june 2019 volume: 23 issue: 2 - turkjem.org · göksun ayvaz, liv hospital, ankara, turkey Ömer...

June 2019

Volume: 23 Issue: 2

ISSN 1301-2193

JOURNAL OF THE SOCIETY OF ENDOCRINOLOGY AND METABOLISM OF TURKEY

COPYRIGHT HOLDER / YAYIN SAHİBİNİN ADISociety of Endocrinology and Metabolism of Turkey / Türkiye Endokrinoloji ve Metabolizma Derneği

LEGAL REPRESENTATIVE / TÜZEL KİŞİ TEMSİLCİSİ ADIL. Füsun Saygılı, MD

MANAGING CLERICAL DIRECTOR / SORUMLU YAZI İŞLERİ MÜDÜRÜNilgün Başkal, MD

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

PUBLICATION TYPE AND PERIODS / YAYININ TÜRÜ VE PERİYODUTurkish Journal of Endocrinology and Metabolism is published 4 (March, June, September and December) times a year.Local perid publication.Turkish Journal of Endocrinology and Metabolism 3 ayda bir olmak üzere yılda 4 sayı (Mart, Haziran, Eylül ve Aralık) yayınlanır.Yaygın/Süreli.

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, Index Copernicus, SCOPUS,TÜBİTAK / ULAKBİM TR Index, TürkMedline, Türkiye Citation Index.

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

Publishing House-Publisher / Basıldığı Yer-Basımcı-YayımcıOrtadoğu Reklam Tanıtım Yayıncılık Turizm Eğitim İnşaat Sanayi ve Ticaret A.Ş. (Türkiye Klinikleri)Nasuh Akar Mah. Türkocağı Cad. No:30 Balgat - Ankara TurkeyPhone / Tel: +90 312 286 56 56Fax / Faks: +90 312 220 04 70E-mail / E-posta: [email protected]: www.turkiyeklinikleri.com

The services of “Article Tracking (Automation)”, “Layout”, “Web Site Design-Operation” and “e-Mailing” are providedby Türkiye Klinikleri.Bu derginin “Makale Takip (Otomasyon)”, “Mizanpaj”, “Web Sitesi Tasarım-İletişim” ve “Toplu e-Posta” hizmetleri Türkiye Klinikleritarafından sağlanmaktadır.

Publication Date: 19.06.2019

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


June / Haziran 2019 Vol / Cilt: 23 No / Sayı: 2

Türkiye Klinikleri

Owner on Behalf of the Society ofEndocrinology and Metabolism of TurkeyL. Füsun Saygılı, Ege University Faculty of Medicine, İzmir, Türkiye

Editor-In-ChiefNilgün Başkal, Ankara University Faculty of Medicine Retired Lecturer,Ankara, Turkey

Deputy EditorMurat Faik Erdoğan, Ankara University Faculty of Medicine, Ankara, Turkey

Associate EditorsHasan Ali Altunbaş, Akdeniz University Faculty of Medicine, Antalya, TurkeyDilek Gogas Yavuz, Marmara University Faculty of Medicine, İstanbul, TurkeyNeslihan Başçıl Tütüncü, Başkent University Faculty of Medicine, Ankara, Turkey

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

Language EditorJennifer Gabriel, California, USA

Honorary BoardSema Akalın, Marmara University Faculty of Medicine Retired Lecturer, İstanbul, TurkeyMetin Arslan, Gazi University Faculty of Medicine Retired Lecturer, Ankara, TurkeyGürbüz Erdoğan, Ufuk University Faculty of Medicine, Ankara, TurkeyOlcay Gedik, Hacettepe University Faculty of Medicine Retired Lecturer, Ankara, TurkeySadi Güngoğdu, Istanbul University Cerrahpaşa Faculty of Medicine Retired Lecturer, İstanbul, Turkey

Hüsrev Hatemi, İstanbul, TurkeyŞazi İmamoğlu, Uludağ University Faculty of Medicine Retired Lecturer, Bursa, TurkeyTaylan Kabalak, Ege University Faculty of Medicine Retired Lecturer, İzmir, TurkeySenay Molvalılar, İstanbul, TurkeyCandeğer Yılmaz, Ege University Faculty of Medicine Retired Lecturer, İzmir, Turkey

Editorial BoardErsin Akarsu, Gaziantep University Faculty of Medicine, Gaziantep, TurkeyMüjde Aktürk, Gazi University Faculty of Medicine, Ankara, TurkeyFaruk Alagöl, Koç University Faculty of Medicine, İstanbul, TurkeyMaria Alevizaki, Athens University School of Medicine, Athens, Greeceİnan Anaforoğlu, Medical Park International Trabzon Hospital, Trabzon, TurkeyYalçın Aral, Bozok University Institute of Health Sciences, Yozgat, TurkeyAyşegül Atmaca, Ondokuz Mayıs University Faculty of Medicine, Samsun, TurkeyGöksun Ayvaz, Liv Hospital, Ankara, TurkeyÖmer Azal, Gulhane Education and Research Hospital, Ankara, TurkeyMustafa Kemal Balcı, Akdeniz University Faculty of Medicine, Antalya, TurkeyJ Paul Banga, University of Duisburg-Essen Faculty of Medicine, GermanyDavid Baylink, Loma Linda University, California, USAFahri Bayram, Erciyes University Faculty of Medicine, Kayseri, TurkeyErol Bolu, Memorial Atasehir Hospital, İstanbul, TurkeySteen Joop Bonnema, Odense University Hospital, DenmarkBekir Çakır, Yıldırım Beyazıt University Faculty of Medicine, Ankara, TurkeyMehtap Çakır, Kent Hospital, İzmir, TurkeyBerrin Çetinarslan, Kocaeli University Faculty of Medicine, Kocaeli, TurkeyAhmet Çorakçı, Ufuk University Faculty of Medicine, Ankara, TurkeyAbdurrahman Çömlekci, Dokuz Eylül University Faculty of Medicine, İzmir, TurkeySelçuk Dağdelen, Hacettepe University Faculty of Medicine, Ankara, TurkeyHatice Sebila Dökmetaş, Istanbul Medipol University Faculty of Medicine, İstanbul, TurkeyLeonidas H Duntas, Evgenideion Hospital, University of Athens, GreeceBelgin Efe, Eskişehir Osmangazi University Faculty of Medicine, Eskişehir, TurkeySevinç Eraslan, Dokuz Eylul University Faculty of Medicine, İzmir, TurkeyTomris Erbaş, Hacettepe University Faculty of Medicine, Ankara, TurkeyMehmet Erdoğan, Ege University Faculty of Medicine İzmir, TurkeyEda Ertörer, Başkent University Adana Dr. Turgut Noyan Hospital, Adana, TurkeyJohn W. Funder, Monash University, Victoria, AustraliaHossein Gharib, Mayo Clinic, Minnesota, USA

Sait Gönen, İstanbul University Cerrahpaşa Faculty of Medicine, İstanbul, TurkeyNilgün Güvener, Okan University Faculty of Medicine, İstanbul, TurkeySerdar Güler, Liv Hospital, Ankara, TurkeySevim Güllü,Ankara University Faculty of Medicine, Ankara, TurkeyAlptekin Gürsoy, Ankara Güven Hospital, Ankara, TurkeyZeliha Hekimsoy, Celal Bayar University Faculty of Medicine, Manisa, TurkeyLarry Jameson, Perelman School of Medicine Univ. Of Pennsylvania, Philadelphia, USAPınar Kadıoğlu, İstanbul University Cerrahpasa Faculty of Medicine, İstanbul, TurkeyAhmet Kaya, Selcuk University Meram Faculty of Medicine, Konya, TurkeyFahrettin Keleştimur, Health Institutes of Turkey, Ankara, TurkeyMustafa Kutlu, Gulhane Education and Research Hospital, Ankara, TurkeyPierre J. Lefebvre, University of Liege Faculty of Medicine, Liege, BelgiumMesut Özkaya, Dr. Ersin Arslan Training and Research Hospital, Gaziantep, TurkeyTae Sun Park, Chonbuk National University Medical School, Jeonju, KoreaAndreas F. H. Pfeiffer, Charité Universitaetsmedizin Berlin, GermanyGilles Russ, Pr Leenhardt La Pitie Salpetriere Hospital, Franceİlhan Satman, İstanbul University İstanbul Faculty of Medicine, İstanbul, TurkeyFüsun Saygılı, Ege University Faculty of Medicine, İzmir, TurkeyAlper Sönmez, Gulhane Education and Research Hospital, Ankara, TurkeyTümay Sözen, Hacettepe University Faculty of Medicine, Ankara, Turkeyİbrahim Şahin, İnönü University Faculty of Medicine, Malatya, TurkeyMustafa Şahin, Ankara University Faculty of Medicine, Ankara, TurkeyRefik Tanakol, İstanbul University İstanbul Faculty of Medicine, İstanbul, TurkeyKubilay Ükinç, Gayrettepe Florence Nightingale Hospital, İstanbul, TurkeyBetül Uğur Altun, Başkent University İstanbul Hospital, İstanbul, TurkeyAli Rıza Uysal, Ankara University Faculty of Medicine, Ankara, TurkeyKürşad Ünlühızarcı, Erciyes University Faculty of Medicine, Kayseri, TurkeyAyşe Kubat Üzüm, İstanbul University İstanbul Faculty of Medicine, İstanbul, TurkeyAnthony Weetman, The University of Sheffield, Sheffield, UKSema Yarman, İstanbul University İstanbul Faculty of Medicine, İstanbul, TurkeyBülent Okan Yıldız, Hacettepe University Faculty of Medicine, Ankara, Turkey


AIMS AND SCOPE

The Turkish Journal of Endocrinology and Metabolism is thepeer-reviewed periodical on clinical and experimental en-docrinology and metabolism diseases and related fields. It isthe official journal of the Society of Endocrinology and Meta-bolism of Turkey and is published quarterly (March, June,September and December) as hardcopy and an electronic jo-urnal at www.turkjem.org. The manuscripts are published inEnglish language.The journal publishes original research papers, reviews andcase reports which primarily focus on clinical endocrinology.The journal's aim is to be the essential reading for both en-docrinologists and clinical practitioners.

Open Access PolicyThe Turkish Journal of Endocrinology and Metabolism is anopen access journal. This journal provides immediate openaccess to its content on the principle that making researchfreely available to the public supports a greater global exc-hange of knowledge.Open Access Policy is based on rules of Budapest Open AccessInitiative (BOAI) http://www.budapestopenaccessinitiative.org/.Instructions for online manuscript submission, current issuesand archives of the journal can be found at www.turkjem.org.Please do not send manuscripts to the editorial office. Forother related issues you may contact the editorial office:

Subscription informationThe Turkish Journal of Endocrinology and Metabolism is dis-tributed free of charge to all endocrinology academicians andinstructors serving in our country. Access to full-text articlesof all issues of the journal is free at the journal's websitewww.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 manuscripts publis-hed in the Turkish Journal of Endocrinology and Metabolismreflect the views of the author(s) and are not the opinions ofthe editors, the editorial board and the publisher. The editors,editorial board and the publisher disclaim any responsibility orliability for such materials.

Advertising PolicyThe Turkish Journal of Endocrinology and Metabolismis Turkish Journal of Endocrinology and Metabolism receivesadvertising support for its print and electronic editions andmaintains editorial integrity through policies that define theEditorial/Advertiser relationship:

Print and electronic advertising does not influence editorialdecisions, and advertising is not an endorsement by the Pub-lisher, Editor, or the Editorial Board.

Turkish Journal of Endocrinology and Metabolism reservesthe right to refuse any advertising for any reason preservingthe conditions consistent with the journal’s high standards ofhealthcare editorial.

Editors have full and final authority for approving print and elect-ronic advertisements and for enforcing the advertising policy.

Print advertisements are interspersed throughout the jour-nal but do not interrupt the flow articles. The journal websitecontains online banner advertising.

To avoid implied endorsement by the Journal, the article, orthe authors of the article; advertisements are not adjacent toarticles addressing the product or its disease state.

The Publisher reserves the right to print the word “Advertise-ment” on any advertisement where it may not be clear, so rea-ders can distinguish readily between advertising and editorial.It is the responsibility of the advertiser and its agencies toadhere to appropriate legal requirements and regulationsFor all advertising information, please contact [email protected]

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 (Turk J Endocrinol Metab) is-sues papers on all aspects of endocrinology. The journal is the scientific pub-lishing organ of the Society of Endocrinology and Metabolism of Turkey and hasbeen published quarterly (March, June, September and December) since1997.In addition to original articles, case reports, review articles, letters tothe editor, educational articles, sections of question and answers, abstractsfrom literature and announcements of congresses/meetings are also pub-lished. Turkish Language Institution dictionary and orthography guide shouldbe taken 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 Endocrinologyand Metabolism. The authors should submit the signed copyright transfer formtogether with their manuscripts. Authors are responsible for the contents ofthe manuscript and accuracy of the references.The authors should guaranteethat their manuscripts has not been published and/or is not under considera-tion for publication in any other periodical. This requirement does not apply topapers presented in scientific meetings and whose summaries, not exceeding250 words, are published. In this case, however, the name, date and place ofthe meeting in which the paper was presented should be stated. The signedstatement of scientific contributions and responsibilities of all authors is re-quired.The Turkish Journal of Endocrinology and Metabolism does not charge any ar-ticle submission or processing charges.

Peer-reviewEditorial policies of the journal are conducted according to the rules advisedby Council of Science Editors and reflected in the Uniform Requirements forManuscripts Submitted to Biomedical Journals: Writing and Editing for Bio-medical Publication (http://www.icmje.org/).Submitted manuscripts are subjected for double-blind peer-review. The sci-entific board guiding the selection of the papers to be published in the Jour-nal consists of elected experts of the Journal and if necessary, selected fromnational and international experts in the relevant field of research. All manu-scripts are reviewed by the editor, section associate editors and at least threeinternal and external expert referees. All research articles undergo review bystatistical editor as well.Submitted manuscripts are also subjected for the evaluation of plagiarism, dupli-cate publication by automatic software. Authors are obliged to acknowledge if theypublished study results in full or in part in form of abstracts.The authors of the accepted manuscripts should be in consent that the editorand associate editors could make corrections without changing the main textof the paper.Manuscript format should be in accordance with Uniform Re-quirements for Manuscripts Submitted to Biomedical Journals: Writing and Ed-iting for Biomedical Publication (http://www.icmje.org/).For details: http://www.turkjem.org/pages/peer-review-ethic-5

General GuidelinesManuscripts can only be submitted electronically through the web site(http://www.turkjem.org) after creating an account. This system allows onlinesubmission and peer-review.The manuscripts are archived according to ICMJE-www.icmje.org, Index Medicus (Medline/PubMed) and Ulakbim-Turkish Medi-cine Index Rules. Rejected manuscripts, except artwork are not returned.For the experimental, clinical and drug human studies, approval by ethical com-mittee and statement on the adherence of the study protocol to the internationalagreements (Helsinki Declaration revised 2013 (https://www.wma.net/wp-con-tent/uploads/2016/11/DoH-Oct2013-JAMA.pdf) are required. In experimental an-imal studies, the authors should indicate that the procedures followed were inaccordance with animal rights (Guide for the care and use of laboratory animals,

https://www.nap.edu/read/12910/chapter/1) and they should obtain animal ethiccommittee approval. The Ethic Committee approval document should be sub-mitted to the Turkish Journal of Endocrinology and Metabolism together withthe manuscript.The approval of the ethic committee, statement on the adherence to internationalguidelines mentioned above and that the patients` informed consent is obtainedshould be indicated in the `Material and Method` section and is required for casereports whenever data/media used could reveal identity of the patient. The dec-laration of the conflict of interest between authors, institutions, acknowledge-ment of any financial or material support, aid is mandatory for authors submittingmanuscript and the statement should appear at the end of manuscript. Review-ers are required to report if any potential conflict of interest exists between re-viewer and authors, institutions.

Original ArticlesClinical research should comprise clinical observation, new techniques or labo-ratory studies. Provided that these manuscripts are written with lower-case let-ters, they should include the title in Turkish/English, the background and the keywords in Turkish/English, introduction, materials and methods, results (findings),discussion, references, tables, charts, pictures and they should be written in ac-cordance with Journal Agent rules. They should not exceed sixteen (A4) pages.It is recommended to present research articles and meta-analysis/systematic re-views article according to the guidelines on specific design of the study: random-ized studies (CONSORT), observational studies (STROBE), studies on diagnosticaccuracy (STARD), meta- analysis and systematic review (PRISMA, MOOSE) andother study designs (www.equator-network.org).

Author InformationThe name and the surname of the authors should be written without abbrevi-ation. The academic titles, the affiliations and the addresses of these affilia-tions should be clearly declared. Furthermore, the contact information of thecorresponding author should be entered to the system. Since e-mail will beused primarily for the contact with the authors, the e-mail of the correspon-ding author should be indicated. In addition the phone and the fax numbersshould be also indicated.

Title PageThis page should include the titles of the manuscript, key words and running ti-tles. In Turkish manuscripts the title in English should also take place. Likely,Turkish title should be mentioned for articles in foreign language. If the contentof the paper has been previously presented or its abstract has been published,an explanation should be made in this page about this issue. If there are anygrants and other financial supports by any institutions or firms for the study, in-formation must be provided by the authors.

AbstractTurkish and English summaries of the manuscript should take place in a man-ner that it will not exceed 250 words. The keywords should be written at theend of the summary. The references should not be cited in the summary sec-tion. As far as possible, use of abbreviations is to be avoided. If any abbrevi-ations are used, they must be taken into consideration independently of theabbreviations used in the text. The summary should be written with four run-ning titles.Purpose: The goal of the study should be clearly stated.Material and Method: The study should be defined, the standard criteria; itshould be also indicated whether the study is randomized or not, whether it isretrospective or prospective, the statistical method, if any, should be indicated.Results (Findings): The detailed result of the study should be given and thestatistical 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. Ifyou are not a native Turkish speaker, please re-enter your English keywords to thearea provided for the Turkish keywords. English key words should be providedfrom Medical Subject Headings (http://www.nlm.nih.gov/mesh/) while Turkishkey words should be provided from http://www.bilimterimleri.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 informa-tion.Materials and MethodsThe study design should be described, it should be indicated whetherit is interventional randomized or observational, whether it is retrospective orprospective, the number of trials, the characteristics, studied variables and spe-cific methods, the used statistical methods should be indicated. If any, it shouldbe 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 unfavorable as-pects and, they should be compared with literature.Study Limitations: Study Limitations and strengths, and directions for fur-ther 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. References shouldbe numbered according to the consecutive citation in the text. Referencesshould be indicated by parenthesis in the text. If there is Turkish Reference,attention should be paid to indicate this. Journal titles should be abbreviatedaccording to the style used in the Index Medicus. All the references, books,papers and similar articles should be cited as references should be writtenaccording to the rules of the International Committee of Medical Journal Ed-itors Uniform Requirements for Manuscripts Submitted to Biomedical Jour-nals (http://www.nlm.nih.gov/bsd/uniform_requirements.html).Journal: The surnames of the authors and the initial of authors’ names, thetitle of the paper, the title of the journal (the original abbreviation stated in thejournal), year, volume and the page numbers.Example: Collin JR, Rathbun JE. Involutional entropion: a review with evalu-ation of a procedure. Arch Ophthalmol. 1978;96:1058-1064.Book with a Single Author: The surname and the initial of the author, thetitle, chapter and section, the name of the editor, title of the book, place ofpublication, name of the printing house, year of print, page numbers.Example: Herbert L. Conjunctivitis, keratitis and infections of periorbital struc-tures. In: Armstrong D, Cohen J, eds. The Infectious Diseases (1st ed).Philadelphia; Mosby Harcourt; 1999;11;1-8.

Book Chapter: The surname and the initial of the author, chapter and section,name of the editor, title of the book, place of publication, name of the print-ing house, year of print, page numbers.Example: O’Brien TP, Green WR. Periocular Infections. In: Feigin RD, CherryJD, eds. Textbook of Pediatric Infectious Diseases (4th ed). Philadelphia; 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 within thetext and a brief descriptive caption should be written. The abbreviations usedshould be definitely explained in the figure’s legend. Especially, the text of tablesshould be easily understandable and should not repeat the data of the main text.Illustrations that already published are acceptable if supplied by permission ofauthors for publication. The details of the pictures should be distinguishable andthey should be recorded in JPEG format and in 500 pixels per inch at least.Case ReportsIt should consist of the title, summary, key words, summary in English, key-words, introduction, case report, discussion and references, the case or thecases should be worth to be presented, it should contribute to literature, andall of them should not exceed 5 papers in (A4) sizes.ReviewIt should include new topics, the own experiences of the author, if possible,and the references also. It should consist of the title in Turkish, the summary,the keywords, the title in English, the summary in English and the keywordsin English.Letters to the EditorThey should be assays in the “review” manner in various topics or the assaysconcerning the articles published in the Turkish Journal of Endocrinology andMetabolism with the contributive content or contents as questions that do notexceed 200 words.Scientific LettersThe manuscripts should be error-free in the summaries compiled from the ar-ticles in other journals, the author names (surname, name) should be written,the journal title should be written with its original abbreviation, its year shouldbe indicated and, the name and he surname of the translator should be indi-cated under the manuscript.Open Access PolicyThis journal provides immediate open access to its content on the principlethat making research freely available to the public supports a greater globalexchange of knowledge.

CorrespondenceAll correspondences can be done to the following postal address or to the fol-lowing e-mail address, where the journal editorial resides:Address: Ankara University Faculty of Medicine, Department of Endocrinologyand 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 Interna-tional Licence (CC BY 4.0)”


CONTENTS

Original Articles77 Importance of Magnetic Resonance Imaging in Pituitary Stalk Interruption Syndrome

Hipofiz Sapı Kesinti Sendromunda Manyetik Rezonans Görüntülemenin ÖnemiEren Gürkan, Yonca Anık, Mine Filiz Çizmecioğlu, Özlem Zeynep Akyay, Berrin Çetinarslan

85 Relation Between Night Eating Syndrome and Academic Grades Among University StudentsÜniversite Öğrencilerinde Gece Yeme Sendromu ve Akademik Derece Arasındaki İlişkiMehrunnisha Ahmad, Faizan Zaffar Kashoo, Mazen Alqahtani, Waqas Sami, Moattar Rizvi, Amira Bushra

92 Thyroid Dysfunction in Alopecia AreataAlopesi Areatada Tiroid DisfonksiyonuSara Saniee, Armaghan Ghareaghaji Zare, Afsaneh Radmehr

97 Effect of Vitamin D Treatment on Glycemic Control, Diastolic Functions,and Carotid Intima-Media Thickness in Patients with Type 2 Diabetes MellitusTip 2 Diabetes Mellitus Hastalarında Vitamin D Replasmanının Glisemik Kontrol,Diyastolik Fonksiyon ve Katoris İntima-Media Kalınlığı Üzerine EtkisiMehtap Evran Olgun, Gamze Akkuş, Mustafa Gök, Çağlar Emre Çağlıyan,İlker Ünal, Murat Sert, Tamer Tetiker

105 Evaluation of DNA Damage in Patients with a Neuroendocrine TumorNöroendokrin Tümörlü Hastalarda DNA Hasarının DeğerlendirilmesiZuhal Hamurcu, Fahri Bayram, Ümmühan Abdülrezzak, Hamiyet Dönmez Altuntaş,Figen Öztürk, Nesrin Delibaşı, Ender Doğan, Erdoğan Sözüer, Alper Yurci, Gülten Sezgin Can,Şebnem Gürsoy, Mustafa Kula, Metin Özkan

Review Article112 Low-Carbohydrate Diets and Type 1 Diabetes

Düşük Karbonhidratlı Diyetler ve Tip 1 DiyabetRukiye Bozbulut, Esra Döğer, Aysun Bideci, Orhun Çamurdan, Peyami Cinaz

June / Haziran 2019 Vol / Cilt: 23 No / Sayı: 2


Case Reports122 Insulin Washout in Fine-Needle Aspiration Fluid for Preoperative Diagnosis of Suspicious Lesion

in Patients with Insulinoma: A Case Reportİnsülinoma Hastalarında Şüpheli Lezyonun Preoperatif Tanısı İçinİnce İğne Aspirasyon Sıvısında İnsülin Yıkama: Bir Olgu SunumuMuhammet Kocabaş, Melia Karaköse, Mustafa Can, Hüseyin Ataseven, İlker Çordan,Mustafa Kulaksızoğlu, Feridun Karakurt

125 Adrenocorticotropic Hormon-Secreting Pheochromocytoma: A Rare Cause of Cushing’s SyndromeAdrenokortikotropik Hormon Salgılayan Feokromositoma: Cushing Sendromunun Nadir Bir NedeniBaşak Bolayır, Damla Okay, Müjde Aktürk, Murat Akın, Aylar Poyraz, Aydın Tuncer Sel,Banu Aktaş Yılmaz, Alev Eroğlu Altınova, Füsun Baloş Törüner, Nuri Çakır

130 Retroperitoneal Castleman Disease Mimicking Paraganglioma in a Patientwith Klinefelter Syndrome: A Case ReportKlinefelter Sendromlu Bir Hastada Paragangliomayı Taklit EdenRetroperitoneal Castleman Hastalığı: Bir Olgu SunumuSema Hepşen, Mustafa Özbek, Erkam Sencar, Pınar Akhanlı, Ata Türker Arıkök, Duray Şeker,İlknur Ünsal, Erman Çakal

135 Congenital Adrenal Hyperplasia as a Cause of Secondary Hypertension in Adults: Three CasesSekonder Hipertansiyon Sebebi Olarak Konjenital Adrenal Hiperplazi: Üç Vakaİnan Anaforoğlu, Ekrem Algün, Kerem Ersoy


EDITORIAL

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Wellbeing can be simply defined as the state of being comfortable, healthy or happy.Having this definition in hand thereare different strata’s in every society where wellbeing requires to be redefined. To elaborate;improvement in the patient'swell-being completely differs from a migrant’s wellbeing. It is a good point to keep in mind as a fact that in the measurementof wellbeing people should be at the center of assessment with their experiences. I addition, wellbeing should be assessedin terms of outcomes not on efforts or money spent. One other dimension is the distribution of wellbeing among individuals;knowing that wellbeing is strongly correlated to the other members within the societies that people live in.

Diabetes has become one of the largest public health problems today. Modern way of living decreasesto physical activity,leads to over nutrition and nutrition transitions that has changed lifestyles which reflect as a negative wellbeingon peoplein overall health. All cited factors not only affects quality of life in terms of health, but in terms of income earned attainment,shortening returns to human capital investment and the psychological discomfort created. Mainly during the twenty firstcentury people understood that wellbeing is not only determined by our average income, but how it is spent. If we closelyexamine the healthcare service we offer to our patients there is more room for prescribing decent living rules than medicinesand dosages. Impaired glucose tolerance in most cases is more important that the raise you expect in your profession. Awider definition of wellbeing entails, income and wealth, jobs and earnings housing, health status, work life balance,education and skills, civic engagement, environmental quality and lastly personal security.

To sum up a more holistic approach to metabolistic disorders are necessary for improving the wellbeing of people onfactors that indirectly hiders wellbeing and welfare society.

For this edition of TurkJEM we have a variety of researches pertaining: “Importance of Magnetic Resonance Imaging inPituitary Stalk Interruption Syndrome”, “Relation Between Night Eating Syndrome and Academic Grades Among UniversityStudents”, “Thyroid Dysfunction in Alopecia Areata”, “Effect of Vitamin D Treatment on Glycemic Control, DiastolicFunctions and Carotid Intima-Media Thickness in Patients with Type 2 Diabetes Mellitus” and “Evaluation of DNA Damagein Patients with a Neuroendocrine Tumor”. As a compilation we have the article of : “Low-Carbohydrate Diet and Type 1Diabetes”. Case studies contain: “Insulin Washout in Fine-Needle Aspiration Fluid for Preoperative Diagnosis of SuspiciousLesion in Patients with Insulinoma:”, “Adrenocorticotropic-Secreting Pheochromocytoma: A Rare Cause of Cushing’sSyndrome”, “Retroperitoneal Castleman Disease Mimicking Paraganglioma in a Patient with Klinefelter Syndrome” and“Congenital Adrenal Hyperplasia as a Cause of Secondary Hypertension in Adults: Three Cases”.

With all these researches and change of seasons again upon us as editor in chief I wish you all a very healthy and pleasantspring time.

WWiitthh mmyy bbeesstt rreeggaarrddss,,

NNiillggüünn BBaaşşkkaall MMDDEEddiittoorr--iinn--CChhiieeff


Address for Correspondence: Eren Gürkan, Mustafa Kemal University Faculty of Medicine,Department of Internal Medicine, Division of Endocrinology and Metabolism, Hatay, Turkey

Phone: +90 5446367484 E-mail: [email protected]: 27/05/2018 Received in revised form: 14/01/2019 Accepted: 03/03/2019 Available online: 01/04/2019

®Copyright 2019 by Turkish Journal of Endocrinology and Metabolism AssociationTurkish Journal of Endocrinology and Metabolism published by Türkiye Klinikleri

Importance of Magnetic Resonance Imagingin Pituitary Stalk Interruption Syndrome

Hipofiz Sapı Kesinti SendromundaManyetik Rezonans Görüntülemenin Önemi

Department of Internal Medicine, Division of Endocrinology and Metabolism, Mustafa Kemal University Faculty of Medicine, Hatay, Turkey*Department of Radiology, Kocaeli University Faculty of Medicine, Kocaeli, Turkey

**Department of Pediatric Endocrinology, Kocaeli University Faculty of Medicine, Kocaeli, Turkey***Clinic of Endocrinology and Metabolism, M. Akif İnan Training and Research Hospital, Şanlıurfa, Turkey

****Department of Internal Medicine, Division of Endocrinology and Metabolism, Kocaeli University Faculty of Medicine, Kocaeli, Turkey

Original ArticleTurk J Endocrinol Metab 2019;23:77-84

IntroductionPituitary insufficiency occurs because of iso-lated or multiple anterior pituitary hormonedeficiency (MPHD). The diagnosis of pitu-itary insufficiency is based on clinical fea-tures including growth retardation, central

hypothyroidism, or delay of secondary sex-ual characteristics. One of the rare causesof pituitary insufficiency is pituitary stalk in-terruption syndrome (PSIS). Although theetiology of PSIS remains unclear, organo-genesis defects caused by a traumatic birth

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Objective: To evaluate the importance of magnetic reso-nance imaging in the treatment and follow-up of patientswith pituitary stalk interruption syndrome. Material andMethods: The study included patients who were admittedto the Endocrinology and Metabolism Clinic of our hospitalfrom 2009 to 2013. Pituitary functions, growth and deve-lopment curves, and magnetic resonance imaging findingsof the patients were evaluated during the follow-up period.Results: The study included three men and two women.Four patients had multiple pituitary hormone deficiency. Allcases were diagnosed with short stature with respect totheir chronological age. Four patients were diagnosed withpituitary stalk interruption syndrome in their childhood. Iso-lated growth hormone deficiency was observed only in onepatient. Conclusion: Pituitary insufficiency should be con-sidered when evaluating pituitary stalk interruptionsyndrome. The presence of pituitary stalk and the change inthe size of the anterior pituitary gland are crucial magneticresonance imaging findings in monitoring pituitary functi-ons. In addition, evaluating the size of the pituitary glandmay allow early detection of pituitary insufficiency in adultpatients with pituitary stalk interruption syndrome.

Keywords: Hypopituitarism; ectopic neurohypophysis;isolated growth hormone deficiency;magnetic resonance imaging; short stature;pituitary stalk interruption syndrome

Amaç: Hipofiz sapı kesinti sendromu hastalarının takip vetedavisinde manyetik rezonans görüntülemenin önemini de-ğerlendirmektir. Gereç ve Yöntemler: Çalışma grubumuz,2009-2013 yılları arasında endokrinoloji ve metabolizmahastalıkları polikliniğimize başvuran hastalardan oluşmak-tadır. Hasta takibinde hipofiz fonksiyonları, büyüme ve ge-lişme eğrileri ve manyetik rezonans görüntüleme bulgularıdeğerlendirmeye alındı. Bulgular: Çalışma grubumuz üçerkek ve iki kadın hastadan oluşmaktadır. Dört hastamızdaçoklu hipofizer hormon yetmezliği saptandı. Hastalarımızınhepsi kronolojik yaşlarına göre kısa boylu olmaları nedeniile değerlendirilirken tanı konuldu. Dört hastamıza çocuk yaşgrubunda tanı konulmuştu. Sadece bir hastada izole bü-yüme hormon eksikliği mevcuttu. Sonuç: Hipofiz sapı ke-sinti sendromlu olguları değerlendirirken hipofiz yetmezliğidikkate alınmalıdır. Manyetik rezonans görüntülemede hipo-fiz sapının varlığı ve ön hipofiz bezinin büyüklüğünün zamaniçinde değişimi, hipofiz bezinin fonksiyonlarının takibindeönemlidir. Ayrıca, hipofiz sapı kesinti sendromlu erişkin yaş-taki hastalarda, hipofiz bezinin büyüklüğünün değerlendi-rilmesi, hipofiz yetmezliğinin erken tanısına olanak sağlaya-bilmektedir.

Anahtar kelimeler: Hipofiz yetmezliği; ektopik nörohipofiz;izole büyüme hormon yetmezliği;manyetik rezonans görüntüleme;boy kısalığı; hipofiz sapı kesinti sendromu

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https://orcid.org/0000-0002-3118-4549

https://orcid.org/0000-0002-8041-8161

https://orcid.org/0000-0001-7340-6368

https://orcid.org/0000-0003-4608-4433

https://orcid.org/0000-0002-6768-2574

and by genetic and environmental factorsare supposed to play a role (1-4). The clini-cal features and magnetic resonance imag-ing (MRI) findings of PSIS have been knownfor a long time. The characteristics of MRIfindings in PSIS include a decrease in thesize of the anterior pituitary gland, increasein or disappearance of the signal in the ec-topic location of the neurohypophysis, hy-poplasia, or absence of the pituitary stalk(5-8). This study aimed to investigate theimportance of MRI in the treatment and fol-low-up of patients with PSIS.

Material and MethodsThis study included patients with PSIS whowere admitted to the Endocrinology and Me-tabolism Clinic of our hospital from 2009 to2013. In addition, this is a retrospectiveclinical observation study; therefore, noethics committee approval was obtained.But, this study was carried out adherence toguidance for ethics review of health-relatedresearch with human participants of theWHO (2011), and the Declaration of Helsinkiof the World Medical Association (2013). Thehormonal levels having a role in the growthand development processes and MRI find-ings were evaluated. Growth hormone (GH)deficiency was demonstrated with at leasttwo growth hormone stimulation tests (withinsulin, clonidine, or L-dopa). Cortisol defi-ciency was determined on the basis of themeasurement of cortisol level in the sametests or the measurements of baselineplasma adrenocorticotropic hormone (ACTH)and cortisol levels, which were performed inthe morning (at 08:00 am). A low-doseACTH stimulation test was performed in re-quired cases. Thyroid hormone deficiencywas determined on the basis of low serum-free thyroxine level that was incompatiblewith the thyroid-stimulating hormone level(<5 µU/mL). Gonadal insufficiency was de-termined by measuring estradiol and testos-terone in relation to follicle-stimulatinghormone and luteinizing hormone.During childhood and adolescence, the diag-nosis of GH insufficiency is based on the fol-lowing criteria (9): 1) height of a child beingless than 2 standard deviation (SD) or 3percentile as compared with a healthy chil-dren; 2) annual growth rate of less than 7cm/year (for those less than three years), of

less than 5 cm/year (from three years to pu-berty), and of less than 6 cm/year (for pu-berty); 3) child-like facial appearance andsmall and short symmetrical body structure;4) normal intelligence; 5) backbone age rel-ative to chronological age; and 6) theplasma level of GH being less than 6 µg/L inat least two GH stimulation tests and theplasma level of insulin-like growth factor 1(IGF-1) being lower than the normal rangeaccording to age and gender. In adult pa-tients, the diagnosis of GH deficiency wasbased on the plasma level of GH (less than3 µg/L) in insulin tolerance test and IGF-1being lower than the normal range accord-ing to age and gender (10).

Magnetic Resonance Imaging TechniqueAll patients were scanned in the supine po-sition using 3 Tesla MRI systems with a headcoil. The images were obtained in the sagit-tal and coronal planes using T1, T2 andsagittal fat-suppressed T1 sequences, coro-nal planar dynamic imaging, and postcon-trast T1 sagittal and coronal planes. Thecross-sectional thicknesses were 1 mm indynamic images and 3 mm in other se-quences. The assessments of the imageswere performed by the same neuroradiolo-gist. The anterior pituitary gland, pituitarystalk size, and location of the neurohypoph-ysis, as well as the presence and localizationof accompanying malformations, were as-sessed. Normal height of the pituitary glandwas accepted as 6 mm (upper surface plainor slightly concave) for patients less than 12years of age, 10 mm for patients in puberty(upper surface convex, more convex ingirls), 9 mm for women and 8 mm for menin young adulthood, and 12 mm for womenin gestation (11). Hypoplastic pituitary glandcould be described as a half-moon-shapedgland observed on the sella with a maximummeasurable height of 2 mm. Radiologicalempty sella was defined in cases for whichthe pituitary gland was not visible but thecerebrospinal fluid cavity invaded the sella.

ResultsThis study included five patients with PSIS:Case 1: an 18-year-old man diagnosed withMPHD while being examined for shortstature; Case 2: an 18-year-old man diag-nosed with MPHD while being examined be-

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cause of short stature at the age of eightyears; Case 3: a 27-year-old woman diag-nosed with MPHD as a result of the evalua-tion after primary amenorrhea; Case 4: a19-year old woman diagnosed with isolatedgrowth hormone deficiency (IGHD) whilebeing examined because of short stature atthe age of ten years; and Case 5: a man di-agnosed with hypogonadism and shortstature at the age of 35 years. Therefore,patients were diagnosed with short staturewith respect to their chronological age.MPHD was observed in our four patients, ex-cept for Case 4. The features of the patientsare presented in Table 1. One case of IGHDand three cases of MPHD were diagnosedduring childhood. MRI findings of the pa-tients according to the type of their hormone

deficiency are presented in Table 2. Accord-ingly, midline defect was observed only inone patient with MPHD. Ectopic neurohy-pophysis was present in all patients. Adeno-hypophysis size was normal from thechildhood of the patient with IGHD. In addi-tion, there was a thin stalk in the same pa-tient (Table 3).In all patients, the neurohypophysis was de-tected in an ectopic location. In addition, itwas localized in the hypothalamus or its sur-roundings in Cases 1, 2, and 3 (Figure 1,Figure 2, Figure 3). Moreover, it was in thepituitary stalk in Case 4 (Figure 4) and waslocalized in the surrounding of the hypothal-amus in Case 5 (Figure 5). In most of ourcases, the height of adenohypophysis wasconsiderably decreased. Adenohypophysis

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Turk J Endocrinol Metab Gürkan et al.2019;23:77-84 Importance of MRI in PSIS

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GH: Growth hormone; FSH: Follicle-stimulating hormone; LH: Luteinizing hormone; ACTH: Adrenocorticotropic hormone; TSH:Thyroid stimulating hormone.

Case Number Age Sex Hormone deficiency

Case 1 18 Male GH, FSH, LH, ACTH, TSH


Case 3 27 Female GH, FSH, LH, ACTH, TSH

Case 4 19 Female GH


Table 1. Age, gender, and pattern of hormone deficiency in the studied cases.

IGHD: Isolated growth hormone deficiency; MPHD: Multiple pituitary hormone deficiencies; EPPBS: Ectopic posterior pituitary brightspot.

IGHD MPHD

Hypoplastic pituitary gland 0 4

Absent stalk 0 4

Thin stalk 1 0

EPPBS (median eminence) 0 4

EPPBS (stalk) 1 0

Midline brain anomalies 0 1

Table 2. Distribution of magnetic resonance imaging findings according to the type of hormonal deficiency in thestudied cases.

IGHD (n=1) MPHD (children) (n=3) MPHD (adult) (n=1)

Adenohypophysis size Normal Small Small

Visualization of a thin stalk Yes No No

EPPBS (Median eminence) Normal Yes Yes

EPPBS (stalk) Yes No No

Table 3. Features of the studied cases according to the magnetic resonance imaging findings.

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Figure 1: a) Coronal post-contrast T1 section, b) sagittal fat-suppressed T1 section. Hyperintensity of the neu-rohypophysis is observed in the vicinity of the ectopically located hypothalamus. Sella has not developed, the he-ight of the adenohypophysis has markedly decreased, and the pituitary stalk is not visible. Cerebellar tonsils areectopic and the Arnold-Chiari type 1 malformation is observed (Case 1).

a b

Figure 2: a) Coronal post-contrast T1 section, b) Sagittal fat-suppressed T1 section. Pituitary stalk does not ap-pear in the coronal section. Neurohypophysis hyperintense signal is observed in the vicinity of the hypothalamus insagittal section. The height of adenohypophysis is observed to be decreased in both sections (Case 2).

a b

Figure 3: a) Coronal post-contrast T1 section, b) Sagittal fat-suppressed T1 section. The pituitary gland is not vi-sible in coronal section. Neurohypophysis is ectopically located in the vicinity of the hypothalamus in the sagittalsection (Case 3).

a b

Figure 4: a) Coronal post-contrast T1 section, b) Sagittal fat-suppressed T1 section. The neurohypophyseal hype-rintense signal is observed to be ectopic and located posterior to the pituitary stalk in the sagittal section. In addi-tion, the pituitary stalk is observed to be long and thin in the coronal section (Case 4).

a b

was not observed only in Case 3 (Figure 3),and it was normal in size in Case 4 (Figure4). Pituitary stalk was not observed in pa-tients with MPHD (Figure 1, Figure 2, Figure3 and Figure 5). Long and thin pituitary stalkwas noted in the patient with IGHD (Figure4). Moreover, in Case 1, cerebellar tonsilswere ectopic and Arnold-Chiari type 1 mal-formation was observed (Figure 1).

DiscussionThe pituitary gland originates from differentembryonic structures and comprises adeno-hypophysis and neurohypophysis (12). Fac-tors such as genetic defects, pituitary stalkinjury, and perinatal trauma may lead to anincomplete downward migration of neurohy-pophysis which in turn results in infusion de-fects (13). Several hypotheses have beenproposed to explain PSIS. The first hypoth-esis is exposure of the pituitary stalk to is-chemia during breech (14). In this study,four of five patients were born by breech.However, the lack of hypoxic damage to theorgans and the structures having the samevascular support, as well as the lack ofpathological evidence, weakens the first hy-pothesis. Second, head trauma duringbreech delivery may cause mechanical rup-ture of the pituitary stalk and stretching ofthe pituitary stalk, pituitary gland, and mo-bile brain structures. This hypothesis seemsto be widely accepted because of the certainincidence of breech delivery in the publishedstudies. Most of these study groups have nogenetic analysis. In addition, MPHD devel-ops in patients with breech presentationwho were delivered via cesarean section(15); this also weakens the second hypoth-

esis. The third hypothesis, on which a con-sensus has been most commonly reached,is congenital hypoplasia or dysplasia be-cause of genetic or organogenesis defects ofthe pituitary gland and resulting pituitary in-sufficiency (2,15).In the study by Bar et al. (16), severe hor-monal abnormalities and radiological findingswere reported in the PSIS cases diagnosedduring the neonatal period. In addition, theyhave reported MPHD at a rate of 100% and anonvisible anterior pituitary lobe at a rate of33% in this group. In this study, MPHD waspresent in four of five childhood cases. PSIS isassociated with several midline malforma-tions such as septal agenesis, partial corpuscallosum agenesis, aqueductal stenosis, opticnerve hypoplasia, and the Arnold-Chiari type1 malformation. The presence of extra-pitu-itary malformations is not associated withmore severe hormonal and radiological char-acteristics (16, 17). In this study, the patientwith Arnold-Chiari type 1 malformation wasconsistent with the literature.In a study on the relationship between pitu-itary gland visibility and pituitary hormonedeficiency, 74 patients with PSIS in whom themost common presenting symptoms wereshort stature and absence of pubertal devel-opment were evaluated and panhypopitu-itarism was reported to be considerably morecommon in those with an invisible pituitarystalk (18). Accordingly, it has been suggestedthat invisible pituitary stalk on contrast-en-hanced pituitary MRI may be an indicator ofclinical severity in PSIS (18-20). The absenceof the pituitary stalk in our case series wasthe most crucial indicator for MPHD. Thisfinding was consistent with those reported in

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Figure 5: a) Coronal post-contrast T1 section, b) sagittal fat-suppressed T1 section. The height of the adenohy-pophysis has decreased extremely and the neurohypophyseal hyperintensity signal can be observed in the ectopiclocation adjacent to the hypothalamus in sagittal section. Pituitary stalk is observed to have interrupted in coronalsection (Case 5).

a b

the previous studies. Maghnie et al. (21) andGenovese et al. (22) emphasized the impor-tance of contrast injection to obtain an opti-mal image of a thin pituitary stalk. Theyobserved that the pituitary stalk could beoverlooked with the use of unenhanced pitu-itary MRI. In cases of isolated pituitary hor-mone deficiency (IPHD), the visualization ofthe stalk in contrast-enhanced images is con-sidered a sign of partial preservation of thehypothalamo-hypophyseal portal blood (23).In our IGHD case, the integrity of the pitu-itary stalk was observed to be preserved.In addition to the clinical findings related tothe absence of the pituitary stalk, thinningof the pituitary stalk demonstrates diseaseprogression from IPHD to MPHD and the an-terior pituitary function is associated withthe changes in the size of the anterior pitu-itary gland. These may allow early detectionof hormone deficiency, particularly duringpuberty (17, 24). In this study, PSIS diag-nosis was established in adulthood in Case5, and all these radiological findings weredemonstrated in this case.

In a large series of PSIS, clinical and hor-monal features and neuroradiological ap-pearances, as well as PIT1, PROP1, HESX1,LHX3/LHX4, PROKR, TGIF, OTX2, and SOX3mutations, which were thought to affectthese characteristics, were investigated.LHX4 and HESX1 mutations were detectedin a group with familial or consanguineousmarriage. The possible genetic variants mayoccur during early embryogenesis and aredemonstrated in Figure 6 (25, 26).In a study conducted to demonstrate an un-derlying genetic etiology in PSIS, GPR161mutations were detected in the mutationanalysis of two affected siblings and one un-affected sibling in a consanguineous family.HESX1, LHX4, OTX2, SOX3, and PROKR2mutations were detected in approximately5% of patients with PSIS (27). The multi-genic pattern was found in PSIS usingwhole-exome sequencing technique (28).According to our opinion, PSIS has multi-genic etiology. The evidence is needed toshow the functional significance of the genesmentioned in the published studies.

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Figure 6: A guide for planning genetic screening for hypopituitary patients based on clinical findings (26).

Study limitationOne of the main limitations of this study isthe lack of genetic evaluation. Another limi-tation is the small sample size. However, ourrare group of patients with PSIS is interest-ing as they have different findings.

ConclusionPSIS is rare but a crucial syndrome becauseof its clinical outcomes. MRI findings willcontinue to assist in the diagnosis and fol-low-up of patients with PSIS until the func-tional significance of the genes that havebeen detected is understood. Therefore, pi-tuitary insufficiency should be consideredwhen evaluating patients with PSIS. Whenthe MRI findings are consistent with PSIS,the presence of pituitary stalk and change inthe size of the anterior pituitary gland areaccepted, as crucial imaging findings reflectthe pituitary gland function. Evaluating thesize of the pituitary gland may provide earlydetection of anterior pituitary hormone defi-ciency in adult patients with PSIS.

Source of FinanceDuring this study, no financial or spiritualsupport was received neither from any phar-maceutical company that has a direct con-nection with the research subject, nor froma company that provides or produces med-ical instruments and materials which maynegatively affect the evaluation process ofthis study.

Conflicts of interestThe authors declare no conflicts of interestwith respect to the research, authorship,and/or publication of this article.

Authorship ContributionsIdea/Concept: Eren Gürkan, Yonca Anık;Design: Eren Gürkan, Özlem Zeynep Akyay,Berrin Çetinarslan, Mine Filiz Çizmecioğlu;Control/Supervision: Eren Gürkan, YoncaAnık, Mine Filiz Çizmecioğlu; Data Collectionand/or Processing: Eren Gürkan, ÖzlemZeynep Akyay, Yonca Anık, Berrin Çeti-narslan, Mine Filiz Çizmecioğlu; Analysisand/or Interpretation: Eren Gürkan, YoncaAnık, Filiz Çizmecioğlu; Literature Review:Eren Gürkan, Mine Filiz Çizmecioğlu, ÖzlemZeynep Akyay, Berrin Çetinarslan; Writing

the Article: Eren Gürkan, Yonca Anık; Criti-cal Review: Eren Gürkan, Yonca Anık; Ref-erences and Fundings: Eren Gürkan, ÖzlemZeynep Akyay, Berrin Çetinarslan; Materials:Eren Gürkan.

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Address for Correspondence: Faizan Zaffar Kashoo, Department of Physical Therapy and Health Rehabilitation,College of Applied Medical Sciences, Majmaah University, Majmaah 11952, Saudi Arabia

Phone: 00966538149226 E-mail: [email protected]: 29/09/2018 Received in revised form: 20/02/2019 Accepted: 03/03/2019 Available online: 01/04/2019


Relation Between Night Eating Syndrome andAcademic Grades Among University Students

Üniversite Öğrencilerinde Gece Yeme Sendromu veAkademik Derece Arasındaki İlişki

Department of Nursing, College of Applied Medical Sciences, Majmaah University, Majmaah, Saudi Arabia*Department of Physical Therapy and Health Rehabilitation, College of Applied Medical Sciences, Majmaah University, Majmaah, Saudi Arabia

**Department of Biostatistics, College of Medicine, Majmaah Saudi Arabia***Department of Medical Physiology, College of Applied Medical Sciences, Majmaah University Majmaah, Province Riyadh, Kingdom of Saudi Arabia


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Objective: Night eating syndrome refers to a condition, cha-racterized by night hyperphagia and nocturnal ingestions thatare often accompanied by an altered sleep and mood pattern.It is very common among students, who become prone tonight eating syndrome owing to sleep deprivation and noc-turnal eating habits. Adherence to such behavior increasesthe chances of poor higher mental function and an altered cir-cadian rhythm, eventually resulting in compromised learningand academic failures. The present study intended to explorethe relationship between night eating syndrome, grade pointaverage, age, and body mass index of students attending col-lege. Material and Methods: The present study was basedon a cross-sectional correlation design to find a correlationbetween night eating syndrome and academic achievementamong students studying in the College of Applied MedicalSciences. Students who participated in the study were askedto complete a paper-based Night Eating Syndrome Diagnos-tic Questionnaire. The participants were categorized into fourgroups, namely, non-night eating syndrome, mild-night ea-ting syndrome, moderate-night eating syndrome, and full-night eating syndrome based on the scores they received inthe questionnaire. The registration department of the Univer-sity provided the grade point average to the students at theend of the academic semester. Results: The questionnaireresults categorized 86 students (35.7%) into mild night eatingsyndrome, 32 (13.3%) into moderate night eating syndrome,and 23 (9.5%) into full night eating syndrome. An increase inthe body mass index was found to be associated with nighteating syndrome, with an odds ratio of 1.113 (95% confi-dence interval, 1.071-1.156), Wald χ2 (1)=29.918, p<0.001.A decrease in the grade point average was associated withnight eating syndrome, with an odds ratio of 2.1876 (95%confidence interval, 1.765-3.886), Wald χ2 (1)=33.318,p<0.001. Conclusion: The present study concluded thatnight eating syndrome exerts detrimental effects on the aca-demic performance of university students.

Keywords: Night eating syndrome; grade point average;body mass index; eating disorder

Amaç: Gece yeme sendromu, genellikle ruh hâli ve uykupaterninde değişikliğin eşlik ettiği gece hiperfajisi ve gecebeslenmeleri ile karakterize bir durumu ifade eder. Uykuyoksunluğu ve gece yeme alışkanlıkları nedeni ile geceyeme sendromuna yatkın hâle gelen öğrenciler arasında çokyaygındır. Bu tür davranışların sürekliliği, yüksek zihinsel iş-levlerde zayıflık ve sirkadiyen ritimde değişiklik riskini artı-rır ve sonunda öğrenmede baskılanmaya ve akademikbaşarısızlıklara neden olur. Bu çalışmada, üniversiteye gidenöğrencilerde gece yeme sendromu, not ortalaması, yaş vebeden kitle indeksi arasındaki ilişkinin incelenmesi amaçla-mıştır. Gereç ve Yöntemler: Bu çalışmada, Uygulamalı TıpBilimleri Üniversitesinde okuyan öğrencilerin akademik ba-şarısı ve gece yeme sendromu arasında bir korelasyon bul-mak için kesitsel korelasyon tasarımı kullanılmıştır.Çalışmaya katılan öğrencilerden, basılı hâldeki Gece YemeSendromu Tanı Anketi’ni doldurmaları istenmiştir. Katılım-cılar ankette aldıkları puanlara gore non-gece yeme sen-dromu, hafif gece yeme sendromu, orta gece yemesendromu ve tam gece yeme sendromu olmak üzere dörtgruba ayrılmışır. Üniversitenin kayıt bölümü, akademikdönem sonunda öğrencilere not ortalaması vermiştir. Bul-gular: Anket sonuçları 86 (%35,7) öğrenciyi hafif geceyeme sendromu, 32 (%13,3) öğrenciyi orta gece yeme sen-dromu ve 23 (%9,5) öğrenciyi tam gece yeme sendromuolarak kategorize etmiştir. Beden kitle indeksindeki artışgece yeme sendromu ile ilişkili bulunmuştur [oddsoranı=1,113 (%95 güven aralığı, 1,071-1,156), Wald χ2

(1)=29.918, p<0,001]. Not ortalamalarındaki azalma geceyeme sendromu ile ilişkili bulunmuştur [Odds oranı=2,1876(%95 güven aralığı, 1,765-3,886), Wald χ2 (1)=33.318,p<0,001]. Sonuç: Bu çalışmada, gece yeme sendromununüniversite öğrencilerinin akademik performansı üzerinde za-rarlı etkileri olduğu sonucuna varılmıştır.

Anahtar kelimeler: Gece yeme sendromu; not ortalaması;beden kitle indeksi; yeme bozukluğu

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https://orcid.org/0000-0001-7948-1190

https://orcid.org/0000-0003-2006-9032

https://orcid.org/0000-0003-3138-1056

https://orcid.org/0000-0002-5729-2919

https://orcid.org/0000-0003-4498-370X

https://orcid.org/0000-0001-8424-7163

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IntroductionNight eating syndrome (NES) was first de-fined by Stunkard among obese individualswho showed resistant to weight loss (1).People who suffer from NES exhibit a non-normative eating behavior and an alteredcircadian pattern of food intake (2). Studieson the prevalence of NES among differentage groups revealed that the risk of devel-oping NES is higher among the young pop-ulation as compared to people belonging toother age groups (3, 4). Students face ahigh level of stress, accompanied by sleepdeprivation and irregular meal timings,which increase the risk of developing NES.A study found the prevalence of NES to behigher in patients who were already suffer-ing from depression and anxiety (5). It hasbeen observed that these individuals useeating as a coping strategy during a stress-ful situation, which, in turn, may result inobesity. There are other eating disorders,such as binge eating disorder (BED), bulimianervosa (BN), and anorexia nervosa (AN),that are related to the impulsive behavior ofan individual toward eating (6). Eating dis-orders, such as Binge eating, are seldomconfused with NES. Although both areclearly distinguishable, e.g., Binge eating isan eating disorder associated with rapidconsumption of large quantity of food (7),whereas NES is related to consumption offood at night with an altered sleep and moodpattern. Allison et al. (8) proposed a diag-nosis criterion, that is, consumption of atleast 25% of the daily meal after theevening meal and two episodes of nocturnaleating per week, led to significant distress.Moreover, at least three of the following cri-teria should be present, morning anorexia,surge to eat between dinner and sleep; in-somnia, a belief that the individual needs toeat to fall asleep; and worsening of mood inthe evening and an altered pattern of eatinglasting for 3 months. NES is now included inthe Diagnostic and Statistical Manual ofMental Disorders, fifth edition with completediagnostic criteria (9).Prevalence of NES in the general populationis approximately 1.1 to 1.5% (10). Theprevalence is high among the people with ahigher BMI, that is, approximately 10%among those in the second and third stagesof obesity. NES displays a positive correla-

tion with body weight in several studies (11-14). There exists sizeable evidence in the lit-erature on the relationship between NES,anxiety, depression, and BMI (15). A recentprospective study revealed that no clear as-sociation exists between obesity and NES(16) although several clinical trials havelinked NES directly to obesity (17, 18). Thisdisparity could be due to the variations in di-agnostic criteria of NES and population char-acteristics.Researchers worldwide have identified cer-tain factors believed to be affecting the ac-ademic performance of students. Thesecould be categorized into academic, demo-graphic, cognitive and psychosocial vari-ables (18). A psychosocial variable ofacademic achievements could be the pres-ence of NES among students. To the best ofour knowledge, no study has been publishedon the relation between the NES and gradepoint average (GPA), making it essential toexplore whether NES affects the academicachievements of students.

Material and MethodsA cross-sectional correlational design wasused to find any association between vari-ables such as age, NES, obesity, and GPA ofstudents. The study was done inagreement with the principles described inthe Declaration of Helsinki.

SubjectsStudents studying in the College of AppliedMedical Sciences, Majmaah Universityagreed to participate in the study. The ethi-cal clearance for the study was obtainedfrom the Ethical Committee of the College ofApplied Medical Sciences, Majmaah Univer-sity with a letter no. MUREC-Dec.16/COM-2016/12) dated 11th December 2016.

Inclusion criteriaInclusion criteria involved students currentlystudying at the College of Applied MedicalSciences, Majmaah University.

Exclusion CriteriaStudents with other eating disorders, suchas BED, BN, and AN, were excluded from thestudy. Out of a total of 253 students, only241 completed the study, 12 students wereexcluded due to various reasons (3 partici-

Ahmad et al. Turk J Endocrinol MetabEffect of NES on Academic Achievements 2019;23:85-91

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pants suffered from BED and other 9 did notcomplete the questionnaire), with the re-sponse rate of 95.3%.

Response from participantsPhase 1: A pilot study on five students re-vealed 99.9% intra- and inter-rater reliabil-ity. The test was introduced in its originalform (English language). The study wasconducted at the beginning of the academicsemester (Jan 2017–June 2018) to avoidanxiety and stress among students due toexaminations. A physiotherapist assessedweight, height, and age of students whoparticipated in the study. Pen- and paper-based Night Eating Syndrome DiagnosticQuestionnaire (NESDQ) (19) was providedto students who were asked to fill the formconfidentially to avoid peer influence andpreserve the anonymity of informationamong students. NESDQ is a valid and reli-able scoring tool, as shown to have a strongpositive correlation with original Night eatingQuestionnaire (20) developed by Allison etal. The NESDQ is designed to obtain infor-mation based on six criteria for the diagno-sis of NES. Participants who completed theNESDQ were placed into four categories,namely, normal, mild, moderate, and full.The NESDQ consists of 21 questions relatedto eating and sleeping, and it takes approx-imately 15 min to complete it. It enquiresabout the perception of a person as nighteater, the frequency of night eating, andpsychosomatic distress associated withnight eating. Several questions in the ques-tionnaire are dichotomized in nature such asyes or no type and some are open-endedquestions. The questionnaire contains ques-tions related to semester, general medicalstatus, smoking history, previous suicide at-tempts, and questions related to BED.Phase 2: University registration departmentprovided the GPA of participants at the endof the academic semester (Jan 2017-June2018).The data were entered and analyzed usingSPSS version 25.0. Frequencies and per-centages were reported for qualitative vari-ables. Normality of the data was checked byone sample Kolmogorov-Smirnov test. Mean+ inter-quartile range (IQR) was reportedfor non-normally distributed quantitativevariables. Correlation between BMI, age,

NES, and GPA was assessed through Spear-man‘s rho correlation. The Kruskal–Wallis Htest was applied to compare NES with quan-titative variables. Ordinal logistic regressionanalysis was performed to identify the pre-dictors for NES. A p-value of <0.05 was con-sidered statistically significant. Spearman’srank-order correlation was considered to de-termine the relationship between NES andage, and BMI and GPA.

Results

Demographic data and sample characteristicsThe number of participants enrolled in thecurrent study was 241. The total number ofmale students was 135 (56%) and femalestudents were 106 (44%). The median ageof the participant was 21.00±2.06, BMI25.73±6.82, and GPA 3.34±0.68. Only 100(41.5%) participants were reported as notsuffering from NES. However, 141 (58.5%)participants were found to be suffering fromNES; they were further classified as mildNES (86, 35.7%), moderate NES (32,13.3%), and full NES (23, 9.5%).

Statistical analysisThe data for age, BMI, and GPA were notdistributed generally, as evident from theone sample K-S test. The distribution of datafor male and female students showed thatthere was a significant difference betweenthe age (p=0.025) and BMI (0.036). How-ever, no significant change in the GPA(0.517) between the selected sample ofmale and female students was detected.There was a strong, positive correlationbetween NES and BMI, which was statisti-cally significant (rs=0.385, p<0.001). Also,a strong, statistically significant, negativecorrelation existed between NES and GPA(rs=-0.320, p<0.001). There was no signif-icant correlation between NES and age.Kruskal-Wallis H test showed that there wasa statistically significant difference in BMIbetween the different subgroups of NES, c2(2)=79.57, p<0.001. Furthermore, therewas a statistically significant difference inthe GPAs between the different subgroupsof NES, c2 (2)=25.55, p<0.001 (Table 1).Tukey’s HSD post-hoc tests were conductedfor multiple comparisons between NES andage, and BMI and GPA. Mean scores for BMI

Turk J Endocrinol Metab Ahmad et al.2019;23:85-91 Effect of NES on Academic Achievements

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were statistically significantly different be-tween non-NES and mild NES (p=0.0001)and non-NES and moderate NES (p<0.0001),but not between non-NES and full NES(p=0.976). Mean GPA scores were statisticallysignificantly different between non-NES andmoderate NES (p<0.0001) and non-NES andfull NES (p<0.0001); however, the differencebetween non-NES and mild NES was not sta-tistically significant (p=0.752; Table 1).The regression analysis was performed bycategorizing non-NES as the referencegroup and other forms of NES (mild, mod-erate, and severe) as the second group. Anincrease in the BMI was associated withNES, with an odds ratio (OR) of 1.113 (95%CI, 1.071-1.156), Wald c2 (1)=29.918,p<0.001. A decrease in the GPA was associ-ated with NES, with an OR of 2.1876 (95%CI, 1.765-3.886), Wald c2 (1)=33.318,p<0.001 (Table 2).

DiscussionThe aim of the present study was to find theassociation between the presence of NESand the academic achievement of students.Our study reported 50% of students to besuffering from NES, which is considerablyhigher as compared to the prevalence in thegeneral population. This difference could beattributed to the fact that college studentshave a tendency to studying late at nightthan the general population, resulting in ahigher level of stress. Another reason for thehigher level of NES in our study could be thesmall sample size and cultural differences.The prevalence of NES is approximately 1%to 2% in the general population (21). Astudy (22) has reported the prevalence ofNES among college students to be 4.2-5.7%. Students tend to study and work lateat night, which, in turn, causes food con-sumption at night; this finally leads to skip-

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*NES: night eating syndrome, BMI: body mass index, GPA: grade average points, n: number of subjects **ANOVA (Analysis of Va-riance) was performed and Tukey's HSD post-hoc tests were used for multiple comparisons. In multiple comparisons: #BMI was sta-tistically significantly different between Non-NES and Mild NES and between Non-NES and Moderate NES, but not between Non- NESand full NES. #GPA scores were statistically significantly different between Non-NES and moderate NES and between Non-NES andfull NES.

Variable Night Eating Syndrome Groups n mean±SD p**

Age Non NES* 100 21.04±2.44 0.319

Mild NES 86 20.95±2.16

Moderate NES 32 21.47±1.81

Full NES 23 20.43±2.09

BMI Non NES 100 21.69±5.35 <0.001#

Mild NES 86 29.43±6.10


Full NES 23 22.22±5.13

GPA Non NES 100 3.59±0.68 <0.001#

Mild NES 86 3.30±0.69


Full NES 23 2.92±0.35

Table 1. Comparison of the night eating syndrome groups with regard to age, BMI, and GPA.

*Variables included in the analysis: BMI, GPA, and Age; **B ±SE: Regression coefficient and its standard error.

Factors related to Night Eating Syndrome

(analyzed by logistic regression)* Beta±SE** p OR (%95 CI)***

†BMI 0.107±0.020 <0.001 1.113 (1.071-1.156)

†GPA -0.993±0.197 <0.001 2.1876 (1.765-3.886)

Constant 3.839±1.656 <0.001

Table 2. Results of the logistic regression analysis of the factors associated with night eating syndrome.

ping of breakfast. Such habits increase thechance of developing a full-fledged NES (23,24). The cause of insomnia and late nighteating is still in the exploratory stage. How-ever, students studying in a college or a uni-versity inevitably experience a lot ofacademic challenges, which eventually dis-rupt their circadian rhythm. Glucose andlipid metabolism are also reported to be im-paired in an individual’s abnormal circadianrhythm (25). This mismatch between thecircadian rhythm and the biological clockmay lead to the development of obesity(26). Another cohort study (27) reportedthat a group of individuals who skippedbreakfast and ate late at night developed in-creased appetite and gained weight. Nostudy exists currently to explain the devel-opment of NES as a consequence of astressful environment or vice versa. It ispossible that a person with insomnia mayengage in eating at night. Research has alsoindicated that sleep deprivation also affectscognitive functions (28). Sleep deprivationhas specifically shown to affect almost allcomponents of cognitive function. In linewith the above-stated studies, the presentstudy reported that students with NESscored low academic grades than their peerswith mild- NES or non-NES. Memory, reten-tion, concentration, and attention span aresome of the most important factors that af-fect academic achievement and perform-ance of students (29).Based on the cut-off score of 25, the presentstudy revealed approximately 50% (n=102)students to be suffering from NES. Of thosehaving NES, 61% (n=36) were females. Al-though our study did not assess the stu-dents for depression and anxiety, otherstudies have reported a moderate level ofdepression in individuals with NES. Individ-uals with NES have shown to display signif-icant mood changes that worsen in theevening (30). Psychiatric disorders such asschizophrenia and BN also display the signsand symptoms of NES (31). Furthermore, astrong relationship exists between the bio-logical rhythm and human behavior suchthat harmony between these two is essentialfor maintaining appropriate human behav-ior. Disturbances in the normal circadianrhythm affect individuals both mentally andphysically.

Multiple comparisons between the groupsrevealed exciting results as no statisticallysignificant difference existed between thegroups in BMI. A previous study comparedthe obese and non-obese NES groups andreported that the non-obese group with NESwas less likely to suffer from depression(32). In the present study, we found thatparticipants with obesity scored higher inthe NESDQ as compared to the non-obeseparticipants. NES may pose a challenge toindividuals with obesity. According to recentstudies, individuals with NES find it consid-erably difficult to lose weight (33, 34). Indi-viduals with NES exhibit insomnia with 1.5to 4.5 awakening per night. Moreover, theoverall quality of sleep gets affected in indi-viduals with NES. Individuals with NES haveshown to display significant mood changesthat worsen in the evening. Studies have re-ported that individuals within the NES groupgained 4.3 to 4.5 kg weight over a period of3-6 years (35, 36). Hypothetically, NEScould lead to obesity as a result of con-sumption of high calories at night. On thecontrary, our study showed a non-significantdifference in BMI between non-NES and fullNES (p<0.976). The reason is due to thevast difference between the number of par-ticipants in non-NES (n=100) and full-NES(n=23). Furthermore, obesity and high BMIin an individual depend on multiple factors,including genetics, level of physical activity,and other physiological factors (37).The statistical significance was reported inthe GPA between all four groups, indicatingthat a higher score in NES is negatively cor-related with the academic performance of astudent. On the contrary, no statistically sig-nificant correlation was found between BMIand GPA. The majority of participants in thefull-NES group secured low academicgrades. In the current study, a low GPA wasstrongly correlated with NES and moderatelycorrelated to BMI. A previous study (38) re-ported NES to be moderately correlated withother eating disorders such as BED and BN.However, literature available on the associ-ation is little. It is also observed that thetotal calorie of food consumed by nighteaters is much lower than those consumedby people with BED and BN. Eating at nightstrongly correlates with an increased proba-bility of developing lifetime anxiety disorder

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(47.4%) as compared to the normal coun-terpart (9.1%) (39).The regression analysis was carried out forBMI, GPA, and NES. It revealed that an in-crease in the BMI increased the chance ofhaving NES by approximately one-fold, anda decrease in the GPA increased the chanceof developing NES by two-folds.One of the limitations of the present studyincluded the participation bias in self-re-porting the symptoms of NES. The cross-sectional study design has predictivelimitation, as exposure and outcome are as-sessed simultaneously. Generalizability ofthe study could be limited to university stu-dents of similar academic environments.

ConclusionThe findings of the present study suggest amoderate to a strong negative correlationbetween NES and GPA or academic per-formance. Mild to moderate BMI and NESalso show a negative correlation with GPA.

RecommendationsTeachers and academic advisors need to bemore vigilant about the signs and symptomsof NES among students. Once identified,academicians must take precautionarymeasures to reduce the burden on studentswithout compromising the educational out-comes. Moreover, a regular campaign on theawareness of NES must be organized. Reg-ular exercise could prove to be beneficial incounteracting the detrimental effects ofNES; however, future studies are warrantedto know the effect of exercise on NES.

AcknowledgmentWe are thankful to the Registration Depart-ment of Majmaah University and all the stu-dents who participated in our study. We arealso thankful to the developers of the NESDQfor permitting us to use their questionnaire.

Source of FinanceThe Study was supported by Health Sci-ences Research Centre, Majmaah University.

Conflict of InterestNo conflicts of interest between the authorsand / or family members of the scientific andmedical committee members or members ofthe potential conflicts of interest, counsel-

ing, expertise, working conditions, shareholding and similar situations in any firm.

Authorship ContributionsIdea/Concept: Mehrunnisha Ahmad, ;FaizanZaffar Kashoo Design: Faizan Zaffar Kashoo,Mazen Alqahtani; Control/Supervision: Mo-attar Rizvi; Data Collection and/or Process-ing: Faizan Zaffar Kashoo, Amira Bushra;Analysis and/or Interpretation: Waqas Sami,Moattar Rizvi; Literature Review: Faizan Zaf-far Kashoo, Mazen Alqahtani; Writing the Ar-ticle: Mehrunnisha Ahmad, Faizan ZaffarKashoo, Mazen Alqahtani, Waqas Sami, Mo-attar Rizvi, Amira Bushra; Critical Review:Faizan Zaffar Kashoo, Waqas Sami; Refer-ences and Fundings: Mazen Alqahtani; Ma-terials: Moattar Rizvi, Amira Bushra.

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Address for Correspondence: Sara Saniee, Department of Dermatology, Sina Hospital, Azadi Avenue, Tabriz, IranPhone: +989122766744 E-mail: [email protected]

Received: 04/11/2018 Received in revised form: 18/03/2019 Accepted: 29/03/2019 Available online: 19/06/2019?


Thyroid Dysfunction in Alopecia AreataAlopesi Areatada Tiroid Disfonksiyonu

Sina Hospital, Department of Dermatology, Azadi Avenue, Tabriz, Iran

IntroductionAlopecia areata (AA) is a common, localized,non-scarring hair loss that may occur on anyhair-bearing skin. It affects 1% of the gen-eral population (1-3). Although the patho-genesis of AA is still not completelyunderstood, genetic, environmental and au-toimmune factors are considered to play,most possibly, a role in its etiology. AA is a

T cell-mediated organ-specific autoimmunedisease (4-6).AA is associated with various autoimmunedisorders such as vitiligo, atopy, Hashimoto’sthyroiditis, diabetes mellitus, psoriasis, celiacdisease, and lupus erythematosus (1, 3, 7,8). Among all these, thyroid disorders, espe-cially hypothyroidism and vitiligo have thestrongest association (1, 5, 9).

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Objective: Alopecia areata is commonly associated withautoimmune disorders such as thyroid dysfunction. Thispaper aims to evaluate thyroid dysfunction in alopeciaareata patients among the Iranian population.Material and Methods: In this case-control study, 80 alo-pecia areata patients were recruited along with 122 age andsex-matched healthy subjects; serum thyroid stimulatinghormone and anti-thyroid peroxidase levels were then com-pared between the groups.Results: All alopecia areata patients had similar rate of in-creased thyroid stimulating hormone (10% vs. 8.2%,p=0.66) and anti-tiroid peroksidaz levels (15.6% vs.23.8%, p=0.14) as compared to the controls. Patients withdisease duration >6 months had significantly higher anti-ti-roid peroksidaz levels (42.9% vs. 16.9%, p=0.01), with nodifference in thyroid stimulating hormone levels (19% vs.6.8%, p=0.1). Female patients also had higher abnormalanti-tiroid peroksidaz levels (35% vs. 12.5%, p=0.01) com-pared to the males.Conclusion: Thyroid stimulating hormone and thyroid an-tibodies are not significantly increased in alopecia areatapatients when compared to the normal population. Thyroidantibodies, however, were found to be increased in femalesand with the progression of disease duration. Therefore,thyroid function and antibodies must be evaluated in alope-cia areata patients, especially in females, and along diffe-rent time periods in individuals having the disease for a longtime.

Keywords: Alopecia areata; thyroid disorders;disease duration

Amaç: Alopesi areata, tiroid disfonksiyonu gibi otoimmünbozukluklarla sıklıkla ilişkilidir. Bu çalışmada, İran populas-yonunda alopesi areata hastalarındaki tiroid disfonksiyonu-nun değerlendirilmesi amaçlanmıştır.Gereç ve Yöntemler: Bu vaka kontrol çalışmasına 80 alo-pesi areata hastası ile yaş ve cinsiyet uyumlu 122 sağlıklıbirey alındı, daha sonra da gruplar arasında serum tiroid sti-müle edici hormon ve anti-tiroid peroksidaz düzeyleri karşı-laştırıldı.Bulgular: Kontrol grubu ile karşılaştırıldığında, alopesiareata hastalarının hepsinde tiroid stimüle edici hormon(%10’a karşı %8,2; p=0,66) ve anti-tiroid peroksidaz dü-zeylerinde (%15,6’ya karşı %23,8; p=0,14) benzer orandaartış mevcuttu. Hastalık süresi >6 ay olan hastalarda anti-tiroid peroksidaz düzeyleri (%42,9’a karşı %16,9; p=0,01)anlamlı olarak daha yüksekti, tiroid stimüle edici hormondüzeyleri (%19’a karşı %6,8; p=0,1) arasında ise fark bu-lunmadı. Kadın hastalarda, erkeklere göre daha yüksekanormal anti-tiroid peroksidaz düzeyleri (%35’e karşı%12,5; p=0,01) mevcuttu.Sonuç: Tiroid stimüle edici hormon ve tiroid antikorları, alo-pesi areata hastalarında normal popülasyona göre anlamlıolarak artmamıştır. Bununla birlikte, tiroid antikorlarının, ka-dınlarda ve hastalık süresinin ilerlemesi ile arttığı bulun-muştur. Bu nedenle, alopesi areata hastalarında tiroidfonksiyonu ve antikorları, özellikle kadınlarda ve uzun sürehastalığı olan bireylerde farklı zaman periyotlarında değer-lendirilmelidir.

Anahtar kelimeler: Alopesi areata; tiroid hastalıkları;hastalık süresi

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https://orcid.org/0000-0002-2632-3428

https://orcid.org/0000-0001-7606-1924

https://orcid.org/0000-0003-2417-1413

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The published data show inconsistencyin the overall prevalence of thyroid dis-eases and thyroid function abnormalities inpatients with AA. Nevertheless, the re-ported prevalence is 8% to 28% in AA pa-tients (3, 10). More case-control studiesare warranted in order to better under-stand the prevalence of thyroid diseasesand thyroid dysfunction in AA. This studyaims to evaluate the rate of thyroid dys-function in AA.

Material and MethodsThis case-control study included 80 pa-tients with AA and 122 normal individualswho visited the dermatology clinic, SinaHospital, Tabriz, Iran in 2017. The partici-pants from both groups were age and sexmatched. Those with acute diffuse and totalalopecia or rapidly progressive AA were ex-cluded from the analysis. Those with othertypes of alopecia and autoimmune derma-tological diseases in the control group andthose consuming any immunosuppressivemedication or having any chronic system-atic diseases, in either of the two groups,as well as pregnant women, were excludedfrom the study.

Ethics StatementThis study was conducted according to theethical principles of the Declaration ofHelsinki and was approved by the ethicscommittee of Tabriz University of MedicalSciences (#58197, approve date: March 4,2017).

SamplesDemographics and laboratory findings of thepatients, including thyroid function tests,anemia, and history of vitiligo or diabetesmellitus as well as the duration of AA wererecorded and the findings between the pa-tient and control groups were compared.Fasting blood samples of all participantswere collected; the concentration of zinc wasdetermined using flame atomic absorptionspectrometry (FAAS) method using the com-mercially available kits (Biorexfars Co. LTD,Tehran, Iran). Thyroid stimulating hormone(TSH) was estimated using a commerciallyavailable enzyme-linked immunosorbentassay (ELISA) kit (Diaplus Inc., Canada)while the anti-thyroid peroxidase (anti-TPO)levels were assayed using ELISA kits(Monobind Inc., USA). The cutoff value ofpositivity for anti-TPO was 40 IU/mL. Thenormal range of TSH was found to be 0.5-5.5 mIU/L.

Statistical analysisAll the data were analyzed using SPSS 22(version 22; SPSS Inc., Chicago, IL). The re-sults were expressed as mean±standard de-viation or percentage. Chi-square test,Fisher’s exact test, and independent T-testwere used to compare data between thegroups. The p-values of less than 0.05 wereconsidered statistically significant.

ResultsDemographic findings of the two groups wereobserved to be similar (Table 1). Disease du-

Fisher’s exact test (**). DM: diabetes mellitus; AA: alopecia areata.

Control (n=122) Case (n=80) P value

Age (years) 29.33±13.30 28.03±12.31 0.48

Gender

Male 61 (50%) 40 (50%) ------

Female 61 (50%) 40 (50%)

Skin type

Type III 105 (88.5%) 64 (80%) 0.09

Type IV 14 (11.5%) 16 (20%)

Familial history of DM 50 (41%) 28 (35%) 0.39

Familial history of thyroid disease 31 (25.4%) 24 (30%) 0.47

Familial history of AA 16 (13.1%) 8 (10%) 0.5

Familial history of vitiligo 4 (3.3%) 4 (5%) 0.71**

Table 1. Demographic findings between the groups.

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ration in the patient group was found to be6.05 ±1.04 months. Three patients (3.8%) inthe patient group were noted to have vitiligo.Laboratory findings are demonstrated inTable 2. Although TSH and anti-TPO levelswere established to be higher in the patientgroup and it had more subjects with abnor-mal TSH and anti-TPO levels, the differencebetween the groups was not significant.The disease duration was observed to bebelow six months in 59 (73.8%) and abovesix months in 21 (26.3%) the participants.The laboratory findings were compared ac-cording to the disease duration (Table 3)which showed significantly lower hemoglo-bin, ferritin and anti-TPO levels in those sub-

jects who were affected with the disease forless than six months. Although the TSH lev-els were also considerably lower in these pa-tients, the difference was not significant.Among AA patients, females had a signifi-cantly higher level of anti-TPO as compared tothe males, and more females had increasedanti-TPO levels than the males (Table 4).

DiscussionIt was observed that the TSH and anti-TPOlevels did not differ significantly between thepatients with AA and healthy individuals.Similarly, Wang and colleagues (11) did notfind any significant difference in TSH, FT3and FT4 levels between AA patients and

Fisher's exact test (**).

Control (n=122) Case (n=80) P-value

Hemoglobin (mg/dL) 14.10 ±1.37 14.22 ±1.50 0.54

Anemia 5 (4.1%) 3 (3.8%) 0.9**

Fasting blood sugar (mg/dL) 90.45 ±12.34 90.56 ±12.05 0.95

Diabetes mellitus 2 (1.6%) 3 (3.8%) 0.38**

Ferritin 69.26 ±5.46 64.38 ±5.72 0.55

Low ferritin 21 (17.2%) 10 (12.5%) 0.36

B12 levels 384.31 ±216.87 337.94 ±263.77 0.17

Low B12 levels 25 (20.5%) 20 (25%) 0.45

TSH 3.03 ±0.39 3.49 ±0.57 0.11

Abnormal TSH 10 (8.2%) 8 (10%) 0.66

Anti-TPO 60.80 ±15.48 95.30 ±32.58 0.19

High anti-TPO 19 (15.6%) 19 (23.8%) 0.14

Table 2. Laboratory findings between the groups.


<6 months (n=59) <6 months (n=21) P-value

Hemoglobin (mg/dL) 14.00±1.44 14.84±1.53 0.02

Anemia 2 (3.4%) 1 (4.8%) ----

Fasting blood sugar (mg/dL) 91.44±12.63 88.09±10.12 0.27

Diabetes mellitus 3 (5.1%) 0 0.56**

Ferritin 57.13±6.20 84.76±56.30 0.02

Low ferritin 9 (15.3%) 1 (4.8%) 0.21**

B12 levels 349.90±290.66 304.33±167.96 0.57

Low B12 levels 16 (27.1%) 4 (19%) 0.46

TSH 3.05±0.53 4.70±1.58 0.19

Abnormal TSH 4 (6.8%) 4 (19%) 0.1**

Anti-TPO 92.22±41.06 103.96±47.27 0.03

High anti-TPO 10 (16.9%) 9 (42.9%) 0.01

Table 3. Laboratory findings between the patients grouped as disease duration <6 and >6 months.

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controls. Also, Rahnama and colleagues (3)found no difference in TSH and anti-TPO lev-els between AA patients and healthy indi-viduals. These authors presumed that therewould be no obvious damage to thyroidfunction in AA patients. Interestingly, Kaurand colleagues (12) observed that AA pa-tients had significantly lower TSH and anti-TPO levels than normal individuals.Unlike the findings of the present study, pre-vious studies have shown a significant in-crease in TSH levels in AA patients (13).Bakry and colleagues (14) also reported sig-nificantly higher levels of TSH and abnormalanti-TPO in AA patients as compared to thatin the healthy individuals. In one of thelargest sample study, Park and colleagues(15) evaluated 1408 patients and observedan increased incidence of thyroid dysfunc-tion and thyroid autoimmunity in AA pa-tients, particularly in those having severeAA. A recent meta-analysis by Lee and col-leagues (16) reported that the prevalence ofthyroid abnormalities and positive auto-an-tibodies were higher in patients with AA ascompared to that in the normal population.The rate of elevation of TSH and anti-TPO lev-els were similar to those found in previouslyreported data. Seyrafi and colleagues (10)observed thyroid disease and autoimmuneantibodies in 8.9% and 51.4% of the individ-uals. Thyroid abnormalities in AA patientswere reported to lie between 8% and 28% (3,10). Bakry et al. (14) also reported hypothy-roidism in 16% of the patients with AA. Pre-vious studies also reported the prevalence ofanti-TPO level (high) to be 48% and 23.7%(1, 14). The geographical location where thestudy was carried out and the prevalence ofautoimmune diseases in that area may haveconsiderable effects on TSH and anti-TPO lev-els. Further, the sample size of the studieswas often different, which could be anothercause for variations in the results obtained.

The present study also observed that the fe-male patients, as compared to the male pa-tients, had significantly higher levels ofanti-TPO; also, the number of female pa-tients had increased anti-TPO levels. TheTSH levels were also observed to be in-significantly higher in females. Thyroid dys-function has been found to affect womenmore commonly (17). Unlike the findings ofthe present study, Saylam Kurtipek and col-leagues (18) found no significant differencebetween male and female AA patients interms of TSH and anti-TPO levels.The present study observed a significant in-crease in the levels of anti-TPO antibodieswith an increase in the duration of the dis-ease. Gonul et al. (19) also reported that thelevels of thyroid antibodies increased withan increase in the duration of the disease.Yet, not all patients with hypothyroidismhave alopecia; thus, it is likely that the mag-nitude of the effect of thyroid hormone onhair growth is variable and its expressionmay be conditioned by local factors andother hormonal influences (14).This study had some limitations. Factors in-cluding geographical, environmental andcultural conditions would have an effect onthe results. Further, no follow-up study as-sessing the possible seasonal changes orchanges after treatment in AA patients wasperformed.

ConclusionThis study demonstrated that among all AApatients, 10% had elevated TSH while23.8% had elevated anti-TPO levels; yet,even with the higher rate of abnormal TSHand anti-TPO in AA patients, the difference isnot significant when compared to that in thehealthy individuals. Thyroid antibodies wereobserved to be increased in females andwith an increase in disease duration; there-fore, thyroid function and antibodies should


Male (n=40) Female (n=40) P value

TSH 3.30 ±0.84 3.67 ±0.78 0.74

Abnormal TSH 2 (5%) 6 (15%) 0.26**

Anti-TPO 22.82 ±7.58 167.78 ±63.05 0.02

High anti-TPO 5 (12.5%) 14 (35%) 0.01

Table 4. TSH and anti-TPO levels between female and male with AA.

be evaluated in AA patients, especially in fe-males and at different intervals, especiallyin those patients who are affected with thedisease since a long time.


Conflict of InterestNo conflicts of interest between the authorsand / or family members of the scientific andmedical committee members or members ofthe potential conflicts of interest, counsel-ing, expertise, working conditions, shareholding and similar situations in any firm.

Authorship ContributionsIdea/Concept: Sara Saniee; Design: SaraSaniee, Armaghan Ghareaghaji Zare, Afsa-neh Radmehr; Control/Supervision: SaraSaniee; Data Collection and/or Processing:Sara Saniee, Armaghan Ghareaghaji Zare,Afsaneh Radmehr; Analysis and/or Interpre-tation: Sara Saniee; Literature Review: SaraSaniee, Afsaneh Radmehr, Armaghan Gha-reaghaji Zare; Writing the Article: Sara Sa-niee, Armaghan Ghareaghaji Zare, AfsanehRadmehr; Critical Review: Radan EnglishEdit Institute; References and Fundings:Tabriz University of Medical Sciences; Mate-rials: Sara Saniee, Armaghan GhareaghajiZare, Afsaneh Radmehr.

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https://doi.org/10.1016/j.jaad.2018.10.066








https://doi.org/10.1111/j.1468-3083.2011.04420.x



https://doi.org/10.1001/jamadermatol.2013.3049

https://doi.org/10.15537/smj.2016.6.13777



https://doi.org/10.4103/0019-5154.123494


https://doi.org/10.1155/2015/435947




https://doi.org/10.1016/j.jdermsci.2016.10.004

https://doi.org/10.1136/jcp.2004.021881

https://doi.org/10.4103/ijt.ijt_32_17





https://doi.org/10.1586/1744666X.2015.1085306


https://doi.org/10.1056/NEJMra1103442



https://doi.org/10.1001/jamadermatol.2013.3049

https://doi.org/10.1186/1471-5945-5-11

Effect of Vitamin D Treatmenton Glycemic Control, Diastolic Functions,

and Carotid Intima-Media Thickness in Patientswith Type 2 Diabetes Mellitus

Tip 2 Diyabetes Mellitus Hastalarında Vitamin D ReplasmanınınGlisemik Kontrol, Diyastolik Fonksiyon ve

Karotis İntima-Media Kalınlığı Üzerine Etkisi

Çukurova University Faculty of Medicine, Department of Internal Medicine, Division of Endocrinology, Adana, Turkey*Çukurova University Faculty of Medicine, Department of Cardiology, Adana, Turkey

**Çukurova University Faculty of Medicine, Department of Biostatistics, Adana, Turkey

Address for Correspondence: Mehtap Evran Olgun, Çukurova University Faculty of Medicine, Deparment of Internal Medicine,Division of Endocrinology, Adana, Turkey

Phone: +90 5327818634 E-mail: [email protected]: 23/11/2018 Received in revised form: 03/05/2019 Accepted: 08/05/2019 Available online: 16/05/2019



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Objective: The purpose of this study was to investigate the influenceof 25(OH)D3 levels on glycemic control, diastolic functions, and caro-tid intima-media thickness in patients with Type 2 diabetes mellitus.Material and Methods: Patients admitted to the endocrinology de-partment, with the diagnosis of Type 2 diabetes mellitus, who wereunder follow-up for at least six months and also had 25(OH)D3 defici-ency [25(OH)D3 levels <20 ng/mL] were included in this study. D3supplement (50.000 IU) was administered to the patients every monthup to six months. Carotid intima-media thickness was measured usingthe B-mode ultrasonography. Diastolic function was evaluated using thetissue doppler imaging by measuring tissue e wave/tissue a wave (e’/a’)and annular E wave/tissue e wave (E/e’) ratios. All the evaluations weremade at baseline and at six months after vitamin D3 supplementation.Results: A total of 45 (27 females, 18 males; mean age: 56.2±7.8years) patients were included in this study. The mean duration of dia-betes was 8.5±6.8 (ranging from 7.0 to 9.0 years) years. It wasfound that even after D3 supplementation, fasting plasma glucoseand Hemoglobin A1C levels did not change, yet, the carotid intima-media thickness reduced (788±100 µm vs. 745±116.8 µm;p=0.009). Diastolic function parameters e’/a’ (0.79±0.21 vs.0.89±0.26; p=0.03) and E/e’ (7.27±1.81 vs. 6.52±1.65; p=0.048)also improved significantly after the therapy.Conclusion: Vitamin D supplementation, in patients with Type 2 dia-betes mellitus, who are also having vitamin D deficiency, seems to bebeneficial in reducing the thickness of carotid intima-media, which is awell-known cardiovascular risk predictor, and in improving diastolicfunctions by vitamin D repletion. Further prospective well-designed stu-dies with a larger patient population are needed to lead a firm conclu-sion in this regard.

Keywords: Type 2 diabetes mellitus; 25(OH)D3; glycemic control;carotid intima-media thickness; diastolic function;vitamin D deficiency

Amaç: Çalışmamızda Tip 2 diabetes mellitus tanısı ile takip ettiğimizhastalarda 25(OH)D3 düzeyleri ve bunun glisemik kontrol, diyastolikfonksiyon ve karotis intima-media kalınlığı üzerine etkilerinin ince-lenmesi amaçlanmıştır.Gereç ve Yöntemler: Çalışmaya endokrinoloji bölümüne başvuranve en az altı ay boyunca Tip 2 diabetes mellitus tanısı ile takip edi-len ve 25(OH)D3 eksikliği [25(OH)D3 seviyesi <20 ng/mL] olanhastalar dâhil edildi. Hastalara altı ay boyunca aylık D3 desteği(50.000 IU) uygulandı. Karotis intima media kalınlığı B-mod ultra-sonografi ile ölçüldü. Diyastolik fonksiyon doku e dalgası/doku a dal-gası (e’/a’) ve anüler E dalgası/doku e dalgası (E/e’) oranlarıölçülerek doku Doppler görüntüleme ile değerlendirildi. Tüm değer-lendirmeler başlangıçta ve vitamin D3 takviyesinden altı ay sonrayapıldı.Bulgular: Çalışmamıza toplam 45 (27 kadın, 18 erkek; ortalamayaş: 56.2±7.8 yıl) hasta alındı. Ortalama diyabet süresi 8.5±6.8 yıl’dı(7.0-9.0). Vitamin D3 takviyesi sonrası açlık plazma glukozu ve He-moglobin A1C düzeyleri değişmedi, ancak karotis intima-media ka-lınlığı azaldı (788±100 µm vs 745±16,8 µm; p=0,009). Diyastolikfonksiyon parametrelerinde e’/a’ (0,79±0,21’e karşı 0,89±0,26;p=0,03) ve E/e’ (7,27±1,81’e karşı 6,52±1,65; p=0,048) tedavidensonra önemli ölçüde iyileşme görüldü.Sonuç: Vitamin D eksikliği olan Tip 2 diabetes mellituslu hastalardaVitamin D takviyesi, iyi bilinen bir kardiyovasküler risk prediktörüolan karotis intima-media kalınlığının azaltılmasında ve diyastolikfonksiyonların iyileştirilmesinde yararlı görünmektedir. Daha kesin so-nuçlar için daha büyük hasta populasyonu ile daha iyi tasarlanmışprospektif çalışmalar gereklidir.

Anahtar kelimeler: Tip 2 diabetes mellitus; 25(OH)D3;glisemik kontrol; karotis intima media kalınlığı;diyastolik fonksiyon; vitamin D eksikliği

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The summary of the study presented as an oral presentation and was publishedin the 52th National Diabetes Congress, 13-18 November 2018, Antalya, Abstract Book (abstract <250 words).

https://orcid.org/0000-0001-5376-9874

https://orcid.org/0000-0002-0976-156X

https://orcid.org/0000-0002-2081-4664

https://orcid.org/0000-0002-2529-4995

https://orcid.org/0000-0002-9485-3295

https://orcid.org/0000-0003-4167-0820

https://orcid.org/0000-0002-1796-3845

IntroductionVitamin D is a steroid prohormone, synthe-sized when the skin is exposed to ultraviolet(UVB) light. It can also be obtained through di-etary intake or supplementation (1). VitaminD exists in two forms: Vitamin D2 (ergocalcif-erol) and D3 (cholecalciferol). Vitamin D (D2and D3) is then subsequently hydroxylated inthe liver by the enzyme 25-hydroxylase toproduce 25 hydroxyvitamin D [25(OH)D] (2,3). 25(OH)D is then further hydroxylated inthe kidneys to form 1,25(OH)2D3, which is thebiologically active form of vitamin D. Theserum level of 25(OH)D with a half-life of threeweeks represent the principal index of vitaminD status (4, 5). The serum concentration of25(OH)D below 20 ng/mL is considered as vi-tamin D deficiency and the treatment target istaken as 25(OH)D levels >30 ng/mL. Dailysupplementation of 1000 IU (maximum 4000IU/day) of D2 or D3 is advised to reach thetarget values (5, 6).In the recent years, vitamin D has beenfound to have a protective role against im-mune dysfunction, myopathy, cancer, hyper-tension (HT), cardiovascular disorders,insulin resistance, metabolic syndrome (MS),and T2DM (5, 7, 8). The gene for VDR wasdiscovered in 1988 and found to be presentin the cells of many tissues, includingparathyroid cells, pancreatic cells,macrophages, keratinocytes, special nervecells, and renal tubular cells. It was observedthat vitamin D receptor regulates approxi-mately 3% of the human genes via its en-docrine effect (6). These mechanisms ofendocrine effects that improve insulin resist-ance, along with suppressed levels of pro-in-flammatory cytokines, may provide anexplanation for the relationship between glu-cose metabolism and vitamin D (7, 9, 10).Earlier studies have shown that vitamin Ddeficiency is associated with increased PTHlevels and the risk of developing HT and car-diovascular disorders, due to the effects ofvitamin D on parathormone (PTH) releaseand its direct effects on renin-angiotensin-aldosterone (RAA) system and cardiac mus-cles (5, 11, 12). In addition, a relationshipbetween vitamin D deficiency and diabeticneuropathy has also been observed (13, 14).An increase in the carotid intima-mediathickness is considered to be a risk factor forcoronary atherosclerosis (15). Serum

25(OH)D levels have been found to be as-sociated with an increase in carotid intima-media thickness at baseline and progressionof carotid intima-media thickness is relatedto other factors of cardiovascular risks, suchas lipoprotein levels (16). Epidemiologicalstudies have also shown that vitamin D sup-port therapy allows better glycemic controlin T2DM patients and reduces the risk ofcardiovascular disorders (7, 17, 18). How-ever, the studies on the effect of Vitamin D3support for neuropathic pain and early riskpredictors for cardiovascular disorders in pa-tients with T2DM having 25(OH)D deficiencyare limited in number.The authors aim to investigate the effect ofvitamin D3 support on insulin resistance,glycemic control, neuropathic pain, and car-diovascular risk predictors in patients withT2DM.

Material and Methods

Inclusion and Exclusion CriteriaThis study was conducted at Cukurova Uni-versity, Faculty of Medicine between January2014 and November 2015 after being ap-proved by the (number of meetings: 28,February 14, 2014). Patients admitted to theendocrinology department, with a diagnosisof T2DM, having 25(OH)D deficiency in theirblood [25(OH)D3 levels <20 ng/mL] wereincluded in this study. Written informed con-sent was obtained from all patients. The pa-tients with chronic liver diseases, chronicrenal failure, decompensated heart failure,secondary osteoporosis, metabolic bone dis-ease, malignancy, and those who receivedCa and vitamin D supplement within thepast three months and with coronary arterydisease were excluded from the study. Thestudy was performed in accordance with theprinciples of the Declaration of Helsinki.

Characteristics of the Patients andManagementAge, sex, duration of T2DM, smoking habitsand medication history, chronic complica-tions of diabetes, and comorbid conditionswere recorded. The patients were made toattend control visits at six-month intervals,during which a physical examination wasconducted, which also included measure-ments for body mass index (BMI) and sys-

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tolic and diastolic blood pressures. The pa-tients were assessed for the development ofdiabetic neuropathy using the LANSS-painscale. The patients with a LANSS-pain scalescore of more than 12 points were consid-ered to be having diabetic neuropathy. Vita-min D supplementation was administered tothe patients for six months at a dose of50,000 IU/month orally.

Laboratory TestsComplete blood count, fasting plasma glu-cose (FPG), HbA1c, insulin, calcium (Ca),inorganic phosphor (P), low-density lipopro-tein (LDL), high-density lipoprotein (HDL)and triglyceride levels were measured atbaseline and after six months. In addition,alanine aminotransferase (ALT), alkalinephosphatase (ALP), and aspartate transam-inase (AST) levels were measured to ruleout liver diseases affecting vitamin D me-tabolism and non-alcoholic fatty liver dis-ease. Also, Lipoprotein (a) (normal: <300mg/L), vitamin B12 (normal range: 126.5-505 pg/mL), PTH (normal range: 12-88pg/mL), and 25(OH)D3 (normal range: 10-60 ng/mL) were measured.Insulin resistance of the patients was as-sessed by the hemostatic model assess-ment-insulin resistance (HOMA-IR) methodand the patients with values ≥2.24 wereconsidered to be insulin resistant: HOMA-IR:FPG (mmol/L)×Insulin (µIU/mL)/22.5 (13).Serum glucose, HDL, LDL, triglyceride,lipoprotein (a), Ca, and P levels were meas-ured using a Beckman Coulter DXC 800 de-vice and the photometric method. HbA1cwas measured using the immunoturbidimet-ric method. 25(OH)D3 levels were measuredusing HPLC (Bio-Rad Laboratories, München,Germany), while insulin, TSH, and PTHlevels were determined using a BeckmanCoulter DXI 800 device and the chemilumi-nescence method.

Echocardiographic AssessmentThe patients underwent B-mode transtho-racic echocardiography and tissue Dopplerimaging at baseline and six months later. B-mode echocardiography was primarily per-formed to rule out any presence of structuralheart disease. The measurements of mitralannular early diastolic wave/tissue Dopplerearly diastolic wave ratio (E/e’) and tissue

Doppler early diastolic wave/atrial contrac-tion wave ratio (e’/a’) were performed in allthe patients. Further, the myocardial per-formance index (MPI) was calculated in theTDI recordings. In accordance with recom-mendations from the American Echocardio-graphy Association, all the procedures werecarried out by a single operator, in the mid-dle of the day, in order to eliminate the ef-fects of circadian changes on diastolicdysfunction.The patients were asked to lie down in ahorizontal position on their backs for themeasurement of carotid intima-media thick-ness with their heads tilted backward. A sin-gle operator carried out the examination ofthe left and right carotid arteries. The pa-tients were initially subjected to a generalmorphological evaluation of both commoncarotid arteries (CCA) and cervical segmentsof the internal carotid artery (ICA), followingthe differentiation of the carotid arteryunder axial and longitudinal plane through Bmode grayscale imaging. Carotid intima-media thickness was measured in the regionnear the carotid bifurcation. Measurementswere made both, in the left and right CCAsand mean values were calculated.

Statistical AnalysisStatistical analysis was performed using theIBM SPSS version 20.0 software (SPSS Inc.,Chicago, IL, USA). The categorical variableswere expressed as numbers and percentages,whereas continuous variables were summa-rized as mean with standard deviation, me-dian, and minimum-maximum, whereverappropriate. The normality of distribution forcontinuous variables was analyzed using theKolmogorov-Smirnov test. For comparison ofbefore-after measurements, paired sample t-test or the Wilcoxon Signed Rank test was ap-plied. To evaluate the correlations betweenmeasurements, Pearson‘s Correlation Coeffi-cient or Spearman‘s Rank Correlation Coeffi-cient was employed.

ResultsThe study included 45 patients (27 females,18 males) with the diagnosis of T2DM whounderwent follow-up for at least six months.The mean age of the patients was 56.2±7.8years (37-69). Demographic features of thepatients, the complications and comorbidi-

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ties are presented in Table 1. Among the pa-tients, 87% were on oral anti-diabetic med-ications. Hypertension was the mostfrequent comorbidity (46%). The LANSS-pain score was found to be ≥12 points in 12patients (32%) and these patients wereconsidered to have neuropathic pain.Clinical response of the patients to vitaminD3 supplementation therapy is summarizedin Table 2. A significant increase in25(OH)D3, Ca, and P levels was observed(p=0.00, p=0.01, p=0.04, respectively).However, the PTH levels were found to de-crease significantly (p=0.025). Althoughthere was a reduction in LANSS-pain score(7.1±6.2 vs. 5.8±5.7; p=0.128), thechange was not statistically significant.The changes in carotid intima-media thick-ness and cardiac functions are listed in Table3. Carotid intima-media thickness of the pa-tients was significantly decreased after vita-min D supplementation (788±100 µm vs.745±116.8 µm; p=0.009). Mitral E/e’ ratiowas decreased (7.27±1.81 vs. 6.52±1.65;p=0.048) and tissue e’/a’ ratio was in-creased (0.79±0.21 vs. 0.89±0.26;p=0.03) significantly after vitamin D ther-apy. However, no significant change was ob-served in MPI values even after the therapy.

DiscussionIn this study, patients with T2DM who weredeficient in 25(OH)D3 were treated with vi-tamin D therapy. After six months of vitaminD supplementation, a significant decrease incarotid intima-media thickness measure-ments along with significant improvements

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Mean±SD

Age (years) 56.2±7.8

Duration of diabetes (years) 8.5±6.8

Body Mass Index (BMI) (kg/m2) 30.9±4.6

Systolic Blood Pressure (mmHg) 136±17.6

Diastolic Blood Pressure (mmHg) 69.8±27

HbA1c (%) 6.6±0.4

Oral antidiabetic (OAD) users N, (%) 39 (87%)

OAD + Insulin users N, (%) 5 (11%)

Only insulin users N, (%) 1 (2%)

Smokers N, (%) 8 (17.8%)

Diabetic nephropathy N, (%) 1 (2.2%)

Diabetic retinopathy N, (%) 1 (2.2%)

Painful diabetic neuropathy N, (%) 12 (32%)

Hypertension N, (%) 13 (28.9%)

Hypertension+Hyperlipidemia N, (%) 8 (17.8%)

Table 1. Demographic and clinical features of thepatients.

* p<0.05** Baseline: Median: 2 (min: 0.86-max: 16.7); six months: Median: 1.95 (min: 0.90-max: 7).# Baseline: Median: 109 (min: 0.7-max: 1366); six months: Median: 105 (min: 5.4-max: 1651).£ Baseline: Median: 7 (min: 0-max: 21), six months: Median: 5 (min: 0-max: 266).

Baseline 6 Months P value

Hemoglobin (g/dL) 13.1±1 13.1±1.1 0.6

Glucose (mg/dL) 128±33 127±26 0.77

HbA1c (%) 6.6±0.4 6.6±0.7 0.9

HOMA-IR 2.9±2.5 2.4±1.5 0.23**

Creatinine (mg/dL) 0.66±0.1 0.7±0.2 0.03*

ALT (U/L) 24±11 22±11 0.24

Calcium (mg/dL) 9.3±0.46 9.5±0.5 0.01*

Phosphorus (mg/dL) 3.7±0.6 3.9±0.5 0.04*

HDL-C (mg/dL) 46±9 45±9 0.16

LDL-C (mg/dL) 122±45 112±42 0.15

Triglycerides (mg/dL) 153±73 152±77 0.9

Lipoprotein (a) (mg/dL) 249±306 229±319 0.26#

PTH (pg/mL) 48±24 41±18 0.025*

25 OH Vit D3 (ng/mL) 16.7±10.6 40.5±18 0.000*

LANSS-pain score 7.1±6.2 5.8±5.7 0.128£

Table 2. The biochemical parameters of the patients at baseline and six months (Mean±SD).

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in diastolic functions of the patients was ob-served.Vitamin D deficiency is a common conditionand some studies have established the rela-tionship between vitamin D deficiency andinsulin resistance, T2DM, and cardiovascu-lar disorders (5, 7, 19).This study aimed to evaluate the effects ofvitamin D supplementation on glycemic con-trol, diabetic neuropathy, diastolic dysfunc-tion, and carotid intima-media thickness(one of the indicators of cardiovascular risk),in patients with T2DM and low serum levelsof 25(OH)D3.In several studies, it has been suggested thatvitamin D plays a functional role in glucosetolerance through its effects on insulin secre-tion and insulin sensitivity. Animal studieshave proved that vitamin D is a fundamentalfactor for normal insulin secretion. Probably,vitamin D decreases insulin resistancethrough its effects on both, regulation of theinsulin receptor gene and, Ca and P metabo-lism (7, 9, 10). Some mechanisms are relatedto the effect of vitamin D, such as the pres-ence of VDR on pancreatic β cells since vita-min D activating 1α hydroxylase is expressedin pancreatic β cells, the presence of VDR inskeletal muscles, and the fact that1,25(OH)2D increases transcription of insulinreceptor genes (12, 13). The studies con-ducted on healthy subjects have shown thatdecreased vitamin D levels cause beta celldysfunction (20-22). Some studies showedthat serum 25(OH)D concentrations were sig-nificantly lower in patients with T2DM as com-

pared to that in healthy controls. Further-more, vitamin D supplementation in 5,677patients with impaired glucose tolerance wasfound to have increased insulin sensitivity in54% of the patients (12, 23, 24).In another study, 300 patients with T2DM,who underwent lifestyle changes and wereadministered metformin, sulfonylurea, or acombination of these medications, receivedvitamin D in a dose of 50,000 IU monthly ora placebo for six months. This study foundthat at least a six-month follow-up periodwas required to observe a significant changein HbA1c values and the patients receiving vi-tamin D supplementation achieved a betterglycemic control (7). In the present study, nosignificant change was observed in glycemiclevels of the patients at six months; though,there was an insignificant decrease in HOMA-IR levels. Despite significant increase in theserum 25(OH)D3 concentrations in the pa-tients at the end of the study, the lack of anysignificant change in glycemic parametersmay be attributed either to near-normalHbA1c values in patients at the baseline, orthe duration of six-month follow-up was in-sufficient to evaluate any change in theHbA1c values, or other individual factors ofthe patients. Vitamin D was used in the dif-ferent dosages and durations in previousstudies (7, 25, 26). Talaei et al. administeredoral vitamin D3 50,000 IU weekly to 100 pa-tients with T2DM for eight weeks and, in con-trast to the findings of the present study,they showed significant decreases in FPG, in-sulin, and HOMA-IR values (12).


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* p<0.05.** EF: Ejection Fraction, E: Peak myocardial early diastolic flow rate, A: Peak myocardial late diastolic flow rate, IVS: Interventri-cular septum, CIMT: Carotid Intima Media Thickness, LA: Left Atrium, MPI: Myocardial Performance Index.

Baseline 6 Months P value

EF (%) 60.5±1.8 60±0.79 0.163

IVS (mm) 9.8±1.3 10.2±1.23 0.038*

LA (mm) 32.6±3.5 33±2.7 0.17

E (cm/sec) 66.3±18 68.2±16.4 0.258

A (cm/sec) 75.4±16.8 75.4±19 0.97

CIMT (µm) 788±100 745±116.8 0.009*

Tissue e/Tissue a 0.79±0.21 0.89±0.26 0.03*

Annular E/Tissue e 7.27±1.81 6.52±1.65 0.048*

MPI left 0.36±0.06 0.36±0.06 0.744

Table 3. Echocardiography, Doppler and carotid intima-media thickness measurements at the baseline and at sixmonths follow-up after correcting vitamin D levels.**

The current International OsteoporosisFoundation Guidelines recommend serum25(OH)D level of 30 ng/mL (75 nmol/L) formaximum PTH suppression (27). In thepresent study, 25(OH)D levels reachedabove 30 ng/mL at the sixth month; and inconsistency with previous studies, PTH lev-els showed a decrease with vitamin D sup-plementation.Clinical studies have shown that vitamin D ex-erts direct influence on cardiomyocytes andindirect influences on the cardiovascular sys-tem through its effects on the circulating hor-mones and calcium levels (28). In addition, ithas been shown that vitamin D levels are as-sociated with hypertension and cardiovascu-lar endpoints and that vitamin Dsupplementation decreased the risk of car-diovascular events (29-31). Wang et al. eval-uated 25(OH)D concentrations in 1,700patients with no cardiovascular disease andshowed that levels below 37 nmol/L increasedthe incidence of cardiovascular events 1.62times (32). The increased risk was associatedwith possible effects of low vitamin D levels,effects of the RAA system with inhibition ofrenin expression and impairment in vascularfunctions, such as inflammation, smoothmuscle hypertrophy, and thrombosis. Somestudies have shown a significant relationshipbetween carotid intima-media thickness andintima-media thickness progression andserum 25(OH)D concentration, which areimportant indicators of atherosclerosis andcoronary artery atherosclerosis (24, 33). Fur-thermore, hypovitaminosis D has been ob-served to be an independent risk factor forincreased carotid intima-media thickness, andvitamin D supplementation has been found tobe associated with improvement in carotid in-tima-media thickness in patients with T2DM,as compared to non-diabetic patients (16, 34,35).In this study, a significant decrease incarotid intima-media thickness measure-ments in patients was observed after vita-min D3 supplementation. On the otherhand, vitamin D supplementation may notbe the only cause of improvement in carotidintima-media thickness; instead, improve-ment in other metabolic parameters mayalso have contributed to this progress. Sig-nificant improvements in Ca and PTH levelsand minimal improvements in HOMA-IR and

lipoprotein (a) levels may have favorably af-fected cardiac functions. Although the meta-bolic benefits and cardio-protective effectsof vitamin D are well known, it could not bemade clear whether vitamin D deficiencyand serum 25(OH)D levels were associatedwith cardiovascular morbidity and mortality.

Study LimitationsThe major limitation of this study was itslimited patient population and relativelyshort term follow-up period. Moreover, thelack of investigations on cardiovascular end-points is another deficit. The fact that thepresent study is not a placebo/controlledstudy is another important limitation.

ConclusionIn conclusion, the most important resultsobserved in this study are the improvementin cardiac diastolic functions and decrease incarotid intima-media thickness after vitaminD supplementation in patients with uncom-plicated T2DM. Although, no improvementsin the metabolic indices associated withglycemic control were observed. However,well-controlled studies with a larger patientpopulation, specifically designed to evaluatecardiovascular mortality and morbidity arewarranted to make a firm conclusion in thisregard.



Ethical statementAll procedures performed in studies involv-ing human participants were in accordance

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with the ethical standards of the institutionaland/or national research committee andwith the 1964 Helsinki declaration and itslater amendments or comparable ethicalstandards.

Authors ContributionsIdea/ Concept: Mehtap Evran Olgun, TamerTetiker; Design: Mehtap Evran Olgun, TamerTetiker; Data collecting: Mehtap EvranOlgun, Gamze Akkuş; Echocardiography:Mustafa Gök, Çağlar Emre Çağlıyan; Statis-tical analysis: İlker Ünal; Writing: MehtapEvran Olgun, Gamze Akkuş; Editing: ÇağlarEmre Çağlıyan, Tamer Tetiker, MuratSert;Review and final approval: MehtapEvran Olgun, Gamze Akkuş, Mustafa Gök,Çağlar Emre Çağlıyan, İlker Ünal, MuratSert, Tamer Tetiker.

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Address for Correspondence: Fahri Bayram, Erciyes University Faculty of Medicine,Department of Endocrinology and Metabolism, Kayseri, TurkeyPhone: +90 352 221 29 99 E-mail: [email protected]

Received: 20/02/2019 Received in revised form: 27/03/2019 Accepted: 14/04/2019 Available online: 03/05/2019


Evaluation of DNA Damagein Patients with a Neuroendocrine Tumor

Nöroendokrin Tümörlü HastalardaDNA Hasarının Değerlendirilmesi

Neuroendocrine Tumor Study Group, Erciyes UniversityDepartment of Medical Biogology, Erciyes University Faculty of Medicine, Kayseri, Turkey

*Department of Endocrinology and Metabolism, Erciyes University Faculty of Medicine, Kayseri, Turkey**Department of Nuclear Medicine, Erciyes University Faculty of Medicine, Kayseri, Turkey

***Deparment of Pathology, Erciyes University Faculty of Medicine, Kayseri, Turkey****Department of Medical Oncology, Erciyes University Faculty of Medicine, Kayseri, Turkey

*****Department of Surgery, Erciyes University Faculty of Medicine, Kayseri, Turkey******Department of Gastroenterology, Erciyes University Faculty of Medicine, Kayseri, Turkey


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Objective: Neuroendocrine tumors develop from the neu-roendocrine cells of the endocrine system. As these tumorsare extremely slow growing compared with other cancers,they often take years to reach a measurable dimension,thus leading to the late diagnosis, which has adverse effectson the survival and quality of life of patients. There is a linkbetween many types of cancer and genomic instability, thusthe markers associated with genomic instability can be usedfor early diagnosis of the disease or cancer-related chan-ges. Comet assay is the most commonly used method totest genomic instability or DNA damage. To the best of ourknowledge, no data are available on DNA damage in pati-ents with neuroendocrine tumors. This study aimed to in-vestigate the possible risk of DNA damage in a patient withneuroendocrine tumors using the comet assay.Material and Methods: The study included 23 patientswith neuroendocrine tumors and 20 age-and sex-matchedhealthy participants. The DNA damage was determinedusing the comet assay for leukocytes obtained from the pe-ripheral blood samples of patients and control participants.Results: We found that the DNA damage was markedly hig-her in the patients with neuroendocrine tumors than controlparticipants (p˂0.05).Conclusion: Our data suggest that genomic instability con-tributes to the development of neuroendocrine tumors. Ho-wever, further investigations are needed to support ourresults, as it is a preliminary report on DNA damage risk inpatients with NETs.

Keywords: Neuroendocrine tumors; comet assay;genomic instability; DNA damage

Amaç: Nöroendokrin tümörler endokrin sistemin nöroen-dokrin hücrelerinden oluşan tümör grubunu temsil etmekte-dir. Bunların çoğu diğer kanserlere kıyasla çok yavaş büyür,belirtilere neden olmaları yıllar sürer ve geç evrede tanıkonur. Genetik değişiklikler ile kanser arasında bir ilişkininvarlığı birçok çalışmayla desteklenmiş olup, genomik karar-sızlık ile ilişkilendirilmiş belirteçlerin birçok hastalığın erkentanısında kullanılmasının yararlı olabileceği ileri sürülmekte-dir. Komet tekniği, genomik karasızlık/DNA hasarını testetmek için en sık kullanılan yöntemdir. Bildiğimiz kadarıyla,nöroendokrin tümörlü hastalarda genomik DNA hasarı ilgiliherhangi bir veri bulunmamaktadır. Çalışmamızda, kometyöntemi ile tedavi almayan nöroendokrin tümörlü hastalardaolası DNA hasarlarının araştırılması amaçlanmıştır.Gereç ve Yöntemler: Araştırmamız, nöroendokrin tümör-ler teşhisi konmuş ve herhangi bir tedavi almamış 23 has-tada ve bu hastalara benzer yaş ve cinsiyette olan 20 sağlıklıkişide yapıldı. Hasta ve sağlıklı kontrollerden alınan perife-ral kan örneklerinden elde edilen lökositlerinde DNA hasarıkomet assay yöntemiyle belirlendi.Bulgular: Nöroendokrin tümörlü hastalarda DNA hasar ora-nının sağlıklı kişilere göre önemli seviyede yüksek olduğu bu-lundu (p˂0.05).Sonuç: Verilerimiz, genomik kararsızlığın nöroendokrin tü-mörlerin oluşuma katkıda bulunabileceğini göstermektedir.Fakat, sunulan çalışma literatürde bir ilk olduğundan, çalış-mamızı desteklemek için daha fazla hasta sayısı ile yapıla-cak araştırmalara gerek olduğu düşünülmektedir.

Anahtar kelimeler: Nöroendokrin tümörler; komet analizi;genomik kararsızlık; DNA hasarı

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https://orcid.org/0000-0001-8434-393x

https://orcid.org/0000-0002-4057-5701

https://orcid.org/0000-0001-6473-5813

https://orcid.org/0000-0002-6320-5404

https://orcid.org/0000-0002-8879-1112

https://orcid.org/0000-0002-0711-4014

https://orcid.org/0000-0001-8774-4368

https://orcid.org/0000-0002-3332-2570

https://orcid.org/0000-0003-2349-1116

https://orcid.org/0000-0001-5537-7882

https://orcid.org/0000-0003-0479-7304

https://orcid.org/0000-0003-0359-0504

https://orcid.org/0000-0001-6180-5716

IntroductionNeuroendocrine tumors (NETs) originatefrom a group of neuroendocrine cells of theendocrine system, which develop into tu-mors. NETs grow extremely slowly com-pared with most other cancers, thus take along time to reach measurable dimensionsand for symptoms to appear, leading to thelate diagnosis that may negatively affect thequality of life of the patients (1).Cancer is a multistep process. A relation-ship between genetic changes and cancerhas been supported by several studies, andit is now well established that there is a linkbetween several types of cancer and ge-nomic instability (2-5). It has been sug-gested that the markers associated withgenomic instability can be explored forearly diagnosis of the disease or cancer-re-lated changes (6-8). Therefore, micronu-cleus, sister chromatid exchange,chromosomal aberrations, or comet assayparameters can be used as cancer risk bio-markers (9). Comet assay is one of themost commonly used methods for measur-ing DNA strand breaks in eukaryotic cells(5,10), as it is an extremely simple andsensitive technique compared with othertechniques (10, 11).Patients with NETs are characterized by cer-tain mutations and chromosomal aberra-tions (12-14). Unrepaired DNA damage hasbeen the most crucial characteristic of sev-eral cancers; however, its presence in pa-tients with NETs is unknown. We believe thatDNA damage may contribute to the NET de-velopment and may be used as a prognosticbiomarker for the diagnosis or treatment ofNET. Thus, in the present study, we aimedto investigate if there is an unrepaired DNAdamage in basal proportion in patients withNET by using comet assay (10, 11).

Material and MethodsPatient group: The study included 23 pa-tients with NETs from the Departments ofEndocrinology and Metabolism, Oncology,Surgery, Pathology, Radiology, Nuclear Med-icine, and Gastroenterology at Medical Fac-ulty of Erciyes University. Out of 23 patients,12 were women and 11 were men aged 18-58 years. All patients were newly diagnosedand had not received medical or surgicaltreatment for NETs.

Control group: The control group includedhealthy participants matched with age andsex. None of them had received any drug formedical or other reasons. All participantswere asked to complete a standardizedquestionnaire to obtain relevant currenthealth status and lifestyle and informationon medical history.This study was approved by the Erciyes Uni-versity Ethics Committee (Protocol No.2013/364, 21.05.2013). All patients andhealthy participants provided written in-formed consent. This study was conductedin accordance with the Declaration ofHelsinki and local laws.

Blood sample collection andlymphocyte isolationAfter completing the questionnaire, bloodsamples (1 mL) were collected in he-parinized tubes from each patient andprocessed on the same day. The trypan blueexclusion test for estimating cell viabilitywas performed, and a viability rate of ≥99%was detected. In addition, 100 µL of theblood sample was suspended in 1 mL ofphosphate buffered saline (PBS). Subse-quently, 100 µL of Histopaque was addedand the cells were centrifuged at 1800 rpmfor 30 min at room temperature. The lym-phocyte band between the sample layer andthe Histopaque solution was then removed.The lymphocytes were washed twice withPBS and then centrifuged for 5 min at 1800rpm and 4°C temperature (15).

Comet assayAll chemicals were purchased from Sigma-Aldrich (St. Louis, USA).Preparation of slides: The comet assay wasperformed according to the method of Singhet al. (16). Microscope slides were coatedwith 0.65% high hot melting agarose(300°C) prepared in PBS. The slides weredried overnight at room temperature andstored at 4°C. Leukocytes isolated from theheparinized blood samples (100 µL) weremixed with 0.65% low melting agarose andthen placed on microscope slides. The slideswere stored at 4°C for 30 min to solidify.Subsequently, the slides were placed in coldlysis solution (2.5 M NaCl, 100 mM EDTA, 10mM Tris HCl [pH 10], 1% Triton X-100, and10% dimethyl sulfoxide) for 45 min at 4°C in

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dark (to allow DNA unfolding). After incuba-tion in the lysis solution, slides were ex-posed to alkaline buffer (electrophoresisbuffer: 0.1 M EDTA, 10 M NaOH buffer, pH7.5) for 30 min at room temperature in thedark (to completely degrade RNA) (15).Electrophoresis: The slides placed in elec-trophoresis buffer were then subjected toelectrophoresis for 30min at 15 V and 300mA. To prevent additional DNA damage, allprocesses were performed in the dark at 4°C. The slides were then washed three times(5 min each) with 0.4 M Tris HCl buffer (neu-tralization buffer, pH 7.5) to neutralize theexcess alkali and remove detergents andstained with ethidium bromide (EtBr; 2µg/mL) (15).Staining and scoring for DNA damage: 50 µLof EtBr (2 µg/mL) was added to each slide.The slides were covered with a coverslip andimmediately analyzed using a fluorescencemicroscope (Nikon) (15, 17). The DNA dam-age was calculated by taking images of 100randomly selected cells at 400× magnifica-tion using a fluorescent microscope and an-alyzed visually according to cometappearance (15, 17).

Each image was classified according to theintensity of the fluorescence in the comettail and was provided a value of 0, 1, 2, 3, or4 (from undamaged class 0 to maximallydamaged class 4) (15, 17). The total cometscore was calculated using the formula:(total comet score=0 (n)+1 (n)+2 (n)+3(n)+4 (n), where n represents the numberof cells in each class (17-19). The slideswere analyzed under blind conditions by atleast two different individuals.

Statistical analysisThe differences between the control partici-pants and patients were measured using theMann-Whitney U test for two independentsamples. Spearman’s ρ correlation test wasused to determine the relationship betweenage and basal DNA damage. The p-value ofless than 0.05 was considered statisticallysignificant. Data were analyzed usingGraphPad program (Prism 5).

ResultsThe clinical findings of patients are shown inTable 1. The comet score in 100 peripheralblood mononuclear cells of patients and con-

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Table 1. Profile of patients at the time enrolment to the study.

Case No Age at blood collection Gender Primary tumor site1 65 M Stomach2 62 F Unknown3 61 F Duodenum4 55 M Stomach5 32 F Duodenum6 29 F Lungs7 52 M Lungs8 62 M Pancreas9 51 M Ileum10 69 M Bladder11 52 M Pancreas12 54 F Stomach13 37 F Stomach14 44 M Pancreas15 57 F Liver16 55 F Unknown17 49 F Unknown18 46 M Small intestine19 74 F Unknown20 50 F Unknown21 51 M Unknown22 50 F Unknown23 28 M Pancreas

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trol participants is shown in Table 2. Thecells with damaged DNA appeared like acomet, whereas undamaged cells showed anintact nucleus without a tail (Figure 1). Thebasal DNA damage frequency (%) betweenthe study and control groups is shown inTable 3. The study group showed signifi-cantly higher basal DNA damage than thecontrol groups (p<0.05; Table 3). Further-more, a significant positive correlation wasobserved between the basal DNA damageand age of control participants (r=0.45,p=0.044; Figure 2a). However, no signifi-cant relationship was noted between thebasal DNA damage and age of patients(r=0.097, p=0.66; Figure 2b).

DiscussionNETs are a heterogeneous group of malig-nancies (20, 21). They are typically less ag-gressive compared with other solid tumors;

therefore, NETs are considered rare tumors(22). The majority of NETs are known assporadic. However, it is reported that NETscan also occur because of inherited familialsyndromes (13, 20, 23). Although the ge-netic basis of NETs is unclear, several genesresponsible for NETs have been identified.These genes are the members of crucialpathways involved in the maintenance oftelomere length, chromatin modification,cell proliferation, response to DNA damage,and cell metabolism. It was shown that thegenes from familial predisposition syn-dromes are similarly mutated in sporadicNETs (24). Moreover, some of the mutatedgenes identified in sporadic tumors were as-sociated with familial cancer syndromescausing NETs (22). These genes associatedwith neuroendocrine tumorigenesis havefunctions in DNA repair and mTOR pathways(22). However, no data exist on the basal


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Figure 1: DNA damage assessed by using the comet assay. Mean comet score and comet classes in the control andpatient groups. The cells were assessed visually and received class 0 (undamaged) to 4 (maximally damaged), ac-cording to the size and shape of the tail.

SD: Standard Deviation, ** p<0.0001.

Comet Class 0 (Mean±SD) 1 (Mean±SD) 2 (Mean±SD) 3 (Mean±SD) 4 (Mean±SD)

Patients 25.13±5.50 25.83±3.75 25.91±3.76 14.35±2.64 10.00±1.89**

Controls 42.40±7.35 33.75±4.54 24.00±5.28 11.35±2.11 4.2±0.70

Table 2. Mean value of each comet class per 100 cells (±standard deviation) in patients and controls.

DNA damage level in patients with NET.Comet test is a powerful technique for quan-tifying and analyzing DNA damage and hasthe advantage of showing DNA damage inindividual cells (25-27). Our comet assayfindings showed increased DNA damage inpatients with NET.Chromosomal instability, one of the causesof NET tumorigenesis, is related to DNAmethylation rather than genomic changes(12, 28-31). However, in this study, thecomet frequency was higher in the periph-eral blood mononuclear cells of patients withNETs. Increased comet frequency reflectsgenomic alterations in patients with NETs.Alterations in multiple pathways such asDNA replication and repair of DNA damagemutations can lead to genomic instability(32). Further, the structurally altered DNA orDNA strand breaks also promote genome in-stability. The comet assay is used to meas-ure structural DNA damage (33). In contrastto previous studies (12, 28-31), our findingsalso indicated the presence of genomic in-stability induced by structural DNA damagein patients with NETs. As genomic instability

is considered a driving force for numerouscancers (32), we believe that structural DNAdamage may be responsible for NET forma-tion.Recent studies indicated that epigeneticmodifications are likely to be a major factorfor neuroendocrine tumorigenesis, whereasmutated oncogenes only play a minor role inpathogenesis (13). However, differentmechanisms such as defective DNA repair,replication, and chromosome maintenancemay contribute to NET development (34). Inaddition, our findings showed that genomicinstability is caused by structural DNA dam-age in patients with NET. Therefore, we be-lieve that genomic instability may contributeto the initiation or progression of NET.In patients with Nijmegen syndrome or Xe-roderma Pigmentosum, who have DNAbreakage, it may be possible to use thecomet assay as an aid to diagnosis (18). Fur-thermore, it is suggested that comet assaycan be used as a reliable clinically potentialtool to identify a disease (5, 33). Therefore,the DNA damage determined using thecomet assay may be a biomarker for NET.

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Figure 2: Correlation between the age and DNA damage frequencies in the controls (a) and patients (b).

SD: Standard Deviation, TCS: Total Comet Score* p<0.05.

Groups Age (years) (Mean±SD) DNA damage (%) (Mean±SD)

Patients with NET (n=23) 51.96±2.37 1.78±0.124*

Controls (n=20) 50.40±1.50 1.42±0.94

p-value 0.59 0.031

Table 3. Basal DNA damage frequency (TCS% according to the formula) in the patients with NET and controls.

ConclusionOur findings indicated that the increasedstructural DNA alterations may promote tu-morigenesis in NETs, and the DNA damagedetermined using the comet assay may be abiomarker for the diagnosis of NETs. However,further studies with large sample sizes areneeded to support our preliminary findings.

Financial ResourcesThe present study was funded by the re-search fund of the Erciyes University (Pro-ject number: TOA-2013-4619).


Authorship ContributionsIdea/Concept: Zuhal Hamurcu, FahriBayram, Hamiyet Dönmez Altuntaş; Design:Zuhal Hamurcu, Fahri Bayram, NesrinDelibaşı; Control/Supervision: ZuhalHamurcu; Data Collection and/or Process-ing: Ümmühan Abdülrezzak, Figen Öztürk,Ender Doğan, Erdoğan Sözüer, Alper Yurci,Gülten Sezgin Can, Şebnem Gürsoy, MustafaKula; Analysis and/or Interpretation: FahriBayram; Literature Review: Zuhal Hamurcu,Fahri Bayram, Ümmühan Abdülrezzak,Hamiyet Dönmez Altuntaş; Writing the Arti-cle: Zuhal Hamurcu, Fahri Bayram, HamiyetDönmez Altuntaş; Critical Review: ZuhalHamurcu, Fahri Bayram; Materials: FahriBayram, Ümmühan Abdülrezzak, EnderDoğan, Erdoğan Sözüer, Alper Yurci, GültenSezgin Can, Şebnem Gürsoy, Mustafa Kula.

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ReviewTurk J Endocrinol Metab 2019;23:112-121

112

Low-Carbohydrate Diets and Type 1 DiabetesDüşük Karbonhidratlı Diyetler ve Tip 1 Diyabet

Gazi University Faculty of Medicine, Division of Pediatric Endocrinology, Ankara, Turkey

Address for Correspondence: Rukiye Bozbulut, Gazi University Faculty of Medicine,Department of Pediatric Endocrinology, Ankara, TurkeyPhone: 03122026033 E-mail: [email protected]



IntroductionType 1 diabetes is characterized by an ab-solute insulin deficiency, which is caused byT-cell-mediated autoimmune destruction ofpancreatic β-cells (1). Type 1 diabetes ac-counts for 5-10% of all global cases of dia-betes mellitus and 90% of the juvenile andadolescent diabetes cases (2, 3). According

to the data obtained from the Diabetes Atlasby the International Diabetes Federation(IDF) (2017), the number of children andadolescents (0-19 years) with type 1 dia-betes is estimated to be 1,106,500 world-wide. Furthermore, it is reported that theannual number of newly diagnosed cases is132,600 (4).

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Despite the significant medical and technological advances,the management of Type 1 diabetes remains unsatisfactory.The most significant challenge herein is the difficulty in con-trolling post-prandial glycemia. The type and amount of car-bohydrates consumed have a greater influence on thepost-prandial hyperglycemia and glycemic variability thanother dietary factors, which consequently generatesinterest in carbohydrate-modified diets for the managementof Type 1 diabetes. Individuals with Type 1 and Type 2 dia-betes prefer low-carbohydrate diet regimens in order to ma-intain glycemic control. Few studies have examined theeffects of a low-carbohydrate diets on the course of glyce-mic control in individuals with Type 1 diabetes. Low-car-bohydrate diets may reduce glycemic fluctuation,hemoglobin A1c levels, and insulin requirement in adultswith Type 1 diabetes. The long-term effects of a low-car-bohydrate diets are not well documented, although it is be-lieved to alter the lipid profile and cause nutrientdeficiencies and cardiac complications in the long term. Inchildren and adolescents with Type 1 diabetes, it may im-prove glucose levels in the short term, although it may leadto growth retardation, deficiency in the intake of vitamin,minerals, and fiber, increase in blood lipids, fatigue, anxi-ety, and social isolation. This review discusses the effects oflow-carbohydrate diets on Type 1 diabetes.

Keywords: Low-carbohydrate diets; Type 1 diabetes;glycemic control

Önemli medikal ve teknolojik ilerlemelere rağmen Tip 1yönetimi yetersiz kalmaktadır. Bu konudaki en önemli zor-luk postprandiyal glisemiyi kontrol etmedeki güçlüktür. Tü-ketilen karbonhidratın türü ve miktarı postprandiyalhipeglisemiyi ve glisemik değişkenliği diğer diyetsel fak-törlerden daha fazla etkilemekte, bu durum da Tip 1 diya-bette karbonhidratı modifiye edilmiş diyetlere ilgiyiartırmaktadır. Tip 1 ve tip 2 diyabetli bireyler, glisemikkontrollerini sağlamak için düşük karbonhidratlı diyet uy-gulamalarını tercih etmektedir. Düşük karbonhidratlı di-yetlerin tip 1 diyabetli bireylerde glisemik seyir üzerineetkisini inceleyen sınırlı sayıda çalışma bulunmaktadır.Erişkin Tip 1 diyabetli bireylerde düşük karbonhidratlı di-yetler glisemik dalgalanmayı, hemoglobin A1c seviyelerinive insülin ihtiyacını azaltabilmektedir. Düşük karbonhid-ratlı diyetin uzun dönem etkileri tam olarak kanıtlanama-makla birlikte, uzun dönemde lipit profilinde değişikliğe,besin ögesi yetersizliği ve kardiyak komplikasyonlaraneden olabilmektedir. Tip 1 diyabetli çocuk ve adolesan-larda kısa dönemde glukoz seviyelerini iyileştirebilmekte,ancak uzun dönemde büyüme geriliğine, vitamin-mineralve posa alımında yetersizliğe, kan lipitlerinde artışa, yor-gunluk, anksiyete ve sosyal izolasyona yol açabilmektedir.Bu çalışmada, düşük karbonhidratlı diyetlerin Tip 1 diyabetüzerindeki etkilerinin tartışılması amaçlanmıştır.

Anahtar kelimeler: Düşük karbonhidratlı diyetler;Tip 1 diyabet; glisemik kontrol

112

https://orcid.org/0000-0003-1368-2605

https://orcid.org/0000-0003-0802-3955

https://orcid.org/0000-0003-4317-9226

https://orcid.org/0000-0003-0302-414X

https://orcid.org/0000-0001-5942-1852

The management of type 1 diabetes re-quires both effort and attention (5). Theoverall purpose of the treatment is toachieve a metabolic balance and thus mini-mize the short-term (hypoglycemia, dia-betic ketoacidosis) and long-termcomplications (retinopathy, nephropathy,neuropathy), and to ensure and maintainnormal growth, development, and emo-tional maturation (6). Measurement of theglycated hemoglobin (HbA1c), which is con-sidered to be the gold standard of glycemiccontrol, is the most significant indicator ofsuccessful treatment (7). It is possible toreduce the microvascular and macrovascu-lar complications of diabetes by loweringHbA1c levels by approximately 7% andlower (8). According to the Journal of theInternational Society for Pediatric and Ado-lescent Diabetes (ISPAD), the HbA1c cut-offin the treatment of type 1 diabetes shouldbe <7.0%, without significant episodes ofhypoglycemia (9). According to the Ameri-can Diabetes Association (ADA), the HbA1cthreshold should be <7.5% for all theyounger age-groups and <7% for adults(1). However, current studies have shownthat only a few individuals have achievedthese targets (10-12). In a multicenter inci-dence study called SEARCH for Diabetes,which investigated diabetes in youth inAmerica, it was observed that 17% of 3947individuals with type 1 diabetes had HbA1clevels higher than 9.5% (13).Despite recent advances in the treatment ofdiabetes, including novel insulin analogs, in-tensive insulin therapies, and new thera-peutic technologies such as continuousglucose monitoring system (CGMS), a sub-stantial number of patients fail to eitherachieve or maintain the target HbA1c levels(14). Therefore, it is stated that the existingtreatments are insufficient and additionalstrategies should be considered. Medical nu-trition therapy (MNT) is one of the most im-portant strategies in the prevention andtreatment of diabetes (15). Deviations inblood glucose levels are a function of theinput of glucose from food, mainly carbohy-drates (16, 17). Therefore, individuals withtype 1 and type 2 diabetes prefer low-car-bohydrate diets to maintain glycemic con-trol, which is also recommended by variousmedia forums (18).

Although some evidence shows that low-carbohydrate diets may be effective forweight loss in obese adults (19, 20), main-tenance of glycemic control and HbA1c inadults with type 2 diabetes, and reductionof the postprandial blood glucose and insulinrequirements (21, 22), scientific researchsupporting these findings in individuals withtype 1 diabetes is scarce (16, 23, 24). Com-pliance with these diets may be difficult andmay pose a health risk to the patient (25). Itis reported that such diets can cause hypo orhyperglycemia, increase the risks of ketosis,and may lead to an increased risk of cardiaccomplications in the long term (26, 27).Thus, the role of low-carbohydrate diets inpatients with diabetes remains unclear (1).To address this gap in the literature, this re-view will discuss the effectiveness of low-carbohydrate diets on the treatment of type1 diabetes.

Definition of a Low-Carbohydrate DietPost-prandial glycemia is the main factor af-fecting the levels of blood glucose and gly-cated hemoglobin in type 1 diabetes (28).MNT plays an important role in maintainingglycemic control (15). Dietary carbohydratesrepresent the most important factor in de-termining post-prandial blood glucose andpre-prandial insulin dose. It is the amountof glucose that is digested, absorbed, andthen circulated in the blood that determinesthe post-prandial blood glucose levels (16).According to the classification by the Amer-ican Diabetes Association (ADA), a diet witha carbohydrate intake of less than 130 g/dayor 26% of the total energy intake is definedas a low-carbohydrate diet (1), while a dietwith a carbohydrate intake of 21-70 g/dayis defined as a very low-carbohydrate diet(29).

Effects of Low-Carbohydrate Diets onGlycemic Control in Individualswith Type 1 DiabetesBefore the discovery of insulin, low-carbo-hydrate diets were used as the only treat-ment for type 1 diabetes. The subsequentdiscovery of insulin and development of flex-ible insulin-treatment methods led to the re-placement of low-carbohydrate diets bymethods that ensured the delivery of insulinin proportion to the carbohydrate intake in

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meals and current blood sugar levels (17).The carbohydrate counting method, whichenables the matching of short-acting insulinboluses with carbohydrate uptake, allows forsignificant flexibility in carbohydrate con-sumption (30). However, errors in predict-ing the carbohydrate content and insulindose, especially in high-carbohydrate meals,results in the inappropriate use of thismethod by individuals with type 1 diabetes(16). The estimated amount of carbohy-drates in the meal is subject to an error ofup to 50% (31), while absorption of insulinmay vary by up to 30% (32). Therefore, in-compatibilities and miscalculations in thecarbohydrate to insulin ratio may lead to un-predictable glucose fluctuations after meals.High insulin doses, especially in response tohigh amounts of carbohydrates, can causeunpredictable fluctuations in blood glucoselevels. It may be possible to minimize thesefluctuations and the risk of hypoglycemia byreducing the number of carbohydrates andinsulin doses. It may also be possible to pro-vide a better and more predictable absorp-tion rate and facilitate more effective use ofinsulin by reducing the amount of insulintaken by individuals (33, 34). This leads tosome individuals with type 1 diabetes, whouse flexible insulin therapy, to substantiallylimit the amount of carbohydrates con-sumed.Some studies have stated that low-carbo-hydrate diet regimens cause a reduction inthe post-prandial blood glucose levels, in-sulin dose, and body mass index (BMI) inindividuals with type 1 diabetes (16, 23,24, 30, 34). A study examining the effectsof a diet containing 30 g/day carbohydrateon glycemic control in adults with type 1and type 2 diabetes reported a more signif-icant improvement in the HbA1c values(8.4% to 5.8%) of individuals with type 2diabetes, compared to the HbA1c values ofindividuals with type 1 diabetes (6.8% to5.5%). In addition, a significant decreasein the amount of insulin administered dailyby individuals with type 1 diabetes (from 47to 30 units), compared to the amount of in-sulin administered daily by individuals withtype 2 diabetes (22.3 to 21.2 units), wasobserved. Furthermore, no incidence of se-vere hypoglycemia was observed duringthe study period of 22 months (34). In an-

other study, it was stated that the carbohy-drate quantities of less than 40 g/day werenot realistic in the general diabetic popula-tion and that such a radical decrease in car-bohydrate amounts could limit the numberof individuals wanting to try the methodand also possibly increase the risk of ke-toacidosis. In this study, 24 patients withtype 1 diabetes were given 70-90 g of car-bohydrate per day (20% of the total energyrequirement) for 12 months, by the end ofwhich, it was observed that the reductionin the amounts of carbohydrates and corre-sponding insulin doses led to a decrease inmean blood glucose as well as fluctuations,improved the HbA1c values, and signifi-cantly decreased in the incidences of hypo-glycemic episodes (nearly 6-fold reduction)(23). Similarly, Krebs et al. (2016) com-pared the effects of low-carbohydrate diet(50-75 g/day) and standard diet onglycemic control, the course of glucose anddaily insulin use, and found that the low-carbohydrate diet reduced the total dailyinsulin requirement, improved the glycemiccontrol, and reduced the BMI. However, inthis study, three of the participants with acarbohydrate-restricted diet reported thattheir insulin doses, given in proportion tothe number of carbohydrates consumed,were not sufficient to control the post-pran-dial blood glucose concentrations. It wassuggested that such a change may occurdue to the fact that gluconeogenesis fromproteins was an important source of glu-cose. It was recommended that patientswho wished to reduce carbohydrate intakeshould consider their protein intake whiledetermining insulin doses and set a pro-tein/insulin ratio (30). In a study conductedby Ranjan et al. (2017) that involved theapplication of isocaloric high-carbohydrate(≥250 g/day) and low-carbohydrate (≤50g/day) diets for one week in individualswith type 1 diabetes, it was observed thatthe glycemic times of the individuals on alow-carbohydrate diet increased, while theirglycemic fluctuations, total insulin, andbolus insulin doses decreased. Althoughfasting ketone levels have been reported toincrease in low-carbohydrate diets, noepisode of diabetic ketoacidosis wasrecorded (24). In another study, the long-term (four years) effects of low-carbohy-

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drate diets (≤75 g/day) on the bodyweight, lipid profile, and HbA1c were inves-tigated. At the end of study, a significant in-crease in the HDL cholesterol levels and adecrease in the HbA1c levels were observedin individuals with type 1 diabetes (16).Leow et al. (2018) reported that althoughketogenic diets (<55 g/day) provided bet-ter HbA1c levels and lower glycemic vari-ability, they were associated withdyslipidemia and more episodes of hypo-glycemia (26). Recently, Eiswirth et al.(2018) studied the impact of a very low-carbohydrate diet (30-50 g/day) on themean blood glucose, daily glycemic vari-ability, and HbA1c values in a patient overa 6-month period. They observed a nearnormalization of glycemic indices(HbA1c=5.3%; average daily blood glu-cose=6.1 mmol/L) with no significant hy-poglycemic episodes and minimal impacton the circulating lipids (35). In a system-atic review by Turton et al. (2018), it wasreported that the overall effect of low-car-bohydrate diets could not be determineddue to significant heterogeneity of the stud-ies involved. According to this review, somestudies reported that low-carbohydratediets effected a significant decrease in theHbA1c levels and total daily insulin dose,while other studies observed non-signifi-cant changes in these parameters. The au-thors also suggested that the intake oflow-carbohydrate diets may result in re-ducing or preventing hyperinsulinemia intype 1 diabetes by decreasing the amountof insulin required for tight glycemic control(17).In addition to direct interventional studies,observational data also demonstrate thebeneficial effects of low-carbohydrate dietson the glycemic control in individuals withtype 1 diabetes. A large observational studyof 1020 European outpatients with type 1 di-abetes showed that low carbohydrate intakewas associated with reduced HbA1c levels(36). An online study examining childrenand adults with type 1 diabetes, which fol-lowed a very low-carbohydrate diet, wascarried out by Lenners et al. (2018). In thisstudy, it was observed that the participants(both adults and children) took a very low-carbohydrate diet (average daily carbohy-drate intake of 36±14 g) over an average of

2.2±3.9 years (1.4±1.2 years for the pedi-atric age group) and their HbA1c valuesafter this diet were 5.67±0.66%(5.71±0.58% in the pediatric age group). Itwas observed that a very low-carbohydratediet provided good glycemic control in chil-dren as well as adults, and only 2% of theparticipants experienced ketoacidosis andhypoglycemia, although a decrease in theheight of the children was observed after thediagnosis was made (37). This study didhave several limitations, including an inabil-ity to confirm all the medical data. In addi-tion, this study was conducted through anonline social media group that increased therisk of selection bias, as the online commu-nity did not represent a general type 1 dia-betic community (38). Apart from this study,only case studies reporting on low-carbohy-drate diets in children and adolescents withtype 1 diabetes are available. In one suchcase study, the long-term effects of a keto-genic diet on a 3.5-year-old girl with type 1diabetes and epilepsy were investigated.During the 15-month observation period, nosevere hypoglycemia or ketoacidosis oc-curred, the HbA1c levels (6.2%) remainedwithin the desired range and no epilepticseizures were recorded. However, the pa-tient refused to follow the ketogenic dietafter 15 months (39). Similarly, in anothercase study, it was reported that a 2-year-oldepileptic patient was given a ketogenic dietafter the diagnosis of type 1 diabetes, andno epileptic seizures and episodes of dia-betic ketoacidosis occurred during the 10-month period when the ketogenic diet andinsulin therapy were administered together(40).It has been reported that low-carbohydratediets may help maintain and increase theamount of insulin produced by certain peo-ple with diabetes, in addition to providingnormal glycemic control. This effect can beeven more beneficial for individuals withtype 2 diabetes who produce some amountof insulin, as well as in patients with type 1diabetes who are in temporary remissionand honeymoon phase (34). The symptomsof diabetes occur when approximately 80%of a person‘s islet cells are destroyed (41). Ithas been reported that high-carbohydratediets can accelerate the death of the re-maining islet cells in diabetic patients and

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115

lead to a process called β-cell depletion(34). It has been shown that high levels ofblood glucose reduce the ability of islet cellsto produce insulin by inhibiting gene ex-pression and binding to critical insulin tran-scription factors (42).It is suggested that these effects, togetherwith the depletion of β-cells, may acceler-ate the destruction of islet cells, increasethe requirement of insulin, and lead topoorer glycemic control. Therefore, it isproposed that low-carbohydrate diets mayhelp in the maintenance of the remainingislet cells, reducing the need for insulin inindividuals with type 2 diabetes by pre-venting the over-activity of islet cells, andhelping individuals with newly-diagnosedtype 1 diabetes to maintain the “honey-moon phase” (34). Toth and Clemens, intwo case studies, examined the effects ofpaleolithic ketogenic diets on the manage-ment of diabetes in 19- and 9-year-oldmale patients with type 1 diabetes. Afterstarting a paleolithic ketogenic diet, theglucose levels of the patients returned tonormal and insulin treatments werestopped (after 6.5 months in the 19-year-old patient and 19 months in the 9-year-oldpatient). Furthermore, the C-peptide levelof the 19-year-old patient increased signif-icantly (more than 3-fold) within twomonths. The researchers reported that alow-carbohydrate diet may halt or reversethe autoimmune process leading to the de-struction of pancreatic β-cells. However,they emphasized that the paleolithic keto-genic diet could only be used in patientswith residual insulin secretion as a singletreatment option (42, 43).Pediatric endocrinologists and dieticians inAustralia and New Zealand reported a seriesof cases examining the effects of low-carbo-hydrate diets on the endocrine and meta-bolic outcomes in children with type 1diabetes. Accordingly, it was shown that thecarbohydrate-restricted diets, which wereapplied to reduce the course of glycemia andinsulin in children, decreased the energy in-take (if the amount of energy from carbohy-drates is not sufficiently obtained from fatand proteins), led to suboptimal growth,caused vitamin and mineral deficiencies, in-creased the metabolic profile causing car-diovascular risk, and increased the risk of

disrupted eating behaviors. In addition, thisstudy reported that the release of growthhormone was suppressed, response to thegrowth hormone decreased as dietary fatbecame the main source of energy, highamount of fat and protein consumptioncaused glycemic fluctuations, and the low-carbohydrate diet led to fatigue, anxiety,and social isolation in individuals (18). Sim-ilarly, The Diabetes Control and Complica-tions Trial (DCCT) examined the associationsof nutritional intake, physiological parame-ters, and daily activities on the averageHbA1c. It was found that lower carbohydrateand higher fat intake were associated withhigher HbA1c levels (44). This could be at-tributed to the fact that patients only tookinsulin for the intake of carbohydrates, butdid not take into account the fat and proteincontent of the diet, thus creating an incom-patibility with the dose of insulin. The resultsof clinical trials in children and adults withtype 1 diabetes are summarized in Table 1and Table 2.

ConclusionA limited number of studies have examinedthe effects of low-carbohydrate diets on thecourse of glycemia in individuals with type 1diabetes. The evidence examining the ef-fects of low-carbohydrate diets on type 1 di-abetes is controversial and contradictory. Asignificant body of research from diversestudy types shows that in the short- tomedium-term, low-carbohydrate diets havethe potential to reduce the average HbA1c,stabilize the blood glucose levels, and de-crease the insulin requirement in patientswith type 1 diabetes. Although the long-term effects of low-carbohydrate diets arenot well documented, the possible compli-cations may include alterations in the lipidprofiles, micronutrient deficiencies, and car-diac complications. Adhering to these dietscan be difficult or restrictive for some pa-tients, and they may even pose health riskssuch as hypoglycemia and ketosis for thepatients. In addition, low-carbohydrate dietsmay be more expensive. Carbohydrate-richfoods (e.g., potato, rice, bread) are cheaperthan protein-rich ones (e.g., meat, fish, anddairy foods). Low-carbohydrate diets have ahigher content of fat and protein, which canalso influence the pattern of post-prandial

116


116

117


117

Authors/year

Duration

Subjects

Diet

Primaryfindings

Dre

ssle

ret

al.,

2010

3915

mon

ths

Ath

ree-

and-

half-

year

-old

girl

1200

kcal

-N

ose

vere

hypo

glyc

emia

orke

toac

idos

is

3:1

(fat

:pro

tein

+ca

rboh

ydra

te)

-N

ocl

inic

ally

over

tse

izur

es

ratio

keto

geni

cdi

et-

Impr

oved

HbA

1cle

vels

Impr

oved

activ

ityle

vels

and

achi

evem

ents

Cas

tane

daet

al.,

2012

4010

mon

ths

Atw

o-ye

ar-o

ldgi

rl4:

1(f

at:p

rote

in+

carb

ohyd

rate

)-

No

epile

ptic

seiz

ure

and

keto

acid

osis

ratio

keto

geni

cdi

et-

Few

mild

epis

odes

ofhy

pogl

ycem

ia

-N

och

ange

inlin

ear

grow

th

Toth

and

Cle

men

s,20

1442

6.5

mon

ths

A19

-yea

rol

dbo

y2:

1(f

at:p

rote

in+

carb

ohyd

rate

)-

Impr

oved

gluc

ose

leve

ls

ratio

keto

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with

intw

om

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s

Toth

and

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1543

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)-

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sulin

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disc

ontin

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prov

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ness

Lenn

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etal

.,20

1637

1.4±

1.2

year

s31

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ild)

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diet

(36±

14g/

d)-

Sig

nific

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redu

ctio

nin

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1c

Age

d9±

4ye

ars

inth

epe

diat

ric

grou

p(1

1%±

2%to

5.71

%±

0.58

%)

-D

ecre

ase

inhe

ight

SD

Ssi

nce

diab

etes

diag

nosi

s

deBoc

ket

al.,

2017

181.

5-4

year

sCas

ese

ries

(6ch

ildre

n)Lo

wca

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tedi

et-

Def

icie

ntto

tale

nerg

yin

take

3.5-

12ye

ars

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5g/

dca

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Def

icie

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thro

pom

etric

mea

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men

ts.

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idpr

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-A

poor

grow

thho

rmon

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spon

se

-Fa

tigue

and

low

enjo

ymen

tfo

rsp

orts

Tabl

e1.

Sum

mar

yof

clin

ical

tria

lsin

child

and

adol

esce

nts

with

type

1di

abet

esan

dpr

imar

yfin

ding

.

118


118

Authors/year

Duration

Subjects

Diet

Primaryfindings

O’N

eill

etal

.,20

0334

21.4

mon

ths

30pa

rtic

ipan

ts(2

0pa

rtic

ipan

tsw

ithVe

rylo

wca

rboh

ydra

tedi

et(3

0g/

d)Bot

hty

pe1

and

type

2di

abet

ics,

ther

e

type

2,10

part

icip

ants

with

type

1)w

asa

sign

ifica

ntim

prov

emen

tin

glyc

emic

cont

rola

ndm

ean

fast

ing

lipid

prof

ile

Nie

lsen

etal

.,20

0523

12m

onth

s22

part

icip

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70-9

0g/

d-T

heH

bAlc

leve

lwas

sign

ifica

ntly

low

ered

Age

d51

±10

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s-T

hem

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nsul

inre

quirem

ents

wer

ere

duce

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leve

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ifica

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ered

-Rat

eof

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ifica

ntly

low

ered

.

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lsen

etal

.,20

1216

4ye

ars

48pa

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ipan

ts(3

1w

omen

)Car

bohy

drat

e-re

strict

eddi

et-M

ean

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1cfo

ral

latt

aind

ers

was

atth

est

art,

Age

d52

±11

.5ye

ars

(75

g/d

orle

ss)

at3

mon

ths

and

4ye

ars

7.6%

±1.

0%,

6.3±

0.7%

,6.

9±1.

0%,

resp

ectiv

ely.

-Sig

nific

ant

rise

inH

DL

chol

este

roll

evel

s

Kre

bset

al.,

2016

3012

wee

ks10

part

icip

ants

Sta

ndar

ddi

etvs

.-S

igni

fican

tre

duct

ion

inH

bA1c

and

daily

insu

lin

(3w

omen

)Lo

wca

rboh

ydra

tedi

et(7

5g/

d)us

ein

carb

ohyd

rate

-res

tric

ted

grou

p

Age

d44

.6±

8.9

Ranj

anet

al.,

2017

241

wee

k10

part

icip

ant

(4w

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ocal

oric

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resu

lted

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ore

time

Age

d48

±10

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Hig

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less

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etal

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1826

1.5

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geni

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artic

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74±

20%

and

3±8%

of

36.1

±6.

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<55

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thei

rtim

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chol

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DL

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rol

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dtr

igly

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Eisw

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835

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uctio

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insu

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se(f

rom

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uctio

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prof

ile,n

osi

gnifi

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hypo

glyc

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even

ts

Tabl

e2.

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mar

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clin

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tria

lsin

adul

tsw

ithty

pe1

diab

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and

prim

ary

findi

ngs.

glycemic homeostasis. A low-carbohydratediet may also cause hyperglycemic effectsdue to fat and protein metabolism to formglucose.Low-carbohydrate diets are not recom-mended for children and adolescents withtype 1 diabetes, as they may hinder theirgrowth and development. Low-carbohydratediets may cause growth retardation; in-crease blood lipids; deficiency of vitamin,minerals, and fiber; increase social isolation,and increase the risk of improper eating be-haviors in children and adolescents. Inter-national clinical guidelines for themanagement of type 1 diabetes offer ahealthy and balanced diet program that con-sists of a variety of nutrients. The recom-mendations on nutrition for individuals withdiabetes, as well as their families, should bebased on scientific evidence and not on tes-timonials. Individuals with diabetes andtheir families that adopt a restrictive nutri-tion program to improve their glycemic con-trol should be carefully monitored andconsulted on the physical and psychosocialeffects of a low-carbohydrate diet by theirdiabetes team. In order to reduce glycemicfluctuations, individuals with type 1 diabetesshould be trained to consume foods with lowglycemic index and low glycemic load, pre-pare the appropriate dose of insulin beforemeals while consuming food containing car-bohydrates, create meal-time routines, min-imize the frequency of snacking, andcalculate the appropriate insulin dose basedon the high amount of fat and proteins con-sumed. In individuals with type 1 diabetes,fulfilling the total energy requirement frombalanced macronutrient sources and in-creasing the quality of diet by consumptionof fruits and vegetables, whole-wheat bread,legumes, and whole grain products can im-prove the metabolic profile.There are some limitations to this review. Inthe evaluated studies, small sample sizes,short follow-up periods, multiple study de-signs, and inadequate dietary reportsyielded different and contradictory resultson the effect of low-carbohydrate diets onglycemic control. In conclusion, more ran-domized controlled trials and evidence onthe long-term effects of low-carbohydratediets on the treatment of type 1 diabetes areneeded.

Source of FinanceThe authors declared that this study re-ceived no financial support.

Conflict of InterestThe authors declare no conflict of interest.

Authorship ContributionsIdea/Concept: Rukiye Bozbulut, Esra DöğerDesign: Rukiye Bozbulut, Esra Döğer, AysunBideci, Orhun Çamurdan, Peyami Cinaz, Con-trol/Supervision: Rukiye Bozbulut, EsraDöğer, Orhun Çamurdan Data Collectionand/or Processing: Rukiye Bozbulut, EsraDöğer, Analysis and/or Interpretation: RukiyeBozbulut, Esra Döğer, Aysun Bideci, OrhunÇamurdan, Peyami Cinaz, Literature Review:Rukiye Bozbulut Writing the article: RukiyeBozbulut, Esra Döğer, Critical Review: RukiyeBozbulut, Esra Döğer, Aysun Bideci, OrhunÇamurdan, Peyami Cinaz, References andFunding: Rukiye Bozbulut, Esra Döğer Mate-rials: Rukiye Bozbulut, Esra Döğer, AysunBideci, Orhun Çamurdan, Peyami Cinaz.

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25.Diamond M, Clark EJ. Low-carbohydrate diets andglycaemic control in type 1 diabetes mellitus. EMJDiabet. 2018;6:70-77.

26.Leow ZZX, Guelfi KJ, Davis EA, Jones TW, FournierPA. The glycaemic benefits of a very-low-carbohydrate ketogenic diet in adults with Type 1diabetes mellitus may be opposed by increasedhypoglycaemia risk and dyslipidaemia. Diabet Med.2018;35:1258-1263. [Crossref] [PubMed]

27.Bilsborough SA, Crowe TC. Low-carbohydrate diets:what are the potential short-and long-term healthimplications? Asia Pac J Clin Nutr. 2003;12:396-404

28.Dzygalo K, Szypowska A. Impact of insulins gluli-sine and aspart on postprandial glycemia after ahigh-glycemic index meal in children with type 1diabetes. Eur J Endocrinol. 2014;170:539-545.[Crossref] [PubMed]

29.Wheeler ML, Dunbar SA, Jaacks LM, Karmally W,Mayer-Davis EJ, Wylie-Rosett J, Yancy WS Jr. Mac-ronutrients, food groups, and eating patterns in themanagement of diabetes a systematic review of theliterature, 2010. Diabetes Care. 2012;35:434-445. [Crossref] [PubMed] [PMC]

30.Krebs JD, Parry Strong A, Cresswell P, Reynolds AN,Hanna A, Haesusler S. A randomised trial of the fea-sibility of a low carbohydrate diet vs standard car-bohydrate counting in adults with type 1 diabetestaking body weight into account. Asia Pac J ClinNutr. 2016;25:78-84.

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31.Waldron S. Controversies in the dietary manage-ment of diabetes in childhood and adolescence. BrJ Hosp Med. 1996;56:450-454.

32.Heinemann L. Variability of insulin absorption andinsulin action. Diabetes Technol Ther. 2002;4:673-682. [Crossref] [PubMed]

33.Feinman RD, Pogozelski WK, Astrup A, BernsteinRK, Fine EJ, Westman EC, Accurso A, Frassetto L,Gower BA, McFarlane SI, Nielsen JV, Krarup T, Sas-low L, Roth KS, Vernon MC, Volek JS, Wilshire GB,Dahlqvist A, Sundberg R, Childers A, Morrison K,Manninen AH, Dashti HM, Wood RJ, Wortman J,Worm N. Dietary carbohydrate restriction as thefirst approach in diabetes management: critical re-view and evidence base. Nutrition. 2015;31:1-13. [Crossref] [PubMed]

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39.Dressler A, Reithofer E, Trimmel-Schwahofer P, Kle-bermasz K, Prayer D, Kasprian G, Rami B, SchoberE, Feucht M. Type 1 diabetes and epilepsy: efficacyand safety of the ketogenic diet. Epilepsia.2010;51:1086-1089. [Crossref] [PubMed]

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https://doi.org/10.1542/peds.2018-1536B

https://doi.org/10.1016/j.nut.2014.06.011



https://doi.org/10.1542/peds.2017-3349





https://doi.org/10.1089/1540419031361345


https://doi.org/10.5348/ijcri-2015121-CR-10582

https://doi.org/10.5348/ijcri-2014124-CR-10435

https://doi.org/10.1089/152091502320798312

https://doi.org/10.3945/ajcn.2008.26498

https://doi.org/10.1046/j.1464-5491.2000.00283.x







https://doi.org/10.1111/j.1528-1167.2010.02543.x

https://doi.org/10.1530/EDM-18-0002


Case ReportTurk J Endocrinol Metab 2019;23:122-124

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Address for Correspondence: Mustafa Can, Necmettin Erbakan University Meram Faculty of Medicine,Department of Endocrinology and Metabolism, Konya, TurkeyPhone: +90 332 223 60 00 E-mail: [email protected]

Received: 08/03/2019 Accepted: 14/05/2019 Available online: 19/06/2019


Insulin Washout in Fine-Needle Aspiration Fluid forPreoperative Diagnosis of Suspicious Lesion in Pati-

ents with Insulinoma: A Case Reportİnsülinoma Hastalarında Şüpheli Lezyonun

Preoperatif Tanısı İçin İnce İğne Aspirasyon Sıvısındaİnsülin Yıkama: Bir Olgu Sunumu

Department of Endocrinology and Metabolism, Necmettin Erbakan University Meram Faculty of Medicine, Konya, Turkey*Department of Gastroenterology, Necmettin Erbakan University Meram Faculty of Medicine, Konya, Turkey

IntroductionInsulinomas form the most common neu-roendocrine tumor of the pancreas. The an-nual incidence of these tumors has beenreported to be about 1 to 4 people per onemillion people years (1). It is most common

in individuals between the age group of 40to 50 years and shows a slightly higher fe-male predeliction (2). Insulinomas aremostly solitary benign tumors, with only lessthan 10% of the cases being malignant. Thegreat majority of insulinomas are sporadic,

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Insulinomas, the most common neuroendocrine tumors ofthe pancreas, are usually solitary in nature. Yet, they may bedifficult to localize. A 29-year-old female patient with neu-rologic complaints including drowsiness, meaningless spe-ech and temporary dementia (not recognizing her relatives),was evaluated for hypoglycemia. According to the critical la-boratories investigations, the patient was found to be havinghyperinsulinemic hypoglycemia. After diagnosing insulinomaby biochemical tests, the tumor was localized usingendoscopic ultrasonography and fine needle aspiration bi-opsy was performed on the insulin washout material to ob-tain a prompt confirmation. After localization of the tumor,subtotal pancreatectomy was performed. The patient’ssymptoms were relieved and did not re-occur. Thus, thiscase report suggests that the insulin washout from fine ne-edle aspiration biopsy can be successfully employed duringndoscopic ultrasonography to obtain a hasty diagnosis sinceit delivers faster results and is a much more convenient app-roach than the pathological examinations. It promptly con-firms the tumor site and may, therefore, be employed incases of difficult tumor localization.

Keywords: Insulinoma; hypoglycemia;endoscopic ultrasonography;washout method

Pankreasın en sık görülen nöroendokrin tümörleri olan in-sülinomalar, genellikle tek bir soliter tümöre bağlı olmala-rına rağmen lokalizasyonları zor olabilmektedir. Uyku hâli,anlamsız konuşmalar ve geçici demans (yakınlarını tanı-mama) gibi nörolojik şikâyetleri olan 29 yaşındaki kadınhasta hipoglisemi nedeni ile değerlendirildi. Kritik laboratu-var tetkiklerine göre hastanın hiperinsülinemik hipoglisemisiolduğu saptandı. İnsülinomanın biyokimyasal tanısını taki-ben, tümörü endoskopik ultrasonografi ile lokalize edildi vehızlı konfirmasyon için ince iğne aspirasyon biyopsi mater-yalinde insülin yıkama yapıldı. Tümörün lokalizasyonundansonra subtotal pankreatektomi yapıldı; hastanın şikâyetleridüzeldi ve yeniden oluşmadı. Bu olgu sunumu, endoskopikultrasonografi sırasında ince iğne aspirasyon biyopsi mater-yalinde insülin yıkama yönteminin hızlı tanı almak için ba-şarılı bir şekilde uygulanabileceğini, çünkü daha hızlı sonuçverdiğini ve patolojik incelemeden çok daha uygun bir biryaklaşım olduğunu düşündürmektedir. İnsülin yıkama yön-temi tümör bölgesini hızlı bir şekilde konfirme etmektedirve bu nedenle tümör lokalizasyonunun zor olduğu vakalardakullanılabilir.

Anahtar kelimeler: İnsülinoma; hipoglisemi;endoskopik ultrasonografi;yıkama yöntemi

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https://orcid.org/0000-0001-8515-8760

https://orcid.org/0000-0001-7629-9625

https://orcid.org/0000-0003-3241-4104

https://orcid.org/0000-0001-7990-8350

https://orcid.org/0000-0002-5225-4905

https://orcid.org/0000-0001-9908-7449

https://orcid.org/0000-0002-6473-4164

with 10% occurring as multiple and as acomponent of Multiple Endocrine Neoplasiasyndrome type 1 (MEN-1).The typical Whipple triad of insulinoma com-prises hypoglycemia symptoms when theblood glucose level is less than 50 mg/dLand improvement of these symptoms withglucose intake. It is diagnosed by hyperin-sulinemia and elevated C-peptide level atthe time of hypoglycemia. The most reliabletest used for its diagnosis is a prolonged su-pervised fasting test as a majority of pa-tients develop hypoglycemia within the first24 h of this test (3, 4).Once hyperinsulinism is confirmed on thebasis of biochemical tests, localization of thetumor becomes a challenging task as theknown pre-operative imaging methods maypose difficulties. Here, the authors presenta case of insulinoma wherein tumor local-ization was done using FNAB with insulinwashout method via Endoscopic Ultrasonog-raphy (EUS) after confirmation of biochem-ical hyperinsulinism.

Case ReportA 29-year-old female patient, with a bloodglucose level of 50 mg/dL, reported to theneurology polyclinic with complaints includingdrowsiness, meaningless speech and tempo-rary dementia (unable to recognize her rela-tives). The patient’s symptoms improvedsoon after administration of oral carbohy-drates and no neurological pathology was de-tected. Subsequently, similar complaintsrepeated several times during the same day,and the patient was referred to the en-docrinology polyclinic. The patient was ad-mitted to the endocrinology department forfurther examination of the etiology of hypo-glycemia. The patient’s past medical historywas nil, she was not on any medications andgave no history of illicit drug use. Physical ex-amination revealed that all the vital functionswere normal. Systemic examination of thepatient was normal. At the time of admission,routine laboratory test results were as fol-lows: serum glucose- 60 mg/dL, TSH-1.37µlU/mL, HbA1c-5%, cortisol- 18 µg/dL. Com-plete blood count, liver function tests, andkidney function tests were all normal. The pa-tient was subjected to a prolonged supervisedfasting test. At the 6th hour of the test, bloodglucose was observed to be 50 mg/dL and at

the same time, the C-peptide and insulin lev-els were 2.66 ng/mL and 25.7 µIU/mL, re-spectively. The insulin/glucose ratio was0.51. Anterior pituitary hormones, calcium,PTH and gastrin levels were examined torule out MEN-1 syndrome and were found tobe normal.No pancreatic mass was detected by abdom-inal magnetic resonance imaging (MRI). EUSrevealed a hyperechoic homogeneous lesion,measuring 17×10 mm with unclear bound-aries, present between the pancreatic bodyand the tail. Fine-needle aspiration of this le-sion was performed under EUS guidance andinsulin wash-out was performed on the biopsymaterial. The insulin level in washout materialwas observed to be 254 µIU/mL. FNAB re-vealed pathologic findings that were consis-tent with those of a pancreaticneuroendocrine tumor (insulinoma). Im-munohistochemical staining was positive forpancytokerin, cd56 and chromogranin. Im-munohistochemical staining for insulin was,likewise, positive. All these findings confirmedthe neuroendocrine nature of the lesion. Theproliferation index Ki-67 was positive in 1-2%of the tumor cells. The patient underwentsubtotal pancreatectomy. The pathology re-sult was reported as follows: pancreatic neu-roendocrine tumor, functional (insulinoma),chromogranin (+), insulin (+), Ki 67 indexwas 4%. In the postoperative follow-up, thepatient’s blood glucose levels were found tobe normal with no hypoglycemia.Informed consent from the patient wastaken prior to the treatment procedures.

DiscussionSurgery appears to be the only potentialmethod of curing patients with insulinomas(5). Therefore, radiological localization ofthe lesion after clinical and biochemical di-agnosis of insulinoma holds great impor-tance. Insulinomas are usually solitarylesions, measuring less than 2 cm, therebymaking its localization difficult (5). Insulino-mas demonstrate their characteristic fea-tures in both CT and MRI, with a reportedsensitivity of 33-64% and 40-90%, respec-tively, for CT and MRI (6, 7). In the presentcase, the lesion could not be visualized inMRI and subsequently, the EUS method wasemployed. EUS is reported to have excellentsensitivity (85-95%) (8, 9). In the study of

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Kann et al., 10 insulinoma patients under-went FNAB with EUS and the diagnostic ac-curacy of FNAB was observed to be 70%(10). In the present case, after localizationof the lesion with EUS, insulin wash-outfrom FNAB was performed at the same ses-sion. The insulin level, in the wash-out sam-ple, was found to be 254 µIU/mL, thusprompting that localization of the tumor withEUS can be confirmed by insulin washout.Earlier studies have shown that the correctcombination of pre-operative localizationmethods for insulinomas helps choose apancreas-sparing approach such as enucle-ation in the treatment plan (11, 12). The au-thors deliberate that better results can beobtained with the combined use of FNAB andinsulin wash-out technique during EUS.Furthermore, the detection of insulin levelsin the washout sample is sufficiently fasterthan that in the pathological result, whichmay make the washout method a muchmore convenient procedure. Further studiesinvolving a large number of patients must beperformed in this field so that a cut-off valuefor the insulin washout method may be pre-sented. Thereafter, insulin washout may be-come a method that can be applied in caseswhere the tumor localization is difficult.

Source of FinanceDuring this study, no financial or spiritual sup-port was received neither from any pharma-ceutical company that has a direct connectionwith the research subject, nor from a companythat provides or produces medical instrumentsand materials which may negatively affect theevaluation process of this study.


Authorship ContributionsIdea/Concept: Melia Karaköse, HüseyinAtaseven; Design: Melia Karaköse, HüseyinAtaseven; Control/Supervision: FeridunKarakurt; Data Collection and/or Processing:Muhammet Kocabaş; Analysis and/or Inter-pretation: Mustafa Kulaksızoğlu; Literature

Review: Muhammet Kocabaş; Writing the Ar-ticle: Melia Karaköse, Muhammet Kocabaş,Mustafa Can; Critical Review: Melia Karaköse,Mustafa Can; References and Fundings:Mustafa Can; Materials: İlker Cordan.

References1. Okabayashi T, Shima Y, Sumiyoshi T, Kozuki A, Ito S,

Ogawa Y, Kobayashi M, Hanazaki K. Diagnosis andmanagement of insulinoma. World J Gastroenterol.2013;19:829-837. [Crossref] [PubMed] [PMC]

2. Zhao YP, Zhan HX, Zhang TP, Cong L, Dai MH, Liao Q,Cai LX. Surgical management of patients with insuli-nomas: result of 292 cases in a single institution. JSurg Oncol. 2011;103:169-174. [Crossref] [PubMed]

3. Grant CS. Insulinoma. Best Pract Res Clin Gas-troenterol. 2005;19:783-798. [Crossref] [PubMed]

4. Vaidakis D, Karoubalis J, Pappa T, Piaditis G, Zo-grafos GN. Pancreatic insulinoma: current issuesand trends. Hepatobiliary Pancreat Dis Int.2010;9:234-241.

5. Christ E, Wild D, Ederer S, Béhé M, Nicolas G, CaplinME, Brändle M, Clerici T, Fischli S, Stettler C, Ell PJ,Seufert J, Gloor B, Perren A, Reubi JC, Forrer F.Glucagon-like peptide-1 receptor imaging for the lo-calisation of insulinomas: a prospective multicentreimaging study. Lancet Diabetes Endocrinol.2013;1:115-122. [Crossref]

6. Sotoudehmanesh R, Hedayat A, Shirazian N,Shahraeeni S, Ainechi S, Zeinali F, Kolahdoozan S.Endoscopic ultrasonography (EUS) in the localiza-tion of insulinoma. Endocrine. 2007;31:238-241.[Crossref] [PubMed]

7. McAuley G, Delaney H, Colville J, Lyburn I, WorsleyD, Govender P, Torreggiani WC. Multimodality pre-operative imaging of pancreatic insulinomas. ClinRadiol. 2005;60:1039-1050. [Crossref] [PubMed]

8. Masciocchi M. Pancreatic imaging. Endocrinol MetabClin North Am. 2017;46:761-781. [Crossref] [PubMed]

9. Nockel P, Babic B, Millo C, Herscovitch P, Patel D,Nilubol N, Sadowski SM, Cochran C, Gorden P, Ke-bebew E. Localization of insulinoma using 68 Ga-DOTATATE PET/CT scan. J Clin Endocrinol Metab.2017;102:195-199. [Crossref] [PubMed] [PMC]

10. Kann PH, Moll R, Bartsch D, Pfützner A, Forst T, Tam-agno G, Goebel JN, Fourkiotis V, Bergmann SR, Colli-enne M. Endoscopic ultrasound-guided fine-needleaspiration biopsy (EUS-FNA) in insulinomas: indica-tions and clinical relevance in a single investigator co-hort of 47 patients. Endocrine. 2017;56:158-163.[Crossref] [PubMed]

11.Goh BK, Ooi LL, Cheow PC, Tan YM, Ong HS, ChungYF, Chow PK, Wong WK, Soo KC. Accurate preoper-ative localization of insulinomas avoids the need forblind resection and reoperation: analysis of a singleinstitution experience with 17 surgically treated tu-mors over 19 years. J Gastrointest Surg.2009;13:1071-1077. [Crossref] [PubMed]

12.Zhang T, Mu Y, Qu L, Wang X, Lv Z, Du J, Guo Q, BaJ, Dou J, Lu J. Accurate combined preoperative lo-calization of insulinomas aid the choice for enucle-ation: a single institution experience over 25 years.J Hepatogastroenterology. 2012;59:1282-1285.[Crossref] [PubMed]

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https://doi.org/10.1016/j.crad.2005.06.005


https://doi.org/10.1002/jso.21773


https://doi.org/10.3748/wjg.v19.i6.829

https://doi.org/10.5754/hge11896

https://doi.org/10.1007/s12020-016-1179-z



https://doi.org/10.1210/jc.2016-3445

https://doi.org/10.1007/s12020-007-0045-4





https://doi.org/10.1016/S2213-8587(13)70049-4


https://doi.org/10.1016/j.ecl.2017.04.006



https://doi.org/10.1016/j.bpg.2005.05.008

https://doi.org/10.1007/s11605-009-0858-y

Address for Correspondence: Başak Bolayır, Gazi University Faculty of Medicine,Department of Internal Medicine, Division of Endocrinology and Metabolism, Ankara, Turkey

Phone: +903122025829 E-mail: [email protected]: 24/10/2018 Received in revised form: 31/01/2019 Accepted: 24/02/2019 Available online: 01/04/2019


Adrenocorticotropic Hormon-SecretingPheochromocytoma: A Rare Cause of

Cushing’s SyndromeAdrenokortikotropik Hormon Salgılayan Feokromositoma:

Cushing Sendromunun Nadir Bir Nedeni

Department of Internal Medicine, Division of Endocrinology and Metabolism, Gazi University Faculty of Medicine, Ankara, Turkey*Department of Internal Medicine, Gazi University Faculty of Medicine, Ankara, Turkey**Department of General Surgery, Gazi University Faculty of Medicine, Ankara, Turkey

***Department of Pathology, Gazi University Faculty of Medicine, Ankara, Turkey****Division of Endocrinology and Metabolism, Yüksek Ihtisas University, Ankara, Turkey


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Pheochromocytoma is a rare cause of ectopic Cushing’ssyndrome and presents a challenge to the clinician in thediagnosis and treatment. In this study, a rare case of adre-nocorticotropic hormone-producing pheochromocytoma ispresented. A 55-years-old man with the symptoms ofhypercortisolism, multidrug-resistant hypertension, and anadrenal mass is presented. The laboratory results were con-sistent with hypercortisolism, high plasma adrenocorticot-ropic hormone, high 24-hour urine metanephrine andnormetanephrine and severe hypokalemia. Abdominal com-puterized tomography showed a 3-cm non-adenoma left ad-renal mass. After preoperative management, leftadrenalectomy was performed. A histopathological exami-nation revealed a 2.5 cm pheochromocytoma with focal po-sitivity for adrenocorticotropic hormone. The patient wasdischarged with full recovery under hydrocortisone replace-ment therapy. Furthermore, six weeks after the operation,24-hour urinary excretion of metanephrine and normeta-nephrine was within normal ranges. In conclusion, an adre-nocorticotropic hormone-producing pheochromocytomashould be considered in patients with clinical manifestationsof ectopic Cushing’s syndrome and adrenal mass.

Keywords: Ectopic Cushing’s syndrome;pheochromocytoma; ACTH staining

Feokromositoma ektopik Cushing senrfomu’nun nadir birnedenidir, tanı ve tedavi aşamalarında klinisyen için güçlükoluşturmaktadır. Çalışmamızda, nadir görülen adrenokorti-kotropik hormon salgılayan feokromositomalı bir hastanınsunulması amaçlanmıştır. Elli beş yaşında erkek hasta; hi-perkortizolizm semptomları, dirençli hipertansiyon ve ad-renal kitle nedeniyle kliniğimize kabul edildi. Laboratuvarbulguları hiperkortizolizmi destekler nitelikte idi. Yüksekplazma adrenokortikotropik hormondüzeyleri, artmış 24-saatlik idrar metanefrin ve normetanefrin düzeyleri ve ciddihipokalemi olduğu görüldü. Abdomen bilgisayarlı tomogra-fisinde sol adrenal bezde 3 cm boyutunda non-adenomatözlezyon saptandı. Preoperatif hazırlık sonrası, sol adrena-lektomi operasyonu yapıldı. Histopatolojik incelemede ad-renokortikotropik hormon ile fokal boyanma gösteren 2,5cm boyutunda feokromositoma rapor edildi. Operasyonsonrası hidrokortizon tedavisi ile taburcu edildi. Operas-yondan altı hafta sonra, 24-saatlik idrar metanefrin ve nor-metanefrin düzeylerinin normal aralıkta olduğu görüldü.Sonuç olarak, adrenokortikotropik hormon-üreten feokro-mositoma ektopik Cushing sendromu düşünülen ve adrenalkitlesi olan hastalarda akılda bulundurulması gereken birtanıdır.

Anahtar kelimeler: Ektopik Cushing sendromu;feokromositoma; ACTH boyama

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Case is presented as a poster at 99th Annual Meeting of the Endocrine Society(ENDO April 01-04 2017, Orlando, FL).

https://orcid.org/0000-0002-3316-3020

https://orcid.org/0000-0003-1276-9215

https://orcid.org/0000-0002-4424-3800

https://orcid.org/0000-0001-6870-4942

https://orcid.org/0000-0003-1987-486x

https://orcid.org/0000-0002-6168-937X

https://orcid.org/0000-0003-4188-2823

https://orcid.org/0000-0003-0457-6560

https://orcid.org/0000-0003-4143-4414

https://orcid.org/0000-0002-6707-7761

IntroductionCushing’s syndrome (CS) is characterized asinappropriately high levels of glucocorti-coids; the signs and symptoms of diseaseresult from the chronic exposure of tissuesto glucocorticoids (1). Endogenous CS is anextremely rare disorder, wherein the major-ity of cases result from adrenocorticotropichormone (ACTH)-secreting pituitary adeno-mas. Ectopic ACTH production by a non-pi-tuitary tumor such as bronchial carcinoidaccounts for approximately 10-15% of CScases (2). Remaining of the cases are ACTH-independent, and adrenal glands are re-sponsible for excess steroids.ACTH-producing pheochromocytoma is arare cause of ectopic CS (3). In cases whenpheochromocytomas co-secretes cate-cholamines and ACTH, they cause severedisease manifestations because of excesscortisol and catecholamine. The patientsmay present with classical signs and symp-toms of CS. Adrenal mass, biochemical hall-marks of ACTH-dependent hypercortisolism,and elevated catecholamine levels indicatethe presence of ACTH-secreting pheochro-mocytoma. We present a rare case of ec-topic ACTH syndrome associated withpheochromocytoma.

Case ReportAn informed consent was obtained from thepatient for case report. A 55-year-old manwho had undergone radiofrequency ablationfor atrioventricular nodal reentrant tachy-cardia was consulted from cardiology to en-docrinology because of resistanthypertension and hypokalemia. The patientsuffered from severe proximal muscle weak-ness, fatigue, polyuria, and polydipsia. Hehad been diagnosed with type 2 diabetesmellitus and hypertension for three years.He had 30 pack-year smoking history.During the physical examination, severesigns of CS were recorded such as proximalmyopathy, central obesity with wasted ex-tremities, easy bruising, skin atrophy, andplethora. No abdominal striae were de-tected. Blood pressure was recorded as150/90 mmHg despite treatment with acombination of an angiotensinogen receptorblocker, a calcium antagonist, a thiazide di-uretic, and a beta-blocker. Initial laboratoryexamination revealed severe hypokalemia

(2.7 mmol/L [reference value: 3.5-5.1]).The tests were consistent with ACTH-depen-dent CS: abnormal low-dose dexametha-sone suppression test (cortisol: 63.0 µg/dL;positive result: >1.8 µg/dL), elevated sali-vary cortisol (17.4 µg/dL, reference value:<0.43 µg/dL), elevated urinary cortisol (290µg/24 h, reference value: 3.5-45 µg/24 h),loss of diurnal variation (morning cortisol:57.8 µg/dL, late-night cortisol: 55.8 µg/dL),and high ACTH level: 241.0 (0-46.0) pg/mL.Thoraco-abdominal computerized tomogra-phy was performed for the etiological inves-tigation of ectopic CS and revealed a 3.5-cmleft adrenal mass with high precontrastHaunsfield unit value (31 HU) and low wash-out value (26%). T2-weighted magnetic res-onance imaging showed a hyperintensemass on the left adrenal (Figure 1). A 24-hour urine collection study revealed ele-vated excretion of metanephrine (1187µg/24 h, reference value: 0-374 µg/24 h)and normetanephrine (1078 µg/24 h, refer-ence: 0-778 µg/24 h; Table 1).For a possible malignancy that may alsocause ectopic ACTH syndrome, metabolicimaging with fluorine-18 fluorodeoxyglucose([18F]-FDG) positron emission tomographywas performed. It revealed pathological FDGuptake in the adrenal mass and also on theright side of the lung. Because of tobaccouse history, bronchoalveolar lavage and en-doscopic bronchial biopsy were performedfor excluding pulmonary malignancy. The re-sults were compatible with pulmonary infec-tion. He was treated with broad-spectrumantibiotics for potential infections. Leftadrenalectomy was planned for the adrenal

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Figure 1: T2-weighted MRI shows high-signal pheoch-romocytoma in the left adrenal gland.

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mass. Potassium replacement for hy-pokalemia and insulin for the treatment ofdiabetes were needed. Alpha-and then beta-blockers were used to control blood pressureand prevent an intraoperative hypertensivecrisis. Furthermore, prophylactic anticoagu-lation was initiated.Metyrapone treatment was initiated to con-trol the symptoms of severe hypercorti-solism. During metyrapone therapy, thepatient suffered from dyspnea, fever, andhypoxia despite ongoing antibiotherapy andprophylactic anticoagulation. Bilateral infil-trates were seen on the chest radiograph.Trimethoprim-sulfamethoxazole and oxy-genation with nasal cannula were initiatedpromptly because of the strong clinicalsuspicion of pneumocystis pneumonia(PCP). The clinical status improved with thistreatment. Left adrenalectomy was per-formed without any complication. Ahistopathological examination revealed a2.5-cm pheochromocytoma without necro-sis, atypical mitoses, extra-adrenal exten-sion, and vascular invasion. Additionalimmunohistochemical staining for ACTH wasfound to be focally positive (Figure 2). Peri-operative corticosteroid coverage was ad-ministered and hydrocortisone replacementtherapy was needed as maintenance ther-apy because of the long-standing suppres-sion of hypothalamic-pituitary axis.Following surgery, hypokalemia, hyperten-sion, and hyperglycemia resolved consider-ably. Insulin treatment was not required and

antihypertensive medications were tapered.Furthermore, six weeks postoperatively, 24-hour urinary excretion of metanephrines andACTH levels were within the normal range(Table 1).

DiscussionPheochromocytoma is a rare cause of ec-topic ACTH syndrome and presents a chal-lenge to the clinician in the diagnosis andtreatment. ACTH-secreting pheochromocy-tomas are the source of ACTH secretion inapproximately 5% of ectopic ACTH-relatedCS. The cases were first described in 1964by Bourgoignie et al. (4). Most of the casesincluded women and ranged in age from 26to 74 years (5).

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Figure 2: Histopathology of the adrenal mass: adreno-medullary tumor with immunopositive staining for ACTH(ACTH staining, IHC ×200).

NA: Non-available; ACTH: Adrenocorticotropic hormone; PAC: Plasma aldosterone concentration; PRA: Plasma renin activity; h: hour.

Laboratory test Preoperative Six weeks after the operation Reference rangeSerum potassium (mmol/L) 2.7 4.5 3.5–5.1

HbA1c (%) 9.5 6.0

Fasting plasma glucose (mg/dL) 211 85 70–100

24-hour urinary cortisol (mcg/24 h) 290 NA 3.5–45

Salivary cortisol (mcg/dL) 17.4 0.075 <0.43

Serum cortisol (mcg/dL) 57.8 10.9 6.2–19.4

Plasma ACTH (pg/mL) 241.0 43.1 0–46

Plasma aldosterone (ng/dL) 3.17 NA 0–16

PAC/PRA ratio ( ng/dL to ng/mL/h) 5.7 NA <20

24-hour urinary noradrenaline (mcg/24 h) 247.0 52.7 23–105

24-hour urinary adrenaline (mcg/24 h) 63.2 1.26 4–20

24-hour urinary metanephrine (mcg/24 h) 1187.0 11.2 0–374

24-hour urinary normetanephrine (mcg/24 h) 1078.0 328.0 0–778

Table 1. Laboratory results before and after adrenalectomy.

Our patient presented with resistant hyper-tension and hypokalemia. Hypertension ismore common in ACTH-producing pheochro-mocytomas than other cases of ectopic CS(5, 6). It may be because of high cortisollevels coexisting with high catecholaminelevels. High mineralocorticoid activity causeshypokalemia, as noted in our patient. Highcortisol levels lead to mineralocorticoidactivity because of saturating 11-β-hydroxysteroid dehydrogenase type 2 en-zymes, which is responsible for cortisolmetabolism.In our case, the diagnosis of ACTH-produc-ing pheochromocytoma was suspected be-cause of hypercortisolism symptoms, highACTH levels, and unilateral adrenal masswith high HU. High catecholamine levelssupported the diagnosis. In 1979, Formansuggested the first criteria for the diagnosisof ACTH-secreting pheochromocytoma,which were revised by Chen in 1995 (7, 8).These criteria are (a) clinical and laboratoryevidence of hypercortisolism, (b) highplasma ACTH levels, (c) biochemical evi-dence of pheochromocytoma and adrenalmass with a bright T2 signal in MRI, (d) res-olution of signs and symptoms of excesscortisol and catecholamine after unilateraladrenalectomy, and (e) rapid normalizationof plasma ACTH levels after adrenalectomy.Our patient met three criteria before surgeryand the other two criteria were fulfilled afteradrenalectomy.Early diagnosis and preoperative prepara-tion are important for complete remissionwithout complications. Severe hypercorti-solism may be a life-threatening condition,particularly in ectopic CS cases. Pulmonarythromboembolism, acute heart failure, acuterespiratory failure, infections, and gut per-foration should be considered. Prophylaxisand treatment with appropriate antibioticsfor infections and anticoagulant prophylaxisfor deep vein thrombosis should not be de-layed. Steroidogenesis inhibitors may beused alone or in combination to control se-vere hypercortisolism, and patients with aserious disease may need intensive care unitmanagement (9). Our patient was diag-nosed with pneumonia during hospitaliza-tion, which required antibiotherapy andoxygenation. Metyrapone was initiated tocontrol severe hypercortisolism and make

the patient clinically stable before surgery.However, after the initiation of cortisol-low-ering agents, PCP can be triggered becauseof immune reconstitution. PCP prophylaxisbefore the initiation of cortisol-loweringtherapy is recommended (10).Postoperatively, immunohistochemicalmarkers indicated focally positive ACTHstaining in our patient and supported the di-agnosis. However, Cassarino et al. reporteda case of suspected ACTH-producingpheochromocytoma with negative immuno-chemistry (11). This may be because of cor-ticotropin-releasing hormone-producingpheochromocytomas. In addition, it hasbeen hypothesized that high-molecular-weight ACTH that is not recognized by typi-cal antibodies can be responsible fornegative immunochemistry. Therefore,ACTH production of the tumor cannot be ex-cluded by negative immunohistochemistryalone.In conclusion, an ACTH-producing pheochro-mocytoma should be considered in patientswith clinical manifestations of severe ectopicCS and adrenal mass. Early diagnosis andappropriate management of fatal complica-tions, such as thrombosis and infections, arecrucial for a successful surgery. In caseswith severe hypercortisolism, preoperativepreparation with steroidogenesis inhibitorsshould be considered.



Authorship ContributionsIdea/Concept: Başak Bolayır, Müjde Aktürk,Nuri Çakır; Design: Alev Eroğlu Altınova,

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Füsun Baloş Törüner; Control/Supervision:Füsun Baloş Törüner, Banu Aktaş Yılmaz; DataCollection and/or Processing: Başak Bolayır,Damla Okay, Aydın Tuncer Sel; Analysisand/or Interpretation: Aylar Poyraz, MuratAkın; Literature Review: Başak Bolayır, DamlaOkay; Writing the Article: Başak Bolayır,Damla Okay; Critical Review: Alev Eroğlu Al-tınova, Füsun Baloş Törüner.

References1. Nieman LK, Biller BM, Findling JW, Newell-Price J,

Savage MO, Stewart PM, Montori VM. The diagnosisof Cushing’s syndrome: an endocrine society clinicalpractice guideline. J Clin Endocrinol Metab.2008;93:1526-1540. [Crossref] [PubMed] [PMC]

2. Nieman LK, Ilias I. Evaluation and treatment ofCushing’s syndrome. Am J Med. 2005;118:1340-1346. [Crossref] [PubMed] [PMC]

3. Ilias I, Torpy DJ, Pacak K, Mullen N, Wesley RA, Nie-man LK. Cushing’s syndrome due to ectopic corti-cotropin secretion: twenty years’ experience at theNational Institutes of Health. J Clin EndocrinolMetab. 2005;90:4955-4962. [Crossref] [PubMed]

4. Bourgoignie J, Dupont JC, Noiret R. Association of apheochromocytoma and Cushing type hypercorti-cism with hyperaldosteronuria. Ann Endocrinol(Paris). 1964;25:269-284.

5. Ballav C, Naziat A, Mihai R, Karavitaki N, AnsorgeO, Grossman AB. Mini-review: pheochromocytomas

causing the ectopic ACTH syndrome. Endocrine.2012;42:69-73. [Crossref] [PubMed]

6. Newell-Price J, Bertagna X, Grossman AB, Nieman LK.Cushing’s syndrome. Lancet. 2006;367:1605-1617.[Crossref]

7. Forman BH, Marban E, Kayne RD, Passarelli NM, Bo-brow SN, Livolsi VA, Merino M, Minor M, Farber LR.Ectopic ACTH syndrome due to pheochromocytoma:case report and review of the literature. Yale J BiolMed. 1979;52:181-189.

8. Chen H, Doppman JL, Chrousos GP, Norton JA, Nie-man LK, Udelsman R. Adrenocorticotropic hormone-secreting pheochromocytomas: the exception to therule. Surgery. 1995;118:988-994. [Crossref]

9. Nieman LK, Biller BM, Findling JW, Murad MH,Newell-Price J, Savage MO, Tabarin A. Treatment ofCushing’s syndrome: an endocrine society clinicalpractice guideline summary of recommendations. JClin Endocrinol Metab. 2015;100:2807-2831.[Crossref] [PubMed] [PMC]

10.van Halem K, Vrolijk L, Pereira AM, de Boer MGJ.Characteristics and mortality of pneumocystis pneu-monia in patients with Cushing’s syndrome: a pleafor timely initiation of chemoprophylaxis. OpenForum Infect Dis. 2017;30:ofx002. [Crossref][PubMed] [PMC]

11.Cassarino MF, Sesta A, Pagliardini L, Losa G, Cav-agnini F, Pecori Giraldi F. AZA-deoxycytidine stimu-lates proopiomelanocortin gene expression andACTH secretion in human pituitary ACTH-secretingtumors. Pituitary. 2014;17:464-469. [Crossref][PubMed]

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https://doi.org/10.1210/jc.2015-1818


https://doi.org/10.1007/s11102-013-0527-8





https://doi.org/10.1210/jc.2008-0125

https://doi.org/10.1007/s11102-013-0527-8

https://doi.org/10.1093/ofid/ofx002

https://doi.org/10.1016/S0039-6060(05)80104-7


https://doi.org/10.1016/j.amjmed.2005.01.059

https://doi.org/10.1007/s12020-012-9646-7


https://doi.org/10.1210/jc.2004-2527

https://doi.org/10.1016/S0140-6736(06)68699-6

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Address for Correspondence: Sema Hepşen, Department of Endocrinology and Metabolism, University of Health Sciences,Diskapi Yildirim Beyazit Training and Research Hospital, Ankara, Turkey

Phone: +90 312 596 2000 E-mail: [email protected]: 11/01/2019 Received in revised form: 10/03/2019 Accepted: 14/04/2019 Available online: 03/05/2019


Retroperitoneal Castleman Disease MimickingParaganglioma in a Patient with

Klinefelter Syndrome: A Case ReportKlinefelter Sendromlu Bir Hastada Paragangliomayı Taklit Eden

Retroperitoneal Castleman Hastalığı: Bir Olgu Sunumu

Department of Endocrinology and Metabolism, University of Health Sciences,Diskapi Yildirim Beyazit Training and Research Hospital, Ankara, Turkey

*Department of Pathology, University of Health Sciences, Diskapi Yildirim Beyazit Training and Research Hospital, Ankara, Turkey**Department of General Surgery, University of Health Sciences, Diskapi Yildirim Beyazit Training and Research Hospital, Ankara, Turkey


IntroductionCastleman disease (CD) is a rare lympho-proliferative disorder with a poorly knownpathogenesis. It is usually seen in youngadults. CD may either present as a unicen-tric or a multicentric disorder. According tothe etiopathogenesis of the unicentric formof the disease, excessive cytokine produc-tion, principally interleukin (IL) 6, is thought

to initiate the vascular endothelial growthfactor (VEGF) release and to promote an-giogenesis in lymphoid cells (1, 2). CD com-monly manifests with an enlarged lymphnode in the cervical, axillary, mediastinal orrarely, even in the retroperitoneal and pelvicregions (3). Unicentric CD commonly pres-ents as an asymptomatic disorder; never-theless, different systemic symptoms may

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Castleman disease progresses with the enlargement of theaffected lymph nodes and represented by a wide range ofsymptoms. This lymphoproliferative disease rarely affects theretroperitoneum. A patient with Klinefelter syndrome was ad-mitted to our clinic following palpitation and sweat attacks. Itwas observed that the urinary catecholamine metaboliteswere elevated and a pararenal mass was found on the leftside. The patient was directed to surgery with the paragan-glioma pre-diagnosis after further examination. Histopatho-logical examination of the excised mass confirmed thediagnosis of Castleman disease. The urinary catecholaminemetabolites returned to near-normal levels at eight weeksafter the surgery. We present a case of Castleman disease ina patient with Klinefelter syndrome, imitating paragangliomaas per the clinical, radiological and laboratory findings.

Keywords: Castleman disease; paraganglioma;Klinefelter syndrome; retroperitoneum

Castleman hastalığı, etkilenen lenf nodunda büyüme ile or-taya çıkar ve birçok farklı semptomla kendini gösterebilir.Bu lenfoproliferatif hastalık, nadiren retroperitoneumu et-kilemektedir. Klinefelter sendromlu bir hasta, çarpıntı veterleme atakları ile kliniğimize başvurdu. İdrar katekola-min metabolitlerinin yükselmiş olduğu gözlenip, sol para-renal bölgede bir kitle saptandı. İleri tetkik edilen hastaparaganglioma ön tanısı ile cerrahiye yönlendirildi. Eksizeedilen kitlenin histopatolojik değerlendirme sonucu Cast-leman hastalığı tanısını doğruladı. Hastanın idrar katekola-min metabolitleri cerrahi sonrası sekizinci haftada normaleyakın seviyelere geriledi. Bu çalışmada, Klinefelter send-romlu bir hastada klinik, radyolojik ve laboratuvar bulgu-ları ile paragangliomayı taklit eden bir Castleman hastalı-ğının sunulması amaçlanmıştır.

Anahtar kelimeler: Castleman hastalığı; paraganglioma;Klinefelter sendromu, retroperitoneum

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The abstract of this case report was presented as “poster presentation”in Endobridge 23-25 October 2018, Antalya, Turkey.

https://orcid.org/0000-0002-1662-3363

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

https://orcid.org/0000-0003-4256-3779

https://orcid.org/0000-0001-5581-4886

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

https://orcid.org/0000-0003-3999-6426

https://orcid.org/ 0000-0003-2816-6734

https://orcid.org/0000-0002-8375-7409

resemble various diseases during the onset(4). This paper reports an unusual presen-tation of retroperitoneal CD, mimickingparaganglioma in a patient with Klinefeltersyndrome.

Case ReportA 38-year old male having Klinefelter syn-drome was referred to our department dueto episodic palpitation and sweat attacks.Personal history of the patient stated nochronic disease and drug use. Patient’sblood pressure was measured to be 140/90mmHg in consecutive evaluations on differ-ent days. The heart rate was recorded to be76 beats/min and the electrocardiogramshowed sinus rhythm. Physical examinationshowed no palpable lymph node, abdominalmass, or hepatosplenomegaly.The hemogram revealed hemoglobin to be13.3 g/dL, white blood cell count to be9,100/mm3 and platelet count to be32,3000/mm3. The liver and renal functiontest results were found to be in the normalrange. Erythrocyte sedimentation rate (ESR)was 38 mm/hour, C-reactive protein (CRP)level was 9.3 mg/L and lactate dehydroge-nase level was 160 U/L (normal). The thy-roid hormone levels were observed to be inthe normal reference range. Urine analysisyielded normal results. An elevation in the24 h urinary catecholamine levels was de-termined wherein metanephrine was 585µg/24 h (44-261 µg/24 h) whilenormetanephrine was 1360 µg/24 h (11-419 µg/24 h). These high measurements ofcatecholamine metabolites were verified byproperly collected three consecutive urinetests.Thoraco-abdominal magnetic resonance(MR) screening was performed for localiza-tion of the probable lesion. Dynamic con-trast-enhanced MR images demonstrated a47×60 mm mass as hypointense on T1-weighted imaging and heterogeneously hy-perintense on T2-weighted imaging, in theretroperitoneal region adjacent to the leftkidney in the anterolateral plane (Figure 1).No concomitant enlarged lymph node wasdetected. Positron emission tomographywith fluorine-18 fluorodeoxyglucose (18F-FDG PET) revealed that the uptake of theleft pararenal mass was similar to that of theliver (SUV max 2.3) (Figure 2).

The patient was taken for surgery after theinitiation of alpha blockage treatment. Theretroperitoneal mass adjacent to the inferiorpole of the left kidney, measuring 50×60mm was excised with its capsule. Histologi-cal examination revealed that the structureof the lymph node was degenerated, as ex-amined on hematoxylin and eosin (H & E)sections. The interfollicular region showedviolent vascular proliferation while the ves-sel walls were seen to be hyalinized (Figure3). The lollipop lesion observed at the ger-minal centers of the follicle is presented inFigure 4.No complications were observed throughoutthe recovery period and the symptoms weredisappeared after the surgery. The preoper-ative ESR and CRP levels that were mildlyelevated were found to improve after thesurgery. The controlled estimation of 24 hurinary catecholamine metabolites collectedeight weeks after the surgery showed that

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Figure 1: Dynamic contrast-enhanced MR image of a47×60 mm mass in the retroperitoneal region adjacentto left kidney.

Figure 2: The similar uptake of 18F-FDG by the left pa-rarenal mass with that of the liver on 18F-FDG PETimage.

the metanephrine level returned to normal(166 µg/24 h) while the normetanephrinelevel decreased to near-normal referencerange (496 µg/24 h).

DiscussionCD is a rare, lymphoproliferative disease hav-ing ill-defined pathogenesis. Although the eti-ology of the unicentric variant of CD remainsunclear, human immunodeficiency virus (HIV)and human herpesvirus 8 (HHV-8) have beenfound to be associated with the developmentof the multicentric variant of this disease (5).Previous studies have shown that increasedlevels of cytokines such as IL-6 and VEGFmay play a principal role in the pathogenesisof the unicentric disease and lead to differentsystemic symptoms (2). The diagnosis of CDis based on histopathologic evaluation. Three

main histopathological variants of unicentricCD have been recognized: the hyaline vascu-lar, plasma cell, and mixed types (6, 7). Thecase reported here is of a unicentric hyalinevascular variant of the disease, which is themost common histopathological type (6). Themulticentric form of the disease commonlypresents with extensive peripheral lym-phadenopathy and systemic symptoms likefever, weight loss, and night sweats (8). Onthe contrary, unicentric CD frequently pres-ents with the asymptomatic manifestation ofan enlarged lymph node (9). This paper re-ports the case of a patient who presentedwith episodic palpitation and sweating with noperipheral lymph node enlargement. Labora-tory findings revealed elevated ESR and CRPlevels, and hemogram abnormalities includ-ing anemia and thrombocytopenia. Althoughmild elevation in the ESR and CRP levels weredetected in the patient; nevertheless, this el-evation was not so high as to consider a ma-lignancy. Elevated urinary catecholaminemetabolites and a visible pararenal mass dur-ing the MR screening enthralled about a para-ganglioma in the patient. The patient wasadvised surgical treatment to excise the iden-tified retroperitoneal mass. The surgery wascompleted successfully and no complicationwas seen during the recovery period.Histopathological evaluation of the massdemonstrated the presence of degeneratedlymph node with hyalinized vessel walls andlollipop appearance of germinal centers, lead-ing to the diagnosis of Castleman disease.The patient’s symptoms subsided after thesurgery. Also, the level of urinary cate-cholamine metabolites came to near-normallevel.Retroperitoneal localization of CD is notcommonly seen and comprises only 11% ofall the cases (10). The gold standard treat-ment for unicentric CD involves completesurgical resection of the lesion (3).Atypical presentation of CD has been re-ported in previous case reports. Kim et al.reported an unusual presentation of thepararenal CD by mimicking systemic lupuserythematosus with persistent tongue ulcersand positive antinuclear antibody and anti-double-strained DNA (11). Some other atyp-ical presentations of CD have been reportedas urosepsis (12), papilledema (13), and hy-percalcemia (14).

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Figure 3: Violent vascular proliferation in the interfolli-cular region and hyalinization in the vessel wall (HE, x20objective).

Figure 4: The lollipop lesion at the follicle germinal cen-ters (HE, X40 objective).

Many growth factors and cytokines includingIL-6, localized in paragangliomas andpheochromocytomas, and immunoreactivecharacteristics of these disorders have beendescribed earlier (15). Clearly increased IL-6 levels was reported in a case of pheochro-mocytoma characterized by symptoms ofinflammatory response including fever andmalaise; the authors commentated that ex-cessive IL-6 secretion may be associatedwith increased normetanephrine level (16).Some other catecholamines secretingpheochromocytomas with over-productionof IL-6 have been demonstrated in the liter-ature previously (17-19). Most of thesecases presented with inflammatory symp-toms and a demonstrative decrease in IL-6levels was seen after the patients werebeing treated either surgically or medically.However, the literature reports only limitedcases of IL-6 over-production in paragan-glioma. Sokabe et al. reported a case in apatient with the systemic inflammatory syn-drome, having increased IL-6 level due to ajugular paraganglioma, without any de-tectable hormone secretion including cate-cholamines (20). Another case report in theliterature presented the coexistence ofCastleman disease and pheochromocytomapossibly by linking up to the expression ofIL-6 by the tumor mass (17). Although wecould not estimate serum IL-6 levels of thepatient, a similar cause and effect relation-ship may explain the elevation in the levelsof catecholamines in the present case.In summary, this case report deals with apatient with Klinefelter syndrome. However,its accompaniment with the CD is excep-tional. Although malignancies like extrago-nadal germ cell tumors or breast cancer arecommonly seen in patients with Klinefeltersyndrome, they are seldom seen in associa-tion with lymphoproliferative diseases (21).The literature reports only one case pre-senting Klinefelter Syndrome and CD con-comitantly in an 11-year-old boy and theauthors commented that Klinefelter syn-drome may make a patient susceptible toCD (22). However, this relationship still re-mains a hypothesis without sufficient evi-dence.The diagnosis of the unicentric CD may bedifficult for the clinician in some cases sincethe disease does not present typical symp-

toms. In this paper, we have reported a dif-ferent presentation of the disease whichmimics the clinical and laboratory findings ofparaganglioma in a patient with Klinefeltersyndrome. Castleman disease as a rarecause of retroperitoneal lesions should,therefore, be kept in mind in patients pre-senting with clinical and laboratory findingsof retroperitoneal paraganglioma.



Authorship ContributionsIdea/Concept: Sema Hepşen, Erkam Sencar;Design: Sema Hepşen, Pınar Akhanlı, ErmanÇakal; Control/Supervision: Erman Çakal,Mustafa Özbek; Data Collection and/or Pro-cessing: Sema Hepşen, Erkam Sencar, AtaTürker Arıkök, Duray Şeker; Analysis and/orInterpretation: Sema Hepşen, Pınar Akhanlı,İlknur Ünsal; Literature Review: Sema Hep-şen, İlknur Ünsal, Erkam Sencar; Writing theArticle: Sema Hepşen; Critical Review: SemaHepşen, Pınar Akhanlı, Erman Çakal; Refer-ences and Fundings: Erman Çakal; MustafaÖzbek; Materials: Ata Türker Arıkök, DurayŞeker, Sema Hepşen.

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Address for Correspondence: İnan Anaforoğlu, Bahçeşehir University Faculty of Medicine,Department of Endocrinology and Metabolism, İstanbul, TurkeyPhone: +90 216 468 44 44 E-mail: [email protected]



Congenital Adrenal Hyperplasia as a Cause ofSecondary Hypertension in Adults: Three Cases

Sekonder Hipertansiyon Sebebi OlarakKonjenital Adrenal Hiperplazi: Üç Vaka

Department of Endocrinology, Bahcesehir University Faculty of Medicine, Department of Endocrinology and Metabolism, Istanbul, Turkey*Giresun Ada Hastanesi, Giresun, Turkey

**Ordu Devlet Hastanesi, Ordu, Turkey


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Congenital adrenal hyperplasia is a group of hereditary di-sorders originating from enzymatic defects in steroidogene-sis, resulting in impaired cortisol synthesis in the adrenalcortex. The rare forms of congenital adrenal hyperplasiacharacterized by hypertension and hypokalemia include 11-β and 17-α hydroxylase deficiencies. We described threecases of congenital adrenal hyperplasia, two with 11-β hy-droxylase and one with 17-α hydroxylase deficiency, eachpresenting with hypertension and hypokalemia in adult-hood. In addition, 11-β hydroxylase deficiency casesshowed precocious puberty with testicular adrenal resttumor and adrenal myelolipoma, whereas the patient with17-α hydroxylase deficiency showed sexual infantilism. Con-genital adrenal hyperplasia is a rare cause of secondary hy-pertension in adults. It is particularly considered in patientswith sexual maturation disorders, such as precocious pu-berty, delayed puberty, or sexual infantilism, and in thosewith hypertension and hypokalemia.

Keywords: Congenital adrenal hyperplasia;secondary hypertension; hypertension;hypokalemia

Konjenital adrenal hiperplaziler; adrenal kortekste bozul-muş kortizol senteziyle sonuçlanan enzimatik defektleresebep olan herediter bir grup hastalıktır. Konjenital adrenalhiperplazilerin hipertansiyon ve hipokalemiye sebep olannadir formları 11-β hidroksilaz ve 17-α hidroksilaz eksikliğiile gider. Bu çalışmada, hipertansiyon ve hipokalemi ilegelen iki erişkin 11-β hidroksilaz ve bir erişkin 17-αhidroksilaz hastasının sunulması amaçlanmıştır. Prekokspuberte öyküsü olan 11-β hidroksilaz hastalarında, aynı za-manda testiküler adrenal rest tümör ve adrenalmiyelolipoma mevcut iken, 17-α hidroksilaz hastamızda daseksüel infantilizim mevcut idi. Konjenital adrenal hiperp-laziler erişkinlerde sekonder hipertansiyonun nadir sebep-lerindendir. Prekoks puberte, gecikmiş puberte veyaseksüel infantilizim gibi seksüel olgunlaşma bozukluklarıve hipertansiyonla birlikte hipokalemi olması durumlarındakonjetinal adrenal hiperplaziler akla gelmelidir.

Anahtar kelimeler: Konjenital adrenal hiperplazi;sekonder hipertansiyon; hipertansiyon;hipokalemi

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This paper was presented as a poster at the 34th Congress of Endocrinology and Metabolism Diseasesof Turkey, 11-15 April 2012, Antalya, Turkey.

IntroductionCongenital adrenal hyperplasia (CAH) is agroup of hereditary disorders originatingfrom enzymatic defects in steroidogenesis,resulting in impaired cortisol synthesis in theadrenal cortex. The most commonly seenform is 21 hydroxylase deficiency, although

this does not lead to hypertension. The rareforms of CAH characterized by hypertensionand hypokalemia include 11-β and 17-α hy-droxylase deficiency (1).In addition, 11-β hydroxylase deficiency isthe second most common cause of CAH,representing 5% to 8% of cases. It is char-

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acterized by excessive production of adrenalandrogens and deoxycorticosterone, leadingto virilization (female pseudohermaphro-ditism) in female fetus and precocious pu-berty in the male infant. Moreover, excessiveandrogen production leads to the develop-ment of premature and inappropriate sec-ondary sexual characteristics in both sexes.In untreated cases, rapid skeletal growthcaused by excessive androgen leads to earlyepiphyseal maturation and thus to shortstature (2).17-α Hydroxylase deficiency is a rare formof CAH, representing only 1% of all cases.The classic symptoms caused by the lack ofthe enzyme are hypertension, hypokalemia,and sexual infantilism. Male fetuses with 17-α hydroxylase deficiency possess an exter-nal genital structure of female phenotypeknown as male pseudohermaphroditism. Infemale fetus, the external genitalia are nor-mal; however, the deficiency causes primaryamenorrhea and secondary sexual charac-teristics do not develop (3).We describe three cases of CAH, two of 11-β hydroxylase and one of 17-β hydroxylasedeficiency, each presenting with hyperten-sion and hypokalemia. In addition, testicularadrenal rest tumor and adrenal myelolipomawere identified in the 11-β hydroxylase de-ficiency cases.

Case ReportsInformed consent was taken from all pa-tients.

Case 1A 27-year-old man with hypertension pre-sented with flu at the internal diseases’clinic. No abnormality apart from hy-pokalemia was identified during routine bio-chemical testing. The patient was started onspironolactone and referred to our clinic. Hishistory revealed that dexamethasone ther-apy had been initiated following CAH diag-nosis at the age of three years when he hadpresented with pubic pilosity and penilegrowth. Therapy was stopped at the age of14 years with the onset of puberty; how-ever, hypertension was not diagnosed.At examination, he was 158 cm tall andweighed 68 kg. Blood pressure was 200/120mmHg. Grade 2 hypertensive retinopathywas present in the ocular fundus, and left

ventricular hypertrophy was observed byechocardiography. The levels of 17-hydrox-yprogesterone, 11-deoxycortisol, andadrenocorticotropic hormone (ACTH) wereelevated. Tests were compatible with 11-βhydroxylase deficiency (Table 1). Subrenalmagnetic resonance imaging (MRI) revealedbilateral diffuse thickening (Figure 1). Scro-tal ultrasonography showed a heteroge-neous, solid 5x5 mm lesion in the left testis,containing pronounced central and periph-eral venous flows with peripheral calcifica-tion. A hypodense nodular area of 10×5 mmin the left scrotal sac was identified in MRIT2 sequences (Figure 2). This was thoughtto be compatible with testicular rest tumor.The patient refused the biopsy examinationof the testicular mass. Spermogram re-vealed azoospermia.The patient was started on dexamethasone.Potassium replacement was prescribed asserum potassium levels were considerablylow. On follow-up after 3 months, he wasnormokalemic and normotensive, with nopotassium replacement or antihypertensiverequirement. Furthermore, we observed adecrease in testicular rest tissue.

Case 2A 41-year-old man presented to the emer-gency department with acute kidney failureassociated with gastroenteritis. Left orchiec-tomy had been performed 6 years ago be-cause of suspected testicular malignity, andhistopathological examination reported dif-fuse coagulation necrosis in the testis. Leftadrenalectomy was performed 3 years agowhen myelolipoma was diagnosed patholog-ically. He had azoospermia-associated infer-tility and was taking eprosartan (600mg/day) for 5 years for hypertension. Hisparents were consanguineous, and he wasthe shortest member of the family (148 cm).Pubic pilosity had begun at approximately 5years of age and beard growth at approxi-mately 8 years.The right testis was 30 mL in volume withhard and irregular margins. Grade 1 and 2hypertensive retinopathy was observed. Leftventricular hypertrophy and an aneurysm inthe ascending aorta were identified byechocardiography. At the time of presenta-tion, the patient’s potassium level was 4.6mmol/L, which decreased to 2.8 mmol/L

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when eprosartan was stopped. 11-β Hy-droxylase deficiency-associated CAH was di-agnosed on the basis of the clinical andlaboratory results (Table 1) and dexametha-sone (0.75 mg/day) therapy was started. Atthe end of the fourth week, the patient wasnormotensive and normokalemic withoutantihypertensive therapy and abnormal lab-oratory values returned to normal.

Case 3A 34-year-old woman was referred to ourclinic because of hypertension and hy-pokalemia. She was receiving antihyperten-sive therapy for the past ten years and hadnever menstruated. Physical examinationrevealed no pubic or axillary pilosity, Tannerstage 1 breast development, prepubertalexternal female genital structures, and arudimentary vaginal cuff. Laboratory testsshowed low levels of cortisol, estradiol,testosterone, and dehydroepiandrosteronesulfate, with high levels of follicle-stimulat-ing hormone (FSH), luteinizing hormone

(LH), ACTH, and progesterone (Table 1). Bi-lateral subrenal hyperplasia was noted onabdominal MRI; however, no uterus or

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Laboratory test Case 1 Case 2 Case 3Basal cortisol (µg/dL) 4.2 12.2 0.7Adrenocorticotropic hormone (pg/mL) 1121 117 72.6

Normal range: 0-46 pg/mLDehydroepiandrosterone sulfate (µg/dL) 351 2350 0.1

Normal range: 35-430 µg/mL17-Hydroxy-progesterone (ng/mL) 25 31.1 -

Normal range: 0-1.39 ng/mLProgesterone (ng/mL) 7.3 28.8 9.37

Normal range: 0.15-1.4 ng/mLFollicle-stimulating hormone (mIU/L) 0.2 0.1 73.2

Normal range: 2.5-10.2 mIU/LLuteinizing hormone (mIU/L) 0.1 0.1 20.2

Normal range: 1.9-12.5 mIU/LFree testosterone (ng/mL) 21 - -

Normal range: 8.7-30 ng/mLTestosterone (ng/dL) 274 1167 0.01

Normal range: 241-827 ng/dLEstradiol (pg/mL) - - 13.1

Normal range: 11-69 pg/mL11-Deoxycortisol (ng/mL) >100 270 -

Normal range: 0-0.5 ng/mL11-Deoxycortitestosterone (pmol/mL) - 18.8 -

Normal range: 0.12-0.60 pmol/mLAldosterone (ng/dL) - - 5.7

Normal range: 7-30 ng/dLRenin activity (ng/mL/s) - - 0.15

Normal range: 0.70-3.30 ng/mL/s

Table 1. Laboratory characteristics of the cases.

Figure 1: Congenital adrenal hyperplasia associatedwith 11-β hydroxylase deficiency: pronounced bilateraladrenal hyperplasia on a subrenal magnetic resonanceimage from Case 1.

ovaries were observed. Karyotype screeningwas performed and reported 46 XX. The pa-tient’s clinical and laboratory findings werecompatible with 17-α hydroxylase defi-ciency, and hypokalemia and hypertensionwere brought under control with dexam-ethasone.

DiscussionTwo forms of CAH lead to excessive accu-mulation of products that induce mineralo-corticoid activity. The deficiency of 11-β and17-α hydroxylase results in excessive pro-duction of steroid 21 hydroxylase that acti-vates mineralocorticoid receptors (4).Although hypertension has been reported inchildren as young as three months old, itcannot generally be reliably determined untillate childhood or adolescence (5).Patients with 11-β hydroxylase deficiencyhave a set of hormonal findings; high serumconcentrations of 11-deoxycortisol, deoxy-corticosterone, DHEA, androstenedione, andtestosterone, with low cortisol and corticos-terone levels (6).Our first two cases were diagnosed becauseof hypertension and hypokalemia in additionto precocious puberty and short final height

which was associated with 11-β hydroxylasedeficiency identified at a relatively later age.Despite insufficient aldosterone productionin 11-β hydroxylase deficiency, excessiveproduction of deoxycorticosterone, a lesspotent mineralocorticoid in vivo, can lead tosalt retention and hypertension. Potassiumdepletion occurs with salt retention; how-ever, hypokalemia is variable. Renin produc-tion can be suppressed secondary to sodiumretention and volume expansion (2, 6).In two cases, azoospermia and the appear-ance compatible with testicular adrenal resttumor were identified in the testis. The tes-ticular biopsy could not be performed; how-ever, a decrease in mass dimensions afterdexamethasone therapy strengthened the di-agnosis of adrenal rest tumor. These tumorsare believed to originate from the aberrantadrenal tissue descending with the testes inthe embryological period. They are commonlyseen in association with high ACTH levels inpatients with inadequately controlled CAH(7). The mechanical effects of these tumorscan lead to obstruction of the seminiferoustubules and ischemic necrosis. Furthermore,the paracrine effects of steroids produced intumor tissue may have a toxic effect on Ley-dig and/or germinal cells. In addition to theselocal effects of testicular adrenal tumors,chronic ACTH elevation secondary to low cor-tisol production in patients with 11-β hydrox-ylase deficiency also suppresses the releaseof FSH and LF, causing excessive accumula-tion of adrenal androgens. These conditionscan lead to decreased testicular size andsperm numbers and male infertility (8).The second case was suspected of testiculartumor, and necrosis was observed in thetestis. In the absence of any histopatholog-ical evidence, this condition may have arisenin association with testicular adrenal resttumor. However, the patient underwent leftadrenalectomy, and the histopathologicalexamination of the specimen removed wascompatible with adrenal myelolipoma.Myelolipomas are rare benign tumors devel-oping from the hematopoietic elements ofthe adrenal glands and mature adipose tis-sue. They are thought to be metaplastic inorigin and associated with the chronic stim-ulation of ACTH and androgens. Myelolipo-mas are frequently reported in cases of CAHassociated with 21 hydroxylase deficiency

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Figure 2: Congenital adrenal hyperplasia associatedwith 11-β hydroxylase deficiency: appearance compati-ble with hypointense testicular adrenal rest tumor (10x4mm) in the left testis on a magnetic resonance T2 se-quence from Case 1.

(9). One previous case of 11-β hydroxylasedeficiency with adrenal myelolipoma hasbeen reported with testicular adrenal resttumor (10). Early occurrence of 11-β hy-droxylase-related CAHs, usually in associa-tion with hypertension, probably explainswhy these tumors are rarely seen (10).In the third case, the patient with a 46 XXkaryotype with primary amenorrhea andsexual infantilism had 17-α hydroxylase de-ficiency. This enzyme deficiency preventsthe synthesis of androgen and cortisol whileincreasing mineralocorticoid synthesis,leading to hypokalemia and hypertension.Aldosterone levels may be normal or lowbecause of the suppression of renin levelsby increasing extracellular volume. Apartfrom its effects in the adrenal cortex, 17-αhydroxylase deficiency also prevents andro-gen and estrogen production in the gonads,leading to hypergonadotropic hypogo-nadism by increasing FSH and LH secretion.Adrenal crises are not typically seen in pa-tients with 17-α hydroxylase deficiency be-cause of increased synthesis ofcorticosterone with weak cortisol activity (3,11). The diagnosis of 17-α hydroxylase de-ficiency is generally based on clinical andlaboratory findings and genetic analysis.The plasma levels of progesterone, corti-costerone, and deoxycorticosterone acetateare typically five to ten times higher thannormal (3). An increased basal proges-terone level has recently been described asa suitable marker in 17-α hydroxylase defi-ciency. Progesterone also increases in 11-βand 21 hydroxylase deficiencies. However,in contrast to 17-α hydroxylase deficiency,these two disorders are the virilizing formsof CAH (12).Hypertension and hypokalemia werebrought under control with dexamethasonetherapy in all three patients. Steroid re-placement reduces the formation of deoxy-corticosterone by reducing ACTH levels andcorrects hypertension and hypokalemia inmost patients (1). However, in patients withprolonged hypertension before diagnosis,potassium-binding diuretics such as spirono-lactone and calcium channel blockers suchas nifedipine may be required. Angiotensin-converting enzyme inhibitors are ineffectivebecause the renin-angiotensin-aldosteronesystem is suppressed (1, 13). Blindness,

retinal vein occlusion, and cardiomyopathyassociated with long-term uncontrolled hy-pertension have been reported in patientswith 11-β hydroxylase deficiency (14, 15).In conclusion, CAH is a rare cause of sec-ondary hypertension in adults. It occurs par-ticularly in patients with sexual maturationdisorders such as precocious puberty, de-layed puberty, or sexual infantilism.

AcknowledgmentEnglish-language editing of this manuscriptwas performed by Patricia French of LeftLane Communications (Chapel Hill, NC,USA).



Authorship ContributionsIdea/Concept: İnan Anaforoğlu, EkremAlgün;Design: İnan Anaforoğlu; Control/Supervision:Ekrem Algün; Data Collection and/or Process-ing: İnan Anaforoğlu, Ekrem Algün, KeremErsoy; Analysis and/or Interpretation: İnanAnaforoğlu, Kerem Ersoy; Literature Review:İnan Anaforoğlu; Writing the Article: İnanAnaforoğlu; Critical Review: Kerem Ersoy,Ekrem Algün; References and Fundings: İnanAnaforoğlu; Materials: İnan Anaforoğlu, EkremAlgün, Kerem Ersoy.

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