouslyarranged outpatient appointment, assessed pa-tients based on a questionnaire seeking informa-tion on the number of hypoglycemic episodesexperienced in the past, status of awareness re-garding hypoglycemia, and socio-demographicinformation. This study reported an incidence of<0.5 episodes per patient-year (16). Anothersurvey conducted in Germany, France, and theUK assessed patients via 11 key questions, in-cluding their understanding, perceptions, anddaily experiences of hypoglycemia, during a 10-min online questionnaire. Also, a cross-sectionalquestionnaire survey including patients withT1DM from six Danish healthcare institutionsevaluated severe hypoglycemic episodes re-ported during the preceding year, and mild hypo-glycemia during the preceding week. Both thesestudies reported an incidence of severe hypo-glycemic episodes of ~1.0-2.4 episodes per pa-tient-year among patients with T1DM (17, 18).Patients with diabetes regularly experience non-severe hypoglycemic episodes (19), with daytimeepisodes being more common than nocturnalepisodes. Patients are often unaware of non-se-vere hypoglycemic episodes, and often do not re-port their self-managed mild to moderatehypoglycemic episodes to their primary careteam (15). This makes it difficult to estimate thetrue incidence of non-severe hypoglycemicepisodes. In addition, surveys have shown thatnocturnal episodes cause anxiety or worry andconcern about the potential negative impact onlong-term health (19-21). Furthermore, noctur-nal episodes appear to have a greater impact onpatients’ daily functioning, and the discomfort ex-perienced during a nocturnal episode can carryover to the next day, causing tiredness, irritabil-ity, lack of concentration, and fluctuating bloodsugar levels (21).

Risk Factors for Hypoglycemia

Risk factors for hypoglycemia are individual-spe-cific and include endogenous insulin deficiency,duration of diabetes, history of hypoglycemia,

misinformation or complete lack of awareness onsymptoms of hypoglycemia, intensive insulin reg-imens or stringent glycemic targets, recent mod-erate or intensive exercise, disrupted sleeppatterns, and renal failure (13). Among the riskfactors, a high proportion of patients with dia-betes reports unawareness or altered awarenessabout symptoms of hypoglycemia (15) as onefactor affecting detection of mild hypoglycemicepisodes. In patients with the lack of awarenessabout hypoglycemia, the risk of severe hypo-glycemia increases threefold (16), as mild hypo-glycemia, which often precedes severe episodes,is not recognized (13).Insulin regimens, particularly those with a highnumber of injections, have also been associatedwith an increased risk of hypoglycemia (14). Inthe multicenter, international prospective obser-vational TREAT study containing a Turkish cohortof patients, the incidence of hypoglycemia washigher in patients treated with a basal-bolus reg-imen compared with a basal-only regimen at sixmonths of treatment (22). The trend remainedunchanged over the 2-year study period, with75% of patients on basal-bolus regimens beinginjected four times per day (22). Similar long-term findings in the UK cohort were reported bythe GAPP2 survey (20). One or more hypo-glycemic episodes were reported during the pre-vious month by 29% of patients on basal insulinand 46% on basal-bolus insulin, while 11% and14% of patients, respectively, reported hypo-glycemia during the past year (20).

Impact of Hypoglycemia

Hypoglycemia and associated symptoms or co-morbidities greatly impact adherence and dosingbehaviors (23), the patients’ quality of life (QoL)(19, 21), and significantly affect economic pro-ductivity (24-26).

Dosing irregularities

A high proportion of patients with diabetes re-port being worried about hypoglycemia. Noctur-nal episodes cause patients more concern thandaytime episodes (19), as they can remain un-detected during the night. Many physicians haveindicated that they would prescribe intensive in-sulin therapy more frequently if it were not forconcerns over hypoglycemia (23). In addition,there is a high level of fear of hypoglycemiaamong patients who have previously experi-enced a severe hypoglycemic episode (27). Thisfear often results in missed injections and non-

34

Emral et al. Turk J Endocrinol MetabHypoglycemia in the Turkish Population 2018;22:32-40

34

adherence to treatment, as patients attempt totake corrective action to avoid recurrent hypo-glycemic episodes (23, 28). A recent single-cen-ter survey (n=345) in Turkey showed thatpatients with T1DM, who had experienced severehypoglycemia, not only had greater levels of fearand anxiety over recurrent hypoglycemia butalso displayed higher treatment adherence be-havior than patients with T2DM (29). This be-havior may be partially attributed to the fact thatpatients with T1DM acknowledge that insulintreatment is indispensable for their well-being,resulting in higher levels of treatment controland self-efficacy to avoid potentially life-threat-ening hypoglycemic episodes than patients withT2DM.Another study assessing dosing irregularities inresponse to self-treated hypoglycemic episodeswas the GAPP2- a multinational, cross-sectionalsurvey (19). In the UK cohort of the GAPP2 sur-vey, 15-25% of patients either reduced, missed,or mistimed at least one dose of insulin duringthe month prior to assessment. In the majority ofcases, this action was intentional, due to con-cerns over hypoglycemia (20). Similar resultswere observed in the Canadian cohort of GAPP2,wherein 23%, 26%, and 13% of patients re-ported missed, mistimed, or reduced doses of in-sulin during the month before assessment (28).These patients also cited concern over the risk ofhypoglycemia as the most common reason for in-tentional dose irregularity (28). Many patientshave also been reported to intentionally maintaina state of hyperglycemia to give themselves a‘safety margin’ to avoid hypoglycemia (17), andto adopt other behaviors associated with avoid-ance of hypoglycemia.

Health-related quality of life

It has been demonstrated that self-reported hy-poglycemic episodes have a strongly negativeimpact on the QoL of patients with T2DM (30).Patients with symptoms of hypoglycemia havereported significantly higher rates of shakiness,sweating, excessive fatigue, drowsiness, im-paired concentration, dizziness, hunger, asthe-nia, and headache, compared with patientswithout hypoglycemia (31). The increase in fre-quency and severity of hypoglycemic symptomsnot only had a detrimental effect on patients’rating of their QoL (30-32), but the mere expe-rience of hypoglycemia was also associated witha higher likelihood of developing depression(30).

Economic impact of hypoglycemia

In addition to the impact on patients’ QoL andtreatment efficacy, the economic impact of hypo-glycemia can be categorized into direct costs totreat severe hypoglycemic episodes, and indirectcosts that arise due to lost work productivity fol-lowing severe or non-severe episodes (26). Al-most half of the Turkish patients with diabetesare aged between 40 and 64 years (2), and goodglycemic control to reduce the risk of hypo-glycemia is essential for the economic well-beingof patients and their families.In 2010, it was estimated that the direct cost ofmanaging major hypoglycemia in Turkey was 87Turkish lira per acute episode (33). Patientshave been demonstrated to increase blood glu-cose monitoring in response to hypoglycemicepisodes (19), which may also increase costsassociated with the management of hypo-glycemia (26).However, the wider economic impact of severeand non-severe episodes (e.g., absence fromwork, impacts on QoL and on careers) is largelyunknown, as few studies based in Turkey haveanalyzed this parameter till date. Data from otherstudies in Europe or the US provide a clear indi-cation of the impact. A recent report of two sur-veys assessing daytime and nocturnalhypoglycemia in 300 patients with T1DM andT2DM highlighted that daytime and nocturnal hy-poglycemic episodes negatively affected patients’sleep and work productivity (26). Nocturnalepisodes appeared to have the highest impact onpatients, with 29% of respondents going to worklate, 16% leaving work early, and 12% missing atleast one day of work due to a nocturnal episode(26). Nocturnal episodes, in particular, have beenshown to not only affect the individual experi-encing hypoglycemia, but also their bed partner(26).A large UK survey on 861 patients with T1DM andT2DM reported that health-related QoL and work-related productivity decreased with increase inthe frequency and severity of hypoglycemia (25).Each episode of nocturnal non-severe hypo-glycemia was reported to be responsible for theloss of productivity corresponding to 3.3-7.5 h(24). A European study reported that 10% of pa-tients surveyed had taken time off work due tosevere hypoglycemia in the past 12 months (17),while severe hypoglycemia resulted in 34 emer-gency room visits per 1000 patients with diabetesin the US (34).

35


35

Reducing the Risk of Hypoglycemia

More than half of all hypoglycemic episodes canbe predicted by regular self-monitoring of bloodglucose levels (35). Hence, self-monitoring ofblood glucose levels by patients, supported byappropriate training on the signs and symptomsof hypoglycemia, is an important strategy in rais-ing awareness on hypoglycemia and reducing therisk of future severe hypoglycemic episodes.However, a recent single-center, questionnaire-based Turkish study (n=380) showed that pa-tients with T1DM, particularly those with chronicdisease, often did not achieve optimal glycemicoutcomes and adopted fewer self-managementbehaviors (36), emphasizing the need for an in-tegrated approach toward monitoring diabetesand patient support. Another study suggestedthat patients’ levels of anxiety and fear of hypo-glycemia should be assessed regularly by the pri-mary care team and that patients should beencouraged to record their concerns or hypo-glycemic experiences in a diary (29).Modern long-acting basal insulin analogs such asinsulin glargine (IGlar), insulin detemir (IDet),and the ultra-long-acting insulin degludec (IDeg),may reduce the risk of hypoglycemia associatedwith diabetes. Published clinical evidence has re-ported that IGlar and IDet have similar, low-riskrates of hypoglycemia. Differences in efficacyamong modern basal insulin analogs weredemonstrated in 2886 patients of the Turkish co-hort in the multinational observational SOLVEstudy, wherein IDet was associated with a lowerrisk of minor hypoglycemia than IGlar (37). Thefindings highlighted the need to customize treat-ment of individual patients to match their clinicalrequirements in an environment, which is slow tointensify diabetes treatment to include insulintherapy (13). However, a pre-planned meta-analysis of seven phase III clinical trials compar-ing IDeg with IGlar on patients with T1DM orT2DM, reported a significantly lower risk of hypo-glycemia associated with IDeg compared to IGlar,in the overall pooled population. The reduction inrisk of hypoglycemia associated with IDeg wasmore evident after stabilization of the dose of in-sulin (>16 weeks) (38), indicating that intensiveblood glucose monitoring may be required shortlyafter initiation of insulin therapy, and also thattreatment with insulin analogs was generally a vi-able option for treatment intensification.Premixed insulins containing bolus injections ofshort-acting insulin (basal-bolus) are an easieralternative to the intensification of basal insulin,

for patients unable to achieve glycemic targetson basal insulin alone. However, premixed insulinformulations have been associated with a slightlyhigher degree of hypoglycemia and weight gainthan basal regimens (5). This view was recentlychallenged, when it was demonstrated thatswitching from a biphasic human insulin premixto a premixed insulin analog could reduce the in-cidence of hypoglycemia (39). The results from asubgroup analysis showed that such a switch de-creased the rates of severe as well as overall hy-poglycemia, and improved glycemic control (40).Several patients preferred premixed insulinanalogs over premixed human insulin, owing totheir more favorable pharmacokinetic profiles,which allowed dosing immediately before or aftera meal and helped avoid late postprandial hypo-glycemia (41). However, despite premixed in-sulins offering better glycemic control andimproved convenience than basal-bolus regi-mens, studies still reported varied effects on theincidence of hypoglycemia. PREFER, a study com-paring premixed insulin and basal-bolus regi-mens, demonstrated a lower incidence of severehypoglycemia for premixed therapy, comparedwith the basal-bolus regimen, while the rates ofnon-severe hypoglycemia, weight gain, and noc-turnal hypoglycemia were similar (42). In con-trast, comparison of premixed insulins and basalinsulin therapy demonstrated a higher overall riskof hypoglycemia with premixed insulin analogs(4, 43).

Guidelines on the Management ofHypoglycemia

The treatment and management of T1DM, T2DM,and diabetes-related complications are governedby international guidelines, which are regularlyupdated (5, 6). In addition, several countries havedeveloped local guidelines to allow for a more tai-lored and relevant treatment approach. Turkishguidelines for the management of diabetes and itscomplications are published and regularly updatedby the Society for Endocrinology and Metabolismof Turkey (44). These guidelines include specificrecommendations for the prevention and man-agement of hypoglycemia (Table 1). One key ele-ment highlighted in the Turkish guidelines was therecommendation for increased awareness of, andadherence to, international and local guidelines onthe prevention and management of hypo-glycemia, in order to minimize the risk of severeand nocturnal hypoglycemia. However, despite theexistence of national guidelines (5, 45) and high

36


36

37


37

FPG: Fasting plasma glucose; HbA1c: Glycosylated hemoglobin; i.m.: Intramuscular; i.v.: Intravenous; NPG: Nocturnal plasma glu-cose; OAD: Oral antidiabetic drug; PG: Plasma glucose; s.c.: Subcutaneous; SEMT: Society of Endocrinology and Metabolism of Tur-key; SMPG: Self-monitored plasma glucose; T1DM: Type 1 diabetes mellitus; T2DM: Type 2 diabetes mellitus.

SEMT Approaches and Recommendations

Hypoglycemia prevention

Education

• After treatment for any hypoglycemic episode, the causes must be reviewed and training should be repeated where necessary• Training must be provided to individuals with diabetes and family members in a timely fashion to increase knowledge andskills in diabetes self-management• Individuals with T2DM who use insulin or insulin secretagogues must be assessed for the risk of hypoglycemiaMonitoring

• All individuals with diabetes and family members must be trained in PG measurement to enable them to adjust therapy onthe basis of the results• Individuals with T2DM, especially elderly patients identified with hypoglycemia associated with sulfonylurea use must bemonitored for 24-48 h• In T1DM SMPG must be an integral part of treatmentTreatments and glycemic targets

• Since the risk of symptomatic hypoglycemia and nocturnal hypoglycemia is lower in individuals receiving basal insulin, long-term acting insulin analogs are preferable to NPH in patients at high hypoglycemic risk• Glycemic targets must be established for pre-pubertal children to minimize hypoglycemia (especially nocturnal):

o Age <6 years: FPG, 100-180 mg/dL; NPG, 110-200 mg/dL; HbA1c, 7.5-8.5%o Age 8-12 years: FPG fast, 100-180 mg/dL; NPG, 100-180 mg/dL; HbA1c <8.0%o Age 13-18 near-adult glycemic targets must be achieved: FPG: 80-120 mg/dL; NPG, 90-130 mg/dL; HbA1c, 6.5-7.0%,48-53 mmol/mol

Nutrition and rescue treatment

• In the individuals with T2DM, the absorption of proteins may increase insulin response without increasing blood glucose con-centration. Consequently, proteins must not be used in acute hypoglycemia or nocturnal hypoglycemia• To avoid recurrent hypoglycemia, after the hypoglycemia has resolved, main meals and snacks must be given at planned in-tervals. If there is a period of more than one hour between one meal and the next, a snack consisting of 15 g carbohydrateand protein must be given.• It is preferable that individuals with diabetes do not take alcohol. Consumption of alcohol may cause various health problemsin individuals with diabetes with impaired glycemic control, individuals at high risk of hypoglycemia or with uncontrolled hy-perlipidemia• Individuals with T1DM must be warned of increased risk of late hypoglycemia if they take alcohol. To reduce hypoglycemicrisk, reduction of alcohol must be exercised and measures such additional carbohydrate consumption, reduction of insulin doseand more frequent SMBG may be appliedHypoglycemia management

Treatment

• Any carbohydrate source containing glucose may be used in case of hypoglycemia, through ingestion of 15-20 g glucose ispreferred• Fat-containing products (e.g., chocolate or wafer) should not be used• Response to treatment of hypoglycemia must be obtained within 10-20 min

o Mild hypoglycemia must be treated with 15g oral carbohydrates (4 sugar cubes, or 150 mL fruit juice or lemonade). PGmust be measured after 15 min, if <80 mg/dL an additional 15g of carbohydrates must be giveno Moderate hypoglycemia must be treated with 20 g carbohydrates (5 sugar cubes, or 200 mL fruit juice or lemonade).PG must be measured after 15 min, if <80 mg/dL an additional 15 g of carbohydrates must be giveno Severe hypoglycemia must be treated with s.c. or i.m. glucagon injection and emergency medical assistance must besummoned

• The relatives of patients with high risk of hypoglycemia should be taught how to administer a glucagon injection• An unconscious patient with severe hypoglycemia, which does not resolve with glucagon should receive 10-25 g i.v. glucose(20-50 mL 50% dextrose within 1-3 min or 50-150 mL 20% dextrose within 5-10 min)Monitoring

• PG levels must be measured one hour after the hypoglycemic event and if necessary additional treatment must be given.

Table 1. Turkish (SEMT) recommendations for hypoglycemia management (44).

levels of input from primary care and specialistteams, optimal outcomes are often not seen inclinical practice (36). To allow patients and physi-cians make informed treatment decisions, and toencourage improved monitoring and prevention ofhypoglycemia, country-specific data on rates ofhypoglycemia and QoL/health-economics impactsare required. Therefore, patients identified to beat s risk of hypoglycemia or those having high lev-els of fear or anxiety of hypoglycemia should bemonitored closely and offered specialist counsel-ing support.

Conclusions and Strategies for the Future

As the prevalence of diabetes increases in Turkey,the Middle East, and North African regions, treat-ment of diabetes and ultimately treatment inten-sification with insulin is inevitable. Intensiveblood glucose-lowering strategies to attainglycemic control are closely associated with therisk of hypoglycemia, which has a strong nega-tive impact on patient QoL, as well as importanthealth-economic consequences. Altered aware-ness of hypoglycemia, coupled with a lack ofcommunication or under-reporting of hypo-glycemia between patients and physicians hascreated lack of real-world data on the actual in-cidence of non-severe and severe hypoglycemicepisodes in insulin-treated patients with diabetesand the scale of the burden of hypoglycemia, inclinical practice in Turkey.A multinational study monitoring the symptoms,management, and prevention of hypoglycemia isrequired. One such study, the IO-HAT (Interna-tional Operations Hypoglycemia Assessment Tool)(46), which enhanced the hitherto limited infor-mation on the prevalence of hypoglycemia incountries such as Turkey, has recently been com-pleted. The IO-HAT study consisted of two partsthat retrospectively and prospectively assessedsevere and non-severe hypoglycemia using pa-tient-led self-assessment questionnaires, and ex-plored associations between hypoglycemia,patient co-morbidities, treatment regimen, andQoL. In addition to the IO-HAT study results,which included a large Turkish cohort (>2000 pa-tients), regular patient self-monitoring of bloodglucose levels, improved patient awareness re-garding symptoms of hypoglycemia, and inte-grated communication between patients andprimary care teams will help in the improvementof hypoglycemia awareness, and reduction in theburden of overall and particularly severe hypo-glycemia in insulin-treated patients with diabetes.

Acknowledgements: Medical writing supportwas provided by ApotheCom and funded by NovoNordisk Region, International Operations AG.Source of Finance: During this study, no finan-cial or spiritual support was received neither fromany pharmaceutical company that has a directconnection with the research subject, nor from acompany that provides or produces medical in-struments and materials which may negativelyaffect the evaluation process of this study.Conflict of Interest: No conflicts of interest be-tween the authors and / or family members ofthe scientific and medical committee members ormembers of the potential conflicts of interest,counseling, expertise, working conditions, shareholding and similar situations in any firm.Funding source: Funding for the developmentof this review was provided by Novo Nordisk A/S.

Authorship ContributionsRifat Emral, Ramazan Sari and Serdar Güler havecritically reviewed and contributed to every stageof the manuscript development.

References1. International Diabetes Federation. IDF Diabetes

Atlas. (7th ed). International Diabetes Federation;2015;136. (Accessed October 2016). Availablefrom: http://www.diabetesatlas.org/resources/2015-atlas.html.

2. Satman I, Omer B, Tutuncu Y, Kalaca S, Gedik S,Dinccag N, Karsidag K, Genc S, Telci A, Canbaz B,Turker F, Yilmaz T, Cakir B, Tuomilehto J. Twelve-year trends in the prevalence and risk factors of di-abetes and prediabetes in Turkish adults. Eur JEpidemiol. 2013;28:169-180.

3. International Diabetes Federation. IDF DiabetesAtlas. (6th ed). Brussels, Belgium: International Di-abetes Federation; 2013;153.

4. Malhan S, Vlachopioti Z. Assessment of the directmedical costs of type 2 diabetes mellitus and itscomplications in Turkey. Dubai: World DiabetesCongress; 2011;1707.

5. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M,Ferrannini E, Nauck M, Peters AL, Tsapas A, WenderR, Matthews DR. Management of hyperglycemia intype 2 diabetes: a patient-centered approach: posi-tion statement of the American Diabetes Associa-tion (ADA) and the European Association for theStudy of Diabetes (EASD). Diabetes Care.2012;35:1364-1379.

6. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M,Ferrannini E, Nauck M, Peters AL, Tsapas A, WenderR, Matthews DR. Management of hyperglycemia intype 2 diabetes, 2015: a patient-centered ap-proach: update to a position statement of the Amer-ican Diabetes Association and the EuropeanAssociation for the Study of Diabetes. DiabetesCare. 2015;38:140-149.

38


38

7. UK Prospective Diabetes Study (UKPDS) Group. In-tensive blood-glucose control with sulfonylureas orinsulin compared with conventional treatment andrisk of complications in patients with type 2 diabetes(UKPDS 33). Lancet. 1998;352:837-853.

8. Writing Team for the Diabetes Control and Complica-tions Trial/Epidemiology of Diabetes Interventions andComplications Research Group. Effect of intensivetherapy on the microvascular complications of type 1diabetes mellitus. JAMA. 2002;287:2563-2569.

9. Nathan DM, Cleary PA, Backlund JY, Genuth SM,Lachin JM, Orchard TJ, Raskin P, Zinman B. Inten-sive diabetes treatment and cardiovascular diseasein patients with type 1 diabetes. N Engl J Med.2005;353:2643-2653.

10.Martin CL, Albers J, Herman WH, Cleary P, Waber-ski B, Greene DA, Stevens MJ, Feldman EL. Neu-ropathy among the diabetes control andcomplications trial cohort 8 years after trial com-pletion. Diabetes Care. 2006;29:340-344.

11.Frier BM. How hypoglycaemia can affect the life ofa person with diabetes. Diabetes Metab Res Rev2008;24:87-92.

12.Cryer PE. Hypoglycaemia: the limiting factor in theglycaemic management of Type I and Type II dia-betes. Diabetologia. 2002;45:937-948.

13.Workgroup on Hypoglycemia, American DiabetesAssociation. Defining and reporting hypoglycemia indiabetes: a report from the American Diabetes As-sociation Workgroup on Hypoglycemia. DiabetesCare. 2005;28:1245-1249.

14.Lüddeke HJ, Sreenan S, Aczel S, Maxeiner S, Yeni-gun M, Kozlovski P, Gydesen H, Dornhorst A. PRE-DICTIVE- a global, prospective observational studyto evaluate insulin detemir treatment in types 1 and2 diabetes: baseline characteristics and predictorsof hypoglycaemia from the European cohort. Dia-betes Obes Metab. 2007;9:428-434.

15.Östenson CG, Geelhoed-Duijvestijn P, Lahtela J,Weitgasser R, Markert Jensen M, Pedersen-Bjer-gaard U. Self-reported non-severe hypoglycaemicevents in Europe. Diabet Med. 2014;31:92-101.

16.Akram K, Pedersen-Bjergaard U, Carstensen B,Borch-Johnsen K, Thorsteinsson B. Frequency andrisk factors of severe hypoglycaemia in insulin-treated Type 2 diabetes: a cross-sectional survey.Diabet Med. 2006;23:750-756.

17.Willis WD, Diago-Cabezudo JI, Madec-Hily A, AslamA. Medical resource use, disturbance of daily life andburden of hypoglycemia in insulin-treated patientswith diabetes: results from a European online sur-vey. Expert Rev Pharmacoecon Outcomes Res.2013;13:123-130.

18.Kristensen PL, Hansen LS, Jespersen MJ, Pedersen-Bjergaard U, Beck-Nielsen H, Christiansen JS, Nør-gaard K, Perrild H, Parving HH, Thorsteinsson B,Tarnow L. Insulin analogues and severe hypogly-caemia in type 1 diabetes. Diabetes Res Clin Pract.2012;96:17-23.

19.Brod M, Rana A, Barnett AH. Impact of self-treatedhypoglycaemia in type 2 diabetes: a multinationalsurvey in patients and physicians. Curr Med ResOpin. 2012;28:1947-1958.

20.Munro N, Barnett AH. Incidence, worry and discus-sion about dosing irregularities and self-treated hy-

poglycaemia among HCPs and patients with type 2diabetes: results from the UK cohort of the GlobalAttitudes of Patient and Physicians (GAPP2) survey.Int J Clin Pract. 2014;68:692-699.

21.Brod M, Pohlman B, Wolden M, Christensen T. Non-severe nocturnal hypoglycemic events: experienceand impacts on patient functioning and well-being.Qual Life Res. 2013;22:997-1004.

22.Oguz A, Benroubi M, Brismar K, Melo P, Morar C,Cleall SP, Giaconia J, Schmitt H. Clinical outcomesafter 24 months of insulin therapy in patients withtype 2 diabetes in five countries: results from theTREAT study. Curr Med Res Opin. 2013;29:911-920.

23.Peyrot M, Barnett AH, Meneghini LF, Schumm-Draeger PM. Insulin adherence behaviours and bar-riers in the multinational Global Attitudes of Patientsand Physicians in Insulin Therapy study. DiabetMed. 2012;29:682-689.

24.Brod M, Wolden M, Christensen T, Bushnell DM. Un-derstanding the economic burden of nonsevere noc-turnal hypoglycemic events: impact on workproductivity, disease management, and resourceutilization. Value Health 2013;16:1140-1149.

25.Davis RE, Morrissey M, Peters JR, Wittrup-Jensen K,Kennedy-Martin T, Currie CJ. Impact of hypogly-caemia on quality of life and productivity in type 1and type 2 diabetes. Curr Med Res Opin.2005;21:1477-1483.

26.Fulcher G, Singer J, Castañeda R, Fraige Filho F,Maffei L, Snyman J, Brod M. The psychosocial andfinancial impact of non-severe hypoglycemic eventson people with diabetes: two international surveys.J Med Econ. 2014;17:751-761.

27.McCoy RG, Van Houten HK, Ziegenfuss JY, Shah ND,Wermers RA, Smith SA. Self-report of hypoglycemiaand health-related quality of life in patients withtype 1 and type 2 diabetes. Endocr Pract. 2013;19:792-799.

28.Leiter LA, Boras D, Woo VC. Dosing irregularitiesand self-treated hypoglycemia in type 2 diabetes:results from the Canadian cohort of an internationalsurvey of patients and healthcare professionals. CanJ Diabetes. 2014;38:38-44.

29.Erol O, Enc N. Hypoglycemia fear and self-efficacyof Turkish patients receiving insulin therapy. AsianNurs Res (Korean Soc Nurs Sci). 2011;5:222-228.

30.Green AJ, Fox KM, Grandy S. Self-reported hypo-glycemia and impact on quality of life and depres-sion among adults with type 2 diabetes mellitus.Diabetes Res Clin Pract. 2012;96:313-318.

31.Alvarez-Guisasola F, Yin DD, Nocea G, Qiu Y, MavrosP. Association of hypoglycemic symptoms with pa-tients' rating of their health-related quality of lifestate: a cross sectional study. Health Qual Life Out-comes. 2010;8:86.

32.Marrett E, Radican L, Davies MJ, Zhang Q. Assess-ment of severity and frequency of self-reported hy-poglycemia on quality of life in patients with type 2diabetes treated with oral antihyperglycemicagents: a survey study. BMC Res Notes. 2011;4:251.

33.Malhan S, Öksüz E, Babineaux S, Ertekin A, PalmerJ. Assessment of the direct medical costs of type 2diabetes mellitus and its complications in Turkey.Turk Jem. 2014;18:39-43.

39


39

40


40

34.Ginde AA, Espinola JA, Camargo CA Jr. Trends anddisparities in U.S. emergency department visits forhypoglycemia, 1993-2005. Diabetes Care. 2008;31:511-513.

35.Kovatchev BP, Cox DJ, Kumar A, Gonder-FrederickL, Clarke WL. Algorithmic evaluation of metaboliccontrol and risk of severe hypoglycemia in type 1and type 2 diabetes using self-monitoring blood glu-cose data. Diabetes Technol Ther. 2003;5:817-828.

36.Ozcan S, Amiel SA, Rogers H, Choudhary P, Cox A,de Zoysa N, Hopkins D, Forbes A. Poorer glycaemiccontrol in type 1 diabetes is associated with reducedself-management and poorer perceived health: across-sectional study. Diabetes Res Clin Pract.2014;106:35-41.

37.Damci T, Emral R, Svendsen AL, Balkir T, Vora J.Lower risk of hypoglycaemia and greater odds forweight loss with initiation of insulin detemir com-pared with insulin glargine in Turkish patients withtype 2 diabetes mellitus: local results of a multina-tional observational study. BMC Endocr Disord.2014;14:61.

38.Ratner RE, Gough SC, Mathieu C, Del Prato S, BodeB, Mersebach H, Endahl L, Zinman B. Hypogly-caemia risk with insulin degludec compared with in-sulin glargine in type 2 and type 1 diabetes: apre-planned meta-analysis of phase 3 trials. Dia-betes Obes Metab. 2013;15:175-184.

39.Mosenzon O, Raz I. Intensification of insulin ther-apy for type 2 diabetic patients in primary care:basal-bolus regimen versus premix insulin analogs:when and for whom? Diabetes Care. 2013;36:S212-218.

40.El Naggar NK, Soewondo P, Khamseh ME, Chen JW,Haddad J. Switching from biphasic human insulin 30to biphasic insulin aspart 30 in type 2 diabetes is

associated with improved glycaemic control and apositive safety profile: results from the A1 chievestudy. Diabetes Res Clin Pract. 2012;98:408-413.

41.Tibaldi JM. Evolution of insulin: from human to ana-log. Am J Med. 2014;127:S25-38.

42.Liebl A, Prager R, Binz K, Kaiser M, Bergenstal R,Gallwitz B. Comparison of insulin analogue regi-mens in people with type 2 diabetes mellitus in thePREFER Study: a randomized controlled trial. Dia-betes Obes Metab. 2009;11:45-52.

43. Ilag LL, Kerr L, Malone JK, Tan MH. Prandial pre-mixed insulin analogue regimens versus basal in-sulin analogue regimens in the management of type2 diabetes: an evidence-based comparison. ClinTher. 2007;29:1254-1270.

44.TEMD Diabetes Mellitus Çalışma ve Eğitim Grubu.TEMD Diabetes Mellitus ve KomplikasyonlarınınTanı, Tedavi ve İzlem Kılavuzu 2016. (8. Baskı).Ankara; Miki Matbaacılık San ve Tic Ltd Şti;2016;219.

45.Diabetes Study Group SEMT. Acute complications ofdiabetes. Satman I, çeviri editörü. Clinical PracticeGuidelines for Diagnosis, Treatment and Follow-upof Diabetes Mellitus and its Complications. (4.Baskı). Turk Jem. İstanbul; Özgün Ofset Tic Ltd Şti;2010:58-67.

46.Khunti K, Alsifri S, Aronson R, Cigrovski Berković M,Enters-Weijnen C, Forsén T, Galstyan G, Geelhoed-Duijvestijn P, Goldfracht M, Gydesen H, Kapur R,Lalic N, Ludvik B, Moberg E, Pedersen-Bjergaard U,Ramachandran A. Rates and predictors of hypogly-caemia in 27 585 people from 24 countries with in-sulin-treated type 1 and type 2 diabetes: the globalHAT study. Diabetes Obes Metab. 2016;18:907-915.

Address for Correspondence: Bünyamin Aydın, Süleyman Demirel University Faculty of Medicine,Department of Endocrinology and Metabolism, Isparta, Turkiye

Phone: 0256 218 18 00 E-mail: [email protected] Received: 23/02/2016 Accepted: 18/09/2016


A Different Cause ofMalignant Hypercalcemia

in a Breast Carcinoma with Bone MetastasisKemik Metastazı Olan Meme Kanserli Bir Hastada

Malign Hiperkalseminin Farklı Bir Nedeni

Süleyman Demirel University Faculty of Medicine, Department of Endocrinology and Metabolism, Isparta, Turkey*Süleyman Demirel University Faculty of Medicine, Department of Nuclear Medicine, Isparta, Turkey

**Süleyman Demirel University Faculty of Medicine, Department of Medical Oncology, Isparta, Turkey***Şifa Hospital Depatment of General Surgery, Isparta, Turkey

Case ReportTurk J Endocrinol Metab 2017;22:41-44

IntroductionThe most common causes of hypercalcemia arePrimary Hyperparathyroidism (PHPT) and ma-lignancies. These two disorders cover 90% ofetiologies leading to hypercalcemia (1). Thecancers where hypercalcemia is mostly seen arebreast carcinoma, lung carcinoma, and multiplemyeloma. Hypercalcemia is observed in 30-40% of breast cancer patients (2). Breast car-cinoma is most frequent cancer in women and

the second cause of death after lung cancer. Themost frequent causes of hypercalcemia in can-cer patients are bone metastasis and paraneo-plastic syndromes (1–4). Malignancies mightalso be found with PHPT. Therefore, in cancerpatients with hypercalcemia, serum parathyroidhormone (PTH) level should be assessed (5).We present this case in order to further empha-size the fact that PHPT might accompany ma-lignancies.

DO

I:10

.251

79/t

jem

.201

7-56

502

Hypercalcemia refers to a condition of calcium levels inblood above the normal range. Most common causes ofhypercalcemia include overactivity of parathyroid glands,also known as primary hyperparathyroidism (PHPT), andmalignancies. These two disorders contribute to 90% ofetiologies leading to hypercalcemia. Various types of can-cer manifest hypercalcemia, including breast carcinoma,lung carcinoma, and multiple myeloma. For instance, hyper-calcemia is observed in 30% to 40% of patients with breastcancer. The occurrence of hypercalcemia in cancers is attri-buted to bone metastasis and paraneoplastic syndromes.Malignancies may also be accompanied by PHPT. Therefore,in cancer patients with hypercalcemia, serum parathyroidhormone (PTH) level should be assessed. In the presentstudy, we present a case of breast cancer with hypercalce-mia to emphasize the role of PHPT in malignancies.

Keywords: Breast cancer; hypercalcemia;positron emission tomography;primary hyperparathyroidism

Hiperkalsemi kandaki kalsiyum seviyesinin normalin üs-tünde olması olarak ifade edilir. Hiperkalseminin en yaygınnedenleri arasında paratiroid bezlerinin aşırı aktivitesi olarakda bilinen primer hiperparatiroidizm (PHPT) ve maligniteleryer alır. Bu iki hastalık, hiperkalsemiye yol açan etiyolojile-rin %90’ına neden olur. Meme karsinomu, akciğer karsi-nomu ve multipl miyeloma dahil olmak üzere çeşitli kansertiplerinde hiperkalsemi görülebilir. Örneğin, meme kanseriolan hastaların %30-40’ında hiperkalsemi görülmektedir.Kanserlerde hiperkalseminin görülmesi, kemik metastazı veparaneoplastik sendromlara bağlanır. Maligniteler de PHPTeşlik edebilir. Bu nedenle, hiperkalsemisi olan kanser has-talarında serum paratiroid hormonu (PTH) düzeyi değerlen-dirilmelidir. Bu olgu sunumunda, malignitelerde PHPT'ninrolünü vurgulamak için hiperkalsemili bir meme kanseri va-kası sunulmaktadır.

Anahtar kelimeler: Meme kanseri; hiperkalsemi;pozitron emisyon tomografisi;primer hiperparatiroidizm

41

https://orcid.org/0000-0003-2059-1074

https://orcid.org/0000-0002-4009-369X

42

Aydın et al. Turk J Endocrinol MetabBreast Cancer, Primary Hyperparathyroidism 2018;22:41-44

42

Case ReportA 37-year-old female patient was admitted toour medical oncology center nearly threemonths ago with a mass in the left breast andleft axilla. Ultrasonographic examination of thebreast revealed a 2.5-cm mass lesion with ir-regular contoured microcalcifications. Patholog-ical examination of tru-cut biopsy revealedinvasive ductal carcinoma. Positron emission to-mography-computerized tomography (PET-CT)was conducted that revealed a multi-centrictumor in the left breast, metastatic lymph nodesin left axilla, and a lytic metastatic lesion in theeighth thoracic vertebra (T8) (Figure 1A). Thepatient underwent modified radical mastectomycombined with axillary lymph node dissection atanother center. The postoperative pathologicexamination of the patient showed estrogen re-ceptor (ER), negative; progesterone receptor(PR), 35% moderately positive; and c-erb-2, 3positive (+) invasive papillary carcinoma. Thus,the patient was diagnosed with metastatic leftbreast carcinoma (T3N3M1, bone metastasis).At admission, the patient presented with weak-ness, loss of appetite, and weight loss. Physicalexamination revealed a blood pressure of110/70 mmHg, heart rate of 88/min, respiratoryrate of 18/min, and body temperature of 36.8°C. Operation scars were present in left breastand left axilla. Initial examinations revealed ahemoglobin (Hb) level of 11.1 g/dL (13.6–17.2); white cells, 7,000 mm3 (5,200–12,400mm3); creatinine, 0.9 mg/dL (0.6–1.3 mg/dL);calcium, 12.4 mg/dL (8.8–10.6 mg/dL); andphosphate, 2 mg/dL (2.5–4.5 mg/dL). Magneticresonance imaging (MRI) verified bone lesionseen in PET-CT. The lesion at T8 found in thethoracic vertebrate MRI with contrast was con-sidered metastasis, and hypercalcemia was pre-dicted to be related to bone metastasis. Thetreatment consisted of chemotherapy with doc-etaxel (80 mg/m2/d) + trastuzumab (8 mg/kgloading dose on day 1) followed by 6 mg/kg onday 1 every 21st day. For bone metastasis, treat-ment comprised zoledronic acid (4 mg/every21st day). During chemotherapy, follow-up cal-cium values were between 12.0 and 12.5mg/dL; no symptom due to hypercalcemia wasobserved. PET-CT was used to evaluate the re-sponse to therapy after six cure chemotherapy;it revealed metastasis in the eighth thoracicvertebra. Further, diffusely increased F–18Florodeoksiglukoz (FDG) uptake by the skeletalsystem was noted, particularly by all costo-

chondral junctions, sternum, and iliac bones assigns of a metabolic bone disorder (Figure 1B).Due to a pre-diagnosis of PHPT, PTH and 25-OHvitamin D3 levels were measured: PTH was1,256 pg/mL (15–65 pg/mL), and 25-OH vita-min D3 was 28.6 ng/mL (20-100 ng/mL).Parathyroid ultrasound (USG) examination re-vealed a 25 × 16-mm hypoechoic parathyroidlesion in the inferior right thyroid lobe. The Tc–99m methoxyisobutyl isonitrile (MIBI) scintigra-phy further reported it to be parathyroidadenoma (Figure 2). Thus, hypercalcemia in thepatient was attributed to parathyroid adenoma,for which ultrasonographic laser ablation andpercutaneous ablation alternatives were sug-gested. Surgery was performed after knowingpatient’s preference. Postoperative pathologicaldiagnosis was parathyroid adenoma. Afterparathyroid surgery, PTH and calcium levels re-turned to normal values.

Literature Review and DiscussionHypercalcemia is a life-threatening electrolytedisorder. Its detection in a patient with breastcancer suffers from poor prognosis, primarily be-cause the presence of hypercalcemia usually in-dicates skeletal metastasis (4).The occurrence of malignancy-associated hyper-calcemia depends on three mechanisms, namelythe production of local cytokines due to osteolyticmetastasis (osteoclast activating factors), the se-cretion of parathyroid hormone-related protein(PTHrP) by tumor cells, and the synthesis of 1,25-dihydroxyvitamin D (calcitriol) by tumor cells (1).In patients with non-metastatic solid tumors,PTHrP is the most common cause of hypercal-cemia (3,5,6). However, since in most patientswith hypercalcemic malignancy, cancer is clinicallyproven, the measurement of PTHrP levels is notrequired. Binding of PTHrP to PTH receptors re-sults in various biological properties of PTH.Breast cancer cells upon metastasis cause thebones to synthesize PTHrP more frequently thansoft tissue tumors or primary tissue tumors. Theresulting osteolysis can be cured by administra-tion of anti-PTHrP antibodies, leading to a rise inserum calcium levels, which, in turn, is associatedwith morbidities related to hypercalcemia (3).Primary hyperparathyroidism is an autonomousdisorder that occurs due to excessive secretionof PTH from parathyroid glands. Of primary hy-perparathyroidism (PHPT), 80 to 85% dependson a single parathyroid adenoma (7). PHPT iscommon in cancer patients. Also, the incidence

of cancer is high in patients with primary hy-perparathyroidism. The mechanisms underlyingthe co-existence of PHPT with certain malig-nancies, including breast cancer, are still un-known (8).Since PHPT may accompany cancer cases, PTHlevels should be measured in cancer patients withhypercalcemia. A high serum level of both PTHrPand PTH indicates PHPT besides malignancy. Inmild hypercalcemia, PHPT should be first taken

into account; if acute and severe hypercalcemiais present, hypercalcemia related to malignancyshould be considered. In cases where serum PTHis high and PTHrP is low, hypercalcemia is attrib-uted to PHPT (3). In our patient, PTH was highbut PTHrP was not assessed.The 18 F-FDG PET-CT scanning is an effective andhighly specific method in tumor staging, re-stag-ing in recurrent metastatic disease, and follow-up of response to therapy in breast cancer (9). It

43

Turk J Endocrinol Metab Aydın et al.2018;22:41-44 Breast Cancer, Primary Hyperparathyroidism

43

Figure 1: Maximum intensity projection (MIP) images of two different 18 F-FDG PET/CT scanning that was performedfor staging and evaluation of response to the therapy in a patient with breast cancer. The first MIP image demonstra-tes increased F–18 FDG uptake in tumor tissue, axillary metastatic lymph nodes, and bone metastasis in the eighththoracic vertebrate (black arrow) (A). Second 18 F-FDG PET/CT MIP image reveals metastasis in eighth thoracic ver-tebrate (black arrow) beside diffusely increased F–18 FDG uptake at skeletal system, particularly at all costochondraljunctions, sternum and iliac bones as signs of a metabolic bone disorder (B).

Figure 2: Tc-99m MIBI parathyroid scintigraphy demonstrating parathyroid adenoma in the inferior of right thyroid lobe.

also contributes to the evaluation of non-onco-logical pathologies as in the case presented.However, 18 F-FDG PET-CT scans must be evalu-ated with caution so that benign cases are notmistakenly reported as metastasis. In our case,the cause of hypercalcemia was first consideredas bone metastasis related to breast cancer.However, since signs of a metabolic bone disorderwere observed in second 18 F-FDG PET-CT, bio-chemical analysis and imaging were performed,and a parathyroid adenoma was found as thecause of hypercalcemia.Clinical presentation of hypercalcemia includegastrointestinal (nausea, vomiting, abdominalcramp, pancreatitis, peptic ulcer), neuromuscu-lar-psychiatric (attention and memory deficits,lethargy, confusion, coma), renal (nephrolithiasis,diabetes incipitus, nephrocalcinosis, dehydration,renal insufficiency), cardiovascular (hypertension,arrhythmia, short QT), and bone symptoms (pain,cystitis fibrosis). Additionally, weight loss mightbe observed in accordance with the etiology (10).None of these were present in our patient.The laboratory results play a key role in deter-mining the severity and etiology of hypercal-cemia. Hypercalcemia is considered mild ifcalcium value is 10 to 12 mg/dL; moderate if 12to 14 mg/dL, and hypercalcemic crisis if 14 to 16mg/dL. Intact PTH levels have a critical role in theinvestigation of etiology of hypercalcemia. LowPTH levels are indicative of malignancy. In theabsence of malignancy, other endocrinopathies(hyperthyroidism, acromegaly, surrenal insuffi-ciency) should be questioned. If PTH value is nor-mal or high, 24-hour urine analysis should beperformed. A low value of 24-hour urine calciumreflects familial hypocalciuric hypercalcemia; ifthe value is high, primary or tertiary hyper-parathyroidism should be investigated (10).The treatment of primary hyperparathyroidismis surgical. Alternatives to surgery include ul-trasonographic laser ablation and percutaneousablation. Both methods can be done when sur-gery is contraindicated. Ablation is performedby USG-guided percutaneous interstitial laserphotocoagulation (ILP) that can detect the dis-eased parathyroid gland. Additionally, ethanolmight be injected into parathyroid adenomapercutaneously or angiographically for ablation(10). As our patient had stage 4 breast carci-noma (bone metastasis) with a life expectancyof nearly two years, ethanol injection wasplanned. But since the patient refused, surgerywas performed.

In conclusion, the involvement of PHPT in malig-nancy cases should be considered. Therefore, pa-tients with malignancy and hypercalcemia, evenif there is a bone metastasis, should be evaluatedfor PTH to exclude PHPT.Source of Finance: During this study, no finan-cial or spiritual support was received neither fromany pharmaceutical company that has a directconnection with the research subject, nor from acompany that provides or produces medical in-struments and materials which may negativelyaffect the evaluation process of this study.Conflict of Interest: No conflicts of interest be-tween the authors and/or family members of thescientific and medical committee members ormembers of the potential conflicts of interest,counseling, expertise, working conditions, shareholding and similar situations in any firm.

Author ContributionsConcept: Bünyamin Aydın Design: SevimSüreyya Çerçi Data Collection or Processing:Murat Koçer, Banu Kale Analysis or Interpreta-tion: Pınar Talip Yörükoğlu, Fatih Çolak LiteratureSearch: Mustafa Yıldız, Celal Çerçi Writing:Bünyamin Aydın Çıkar.

References1. Stewart AF. Clinical practice. Hypercalcemia associated with

cancer. N Engl J Med. 2005;352:373-379.2. Michels KB, Xue F, Brandt L, Ekbom A. Hyperparathyroidism

and subsequent incidence of breast cancer. Int J Cancer.2004;110:449-451.

3. Ratcliffe WA, Hutchesson AC, Bundred NJ, Ratcliffe JG. Roleof assays for parathyroid-hormone-related protein in in-vestigation of hypercalcaemia. Lancet. 1992;339:164-167.

4. Lee SH, Kim BH, Bae MJ, Yi YS, Kim WJ, Jeon YK, Kim SS,Kim YK, Kim IJ. Concurrence of primary hyperparathyroi-dism and metastatic breast carcinoma affected a parathy-roid gland. J Clin Endocrinol Metab. 2013;98:3127-3130.

5. Hutchesson AC, Bundred NJ, Ratcliffe WA. Survival inhypercalcaemic patients with cancer and co-existing pri-mary hyperparathyroidism. Postgrad Med J. 1995;71:28-31.

6. Guise TA, Yin JJ, Taylor SD, Kumagai Y, Dallas M, Boyce BF,Yoneda T, Mundy GR. Evidence for a causal role of pa-rathyroid hormone-related protein in the pathogenesis ofhuman breast cancer-mediated osteolysis. J Clin Invest.1996;98:1544-1549.

7. Taniegra ED. Hyperparathyroidism. Am Fam Physician.2004;69:333-339.

8. Norenstedt S, Granath F, Ekbom A, Bergh J, Lambe M,Adolfsson J, Warnberg F, Zedenius J, Nilsson IL. Breast can-cer associated with primary hyperparathyroidism: a nestedcase control study. Clin Epidemiol. 2011;3:103-106.

9. Czernin J. FDG-PET in breast cancer: a different view of itsclinical usefulness. Mol Imaging Biol. 2002;4:35-45.

10. Carroll MF, Schade DS. A practical approach to hypercalce-mia. Am Fam Physician. 2003;67:1959-1966.

11. Howell P, Kariampuzha S, Kipgen W, Baker MZ, Tytle TL,Williams GR, Scofield RH. Non-surgical therapy of primaryhyperparathyroidism. J Okla State Med Assoc. 2001;94:561-565.

44

Aydın et al. Turk J Endocrinol MetabBreast Cancer, Primary Hyperparathyroidism 2018;22:41-44

44

Address for Correspondence: Nilüfer Özdemir Kutbay, Ege University Faculty of Medicine,Department of Endocrinology and Metabolism, İzmir, Turkey



Two Siblings with Triple-A Syndrome:Endocrinologic and Neurologic Features

Triple A Sendromlu İki Kardeş:Endokrinolojik ve Nörolojik Özellikler

Ege University Faculty of Medicine, Department of Endocrinology and Metabolism, İzmir, Turkey*Ege University Faculty of Medicine, Department of Internal Medicine, İzmir, Turkey

**Ege University Faculty of Medicine, Department of Neurology, İzmir, Turkey***Ege University Faculty of Medicine, Department of Gastroenterology, İzmir, Turkey

Case ReportTurk J Endocrinol Metab 2018;22:45-49

IntroductionTriple-A syndrome is an autosomal recessive dis-order that was first described in 1978 by J. All-grove (1). Most prominent characteristics oftriple-A syndrome include esophageal achalasia,alacrima, and adrenal insufficiency. It is a rareand multi-systemic syndrome, characterized byprogressive nerve degeneration; autonomicnerve system findings could also be present (2).It is a genetic disorder with an autosomal reces-sive pattern involving a mutation in the AAAS(Achalasia-Addisonianism-Alacrima Syndrome)gene coding for the protein called ALADIN(Alacrima Achalasia aDrenal Insufficiency Neu-

rologic disorder) (3,4). The neurologic manifes-tations of the syndrome have largely been ig-nored and not extensively studied for a long time.Gazzarian et al. defined this syndrome as 4A in-stead of 3A owing to the association with auto-nomic nervous system findings (5). In thepresent study, we present two cases with the di-agnosis of triple-A syndrome where we studiedthe association of this syndrome with neurologicmanifestations.

Case 1

A 28-year-old female patient presented with hy-perpotassemia, hyperpigmentation, and hypocor-tisolemia and was initially diagnosed with adrenal

DO

I:10

.251

79/t

jem

.201

7-56

501

Triple-A syndrome is a rare, multi-systemic disease and ischaracterized by adrenal insufficiency, achalasia, or alac-rima. The symptoms may also involve neurologic manife-stations, including pyramidal findings and peripheral motorneuropathy. Other findings include autonomic dysfunctionand cerebellar ataxia. In the present study, we present thecase of two siblings with triple-A syndrome with neurologicmanifestations. The neurologic abnormalities can lead tomisdiagnosis owing to resemblance to the manifestations ofother neurologic disorders. Therefore, the cases with triple-A syndrome should be carefully evaluated and examined forclinical and neurophysiologic signs.

Keywords: Triple-A syndrome; adrenal insufficiency;peripheral neuropathy

Triple A Sendromu nadir bir multisistemik hastalıktır veadrenal yetmezlik, alakrima veya akalazya ile karakteri-zedir. Semptomlar, piramidal bulgular ve periferik motornöropati de dahil olmak üzere nörolojik belirtileri de içe-rebilir. Diğer bulgular arasında otonomik disfonksiyon veserebellar ataksi bulunur. Bu çalışmada, nörolojik bulgu-ların eşlik ettiği Triple A Sendromlu iki kardeşi sunuyoruz.Bu nörolojik anormallikler diğer nörolojik hastalıkların bul-gularına benzerliği nedeniyle yanlış tanıya yol açabilir.Bu nedenle, Triple-A sendromu olan olgular dikkatlice de-ğerlendirilmeli, klinik ve nörofizyolojik olarak incelenme-lidir.

Anahtar kelimeler: Triple-A sendromu; adrenal yetmezlik;periferal nöropati

45

https://orcid.org/0000-0003-1809-2655

https://orcid.org/0000-0002-4451-6530

https://orcid.org/0000-0003-0533-3122

https://orcid.org/0000-0001-6072-2062

https://orcid.org/0000-0002-0300-3923

https://orcid.org/0000-0002-3057-6452

https://orcid.org/0000-0002-2071-7362

https://orcid.org/0000-0001-6078-5944

https://orcid.org/0000-0002-0719-988X

46

Özdemir Kutbay et al. Turk J Endocrinol MetabTwo Siblings with Triple-A Syndrome 2018;22:45-49

46

insufficiency. She was referred to our hospitalwith complaints of weakness and fatigue at theage of 11 years. She was later referred to thegastroenterology department with complaints ofdysphagia when she was 18 years old and on hy-drocortisone treatment. Esophagography re-vealed achalasia and balloon dilatation wasperformed (Figure 1a, 1b). After the detection ofxerophthalmia, she was diagnosed with triple-Asyndrome due to the presence of alacrima withadrenal insufficiency and achalasia. As her weak-ness and fatigue persisted, she was examined forneurologic signs. Deep tendon reflexes were in-creased with the presence of proximal muscleweakness. The findings of electromyography(EMG) were compatible with axonal sensory-motor polyneuropathy (Table 1). Autonomic neu-ropathy tests were normal.

Case 2

A 21-year-old male patient (brother of Case 1)was examined at the age of three years owing tofamily history and diagnosed with adrenal insuf-ficiency and achalasia. He was referred to ourclinic with the development of xerophthalmia andwas diagnosed with triple-A syndrome. We con-ducted balloon dilatation to treat achalasia in thegastroenterology department. His blood pressurewas 100/60 mmHg, and he complained of weak-ness and fatigue. His 25-hydroxylase vitamin Dlevel was 35 nmol/L and was administered theinitial loading dose of vitamin D replacement.Later, the maintenance dose was preferred. Neu-rologic examination revealed increased deep ten-don reflexes and dysarthria. Muscles wereatrophic in all extremities (Figure 2a, 2b). EMGfindings suggested polyneuropathy. However,motor neuropathy was the dominant manifesta-

tion in EMG (Table 2). Autonomic neuropathytests were normal.

DiscussionThe patients with triple-A syndrome usually pres-ent endocrinologic and gastroenterologic symp-toms at the time of diagnosis. Neurologicmanifestations could be seen later, leading tothese getting missed out if the clinician is un-aware of the presence of neurologic manifesta-tions. Here, we present two cases with triple-Asyndrome with neurologic manifestations.Triple-A syndrome is primarily characterized byadrenal insufficiency, achalasia, and alacrima.Adrenal insufficiency and achalasia are usuallymanifested during the first decade of life. Acha-lasia is present in about 75% of cases and usu-ally manifests as dysphagia, especially for liquids,whereas adrenal insufficiency manifests as hypo-glycemia and hypotension. Main features of ad-

Figure 1: a) Esophageal constriction b) Scene ofesophagus after dilatation (Case 1).

CMAP: Compound Muscle Action Potential; SNAP: Sensory Nerve Action Potential; NR: No response.

Amplitude Distal latency Conduction Velocity

(CMAP:mV, SNAP: µV) (msec) (m/sec)

R L R L R L

Median SNAP 21 (>20) 24 (>20) 2.1 (>3.8) 2 (>3.8) 59 (>45) 55 (>45)

Ulnar SNAP 12 (>20) 15 (>20) 2.4 (>3.8) 2.2 (>3.8) 49 (>45) 57 (>45)

Median CMAP 10 (>5) 7 (>5) 3 (>3.9) 3.1 (>3.9) 55 (>50) 52 (>50)

Ulnar CMAP 2 (>5) 0.5 (>5) 4.5 (>3.1) 3.4 (>3.1) 43 (>50) 49 (>50)

Peroneal CMAP 3.5 (>4) 3.8 (>4.7) 45 (>40)

Posterior tibial CMAP 1 (>5) 4.7 (>5.5) 45 (>40)

Sural SNAP NR (>8) NR (>8)

Table 1. Neurophysiologic examination of case 1.

renal insufficiency include fatigue, loss of ap-petite, weight loss, low blood pressure, and dark-ening of the skin. It occurs due to primaryadrenal insufficiency. Mineralocorticoid produc-tion is preserved in most patients with triple-Asyndrome but may be impaired in 15% of pa-tients. The third major feature of triple-A syn-drome is a reduced or absent ability to secretetears (alacrima). Most people with triple-A syn-drome have all three features, although somepresent only two (6).The retrospective study conducted by Vallet et al.(7) presented eight cases of triple-A syndromewith neurologic manifestations. Age at the onsetranged from one month to 20 years. Two casesmanifested symptoms during early childhood andincluded adrenal insufficiency and achalasia.Neurologic symptoms in these cases were noticedduring teenage. The other six cases presentedneurologic symptoms as initial symptoms thatoccurred from early childhood to early adulthood.There was a delay of at least 17 years before thediagnosis of triple-A syndrome was made. When

adrenal insufficiency and achalasia are present atthe time of diagnosis of triple-A syndrome, neu-rologic dysfunction could be coexisting. In pedi-atric cases of triple-A syndrome, adrenalinsufficiency, achalasia, and alacrima are usuallypresent at the time of diagnosis; however, thesecould be missing in adult- or late-onset triple-Asyndrome. Thus, in patients presenting neuro-logic dysfunction as the predominant clinicalmanifestation, it is useful to search for the his-tory of achalasia and alacrima and perform hor-mone assay for adrenal insufficiency. The mainneurologic pathology, in eight cases reported byVallet et al. (7), included pyramidal syndromeand peripheral neuropathy. Peripheral neuropa-thy resulted in distal wasting and orthopedic de-formation such as pes cavus (7). Further, motorfibers were more affected, and few patients hada sensory deficit. In the present study, the casesmanifested sensory–motor neuropathy. The EMGfindings of the two cases are presented in Table1 and 2. A decrease in amplitude values wascompatible with axonal neuropathy. EMG valuesrevealed motor neuropathy to be more promi-nent. Needle EMG also ruled out myopathy. TheEMG recordings pointed to sensory-motor neu-ropathy in our cases that resulted in wasting ofhand muscles and pes cavus in case 2. The dif-ferential diagnosis of axonal sensorimotor pe-ripheral polyneuropathy revealed a dominanthereditary polyneuropathy due to distinct mus-cular atrophy in distal muscles. However, this di-agnosis was eliminated owing to the absence ofsimilar symptoms in upper zones and the ab-sence of an increase of deep tendon reflexes inthe neurologic examination. The laboratory test,done for acquired polyneuropathy, revealed nor-

47

Turk J Endocrinol Metab Özdemir Kutbay et al.2018;22:45-49 Two Siblings with Triple-A Syndrome

47

Figure 2: a) Hand muscle atrophy (Case 2) b) Pescavus (Case 2).

CMAP: Compound Muscle Action Potential; SNAP: Sensory Nerve Action Potential.

Amplitude Distal latency Proximal latency Conduction Velocity

(CMAP:mV, SNAP: µV) (msec) (msec) (m/sec)

R R R R

Median SNAP 12 (>20) 2.6 (>3.8) 42 (>45)

Ulnar SNAP 17 (>20) 2.4 (>3.8) 47 (>45)

Median CMAP 10 (>5) 4.1 (>3.9) 10.7 38 (>50)

Ulnar CMAP 0.4 (>5) 4.5 (>3.1) 10.2 34 (>50)

Peroneal CMAP 2 (>4) 6.1 (>4.7) 16.1 31 (>40)

Posterior tibial CMAP 0.4 (>5) 5.2 (>5.5) 16.3 34 (>40)

Sural SNAP 10 (>8) 3.7 (>3.8) 38 (>45)

Table 2. Neurophysiologic examination of case 2.

mal values, and no medication was reported inpatient’s history that could lead to polyneuropa-thy. In the light of all these, neuropathy was con-sidered to be associated with this syndromealong with the presence of usual symptoms of thesyndrome.Autonomic neuropathy and ataxic gait originat-ing from cerebellum were present in the casesstudied by Vallet et al. (7). These were not ob-served in our cases. Autonomic dysfunction, suchas orthostatic hypotension, bladder dysfunction,diarrhea or constipation, sexual dysfunction, anddyshidrosis, was present in six cases reported byVallet et al. (7). Bulbar and facial deficiencieswere observed in all eight patients; velar insuffi-ciency, tongue amyotrophy, and orbicularis orisdysfunction were observed to various degrees(7). In our study, case 2 had dysarthria as a bul-bar dysfunction. Bulbar symptoms can be con-fusing and difficult to differentiate from achalasia.Both bulbar dysfunction and achalasia can causeswallowing difficulties. In bulbar dysfunction,dysphagia is associated with dysfunctioning of IX,X, and XI cranial nerves. On the other hand,achalasia only causes lower dysphagia of esoph-agus. In our cases, no autonomic dysfunction ex-isted.The cognitive deficit can be present as neuro-logic manifestation. For instance, cases studiedby Vallet et al. (7) presented with frequent andmild cognitive dysfunction; however, this findingwas not present.The neurologic findings misdiagnosed in all pa-tients at the beginning were juvenile amyotrophiclateral sclerosis (ALS), spinocerebellar ataxia,spinal muscular amyotrophy, mitochondriopathy,adrenoleukodystrophy, multiple sclerosis, andCharcot-Marie-Tooth neuropathy (7). The final di-agnosis of the triple-A syndrome with neurologicmanifestations in the study by Vallet et al. (7)was made by a team of neurologist, gastroen-terologist, and endocrinologist. In these eightcases, genetic analysis was also performed,which, unfortunately, could not be performed inour cases.Apart from the study of Vallet et al., other reportsfrom the literature describe peripheral neuropa-thy and pyramidal syndrome as other neurologicmanifestations (2, 8–10). The most commonneurologic manifestation was lower limb weak-ness in the study of Nakamura et al. (11) whodescribed six cases. All patients presented upperand lower motor neuron signs. Sensory distur-bance and autonomic dysfunction were observed

in 29% and 57%, respectively. This study groupindicated hyperreflexia as a remarkable findingof triple-A syndrome that distinguished this dis-ease from other causes of peripheral neuropathy.In the present study, increased deep tendon re-flexes reflected pyramidal syndrome.Peripheral nerve pathology is not a well-knownfinding of triple-A syndrome with an unclear eti-ology. The presence of sural nerve biopsy hasbeen described by a few reports. The two casesin the present study presented axonal degenera-tion and a loss of myelinated and unmyelinatednerve fibers (8, 10). Previous reports have at-tributed the manifestation of neuropathy to a de-fect in ACTH receptors present on neurons/gliawith secondary demyelination; however, furtherstudies did not support this theory (12).The study of Nakamura et al. (11) involved adult-or late-onset triple-A syndrome with achalasiawhere the diagnosis was made after neurologicsymptoms appeared. Achalasia is an importantmanifestation of triple-A syndrome diagnosis. Allpatients in the study conducted by Nakamura etal. had alacrima. On the contrary, adrenal insuf-ficiency was absent in late-onset triple-A cases inthe study. Regular follow-ups of these patientsare required to keep a check on the levels of cor-tisone hormone, the non-compliance to whichmay lead to the missing out of the crisis.

ConclusionPeripheral neuropathy is a common neurologicfinding in patients with triple-A syndrome. Thechances of neurologic manifestations getting mis-diagnosed as some other neurologic pathologiesremain high. Therefore, an association of neuro-logic manifestations with triple-A syndromeshould be considered during its diagnosis. Acha-lasia and alacrima serve as important clues forthe diagnosis. An awareness of the association ofneurologic manifestations with triple-A syndromeallows us to follow incomplete neurologic findingswith appropriate tests, leading to a better diag-nosis.

Author ContributionsConcept: Nilufer Ozdemir Kutbay, Banu SarerYurekli, Fatma Keklik, Design: Nilufer OzdemirKutbay, Banu Sarer Yurekli, Data Collection orProcessing: Nilufer Ozdemir Kutbay, Fatma Kek-lik, Gokce Kavasoglu, Nevin Oruc, Analysis or In-terpretation: Nilufer Ozdemir Kutbay, Banu SarerYurekli, Gokce Kavasoglu, Mehmet Erdogan, Lit-erature Search: Nilufer Ozdemir Kutbay, Sevki

48

Özdemir Kutbay et al. Turk J Endocrinol MetabTwo Siblings with Triple-A Syndrome 2018;22:45-49

48

Cetinkalp, Gokhan Ozgen, Fusun Saygili, Writing:Nilufer Ozdemir Kutbay, Banu Sarer Yurekli,Fatma Keklik.Conflict of Interest: No conflict of interest isdeclared by the authors.Financial Disclosure: The authors declared thatthis study received no financial support.

References1. Allgrove J, Clayden GS, Grant DB, Macaulay JC. Fa-

milial glucocorticoid deficiency with achalasia of thecardia and deficient tear production. Lancet.1978;17:1284-1286.

2. Grant D, Barnes N, Dumic M, Ginalska-MalinowskaM, Milla PJ, von Petrykowski W, Rowlatt RJ,Steendijk R, Wales JH, Werder E. Neurological andadrenal dysfunction in the adrenal insufficiency/alacrima/achalasia (3A) syndrome. Arch Dis Child.1993;68:779-782.

3. Handschug K, Sperling S, Yoon SJ, Hennig S, ClarkAJ, Huebner A. Triple A syndrome is caused by mu-tations in AAAS, a new WD-repeat protein gene.Hum Mol Genet. 2001;10:283-290.

4. Cronshaw JM, Matunis MJ. The nuclear pore com-plex protein ALADIN is mislocalized in triple A syn-drome. Proc Natl Acad Sci U S A. 2003;100:5823-5827.

5. Gazarian MM, Cowbell CT, Bonney, Grigor WG. The“4A” syndrome: adrenocortical insufficiency associ-

ated with achalasia, alacrima, autonomic and neu-rological features. Eur J Pediatr. 1995;154:18-23.

6. Misgar RA, Pala NA, Ramzan M, Wani AI, Bashir MI,Laway BA. Allgrove (Triple A) syndrome: a case re-port from the Kashmir Valley. Endocrinol Metab(Seoul). 2015;30:604-606.

7. Vallet AE, Verschueren A, Petiot P, Nicolino M,Roman S, Pouget J, Vial C. Neurological features inadult Triple-A (Allgrove) syndrome. J Neurol.2012;259:39-46.

8. Kimber J, McLean BN, Prevett M, Hammans SR. All-grove or 4 “A” syndrome: an autosomal recessivesyndrome causing multisystem neurological dis-ease. J Neurol Neurosurg Psychiatry. 2003;74:654-657.

9. Houlden H, Smith S, De Carvalho M, Blake J, Math-ias C, Wood NW, Reilly MM. Clinical and geneticcharacterization of families with triple A (Allgrove)syndrome. Brain. 2002;125:2681-2690.

10.Bentes C, Santos-Bento M, de Sá J, de Lurdes SalesLuís M, de Carvalho M. Allgrove syndrome in adult-hood. Muscle Nerve. 2001;24:292-296.

11.Nakamura K, Yoshida K, Yoshinaga T, Kodaira M,Shimojima Y, Takei Y, Morita H, Kayanuma K, IkedaS. Adult or late-onset triple A syndrome: case re-port and literature review. J Neurol Sci.2010;297:85-88.

12.Stuckey BG, Mastaglia FL, Reed WD, Pullan PT. Glu-cocorticoid insufficiency, achalasia, alacrima withautonomic and motor neuropathy. Ann Intern Med.1987;106:62-64.

49

Turk J Endocrinol Metab Özdemir Kutbay et al.2018;22:45-49 Two Siblings with Triple-A Syndrome

49

50 Case ReportTurk J Endocrinol Metab 2018;22:50-53

50

Address for Correspondence: Aslıhan Taraktaş, Health Sciences University Fatih Sultan Mehmet Education Research Hospital,Clinic of Physical Medicine and Rehabilitation, İstanbul, Turkey



Pregnancy-Associated Osteoporosis:Long-term Follow-up of a Patient

with Two PregnanciesGebelikle İlişkili Osteoporoz:

İki Gebeliği Boyunca Hastanın Uzun Dönem Takibi

Health Sciences University Fatih Sultan Mehmet Education Research Hospital, Clinic of Physical Medicine and Rehabilitation, İstanbul, Turkey

DO

I:10

.251

79/t

jem

.201

7-56

508

Pregnancy and lactation-associated osteoporosis (PLO) is arare condition. Its pathogenesis and etiology are unknown.It is frequently observed in the last trimester of pregnancyand during lactation period in primigravida. The symptomsmay begin with back and hip pain. In addition, it could becomplicated by osteoporotic fractures and disability. Here,we report a long-term (7 years) follow-up of a 29-year-oldpatient who underwent two pregnancies and was diagnosedwith PLO both the times. The first time this patient was ad-mitted to our outpatient clinic with a complaint of severeback pain, she was in the lactation period of her first preg-nancy. Laboratory findings, X-ray imaging and densitometryrevealed osteomalacia (25-OH Vit D = 6.8 ng/dL), multiplevertebral fractures (T6-T9-T11-T12-L1), and osteoporosis(L1–L4 T-score: –4.6). After the treatment for vitamin D de-ficiency, she was treated with risedronate and Ca-vitamin Dsupplementation. At the end of the 2-year follow-up, sheterminated the use of risedronate [by her own decision] andcontinued with the Ca–vitamin D supplementation. Sixyears after the first pregnancy, she became pregnant again.In the postpartum period, she complained about gait diffi-culty, and severe hip and back pain. With the help of labo-ratory results, imaging, and densitometry (L1–L4 T-score:–3.9), she was diagnosed with PLO second time, and wastreated with zoledronic acid, in addition to Ca–vitamin Dsupplementation. Once back pain occurs in the postpartumperiod, PLO should be considered in differential diagnosiseven if the patient is taking Ca–vitamin D supplementation.

Keywords: Pregnancy; osteoporosis; lactation;vitamin D; bisphosphonates

Gebelik ve laktasyon ile ilişkili osteoporoz (GLO) patoge-nezi ve etyolojisi bilinmeyen nadir bir durumdur. Sıklıklailk gebeliğin son üç ayında ve laktasyon periyodunda gö-rülür. Semptomlar bel ve kalça ağrısı ile başlayabilir, os-teoporotik kırıklar ve disabilite eşlik edebilir. Bu vakatakdiminde her iki gebeliğinde de GLO teşhis edilen 29 ya-şında bir hastanın uzun dönem (7 yıl) takiplerini sunduk.Hasta polikliniğimize şiddetli sırt ağrısı şikayetiyle baş-vurduğunda ilk gebeliğinin laktasyon periyodundaydı. La-boratuar bulguları, X-ray görüntüleme ve dansitometrisonucunda osteomalazi (25-OH Vit D= 6.8 ng/dL), mul-tiple vertebra kırıkları (T6-T9-T11-T12-L1) ve osteoporoz(L1–L4 T-score: –4.6) tespit edildi. Tedavisine, D vitaminireplasmanı sonrası risedronat ve Ca-D vitamin ile devamedildi. İki yıllık takibin sonunda hasta (kendi isteğiyle) ri-sedronat kullanımını keserek Ca-D vitamini kullanmayısürdürdü. Ilk gebeliğinden altı yıl sonra tekrar gebe kaldı.Postpartum periyodda yürüme güçlüğü, şiddetli sırt vekalça ağrısı yakınmaları olan hastaya laboratuar, görüntü-leme ve dansitometri (L1–L4 T-score: -3.9) bulgularınınsonucunda ikinci defa GLO tanısı konuldu. Hastaya Ca- Dvitamini takviyesine ek olarak zoledronik asit tedavisi uy-gulandı. Postpartum periyodda sırt ağrısı ile başvuran has-talarda; hasta Ca-D vitamini takviyesi kullansa bile ayırıcıtanıda GLO akla gelmelidir.

Anahtar kelimeler: Gebelik; osteoporoz; laktasyon;D vitamini; bifosfonatlar

https://orcid.org/0000-0002-1050-9666

https://orcid.org/0000-0002-5491-5383

https://orcid.org/0000-0002-3824-4428

https://orcid.org/0000-0002-7686-1347

https://orcid.org/0000-0003-4506-8570

IntroductionOsteoporosis (OP) is the deficiency of bone min-eral density (BMD) and microarchitectural deteri-oration of bone tissue (1). Although OP is acommon condition, pregnancy and lactation-as-sociated osteoporosis (PLO) is a rare condition,characterized by the occurrence of fractures dur-ing late pregnancy or postpartum period withoutany underlying disorders (2). Approximately 100cases have been described in the literature sincethe first definition of PLO (3). Here, we report a7-year follow-up of a PLO patient, with lowerback pain due to several vertebral fractures dur-ing her first pregnancy, and hip pain during thesecond pregnancy. This case differs remarkablyfrom the other PLO cases in the literature due tothe development of OP after both the pregnan-cies.

CaseA 22-year-old primigravid woman was admittedto the outpatient clinic with a complaint of lowerback pain that began in the last trimester of herpregnancy. Her pain worsened during the lacta-tion period.The patient had no history of any chronic disease,including endocrine or metabolic disorders,smoking, and drug or alcohol use, which could af-fect bone metabolism. Upon physical examina-tion, palpation of the processus spinosi ofthoracolumbar vertebrae and paravertebral mus-cles were painful, and the range of motion in thethoracolumbar region was restricted. Anteropos-terior and lateral roentgenograms of thoracolum-bar vertebrae revealed multiple vertebralfractures (T6-T9-T11-T12-L1). Dual-energy X-rayabsorptiometry (DXA) analysis revealed de-creased BMD in the lumbar spine (L1–L4 T-score:–4.6) and proximal femur (femur neck T-score: –2.4). The laboratory analysis revealed decreasedlevels of 25-OH vit D (6.8 ng/dL), increased lev-els of alkaline phosphatase (ALP) (141 IU/L), andparathyroid hormone (PTH) (98 ng/L) in blood,along with uncountable levels of Ca in urine. Totalblood count, sedimentation rate, C-reactive pro-tein levels, levels of Ca and P in blood, and thethyroid and liver function tests were normal.On the basis of the clinical and laboratory find-ings, the patient was diagnosed with osteomala-cia and PLO. After normal vitamin D levels wereachieved with oral supplementation of elemen-tary Ca (1200 mg/day), vitamin D (800 IU/day)and risedronate (35 mg/week) treatment was ini-tiated. She was asked to cease breastfeeding.

The patient was recommended the use thora-columbosacral orthosis. A home-based rehabili-tation program, including muscle strengthening,and range of motion and relaxation exercises,was prescribed.In the third month of the follow-up, her back paindecreased, with normal levels of vitamin D, PTH,and ALP. At the end of the first year of follow-up,she had no complaint of back pain. Her medicaltreatment (Ca, vitamin D, and risedronate) wascontinued for two years. She complained aboutthe weekly regime of risedronate and discontin-ued the bisphosphonate treatment. However, sheadhered to the daily Ca and vitamin D supple-mentation. The vitamin D levels and the DXA re-sults of the patient are listed in Table 1.After six years, she became pregnant with hersecond child. Pregnancy was uneventful. The pa-tient’s back pain and severe hip pain appeared attwo months postpartum. She experienced diffi-culty in walking. Upon physical examination, therange of motion in the thoracolumbar region andhips were painful and restricted, with greaterpain in the hips. Laboratory evaluations (includ-ing vitamin D, PTH, Ca, and ALP) were normal.The results of spinal radiography and magneticresonance imaging (MRI) of the hips were exam-ined. DXA revealed osteoporosis, with L1–L4 T-score= -3.9 and femur neck T-score= -1.5. Nonew fractures were detected on the thoracolum-bar roentgenogram, and the MRI revealed bilat-eral bone marrow edema of femoral head andneck (Figure 1).The clinical picture was identified as PLO. The pa-tient was advised to cease breastfeeding. Zole-dronic acid (5 mg/year) treatment was added tothe daily Ca and vitamin D supplementation afterthe cessation of breastfeeding. Rest, activity lim-itation, and non-steroidal anti-inflammatorydrugs were recommended for pain control. Herpain and difficulty in gait diminished within threemonths.

DiscussionPLO was first described by Nordin & Roper. Theexact prevalence of PLO is unknown to date be-cause the literature about this condition is limitedto a small number of case reports (3). It is definedas a rare condition that develops in the lasttrimester of pregnancy or postpartum in lactationperiod, primarily in the first pregnancy. It mostlybecomes complicated with fractures in the verte-brae, hip, and sacrum (1). Its etiology is not cer-tain and a precise mechanism has not been

51

Turk J Endocrinol Metab Taraktaş et al.2018;22:50-53 Pregnancy-Associated Osteoporosis

51

52

Taraktaş et al. Turk J Endocrinol MetabPregnancy-Associated Osteoporosis 2018;22:50-53

52

substantiated to date. On the other hand, thereare particular risk factors, which include poor nu-trition, family history of osteoporotic fractures, ge-netic factors, physical inactivity, low body weight,vitamin D deficiency, smoking, drug usage (corti-costeroids, etc.), and the secondary causes of OP(4). When our patient was first diagnosed withPLO, the risk factors identified were low bodyweight and vitamin D deficiency, and that she wasa primigravida. She had no chronic disorder ordrug usage history, and no other factor leading tosecondary OP. During pregnancy, calcium absorp-tion from the intestine increases to ensure fetalcalcium needs. If this adaptation is not enough tofulfill the calcium demand, maternal bones faceresorption during the third trimester. Trabecularbone mineral density may decrease up to 5%–10% in the subsequent lactation period, due tovarious hormonal changes that occur in order tosupply calcium to milk (5). However, maternalskeleton recovers approximately 6–12 months

after weaning, by means of uncertain mechanisms(6). This physiological resorption and recoveryprocess is not related to the number of gravidities,breastfeeding length, or to further diagnosis of os-teoporosis or fragility fractures (7–9).The role of vitamin D in the modulation of in-creased intestinal transport of calcium needs tobe further clarified. Despite the fact that our pa-tient’s vitamin D levels were normal, both beforeand during the second pregnancy, OP was ob-served again. It is difficult to provide a clear com-ment due to the varied results of different studiesexamining the relationship between BMD and vi-tamin D. Although certain studies have reportedan association between low vitamin D levels andlow BMD (10), this relationship has not beendemonstrated in other studies (11).The most common symptom of PLO is back pain,especially in the thoracolumbar region. Intensepain is observed when PLO is complicated withfractures. This intense and sustained pain limits

L1-L4 BMD values L1-L4 Femur Neck BMD values Femur Neck vitamin D

(gr/cm2) T-Score (gr/cm2) T-score (ng/dL)

2008 (after first pregnancy) 0.525 –4.6 0.454 –2.4 6.8

2009 0.705 –3.1 0.749 –1.6 29

2010 0.729 –2.9 0.469 –2.3 37

2011 0.729 –2.9 0.469 –2.3 34

2012 0.729 –2.9 0.454 –2.4 31.6

2013 0.753 –2.7 0.454 –2.4 37

2014 0.753 –2.7 0.439 –2.5 24.77

2015 (after second pregnancy) 0.669 –3.9 0.764 –1.5 36.4

Table 1. DXA scores and D vitamin levels.

Figure 1: Thoracolumbar roentgenogram and magnetic resonance imaging of hips.

53

Turk J Endocrinol Metab Taraktaş et al.2018;22:50-53 Pregnancy-Associated Osteoporosis

53

the patient’s daily life activities and even leads todifficulty in gait (2). While our patient was suf-fering from severe back pain during her firstpregnancy, difficulty in gait was the predominantsymptom during her second pregnancy.Thoracolumbar pain during pregnancy should beexamined carefully, and imaging may be per-formed when required. The patients with ongoingsymptoms after delivery or during the lactationperiod should be investigated through radiologicalexamination, including thoracolumbar verte-brae/hip radiography, MRI, and DXA. Our patienthad multiple vertebral fractures, with low BMD inthe first pregnancy. Then, in the second preg-nancy, patient’s DXA scores and bilateral hip MRIwere compatible with OP, without a new fracture.Consistent with the literature, our patient’s BMDin the lumbar spine was observed to be lowerthan that in the femoral region in the repeatedDXA measurements (12).The limited literature available regarding thetreatment of PLO concerns the use of bisphos-phonates, strontium ranelate, and teriparatide,together with supplementation of Ca and vitaminD (1). The literature lacks a treatment algorithmor guidelines concerning the efficacy of differenttreatments. Therefore, the medical treatmentshould be customized for each individual patientthrough a detailed assessment, together with theappropriate rehabilitation program.In our case, we first initiated risedronate treat-ment together with Ca and vitamin D supple-mentation. In the second pregnancy of thepatient, another bisphosphonate-zoledronic acid-was preferred due to the single-dose regimen,which was more convenient for our patient.In conclusion, PLO may reoccur with each preg-nancy and this should be kept in mind. Therefore,it is important to continue the follow-up with thepatient. Further, bisphosphonates are safe agentsthat could be used in the treatment of PLO.

Author ContributionsConcept: Aslıhan Taraktaş. Design: AslıhanTaraktaş, Feyza Ünlü Özkan. Data Collection or

Processing: Aslıhan Taraktaş; Özge G. İlleez.Analysis or Interpretation: Duygu Geler Külcü,İlknur Aktaş. Literature Search: Aslıhan Taraktaş.Writing: Aslıhan Taraktaş, Feyza Ünlü Özkan.Conflict of Interest: No conflict of interest wasdeclared by the authors.Financial Disclosure: The authors declared thatthis study received no financial support.

References1. Akyüz G, Bayındır Ö. Pregnancy associated osteo-

porosis. Turk J Phys Med Rehab. 2013;59:145-150.2. Khovidhunkit W, Epstein S. Osteoporosis in preg-

nancy. Osteoporosis Int. 1996;6:345-354.3. Nordin BE, Roper A. Post-pregnancy osteoporosis; a

syndrome? Lancet. 1955;268:431-434.4. Di Gregorio S, Danilowicz K, Rubin Z, Mautalen C.

Osteoporosis with vertebral fractures associatedwith pregnancy and lactation. Nutrition.2000;16:1052-1055.

5. Sanz-Salvador L, García-Pérez MÁ, Tarín JJ, Cano A.Bone metabolic changes during pregnancy: a periodof vulnerability to osteoporosis and fracture. Eur JEndocrinol. 2015;172:R53-65.

6. Polatti F, Capuzzo E, Viazzo F, Colleoni R, Klersy C.Bone mineral changes during and after lactation.Obstet Gynecol. 1999;94:52-56.

7. Tuppurainen M, Kröger H, Saarikoski S, HonkanenR, Alhava E. The effect of gynecological risk factorson lumbar and femoral bone mineral density in peri-and postmenopausal women. Maturitas.1995;21:137-145.

8. Ip S, Chung M, Raman G, Chew P, Magula N, De-vine D, Trikalinos T, Lau J. Breastfeeding and ma-ternal and infant health outcomes in developedcountries. Evid Rep Technol Assess (Full Rep).2007;153:1-186.

9. Kauppi M, Heliövaara M, Impivaara O, Knekt P, JulaA. Parity and risk of hip fracture in postmenopausalwomen. Osteoporosis Int. 2011;22:1765-1771.

10.Adami S, Bertoldo F, Braga V, Fracassi E, Gatti D,Gandolini G, Minisola S, Battista Rini G. 25-hydroxyvitamin D levels in healthy premenopausal women:association with bone turnover markers and bonemineral density. Bone. 2009;45:423-426.

11.Hosseinpanah F, Rambod M, Hossein-nejad A, Lari-jani B, Azizi F. Association between vitamin D andbone mineral density in Iranian postmenopausalwomen. J Bone Miner Metab. 2008;26:86-92.

12.O’Sullivan SM, Grey AB, Singh R, Reid IR. Bisp-hosphonates in pregnancy and lactation-associatedosteoporosis. Osteoporos Int. 2006;17:1008-1012.

54 Invited ReviewTurk J Endocrinol Metab 2018;22:54-56

54

Address for Correspondence: Gülşah Yenidünya Yalın, Başkent University Istanbul Hospital, Department of Internal Medicine,Division of Endocrinology and Metabolic Diseases, İstanbul, Turkey

Phone: 90 216 554 15 00 E-mail: [email protected] Received: 08/08/2017 Accepted: 18/08/2017


Review of Clinical Recommendations onProlactinoma and Pregnancy

Prolaktinoma ve Gebeliğe Dair Klinik ÖnerilerinGözden Geçirilmesi

Başkent University İstanbul Hospital, Department of Internal Medicine, Division of Endocrinology and Metabolic Diseases, İstanbul, Turkey*Bakırköy Dr. Sadi Konuk Training and Research Hospital. Department of Internal Medicine,

Division of Endocrinology and Metabolic Diseases, İstanbul, Turkey**İstanbul University, Istanbul Faculty of Medicine, Department of Internal Medicine,

Division of Endocrinology and Metabolic Diseases, İstanbul, Turkey

DO

I:10

.251

79/t

jem

.201

7-57

578

Prolactinomas are the most common hormone-secreting pi-tuitary adenomas. Prolactinomas account for nearly 30–40percent of all the pituitary adenomas. Although it affects in-dividuals over a wide age range, it is more common in 20–40-year-old female patients, who are in their reproductiveage. Prolactinomas may cause hypogonadism, menstrualcycle dysfunction (oligomenorrhea or amenorrhea) and in-fertility (luteal phase abnormalities or anovulation) in pre-menopausal women. When pregnancy is excluded,hyperprolactinemia in approximately 10 to 20 percent of thepatients results in amenorrhea. Women with untreated pro-lactinomas are generally unable to achieve pregnancy, asthe hyperprolactinemia affects the pulsatility of go-nadotropin-releasing hormone (GnRH) and diminishes folli-cle-stimulating hormone (FSH) as well as luteinizinghormone (LH) secretion. The sum of these effects inducesamenorrhea, infertility, and hypogonadism, thereby posingdifficulties in fertility. Therefore, in most women prolactin-oma is diagnosed prior to conception. However, ovulationand fertility usually improve after proper diagnosis andtreatment of prolactinoma. Therefore, during the surveil-lance of these patients, the onset of pregnancy is a com-mon phenomenon. Management of these pregnancies maysometimes be challenging and require a multidisciplinaryapproach involving an endocrinologist, a gynecologist, a ra-diologist and an experienced neurosurgeon in order toachieve the best outcomes both for the patient as well theinfant. In this report, the authors aim to summarize theconsensus statements and the current guidelines for clinicalpractice.

Keywords: Prolactinoma; pregnancy; dopamine agonists

Prolaktinomalar en sık görülen fonksiyonel hipofiz adenomlarıolup tüm hipofiz adenomlarının yaklaşık %30-40 kadarını olu-şturmaktadır. Her yaşta görülebilmekle birlikte 20-40 yaşlarıarasındaki üreme çağındaki kadınlarda daha sık ortayaçıkmaktadırlar. Prolaktinomada klinik tablo prolaktin düzey-lerinin yüksekliği ile ilişkili olup galaktore ve gonadal fonksi-yonlar üzerindeki sekonder etkiler sonucu ortaya çıkmaktadır.Premenapozal kadınlarda hipogonadizm, menstruel siklus bo-zuklukları (oligomenore ya da amenore) ve infertilite (lutealfaz defekti ya da anovulasyon) ile prezente olabilmektedir.Hiperprolaktinemi, gebelik olmaksızın gelişen amenore ne-denlerinin yaklaşık %10-20 kadarını oluşturmaktadır. Yüksekserum prolaktin düzeyleri, gonadotropin salgılatıcı hormondüzeylerini baskılayarak luteinizan hormon (LH) ve follikül sti-mulan hormon (FSH) salgısını azaltarak menstruel siklus dü-zensizlikleri ve hipogonadizme neden olduğundan tedaviedilmeyen prolaktinomalı kadınlarda genellikle fertilitedeazalma söz konusudur. Bu nedenle prolaktinoma hastalarındatanı, gebelik öncesi fertilite tetkikleri sırasında da konulabil-mekte olup çoğunlukla konsepsiyon öncesinde ortayaçıkmaktadır. Ancak prolaktinomanın doğru tanı ve tedavisisonrası genellikle ovulasyon ve fertilite düzeldiğinden, pro-laktinoma hastalarının takipleri sırasında gebelik gelişimi denadir rastlanılan bir durum değildir. Sonuç olarak prolakti-noma tedavisi sırasında araya giren gebeliklerin yönetimlerisırasında bir takım zorluklarla karşılaşılabileceğinden endok-rinolog, jinekolog, radyolog ve tecrübeli bir beyin cerrahisiuzmanı tarafından multidisipliner bir yaklaşımla ele alınmalarıönerilmektedir. Bu derlemede mevcut klinik kılavuzlar vekonsensus önerilerinin ışığında prolaktinoma ve gebelik ko-nusundaki güncel yaklaşımlar özetlenmektedir.

Anahtar kelimeler: Prolaktinoma; gebelik; dopamin agonistleri

Prolactinomas are the most common out of allthe hormone-secreting pituitary adenomas.Women with untreated prolactinomas are notable to achieve pregnancy, as the hyperpro-lactinemia affects the pulsatility of GnRH, dimin-ishes FSH and LH secretion and inducesamenorrhea, infertility, and hypogonadism,thereby posing difficulties in fertility (1). For thisreason, in most cases, prolactinoma is diagnosedprior to conception. Nevertheless, ovulation andfertility are normally improved by proper diagno-sis and treatment. As a result, prolactinomas in apregnant woman are certainly challenging andrequire a multidisciplinary approach involving anendocrinologist, a gynecologist, a radiologist andan experienced neurosurgeon to achieve the bestoutcome. In this report, the authors aim to sum-marize the consensus statements and the currentguidelines for clinical practice.

Guideline RecommendationsRegarding Preconception Period inPatients with ProlactinomasThe risk of enlargement of a microprolactinomaduring pregnancy is nearly 1.5–4.5% with symp-tomatic growth occurring in about 2% of thecases. However, the risk of symptomatic enlarge-ment of a macroprolactinoma is greater than 15%(2, 3). The currently available dopamine agonists(DAs) include bromocriptine, cabergoline, andquinagolide (the latter is not approved for use inthe United States). It should be noted that therestoration of ovulation, once DA therapy hasbeen started, occurs even before normopro-lactinemia is achieved and the patient should beinformed about this outcome (4). In women whoare treated before conception, DA may also in-duce shrinkage of the pituitary tumor (a reduc-tion of greater than 25% is expected in the tumorsize in around 70% of the patients) (5).■ Achieving a normalization of PRL levels and atumor size <10 mm before conception is recom-mended for macroadenomas (6, 7).■ In women of childbearing age, the use of me-chanical contraception should be advised oncedrug treatment has been initiated for macroade-nomas. This is because ovulation and fertilitymay rapidly be recovered after the normalizationof PRL levels (6, 8).■ Transsphenoidal adenomectomy may be an op-tion for women with microadenoma or macroade-noma that is either intolerant or refractory toDas, or prepregnancy tumor debulking by sur-gery (thereby decreasing the risk of clinically sig-

nificant enlargement during pregnancy) would bean option in cases of macroadenomas that do notdecrease in size with DA treatment or in thosewho cannot tolerate bromocriptine or cabergoline(6, 8). Transsphenoidal surgery may also causehypopituitarism, thus requiring the subsequentuse of assisted reproduction techniques such asinduction of ovulation with gonadotropins andlifelong hormone replacement therapy (6-9). It isfor this reason that resumption of the DA is prob-ably less harmful to the mother and the fetus ascompared to surgery (6). Therefore, the team-work of multidisciplinary specialists is requiredfor the careful planning of pregnancy in womenwith prolactinoma. Ideally, this should arise be-fore conception, so that a full assessment of therisks and benefits of DA therapy can be assessedduring pregnancy (10).■ Whenever pregnancy is planned or detected inmacroadenomas, cabergoline should be discon-tinued and bromocriptine should be introducedalthough this drug also crosses the placental bar-rier (6). Bromocriptine is the “oldest” of all thedopamine agonists and has been tested more ex-tensively than the other compounds, but there isfar less published experience with cabergoline(8). Therefore, bromocriptine has been shown tobe safe for use during early gestation (up to thefirst four weeks after conception, a critical periodfor early organogenesis).■ In women with microprolactinomas who wantto become pregnant, the use of clomiphene cit-rate or gonadotropin therapy is suggested whenovulation cannot be restored by DAs alone (6).

Guideline RecommendationsRelated to pregnancy inPatients with Prolactinoma■ Women with prolactinomas must be instructedto discontinue DA therapy as soon as they dis-cover that they are pregnant (6-8, 10). In se-lected patients with macroadenomas who are onDA therapy and become pregnant and who havenot had prior tumor debulking by surgery, it maybe sensible to continue DA throughout the preg-nancy, especially if the tumor is invasive or isabutting the optic chiasm (6, 8, 10).■ When symptomatic tumor growth occurs (pres-ence of a headache or visual deterioration),treatment with bromocriptine should berestarted, if previously discontinued (6, 8). If theenlarged tumor does not respond to reinstitutionwith DA therapy within 2–3 weeks, transsphe-noidal surgery (in the second trimester) or deliv-

55

Turk J Endocrinol Metab Yenidünya Yalın et al.2018;22:54-56 Review of Prolactinoma and Pregnancy

55

56

Yenidünya Yalın et al. Turk J Endocrinol MetabReview of Prolactinoma and Pregnancy 2018;22:54-56

56

ery (if the pregnancy is far enough) must be con-sidered (6-8, 10).■ There is no evidence of increased teratogenic-ity associated with the use of bromocriptine orcabergoline during pregnancy (6, 8, 10).Quinagolide, on the other hand, has shown apoor safety profile in the relatively small numberof pregnancies that have been reported, and itshould not be prescribed to women who wish tobecome pregnant (8).■ In pregnant patients with prolactinomas, per-forming serum prolactin measurements duringpregnancy is not recommended. This is for thereason that in normal pregnancy, serum prolactinlevels increase 10-fold, reaching levels of 150 to300 g/Liter by term (6-8).■ In general, microprolactinomas and macropro-lactinomas that are localized to the sella do notundergo symptomatic growth during pregnancy,therefore the use of routine pituitary MRI duringpregnancy is not recommended in these patients.Because the risk of symptomatic tumor growth islow, these patients may be followed up by clini-cal examination during each trimester, unlessthere is clinical evidence of tumor growth bysymptoms such as headaches or visual deterio-ration (6-10). However, formal assessment of thevisual fields in macroprolactinoma should be per-formed every three months or even more fre-quently if the adenoma prior to conception isclose to the optic chiasm (8). When such clinicalmanifestations appear, imaging must be per-formed with unenhanced MRI. If the growth ofthe pituitary mass is identified, re-institution ofDA (preferably bromocriptine) for the remainderof the pregnancy may provide a control over thetumor and in addition, monthly clinical assess-ment is required (including visual fields).There-fore, the onset of a new or a worseningheadache, or a change in vision or both, man-dates the urgent performance of formal visualfield testing and a pituitary MRI without the useof gadolinium (6-8).

Guideline RecommendationsRelated to the Postpartum Period inPatients with Prolactinoma■ Women wishing to breastfeed their infantsshould not be given DA because the resulting de-crease in serum PRL levels will impair lactation.There are no data available suggesting that breast-feeding leads to an increase in tumor size (6, 7).■ The spontaneous remission of hyperprolactine-mia has only been reported in women with mi-croprolactinomas. In these cases, long-term

discontinuation of treatment with DAs after birth,along with regular monitoring for at least fiveyears may be considered (6).Source of Finance: During this study, no finan-cial or spiritual support was received neither fromany pharmaceutical company that has a directconnection with the research subject, nor from acompany that provides or produces medical in-struments and materials which may negativelyaffect the evaluation process of this study.Conflict of Interest: No conflicts of interest be-tween the authors and / or family members ofthe scientific and medical committee members ormembers of the potential conflicts of interest,counseling, expertise, working conditions, shareholding and similar situations in any firm.

Authorship ContributionsIdea/Concept: Sema Yarman, Gülşah Yalın; De-sign: Gülşah Yalın, Sema Yarman; Control/Su-pervision: Sema Yarman; Data Collection and/orProcessing: Gülşah Yalın, Sema Doğanşen;Analysis and/or Interpretation: Sema Yarman,Gülşah Yalın; Literature Review: Gülşah Yalın,Sema Doğanşen; Writing the Article: SemaYarman, Gülşah Yalın; Critical Review: SemaYarman; References and Fundings: SemaYarman; Materials: Gülşah Yalın, Sema Yarman.

References1. Kaiser UB. Hyperprolactinemia and infertility: new insights.

J Clin Invest. 2012;122(10):3467-3468.2. Molitch ME. Pregnancy and the hyperprolactinemic woman.

N Engl J Med. 1985;312(21):1364-1370.3. Karaca Z, Tanriverdi F, Unluhizarci K, Kelestimur F. Preg-

nancy and pituitary disorders. Eur J Endocrinol. 2010;162(3):453-475.

4. de Bernal M, de Villamizar M. Restoration of ovarian func-tion by low nocturnal single daily doses of bromocryptine inpatients with the galactorrhea-amenorrhea syndrome. Fer-til Steril. 1982;37(3): 392-396.

5. Molitch ME. Medical management of prolactin-secreting pi-tuitary adenomas. Pituitary. 2002;5(2): 55-65.

6. Halperin Rabinovich I, Cámara Gómez R, García Mouriz M,Ollero García-Agulló D. Clinical guidelines for diagnosis andtreatment of prolactinoma and hyperprolactinemia. En-docrinol Nutr. 2013;60(6):308-319.

7. Casanueva FF, Molitch ME, Schlechte JA, Abs R, Bonert V,Bronstein MD, Brue T, Cappabianca P, Colao A, Fahlbusch R,Fideleff H, Hadani M, Kelly P, Kleinberg D, Laws E, Marek J,Scanlon M, Sobrinho LG, Wass JA, Giustina A. Guidelines ofthe Pituitary Society for the diagnosis and management ofprolactinomas. Clin Endocrinol (Oxf). 2006;65(2):265-273.

8. Melmed S, Casanueva FF, Hoffman AR, Kleinberg DL,Montori VM, Schlechte JA, Wass JA. Diagnosis and treat-ment of hyperprolactinemia: an Endocrine Society clinicalpractice guideline. J Clin Endocrinol Metab. 2011;96(2):273-288.

9. Chrisoulidou A, Boudina M, Karavitaki N, Bili E, Wass J. Pi-tuitary disorders in pregnancy. Hormones (Athens).2015;14(1):70-80.

10. Serri O, Chik CL, Ur E, Ezzat S. Diagnosis and managementof hyperprolactinemia. CMAJ. 2003;69(6): 575-581.

journal of the society of endocrinology and … · 2019-05-09 · sevim güllü, md...

Documents