Honorary Board · Murat Faik Erdoğan, Ankara, Turkey Associate Editors Hasan Ali Altunbaş, Antalya, Turkey Dilek Gogas Yavuz , İstanbul, Turkey Serkan Yener , İzmir, Turkey Statistical

OOwwnneerr oonn bbeehhaallff ooff tthhee SSoocciieettyy ooff EEnnddooccrriinnoollooggyy aanndd MMeettaabboolliissmm ooff TTuurrkkeeyy

Sevim Güllü, Ankara, Turkey

EEddiittoorr--IInn--CChhiieeffNilgün Başkal, Ankara, Turkey

DDeeppuuttyy EEddiittoorrMurat Faik Erdoğan, Ankara, Turkey

AAssssoocciiaattee EEddiittoorrssHasan Ali Altunbaş, Antalya, TurkeyDilek Gogas Yavuz , İstanbul, TurkeySerkan Yener , İzmir, Turkey

SSttaattiissttiiccaall CCoonnssuullttaannttAtilla Halil Elhan, Ankara, TurkeyLevent Dönmez, Ankara, TurkeyDerya Öztuna, Ankara, TurkeyCan Ateş, Van, Turkey

LLaanngguuaaggee EEddiittoorrJennifer Gabriel, California, USA

HHoonnoorraarryy BBooaarrdd

Sema Akalın, İstanbul, Turkey

Metin Arslan, Ankara, Turkey

Gürbüz Erdoğan, Ankara, Turkey

Olcay Gedik, Ankara, Turkey

Sadi Güngoğdu, İstanbul, Turkey

Hüsrev Hatemi, İstanbul, Turkey

Şazi İmamoğlu, Bursa, Turkey

Taylan Kabalak, İzmir, Turkey

Senay Molvalılar, İstanbul, Turkey

Candeğer Yılmaz, İzmir, Turkey

EEddiittoorriiaall BBooaarrdd

Ersin Akarsu, Gaziantep, Turkey

Müjde Aktürk, Ankara, Turkey

İnan Anaforoğlu, İstanbul, Turkey

Ayşegül Atmaca, Samsun, Turkey

Mustafa Kemal Balcı, Antalya, Turkey

Neslihan Başçıl Tütüncü, Ankara, Turkey

David Baylink, California, Usa

Fahri Bayram, Kayseri, Turkey

Mehtap Çakır, İzmir, Turkey

Abdurrahman Çömlekci, İzmir, Turkey

Selçuk Dağdelen, Ankara, Turkey

Leslie J. Degroot, Kingston, Usa

Tomris Erbaş, Ankara, Turkey

Mehmet Erdoğan, İzmir, Turkey

Eda Ertörer, Adana, Turkey

John W. Funder, Victoria, Australia

Hossein Gharib, Minnesota, Usa

Nilgün Güvener, İstanbul, Turkey

Serdar Güler, Ankara, Turkey

Alptekin Gürsoy, Ankara, Turkey

Zeliha Hekimsoy, Manisa, Turkey

Larry Jameson, Philadelphia, Usa

Pınar Kadıoğlu, İstanbul, Turkey

Pierre J. Lefebvre, Liege, Belgium

Mesut Özkaya, Gaziantep, Turkey

İlhan Satman, İstanbul, Turkey

Füsun Saygılı, İzmir, Turkey

Alper Sönmez, Ankara, Turkey

İbrahim Şahin, Malatya, Turkey

Mustafa Şahin, Ankara, Turkey

Kubilay Ukinç, Çanakkale, Turkey

Betül Uğur Altun, İstanbul, Turkey

Kürşad Ünlühızarcı, Kayseri, Turkey

Ayşe Kubat Üzüm, İstanbul, Turkey

Anthony Weetman, Sheffield, UK

Bülent Okan Yıldız, Ankara, Turkey

AAddvviissoorryy BBooaarrdd

Faruk Alagöl, İstanbul, Turkey

Yalçın Aral, Ankara, Turkey

Göksun Ayvaz, Ankara, Turkey

Ömer Azal, Ankara, Turkey

Erol Bolu, İstanbul, Turkey

Berrin Çetinarslan, Kocaeli, Turkey

Ahmet Çorakçı, Ankara, Turkey

Hatice Sebila Dökmetaş, İstanbul, Turkey

Belgin Efe, Eskişehir, Turkey

Sevinç Eraslan, İzmir, Turkey

Sait Gönen, İstanbul, Turkey

Ahmet Kaya, Konya, Turkey

Fahrettin Keleştimur, Kayseri, Turkey

Mustafa Kutlu, Ankara, Turkey

Tümay Sözen, Ankara, Turkey

Refik Tanakol, İstanbul, Turkey

Ali Rıza Uysal, Ankara, Turkey

Sema Yarman, İstanbul, Turkey

A-I

AIMS AND SCOPE

The Turkish Journal of Endocrinology and Metabolism is the peer-reviewed periodical on clinical and experimental endocrinology and metabolism diseases and re-lated fields. It is the official journal of the Society of Endocrinology and Metabolism of Turkey and is published quarterly (March, June, September and December) ashardcopy and an electronic journal at www.turkjem.org. The manuscripts are published in English language.The journal publishes original research papers, reviews and case reports which primarily focus on clinical endocrinology. The journal's aim is to be the essential rea-ding for both endocrinologists and clinical practitioners.

TThhee TTuurrkkiisshh JJoouurrnnaall ooff EEnnddooccrriinnoollooggyy aanndd MMeettaabboolliissmm iiss iinnddeexxeedd iinn EEmmeerrggiinngg SSoouurrcceess ooff CCiittaattiioonn IInnddeexx ((EESSCCII)),, BBrriittiisshh LLiibbrraarryy,, CCIINNAAHHLL,, DDiirreeccttoorryy ooff OOppeenn AAcccceessss JJoo--uurrnnaallss ((DDOOAAJJ)),, EEBBSSCCOO,, EEMMBBAASSEE,, SSCCOOPPUUSS,, TTüübbiittaakk // UUllaakkbbiimm TTRR IInnddeexx,, TTüürrkkMMeeddlliinnee,, TTüürrkkiiyyee CCiittaattiioonn IInnddeexx..

OOppeenn AAcccceessss PPoolliiccyyThe Turkish Journal of Endocrinology and Metabolism is an open access journal. This journal provides immediate open access to its content on the principle that ma-king research freely available to the public supports a greater global exchange of knowledge.Open Access Policy is based on rules of Budapest Open Access Initiative (BOAI) http://www.budapestopenaccessinitiative.org/.Instructions for online manuscript submission, current issues and archives of the journal can be found at www.turkjem.org. Please do not send manuscripts to the edi-torial office. For other related issues you may contact the editorial office:

SSuubbssccrriippttiioonn iinnffoorrmmaattiioonn

The Turkish Journal of Endocrinology and Metabolism is distributed free of charge to all endocrinology academicians and instructors serving in our country. Access

to full-text articles of all issues of the journal is free at the journal's website www.turkjem.org

IInnssttrruuccttiioonnss ffoorr aauutthhoorrssInstructions for authors are published in the journal pages and can be accessed at the web site of the journal www.turkjem.org

MMaatteerriiaall DDiissccllaaiimmeerrStatements or opinions expressed in the manuscripts published in the Turkish Journal of Endocrinology and Metabolism reflect the views of the author(s) and are not theopinions of the editors, the editorial board and the publisher. The editors, editorial board and the publisher disclaim any responsibility or liability for such materials.

TThhee jjoouurrnnaall iiss pprriinntteedd oonn aacciidd--ffrreeee ppaappeerr..

All rights are reserved. Rights to the use and reproduction, including in the electronic media, of all communications, papers,photographs and illustrations appearing in this journal belong to the Turkish Journal of Endocrinology and Metabolism. Repro-duction without prior written permission of part or all of any material is forbidden. The journal complies with the Professional Prin-ciples of the Press.

The paper used the print this journal conforms to ISO 9706: 1994 standard (Requirements for Permanence). The Narional Lib-rary of medicine suggests that biomedical 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 themanuscripts and abstracts in English and publishing process are realized by Türkiye Klinikleri.

A-II

TTHHEE OOWWNNEERR OONN BBEEHHAALLFF OOFF TTUURRKKIISSHH JJOOUURRNNAALL OOFF EENNDDOOCCRRIINNOOLLOOGGYY AANNDD MMEETTAABBOOLLIISSMM OOFF TTUURRKKEEYY

Sevim Güllü, MD

MMAANNAAGGIINNGG CCLLEERRIICCAALL DDIIRREECCTTOORR

Nilgün Başkal, MD

AADDRREESSSS FFOORR MMAANNAAGGEEMMEENNTT

Turkish Journal of Endocrinology and Metabolism of Turkey

Meşrutiyet Caddesi No: 29/12 Kızılay, Ankara, TURKEY

Phone: +90 312 425 20 72

Fax: +90 312 425 20 98

web: www.turkjem.org

E-mail: [email protected]

PPuubblliiccaattiioonn TTyyppee aanndd PPeerriiooddssTurkish Journal of Endocrinology and Metabolism of Turkey is published 4 (March, June, September and December) times a year.Local perid publication.

FFoorr rreeqquueessttss ccoonncceerrnniinngg ssuubbssccrriippttiioonn iinnffoorrmmaattiioonn aanndd aaddvveerrttiissiinngg,, pplleeaassee ccoonnttaacctt tthhee PPuubblliisshheerr::

Publishing House: Türkiye Klinikleri

Address: Nasuh Akar Mah. Türkocağı Cad. No:30 Balgat - Ankara Turkey

Telephone: +90 312 286 56 56

Fax: +90 312 220 04 70


Web page: www.turkiyeklinikleri.com

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

A-III

Publication Date: 29.12.2017

ISSN: 1301-2193

E-ISSN: 1308-9846

Turkish Journal of Endocrinology and Metabolism issues papers on all aspects of en-docrinology. The journal is the scientific publishing organ of the Society of Endocrinol-ogy and Metabolism of Turkey and has been published quarterly (March, June,September and December) since 1997.In addition to original articles, case reports, reviewarticles, letters to the editor, educational articles, sections of question and answers, ab-stracts from literature and announcements of congresses/meetings are also pub-lished.Turkish Language Institution dictionary and orthography guide should be taken asbasic for literary. The idioms used should be checked.The scientific and ethical liabilityof the manuscripts belongs to the authors and the copyright of the manuscripts belongsto the Turkish Journal of Endocrinology and Metabolism. The authors should submit thesigned copyright transfer form together with their manuscripts. Authors are responsiblefor the contents of the manuscript and accuracy of the references.The authors shouldguarantee that their manuscripts has not been published and/or is not under consider-ation for publication in any other periodical. This requirement does not apply to paperspresented in scientific meetings and whose summaries, not exceeding 250 words, arepublished. In this case, however, the name, date and place of the meeting in which thepaper was presented should be stated. The signed statement of scientific contributionsand responsibilities of all authors is required.

The Turkish Journal of Endocrinology and Metabolism does not charge any article sub-mission or processing charges.

PPeeeerr--rreevviieewwEditorial policies of the journal are conducted according to the rules advised by Coun-cil of Science Editors and reflected in the Uniform Requirements for Manuscripts Sub-mitted to Biomedical Journals: Writing and Editing for Biomedical Publication(http://www.icmje.org/).

Submitted manuscripts are subjected for double-blind peer-review. The scientific boardguiding the selection of the papers to be published in the Journal consists of electedexperts of the Journal and if necessary, selected from national and international expertsin the relevant field of research. All manuscripts are reviewed by the editor, section as-sociate editors and at least three internal and external expert referees. All research ar-ticles undergo review by statistical editor as well.

Submitted manuscripts are also subjected for the evaluation of plagiarism, duplicatepublication by automatic software. Authors are obliged to acknowledge if they pub-lished study results in full or in part in form of abstracts.

The authors of the accepted manuscripts should be in consent that the editor and as-sociate editors could make corrections without changing the main text of thepaper.Manuscript format should be in accordance with Uniform Requirements for Man-uscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical Publica-tion (http://www.icmje.org/).

GGeenneerraall GGuuiiddeelliinneessManuscripts can only be submitted electronically through the web site (http://www.turk-jem.org) after creating an account. This system allows online submission and peer-re-view.The manuscripts are archived according to ICMJE-www.icmje.org, Index Medicus(Medline/PubMed) and Ulakbim-Turkish Medicine Index Rules. Rejected manuscripts,except artwork are not returned.

For the experimental, clinical and drug human studies, approval by ethical committee andstatement on the adherence of the study protocol to the international agreements (HelsinkiDeclaration revised 2013 (www.wma.net/en/30publications/10policies/b3/) are required. In ex-perimental animal studies, the authors should indicate that the procedures followed were in ac-cordance with animal rights (Guide for the care and use of laboratory animals,www.nap.edu.catalog/5140.html) and they should obtain animal ethic committee approval.

The Ethic Committee approval document should be submitted to the Turkish Journal of En-docrinology and Metabolism together with the manuscript.

The approval of the ethic committee, statement on the adherence to international guidelinesmentioned above and that the patients` informed consent is obtained should be indicatedin the `Material and Method` section and is required for case reports whenever data/mediaused could reveal identity of the patient. The declaration of the conflict of interest betweenauthors, institutions, acknowledgement of any financial or material support, aid is manda-tory for authors submitting manuscript and the statement should appear at the end of man-uscript. Reviewers are required to report if any potential conflict of interest exists betweenreviewer and authors, institutions.

OOrriiggiinnaall AArrttiicclleessClinical research should comprise clinical observation, new techniques or laboratorystudies. Provided that these manuscripts are written with lower-case letters, they shouldinclude the title in Turkish/English, the background and the key words in Turkish/Eng-lish, introduction, materials and methods, results (findings), discussion, references, ta-bles, charts, pictures and they should be written in accordance with Journal Agent rules.They should not exceed sixteen (A4) pages.

It is recommended to present research articles and meta-analysis/systematic reviewsarticle according to the guidelines on specific design of the study: randomized studies(CONSORT), observational studies (STROBE), studies on diagnostic accuracy (STARD),meta- analysis and systematic review (PRISMA, MOOSE) and other study designs(www.equator-network.org).

AAuutthhoorr IInnffoorrmmaattiioonnThe name and the surname of the authors should be written without abbreviation. Theacademic titles, the affiliations and the addresses of these affiliations should be clearlydeclared. Furthermore, the contact information of the corresponding author should beentered to the system. Since e-mail will be used primarily for the contact with the au-thors, the e-mail of the corresponding author should be indicated. In addition the phoneand the fax numbers should be also indicated.

TTiittllee PPaaggeeThis page should include the titles of the manuscript, key words and running titles. In Turk-ish manuscripts the title in English should also take place. Likely, Turkish title should bementioned for articles in foreign language. If the content of the paper has been previouslypresented or its abstract has been published, an explanation should be made in this pageabout this issue. If there are any grants and other financial supports by any institutions orfirms for the study, information must be provided by the authors.

AAbbssttrraaccttTurkish and English summaries of the manuscript should take place in a manner that it willnot exceed 250 words. The keywords should be written at the end of the summary. Thereferences should not be cited in the summary section. As far as possible, use of abbrevi-ations is to be avoided. If any abbreviations are used, they must be taken into considera-tion independently of the abbreviations used in the text. The summary should be writtenwith four running titles.

PPuurrppoossee:: The goal of the study should be clearly stated.

MMaatteerriiaall aanndd MMeetthhoodd:: The study should be defined, the standard criteria; it should bealso indicated whether the study is randomized or not, whether it is retrospective orprospective, the statistical method, if any, should be indicated.

RReessuullttss ((FFiinnddiinnggss)):: The detailed result of the study should be given and the statistical sig-nificance level should be indicated.

DDiissccuussssiioonn:: It should reflect the results of the study, the favorable and unfavorable as-pects should be declared.

INSTRUCTIONS FOR AUTHORS

A-IV

KKeeyy wwoorrddss:: At least three and maximum eight key words. (in English and in Turkish) Donot use abbreviations in the key words. Turkish key words will be provided by the edi-torial office for the authors who are not Turkish speakers. If you are not a native Turkishspeaker, please re-enter your English keywords to the area provided for the Turkish key-words. English key words should be provided from Medical Subject Headings(http://www.nlm.nih.gov/mesh/) while Turkish key words should be provided fromhttp://www.bilimterimleri.com.

Original researches should have the following sections;

IInnttrroodduuccttiioonnBrief explanation about the topic should be done, the objective of the study should beindicated and these should be supported by the literature information.

MMaatteerriiaallss aanndd MMeetthhooddssThe study design should be described, it should be indicated whether it is interven-tional randomized or observational, whether it is retrospective or prospective, the num-ber of trials, the characteristics, studied variables and specific methods, the usedstatistical methods should be indicated. If any, it should be indicated that the resultsshould be scrutinized.

RReessuullttss ((FFiinnddiinnggss))The results should be given, the tables and the pictures should be given in numericalorder and, the results should be indicated as % and/or p-values.

DDiissccuussssiioonnThe obtained values should be discussed with its favorable and unfavorable aspectsand, they should be compared with literature.

SSttuuddyy LLiimmiittaattiioonnss:: Study Limitations and strengths, and directions for further research orimplication must be discussed.

CCoonncclluussiioonn:: The conclusion of the study should be highlighted.

Authors contributions, Declaration of conflict of interest and Acknowledgements shouldappear at the end of the main text of manuscript.

RReeffeerreenncceessAccuracy of reference data is the author’s responsibility. References should be numberedaccording to the consecutive citation in the text. References should be indicated by paren-thesis in the text. If there is Turkish Reference, attention should be paid to indicate this.Journal titles should be abbreviated according to the style used in the Index Medicus. Allthe references, books, papers and similar articles should be cited as references should bewritten according to the rules of the International Committee of Medical Journal EditorsUniform Requirements for Manuscripts Submitted to Biomedical Journals(http://www.nlm.nih.gov/bsd/uniform_requirements.html).

JJoouurrnnaall:: The surnames of the authors and the initial of authors’ names, the title of thepaper, the title of the journal (the original abbreviation stated in the journal), year, vol-ume and the page numbers.

EExxaammppllee:: Collin JR, Rathbun JE. Involutional entropion: a review with evaluation of aprocedure. Arch Ophthalmol. 1978;96:1058-1064.

BBooookk wwiitthh aa SSiinnggllee AAuutthhoorr:: The surname and the initial of the author, the title, chapterand section, the name of the editor, title of the book, place of publication, name of theprinting house, year of print, page numbers.

EExxaammppllee:: Herbert L. Conjunctivitis, keratitis and infections of periorbital structures. In:Armstrong D, Cohen J, eds. The Infectious Diseases (1st ed). Philadelphia; Mosby Har-court; 1999;11;1-8.

BBooookk CChhaapptteerr:: The surname and the initial of the author, chapter and section, name ofthe editor, title of the book, place of publication, name of the printing house, year ofprint, page numbers.

EExxaammppllee:: O’Brien TP, Green WR. Periocular Infections. In: Feigin RD, Cherry JD, eds.Textbook of Pediatric Infectious Diseases (4th ed). Philadelphia; W.B. Saunders Com-pany;1998:1273-1278.

VViissuuaall MMaatteerriiaallss ((TTaabblleess,, GGrraapphhiiccss,, FFiigguurreess,, aanndd PPiiccttuurreess)):: All tables, graphics or figuresshould be enumerated according to the sequence within the text and a brief descrip-tive caption should be written. The abbreviations used should be definitely explainedin the figure’s legend. Especially, the text of tables should be easily understandableand should not repeat the data of the main text. Illustrations that already published areacceptable if supplied by permission of authors for publication. The details of the pic-tures should be distinguishable and they should be recorded in JPEG format and in 500pixels per inch at least.

CCaassee RReeppoorrttssIt should consist of the title, summary, key words, summary in English, keywords, intro-duction, case report, discussion and references, the case or the cases should be worthto be presented, it should contribute to literature, and all of them should not exceed 5papers in (A4) sizes.

RReevviieewwIt should include new topics, the own experiences of the author, if possible, and thereferences also. It should consist of the title in Turkish, the summary, the keywords, thetitle in English, the summary in English and the keywords in English.

LLeetttteerrss ttoo tthhee EEddiittoorrThey should be assays in the “review” manner in various topics or the assays concerningthe articles published in the Turkish Journal of Endocrinology and Metabolism with thecontributive content or contents as questions that do not exceed 200 words.

SScciieennttiiffiicc LLeetttteerrssThe manuscripts should be error-free in the summaries compiled from the articles inother journals, the author names (surname, name) should be written, the journal titleshould be written with its original abbreviation, its year should be indicated and, thename and he surname of the translator should be indicated under the manuscript.

OOppeenn AAcccceessss PPoolliiccyyThis journal provides immediate open access to its content on the principle that mak-ing research freely available to the public supports a greater global exchange of knowl-edge.

CCoorrrreessppoonnddeenncceeAll correspondences can be done to the following postal address or to the following e-mail address, where the journal editorial resides:

Address: Ankara University Faculty of Medicine, Department of Endocrinology and Me-tabolism, Ankara, Turkey

Phone: +90 312 508 21 00

Fax: +90 312 309 45 05


“This journal licenced under the terms of the Creative Commons 4.0 International Li-cence (CC BY 4.0)”

INSTRUCTIONS FOR AUTHORS

A-V

A-VI

CONTENTS

Original Ar"cles97 Effect of Exenatide on Aortic Stiffness and Blood Pressure Parameters

Eksenatidin Aortik Sertlik ve Kan Basıncı Parametreleri Üzerine EtkisiEren GÜRKAN, İlhan TARKUN, Tayfun ŞAHİN

104 Health Problems Accompanying Hypothyroidism in Patients in EcuadorEkvador'daki Hastalarda Hipotiroidi ile Birlikte Görülen Sağlık SorunlarıÓscar Luís VACA CEVALLOS, Miguel Ángel GARCÍA BEREGUIAIN, Miguel Ángel BLASCO CARLOS

108 Evaluation of the Relationship Between Thyroid Functions and Dry Eye Symptoms in Patients with Hashimoto ThyroiditisHashimoto Tiroiditi Tanılı Hastalarda Kuru Göz Semptomlarının Tiroid Fonksiyonları ile Olan İlişkisinin DeğerlendirilmesiGülşah Y. YALIN, Fuat CENİK, Nihat SAYIN, Hüseyin ÇELİK, Abdülbaki KUMBASAR

113 The Role of FTO Gene Alleles on the Diet and Metabolic Risk Factors in the Subjects with DiabetesFTO Gen Alellerinin Diyabetli Kişilerde Diyet ve Metabolik Risk Faktörleri Üzerindeki RolüAsher FAWWAD, Iftikhar Ahmed SIDDIQUI, Fariha SHAHEEN, Rubina HAKEEM, Nazish WARIS, Syeda Nuzhat NAWAB, Syed Muhammad SHAHID, Anna PARKER, Abdul BASIT

120 Coexistence of Autoimmune and Allergic Diseases with Autoimmune Thyroid DiseasesOtoimmün Tiroid Hastalıklarıyla Birlikte Seyreden Otoimmün ve Allerjik Hastalıklarİffet DAĞDELEN DURAN, Kemal AĞBAHT, İrfan SOYKAN, Sevim GÜLLÜ

Review Ar"cle127 The Role of Gluten-free Diet and Intestinal Microbiota on Glycemic Control and Diabetes Development

Glutensiz Diet, İntestinal Mikrobiotanın Glisemik Kontrol ve Diyabet Gelişimindeki RolüEvrim ÇAKIR, Esra ATAOĞLU, Mustafa YENİGÜN

December 2017 Volume: 21 Issue: 4

Case Reports131 Mauriac Syndrome: Case Report and Review of the Literature

Mauriac Sendromu: Olgu Sunumu ve Literatürün Gözden GeçirilmesiÖmercan TOPALOĞLU, Sibel DEMİRAL SEZER, Bilgin DEMİR, Derya AKARKEN

136 Acromegaly and Pregnancy: Five New CasesAkromegali ve Gebelik: Beş Yeni VakaElif ÖNDER, Yusuf AYDIN, Tuba SOYSAL, Mazhar TUNA, Adem GÜNGÖR

Invited Review140 Summary of Bariatric Surgery Guideline of the Society of Endocrinology and Metabolism of Turkey

Türkiye Endokrinoloji ve Metabolizma Derneği Bariatrik Cerrahi Kılavuzu Özeti Tevfik SABUNCU, Sinem KIYICI, Mehmet Ali EREN, Seda SANCAK, Alper SÖNMEZ, Sibel GÜLDİKEN, Faruk KUTLUTÜRK, İbrahim ŞAHİN, Murat YILMAZ, Fahri BAYRAM

A-VII

A-VIII

EDITORIAL

DDeeaarr eesstteeeemmeedd rreeaaddeerrss ooff TTuurrkkJJEEMM FFaammiillyy,,

Recently the World Health Organization has made very important observations related to obesity. On a global scale obesity has nearlytripled since 1975. In 2016, more than 1.9 billion adults, 18 years and older, were overweight. Of these over 650 million were obese. 39%of adults aged 18 years and over were overweight in 2016, and 13% were obese. Most of the world's population live in countries whereoverweight and obesity kills more people than underweight. 41 million children under the age of 5 were overweight or obese in 2016.Over 340 million children and adolescents aged 5-19 were overweight or obese in 2016. Obesity is preventable.

The report concludes that cardiovascular diseases (mainly heart disease and stroke) were the leading cause of death in 2012 followed bydiabetes; musculoskeletal disorders (especially osteoarthritis-a highly disabling degenerative disease of the joints); some cancers (in-cluding endometrial, breast, ovarian, prostate, liver, gallbladder, kidney, and colon). We can simply add permanent loss in quality of lifedue to an outcome that can be cured.

Major reasons of becoming obese can be stated as, consuming too many calories; leading a sedentary lifestyle; not sleeping enough;endocrine disruptors such as some foods that interfere with lipid metabolism; lower rates of smoking (smoking suppresses appetite); med-ications that make patients put on weight; is obesity self-perpetuating; and the obesities genetic foundations. Among these consumingtoo many calories, sedentary lifestyle, and smoking is directly linked of whether one understands the threats of obesity.

Major rule of change in behavior is closely related to understanding and internalizing the real dimension of threats. Thus, with awarenessefforts we can really reduce the increasing trends in obesity. As the duration of life span improves the cost of obesity further increaseshaving direct impact on the quality of life. As controllable factors can be inhibited through self-regulation the effects of obesity on qual-ity of life should and could be reduced.

In our fall issue we have the following paper contributions:

Effect of Exenatide on Aortic Stiffness and Blood Pressure Parameters; Health Problems Accompanying Hypothyroidism in Patients inEcuador; Evaluation of the Relationship Between Thyroid Functions and Dry Eye Symptoms in Patients with Hashimoto Thyroiditis; TheRole of FTO Gene Alleles on the Diet and Metabolic Risk Factors in the Subjects with Diabetes; Coexistence of Autoimmune and Aller-gic Diseases with Autoimmune Thyroid Diseases; The Role of Gluten-free Diet and Intestinal Microbiota on Glycemic Control and Dia-betes Development; Mauriac Syndrome: Case Report and Review of the Literature; Acromegaly and Pregnancy: Five New Cases; Summaryof Bariatric Surgery Guideline of the Society of Endocrinology and Metabolism of Turkey.

Your support as a researcher or as a reader motivates the sleepless night of the contributors. I wish all the Turk JEM family a happy fallseason. Efforts towards improvement in health conditions is the major source of investment in human capital which is the key element ofwelfare at all levels.

WWiitthh mmyy bbeesstt rreeggaarrddss,,

NNiillggüünn BBaaşşkkaall MMDDEEddiittoorr--iinn--CChhiieeff

Introduction

Cardiovascular diseases are the major cause of mortality and mor-bidity for patients with type 2 diabetes. Majority of these patientshave comorbidities such as hypertension, dyslipidemia, and obe-

sity. Besides glucose control, cardiovascular protection depends oncontrolling comorbidities (1–3).Arterial stiffness is a term used to describe the viscoelastic proper-ties of the vessel wall. It is associated with aging and well-knownatherosclerotic risk factors such as diabetes mellitus (DM) and hy-

97

EEffffeecctt ooff EExxeennaattiiddee oonn AAoorrttiicc SSttiiffffnneessss aanndd BBlloooodd PPrreessssuurree PPaarraammeetteerrssEEkksseennaattiiddiinn AAoorrttiikk SSeerrttlliikk vvee KKaann BBaassıınnccıı PPaarraammeettrreelleerrii ÜÜzzeerriinnee EEttkkiissii

Mustafa Kemal University School of Medicine, Department of Endocrinology and Metabolism, Hatay, Turkey*Kocaeli University School of Medicine, Department of Endocrinology and Metabolism, Kocaeli, Turkey

**Kocaeli University School of Medicine, Department of Cardiology, Kocaeli, Turkey

Purpose: To evaluate the effects of exenatide and insulin glargine on systolic and diastolic blood pressure, pulse pressure, and aortic stiff-ness parameters. Materials and Methods: Thirty-four patients with type 2 diabetes who were receiving metformin treatment for at least two months but naivefor insulin and incretin based treatments, with body mass index (BMI) = 25-45 kg/m2, were randomized into exenatide a glucagon like pep-tide-1 (GLP–1) analog and insulin glargine arms and were followed for 26 weeks. Aortic stiffness parameters were calculated using transt-horacic echocardiography and hemodynamic data. Body weight and total body fat mass were measured by bioimpedance analysis.Results: There was no signicant change in systolic and diastolic blood pressures in both arms. When the effects on aortic stiffness para-meters were evaluated there was no signicant difference in the baseline and outcome values of both arms. Changes in body weight hada negative correlation with aortic stiffness β index (r=–0.322) and a positive correlation with aortic distensibility (r=0.386). Discussion: Throughout the study period, exenatide and insulin glargine had a neutral effect on blood pressure parameters. Exenatide didnot cause any change in aortic stiffness parameters. A 26-week exenatide treatment leads to loss of body weight and fat mass along withglycemic regulation. Body weight and fat mass loss have a positive impact on aortic stiffness indicators. Keywords: Exenatide, insulin glargine, blood pressure, aortic stiffness, atherosclerosis

Amaç: Eksenatid ile insülin glarjinin sistolik ve diyastolik kan basıncı, nabız basıncı ve aortik sertlik parametreleri üzerine etkinliğini değer-lendirmek.Gereç ve Yöntemler: Başlangıçta en az 2 ay metformin tedavisi alan, insülin ve inkretin bazlı tedaviler için naif, vücut kitle indeksi (VKİ) =25-45 kg/m2 aralığında olan 34 tip 2 diyabetli hasta, glukagon like peptit-1 (GLP-1) analogu olan eksenatid ve insülin glarjin kollarına ran-domize edildi. 26 hafta boyunca izlendi. Aortik sertlik ölçümü transtorasik ekokardiogra ve hemodinamik veriler kullanılarak hesaplandı.Vücut ağırlığı ve total vücut yağ kütlesi biyoimpedansla ölçüldü. Bulgular: Her iki çalışma kolunda sistolik ve diyastolik kan basıncında anlamlı değişiklik görülmedi. Aortik serlik parametrelerine etkileri de-ğerlendirildiğinde başlangıç ve sonuç değerlerinde anlamlı farklılık tespit edilmedi. Aortik sertlik β-indeksi ile kilo değişimi arasında negatif(r=–0.322) ve aortik distansibilite ile kilo değişimi arasında pozitif korelasyon tespit edildi (r=0.386).Tartışma: Eksenatid ve insulin glarjin çalışma periyodu boyunca kan basıncı parametrelerine nötral etki göstermiştir. Eksenatid aortik sert-lik parametrelerinde değişikliğe neden olmamıştır. 26 haftalık eksenatid tedavisi glisemik regülasyon yanında, vücut ağırlığı ve yağ kütlesikaybına neden olmaktadır. Vücut ağırlığı ve yağ kütlesi kaybı aortic sertlik belirteçlerine olumlu etmektedir.Anahtar kelimeler: Eksenatid, insülin glarjin, kan basıncı, aortik sertlik, ateroskleroz

Address for Correspondence: Eren Gürkan, Mustafa Kemal University School of Medicine, Department of Endocrinology and Metabolism, Hatay, TurkeyPhone: 0326 229 10 00 E-mail: [email protected] Received: 06.02.2017 Accepted: 08.12.2017

®Copyright 2017 by Turkish Journal of Endocrinology and Metabolism AssociationTurkish Journal of Endocrinology and Metabolism published by Türkiye Klinikleri

97Original ArticleDOI: 10.25179/tjem.2017-56552Turk J Endocrinol Metab 2017;21:97-103

pertension (4–7). The stiffness of larger arteries may be an indica-tor or cause of coronary atherosclerosis. It may play a role in thedevelopment of coronary ischemia, completely independent ofcoronary atherosclerosis. Increased aortic stiffness is an indicatorof a widespread atherosclerotic involvement of the vascular sys-tem (8–9). Arterial stiffness and pulse pressure increase are widely used pa-rameters in the prediction of cardiovascular disease developmentand mortality in the general population and among type 2 diabeticpatients (10–12). The aorta is widely used to measure arterial stiff-ness. The most important aortic stiffness indicators are aortic dis-tensibility and aortic stiffness � index (13–15). Many studies have revealed that aortic elasticity parameters areimpaired in type 2 DM (16). Increased arterial stiffness may be oneof the considerable causes in understanding the relationship be-tween DM and increased cardiovascular risk as arterial stiffness isfrequently observed in both cases (17). As the arteries stiffen, pulse pressure depending on systolic pres-sure increases. Increase in systolic pressure triggers left ventriclehypertrophy, and ventricular stiffness leads to diastolic dysfunctionand heart failure. A concomitant decrease in diastolic pressure re-duces coronary blood flow and leads to ischemia (18–19). The aim of this study was to compare the effects of two antidia-betics with similar glycemic effectiveness, the glucagon-like pep-tide–1 (GLP–1) agonist, exenatide, and insulin glargine, on bloodpressure and aortic stiffness parameters.

Materials and Methods

The study was performed between June 2011 and December 2012at one study site in Turkey. In total, 60 patients were screened, ofwhich 34 patients were randomized using a permutated block ran-domization scheme. This investigation was designed to evaluate the treatment and ef-ficacy of a 26-week, randomized, open-label, two-arm parallelgroup study. The study protocol was approved by the Ethical Com-mittee of the Kocaeli University, Turkey. The study included type 2DM patients whose age was between 40 and 70 years, with a he-moglobin A1c (HbA1c) level of 7%–9.5% (53–80 mmol/mol), a bodymass index (BMI) of 25–45 kg/m2, and who have regularly usedmetformin 2 × 1g/day for at least two months. The patients with ahistory of insulin- or incretin-based treatments were excluded. Thepatients who had changes in the drug groups effective in the car-diovascular system and glucose control during the last threemonths were not included in the study. The subjects with a previ-ous coronary angioplasty, acute coronary syndrome, and cere-brovascular event within six months; impaired hepatic and renalfunction; systolic blood pressure ≥180 mmHg, diastolic blood pres-sure ≥100 mmHg, or uncontrolled hypertension (HT); and activesmokers were excluded. Twelve female and five male patientswere included in the exenatide arm, and ten female and sevenmale patients were included in the insulin glargine arm. The studyarms continued receiving metformin 2 g/day. One arm receivedexenatide 5 µg 2 × 1 s.c. at least 30 min before meals for fourweeks. This dose was subsequently increased to 2 × 10 mcg s.c.and exenatide was continued for six months in total. The patients

in the other arm were started on insulin glargine 0.2 U/kg. Insulininjection was administered at bedtime. The dose was increasedby two units in patients with a mean 3-day fasting plasma glucose(FPG) ≥100 mg/dL, which was obtained through phone visits. Doseincrease was continued until FPG was between 80 and 99 mg/dL.When an FPG value of ≤60 mg/dL was achieved, the previous dosewas started again and no new dose adjustments were made ear-lier than a week. The patients were assessed at weeks 0, 4, 12,and 26. They were evaluated at all visits through BMI measure-ments, blood pressure controls, routine biochemistry, and assess-ment of drug side effects. None of the participating patientsexperienced serious drug-related side effects. Two patients in thetreatment arms were excluded later, one because of major de-pression-related treatment incompliance and another because ofnon-attendance to visits.

Body weight and total body fat mass assessment

The body weight and total body fat mass were measured usingthe bioimpedance analysis technique by using a Tanita BC-418body composition analyser device. Waist circumference wasmeasured at the central point of the space between the iliac crestand the lower limit of the arch. The measurements were performedin the morning on an empty stomach at screening and follow-upvisits.

BBlloooodd pprreessssuurree mmeeaassuurreemmeennttss

Echocardiographic measurements and blood pressure weremeasured by a specialized cardiologist. The cardiologist wasblinded to the study groups. Simultaneous blood pressure meas-urement with echocardiographic examination was performed. Themeasurements were performed in the supine position with asphygmomanometer. Korotkoff phase b2 and V were used to de-termine systolic and diastolic blood pressures. The average of threemeasurements was noted.

AAoorrttiicc ssttiiffffnneessss ppaarraammeetteerrss aasssseessssmmeenntt

Aortic stiffness β�index and distensibility were assessed using ahigh-resolution GE Vivid 7 Dimension (GE, Davis Medical Electron-ics, USA) ultrasound device. The measurements were made ac-cording to the American Society of Echocardiography’s proposedcriteria (20). The image position was monitored with the proximalaorta right coronary and non-coronary valve cusps on theparasternal long axis were obtained clearly. Aortic sections weretaken with M-mode from the line of coaptation of the aortic valve2-cm proximal. Systolic and diastolic aortic lumen diameters weremeasured from the received section (Figure 1). The average of fiveconsecutive cycles, while the data were received from the meas-urement, was regarded as essential. Aortic stiffness � index andaortic distensibility obtained using echocardiographic and hemo-dynamic data were calculated.

Hemodynamic measurements

Pulse pressure (mmHg) = Systolic blood pressure – diastolic bloodpressure (N; 20–40 mmHg)Aortic stiffness β index was calculated as follows (20–21).

Gürkan et al. Turk J Endocrinol MetabAortic Stiffness, GLP-1 Analog Therapy 2017;21:97-103

98

Aortic stiffness index = log (SBP/DBP)/[(Aomax - Aomin)/Aomin] Ao: aorta; DBP: diastolic blood pressure; SBP: systolic blood pressure Aortic distensibility was calculated as follows (22).Aorta distensibility = 2 × [(Systolic aortic diameter - Diastolic aorticdiameter)/(Diastolic aortic diameter)] × (Aortic pulse pressure)

Biochemical parameters

By using an Abbott Architect c16000 device, fasting plasma glu-cose was measured by the hexokinase method, triglyceride by theglycerol phosphate oxidase method, and total cholesterol by theenzymatic method. The calculation was done using the Friedewaldformula for low density lipoprotein (LDL) cholesterol. HbA1c wasmeasured by the high performance liquid chromatography (HPLC)technique using a Shimadzu HPLC system, Shimadzu Corporation,JAPAN.

Statistical assessment

PASW 18.0 for Windows program was used for statistical analy-sis. Descriptive statistics are presented as number and percentagefor categorical variables, and mean, standard deviation, median,percentile 25 (Q1), and percentile 75 (Q3) are used to present nu-merical variables. Data assessment was conducted using the un-paired t-test for the pairwise group comparisons of the variableswith a normal distribution; paired t-test for the comparisons be-tween pretreatment and posttreatment values; the Mann–WhitneyU test for the pairwise group comparisons of variables with ab-normal distribution; the Wilcoxon signed rank test for pretreatmentand posttreatment comparisons; a chi-square test for the com-parisons of qualitative data and descriptive statistical methods(mean, standard deviation, median, and interquartile range). Theresults were evaluated at a significance level of p < 0.05 and 95%

confidence interval. The study groups were named as exenatide(group E) and insulin glargine (group I).

Results

The demographic data of Groups E and I are presented in Table 1.No difference was observed between the groups in terms of age,gender, and mean duration of diabetes.As shown in Table 1, posttreatment body weight, mean body fatmass, and body mass index values were significantly lower inGroup E, compared with their pretreatment values. In both treat-ment groups, waist circumferences decreased significantly. The pre- and posttreatment percentage changes in fasting bloodglucose were significantly higher in Group E than in Group I. Serumtriglyceride levels decreased significantly in Group I, compared withtheir pre-treatment levels. The pre- and posttreatment percentagechanges in triglyceride, LDL-cholesterol, and HDL-cholesterol lev-els in both groups were not statistically significant. HbA1c valueshad significantly declined with treatment in both groups, butthere was no statistically significant difference between thegroups (Table 1). There was no significant difference between the effects of drugson the cardiovascular system between both groups (Table 2).The comorbidities of the study groups are presented in Table 3.

i. Blood pressure

There was no significant difference between pre- and posttreat-ment pulse pressures in Groups E and I, and pulse pressure didnot change significantly with the treatment in both groups. Systolicand diastolic blood pressures did not change in both groups. Nostatistically significant difference was observed between the groups(Table 4).

Turk J Endocrinol Metab Gürkan et al.2017;21:97-103 Aortic Stiffness, GLP-1 Analog Therapy 99

Figure 1: Ultrasound-derived arterial properties are used to determine local arterial stiffness. The two thick blue lines represent the vessel wall movementduring the cardiac cycle (2).


100

Exenatide group Insulin glargine group p*

Mean ±SD Mean ±SD

Age 52.18 ±7.26 53.12 ±6.99 0.703

Sex Male 5 (29.4%) 7 (41.2%) 0.473

Female 12 (70.6%) 10 (58.8%)

DM age (years) 6.88 ±3.26 7.59 ±4.26 0.591

Body weight (kg) pre-treatment 94.34 ±11.77 90.51 ±14.32 0.401

posttreatment 88.79 ±12.94 89.66 ±14.43 0.855

p‡ 0.001 0.293

BMI (kg/m2) pre-treatment 35.89 ±3.7 33.21 ±4.45 0.065

posttreatment 33.98 ±4.15 33.02 ±4.57 0.382

P‡ 0.001 0.57

Total body fat mass (kg) pre-treatment 36.37 ±6.91 32.46 ±7.28 0.137

posttreatment 32.29 ±7.19 33.3 ±9.02 0.735

P‡ 0.009 0.509

Waist circumference (cm) pre-treatment 112.47 ±10.35 107.41 ±11.41 0.265

posttreatment 107.79 ±8.21 106.06 ±10.87 0.603

P‡ 0.006 0.024

HbA1c (%) pre-treatment 7.95 ±0.81 8.11 ±0.76 0.558

posttreatment 6.73 ±0.75 6.68 ±0.83 0.833

P‡ 0.001 0.001

hs-CRP pre-treatment Median ±SD 0.87 ±0.89 0.49 ±0.42 0.221†

Median (IQR) 0.6 (0.26–1.02) 0.33 (0.19–0.8)

post-treatment Median ±SD 0.52 ±0.47 0.44 ±0.47 0.524†

Median (IQR) 0.33 (0.16–1.02) 0.25 (0.13–0.63)

p‼ 0.017 0.469

Triglyceride pre-treatment 173.29 ±89.38 226 ±87.32 0.092

post-treatment 146.53 ±98.96 158.35 ±62.2 0.679

p‡ 0.217 0.001

HDL-cholesterol pre-treatment 44.82 ±12.06 39.29 ±8.84 0.137

post-treatment 40.65 ±8.82 40.12 ±7.22 0.849

p‡ 0.079 0.558

LDL-cholesterol pre-treatment 115.82 ±25.75 110.18 ±34.96 0.595

post-treatment 102.88 ±31.43 103.53 ±32.08 0.953

p‡ 0.150 0.367

Endothelin–1 pre-treatment Median ±SD 16.09 ±4.96 11.19 ±5.76 0.016†

Median (IQR) 15.93 (11.57–19.78) 11.09 (9–14.37)

post-treatment Median ±SD 12.35 ±5.65 20.06 ±9.79 0.016†

Median (IQR) 12.07 (10.76–14.15) 17.96 (11.83–24.43)

p‼ 0.026 0.008

DM: Diabetes mellitus, BMI: Body mass index, Hb: Hemoglobin, hs-CRP: High sensitive-CRP

* Independent t-test, ‡ paired test, †Mann-Whitney U test, ‼Wilcoxon Test, +Chi Square.

Table 1. Demographic data and pre- and post-treatment anthropometric measurements, metabolic proles and changes from baseline (%).

Groups β-blockers (%) ACE/ARB (%) Statin (%) Fibrate (%)

Exenatide 24 88 76 12

Insulin glargine 22 88 76 6

ACE: Angiotensin-converting enzyme/ARB: Angiotensin receptor blocker.

Table 2. Distribution of the medications received by our study groupsprior to the study.

Exenatide group Insulin glargine group

Hypertension 17 (100%) 14 (82%)

Coronary artery disease 2 (12%) 1 (6%)

Sedentary lifestyle 1 (6%) 4 (24%)

Dyslipidemia 15 (88%) 14 (82%)

Smoking 1 (6%) 1 (6%)

Table 3. The co-morbidities among the study groups.

ii. Aortic stiffness

No statistically significant difference was observed between themean pre- and post-treatment aortic stiffness and distensibility in-dices in Groups I and E. No statistically significant difference wasobserved between both groups (Table 4).

iii. Relationship between certain variables and blood pressure andaortic stiffness parameters

Changes in body weight had a negative correlation with aortic stiff-ness � index and a positive correlation with aortic distensibility(Table 5).

Discussion

There are indirect methods of evaluating arterial stiffness, such asaortic stiffness � index, aortic distensibility, and aortic pulse wavevelocity (PWV). Faster PWV, increased � index, and reduced disten-sibility are indicators of a stiffened aorta (10–20). No statistically significant difference was observed between ourstudy groups with respect to pre- to posttreatment changes in aor-tic stiffness parameters. In our 26-week study, there was an average weight loss of 5.55kg in Group E and of 0.85 kg in Group I, with a difference of ap-


Exenatide group Insulin glargine group

Parameters Median (IQR) Median (IQR) p†

Pulse pressure Pre-treatment 50 (40–70) 50 (40–60) 0.487

Post-treatment 50 (50–60) 50 (45–55) 0.447

p‡ 0.827 1.000

Systolic blood pressure Pre-treatment 140 (130–150) 130 (120–150) 0.302

Post-treatment 140 (120–150) 130 (120–140) 0.321

p‡ 0.747 0.811

Diastolic blood pressure Pre-treatment 80 (80–90) 80 (80–90) 0.406

Post-treatment 80 (70–90) r 0.544

p‡ 0.385 0.496

Aortic stiffness β-index Pre-treatment 2.67 (2.47–5.09) 3.73 (2.86–4.01) 0.326

Post-treatment 2.41 (1.9–3.52) 3.29 (1.89–4.74) 0.344

p‡ 0.868 0.102

Aortic distensibility Pre-treatment 6.09 (4.94–8.03) 6.44 (4.36–7.28) 0.389

Post-treatment 7.18 (6–10.73) 6.05 (4.28–8.81) 0.102

p‡ 0.653 0.227

Change from baseline (%) p†

Pulse pressure 0 (–14.29–25) 0 (–16.67–25) 0.821

Systolic blood pressure 0 (–6.67–6.67) 0 (–6.67–7.69) 0.848

Diastolic blood pressure 0 (–11.11–0) 0 (–10–0) 0.764

Aortic β-stiffness index –20.78 (–47.27–1.49) –10.61 (–47.62–67.71) 0.344

Aortic distensibility 21.37 (–2.88–96.9) –0.22 (–32.91–60.55) 0.293‡ Wilcoxon Signed Rank Test, †Mann-Whitney U Test.

Table 4. Pre- and post-treatment blood pressure and aortic stiffness parameters and change from baseline (%).

Change from baseline (%) BMI Waist circumference Fat mass (% ) Weight

Pulse pressure% r 0.197 0.188 0.015 0.209

p 0.264 0.288 0.938 0.235

Systolic pressure% r 0.288 0.285 0.094 0.24

p 0.098 0.102 0.615 0.172

Diastolic pressure% r 0.238 0.243 0.149 0.143

p 0.175 0.167 0.422 0.418

AO Stiffness β- index r –0.322 –0.29 0.051 –0.39

p 0.063 0.096 0.784 0.023

AO Distensibility r 0.386 0.259 0.043 0.405

p 0.024 0.139 0.818 0.018

Table 5. Correlation of the parameters related blood pressure and aortic stiffness parameters with certain variables.

proximately 4.7 kg between the groups. Weight loss improves ar-terial stiffness (21–23). Type 2 diabetes patients that receive weightloss treatment experience a reduction in the level of arterial stiff-ness besides improvements in their metabolic dysfunction (24). In-deed, there was a negative correlation between weight loss andaortic stiffness index and a positive correlation with aortic disten-sibility in our study (Table 5).While there was a 4-kg reduction in body fat mass in Group E, therewas a 0.8-kg increase in body fat mass Group I. There was a dif-ference of approximately 4.8 kg (16%) in fat mass between bothgroups (Table 1). In a one-year study comparing insulin glarginewith exenatide, a difference of 2.9 kg (13%) in the fat mass loss wasobserved (25). An association independent of age and systolic hy-pertension was observed between PWV and body weight, PWVand waist circumference, and PWV and total fat mass (particularlyvisceral fat mass) (20, 26–30). In a 26-week liraglutide (a GLP–1 ag-onist) study, reduction in fat mass actually occurred in visceral fatmass (31). In our study, a neutral change was observed in the ar-terial stiffness parameters in Group E. Exenatide use among obesetype 2 DM patients with high cardiovascular risk has been demon-strated to improve PWV in addition to the reduction in glycemic reg-ulation, body weight, and body fat mass (32). Although nostatistically significant relationship was determined between thereduction in fat mass and aortic stiffness parameters in Group E;the results of studies conducted with similar study groups arepromising (25, 32).No statistically significant changes were observed between thepre- and posttreatment measurements of blood pressure param-eters in two study groups. (Table 4). A reduction of 1–5 mmHg insystolic and diastolic blood pressures has been observed in thestudies using exenatide (33, 34). This effect of exenatide was as-sociated with renal water and sodium loss as reported in the stud-ies with animal models and was independent of othercardiovascular risk factors (35).The impairment of arterial elasticity is known to be the initiator ofearly vascular pathology, that is, atherosclerosis, among patientswith diabetes (35-37). Additionally, increased aortic stiffness thatresembles atherosclerosis of the aorta can be a significant indica-tor of peripheral vascular disease among patients with diabetes(38). Increased arterial stiffness is associated with reduced FMD(39). Previously, we had determined that the effects of the GLP–1 agonist,exenatide, were in favor of FMD increase (40). Here, we observedthat exenatide has a positive impact on weight and fat mass loss(Table 5). Weight and fat mass loss have a positive impact on aor-tic stiffness indicators. Hence, exenatide may positively affect aor-tic stiffness parameters over time.Besides the glucose control, GLP-1 agonist treatment has positiveimpacts on cardiovascular comorbidities.Our study has some advantages. During the study, the previouslyreported mild and medium intensity side effects in both arms wereat a tolerable level. In addition, no patients had deterioration ofrenal function and pancreatitis attacks. The disadvantages of ourstudy are its open-label randomization and a relatively short studyperiod.

Author Contributions

Ethics: Yes. Patient approval: Yes. Concept: Eren Gürkan, TayfunŞahin. Design: Eren Gürkan, Tayfun Şahin. Data Collection or Pro-cessing: Eren Gürkan, Tayfun Şahin, İlhan Tarkun. Analysis or In-terpretation: Eren Gürkan, İlhan Tarkun, Tayfun Şahin. LiteratureSearch: Eren Gürkan. Writing: Eren Gürkan. Conflict of Interest: Theauthors declare that they have no conflict of interest. Financial Dis-closure: There is no organization that funded our research.SSttaatteemmeenntt ooff HHuummaann aanndd AAnniimmaall RRiigghhttss:: All procedure followedwere in accordance with the ethical standards of the responsiblecommittee on human experimentation (institutional and national)and with the Helsinki declaration of 1975, as revised in 2008 (5).SSttaatteemmeenntt ooff IInnffoorrmmeedd CCoonnsseenntt:: Informed consent was obtainedfrom all patients for being included in the study.

References1. Rydén L, Standl E, Bartnik M, Van den Berghe G, Betteridge J, de Boer

MJ, Cosentino F, Jönsson B, Laakso M, Malmberg K, Priori S, OstergrenJ, Tuomilehto J, Thrainsdottir I, Vanhorebeek I, Stramba-Badiale M,Lindgren P, Qiao Q, Priori SG, Blanc JJ, Budaj A, Camm J, Dean V, Deck-ers J, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Oster-spey A, Tamargo J, Zamorano JL, Deckers JW, Bertrand M,Charbonnel B, Erdmann E, Ferrannini E, Flyvbjerg A, Gohlke H, Jua-natey JR, Graham I, Monteiro PF, Parhofer K, Pyörälä K, Raz I, Sch-ernthaner G, Volpe M, Wood D. Guidelines on diabetes, pre-diabetes,and cardiovascular diseases: executive summary. The Task Force onDiabetes and Cardiovascular Diseases of the European Society ofCardiology (ESC) and of the European Association for the Study of Di-abetes (EASD). Eur Heart J. 2007;28:88-136.

2. Stehouwer CD, Ferreira I. Diabetes, lipids and other cardiovascularrisk factors. In: Safar ME, O’Rourke MF, eds. Arterial Stiffness in Hy-pertension (1st ed). London: Elsevier; 2006:427-456.

3. Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C,Hayoz D, Pannier B, Vlachopoulos C, Wilkinson I, Struijker-Boudier H.Expert consensus document on arterial stiffness: methodological is-sues and clinical applications. Eur Heart J. 2006;27:2588-2605.

4. Cruickshank K, Riste L, Anderson SG, Wright JS, Dunn G, Gosling RG.Aortic pulse-wave velocity and its relationship to mortality in diabetesand glucose intolerance: an integrated index of vascular function?Circulation. 2002;106:2085-2090.

5. Franklin SS, Khan SA, Wong ND, Larson MG, Levy D. Is pulse pressureuseful in predicting risk for coronary heart disease? The Framinghamheart study. Circulation. 1999;100:354-360.

6. Nichols WW, O’Rourke MF. McDonald’s Blood Flow in Arteries: Theo-retical, Experimental and Clinical Principles (5th ed). London: HodderArnold; 2005:570.

7. Haffner SM, Stern MP, Hazuda HP, Mitchell BD, Patterson JK. Cardio-vascular risk factors in confirmed prediabetic individuals. Does theclock for coronary heart disease start ticking before the onset of clin-ical diabetes? JAMA. 1990;263:2893-2898.

8. Haffner SM, Mykkänen L, Festa A, Burke JP, Stern MP. Insulin-resistantprediabetic subjects have more atherogenic risk factors than insulin-sensitive prediabetic subjects: implications for preventing coronary heartdisease during the prediabetic state. Circulation. 2000;101:975-980.

9. Aoun S, Blacher J, Safar ME, Mourad JJ. Diabetes mellitus and renalfailure: effects on large artery stiffness. J Hum Hypertens. 2001;15:693-700.

10. Stefanadis C, Dernellis J, Vlachopoulos C, Tsioufis C, Tsiamis E,Toutouzas K, Pitsavos C, Toutouzas P. Aortic function in arterial hy-pertension determined by pressure-diameter relation: effects of dil-tiazem. Circulation. 1997;96:1853-1858.


102

11. Xu J, Shiota T, Omoto R, Zhou X, Kyo S, Ishii M, Rice MJ, Sahn DJ. In-travascular ultrasound assessment of regional aortic wall stiffness,distensibility, and compliance in patients with coarctation of aorta.Am Heart J. 1997;134:93-98.

12. Oxlund H, Rasmussen LM, Andreassen TT, Heickendorff L. Increasedaortic stiffness in patients with type 1 (insulin-dependent) diabetesmellitus. Diabetologia. 1989;32:748-752.

13. Hickler RB. Aortic and large artery stiffness: current methodology andclinical correlations. Clin Cardiol. 1990;13:317-322.

14. Hirai T, Sasayama S, Kawasaki T, Yagi S. Stiffness of systemic arteriesin patients with myocardial infarction. A noninvasive method to pre-dict severity of coronary atherosclerosis. Circulation. 1989;80:78-86.

15. Kawasaki T, Sasayama S, Yagi S, Asakawa T, Hirai T. Non-invasive as-sessment of the age related changes in stiffness of major branchesof the human arteries. Cardiovasc Res. 1987;21:678-687.

16. Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C,Hayoz D, Pannier B, Vlachopoulos C, Wilkinson I, Struijker-Boudier H;European Network for Non-invasive Investigation of Large Arteries.Expert consensus document on arterial stiffness: methodological is-sues and clinical applications. Eur Heart J. 2006;27:2588-2605.

17. Hickler RB. Aortic and large artery stiffness: current methodology andclinical correlations. Clin Cardiol. 1990;13:317-322.

18. Fukui M, Kitagawa Y, Nakamura N, Mogami S, Ohnishi M, Hirata C,Ichio N, Wada K, Kamiuchi K, Shigeta M, Sawada M, Hasegawa G,Yoshikawa T. Augmentation of central arterial pressure as a markerof atherosclerosis in patients with type 2 diabetes. Diabetes Res ClinPract. 2003;59:153-161.

19. Hermans MM, Henry R, Dekker JM, Kooman JP, Kostense PJ, NijpelsG, Heine RJ, Stehouwer CD. Estimated glomerular filtration rate andurinary albumin excretion are independently associated with greaterarterial stiffness: the Hoorn Study. J Am Soc Nephrol. 2007;18:1942-1952.

20. Sutton-Tyrrell K, Newman A, Simonsick EM, Havlik R, Pahor M, LakattaE, Spurgeon H, Vaitkevicius P. Aortic stiffness is associated with vis-ceral adiposity in older adults enrolled in the study of health, aging,and body composition. Hypertension. 2001;38:429-433.

21. Petersen KS, Blanch N, Keogh JB, Clifton PM. Effect of weight loss onpulse wave velocity: systematic review and meta-analysis. Arte-rioscler Thromb Vasc Biol. 2015;35:243-252.

22. Seifalian AM, Filippatos TD, Joshi J, Mikhailidis DP. Obesity and arte-rial compliance alterations. Curr Vasc Pharmacol. 2010;8:155-168.

23. Iguchi A, Yamakage H, Tochiya M, Muranaka K, Sasaki Y, Kono S, Shi-matsu A, Satoh-Asahara N. Effects of weight reduction therapy onobstructive sleep apnea syndrome and arterial stiffness in patientswith obesity and metabolic syndrome. J Atheroscler Thromb.2013;20:807-820.

24. Barinas-Mitchell E, Kuller LH, Sutton-Tyrrell K, Hegazi R, Harper P,Mancino J, Kelley DE. Effect of weight loss and nutritional interventionon arterial stiffness in type 2 diabetes. Diabetes Care. 2006;29:2218-2222.

25. Bunck MC, Diamant M, Eliasson B, Cornér A, Shaginian RM, Heine RJ,Taskinen MR, Yki-Järvinen H, Smith U. Exenatide affects circulatingcardiovascular risk biomarkers independently of changes in bodycomposition. Diabetes Care. 2010;33:1734-1737.

26. Diamant M, Lamb HJ, van de Ree MA, Endert EL, Groeneveld Y, BotsML, Kostense PJ, Radder JK. The association between abdominal vis-ceral fat and carotid stiffness is mediated by circulating inflamma-

tory markers in uncomplicated type 2 diabetes. J Clin EndocrinolMetab. 2005;90:1495-1501.

27. Orr JS, Gentile CL, Davy BM, Davy KP. Large artery stiffening withweight gain in humans: role of visceral fat accumulation. Hyperten-sion. 2008;51:1519-1524.

28. Arner P, Backdahl J, Hemmingsson P, Stenvinkel P, Eriksson-Hogling D,Näslund E, Thorell A, Andersson DP, Caidahl K, Rydén M. Regionalvariations in the relationship between arterial stiffness and adipocytevolume or number in obese subjects. Int J Obes (Lond). 2014;39:222-227.

29. Hacıhamdioğlu B, Öçal G, Berberoğlu M, Sıklar Z, Fitöz S, Tutar E, Ner-gisoğlu G, Savaş Erdeve S, Çamtosun E. Preperitoneal fat tissue maybe associated with arterial stiffness in obese adolescents. UltrasoundMed Biol. 2014;40:871-876.

30. Britton KA, Wang N, Palmisano J, Corsini E, Schlett CL, Hoffmann U,Larson MG, Vasan RS, Vita JA, Mitchell GF, Benjamin EJ, Hamburg NM,Fox CS. Thoracic periaortic and visceral adipose tissue and theircross-sectional associations with measures of vascular function.Obesity (Silver Spring). 2013;21:1496-1503.

31. Jendle J, Nauck MA, Matthews DR, Frid A, Hermansen K, Düring M,Zdravkovic M, Strauss BJ, Garber AJ. LEAD-2 and LEAD-3 StudyGroups. Weight loss with liraglutide, a once-daily human glucagon-like peptide-1 analogue for type 2 diabetes treatment as monother-apy or added to metformin, is primarily as a result of a reduction infat tissue. Diabetes Obes Metab. 2009;11:1163-1172.

32. Hong JY, Park KY, Kim BJ, Hwang WM, Kim DH, Lim DM. Effects ofshort-term exenatide treatment on regional fat distribution, glycatedhemoglobin levels, and aortic pulse wave velocity of obese type 2 di-abetes mellitus patients. Endocrinol Metab (Seoul). 2016;31:80-85.

33. Wang B, Zhong J, Lin H, Zhao Z, Yan Z, He H, Ni Y, Liu D, Zhu Z. Bloodpressure-lowering effects of GLP-1 receptor agonists exenatide andliraglutide: a meta-analysis of clinical trials. Diabetes Obes Metab.2013;15:737-749.

34. Katout M, Zhu H, Rutsky J, Shah P, Brook RD, Zhong J, Rajagopalan S.Effect of GLP-1 mimetics on blood pressure and relationship to weightloss and glycemia lowering: results of a systematic meta-analysisand meta-regression. Am J Hypertens. 2014;27:130-139.

35. Rieg T, Gerasimova M, Murray F, Masuda T, Tang T, Rose M, DruckerDJ, Vallon V. Natriuretic effect by exendin-4, but not the DPP-4 inhibitoralogliptin, is mediated via the GLP-1 receptor and preserved in obesetype 2 diabetic mice. Am J Physiol Renal Physiol. 2012;303:F963-971.

36. Bierman EL. George Lyman Duff Memorial Lecture. Atherogenesis indiabetes. Arterioscler Thromb. 1992;12:647-656.

37. Oxlund H, Rasmussen LM, Andreassen TT, Heickendorff L. Increasedaortic stiffness in patients with type 1 (insulin-dependent) diabetesmellitus. Diabetologia. 1989;32:748-752.

38. Dagdelen S, Ergelen M, Soydinc S, Yaymacı B, İzgi A, Kurtoğlu N, Din-dar İ. [Diyabetik koroner arter hastalarında aortik stiffness ve disten-sibilite değişimi ve gliserol trinitrat etkisi]. Türk Kardiyol Dern Arş.2001;29:413-419.

39. Endo K, Saiki A, Ohira M, Miyashita Y, Shirai K. Cardio-ankle vascularindex may reflect endothelial function in type 2 diabetes. Int J ClinPract. 2011;65:1200-1201.

40. Gurkan E, Tarkun I, Sahin T, Cetinarslan B, Canturk Z. Evaluation ofexenatide versus insulin glargine for the impact on endothelial func-tions and cardiovascular risk markers. Diabetes Res Clin Pract.2014;106:567-575.


104

Introduction

The thyroid gland hormonally regulates a broad spectrum of meta-bolic functions, and alterations in the thyroid gland are associatedwith pathologies that have a high prevalence in the populationworldwide (1). Morbidities such as cardiovascular risks, lipid profilealteration, and obesity are found to be much higher in patients with

clinical HT (2–5). Even an association of HT with diabetes mellitushas been reported (6,7). A complete removal of the thyroid glandleads to accelerated atherosclerosis in rats, while humans com-monly develop hypertension and dyslipidemia after thyroidectomy(8,9). The focus of most medical practices on the unilateral man-agement of metabolic syndromes such as hypertension, dyslipi-demia, and hyperglycemia, without a thorough investigation of the

HHeeaalltthh PPrroobblleemmss AAccccoommppaannyyiinngg HHyyppootthhyyrrooiiddiissmm iinn PPaattiieennttss iinn EEccuuaaddoorrEEkkvvaaddoorr''ddaakkii HHaassttaallaarrddaa HHiippoottiirrooiiddii iillee BBiirrlliikkttee GGöörrüülleenn SSaağğllııkk SSoorruunnllaarrıı

Universidad Central del Ecuador, Hospital Docente "Carlos Andrade Marín", Unidad de Prevención e Investigación Neuroendocrinovascular, *ESPOL Polytechnic University. Escuela Superior Politécnica del Litoral, ESPOL. CIBE y FCV. Campus Gustavo Galindo,

**Universidad Católica de Santiago de Guayaquil. Instituto de Biomedicina. Facultad de Ciencias Médicas. Guayaquil, Ecuador

Purpose: The thyroid gland regulates a range of physiological functions through its hormonal secretions and multiple metabolic dysfunc-tions can arise from its functional anomalies. In this paper, the correlation between hypothyroidism (HT) and other diseases with particu-lar emphasis on vascular risks have been studied.Materials and Methods: Out of 11,520 adult patients who received medical care in external consultation of a public clinic of the EcuadorianInstitute of Social Security and in the Private Unit of Prevention Neuro-endocrine-vascular of Quito (Neurosciences Institute), 645 patients di-agnosed with HT were studied. Results: As compared to the general population, there was a signicantly higher frequency of the following diseases among HT patients:dyslipidemia (67.0% vs. 1.4%), arterial hypertension (36.0% vs. 9.3%), obesity (35.0% vs. 24.3%), and hyperglycemia (18.0% vs. 3.4%). HTpatients also exhibited various health hazards like cardiomegaly (18%), stroke (17%), and acute myocardial infarction (9%). Primary HT ex-hibits an incidence index with higher occurrences in the women (75.0%).Conclusion: This study proposes, to this Hospital and the Ecuadorian Government, the implementation of greater effort in the diagnosisand research of root causes of HT in favor of prevention, and not just the control of co-morbidities, with the aim of enhancing the qualityof life and prognosis for patients.Keywords: Hypothyroidism, vascular risks, dyslipidemia, arterial hypertension, obesity, hyperglycemia

Amaç: Tiroid bezi hormonal sekresyonlarla çeşitli zyolojik fonksiyonları düzenler ve fonksiyonel anomalilerinden çoklu metabolik fonksi-yon bozuklukları ortaya çıkabilir. Bu yazıda, hipotirodizim (HT) ile diğer hastalıklar -özellikle vasküler riskler üzerine odaklanılarak- arasın-daki korelasyon çalışılmıştır.Gereç ve Yöntemler: Ekvador Sosyal Güvenlik Enstitüsü kamu kliniği ve Quito (Nörobilim Enstitüsü) Nöro-endokrin-vasküler Önleme ÖzelBiriminde dışardan konsülte edilerek tıbbi bakım alan 11.520 erişkin hasta arasından HT tanısı alan 645 hasta çalışmaya alınmıştır. Bulgular: Genel popülasyona kıyasla, HT hastalarında aşağıdaki hastalıkların görülme sıklığı anlamlı şekilde daha yüksektir: dislipidemi(%67,0'a karşı %1,4), arteriyel hipertansiyon (%36,0'a karşı %9,3), obezite (%35,0’a karşı %24,3) ve hiperglisemi (%18,0’a karşı %3,4). HT has-talarında ayrıca kardiyomegali (%18), inme (%17) ve akut miyokard infarktüsü (%9) gibi çeşitli sağlık riskleri de görülmüştür. Primer HT, ka-dınlarda daha yüksek oranlarda insidans indeksi sergilemektedir (%75,0).Sonuç: Bu çalışma, bu hastaneye ve Ekvador hükümetine, hastaların yaşam kalitesini ve prognozunu iyileştirmek amacıyla yalnızca eşlikeden hastalıkların kontrolünü değil, HT'nin önlenmesi için temel nedenlerinin teşhisi ve araştırılmasına yönelik daha fazla çaba gösteril-mesini önermektedir.Anahtar kelimeler: Hipotiroidizm, vasküler riskler, dislipidemi, arteriyel hipertansiyon, obezite, hiperglisemi

Address for Correspondence: Miguel Ángel Blasco Carlos, ESPOL Polytechnic University. Escuela Superior Politécnica del Litoral, ESPOL. CIBE y FCV. Campus Gustavo Galindo, Ecuador

E-mail: [email protected] Received: 16.05.2017 Accepted: 28.11.2017


Original ArticleDOI: 10.25179/tjem.2017-56580

Turk J Endocrinol Metab 2017;21:104-107

underlying pathogenic cause, seems to lead to an under-diagno-sis of HT (10–14). The present study focuses on a comprehensiveanalysis of diseases accompanied and perhaps caused by a dys-functional thyroid gland.

Methods

This study was carried out in two hospitals in Quito (Ecuador), anarea that has low levels of natural iodine in the environment thatdrastically increases the incidence of HT (15,16). The percentages ofdifferent metabolic/vascular diseases were stratified by genderand age. Totally, 11,520 adult patients were analyzed over a period of sevenyears at the Carlos Andrade Marín Hospital of the Institute of So-cial Security and at the Private Unit of Prevention Neuro-endocrine-vascular of Quito (Neurosciences Institute).HT was confirmed with thyrotropin (TSH) and free thyroxine (FT4)measurement with Electrochemiluminescence Immunoassay(ECLIA) using ECLusys FT4 and TSH Kits (Roche Diagnostics GmbH,Mannheim, Germany). The following values of the thyroid hor-mones for adults were used as a baseline for indexing health sta-tus: FT4, 0.8-1.6 ng/dL; TSH, 0.2-4.5 µU/mL. The incidences ofelevated TSH and low FT4 levels were considered an indication ofHT.The coincidences of dyslipidemia, hypertension, obesity, hyper-glycemia, cardiomegaly, cardiovascular disease, and myocardialinfarction, along with HT were determined. These data were strat-ified by gender and ranged groups of ten years for age, from 20 to89 years old.Obesity was defined as a body mass index (BMI) equal to orgreater than 30 kg/m2. Blood pressure was measured using amanual sphygmomanometer to confirm the presence of hyper-tension (defined as systolic pressure higher than 140 mmHg or adiastolic pressure higher than 90-99 mmHg). Pre-prandial labora-tory tests were done for glucose, lipid profile, uric acid, and serumelectrolytes. A baseline fasting blood glucose concentration of ≥7mmol/L was considered as an indicator of hyperglycemia. Dyslipi-demia was determined by an incidence of higher serum levels oftotal cholesterol, triglycerides, and LDL recorded at greater than the90th percentile, and lower levels of HDL below the 10th percentile.Depending on the presence of symptoms, nuclear magnetic reso-nance (NMR) was performed with a Siemens Magnetom Sym-phony 1.5T®, in axial, coronal, and sagittal planes, to detectcerebrovascular diseases. Teleradiographies (X-ray images) for de-tecting cardiomegaly, were all taken in the posteroanterior posi-tion and were recorded, either with the Shimadzu Flexavision F3package, using an X-ray tube (400 KHU) in the initial phases of thestudy, or later with a Siemens Vertix digital radiography system,with X-ray tube assembly Optilix 150/30/50 C.Additionally, the medical history of these patients was studied todetermine the incidence of neuropathy, depression, bradypsychia,gout disease, constipation, insomnia, and endocrine anemia. Thepatients diagnosed with HT were prescribed replacement therapywith synthetic thyroxine (T4) with initial doses being carefully se-lected on the basis of the patient’s weight, age, and accompany-ing medical conditions.

Statistical analysisThe statistical evaluation of the data was performed by Student’st-test and a chi-Square test, using a significance level of 0.05. Thisstudy was conducted with the informed consent of the patients andtheir families and with meticulous care taken to keep patient in-formation confidential.

Results

Prevalence of HTThe sample of patients with a clinical diagnosis of HT was made upof 645 people, representing the 5.60% of all patients registeredwith a higher incidence among women (7.50% vs. 3.18%; p<0.05).Chronic autoimmune thyroiditis was the most common underlyingetiology of HT (65%) followed by the environmental iodine defi-ciency (22%), and drug-induced inhibition of production of thyroidhormones (1%).

Relationship with other diseasesThe HT patients presented with significantly higher rates (p<0.05)of dyslipidemia, arterial hypertension, obesity, and hyperglycemia.Dyslipidemia was observed in 67.0% of patients compared to 1.4%of the total Ecuadorian population (17). Thirty-six percent of the HTpatients exhibited arterial hypertension, compared to 9.3% in thegeneral population (18), and 35.0% exhibited a higher obesity ratio,compared to 24.3% (19). Hyperglycemia was recorded in 18% vs.3.4% in the general population (20).The HT patients presented with various cardiovascular diseases:cardiomegaly (18%), stroke (17%), and acute myocardial infarction(9%) (Table 1). Sixty-two percent of the HT patients demonstrated allthree symptoms: dyslipidemia, hyperglycemia, and hypertension. The patients were stratified in 10-year exclusive ranges beginningfrom the age of 20. The details of patients depicting stratificationbased on age intervals are presented in Tables 2 and 3. Dyslipi-demia, high blood pressure and hyperglycemia, and obesity weremore common in the 50-79 years, 60-69 years, and 70-79 yearsgroups, respectively. Other co-morbidities associated with HT in patients were as fol-lows: neuropathy (23%), depression (64%), bradypsychia (13%),gout disease (11%), constipation (9%), insomnia (7%), and endocrineanemia (5%). After substitution treatment with synthetic T4, the TSHlevels in all HT patients increased to >0.2 µU/mL.

Turk J Endocrinol Metab Cevallos et al.2017;21:104-7 Hypothyroid Patients in the Ecuadorian Population 105

Number of patients

Male Female Total Percentage

Dyslipidemia 85 347 432 67

Arterial hypertension 49 183 232 36

Obesity 62 163 225 35

Hyperglycemia 43 73 116 18

Cardiomegaly 5 12 17 17

Stroke 9 8 17 17

Acute myocardial infarction 6 3 9 9

Table 1. The demographics of the HT patients with other metabolic-vascular diseases, classified by gender (male/female), out of 11520 adult patients.

Cevallos et al. Turk J Endocrinol MetabHypothyroid Patients in the Ecuadorian Population 2017;21:104-7

106

Discussion

An analysis of accompanying health problems in the HT patients ina population of the Andes (Quito, Ecuador) was made in this lon-gitudinal study. In this area, owing to a low level of environmentaliodine (EI), the population exhibits a high incidence of HT (5.6%),with the incidence being two times higher in women than in men.The higher incidence of HT in women may be due to a decrease inthe estrogenic vascular protection post 45 years of age (21). How-ever, an age range over 80 years did not show any difference be-tween genders; this may be due to the underlying autoimmunemechanisms for most types of thyroid diseases (3). A possible explanation for the correlation between HT and dyslipi-demia is that HT causes alterations in the composition and trans-port of lipoproteins, as well as the lipids synthesis and metabolism(2–4). HT is also associated with hypercholesterolemia, due to anincrease in the level of total and LDL (low-density lipoprotein) cho-lesterol, ApoB (apolipoprotein B), and possibly triglycerides con-centration (22). As depicted by the results, higher rates of hypertension were foundamong HT patients than in the general population. In fact, a directrelation between systolic (but not diastolic) blood pressure and thelevel of triiodothyronine in the blood (23) is documented in HT pa-tients in other studies.

In this study, HT patients showed a higher rate of obesity than thegeneral population.. The deficiency of thyroid hormones, knownmodulators of adaptive thermogenesis, may lead to an increase inthe body weight due to the growth of mucin deposits and waterand salt retention (24). However, it is still unclear that which is thecause and which is the effect, since it also known that extremeobesity leads to an increase in TSH due to an abnormality in the hy-pothalamic-pituitary-thyroid axis (5). The higher prevalence of hyperglycemia among HT patients couldbe because both diseases share susceptible causal genes and co-exist with other organ-specific autoimmune diseases. Therefore, athyroidal dysfunction should compromise metabolic control, com-pounding the risk of cardiovascular diseases in diabetic patients(25). A high prevalence of cardiovascular diseases in HT patients is con-sistent with the fact that one of the most characteristic symptomsto detect HT is related to the effect of the thyroid hormone on thecardiovascular system (26) and stroke (27). This effect of HT on thecardiovascular system is related to cardiac output, cardiac con-tractility, myocardial oxygen consumption, variation in blood pres-sure, and systemic vascular resistance (28), and may even induceatrial fibrillation.A timely management of HT could lead to an improved quality oflife in the patients suffering from different related diseases like

Percentage of HT patients

Male Female Total

Age Frequency Percentage Frequency Percentage Frequency Percentage

20-29 35 0,3 115 1 150 1,3

30-39 115 1 115 1 230 2

40-49 207 1,8 691 6 899 7,8

50-59 495 4,3 2074 18 2569 22,3

60-69 991 8,6 3087 26,8 4078 35,4

70-79 852 7,4 2419 21 3272 28,4

80-89 92 0,8 230 2 323 2,8

Total 2788 24,2 8732 75,8 11520 100

Table 2. The frequency and percentage of HT patients (with TSH >4.5 µU/mL and FT4 <0.8 ng/dL, or FT3 >4.3 pg/mL), classified by gender(male/female) and age, out of 11520 adult patients who received attention.

Percentage of HT patients suffering different diseases

Arterial hypertension Hyperglycemia Obesity Dyslipidemia

Age Male Female Total Male Female Total Male Female Total Male Female Total

20-29 0.0 0.8 0.8 0.0 0.0 0.0 0.0 3.5 3.5 0.4 1.0 1.4

30-39 0.0 2.6 2.6 0.0 1.2 1.2 3.5 13.3 16.8 0.9 1.0 1.9

40-49 0.0 4.3 4.3 1.2 1.2 2.4 0.0 13.3 13.3 1.8 6.0 7.8

50-59 2.6 9.5 12.1 1.2 8.6 9.8 0.0 14.0 14.0 4.3 18.0 22.3

60-69 9.9 29.3 39.2 13.0 37.0 50.0 7.5 14.0 21.5 8.6 24.6 33.2

70-79 2.6 33.6 36.2 4.6 29.0 33.6 4.4 20.3 24.7 7.4 21.0 28.4

80-89 0.8 4.0 4.8 1.5 1.5 3.0 0.0 6.2 6.2 3.0 2.0 5.0

Total 15.9 84.1 100.0 21.5 78.5 100.0 15.4 84.6 100.0 26.4 73.6 100.0

Table 3. The percentage of HT patients suffering arterial hypertension, hyperglycemia, obesity, and dyslipidemia classified by gender (male/female) and age, out of 645 adult patients (92 patients per age).

Turk J Endocrinol Metab Cevallos et al.2017;21:104-7 Hypothyroid Patients in the Ecuadorian Population 107

stroke and accelerated atherosclerosis. Improving myocardial con-tractility could thus lead to the vascular recovery and reduce therisk of acute myocardial infarction. Dyslipidemia could also be con-trolled with the management of HT, boosting this hypertension cureand reducing the risk of other co-morbidities (1,18). A major prob-lem with the diagnosis of HT is that it is often not obvious and re-quires a high degree of suspicion. To make a correct diagnosis thedetermination of TSH is required since there are no specific clinicalmanifestations or pathognomonic signs associated with this dis-order. This determination is necessary when patients show symp-toms suggestive of HT, such as constipation, fatigue, dry skin,hoarseness, muscle weakness, etc.The high prevalence of HT in Latin America, mostly under-diag-nosed, must prompt both government and private health man-agement institutions to undertake all types of training campaigns fortheir medical personnel to implement new clinical measures. Itshould involve third generation laboratory tests, as in the case ofthe “Equinoccial” scale used in the clinical phase of this study. Globalhealth policies are generally directed toward the control of pre-ventable risk factors, and not their elimination. A significant ad-vancement in the neuroendocrine-metabolic pathogenic researchis required, which could be more effective in reducing vascular mor-bidity-mortalities and disabilities arising from cerebral infarctions.An improved coverage of the control of hypertension, hyper-glycemia, dyslipidemia, and smoking is not enough; efforts need tobe made to reduce stroke-induced mortality for which the socioe-conomic cost is among the highest of all chronic diseases (29).In conclusion, this study proposes, to this Hospital and the Ecuado-rian Government, the implementation of greater effort in the diag-nosis and research of root causes of HT in favor of prevention, andnot just the control of co-morbidities, with the aim of enhancing thequality of life and prognosis for patients.


Idea/Concept: Óscar Luís Vaca Cevallos; Design: Óscar Luís VacaCevallos; Control/Supervision: Óscar Luís Vaca Cevallos; Data Col-lection And/Or Processing: Miguel Ángel Blasco Carlos, Óscar LuísVaca Cevallos; Analysis And/Or Interpretation: Miguel Ángel BlascoCarlos, Óscar Luís Vaca Cevallos, Miguel Ángel García Bereguiain;Literature Review: Miguel Ángel Blasco Carlos, Miguel Ángel Gar-cía Bereguiain; Writing The Article: Miguel Ángel Blasco Carlos; Crit-ical Review: Ángel García Bereguiain; References And Fundings:Óscar Luís Vaca Cevallos; Materials: Óscar Luís Vaca Cevallos.Conflict of Interest: The authors declare that they have no conflict ofinterest. Financial Disclosure: There is no organization that fundedour research.

References1. Rizos CV, Elisaf MS, Liberopoulos EN. Effects of thyroid dysfunction on

lipid profile. Open Cardiovasc Med J. 2011;5:76-84.2. Friis T, Pedersen LR. Serum lipids in hyper-and hypothyroidism before

and after treatment. Clin Chim Acta. 1987;162:155-163.3. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thy-

roid disease prevalence study. Arch Intern Med. 2000;160:526-534.4. Duntas LH. Thyroid disease and lipids. Thyroid. 2002;12:287-293.5. Verma A, Jayaraman M, Kumar HK, Modi KD. Hypothyroidism and

obesity. Cause or effect? Saudi Med J. 2008;29:1135-1138.

6. Hecht A, Gershberg H. Diabetes mellitus and primary HT. Metabo-lism. 1968;17:108-113.

7. Patricia W. Thyroid disease and diabetes. Clin Diabetes. 2000;18:1.8. Liberopoulos EN, Elisaf MS. Dyslipidemia in patients with thyroid dis-

orders. Hormones (Athens). 2002;1:218-223.9. Squizzato A, Gerdes VE, Brandjes DP, Büller HR, Stam J. Thyroid dis-

eases and cerebrovascular disease. Stroke. 2005;36:2302-2310.10. Adams HP Jr, Bendixen BH, Kappelle LT, Biller J, Love BB, Gordon DL,

Marsh EE 3rd. Classification of subtype of acute ischemia stroke. Def-initions for use in a multicenter clinical trial. TOAST. Trial of Org 10172in Acute Stroke Treatment. Stroke. 1993;24:35-41.

11. Bonita R, Beaglehole R, Asplund K. The worldwide problem of stroke.Curr Opin Neurol. 1994;7:5-10.

12. Láinez Andrés JM, Santonja Llabata JM. Historia natural de la enfer-medad vascular cerebral. In: Castillo Sánches J, Álvarez Sabín, MartíVilalta JL, Martínez Vila F, Matías Guiu J, eds. Manual de Enfer-medades Vasculares Cerebrales (1st ed). Barcelona, JR: Prous;1995:55-60.

13. Sacco RL. Risk factors and outcomes for ischemic stroke. Neurology.1995;45:10-14.

14. Sánchez-Pérez RM, Moltó JM, Medrano V, Beltrán I, Díaz-Marín C.[Atherosclerosis and brain circulation]. Rev Neurol. 1999;28:1109-1115.

15. Brent GA. Environmental exposures and autoimmune thyroid dis-ease. Thyroid. 2010;20:755-761.

16. Puri KS, Suresh KR, Gogtay NJ, Thatte UM. Declaration of Helsinki,2008: implications for stakeholders in research. J Postgrad Med.2009;55:131-134.

17. Doring P. Prevalencia de dislipemias en pacientes atendidos en laClínica Universitaria USFQ. Tesis de Grado: USFQ, Quito; 2005:73.

18. OPS/OMS. Revista informativa. Representación de Ecuador 2014:101.http://www.paho.org/ecu/index.php?option=com_ docman&view=download&category_slug=documentos-2014&alias=509-boletin-informativo-n0-32-junio-2014-1&Itemid=59, Accessed 20 February2014.

19. Freire W, Rojas E, Pazmiño L, Fornasini M, Tito S, Buendía P, WatersWF, Salinas J, Álvarez P. Encuesta Nacional de Salud Bienestar y En-vejecimiento. SABE I. Ecuador 2009-2010. Quito-Ecuador: Ministeriode Inclusión Económica y Social- Programa Aliméntate Ecuador/USFQ; 2010:31.

20. Freire WB, Ramírez MJ, Belmont P, Mendieta MJ, Silva MK, Romero N,Sáenz K, Piñeiros P, Gómez LF, Monge R. Encuesta Nacional de Saludy Nutrición del Ecuador ENSANUT-ECU 2011-2013. Quito Ecuador: Min-isterio de Salud Pública. Instituto nacional de Estadística y Censos;2014:113.

21. Morganti S, Ceda GP, Saccani M, Milli B, Ugolotti D, Prampolini R, Mag-gio M, Valenti G, Ceresini G. Thyroid disease in the elderly: sex-re-lated differences in clinical expression. J Endocrinol Invest.2005;28:101-104.

22. Pearce EN. Hypothyroidism and dyslipidemia: modern concepts andapproaches. Curr Cardiol Rep. 2004;6:451-456.

23. Saito I, Ito K, Saruta T. Hypothyroidism as a cause of hypertension.Hypertension. 1983;5:112-115.

24. Seppel T, Kosel A, Schlaghecke R. Bioelectric impedance assessmentof body composition in thyroid disease. Eur J Endocrinol.1997;136:493-498.

25. Kadiyala R, Peter R, Okosieme OE. Thyroid dysfunction in patients withdiabetes: clinical implications and screening strategies. Int J Clin Pract.2010;64:1130-1139.

26. Danzi S, Klein I. Thyroid hormone and the cardiovascular system. Min-erva Endocrinol. 2004;29:139-150.

27. Vaca O. Hipotiroidismo, precursor de riesgo cerebrovascular y car-diovascular. Espejo de la Salud, Fesalud; 2008:35.

28. Kahaly GJ, Dillmann WH. Thyroid hormone action in the heart. En-docr Rev. 2005;26:704-728.

29. Cappola AR, Fried LP, Arnold AM, Danese MD, Kuller LH, Burke GL,Tracy RP, Ladenson PW. Thyroid status, cardiovascular risk, and mor-tality in older adults. JAMA. 2006;295:1033-1041.

EEvvaalluuaattiioonn ooff tthhee RReellaattiioonnsshhiipp BBeettwweeeenn TThhyyrrooiidd FFuunnccttiioonnss aanndd DDrryy EEyyee SSyymmppttoommss iinn PPaattiieennttss wwiitthh HHaasshhiimmoottoo TThhyyrrooiiddiittiissHHaasshhiimmoottoo TTiirrooiiddiittii TTaannııllıı HHaassttaallaarrddaa KKuurruu GGöözz SSeemmppttoommllaarrıınnıınn TTiirrooiidd FFoonnkkssiiyyoonnllaarrıı iillee OOllaann İİlliişşkkiissiinniinn DDeeğğeerrlleennddiirriillmmeessii

Kanuni Sultan Suleyman Research and Training Hospital, Department of Internal Medicine, Division of Endocrinology and Metabolic Diseases, Istanbul, Turkey *Kanuni Sultan Suleyman Research and Training Hospital Department of Internal Medicine, Istanbul, Turkey**Kanuni Sultan Suleyman Research and Training Hospital, Department of Ophthalmology, Istanbul, Turkey

Purpose: Dry eye is the most common symptom of thyroid-associated ophthalmopathy in Hashimoto thyroiditis. Ocular surface inam-mation, tear hyperosmolarity and overproduction of inammatory cytokines are responsible for the development of this process. In thisstudy, we aimed to investigate the relationship between thyroid functions and dry eye symptoms in patients with Hashimoto thyroiditis.Materials and Methods: The patients, diagnosed with Hashimoto thyroiditis (n:125), were included in this monocenter cross-sectional study.The study population was divided into three groups: euthyroidism (Group–1, n:48), subclinical hypothyroidism (Group–2, n:38) and overthypothyroidism (Group–3, n:39). The groups were compared based on the presence of dry eye syndrome, Schirmer tests, OSDI scores ofpatients with dry eye diagnosis and tear break-up time. The results were analyzed with ANOVA and Spearman’s correlation test. Results: No signicant difference was found in the frequency of dry eye syndrome between the groups (p = 0.1). There was no differencein the Schirmer scores and tear break-up time measurements (p = 0.6 and 0.2). The severity of OSDI scores was signicantly milder in thepatients with dry eye diagnosis, in the euthyroid group (p = 0.03). Serum fT3 levels positively correlated with tear break up time measure-ments (p = 0.004, r = 0.302) and negatively correlated with presence of dry eye syndrome (p = 0.03, r = –0.981). Discussion: Although dry eye symptoms tend to be milder in euthyroid patients, the frequency of dry eye syndrome is similar in patientswith Hashimoto thyroiditis, independent of thyroid function status. Keywords: Dry eye, OSDI, Hashimoto thyroiditis

Amaç: Hashimoto tiroiditi tanısı olan hastalarda tiroid fonksiyonlarının durumu ile kuru göz semptomlarının şiddeti arasındaki ilişkinin de-ğerlendirilmesi amaçlanmıştır. Gereç ve Yöntemler: Prospektif klinik çalışmaya 125 Hashimoto tiroiditi tanılı hasta dahil edilmiştir. Hastalar tiroid fonksiyon durumlarınagöre ötiroid (Grup–1, n:48), subklinik hipotiroid (Grup–2, n:38) ve aşikar hipotiroid (Grup–3, n:39) olmak üzere üç gruba ayrılmıştır. Kuru göztanısı, Schirmer testi, gözyaşı kırılma zamanı ve OSDI anket sonuçlarına göre konulmuştur. Kuru göz tanısı olan hastalarda semptomlarınşiddeti OSDI anketlerine gore belirlenerek tiroid fonksiyon durumu ile ilişkisi araştırılmıştır. Verilerin analizinde ANOVA ve post-hoc Tukey testi,korelasyon analizinde Spearman Korelasyon analizi kullanılmıştır.Bulgular: Gruplar arasında kuru göz tanısının sıklığı arasında anlamlı fark izlenmedi (p = 0.1). Ötiroid grupta OSDI skorları belirgin olarakdaha düşük izlendi (p = 0.03). Serum sT3 düzeyleri ile gözyaşı kırılma zamanı arasında pozitif korelasyon (p = 0.004, r = 0.302) tespitedildi. Ayrıca serum sT3 düzeylerinin kuru göz sıklığı ile negatif korelasyon gösterdiği izlendi (p = 0.03, r = –0.981).Tartışma: Ötiroid hashimoto tiroiditi tanılı hastalarda, göz kuruluğu semptomları daha haf seyretmekte olsa da kuru göz sıklığının has-himoto tiroiditi tanılı hastalarda tiroid fonksiyon durumundan bağımsız olarak benzer oranlarda görüldüğü tespit edilmiştir. Anahtar kelimeler: Kuru göz, OSDI, Hashimoto tiroiditi

Address for Correspondence: Gülşah Yenidünya Yalın, Baskent University Istanbul Research Hospital, Department of Internal Medicine, Division of Endocrinology and Metabolism Disorders, Istanbul, Turkey

Phone: +90 212 214 20 00 E-mail: [email protected] Received: 15.06.2017 Accepted: 08.11.2017


108 Original ArticleDOI: 10.25179/tjem.2017-56971


Introduction

Dry eye is one of the most common clinical problems with severaladverse effects on the quality of life (1, 2). This disorder may be amanifestation of several systemic or autoimmune disorders in-cluding autoimmune thyroiditis and hypothyroidism (3). Dry eyesyndrome may affect visual acuity and daily activities, along withsocial and physical skills, resulting in significant decrease in thequality of life (4, 5). Any defect in the lacrimal gland, eyelid, and theocular surface may lead to this syndrome (6).Dry eye is also the most common finding of thyroid-associatedophthalmopathy (TAO) (7) in thyroid disorders such as Graves’ dis-ease and Hashimoto thyroiditis (8). TAO is defined as an autoim-mune disease of the extraocular muscle tissue and the lacrimalglands, characterized by extraocular myopathy, optic neuropathy,and ocular surface inflammation (9). The exact etiopathogenesishas been not established currently and several factors are consid-ered to be responsible for the development of this disorder. Themost common factors are T cell-dependent ocular surface inflam-mation, increased tear film evaporation and hyperosmolarity dueto proptosis, especially in Graves’ disease. Additionally, the effect ofseveral inflammatory cytokines such as IL1-α, IL-4, and IGF-1 mayplay a role in this process (8). Recently, in addition to these factors,thyroid hormone receptors β-1 (Thrb-1), which are located onlacrimal glands, were found to be responsible for the developmentof dry eye (10). These receptors are known to cause susceptibilitytoward hypothyroidism, by converting the lacrimal glands as a tar-get tissue for thyroid hormones. Although there exist a large number of studies involving the pres-ence of dry eye in patients with Graves ophthalmopathy (7,9,11,12,),the number of such studies in patients with Hashimoto thyroiditisis still very limited. In this study, we aimed to investigate the rela-tionship between thyroid functions and dry eye symptoms in pa-tients with diagnosis of Hashimoto thyroiditis.

MMaatteerriiaallss aanndd MMeetthhooddss

Study Group: A total of 125 patients (Females:115 and Males:10,with a median age of 38 years, ranging between 18–75 years) whowere admitted to endocrinology and metabolism outpatient clinic,between March 1, 2016 and June 1, 2016, with the diagnosis ofHashimoto thyroiditis, were included in the study. The patients witha history of thyroidectomy, eye or eyelid surgery, eye or eyelid ab-normalities (proptosis, exophthalmos), prior diagnosis of dry eyeor additional eye pathology, the presence of a rheumatologic dis-ease associated with dry eye syndrome (Sjogren’s disease,rheumatoid arthritis) were excluded from the study groups. The pa-tients were divided into three groups according to their thyroidfunction levels and clinical situations such as: euthyroid patients(Group-1; asymptomatic with normal free T4 (fT4) and thyroid stim-ulating hormone (TSH) levels, n:49, F/M:46/2), subclinical hypothy-roid patients ( Group-2; asymptomatic with normal fT4 andelevated TSH levels (5–10 mIU/L), n:38 , F/M:33/5) and patients withovert hypothyroidism (Group-3; symptomatic with normal fT4 andelevated TSH levels (>10 mIU/L) or decreased fT4 and elevated TSHlevels (>5 mIU/L), n:39, F/M:36/3). The diagnosis of Hashimoto thy-

roiditis was based on the standard clinical criteria, thyroid functiontests of autoantibody levels, and thyroid ultrasonography imaging(13). Serum free T3 (fT3) and free T4 (fT4) were measured with acompetitive enzyme immunoassay. Serum TSH, thyroid peroxidaseantibody (TPOAb) and thyroglobulin antibody (TgAb) levels weremeasured using two-site immunoenzymometric assay. The pres-ence of dry eye syndrome was compared between each group.Ocular Surface Disease Index (OSDI ) questionnaire, tear break-uptime (TBUT ) and Schirmer I tests were applied for the clinical eval-uation of dry eye syndrome.Ocular Surface Disease Index (OSDI ) questionnaire: The presenceand the severity of the dry eye symptoms related to ocular irritationwere evaluated with the scoring system of OSDI questionnaire.OSDI questionnaire consisted of twelve questions and three cate-gories namely, ocular symptoms, visional functions, and environ-mental factors. The patients scored each symptom in all thecategories, between 0–4 according to their frequencies and sever-ities (0: never, 4: most often) (14). OSDI score was calculated withthe standardized formula: Total score � 25/number of valid ques-tions. The scores were defined as normal (0–12.5) or abnormal(>12.5), with mild (12.5–27.8), moderate (27.8–75) to severe (75–100) dry eye symptom, in a scoring system having a range of 0–100. The mean OSDI score was compared between each group Measurement of tear break-up time (TBUT ): A strip moistened withfluorescein sodium was applied to the inferior conjunctival region ineach eye of the patient. After the strip was removed, the patientwas asked to blink for three times in order to gain a homogenousdistribution. The time interval between the initial break-up and theformation of the first rupture of the tear film was recorded threetimes and the average of the measurements was recordedas TBUT score. Measurement of Schirmer I: A no. 41 Whatman filter strip wasplaced on the mid and lateral junction of the inferior fornix and theprocess was carried out in a dim environment without stimulant oflight. No topical anesthesia was used prior to the evaluation. After5 min, the strips were removed and the wet part of the strip wasmeasured in millimeters to define Schirmer scores. The resultsbelow 5 mm were accepted as a strong indication for dry eye syn-drome and results below 10 mm were defined as aqueous teardeficiency. Diagnosis of dry eye syndrome was established in pa-tients with abnormal OSDI scores (>12.5) and Schirmer I resultbelow 10 mm or TBUT below 10 s; or patients with normal SchirmerI and TBUT results but who had moderate or severe levels of OSDİscores; or patients with a Schirmer score of below 5 mm. OSDIquestionnaires, TBUT, and Schirmer I tests were evaluated and per-formed at a single center by the same ophthalmologist, for eachpatient. This study was approved by the ethics committee of ourhospital and a written informed consent was obtained from all par-ticipants. All the procedures were performed in accordance withthe Declaration of Helsinki.

Statistical Analysis

The distribution of variables was evaluated using the KolmogorovSmirnov test. The mean, standard deviation [SD], median, mini-mum, maximum, frequency and percentage values were reported

Turk J Endocrinol Metab Yalın et al.2017;21:108-112 Dry Eye Syndrome and Hashimoto Thyroiditis 109

Yalın et al. Turk J Endocrinol MetabDry Eye Syndrome and Hashimoto Thyroiditis 2017;21:108-112

110

for each data. All the between-group comparisons were analyzedusing ANOVA and post-hoc Tukey‘s test. Kruskal-Wallis test, chi-square test, and Spearman’s test were performed for the analysisof OSDI scores, categorical variables, correlation, respectively, witha statistical significance of p <0.05. All the statistical calculationswere performed with SPSS 22.0 Package.

Results

The study included patients who were recently diagnosed withHashimoto thyroiditis (n:125, F:115, M:10) and had euthyroidism(n:48, 38.4%), subclinical hypothyroidism (n:38, 30.4%) or overthypothyroidism (n:39, 31.2%) according to their baseline thyroidfunctions. The mean age of the patients was 39.3 ±11.8 (18–75;38 years) and mean TSH level was 10.1 ±16.4 (0.1– 100; 5 mIU/L)(mean ±s.d, min-max; median). The distribution of age, durationof diagnosis and levels of TSH, fT4, fT3, and autoantibody ac-

cording to thyroid function status, are summarized in Table 1. Themedian value of OSDI questionnaire score was 9 (24.4 ±19.5;0.0–90). OSDI was evaluated as normal in 33.6% of the patients(n:42) while in the remaining, the scores indicated the presenceof mild (29.6%, n:37) or moderate (36.8%, n:46) dry eye symp-toms. There were no significant differences between the Schirmertest results (p = 0.6) and TBUT values (p = 0.2)between the three groups (Table 2). Mean values of OSDI scoreswere similar in euthyroid (23.7), subclinical (24.8) and overt hy-pothyroid patients (25.1). However, when the severity of OSDIscores was compared between the three groups of patients withdry eye diagnosis, euthyroidism tended to be mostly related withmilder scores, while the patients with subclinical or overt hy-pothyroidism were more prone to having higher results (p=0.03)in the OSDI questionnaire (Table 2). Dry eye syndrome diagnosisbased on OSDI score, Schirmer test and tear break-up time, didnot show any significant difference between the three groups

Euthyroidism Subclinical Hypothyroidism Overt Hypothyroidism

Median, mean ±SD n: 48 (38.4%) n:38 (30.4%) n: 39 (31.2%) p

Age 39.5, 37.0, 37.1, 0.7

40.3 ± 10.5 38.6 ± 12.0 38.6 ± 13.1

Duration of Diagnosis (years) 3.7 ± 1.81 3.3± 2.1 3.8 ± 1.83 0.2

TSH 2.1, 5.8, 13.8, 0.001*

1.9 ± 1.1 6.1 ± 1.3 24.3 ± 23.8

fT4 1.34, 1.17, 0.88, 0.3

1.21±0.28 1.13±0.26 1.07±0.32

fT3 2.98 2.93 2.83, 0.4

3.0±0.61 3.0±0.37 2.7±0.51

Anti Tg 232.7, 242.5, 376.9, 0.06

282.7 ± 271.4 531.2 ± 925.1 920.1 ± 1361.8

Anti TPO 269.3, 194.7, 473.9, 0.01°

265.8 ± 192.2 228.3 ± 168.1 381.9 ± 220.5

TSH: Thyroid stimulating hormone, fT4: free T4, fT3: free T3, Anti Tg: antithyroglobulin antibody, Anti TPO: anti-thyroid peroxidase antibody. *post hoc analysis is signicant

between overt hypothyroidism-euthyroidism and overt hypothyroidism-subclinical hypothyroidism. ° post hoc analysis is signicant between overt hypothyroidism and

subclinical hypothyroidism.

Table 1. The distribution of age, duration of diagnosis, and laboratory results according to thyroid status.

Euthyroidism Subclinical Hypothyroidism Overt Hypothyroidism

Median, mean ±SD n: 48 (38.4%) n:38 (30.4%) n: 39 (31.2%) p

OSDI score in patients with 13.5, 17.7, 32.2, 0.03*

dry eye diagnosis 19.7 ± 20.3 28.6 ± 19.1 38.1 ± 19.5

Schirmer's (mm) 24, 23, 21, 0.6

20.6 ± 8.7 21.6 ±9.9 19.2 ±10.2

Tear Break-Up Time (sec.) 10.5, 10, 10, 0.2

10.4 ±2.0 10.1 ±2.3 9.7 ±2.4

Palpebral Angle (mm) 10.4, 10.1, 9.8 0.2

11.04 ±1.22 10.69 ±1.49 10.38 ±2.03

OSDI: Ocular Surface Disease Index, * post hoc analysis is signicant between overt hypothyroidism and euthyroidism.

Table 2. Distribution of OSDI scores, Schirmer's test, tear break-up time and palpebral angle according to thyroid status.

Turk J Endocrinol Metab Yalın et al.2017;21:108-112 Dry Eye Syndrome and Hashimoto Thyroiditis 111

(p=0.1). Spearman’s correlation analysis revealed the presence ofnegative correlation between fT3 levels and dry eye diagnosis (p= 0.03, r= –0. 98) and plasma fT3 levels were seen to positivelycorrelate with TBUT values (p = 0.004, r = 0.30). The decrease infT3 levels resulted in a decrease of TBUT scores and an increasein the frequency of dry eye diagnosis (Table 3). Even though therewas no significant correlation between OSDI scores and the re-sults of Schirmer or TBUT tests, a significant correlation (p = 0.001,r = 0.685) was seen between OSDI scores and dry eye diagno-sis, as predicted (Table 3).

DDiissccuussssiioonn

Dry eye syndrome has been linked to Hashimoto thyroiditis, withdecreased Schirmer test results, TBUT measurements and higherOSDI scores (15). The risk factors for the development of dry eyeare decreased fT4 levels and the presence of proptosis. In order todecrease the prevalence of dry eye in these patients, levothyroxinetreatment was formerly recommended (15). This study revealed asimilar frequency of dry eye syndrome diagnosis among patientswith hashimoto thyroiditis irrespective of their thyroid function sta-tus. Similarly, the frequency of the presence of dry eye was com-parable between the groups, which was independent of thepatient’s thyroid function status. Additionally, there was no signifi-cant correlation between dry eye and fT4 levels, but fT3 levelsshowed a significant negative correlation with dry eye syndromeand positive correlation with TBUT. The decrease in fT3 levels re-sulted in lower TBUT measurements and increased dry eye diag-nosis. This relation may be explained by the fact that most of theeffects of thyroid hormones on peripheral receptors are mediatedby fT3 levels (16). The etiopathogenesis of dry eye syndrome related with TAO havebeen investigated in several recent studies (7, 9–12). One of themain factors is an increase in tear film evaporation due to propto-sis which subsequently causes tear hyperosmolarity and a de-creased TBUT (17,18). Tear film hyperosmolarity has been shownto induce dry eye syndrome via inflammatory processes by induc-ing several inflammatory cytokines such as Interleukin-1 (IL- 1), TNF-α and MMP-9 (19). It has been reported that tear hyperosmolaritycauses dry eye syndrome because of ocular surface damage,

which activates mitogen active protein kinase signal (MAPK) path-ways and induces MMP-9 expression (19, 20). In 1983 Gilbard et al.showed that tear osmolarity was significantly elevated in patientswith dry eye syndrome and TAO (12). Proptosis and increase inpalpebral angle are few of the many responsible factors in the de-velopment of the dry eye in TAO, particularly in Graves’s disease.However, a previous study demonstrated that the presence of sig-nificant ocular surface inflammation and dry eye symptoms in pa-tients with Graves’s disease was not dependent on either thedegree of proptosis or the palpebral angle measurement (21). Thepresence of inflammation was seen with diffused lymphocyte infil-tration and grade 2–3 metaplasia, in the temporal interpalpebralregion. This proved that ocular inflammation is also responsible forthe development of dry eye syndrome, which is independent of thedegree of proptosis (21).The majority of the studies pertaining to dry eye syndrome andTAO have been conducted with Graves patients (7,9,11,12) and ithas been seen that the studies on Hashimoto thyroiditis arerather limited (12,15). Previous experiments have shown thatchronic deficiency of thyroid hormones causes ocular surface ab-normalities and dry eye syndrome (10). In 2007, Dias et al. sug-gested that lacrimal glands express receptors of thyroid hormoneβ-1 (Thrb), due to which they become a target tissue for thyroidhormones and thereby are susceptible to hypothyroidism. Fur-thermore, the chronic deficiency of thyroid hormones has beenshown to be related to a modification in Thrb receptor expres-sion, leading to diminished tear secretion and dry eye syndrome(10). Thyroid hormone regulates the oxidative metabolism through itsnuclear Thrb receptors and therefore chronic hypothyroidism re-sults in increased oxidative stress (22,23). Immunohistochemicalanalysis indicates the presence of Thrb receptors in the acinarand ductal cells of lacrimal glands and in the nuclei of epithe-lial cells that line the corneal and conjunctival surface and it hasbeen seen that these receptors are upregulated during hypothy-roidism (10). Hence, the presence of hypothyroidism may have anadverse effect on lacrimal gland as well as corneal and conjuncti-val epithelial cells which are susceptible to low thyroid hormonelevels (via Thrb receptors). The upregulation of these receptors isconsidered to be a compensatory mechanism, which is irreversible

OSDI Score Schirmer's test (mm) Tear Break Up Time (sec) Dry eye

Anti Tg p=0.6 r=0.04 0.3 0.12 0.7 0.03 0.4 0.69

Anti TPO 0.1 –0.14 0.5 0.06 0.7 –0.03 0.2 0.12

TSH 0.5 –0.05 0.8 0.02 0.1 –0.14 0.2 0.12

fT4 0.9 0.01 0.1 –0.17 0.8 0.02 0.1 –0.13

fT3 0.7 –0.03 0.1 0.16 0.004 0.30 0.03 –0.19

Age 0.2 0.11 0.1 –0.15 0.7 –0.03 0.1 0.14

OSDI Score 0.2 0.12 0.8 –0.01 0.001 0.68

Anti Tg: antithyroglobulin antibody, Anti TPO: anti-thyroid peroxidase antibody

fT4: free T4, fT3: free T3, TSH: thyroid stimulating hormone, OSDI: Ocular Surface Disease Index.

Table 3. Correlation of clinical and laboratory parameters with dry eye syndrome.

in nature, as the number of receptors does not return to baselinelevels even after the improvement of hypothyroidism (10). This couldbe the reason for the similar rates of dry eye syndrome that wasobserved in our patients who had different thyroid hormone lev-els. The similar frequencies of dry eye symptoms in euthyroid pa-tients may be due to the persistent upregulation of the Thrbreceptors which had occurred during an early period of hypothy-roidism. Moreover, our study also revealed that the patients with euthy-roidism, who were also diagnosed with dry eye syndrome, weremore prone to obtain lower scores on OSDI questionnaire,whereas patients with subclinical or overt hypothyroidism tendedto get higher scores that indicated severe dry eye symptoms. Thisimplied that even though the frequency of dry eye syndrome wassimilar between each group, euthyroid patients had milder dry eyesymptoms with lower OSDI scores. The amelioration in the symp-toms might have been due to improvement in Thrb receptor up-regulation. Nevertheless, further clinical and experimental studieswith wider patient series are needed in order to reach definitiveconclusions. The limitation of our study was that exophthalmometer meas-urements of the patients could not be performed because oftechnical difficulties. It is possible that the improvement in theproptosis also had an effect on the amelioration of dry eyesymptoms. It has been shown that the improvement of thyroidfunctions, which results in lowering of intraorbital glycosamino-glycan levels, may resolve the proptosis and palpebral anglewidening (8). However, no statistically significant difference wasfound in the palpebral angle measurements between the threegroups.

Conclusion

Dry eye is a common clinical problem seen during the manage-ment of hypothyroidism. Thus, ocular symptoms and signsshould also be evaluated carefully in the surveillance of patientswith Hashimoto thyroiditis. Levothyroxine replacement therapynot only improves several clinical factors but also provides ben-efit in the clinical care of these patients by alleviating the dry eyesymptoms and improving daily activities. Further studies withwider population groups are needed in order to understand and improve the quality of life in patients with Hashimoto thy-roiditis.

AAuutthhoorr CCoonnttrriibbuuttiioonnss

Idea/Concept: Gülşah Yalın, Hüseyin Çelik; Design: Fuat Cenik,Gülşah Yalın; Control/Supervision: Abdülbaki Kumbasar; Data Col-lection and/or Processing: Nihat Sayın; Analysis and/or Interpre-tation: Fuat Cenik, Gülşah Yalın; Literature Review: Gülşah Yalın,Hüseyin Çelik; Writing the Article: Gülşah Yalın; Critical Review: Ab-dülbaki Kumbasar; References and Fundings: Fuat Cenik; Materi-als: Nihat Sayın.Conflict of Interest: The authors declare that they have no conflict ofinterest. Financial Disclosure: There is no organization that fundedour research.

References1. Lemp MA. Report of the National Eye Institute/Industry workshop on

clinical trials in dry eyes. CLAO J. 1995;21:221-232.2. Moss SE, Klein R, Klein BE. Prevalence of and risk factors for dry eye

syndrome. Arch Ophthalmol. 2000;118:1264-1268.3. Shashikala P. Prevalence of dry eye in hypothyroidism. Int J Clin Case

Invest. 2013;46:51.4. Pflugfelder SC. Prevalence, burden, and pharmacoeconomics of dry

eye disease. Am J Manag Care. 2008�14:102-106.5. Schiffman RM, Walt JG, Jacobsen G, Doyle JJ, Lebovics G, Sumner W.

Utility assessment among patients with dry eye disease. Ophthal-mology. 2003�110:1412-1419.

6. Stern ME, Beuerman RW, Fox RI, Gao J, Mircheff AK, Pflugfelder SC.The pathology of dry eye: the interaction between the ocular surfaceand lacrimal glands. Cornea. 1998�17:584-589.

7. Nowak M, Marek B, Kos-Kud�a B, Kajdaniuk D, Siemi�ska L. [Tearfilm profile in patients with active thyroid orbitopathy]. Klin Oczna.2005;107:479-482.

8. Yamada M, Li AW, Wall JR. Thyroid-associated ophthalmopathy: clin-ical features, pathogenesis, and management. Crit Rev Clin Lab Sci.2000;37:523-549.

9. Burch HB, Wartofsky L. Graves’ ophthalmopathy: current concepts re-garding pathogenesis and management. Endocr Rev. 1993;14:747-793.

10. Dias AC, Módulo CM, Jorge AG, Braz AM, Jordão AA Jr, Filho RB, dePaula JS, Rocha EM. Influence of thyroid hormone on thyroid hormonereceptor beta-1 expression and lacrimal gland and ocular surfacemorphology. Invest Ophthalmol Vis Sci. 2007;48:3038-3042.

11. Eckstein AK, Finkenrath A, Heiligenhaus A, Renzing-Köhler K, Esser J,Krüger C, Quadbeck B, Steuhl KP, Gieseler RK. Dry eye syndrome inthyroid-associated ophthalmopathy: lacrimal expression of TSH re-ceptor suggests the involvement of TSHR-specific autoantibodies.Acta Ophthalmol Scand. 2004;82:291-297.

12. Gilbard JP, Farris RL. Ocular surface drying and tear film osmolarity inthyroid eye disease. Acta Ophthalmol (Copench). 1983;61:108-116.

13. Klee GG, Hay ID. Biochemical testing of thyroid function. EndocrinolMetab Clin North Am. 1997;26:763-775.

14. Sullivan BD, Whitmer D, Nichols KK, Tomlinson A, Foulks GN, GeerlingG, Pepose JS, Kosheleff V, Porreco A, Lemp MA. An objective ap-proach to dry eye disease severity. Invest Ophthalmol Vis Sci.2010�51:6125-6130.

15. Kan E, Kılıçkan E, Ecemiş G, Beyazyildiz E, Çolak R. Presence of dryeye in patients with Hashimoto’s thyroiditis. J Ophthalmol.2014;2014:754923.

16. Larsen PR, Silva JE, Kaplan MM. Relationships between circulatingand intracellular thyroid hormones: physiological and clinical impli-cations. Endocr Rev. 1981;2:87-102.

17. Bartley GB, Fatourechi V, Kadrmas EF, Jacobsen SJ, Ilstrup DM, GarrityJA, Gorman CA. Clinical features of Graves’ ophtalmopathy in an in-cidence cohort. Am J Ophtalmol. 1996;121:284-290.

18. Perros P, Kendall-Taylor P. Pathogenic mechanisms in tyroid-associ-ated ophtalmopathy. J Intern Med. 1992;231:205-211.

19. Pflugfelder SC, Farley W, Luo L, Chen LZ, de Paiva CS, Olmos LC, LiDQ, Fini ME. Matrix metalloproteinase-9 knockout confers resistanceto corneal epithelial barrier disruption in experimental dry eye. Am JPathol. 2005;166:61-71.

20. Luo L, Li DQ, Doshi A, Farley W, Corrales RM, Pflugfelder SC. Experi-mental dry eye stimulates production of inflammatory cytokines andMMP-9 and activates MAPK signaling pathways on the ocular sur-face. Invest Ophthalmol Vis Sci. 2004;45:4293-4301.

21. Gürdal C, Saraç O, Genç I, Kırımlıoğlu H, Takmaz T, Can I. Ocular sur-face and dry eye in Graves’ disease. Curr Eye Res. 2011;36:8-13.

22. Lazar MA. Thyroid hormone receptors: multiple forms, multiple pos-sibilities. Endocr Rev. 1993;14:184-193.

23. Brent GA. The molecular basis of thyroid hormone action. N Engl JMed. 1994;331:847-853.

Yalın et al. Turk J Endocrinol MetabDry Eye Syndrome and Hashimoto Thyroiditis 2017;21:108-112

112

113

TThhee RRoollee ooff FFTTOO GGeennee AAlllleelleess oonn tthhee DDiieett aanndd MMeettaabboolliicc RRiisskk FFaaccttoorrss iinn tthhee SSuubbjjeeccttss wwiitthh DDiiaabbeetteessFFTTOO GGeenn AAlleelllleerriinniinn DDiiyyaabbeettllii KKiişşiilleerrddee DDiiyyeett vvee MMeettaabboolliikk RRiisskk FFaakkttöörrlleerrii ÜÜzzeerriinnddeekkii RRoollüü

Baqai Medical University, Baqai Institute of Diabetology and Endocrinology, Karachi, Pakistan*Baqai Medical University, Department of Biochemistry, Karachi, Pakistan

**University of Karachi, The Karachi Institute of Biotechnology and Genetic Engineering (KIBGE), Karachi, Pakistan***Anaheim Clinical Trials, Anaheim, USA

Purpose: To evaluate the effect of differential food intake on metabolic risk markers in Type 2 diabetic individuals with diverse FTO gene alleles.Materials and Methods: The study was conducted at Baqai Institute of Diabetology and Endocrinology (BIDE) Karachi, Pakistan between March 2011 andMay 2013. The present study is based on a previously published case-control study that indicates the association of different FTO gene with type 2 diabe-tes. The structured questionnaire was used to gather anthropometric, biochemical, and clinical data. Single nucleotide polymorphism (SNP) in FTO gene wasanalyzed using Amplication Refractory Mutation System-Polymerase Chain Reaction (ARMS-PCR). The nutritional data were collected using a 24-hour die-tary recall questionnaire completed by a trained dietitian. The variations in energy and macronutrient intake of subjects having different FTO gene alleleswere investigated and evaluated for correlations between energy and macronutrient intake and metabolic risk variables in three FTO-gene-allele groups.Results: Overall, 198 adult subjects with type 2 diabetes (T2D) were recruited and categorized into three genotype groups: TT, AA and AT with the mean ageof 49.7 ±9.7, 49.3 ±10.6 and 50.2 ±8.8 years, respectively. A close association was observed between the minor allele A at rs9939609 and type 2 diabe-tes. A linear correlation was observed between diet and metabolic prole markers such as BMI, waist circumference, blood pressure, and lipid proleamong high-risk alleles AA. The associations of energy intake and percent level of carbohydrate and protein intake with metabolic syndrome were signi-cantly higher among risk alleles AA (P<0.05). However, the majority of the biochemical parameters and dietary components were found to be statisticallyinsignicant (p>0.05).Discussion: Genetic prole is likely to affect both dietary habits as well as the association between diet and metabolic syndrome markers. This study conclu-des that diet-disease associations are more prominent in individuals having risk alleles AA as compared to protective alleles TT and heterozygous alleles AT. Keywords: Diet, T2DM, FTO, nutrigenomics

Amaç: Farklı FTO gen alellerine sahip Tip 2 diyabetli bireylerde çeşitli gıda alımının metabolik risk belirteçleri üzerindeki etkisini değerlendirmek.Gereç ve Yöntemler: Çalışma, Mart 2011 ile Mayıs 2013 arasında Baqai Diabetoloji ve Endokrinoloji Enstitüsü (BIDE) Karachi, Pakistan'da gerçekleştirildi. Buçalışma, farklı FTO genlerinin Tip 2 diyabet ile ilişkisini gösteren önceden yayımlanmış bir vaka kontrol çalışmasına dayanmaktadır. Antropometrik, biyo-kimyasal ve klinik verileri toplamak için yapılandırılmış anket kullanılmıştır. FTO genindeki tek nükleotid polimorzmi (SNP), Amplikasyon Refrakter Mutas-yon Sistemi-Polimeraz Zincir Reaksiyonu (ARMS-PCR) kullanılarak analiz edildi. Beslenme verileri, eğitimli bir diyetisyen tarafından doldurulmuş 24 saatlikbir diyet hatırlatma anketi kullanılarak toplandı. Farklı FTO gen alellerine sahip bireylerin enerji ve makro besin alımındaki değişiklikler araştırıldı ve üç FTO-gen-alel grubundaki enerji, makrobesin alımı ve metabolik risk değişkenleri arasındaki korelasyonlar açısından değerlendirildi.Bulgular: Genel olarak, Tip 2 diyabetli (T2D) 198 erişkin hasta çalışmaya alındı ve üç genotip grubuna ayrıldı: yaş ortalaması sırasıyla 49.7±9.7, 49.3±10.6ve 50.2±8.8 olan TT, AA ve AT. Tip 2 diyabet ile rs9939609'daki minör alel A arasında yakın bir ilişki gözlemlendi. Yüksek riskli AA alelleri içinde diyet ve BKİ,bel çevresi, kan basıncı ve lipid proli gibi metabolik prol belirteçleri arasında lineer bir korelasyon gözlemlendi. Metabolik sendrom ile enerji alımı ve kar-bonhidrat ve protein alımı düzeyleri arasındaki ilişki, AA risk alelleri arasında anlamlı derecede yüksekti (p<0.05). Bununla birlikte, biyokimyasal paramet-relerin ve diyet bileşenlerinin çoğunluğu istatistiksel olarak anlamsız bulundu (p> 0.05).Tartışma: Genetik prolin hem beslenme alışkanlıklarını hem de diyet ile metabolik sendrom belirteçleri arasındaki ilişkiyi etkilemesi muhtemeldir. Bu çalış-mada, koruyucu alel TT ve heterozigot alel AT'ye kıyasla, risk aleli AA olan bireylerde diyet-hastalık ilişkisinin daha belirgin olduğu sonucuna varılmıştır.Anahtar kelimeler: Diyet, T2DM, FTO, nutrigenomikler

Address for Correspondence: Asher Fawwad, Baqai Medical University, Baqai Institute of Diabetology and Endocrinology, Karachi, PakistanPhone: 92 21 36688897, 92 21 36608565, 92 21 36707179 E-mail: [email protected]; [email protected] Received: 21.06.2017 Accepted: 23.11.2017


113Original ArticleDOI: 10.25179/tjem.2017-57015Turk J Endocrinol Metab 2017;21:113-119

Introduction

As reported by GWAS (Genome-wide Association Studies), the FTOgene (fat mass and obesity associated gene) and obesity are cor-related (1,2).Several independent studies in different ethnic European individu-als have also recognized a strong association between that theFTO gene and obesity (2,3). The association between FTO and BMIhas also been reported in non-European inhabitants includingSouth Asians (4–6). In a previous work, the correlation betweenFTO single nucleotide polymorphisms (SNPs) and obesity wasfound to be non-significant (7,8). However, it was found that trans-lation of FTO SNPs accounts dissimilar variations in BMI (0.16–0.20%) in Asian populations than in Europeans (9).Earlier studies have reported an association between FTO SNPsand increased risk of type 2 diabetes (T2DM), and in the majorityof the cases, it is affected by obesity. However, there are some re-ports indicating an independent association of SNPs with the riskof diabetes (10). Although a significant association of FTO (rs9939609) variant with T2DM among South Asians has been re-ported, its link with obesity, metabolic syndrome and T2DM is stillnot clear (11). The FTO variant for allele ‘A’ (rs 9939609) is linked tothe high risk of developing diabetes, which is strongly arbitrated byBMI. However, the results vary among South Asians (12).The effect of genetic polymorphisms on nutrient metabolism hasalso been described in the epidemiological studies showing adirect relation of unhealthy diet with chronic diseases includingcancer, diabetes, rheumatoid arthritis, osteoporosis, and cardio-vascular diseases. The genetic variations having an impact on nu-trient metabolism can be understood by having the knowledge ofthe processes involved in digestion, absorption, transport, bio-transformation, uptake, and elimination. A more specific under-standing can be generated by studying the metabolism of ingestedbioactive food ingredients (13).The adults having high-risk alleles have been reported to havehigher requirements for energy, macronutrients intake, and un-healthy eating habits (14). The genetic variants have also beenshown to have an influence on metabolic response to food com-ponents (15). It implies that the higher risk for diabetes among AAallele is probably mediated through the impact of genes on food in-take or differential impact of dietary variations on the metabolicprofile. The present study explored variations in dietary intakes andlinks between diet and metabolic risk markers in T2DM having var-ious risk alleles.

Material and Methods

A total of 198 subjects (110 males and 88 females) visiting the out-patient department (OPD) of Baqai Institute of Diabetology and En-docrinology (BIDE) were enrolled in the study. The study period wasfrom March 2011 to May 2013. Ethical approval was taken from theInstitutional Review Board (IRB) of BIDE. The present study is basedon a previously published case-control study that described theassociation of different FTO genes with T2DM; where TT representsa homozygous protective allele, AA is homozygous risk allele andAT is heterozygous allele (16). The basic clinical, demographic, and

genetic data were taken from a previous study. The dietary data forthis study were specifically collected through a 24-hour dietary re-call questionnaire (17).The study subjects were grouped on the basis of BMI and waistcircumference, obesity traits, and hypertension among FTO genevariants. The measurements of weight, height and blood pressurewere obtained by the paramedical staff. Body mass index (BMI)was calculated by measuring weight in kilogram and height inmeter square. According to the Asian guidelines, BMI ≥ 23 kg/m2

is considered as overweight (18). The standard measurement forcentral obesity comprised of the waist circumference ≥ 90 cm inmen and ≥ 80 cm in women (19). Subjects having blood pressureabove 130/85 mmHg or already on anti-hypertensive medicationor if they had a self-reported history of hypertension are included(20).All subjects were evaluated for their diet by a registered dietitian(RD). The RD estimated the number of food intakes by various foodgroups and the details of carbohydrates, proteins, and lipids con-sumed daily. This information was entered in the institution’s (tai-lor made) hospital management system (BIDE-HMS) software. HMScalculated and stored the data about intake of calories andmacronutrients for each patient. The subjects were also groupedaccording to their dietary intake in high or low intake categoriesfor energy and macronutrients. The energy requirement for eachpatient as per their physical activity was estimated using Mifflin’sformula (21).The subjects having different FTO variants were compared for theirenergy requirements and percentages of calories from variousmacronutrients. The proportion of subjects having high or low riskwithin high or low dietary intake groups were calculated separatelyfor each genetic variant group and the differences were observedin the strength of diet-disease.

Statistical Analysis

Statistical Package for Social Science (SPSS ver.16.0) was used fordata analysis. The continuous data were presented by mean ±SDand categorical data in number and percentage. For examining the differences in diet-disease relationship, the dif-ferences in the linear association between (correlation Pearson’s)diet and clinical variables were evaluated. Genetic variation in diet-disease associations was also estimated by non-parametric meth-ods. The frequencies of alleles were analyzed by Hardy-Weinbergequilibrium. ANOVA and chi-square test were applied to determinethe statistical significance of variations in means and percentages,respectively. The statistical significance level for results wasP<0.05.

Results

A total of 198 type 2 diabetes (T2DM) subjects were recruited in thisstudy. They were categorized according to their allele types(TT=53%, AA=88%& AT=57%), as described in a previous study.The mean age subjects in TT, AA and AT group was 49.7 ±9.7,49.3 ±10.6 and 50.2 ±8.8 years, respectively. Table 1 shows acomparison of basic clinical characteristics and dietary compo-nents among different allele groups. The differences observed for

Fawwad et al. Turk J Endocrinol MetabGene, Diet, and Disease Relationships 2017;21:113-119

114

the majority of the clinical characteristics were statistically insignif-icant. The BMI was not statistically significant for all groups exceptthe protective allele TT, which was observed to have higher centralobesity among the groups. As compared to risk genotype AA andheterozygous genotype AT groups, the allele TT was observed tohave a significantly lower frequency of hypertension. Biochemicalparameters like HbA1c, cholesterol, triglyceride, HDL, LDL, and cre-atinine were not observed to have statistically significant differ-ences among the groups. The total calorie intake of allele AT groupwas found to be significantly lower in contrast to other groups(p<0.021). However, in terms of energy intake percentage of re-quirements was found to be statistically insignificant amonggroups.Table 2 shows a correlation (Pearson’s) of the dietary componentwith hypertension and lipid profile variables in different FTO alle-les. The link of BMI and waist circumference with dietary factorswas found to be more pronounced and statistically significant forrisk alleles AA. Blood pressure was observed to be similar in risk al-leles AA and protective alleles TT. The percentage of calories ob-tained from fat has a positive and significant correlation while thatof from carbohydrates was observed to have a significant negativecorrelation with SBP in both risk alleles AA and protective alleles TT.

DBP was found to have a positive and significant correlation onlyin protective alleles TT. No consistent pattern in the correlation be-tween lipid profile and dietary factors were observed, however, itvaried according to risk alleles. There were significant differencesin protective alleles TT and heterozygous alleles AT for LDL-choles-terol and serum triglycerides, respectively.Table 3 and 4 describes the association between categories ofmetabolic syndrome risk indicators with that of energy intake, pro-tein, and carbohydrate. Higher energy intake and metabolic syn-drome markers were found to be significantly associated with riskalleles AA. Higher energy intake and protein intake were also re-lated to a higher frequency of hypertension and their link wasprominent and statistically significant in risk alleles AA, while re-sults were found statistically insignificant for intake of carbohydrate.

Discussion

FTO gene SNP has been linked to polygenic obesity. In earlier stud-ies, BMI-increasing alleles of FTO variants were reported to havean association with increased food intake, total energy intake, fator protein intake, implying the link of diet with BMI (22–24). It hasalso been reported that physical activity may decrease the effect of

Turk J Endocrinol Metab Fawwad et al.2017;21:113-119 Gene, Diet, and Disease Relationships 115

Allele Groups

Characteristics TT (N=53) AA (N=88) AT (N=57) P-value

Age (years) 49.7 ±9.7 49.3 ±10.6 50.2 ±8.8 0.845

Male [n (%)] 33(62.3) 50(56.8) 27(47.4) 0.277

Female [n (%)] 20(37.7) 38(43.2) 30(52.6)

Body Mass Index(kg/m²) 29.7 ±5.6 29 ±5.1 29.5 ±5.4 0.685

Systolic BP (mmHg) 125.09 ±14.19 129.68 ±18.55 133.77 ±19.05 0.038

Diastolic BP (mmHg) 77.26 ±8.18 80.85 ±9.44 81.75 ±11.12 0.036

Waist Circumference (cm) 40.94 ±10.94 39.01 ±10.1 38.6 ±4.51 0.370

HbA1c (%) 9.4 ±2.01 9.5 ±2.1 8.95 ±1.98 0.255

Total Cholesterol (mg/dL) 183.8 ±39.3 177.8 ±52 177.4 ±44.6 0.809

Triglycerides (mg/dL) 231.9 ±262.3 174.2 ±139.6 157.6 ±118.6 0.154

High Density Lipoprotein (mg/dL) 40.6 ±11.6 37.4 ±10.4 40.3 ±11.2 0.273

Low Density Lipoprotein (mg/dL) 110.7 ±33.4 100.4 ±37 101.4 ±40.9 0.37

Creatinine (mg/dL) 1.1 ±0.3 1.1 ±0.3 1.2 ±1.2 0.36

DDiieettaarryy CCoommppoonneenntt

Fat% of Calories 35.28 ±10.69 33.97 ±8.11 34.45 ±8.27 0.702

Protein% of Calories 14.05 ±3.01 14.44 ±2.27 13.89 ±2.30 0.391

CHO% of Calories 50.67 ±8.77 51.58 ±7.38 51.65 ±7.51 0.755

Energy (Calories) 2022 ±659 1964 ±604 1739 ±412 0.021*

Energy (% of requirement) 103.52 ±27.4 103.3 ±29.94 113.31 ±30.01 0.101

FFoooodd CCoommpplliiaannccee

Good compliance [n (%)] 2 (3.8) 10 (11.4) 8 (14) 0.282

Partial-compliance [n (%)] 42 (79.2) 70 (79.5) 43 (75.4)

No or Poor compliance [n (%)] 9 (17) 8 (9.1) 6 (10.5)

Data presented as mean ±SD or n (%)

ANOVA and chi-square test were performed for group comparison.

* P<0.05, ** P<0.01, considered statistically signicant.

Table 1. Basic and clinical characteristics of subjects carrying different FTO alleles

FTO on BMI, especially in old age. Many other studies have re-ported similar results about the relation of dietary factors with obe-sity (25). In a previous study, a strong association between FTOvariant and Type 2 diabetes in South Asians was reported. The clin-ical results of the current study are based on a diet-diseaserelationship with risk alleles AA, protective alleles TT and heterozy-gous alleles AT. The FTO genotype effect through adiposity was notreported to have an impact on insulin resistance and diabetes (26).In another randomized long-term dietary intervention case study,the influence of FTO genetic variance along with dietary macronu-trients was observed on alteration in insulin resistance. An associ-ation of energy and macronutrient intake along with other clinicalfactors was observed among subgroups type-2 diabetes with var-ious FTO gene alleles. Minor yet statistically significant differenceswere found to be associated with FTO genotype in the sources ofdietary energy intake. It was observed that the individuals carrying

the FTO risk allele consumed significantly higher proportions of di-etary energy from fats and proteins. It was also found that FTOlinked with BMI and waist circumference are the key indicators ofmetabolic syndrome mainly CVD. The impact of increased BMI onpublic health has been reported as an increment of one unit is as-sociated with an 8% increase in the risk of coronary heart disease,which is more prominent in younger age as it increases the overallrisk of death (27). The physical inactivity in South East Asians (17%)was reported to be about half to that of the Europeans (34.8%) (28).This results in developing obesity in physically inactive individualsas compared to physically active ones. The positive correlation be-tween FTO gene and a high fiber intake on lowering BMI and waistcircumference was reported in this study. The subjects who gen-erally consume low dietary fibers have increased BMI. In anotherstudy, it was reported that FTO expression is decreased by glucoseand amino acid deprivation, implying the role of FTO in sensing of


116

Body mass index Waist circumference Systolic blood Diastolic blood LDL-cholesterol Serum Triglyceride

(kg/m2) (cm) pressure (mmHg) pressure (mmHg) (mg/dL) (mg/dL)

AA AT TT AA AT TT AA AT TT AA AT TT AA AT TT AA AT TT

Percent calories from Fat 0.32* 0.09 0.05 0.38** 0.12 0.04 0.35** 0.08 0.22* 0.17 0.08 0.12 0.26 0.27 0.27* 0.00 0.01 0.06

Fat in grams 0.15 0.23 0.13 0.56** 0.23 0.02 0.10 0.06 0.08 0.03 0.04 0.02 0.05 0.25 0.21 0.00 0.10 0.12

Percent calories from 0.36* 0.11 0.03 0.37** 0.16 0.00 –0.32* 0.02 –0.22* 0.13 0.14 0.10 0.38 0.22 0.42 0.58 0.45** 0.09

Carbohydrates (CHO)

Percent calories from Proteins 0.01 0.05 0.10 0.16 0.09 0.17 0.22 0.22 0.11 0.22 0.15 0.12 0.31 0.22 0.25* 0.00 0.01 0.03

Protein in grams 0.00 0.11 0.00 0.32* 0.13 0.20 0.28* 0.15 0.15 0.16 0.03 0.08 0.14 0.24 0.21 0.12 0.11 0.23

Energy balance 0.33* 0.32* 0.19 0.11 0.38** 0.02 0.17 0.17 0.03 0.14 0.12 0.05 0.53 0.52 0.21 0.01 0.18 0.02

Energy (Kcal) 0.00 0.14 0.11 0.17 0.14 0.16 0.06 0.21 0.07 0.12 0.04 0.44** 0.54 0.59 0.10 0.14 0.13 0.02

Pearson's correlation was applied.


Table 2. Correlation between dietary components (Fat, CHO, Protein, and Energy) with BMI, hypertension and lipid prole.

Genotype Information

TT AA AT

Adequate energy Excess Energy Adequate energy Excess energy Adequate energy Excess energy

≤100% ≥100% ≤100% ≥100% ≤100% ≥100%

BMI categories Overweight 95.8% 93.1% 86% 97.8% 83.3% 94.9%

Non-overweight 4.2% 6.9% 14% 2.2% 16.7% 5.1%

P-value 0.66 0.04* 0.15

Central obesity Normal 17.4% 10.7% 34.2% 13.3% 22.2% 11.4%

Central obesity 82.6% 89.3% 65.8% 86.7% 77.8% 88.6%

P-value 0.49 0.02* 0.29

Hypertension Hypertensive 12.5% 34.5% 37.2% 57.8% 61.1% 51.3%

Non-hypertensive 87.5% 65.5% 62.8% 42.2% 38.9% 48.7%

P-value 0.06 0.05 0.48

Overweight; BMI>23

Non-overweight; BMI<23

Hypertension; 130/85 mmHg

Chi-square was performed for group comparisons.


Table 3. Associations between Energy Intake and metabolic syndrome markers (BMI, central obesity, and hypertension) in different FTO alleles.

cellular nutrients (29). In this study, the observed rates of obesity oroverweight were similar in FTO variants while diet-disease rela-tionships were found to be different. In this study, FTO risk alleles(AA) were observed to be more responsive to dietary changes thanother variants (30). The reduction in food-craving response to ahigh-protein diet intake is also associated with the FTO A allele.This suggests a greater promise for dietary interventions for con-trolling certain complication in type-2 diabetics with AA genotype.Further research is needed to understand the sensitivity of AAgenotype toward dietary requirements and its influence on meta-bolic response to energy and macronutrient intakes. The currentstudy has shown that the effect of the FTO gene can be modulatedby the intake of carbohydrate and dietary fibers. It also suggests amore pronounced influence of SNP in subjects who also consumehigh carbohydrate and dietary fibers. in a large amount.

Conclusion

Genetic profiles are likely to affect both the dietary pattern and therelationship between diet and metabolic syndrome markers. This

study concluded that the association between diet and disease ismore pronounced in the high-risk genotype AA compared to pro-tective genotype TT and heterozygous genotype AT.

Limitations

Inadequate sample size and simple sampling with a single di-etary data input are the major limitations of this study. The lim-ited number of subjects from a single tertiary care unit without acontrol population further added to the disadvantages. Thiscould put limits on real implications and the effect the general-izability of this study. However, with limited reported data fromthis part of the world on genetic influence and data from the cur-rent research will be incremental for future studies accountingall these shortfalls.

Acknowledgements

We acknowledge the support of Research Department and DietDepartment of BIDE. We are also thankful to Dr. Syeda NuzhatNawab from the Karachi Institute of Biotechnology and Genetic En-


Genotype information

TT AA AT

Carbohydrate adequacy (%) Carbohydrate adequacy (%) Carbohydrate adequacy (%)

Low Med High Low Med High Low Med High

>50% E 50–60%E >60%E >50% E 50–60%E >60%E >50% E 50–60%E >60%E

BMI categories Over weight 94.1% 94.1% 100% 91.7% 95% 83.3% 89.5% 91.4% 100%

Non-overweight 5.9% 5.9% 8.3% 5.0% 16.7% 10.5% 8.6%

P-value 0.94 0.42 0.83

Central obesity Normal 18.8% 12.1% 0% 12.1% 28.2% 36.4% 17.6% 15.2%

Central obesity 81.3% 87.9% 100.0% 87.9% 71.8% 63.6% 82.4% 84.8% 100.0%

P-value 0.694 0.14 0.77

Hypertension Hypertensive 23.5% 26.5% 0 50.0% 52.5% 25.0% 63.2% 51.4% 33.3%

Non-hypertensive 76.5% 73.5% 100.0% 50.0% 47.5% 75.0% 36.8% 48.6% 66.7%

0.69 0.23 0.53

Protein adequacy (%) Protein adequacy (%) Protein adequacy (%)

<.8 g/k .8–1 g/K >1 g/K <.8 g/k .8–1 g/K >1 g/K <.8 g/k .8–1 g/K >1 g/K

BMI categories Over weight 0% 0% 15.8% 0% 0% 21.2% 3.6% 0% 33.3%

Central obesity Non-overweight 100% 100% 84.2% 100% 100% 78.8% 96.4% 100% 66.7%

P-value 0.05 0.00** 0.00**

Normal 4.8% 8.3% 27.8% 12.9% 9.5% 41.9% 11.1% 7.7% 33.3%

Central obesity 95.2% 91.7% 72.2% 87.1% 90.5% 58.1% 88.9% 92.3% 66.7%

P-value 0.09 0.00* 0.13

Hypertension Yes 57.1% 76.9% 94.7%* 40.6% 40.9% 69.7% 32.1% 56.3% 58.3%

No 42.9% 23.1% 5.3% 59.4% 59.1% 30.3% 67.9% 43.8% 41.7%

P-value 0.02* 0.03* 0.16

Overweight; BMI>23

Non-overweight; BMI<23

Hypertension; 130/85 mmHg

E; energy.

Chi-square was performed for group comparisons.


Table 4. Associations between carbohydrate and protein intake with metabolic syndrome markers (BMI, central obesity, and hypertension) in different FTO alleles.

gineering (KIBGE), the University of Karachi for facilitating the DNAanalysis at their institute.

Ethics

All procedures performed in this study involving human partici-pants were in accordance with the ethical standards of the institu-tional and/or national research committee and with the 1964Helsinki declaration and its later amendments or comparable eth-ical standards. Ethical approval was also obtained from the Insti-tutional Review Board (IRB) of Baqai Institute of Diabetology andEndocrinology, Baqai Medical University.

AAuutthhoorr CCoonnttrriibbuuttiioonnss

Idea/Concept: Asher Fawwad, Iftikhar Ahmed Siddiqui, Abdul Basit;Design: Asher Fawwad, Iftikhar Ahmed Siddiqui, Abdul Basit; Con-trol/Supervision: Asher Fawwad; Data Collection and/or Process-ing: Asher Fawwad, Fariha Shaheen, Rubina Hakeem, SyedaNuzhat Nawab; Analysis and/or Interpretation: Fariha Shaheen,Rubina Hakeem, Syeda Nuzhat Nawab, Asher Fawwad; LiteratureReview: Asher Fawwad, Nazish Waris, Fariha Shaheen; Writing theArticle: Asher Fawwad, Nazish Waris, Fariha Shaheen, Rubina Ha-keem; Critical Review: Syed Muhammad Shahid, Asher Fawwad,Abdul Basit, Iftikhar Ahmed Siddiqui; References and Fundings:Nazish Waris; Materials: Asher Fawwad, Syeda Nuzhat Nawab.Conflict of Interest: The authors declare that they have no conflict ofinterest. Financial Disclosure: There is no organization that fundedour research.

RReeffeerreenncceess

1. Scuteri A, Sanna S, Chen WM, Uda M, Albai G, Strait J, Najjar S, Na-garaja R, Orrú M, Usala G, Dei M, Lai S, Maschio A, Busonero F, MulasA, Ehret GB, Fink AA, Weder AB, Cooper RS, Galan P, Chakravarti A,Schlessinger D, Cao A, Lakatta E, Abecasis GR. Genome-wide asso-ciation scan shows genetic variants in the FTO gene are associatedwith obesity-related traits. PLoS Genet. 2007;3:e115.

2. Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lind-gren CM, Perry JR, Elliott KS, Lango H, Rayner NW, Shields B, HarriesLW, Barrett JC, Ellard S, Groves CJ, Knight B, Patch AM, Ness AR,Ebrahim S, Lawlor DA, Ring SM, Ben-Shlomo Y, Jarvelin MR, Sovio U,Bennett AJ, Melzer D, Ferrucci L, Loos RJ, Barroso I, Wareham NJ,Karpe F, Owen KR, Cardon LR, Walker M, Hitman GA, Palmer CN,Doney AS, Morris AD, Smith GD, Hattersley AT, McCarthy MI. A com-mon variant in the FTO gene is associated with body mass index andpredisposes to childhood and adult obesity. Science. 2007;316:889-894.

3. Hinney A, Nguyen TT, Scherag A, Friedel S, Brönner G, Müller TD,Grallert H, Illig T, Wichmann HE, Rief W, Schäfer H, Hebebrand J.Genome wide association (GWA) study for early onset extreme obe-sity supports the role of fat mass and obesity associated gene (FTO)variants. PLoS One. 2007;2:e1361.

4. Moore SC, Gunter MJ, Daniel CR, Reddy KS, George PS, YurgalevitchS, Devasenapathy N, Ramakrishnan L, Chatterjee N, Chanock SJ,Berndt SI, Mathew A, Prabhakaran D, Sinha R. Common genetic vari-ants and central adiposity among Asian-Indians. Obesity (SilverSpring). 2012;20:1902-1908.

5. Okada Y, Kubo M, Ohmiya H, Takahashi A, Kumasaka N, Hosono N,Maeda S, Wen W, Dorajoo R, Go MJ, Zheng W, Kato N, Wu JY, Lu Q,Tsunoda T, Yamamoto K, Nakamura Y, Kamatani N, Tanaka T. Com-mon variants at CDKAL1 and KLF9 are associated with body massindex in east Asian populations. Nat Genet. 2012;44:302-306.

6. Vasan SK, Fall T, Neville MJ, Antonisamy B, Fall CH, Geethanjali FS,Gu HF, Raghupathy P, Samuel P, Thomas N, Brismar K, Ingelsson E,Karpe F. Associations of variants in FTO and near MC4R with obe-sity traits in South Asian Indians. Obesity (Silver Spring).2012;20:2268-2277.

7. Fawwad A, Siddiqui IA, Basit A, Zeeshan NF, Shahid SM, Nawab SN,Siddiqui S. Common variant within the FTO gene, rs9939609, obesityand type 2 diabetes in population of Karachi, Pakistan. DiabetesMetab Syndr. 2016;10:43-47.

8. Karns R, Viali S, Tuitele J, Sun G, Cheng H, Weeks DE, McGarvey ST,Deka R. Common variants in FTO are not significantly associated withobesity-related phenotypes among Samoans of Polynesia. Ann HumGenet. 2012;76:17-24.

9. Li H, Kilpeläinen TO, Liu C, Zhu J, Liu Y, Hu C, Yang Z, Zhang W, BaoW, Cha S, Wu Y, Yang T, Sekine A, Choi BY, Yajnik CS, Zhou D, TakeuchiF, Yamamoto K, Chan JC, Mani KR, Been LF, Imamura M, NakashimaE, Lee N, Fujisawa T, Karasawa S, Wen W, Joglekar CV, Lu W, ChangY, Xiang Y, Gao Y, Liu S, Song Y, Kwak SH, Shin HD, Park KS, Fall CH,Kim JY, Sham PC, Lam KS, Zheng W, Shu X, Deng H, Ikegami H, Kr-ishnaveni GV, Sanghera DK, Chuang L, Liu L, Hu R, Kim Y, Daimon M,Hotta K, Jia W, Kooner JS, Chambers JC, Chandak GR, Ma RC, MaedaS, Dorajoo R, Yokota M, Takayanagi R, Kato N, Lin X, Loos RJ. Associ-ation of genetic variation in FTO with risk of obesity and type 2 dia-betes with data from 96,551 East and South Asians. Diabetologia.2012;55:981-995.

10. Kong X, Xing X, Hong J, Zhang X, Yang W. Genetic variants associ-ated with lean and obese type 2 diabetes in a Han Chinese popula-tion: a case-control study. Medicine (Baltimore). 2016;95:e3841.

11. Sanghera DK, Ortega L, Han S, Singh J, Ralhan SK, Wander GS, MehraNK, Mulvihill JJ, Ferrell RE, Nath SK, Kamboh MI. Impact of nine com-mon type 2 diabetes risk polymorphisms in Asian Indian Sikhs:PPARG2 (Pro12Ala), IGF2BP2, TCF7L2 and FTO variants confer a sig-nificant risk. BMC Med Genet 2008;9:59.

12. Rees SD, Islam M, Hydrie MZ, Chaudhary B, Bellary S, Hashmi S,O’Hare JP, Kumar S, Sanghera DK, Chaturvedi N, Barnett AH, SheraAS, Weedon MN, Basit A, Frayling TM, Kelly MA, Jafar TH. An FTO vari-ant is associated with Type 2 diabetes in South Asian populationsafter accounting for body mass index and waist circumference. Dia-bet Med. 2011;28:673-680.

13. El-Sohemy A. Nutrigenetics. Forum Nutr. 2007;60:25-30.14. Qi Q, Downer MK, Kilpelainen TO, Taal HR, Barton SJ, Ntalla I, Standl

M, Boraska V, Huikari V, Kiefte-de Jong JC, Körner A, Lakka TA, Liu G,Magnusson J, Okuda M, Raitakari O, Richmond R, Scott RA, Bailey ME,Scheuermann K, Holloway JW, Inskip H, Isasi CR, Mossavar-RahmaniY, Jaddoe VW, Laitinen J, Lindi V, Melén E, Pitsiladis Y, Pitkänen N,Snieder H, Heinrich J, Timpson NJ, Wang T, Yuji H, Zeggini E, De-doussis GV, Kaplan RC, Wylie-Rosett J, Loos RJ, Hu FB, Qi L. Dietary in-take, FTO genetic variants, and adiposity: a combined analysis of over16,000 children and adolescents. Diabetes. 2015;64:2467-2476.

15. Loria-Kohen V, Espinosa-Salinas I, Marcos-Pasero H, Lourenço-Nogueira T, Herranz J, Molina S, Reglero G, Ramirez de Molina A.Polymorphism in the CLOCK gene may influence the effect of fat in-take reduction on weight loss. Nutrition. 2016;32:453-460.

16. Fawwad A, Siddiqui IA, Basit A, Zeeshan NF, Shahid SM, Nawab SN,Siddiqui S. Common variant within the FTO gene, rs9939609, obesityand type 2 diabetes in population of Karachi, Pakistan. DiabetesMetab Syndr. 2016;10:43-47.

17. Shim JS, Oh K, Kim HC. Dietary assessment methods in epidemio-logic studies. Epidemiol Health. 2014;36:e2014009.

18. World Health Organization. The Asia-Pacific perspective, redefiningobesity and its treatment. International Diabetes Institute, HealthCommunications Australia Pvt. Ltd; 2000:50 (Last reviewed December06, 2016).

19. International Diabetes Federation. The IDF consensus worldwide def-inition of the metabolic syndrome. Belgium: International DiabetesFederation; 2006:24 (Last reviewed December 06, 2016).


118

20. American Diabetes Association. Standards of medical care in dia-betes--2008. Diab Care. 2008;31:S12-54.

21. Mifflin MD, St Jeor ST, Hill LA, Scott BJ, Daugherty SA, Koh YO. A newpredictive equation for resting energy expenditure in healthy individ-uals. Am J Clin Nutr. 1990;51:241-247.

22. Lee HJ, Kim IK, Kang JH, Ahn Y, Han BG, Lee JY, Song J. Effects of com-mon FTO gene variants associated with BMI on dietary intake andphysical activity in Koreans. Clin Chim Acta. 2010;411:1716-1722.

23. McCaffery JM, Papandonatos GD, Peter I, Huggins GS, Raynor HA,Delahanty LM, Cheskin LJ, Balasubramanyam A, Wagenknecht LE,Wing RR. Obesity susceptibility loci and dietary intake in the LookAHEAD Trial. Am J Clin Nutr. 2012;95:1477-1486.

24. Brunkwall L, Ericson U, Hellstrand S, Gullberg B, Orho-Melander M,Sonestedt E. Genetic variation in the fat mass and obesity-associatedgene (FTO) in association with food preferences in healthy adults.Food Nutr Res. 2013;57:20028.

25. Moleres A, Ochoa MC, Rendo-Urteaga T, Martínez-González MA, Az-cona San Julián MC, Martínez JA, Marti A; GENOI. Dietary fatty aciddistribution modifies obesity risk linked to the rs9939609 polymor-phism of the fat mass and obesity-associated gene in a Spanishcase-control study of children. Br J Nutr. 2012;107:533-538.

26. Bressler J, Kao WH, Pankow JS, Boerwinkle E. Risk of type 2 dia-betes and obesity is differentially associated with variation in FTOin whites and African-Americans in the ARIC study. PLoS One.2010;5:e10521.

27. Adams KF, Schatzkin A, Harris TB, Kipnis V, Mouw T, Ballard-BarbashR, Hollenbeck A, Leitzmann MF. Overweight, obesity, and mortality ina large prospective cohort of persons 50 to 71 years old. N Engl J Med.2006;355:763-778.

28. Hallal PC, Andersen LB, Bull FC, Guthold R, Haskell W, Ekelund U.Global physical activity levels: surveillance progress, pitfalls, andprospects. Lancet. 2012;380:247-257.

29. Gulati P, Cheung MK, Antrobus R, Church CD, Harding HP, Tung YC,Rimmington D, Ma M, Ron D, Lehner PJ, Ashcroft FM, Cox RD, Coll AP,O'Rahilly S, Yeo GS. Role for the obesity-related FTO gene in the cel-lular sensing of amino acids. Proc Natl Acad Sci U S A. 2013;110:2557-2562.

30. de Luis DA, Aller R, Izaola O, Primo D, Urdiales S, Romero E. Effects ofa high-protein/low-carbohydrate diet versus a standard hypocaloricdiet on weight and cardiovascular risk factors: role of a genetic vari-ation in the rs9939609 FTO gene variant. J Nutrigenet Nutrigenomics.2015;8:128-136.


120

CCooeexxiisstteennccee ooff AAuuttooiimmmmuunnee aanndd AAlllleerrggiicc DDiisseeaasseess wwiitthhAAuuttooiimmmmuunnee TThhyyrrooiidd DDiisseeaasseessOOttooiimmmmüünn TTiirrooiidd HHaassttaallııkkllaarrııyyllaa BBiirrlliikkttee SSeeyyrreeddeenn OOttooiimmmmüünn vvee AAlllleerrjjiikk HHaassttaallııkkllaarr

Ankara University Faculty of Medicine, Department of Endocrinology and Metabolic Diseases, Ankara, Turkey*Ankara University Faculty of Medicine, Department of Gastroenterohepatology, Ankara, Turkey

Background: Sometimes, the patients with autoimmune thyroiditis show certain symptoms despite having serum thyroid hormone levels within the desi-red range. In addition, the dose of levothyroxine replacement may vary in the patients with hypothyroidism. These factors directly inuence clinical practi-ces and may, to some extent, be associated with other immunological/allergic diseases that accompany autoimmune thyroid diseases (ATDs). Purpose: To document the other autoimmune/allergic disorders in patients during follow-up for ATDs. Materials and Methods: During the study period, 274 patients diagnosed with, and/or at follow-up for Hashimoto’s thyroiditis (HT), and 53 with Graves’ di-sease (GD) were included in the study. All the patients were examined and were subjected to further investigations when the presence of other autoim-mune/allergic diseases was suspected.Results: A total of 65 patients with HT (23.8%) and seven patients with GD (13.2%) had at least one additional clinical autoimmune/allergic disorder. Twenty-eight (10.2%) patients with HT had gastrointestinal disorders (chronic atrophic gastritis and celiac disease), 19 (6.6%) had allergies (asthma, chronic urtica-ria, and rhinosinusitis), 12 (4.4%) had rheumatological disorders (rheumatoid arthritis), 10 (3.7%) had skin problems (vitiligo and psoriasis), four (1.5%) hadendocrinological disorders (hypoparathyroidism, type–1 diabetes mellitus, and hypophysitis), one (0.4%) had hematological disease (idiopathic throm-bocytopenic purpura), and one (0.4%) had renal disorder (crescentic glomerulonephritis). The prevalence patterns were similar in the patients with GD. Inaddition, 50 (18.2%) patients with HT and one (1.9%) with GD were observed to have vitamin B12 decient-anemia (p=0.001). Furthermore, 28 (10.2%) pati-ents with HT and one (1.9%) with GD had dimorphic anemia (both vitamin B12 and iron deciencies).Discussion: The patients with ATDs are prone to additional autoimmune/allergic diseases, and it can be said that the patients with autoimmune thyroid di-seases sometimes have more than just thyroid disease. The most involved organ system in both HT and GD is the gastrointestinal tract. This involvementprobably plays a role in the exacerbation of some symptoms by causing anemia resulting from a deciency of both vitamin B12 and iron, especially in pa-tients with HT. Keywords: Hashimoto’s thyroiditis; Graves’ disease, allergic diseases, chronic atrophic gastritis, autoimmune disorders, vitamin B12 deciency

Giriş: Bazen serum tiroid hormon düzeyleri normal aralıkta olsa da otoimmün tiroiditli hastalar semptomatik olabilirler. Diğer yandan, hipotiroidi hastala-rında levotiroksin replasman dozu değişkenlik gösterebilir. Klinik yaklaşımı değiştiren bu faktörler bir miktar otoimmün tiroid hastalığına(OTH) eşlik eden diğerimmünolojik/alerjik hastalıklarla ilişkili olabilir. Amaç: OTH için takipteki hastalardaki diğer otoimmün/ alerjik hastalıkları araştırmakGereç ve Yöntemler: Çalışma boyunca tanı konulan ya da takip altındaki 274 Hashimoto Tiroiditi (HT) ve 53 Graves’ hastalığı (GH) hastası çalışmaya dahiledildi. Tüm hastalardan anamnez alınıp hastalar muayene edildikten sonra otoimmün /allerjik hastalıklar için şüphede olunanlara ek tetkik yapıldı. Bulgular: 65 (23.8%) HT hastası ve 7 (13.2%) GD hastasının ek olarak en az bir klinik otoimmün/allerjik hastalığı mevcuttu. HT hastalarında hastalıklarındağılımları: 28 (10.2%) gastrointestinal (kronik atrok gastrit, çölyak hastalığı, vb), 19 (6.6%) allerjik (astım, kronik ürtiker, rinosinüzit), 12 (4.4%) romatolojik (ro-matoid artrit,vb), 10 (3.7%) cilt (vitiligo, psöriazis, vb), 4(1.5%) endokrinolojik (hipoparatiroidi, tip1 diabetes mellitus, hipozit), 1(0.4%) hematolojik (idiopatik trom-bositopenik purpura), 1(0.4%) renal (kresenterik glomerulonefrit) şeklindeydi. GD grubunda bu dağılım benzerdi. Ek olarak, 50(18.2%) HT hastasında ve1(1.9%) GD hastasında vitamin B12 eksikliği anemisi mevcuttu (p=0.001). 28 (10.2%) HT ve 1 (1.9%) GD hastasında dimork (vitamin B12 ve demir eksikliği bir-likte) anemi mevcuttu.Tartışma: OTH hastaları ek otoimmün/allerjik hastalıklara yatkındırlar ve söylenebilir ki otoimmün nedenli tiroid hastalığı olanlarda sadece tiroid hastalığıyoktur. Her iki tip OTH’nda da en çok tutulan organ sistemi gastrointestinal sistemdir. Muhtemelen bu tutulum özellikle HT hastalarında hem vitamin B12hem demir eksikliğine neden olup anemiye yol açarak bazı semptomların artışına sebep olmaktadır. Anahtar kelimeler: Hashimoto tiroiditi, Graves’ hastalığı, allerjik hastalıklar, kronik atrok gastrit, otoimmün hastalıklar, vitamin B12 eksikliği

Address for Correspondence: İffet Dağdelen Duran, Ankara University Faculty of Medicine, Department of Endocrinology and Metabolic Diseases, Ankara, TurkeyPhone: +90.5057375584 E-mail: [email protected] Received: 25.10.2017 Accepted: 21.12.2017


Original ArticleDOI: 10.25179/tjem.2017-58031


Introduction

Hashimoto’s thyroiditis (HT) and Graves’ disease (GD) are twomajor forms of autoimmune thyroid diseases. Hashimoto’s thy-roiditis is the most common cause of hypothyroidism, whereas GDis the leading cause of hyperthyroidism in young and middle-agedwomen (1, 2). In clinical practice, these patients usually have agreater variety and number of complaints than patients with otherthyroid disorders (3). The symptoms, which appear to be inde-pendent of thyroid hormone levels in patients with HT, becomemore pronounced with changes in hormone levels in patients withGD (4, 5). On the other hand, inadequate thyroid hormone re-placement remains a problem in the patients with hypothyroidism,who are on levothyroxine replacement, despite frequent monitor-ing and dose adjustments (6). Furthermore, the levothyroxine re-placement dose varies depending on whether the thyroid diseaseis autoimmune or due to some other cause (7). These observations in clinical practice have led to the investigationof factors associated with other autoimmune diseases, which maycontribute to such variations. For example, HT patients with pari-etal-cell antibodies have been found to require higher replacementdoses of levothyroxine. The presence of anemia indicates undiag-nosed atrophic gastritis (8), and hence the measurement of serumparietal-cell antibodies has been recommended in patients withan unexplained high requirement of levothyroxine (9). The atypicalceliac disease also increases the requirement of thyroid hormonereplacement (10).Apart from these, it is believed that a patient with an autoimmunedisease has a tendency to develop other forms of autoimmune orallergic diseases (11). Autoimmune disorders also have a tendencyto appear in one family as several cases or in a single patient asmultiple types. The routes of induction, pathogenesis, and treat-ment modalities may be influenced by many of these factors (12).As in most of the autoimmune diseases, the risk of development ofautoimmune thyroiditis is determined by genetic and environmen-tal factors. The HLA-DR polymorphisms such as HLA-DR3, -DR4,and -DR5 in Caucasians; HLA-B8, cytotoxic T-lymphocyte antigen(CTLA–4), CD40, protein tyrosine phosphatase–22 (PTPN22), thy-roglobulin, and thyroid-stimulating hormone receptor (TSHR) genepolymorphisms have been observed to be associated with au-toimmune thyroid diseases (13). Other autoimmune diseases arealso observed to be associated with genetic factors; this providesinsight into the relationship between autoimmune thyroid diseasesand other autoimmune diseases such as type 1A diabetes mellitus,Addison’s disease, pernicious anemia, vitiligo, rheumatoid arthri-tis, systemic lupus erythematosus, and Sjogren’s syndrome. Eachof these disorders can be divided into many stages, beginning withgenetic susceptibility, environmental triggers, active autoimmunity,and finally metabolic derangements with overt symptoms of dis-ease (14). The aim of the present study was to document the additional au-toimmune/allergic disorders in Turkish patients at follow-up for au-toimmune thyroid diseases. Presently, no large-scale trialsdescribing the cost-benefit ratio of auto-antibody screening forevaluation of autoimmune conditions exist, and hence cliniciansare advised to use individual judgment combined with improved

awareness to identify the ideal subjects (15). Therefore, wescreened patients with symptoms which could not be explainedby the current thyroid function status for potential accompanyingautoimmune/allergic diseases.

Subjects and Methods

This was a descriptive study. All patients diagnosed with autoim-mune thyroiditis (AIT): HT or GD, who attended the Thyroid DiseasesClinic at Ankara University’s Ibn-i Sina Hospital between November2008 and April 2009 and who were older than 18 years, were of-fered to be enrolled in the study. The study was approved by theLocal Clinical Research Ethics Committee and it adheres to the prin-ciples outlined in the Declaration of Helsinki. A written consent wasobtained by each patient enrolled. All subjects were systemicallyquestioned for each symptom that could be related to incorrectlyfunctioning body systems. The subjects who reported having symp-toms unexplainable with the current thyroid disease status werescreened for potential additional autoimmune/allergic disease(s).The diagnosis of other autoimmune diseases was made by a spe-cialist in the related department, following the criteria for each dis-ease described below. Each patient was asked for possible symptoms of the autoimmunediseases being screened. The symptoms reported by the patientdirected the clinician to examine specific disease(s). For example,if the patient had arthritis, the clinician checked for RheumatoidArthritis, while if xerostomia was reported during systematic ques-tioning, Sjogren’s syndrome was investigated. Some additional rec-ommended laboratory tests were also performed to facilitate theaccurate diagnosis. Specifically, when anemia associated with de-ficiency of iron or vitamin B12 was encountered, a gastroduo-denoscopy was performed. The diagnostic criteria used to confirmthe coexisting autoimmune or allergic diseases and the laboratorytools implemented to support the findings are listed in Table 1 (16–39). For example, the level of anti-transglutaminase Ig-A antibodywas measured to confirm celiac disease, and antibody positive pa-tients were subjected to duodenal biopsy (as described in sup-portive laboratory methods in Table 1).

Definitions

Iron deficiency anemia: low serum ferritin, red cell microcytosis orhypochromia in the absence of chronic disease or hemoglo-binopathiesVitamin B12 deficiency anemia: low cobalamin, macrocytic anemiaor macrocytosis with oval macrocytes or hyper-segmented neu-trophils or pancytopeniaDimorphic anemia: low serum cobalamin and ferritin levels withanemiaHashimoto’s thyroiditis: serologically increased levels of anti-TPO(anti-thyroid peroxidase) and/or anti-Tg (anti-thyroglobulin), alongwith diffuse hypo-echogenicity, heterogeneity, and pseudo-nod-ules on ultrasonography.Graves’ disease: diffuse thyromegaly associated with heterogene-ity on ultrasonography, and the increased levels of thyroid stimu-lating hormone receptor antibody (Trab) in serum.

Turk J Endocrinol Metab Dağdelen Duran et al.2017;21:120-126 Autoimmune-Allergic Diseases with Autoimmune Thyroid Diseases 121

Dağdelen Duran et al. Turk J Endocrinol MetabAutoimmune-Allergic Diseases with Autoimmune Thyroid Diseases 2017;21:120-126

122

Autoimmune or allergic disease Diagnostic criteria Supportive laboratory methods

Chronic atrophic gastritis Atrophy of the corpus and fundus, and the presence of Gastric corpus and fundus biopsy

circulating autoantibodies to the parietal cell (PCA)

and their secretory product, intrinsic factor (AIF) (16)

Celiac disease Working Group report of the second World Congress of anti-tTG (anti-tissue transglutaminase) IgA,

Pediatric Gastroenterology, Hepatology, and Nutrition (17) duodenum biopsy

Autoimmune pancreatitis Diagnostic criteria derived from the combination of HISORt CT (Computed Tomography) and

(histology, imaging, serology, other organ involvement, biopsy of pancreas

and its response to steroid therapy) (18)

Ulcerative colitis Second European evidence-based consensus on the Colonoscopy, preferably with ileoscopy, and

diagnosis and management of ulcerative colitis (19) segmental biopsies including the rectum

Primary biliary cirrhosis Fatigue, pruritus, cholestasis, elevated serum AMA AST, ALT, ALP, GGT, direct/indirect bilirubin,

(antimitochondrial antibody), percutaneous liver serum AMA

biopsy ndings (20)

Asthma National Asthma Education and Prevention Program 2007 Spirometry

report (Expert Panel Report 3 [EPR–3] (21)

Chronic urticaria The EAACI/GA(2) LEN/EDF/WAO Guideline for the denition, Lesional skin biopsy

classication, diagnosis, and management of urticaria:

the 2013 revision and update. (22)

Allergic rhinosinusitis The European Position Paper on Rhinosinusitis and Nasendoscopy

Nasal Polyps 2012 (23)

Rheumatoid arthritis The American Rheumatism Association 1987 revised Radiography of the hand including the wrist,

criteria for the classication of rheumatoid arthritis (24) RF (Rheumatoid Factor)

Systemic lupus erythematosus 1982 ACR (American College of Rheumatology) revised criteria (25) Complete Blood Count, serum creatinine,

24 h urine protein, Antinuclear antibody,

anti-Double stranded DNA antibody

Still disease Yamaguchi criteria (26) CBC, AST, ALT, ANA, RF

Sjögren syndrome Revised version of the European criteria proposed Schirmer’s test, saliva test, Antibodies to Ro (SSA)

by the American-European Consensus Group (27) and La (SSB) antigens, salivary gland biopsy

Behçet’s disease International Study Group for Behçet's Disease (28) Pathergy test

Ankylosing spondylitis Modied New York Criteria (29) Sacroiliac radiography

Sarcoidosis The noncaseating granulomatous inammation in the Biopsy of the involved organ

respiratory tract, eye, skin, liver, spleen, heart,

nervous system or musculoskeletal organs (30)

Mixed connective tissue disease Alarcon-Segovia classication (31) Cold water test, anti-RNP (anti-ribonucleoprotein)

Vitiligo Consensus report of the Vitiligo European Task Force (32) Wood's lamp examination

Psoriasis Lesions exhibiting erythema, induration, and scaling, Histopathology

skin biopsy ndings (33)

Idiopathic pruritus European Guideline on Chronic Pruritus (34) CBC, ESR, creatinine, alkaline phosphatase,

liver enzymes, bilirubin, TSH, glucose, serum iron,

ferritin, hepatitis serology, cholesterol triglycerides

Total alopecia Complete non-scarring loss of scalp hair

Hypoparathyroidism Hypoparathyroidism not occurring after a surgical Serum PTH, Calcium, Phosphorus

procedure or any other well-dened cause (35)

Type–1 diabetes mellitus Report of the Expert Committee on the Diagnosis Two separate measurements of plasma glucose,

and Classication of Diabetes Mellitus (36) plasma C-peptid, insulin, anti-glutamic acid

decarboxylase antibody

Hypophysitis Compression symptoms (a headache, visual impairment), Magnetic resonance imaging

hypopituitarism, diabetes insipidus or hyperprolactinemia (37)

Immune thrombocytopenia American Society of Hematology Clinical Practice Guideline (38) CBC, Peripheral blood smear

Crescentic glomerulonephritis Edema, hypertension and gross hematuria, and evidence Renal biopsy

of acute renal failure (39)

Table 1. Diagnostic criteria that were employed to diagnose coexisting autoimmune or allergic diseases, and the laboratory methods that suppor-ted these diagnoses.


Hormone assays

Thyroid-specific antibodies (anti-TPO and anti-Tg) were measuredby an electrochemiluminescence method (ECLIA) (Elecsys 2010,Roche Diagnostics, Indianapolis, USA). The normal ranges were 0–34 IU/mL and 0–9 IU/mL for anti-Tg and anti-TPO, respectively. Thy-roid receptor antibody(Trab) was measured by a radioreceptorassay (Radim Diagnostics, Pomezia, Italy). The normal level (neg-ative) was <9 IU/L, while 9–14 IU/L was borderline and >14 IU/Lwas positive. TSH (Thyrotropin) was measured by ECLIA Immulite2000 (Diagnostic Products Corp, Los Angeles, CA, USA).

Statistical analysis

The normally distributed continuous variables were expressed asthe mean and standard deviation (mean ±SD), and were com-pared using Student’s t-test or one-way ANOVA. Non-normally dis-tributed continuous variables were expressed as median andinterquartile ranges 25 and 75 [median (IQR 25-IQR 75)], and werecompared using the Mann-Whitney U test or Kruskal-Wallis test.When performing correlation and regression analysis, non-nor-mally distributed continuous variables were log-transformed. Theevaluation of normality was performed with the Kolmogorov-Smirnov test. The categorical variables were compared using Pear-son‘s chi-squared or Fisher’s exact test. The p values below 0.05were considered to be statistically significant. The software SPSSv.17.0 (SPSS, Chicago, IL) was used for all statistical calculations andgraphical presentation.

Results

Although 338 patients with AIT were initially chosen for participa-tion in the study, some patients opted out before giving their con-sent. Thus, a total of 327 patients (289 female) with autoimmune

disorders (274 with HI and 53 with GD) were admitted and includedin the study. The median disease duration from the time of diag-nosis was four years (2–8 years) in case of HT, and 0.5 years (0–4years) in case of GD (p<.001). The prevalence of HT in all the stud-ied female patients was 87.5% (n=253), whereas in males it was55.3% (n=21) (p< 0.001). Overall, 65 (23.7%) patients with HT (48with additional autoimmune diseases and 19 with allergic dis-eases, of which two had both additional autoimmune and allergicdiseases), and seven patients with GD (five of which had additionalautoimmune diseases and two had allergic-based diseases) werefound to have at least one additional autoimmune/allergic dis-ease(s). The details of co-existing additional autoimmune/allergicdiseases are given in Tables 2 and 3. The most prevalent additionalautoimmune diseases were related to the gastrointestinal tract,

Hashimoto Graves’ Disease

thyroiditis (n=274) (n=53) p-value

Age (years) 45.6 ±12.2 46.3 ±12.4 NS

Gender, male (n,%) 21 (7.7) 17 (32.1) < .001

Age at diagnosis 40.0 ±12.2 43.7 ±11.5 NS

TSH, at diagnosis (µIU/mL) 6.8 (2.4–11.5) 0.02 (0.01–0.04) <.001

Anti-tpo, at diagnosis (0–9 IU/mL) 253 (79–968) 153 (25–652) .025

Anti-tg, at diagnosis (0–4 IU/mL) 102 (25–418) 18 (2–76) < .001

Anti-tpo, current (0–9 IU/mL) 175 (39–426) 300 (46–834) NS

Anti-tg, current (0–4 IU/mL) 51 (10–223) 15 (1–93) .032

Vitamin B12 (pg/mL) 294 (214–431) 223 (161–371) .022

Ferritin (ng/mL) 16 (7–35) 32 (12–71) NS

Vitamin B12 deciency, n (%) 50 (18.2) 1 (1.9) .001

Iron deciency, n (%) 58 (21.2) 4 (7.5) .021

Both deciencies 28 (10.2) 1 (1.9) .002

*Vitamin B12 deciency was considered if the patient was on vitamin B12 replace-

ment, or if the vitamin B12 levels were <200 pg/mL

*İron deciency was considered if the patient was on iron replacement, or if they

had anemia with ferritin levels <30 ng/mL.

Table 2. Some characteristics and comparison of the patients withautoimmune thyroid disorders.

Hashimoto Graves’ Disease

thyroiditis (n=274) (n=53) p-value

Gastrointestinal* 28 (10.2) 2 (3.8) NS

Chronic atrophic gastritis 21 (7.7) 1 (1.9) NS

Celiac disease 7 (2.6) 0 NS

Autoimmune pancreatitis 1 (0.4) 0 NS

Ulcerative colitis 0 1 (1.9) NS

Primary biliary cirrhosis 1 (0.4) 0 NS

Allergic 19 (6.9) 2 (3.8) NS

Asthma 13 (4.7) 0 NS

Chronic urticarial 2 (0.7) 1 (1.9) NS

Rhinosinusitis 5 (1.8) 1 (1.9) NS

Rheumatological 11 (4.0) 0 NS

Rheumatoid arthritis 2 (0.7) 0 NS

Systemic lupus erythematosus 1 (0.4) 0 NS

Still disease 1 (0.4) 0 NS

Sjögren syndrome 2 (0.7) 0 NS

Behçet’s disease 1 (0.4) 0 NS

Ankylosing spondylitis 1 (0.4) 0 NS

Mixed connective tissue disease 3 (1.1) 0 NS

Skin** 9 (3.3) 2 (3.8) NS

Vitiligo 4 (1.5) 2 (3.8) NS

Psoriasis 3 (1.1) 0 NS

Idiopathic pruritus 3 (1.1) 0 NS

Total alopecia 1 (0.4) 0 NS

Endocrinological 4 (1.5) 0 NS

Idiopathic hypoparathyroidism 2 (0.7) 0 NS

Type–1 diabetes mellitus 1 (0.4) 0 NS

Hypophysitis 1 (0.4) 0 NS

Others

Immune thrombocytopenia 1 (0.4) 1 (1.9) NS

Crescentic glomerulonephritis 1 (0.4) 0 NS

Sarcoidosis 1 (0.4) 1 (1.9) NS

* Two patients had more than one additional autoimmunity related gastrointestinal

diseases.

**Two patients had more than one additional autoimmunity related skin diseases.

Table 3. The distribution of the coexisting autoimmune and allergic-based diseases in patients with Hashimoto’s thyroiditis and Graves’ disease.

encountered in 10.2% of the HT patients and 3.8% of the GD patients.This was followed by allergic diseases, found in 19 (6.9%) patientswith HT and 3.8% of GD patients. The most prevalent autoim-mune/allergic diseases in patients with HT were chronic atrophicgastritis (7.7%), asthma (4.7%), celiac disease (2.6%), and vitiligo(1.5%). The overall prevalence of rheumatological, dermatological,and endocrinological (excluding thyroid) autoimmune diseases inpatients with HT was 4.0%, 3.3%, and 1.5%, respectively (Table 3). Although the overall levels of serum vitamin B12 were lower in pa-tients with GD, the frequencies of both vitamin B12 and iron defi-ciencies were higher in patients with HT (Table 2). Hashimoto’sthyroiditis patients with accompanying autoimmune gastrointesti-nal diseases had higher frequencies of anemia due to vitamin B12and iron deficiency; their disease duration and current thyroid sta-tus was similar to HT patients without additional autoimmune gas-trointestinal diseases (Table 4). There was no correlation between the titers of anti-TPO or anti-Tgand the development of autoimmune and/or allergic diseases.However, the patients with dimorphic anemia had higher titers ofanti-TPO compared to patients without anemia (p=0.03).There were eight patients with more than one additional autoim-mune disease, all of whom had Hashimoto’s thyroiditis (Table 5).

Discussion

The patients with a primary diagnosis of an autoimmune thyroid dis-ease are at substantially increased risk of coexisting autoimmune andallergic diseases (11, 40–42). In our Turkish unit at a tertiary care uni-versity hospital, we found that 23.7% patients with HT and 13.2% pa-tients with GD had at least one additional clinical autoimmune and/orallergic disorder. The most prevalent coexisting organ-specific autoim-mune disorders (chronic atrophic gastritis and celiac disease) involvedthe gastrointestinal tract, followed by allergic asthma and vitiligo. Prob-ably, both iron and cobalamin deficiencies were also highly associatedwith gastrointestinal tract involvements, especially in HT patients.Although several autoimmune diseases are individually rare, theyhave been estimated to collectively afflict about 3% of the population(43). The hypothesis that autoimmune diseases tend to coexist in thesame person has been investigated in few studies on a large scale(11, 44). One of such studies, a cross-sectional multicenter study of3286 Caucasian subjects (2791 with GD and 495 with HT), reportedthat the frequency of another autoimmune disorder in patients withGD and HT is 9.7% and 14.3%, respectively. The study reportedrheumatoid arthritis as the most common coexisting autoimmunedisorder. The relative risks of almost all other autoimmune diseases(systemic lupus erythematosus,, Addison’s disease, and celiac dis-ease) accompanying GD or HT were calculated to be more than 10times of the frequency of each autoimmune disease in the generalpopulation (11). In the present study, we found that 17.5% of HT pa-tients had at least one additional autoimmune disease, and 6.9%had allergic diseases. The prevalence of additional autoimmune dis-eases and allergic diseases in case of GD patients was 9.4% and3.8%, respectively. With respect to the overall prevalence of coexist-ing autoimmune diseases, our results are consistent with the afore-mentioned study. However, the most prevalent additionalautoimmune disorder in our study was chronic atrophic gastritis, fol-lowed by celiac disease. The discrepancy between our findings andthose of Boelaert et al. could be associated with several factors. First,as observed in the majority of autoimmune diseases, the develop-ment of clinical rheumatoid arthritis is collectively influenced by mul-tiple environmental and genetic risk factors, but the exact cellularmechanisms are unclear. Geographical distribution could be one ofthe environmental factors possibly associated with susceptibility (45).Secondly, the diagnosis of rheumatoid arthritis is primarily based onthe patient’s symptomatology, and the presence of symptoms maybe subjective in some cases. Since we investigated rheumatoidarthritis only in ATD patients with symptoms that could not be ex-plained by their current thyroid function status, it is likely that we un-derdiagnosed latent rheumatoid arthritis in some cases. Thirdly,since we examined all patients with iron or vitamin B12 deficiencyrelated anemia by gastroduodenoscopy, our observed prevalence ofchronic atrophic gastritis and celiac disease may be higher than thatreported in the literature. A study on North Italian patients with au-toimmune thyroid disease also reported celiac disease (clinical, silentor latent) to be present in 5.4% of the patients (46). The associations between autoimmune thyroid diseases and al-lergic disorders have been studied in a lesser detail. A Polish studyunit comprising 255 patients with either HT or GD reported that5.1% of the study population had co-existing bronchial asthma and


124

With Without

accompanying accompanying

autoimmune autoimmune

gastrointestinal gastrointestinal

disease(s) (n=28) disease (n=246) p-value

Age 49.1 ±10.5 45.1 ±12.3 .078

Gender, male (n,%) 1 (3.6) 20 (8.1) NS

Vitamin B12 deciency 11 (39.3) 39 (15.9) .002

Iron deciency 12 (42.9) 46 (18.7) .003

Both deciencies 7 (25.0) 21 (8.5) .002

Disease duration, years 2.5 (0.5–7.0) 2.0 (0.4–5.0) NS

Hypothyroid (on LT4 replacement) 20 (71.4) 172 (69.9) NS

Table 4. Some characteristics of the patients with Hashimoto’s thyroiditis with and without additional autoimmune gastroenterologic involvements.

Thyroid Age/ Age at Additional autoimmune

Patient disease gender diagnosis diseases

Patient1 H.T. 55/F 38 Sjögren’s syndrome/CAG

Patient 2 H.T. 56/M 46 CAG/CD

Patient 3 H.T. 42/F 32 CAG/CD

Patient 4 H.T. 49/F 46 AS/rhinosinusitis

Patient 5 H.T. 41/F 37 Still disease/CAG

Patient 6 H.T. 49/F 42 CD/asthma

Patient 7 H.T. 27/F 27 Psoriasis/vitiligo

Patient 8 H.T. 56/F 49 Vitiligo/idiopathic pruritus

H.T.: Hashimoto’s thyroiditis; F: Female; M: Male; CAG.Chronic Atrophic Gastritis;

CD: Celiac Disease; AS: Ankylosing Spondylitis.

Table 5. Some characteristics of the patients with more than one additional immunological/allergic disease.

1.2% had allergic rhinitis (47). Our findings are consistent with theseresults. Another study carried out several decades ago proposeda link between chronic urticaria and autoimmune thyroid diseases,although the mechanisms of the apparent association betweenchronic urticaria and serological evidence of thyroid autoimmunitywere not clear (48). A group of researchers has suggested thatthere could be a skin mast cell autoreactivity in HT patients, irre-spective of autoreactive chronic urticaria (49). Our study highlights that deficiency of cobalamin and iron, which waspresent in a substantial proportion (18.2% and 21.2%, respectively) ofpatients with HT, which could be a clinically important finding. Such ahigh prevalence of cobalamin and iron deficiency was not observedin the patients with GD. Moreover, the coexistence of both deficiencieswas observed in 10.2% of the patients with HT. As expected, the riskof both cobalamin and iron deficiencies increases if an autoimmunedisease involving the gastrointestinal tract coexists with the autoim-mune thyroid disease (50). Cobalamin deficiency may exacerbate oreven by itself cause symptoms such as depression, mania, irritabil-ity, paranoia, delusions, and emotional lability (51). We could not establish a relationship between titers of anti-TPO oranti-Tg and the development of autoimmune and allergic diseases.However, a higher titer of anti-TPO (but not anti-Tg) may be asso-ciated with a higher prevalence of dimorphic anemia.To summarize, some of the significant diseases and/or conditionscoexisting with autoimmune thyroid diseases should be investi-gated in terms of cause-effect relationship, in future studies.It has to be emphasized that our study has several limitations. First,the study was carried out at a single tertiary care center in Ankara.Our results may not represent the exact prevalence of autoim-mune/allergic disorders coexisting with autoimmune thyroid disor-ders. Indeed, our aim was not to document the exact prevalence butto highlight the co-morbid conditions associated with autoimmunethyroid diseases. However, due to the recent health insurance policiesin Turkey, a wide range of patients have access to healthcare in ter-tiary care facilities, and hence these results may provide baseline in-formation on the prevalence of the studied associations. Secondly,our study was designed to document associated comorbidities onlyin symptomatic patients and did not consider latent diseases. There-fore, the subjects without symptoms but might be positive for thestudied antibodies were probably not considered in our study. Thirdly,a greater study population would be required to document the morerarely encountered autoimmune diseases such as myasthenia gravis,multiple sclerosis, Addison’s disease, premature ovarian failure, andso on. In addition, the comparison of coexisting diseases associatedwith either GD or HT may not be ideal, as the disease duration for HTwas longer than GD in our study population. In addition, the in-creased rate of iron deficiency in HT is perhaps explained by thehigher number of menstruating females in this group. The chronic at-rophic gastritis could also have been caused by non-autoimmuneconditions such as infection by H. pylori, which might be distinguishedby appropriate tests. The other causes of cobalamin deficiency suchas metformin use and dietary deficiency were not excluded, althoughthese causes can be ruled out in our study population.We do acknowledge that the value of diagnosing overt disease(s)with typical clinical signs/symptoms would seem limited but early

diagnosis of the disease would facilitate its control and reduce thecost of treatment, rather than if it was diagnosed late.In conclusion, patients with autoimmune thyroid disorders some-times have more than just the thyroid disease, and they should beevaluated according to their symptoms since more than 20% ofthem could potentially have coexisting autoimmune and/or aller-gic diseases. The evaluation of the upper gastrointestinal tract maybe useful in such patients, especially, if they have iron and/orcobalamin deficiencies.


Idea/Concept: Sevim Güllü; Design: Sevim Güllü; Control/Supervi-sion: Sevim Güllü, İffet Dağdelen Duran; Data Collection and/orProcessing: İffet Dağdelen Duran; Analysis and/or Interpretation:Kemal Ağbaht; Literature Review: İffet Dağdelen Duran, KemalAğbaht; Writing the Article: Kemal Ağbaht, Kemal Ağbaht; CriticalReview: Kemal Ağbaht, Kemal Ağbaht; References and Fundings:Kemal Ağbaht, Kemal Ağbaht; Materials: İrfan Soykan.Conflict of Interest: The authors declare that they have no conflict ofinterest. Financial Disclosure: There is no organization that fundedour research.

References1. Dayan CM, Daniels GH. Chronic autoimmune thyroiditis. N Engl J

Med. 1996;335:99-107.2. Weetman AP. Graves' disease. N Engl J Med. 2000;343:1236-1248.3. Müssig K, Künle A, Säuberlich AL, Weinert C, Ethofer T, Saur R, Klein

R, Häring HU, Klingberg S, Gallwitz B, Leyhe T. Thyroid peroxidase an-tibody positivity is associated associated with Hashimoto's thyroiditis.Brain Behav Immun. 2012;26:559-563.

4. Giynas Ayhan M, Uguz F, Askin R, Gonen MS. The prevalence of de-pression and anxiety disorders in patients with euthyroid Hashimoto'sthyroiditis: a comparative study. Gen Hosp Psychiatry. 2013;36:95-98.

5. Ott J, Promberger R, Kober F, Neuhold N, Tea M, Huber JC, HermannM. Hashimoto's thyroiditis affects symptom load and quality of lifeunrelated to hypothyroidism: a prospective case-control study inwomen undergoing thyroidectomy for benign goiter. Thyroid.2011;21:161-167.

6. Okosieme OE, Belludi G, Spittle K, Kadiyala R, Richards J. Adequacyof thyroid hormone replacement in a general population. QJM.2011;104:395-401.

7. Gordon MB, Gordon MS. Variations in adequate levothyroxine re-placement therapy in patients with different causes of hypothy-roidism. Endocr Pract. 1999;5:233-238.

8. Gerenova JB, Manolova IM, Tzoneva VI. Clinical significance of au-toantibodies to parietal cells in patients with autoimmune thyroid dis-eases. Folia Med (Plovdiv). 2013;55:26-32.

9. Checchi S, Montanaro A, Pasqui L, Ciuoli C, De Palo V, Chiappetta MC,Pacini F. L-thyroxine requirement in patients with autoimmune hy-pothyroidism and parietal cell antibodies. J Clin Endocrinol Metab.2008;93:465-469.

10. Virili C, Bassotti G, Santaguida MG, Iuorio R, Del Duca SC, Mercuri V,Picarelli A, Gargiulo P, Gargano L, Centanni M. Atypical celiac diseaseas cause of increased need for thyroxine: a systematic study. J ClinEndocrinol Metab. 2012;97:E419-422.

11. Boelaert K, Newby PR, Simmonds MJ, Holder RL, Carr-Smith JD,Heward JM, Manji N, Allahabadia A, Armitage M, Chatterjee KV,Lazarus JH, Pearce SH, Vaidya B, Gough SC, Franklyn JA. Prevalenceand relative risk of other autoimmune diseases in subjects with au-toimmune thyroid disease. Am J Med. 2010;123:183.e1-9.

12. Reveille JD. The genetic basis of autoantibody production. Autoim-mun Rev. 2006;5:389-398.


13. Jacobson EM, Tomer Y. The genetic basis of thyroid autoimmunity.Thyroid. 2007;17:949-961.

14. Michels AW, Eisenbarth GS. Immunologic endocrine disorders. J Al-lergy Clin Immunol. 2010;125:S226-237.

15. Weetman AP. Non-thyroid autoantibodies in autoimmune thyroid dis-ease. Best Pract Res Clin Endocrinol Metab. 2005;19:17-32.

16. Dixon MF, Genta RM, Yardley JH, Correa P. Classification and gradingof gastritis. The updated Sydney System. International Workshop onthe Histopathology of Gastritis, Houston 1994. Am J Surg Pathol.1996;20:1161-1181.

17. Bhutta ZA, Ghishan F, Lindley K, Memon IA, Mittal S, Rhoads JM. Per-sistent and chronic diarrhea and malabsorption: Working Group reportof the second World Congress of Pediatric Gastroenterology, Hepatol-ogy, and Nutrition. J Pediatr Gastroenterol Nutr. 2004;39:S711-716.

18. Chari ST, Smyrk TC, Levy MJ, Topazian MD, Takahashi N, Zhang L,Clain JE, Pearson RK, Petersen BT, Vege SS, Farnell MB. Diagnosis ofautoimmune pancreatitis: the Mayo Clinic experience. Clin Gas-troenterol Hepatol. 2006;4:1010-1016.

19. Dignass A, Eliakim R, Magro F, Maaser C, Chowers Y, Geboes K,Mantzaris G, Reinisch W, Colombel JF, Vermeire S, Travis S, LindsayJO, Van Assche G. Second European evidence-based consensus onthe diagnosis and management of ulcerative colitis part 1: definitionsand diagnosis. J Crohns Colitis. 2012;6:965-990.

20. European Association for the Study of the Liver. EASL Clinical PracticeGuidelines: management of cholestatic liver diseases. J Hepatol.2009;51:237-267.

21. National Asthma Education and Prevention Program. Expert Panel Report3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma-Summary Report 2007. J Allergy Clin Immunol. 2007;120:S94-138.

22. Zuberbier T, Aberer W, Asero R, Bindslev-Jensen C, Brzoza Z, Canon-ica GW, Church MK, Ensina LF, Giménez-Arnau A, Godse K, GonçaloM, Grattan C, Hebert J, Hide M, Kaplan A, Kapp A, Abdul Latiff AH,Mathelier-Fusade P, Metz M, Nast A, Saini SS, Sánchez-Borges M,Schmid-Grendelmeier P, Simons FE, Staubach P, Sussman G, Toubi E,Vena GA, Wedi B, Zhu XJ, Maurer M. The EAACI/GA(2) LEN/EDF/WAOGuideline for the definition, classification, diagnosis, and managementof urticaria: the 2013 revision and update. Allergy. 2014;69:868-887.

23. Fokkens WJ, Lund VJ, Mullol J, Bachert C, Alobid I, Baroody F, Cohen N,Cervin A, Douglas R, Gevaert P, Georgalas C, Goossens H, Harvey R,Hellings P, Hopkins C, Jones N, Joos G, Kalogjera L, Kern B, Kowalski M,Price D, Riechelmann H, Schlosser R, Senior B, Thomas M, Toskala E,Voegels R, Wang de Y, Wormald PJ. European Position Paper on Rhi-nosinusitis and Nasal Polyps 2012. Rhinol Suppl. 2012;23:3.

24. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS,Healey LA, Kaplan SR, Liang MH, Luthra HS. The American Rheuma-tism Association 1987 revised criteria for the classification of rheuma-toid arthritis. Arthritis Rheum. 1988;31:315-324.

25. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, SchallerJG, Talal N, Winchester RJ. The 1982 revised criteria for the classificationof systemic lupus erythematosus. Arthritis Rheum. 1982;25:1271-1277.

26. Yamaguchi M, Ohta A, Tsunematsu T, Kasukawa R, Mizushima Y,Kashiwagi H, Kashiwazaki S, Tanimoto K, Matsumoto Y, Ota T. Pre-liminary criteria for classification of adult Still’s disease. J Rheumatol.1992;19:424-430.

27. Vitali C, Bombardieri S, Jonsson R, Moutsopoulos HM, Alexander EL,Carsons SE, Daniels TE, Fox PC, Fox RI, Kassan SS, Pillemer SR, TalalN, Weisman MH; European Study Group on Classification Criteria forSjögren's Syndrome. Classification criteria for Sjögren's syndrome: arevised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis. 2002;61:554-558.

28. Criteria for diagnosis of Behçet's disease. International Study Groupfor Behçet's Disease. Lancet. 1990;335:1078-1080.

29. van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic cri-teria for ankylosing spondylitis. A proposal for modification of theNew York criteria. Arthritis Rheum. 1984;27:361-368.

30. Iannuzzi MC, Rybicki BA, Teirstein AS. Sarcoidosis. N Engl J Med2007;357:2153-2165.

31. Alarcón-Segovia D. Mixed connective tissue disease: a disorder ofimmune regulation. Semin Arthritis Rheum. 1983;13:114-120.

32. Taïeb A, Picardo M. The definition and assessment of vitiligo: a con-sensus report of the Vitiligo European Task Force. Pigment Cell Res.2007;20:27-35.

33. National Clinical Guideline Centre (UK). Psoriasis: Assessment andManagement. London: Royal College of Physicians (UK); 2012:57.

34. Weisshaar E, Szepietowski JC, Darsow U, Misery L, Wallengren J, Met-tang T, Gieler U, Lotti T, Lambert J, Maisel P, Streit M, Greaves MW,Carmichael AJ, Tschachler E, Ring J, Ständer S. European guidelineon chronic pruritus. Acta Derm Venereol. 2012;92:563-581.

35. Shoback D. Clinical practice. Hypoparathyroidism. N Engl J Med.2008;359:391-403.

36. Expert Committee on the Diagnosis and Classification of DiabetesMellitus. Report of the expert committee on the diagnosis and clas-sification of diabetes mellitus. Diabetes Care. 2003;26:S5-20.

37. Català Bauset M, Gilsanz Peral A, Girbés Borràs J, Zugasti Murillo A,Moreno Esteban B, Halperin Rabinovich I, Obiols Alfonso G, Picó Al-fonso A, Del Pozo Picó C, Soto Moreno A, Torres Vela E, Tortosa HenziF, Lucas Morante T, Páramo Fernández C, Varela da Ousa C, VillabonaArtero C. Clinical practice guideline for the diagnosis and treatmentof hypophysitis. Endocrinol Nutr. 2008;55:44-53.

38. Neunert C, Lim W, Crowther M, Cohen A, Solberg L Jr, Crowther MA;American Society of Hematology. The American Society of Hematol-ogy 2011 evidence-based practice guideline for immune thrombocy-topenia. Blood. 2011;117:4190-4207.

39. Radhakrishnan J, Cattran DC. The KDIGO practice guideline onglomerulonephritis: reading between the (guide)lines--application tothe individual patient. Kidney Int. 2012;82:840-856.

40. Berti I, Trevisiol C, Tommasini A, Città A, Neri E, Geatti O, GiammariniA, Ventura A, Not T. Usefulness of screening program for celiac dis-ease in autoimmune thyroiditis. Dig Dis Sci. 2000;45:403-406.

41. Shong YK, Kim JA. Vitiligo in autoimmune thyroid disease. Thyroidol-ogy. 1991;3:89-91.

42. De Block CE, De Leeuw IH, Vertommen JJ, Rooman RP, Du Caju MV,Van Campenhout CM, Weyler JJ, Winnock F, Van Autreve J, Gorus FK.Beta-cell, thyroid, gastric, adrenal and coeliac autoimmunity and HLA-DQ types in type 1 diabetes. Clin Exp Immunol. 2001;126:236-241.

43. Jacobson DL, Gange SJ, Rose NR, Graham NM. Epidemiology andestimated population burden of selected autoimmune diseases inthe United States. Clin Immunol Immunopathol. 1997;84:223-243.

44. Somers EC, Thomas SL, Smeeth L, Hall AJ. Are individuals with an au-toimmune disease at higher risk of a second autoimmune disorder?Am J Epidemiol. 2009;169:749-755.

45. Benson RA, Brewer JM, Platt AM. Mechanisms of autoimmunity inhuman diseases: a critical review of current dogma. Curr OpinRheumatol. 2014;26:197-203.

46. Spadaccino AC, Basso D, Chiarelli S, Albergoni MP, D'Odorico A, Ple-bani M, Pedini B, Lazzarotto F, Betterle C. Celiac disease in North Ital-ian patients with autoimmune thyroid diseases. Autoimmunity.2008;41:116-121.

47. Przybylik-Mazurek E, Kotlinowska B, Kasztelnik M, Stefańska A,Huszno B. [Autoimmunological and allergic disorders with Hashimotoand Graves disease]. Przegl Lek. 2006;63:719-722.

48. Bagnasco M, Minciullo PL, Saraceno GS, Gangemi S, Benvenga S. Ur-ticaria and thyroid autoimmunity. Thyroid. 2011;21:401-410.

49. Turkoglu Z, Zindanci I, Turkoglu O, Can B, Kavala M, Tamer G, UlucayV, Akyer E. Skin autoreactivity in Hashimoto's thyroiditis patients with-out urticaria: autologous serum skin test positivity correlation withthyroid antibodies, sonographical volume and grading. Eur J Derma-tol. 2012;22:345-350.

50. Hershko C, Ronson A, Souroujon M, Maschler I, Heyd J, Patz J. Vari-able hematologic presentation of autoimmune gastritis: age-relatedprogression from iron deficiency to cobalamin depletion. Blood.2006;107:1673-1679.

51. Stabler SP. Clinical practice. Vitamin B12 deficiency. N Engl J Med2013;368:149-160.


126

Introduction

Gluten is an important ingredient of wheat protein, as about 90%of the total protein content is gluten. Besides, it is also present inbarley, oat, and rye (1–3), and these gluten-rich cereals constitute

the major part of our diet. Gluten is a water-insoluble protein andconsists of two major fractions, i.e., gliadin and glutenin. Gliadin isthe aqueous alcohol-soluble fraction, and its firm peptide config-uration renders it resistant to lytic enzyme system in the gastroin-testinal tract and this distinct resistance is considered to trigger

127

TThhee RRoollee ooff GGlluutteenn--ffrreeee DDiieett aanndd IInntteessttiinnaall MMiiccrroobbiioottaaoonn GGllyycceemmiicc CCoonnttrrooll aanndd DDiiaabbeetteess DDeevveellooppmmeennttGGlluutteennssiizz DDiieett,, İİnntteessttiinnaall MMiikkrroobbiioottaannıınn GGlliisseemmiikk KKoonnttrrooll vvee DDiiyyaabbeett GGeelliişşiimmiinnddeekkii RRoollüü

Haseki Training and Research Hospital, Department of Endocrinology and Metabolic Diseases, İstanbul, Turkey

A gluten-free diet offers immense health benets in certain autoimmune diseases including dermatitis herpetiformis, rheumatoid arthritis,and neurologic disorders; besides its therapeutic potential has also been documented in other conditions such as diabetes mellitus, HIV-associated enteropathy, and celiac disease.In animal models, a gluten-free diet has been associated with the reduced auto-inammatory process, altered inammatory cytokine res-ponse as well as intestinal microbiota leading to lower the incidence of diabetes. The acidic environment has also been shown to affectthe gut microbiota resulting in reduced incidence and delayed onset of diabetes in genetically predisposed individuals.In the current article, it has been proposed that intestinal microbiota play a major role in stimulating an immunological response; and theacidic environment affects the gut microbiota, and thus improves the immunological milieu. Gluten-free diets positively boost the immu-nological response in animal models and combat with autoimmune diseases in human beings by affecting the gut ora. The associationbetween gluten-free diet, gut ora, immunological response, and environment may play a decisive role in plummeting the advancementof diabetes.

Keywords: Gluten-free diet, cytokines, intestinal microbiota, acidic environment, diabetes mellitus

Glutensiz diyet, dermatit herpetiformis, romatoid artrit ve nörolojik bozukluklar gibi otoimmün hastalıklarda sağlığa faydalı etkiler sun-maktadır; ayrıca diabetes mellitus, HIV ile ilişkili enteropati ve çölyak hastalığında da tedavideki olumlu etkinliği bildirilmiştir. Hayvan modellerinde, glutensiz diyet otoinamatuvar süreçde baskılanma ve değişen inamatuvar sitokin yanıtı ile diyabet insidansındaazaltmaya yol açan bağırsak mikrobiyota değişimi ile ilişkilendirilmiştir. Asidik ortamın bağırsak mikrobiyota ortamını etkilediği ve genetikolarak yatkın bireylerde diyabet insidansı azalttığı ve diyabetin başlamasını geciktirdiği gösterilmiştir.Bu makale ile bağırsak mikrobiyotasının immünolojik cevabı uyarmada önemli bir rol oynadığı sunulmaktadır; ve asidik ortam bağırsak mik-robiyotasını etkileyerek immünolojik ortamı geliştirir. Glutensiz diyet, bağırsak orasını etkileyerek hayvan modellerinde immünolojik yanıttave insanda otoimmün hastalıklarla mücadelede olumlu yönde destek sağlamaktadır. Glutensiz diyet, bağırsak orası, immünolojik tepkive immünolojik ortam arasındaki ilişki, diyabetin ilerlemesini azaltmada belirleyici rol oynayabilir.

Anahtar kelimeler: Glutensiz diet, sitokinler, intestinal mikrobiota, asidik çevre, diabetes mellitus

Address for Correspondence: Evrim Çakır, Haseki Training and Research Hospital Department of Endocrinology and Metabolic Diseases, İstanbul, TurkeyPhone: 90 212 529 44 00 E-mail: [email protected] Received: 15.06.2016 Accepted: 21.09.2017


127ReviewDOI: 10.25179/tjem.2017-56528Turk J Endocrinol Metab 2017;21:127-130

immune reactions and gluten sensitive diseases. Gluten reactionshave recently been classified into three categories viz. allergic (wheatallergy), autoimmune (celiac disease, dermatitis herpetiformis, andgluten ataxia), and possibly immune-mediated (gluten sensitivity) (4).These reactions are perceived to be involved in the etiology of theunderlying basis of autoimmune and idiopathic disease.

TThhee GGlluutteenn--RRiicchh WWhheeaatt--FFlloouurr DDiieett aanndd DDiiaabbeetteess MMeelllliittuuss

The gluten-containing wheat-flour diet has been associated withan increased frequency of diabetes mellitus in animals. In non-di-abetic mice, feeding with wheat-flour diet increased the incidenceof diabetes mellitus and insulitis severity, whereas feeding with hy-drolyzed casein diet was found to reduce the incidence of diabetes.On the contrary, feeding a hypo-allergenic soybean-protein hy-drolysate resulted in an incidence of diabetes mellitus and insuli-tis severity similar to that of the soybean-meal-fed group. It isassumed that protein hydrolysis may not affect occurrence andseverity of diabetes (5). This study shows that feeding with thewheat-flour diet despite the presence of hydrolyzed protein playsa major role in the progression of diabetes. Concerning this study,mice fed on a wheat-based diet exhibited a higher incidence of di-abetes, the signs of small intestinal enteropathy and higher mu-cosal levels of pro-inflammatory cytokines (6). In addition,wheat-free and barley protein-free diet were also found to be as-sociated with reduced incidence and delayed onset of diabetes.Likewise, reduced insulin autoantibodies and lower insulitis scoreswere also recorded. Furthermore, the supplementation of fish-oil orvitamin D3 to the wheat-free diet did not provide any additionalbenefit toward subsiding the incidence of diabetes mellitus (7).These findings postulate that gluten content of wheat-based dietmight have been associated with the increased incidence of dia-betes.

EEvviiddeennccee ffoorr BBeenneeffiittss ooff GGlluutteenn--FFrreeee DDiieett OOtthheerr TThhaannDDiiaabbeetteess MMeelllliittuuss

A gluten-free diet has been exhibited to deliver positive health ben-efits in certain autoimmune disease including dermatitis herpeti-formis, neurological disorders, rheumatoid arthritis, along withother conditions such as diabetes mellitus, HIV-associated en-teropathy and celiac disease (8). In patients with IgA nephropathy, the average level of IgA was sig-nificantly declined in about 81.8% of cases with complete normal-ization in 63.6% patients after six months to one year of agluten-free diet (9).In a controlled case study, about 66 patients with active rheuma-toid arthritis (RA) were evaluated and randomly kept on either agluten-free vegan diet (38 patients) or a well-balanced non-vegandiet (28 patients) for one year. The improvement ratio of RA in thegluten-free vegan diet was 40.5%, against the 4% in the non-vegangroup after the stipulated follow up period. Furthermore, the levelsof immunoglobulin G (IgG) antibody against gliadin and beta-lac-toglobulin were found to be lower in the gluten-free vegan groupthan the non-vegan group (10).

Besides, in case of diseases with uncertain etiology, a gluten-freediet has also been shown to offer encouraging benefits. In a ques-tionnaire-based survey study, strictly gluten and/or casein-free dietwere also found to improve autism spectrum disorders (ASD) be-haviors, physiological symptoms, and social behaviors (p< 0.05).The study consists of a parental report of data collected on the ef-ficacy of the gluten-free and/or casein-free diet using a 90-itemonline questionnaire from 387 parents or primary caregivers of chil-dren diagnosed with ASD. Authors suggested that various factorsincluding gastrointestinal and immune system could play a role inresponse to diet interventions (11).Furthermore, the gluten-free diet has recently been used for man-agement of painful endometriosis-related symptoms. The VisualAnalogue Scale (VAS) was used to assess the painful symptomsfor dysmenorrhea, non-menstrual pelvic pain, and dyspareunia in207 patients. A significant improvement was recorded in painsymptoms in 156 patients (75%) after 12 months of diet. Interest-ingly, a substantial increase in the scores for all domains of physi-cal functioning, general health perception, vitality, socialfunctioning, and mental health was also recorded in all the pa-tients (12). The mechanism of pain-related symptoms might be re-lated to immune regulation of gut flora. It has been advocated thatgluten-free diet considerably contributes toward the improvementof immunological response and alleviation of immunological dis-eases severity.

IInntteessttiinnaall MMiiccrroobbiioottaa,, IImmmmuunnoollooggiiccaall MMiilliieeuu,, AAcciiddiicc ppHH WWaatteerr MMiilliieeuu,, aanndd GGlluutteenn--FFrreeee DDiieett

In animal models, a gluten-free diet has been associated with sup-pressing auto-inflammatory process, improving inflammatory cy-tokine secretion, and altering intestinal microbiota leading to apoor incidence of diabetes.Dietary habits have a profound effect on both intestinal microbiotaand glycemia. In non-obese diabetic mice, a gluten-containing dietwas found to increase the prevalence of hyperglycemia, while thegluten-free diet decreased it. Besides, the fecal microbiota wasalso found to change according to the dietary contents. Bifidobac-terium spp. were predominant in gluten-containing diet, whereasin gluten-free diet Akkermansia spp. were prevalent (13).The gluten-free diet has been associated with lower incidence anddelayed onset of diabetes after 320-day follow-up compared tostandard diet in mouse models (14).In an interim three-week observation study, 9 out of 19 (47%) non-obese diabetic mice on a standard diet developed diabetes, while1 out of 19 (5%) developed diabetes on a gluten-free diet. This re-duced diabetes occurrence could be attributed to the distinct fecalbacterial composition (15).It has been shown that mice on a gluten-free diet had lower in-sulitis along with lower expression of natural killer group 2D(NKG2D) on natural killer (NK) cells and CD8+ T cells in spleen, au-ricular lymph nodes and pancreas-associated lymph nodes (16).Alterations in intestinal microbiota have been indicated to reducethe risk of diabetes in mice. The authors suggested that progres-sion of type-1 diabetes to later stages might have been delayed byearly dietary management creating an acidic environment in ge-

Çakır et al. Turk J Endocrinol MetabGluten-Free Diet and Intestinal Microbiota in Diabetes Development 2017;21:127-130

128

netically predisposed individuals (17). In murine models with type-1 diabetes, the intestinal flora was shown to alter in favor of bac-teroids in comparison to healthy controls (18, 19). The modifiedcomposition of microflora apparently affects T cells especially in-terleukin–17 (IL-17) producing T helper (Th) and regulatory T cells(20–24). The T helper 17 (Th17) cells play a potential role in protect-ing the pathogens and inducing inflammation and autoimmunity(25–27), whereas regulatory T cells prevent inflammation and con-fer immune tolerance (25, 28, 29). Recent studies have reportedthat segmented filamentous bacteria played a crucial role in in-ducing Th17 cells localized in lamina propria of intestinal mucosaand lenfoid tissue (24, 30). Besides, increased IL-17 secreting T cellshave also been observed in newly started type–1 diabetes (31).Furthermore, the consumption of acidic water has also been re-ported to influence intestinal microbiota and the levels of Th17 andT regulatory cells. Such an alteration in the fluidic pH has also beenfound to be associated with reduced occurrence of diabetes (17).In a recent study, pregnant non-obese diabetic mice were fed ona gluten-free diet and their off-spring were marked with increasedAkkermansia and Probacteria species. Further, the gluten-free fedoffspring reportedly exhibited increased regulatory T cells and re-duced gene expression of intestinal pro-inflammatory cytokines.In fetal and early postnatal stages, the gluten-free diet has beenwitnessed to reduce the incidence of diabetes in mouse modelsand it has been suggested that an altered intestinal microbiotamay transform the intestinal and pancreatic immunological milieuto less inflammatory state (32).It has been shown that the gut microbiota, type-1 diabetes inci-dence and rate of disease progression are significantly affected bythe pH of water consumed. In acidic water, the transferred seg-mented filamentous bacteria suppressed the incidence of insulitisas well as type-1 diabetes in mice model (33).These animal models advocate that intestinal microbiota play adominant role in stimulating the immunological response, andacidic environment of intestine affects the gut microbiota and con-sequently alters the immunological status.

GGlluutteenn--FFrreeee DDiieett iinn HHuummaann SSttuuddiieess

The controlled and follow-up studies conducted in humans con-cerning gluten-free diet are scarce. In a recent study, 21 healthyvolunteers were subjected to a gluten-free diet and observed forfour weeks. After follow-up period, there was noticed a significantdifference in the gut microbiota, where the class of clostridia wassignificantly reduced (34).In human models, after a six-month of follow-up, the gluten-freediet did not affect autoantibody titers in individuals at high risk oftype–1 diabetes. However, diet showed a beneficial effect on in-sulin secretion in individuals at high risk for type–1 diabetes (35).This could also be due to the limited follow-up period.In a study carried out in Spain, about 10 healthy subjects werefollowed over a month on gluten-free diet. In fecal analyses,there was observed a significant reduction in Bifidobacteriumand Lactobacillus groups while the notable upsurge in Es-cherichia coli and Enterobacteriaceae. Likewise, in a cytokineanalysis following the gluten-free diet, titration of cytokines TNF-

α, IFN-ƴ, and the chemokine IL–8 were reported to decline sig-nificantly (36).In the light of recent evidence, the gluten-free diet may probablychange the gastric pH to the acidic leading to alteration in gut mi-crobiota and cytokine production cells. The acidic environment cou-pled with altered flora seems to reduce the diabetes incidenceassociated with a gluten-free diet.Although the human studies have revealed an association ofgluten-free diet with altered intestinal microbiota and improvementin inflammatory cytokines production. However, further studies arestill required to evaluate the correlation between gluten-free dietand intestinal microbiota composition and to determine their clin-ical benefits in a comprehensive manner.

CCoonncclluussiioonn

Diabetes mellitus displays an increasing prevalence throughout theworld. The consumption of floury foods containing gluten may beresponsible for the higher incidence of diabetes. The gluten-freediet has shown a beneficial effect on stimulating an immunologi-cal response in animal models and subsiding autoimmune dis-ease in human beings by altering the intestinal flora. Gastric pHand intestinal microbiota vary according to food consumption andthese alterations play important roles in abating the immunologi-cal dysregulation. In relation to these conclusions, the gluten-freediet has been revealed to reduce the incidence of diabetes in ani-mal models and improve insulin response in human beings. How-ever, further studies are still required to assess the cross-talksbetween gluten-free diet, gastric pH, intestinal microbiota and pro-gression of diabetes.


Concept: Evrim Cakir.Design: Evrim Cakir. Data Collection or Pro-cessing: Evrim Cakir. Analysis or Interpretation: Evrim Cakir. Litera-ture Search: Evrim Cakir, Esra Ataoglu, Mustafa Yenigun. Writing:Evrim Cakir, Esra Ataoglu, Mustafa Yenigun. Conflict of Interest: No conflict of interest was declared by the authors.Financial Disclosure: The authors declared that this study receivedno financial support.

References1. Balakireva AV, Zamyatnin AA. Properties of gluten intolerance: gluten

structure, evolution, pathogenicity and detoxification capabilities. Nu-trients. 2016;8.

2. Wieser H. Chemistry of gluten proteins. Food Microbiol. 2007;24:115-119.3. Biesiekierski JR. What is gluten? J Gastroenterol Hepatol. 2017;32:78-81.4. Sapone A, Bai JC, Ciacci C, Dolinsek J, Green PH, Hadjivassiliou M,

Kaukinen K, Rostami K, Sanders DS, Schumann M, Ullrich R, VillaltaD, Volta U, Catassi C, Fasano A. Spectrum of gluten-related disorders:consensus on new nomenclature and classification. BMC Med.2012;10:13.

5. Hoorfar J, Buschard K, Dagnaes-Hansen F. Prophylactic nutritionalmodification of the incidence of diabetes in autoimmune non-obesediabetic (NOD) mice. Br J Nutr. 1993;69:597-607.

6. Maurano F, Mazzarella G, Luongo D, Stefanile R, D'Arienzo R, Rossi M,Auricchio S, Troncone R. Small intestinal enteropathy in non-obese dia-betic mice fed a diet containing wheat. Diabetologia. 2005;48:931-937.

Turk J Endocrinol Metab Çakır et al.2017;21:127-130 Gluten-Free Diet and Intestinal Microbiota in Diabetes Development 129

7. Schmid S, Koczwara K, Schwinghammer S, Lampasona V, Ziegler AG,Bonifacio E. Delayed exposure to wheat and barley proteins reducesdiabetes incidence in non-obese diabetic mice. Clin Immunol.2004;111:108-118.

8. El-Chammas K, Danner E. Gluten-free diet in nonceliac disease. NutrClin Pract. 2011;26:294-299.

9. Coppo R, Roccatello D, Amore A, Quattrocchio G, Molino A, GianoglioB, Amoroso A, Bajardi P, Piccoli G. Effects of a gluten-free diet in pri-mary IgA nephropathy. Clin Nephrol. 1990;33:72-86.

10. Hafström I, Ringertz B, Spångberg A, von Zweigbergk L, BrannemarkS, Nylander I, Rönnelid J, Laasonen L, Klareskog L. A vegan diet freeof gluten improves the signs and symptoms of rheumatoid arthritis:the effects on arthritis correlate with a reduction in antibodies to foodantigens. Rheumatology (Oxford). 2001;40:1175-1179.

11. Pennesi CM, Klein LC. Effectiveness of the gluten-free, casein-free dietfor children diagnosed with autism spectrum disorder: based onparental report. Nutr Neurosci. 2012;15:85-91.

12. Marziali M, Venza M, Lazzaro S, Lazzaro A, Micossi C, Stolfi VM.Gluten-free diet: a new strategy for management of painful en-dometriosis related symptoms? Minerva Chir. 2012;67:499-504.

13. Marietta EV, Gomez AM, Yeoman C, Tilahun AY, Clark CR, Luckey DH,Murray JA, White BA, Kudva YC, Rajagopalan G. Low incidence ofspontaneous type 1 diabetes in non-obese diabetic mice raised ongluten-free diets is associated with changes in the intestinal micro-biome. PLoS One. 2013;8:e78687.

14. Funda DP, Kaas A, Bock T, Tlaskalová-Hogenová H, Buschard K.Gluten-free diet prevents diabetes in NOD mice. Diabetes Metab ResRev. 1999;15:323-327.

15. Hansen AK, Ling F, Kaas A, Funda DP, Farlov H, Buschard K. Diabetespreventive gluten-free diet decreases the number of caecal bacteriain non-obese diabetic mice. Diabetes Metab Res Rev. 2006;22:220-225.

16. Adlercreutz EH, Weile C, Larsen J, Engkilde K, Agardh D, Buschard K,Antvorskov JC. A gluten-free diet lowers NKG2D and ligand expres-sion in BALB/c and non-obese diabetic (NOD) mice. Clin Exp Immunol.2014;177:391-403.

17. Wolf KJ, Daft JG, Tanner SM, Hartmann R, Khafipour E, Lorenz RG.Consumption of acidic water alters the gut microbiome and de-creases the risk of diabetes in NOD mice. J Histochem Cytochem.2014;62:237-250.

18. Brown CT, Davis-Richardson AG, Giongo A, Gano KA, Crabb DB,Mukherjee N, Casella G, Drew JC, Ilonen J, Knip M, Hyöty H, VeijolaR, Simell T, Simell O, Neu J, Wasserfall CH, Schatz D, Atkinson MA,Triplett EW. Gut microbiome metagenomics analysis suggests a func-tional model for the development of autoimmunity for type 1 diabetes.PLoS One. 2011;6:e25792.

19. Giongo A, Gano KA, Crabb DB, Mukherjee N, Novelo LL, Casella G,Drew JC, Ilonen J, Knip M, Hyöty H, Veijola R, Simell T, Simell O, NeuJ, Wasserfall CH, Schatz D, Atkinson MA, Triplett EW. Toward definingthe autoimmune microbiome for type 1 diabetes. ISME J. 2011;5:82-91.

20. Atarashi K, Tanoue T, Shima T, Imaoka A, Kuwahara T, Momose Y,Cheng G, Yamasaki S, Saito T, Ohba Y, Taniguchi T, Takeda K, Hori S,Ivanov II, Umesaki Y, Itoh K, Honda K. Induction of colonic regulatoryT cells by indigenous Clostridium species. Science. 2011;331:337-341.

21. Chiba T, Seno H. Indigenous clostridium species regulate systemicimmune responses by induction of colonic regulatory T cells. Gas-troenterology 2011;141:1114-1116.

22. Ivanov II, Atarashi K, Manel N, Brodie EL, Shima T, Karaoz U, Wei D,Goldfarb KC, Santee CA, Lynch SV, Tanoue T, Imaoka A, Itoh K, TakedaK, Umesaki Y, Honda K, Littman DR. Induction of intestinal Th17 cellsby segmented filamentous bacteria. Cell. 2009;139:485-498.

23. Kriegel MA, Sefik E, Hill JA, Wu HJ, Benoist C, Mathis D. Naturallytransmitted segmented filamentous bacteria segregate with diabetesprotection in nonobese diabetic mice. Proc Natl Acad Sci U S A.2011;108:11548-11553.

24. Geem D, Medina-Contreras O, McBride M, Newberry RD, Koni PA,Denning TL. Specific microbiota-induced intestinal Th17 differentiationrequires MHC class II but not GALT and mesenteric lymph nodes. J Im-munol. 2014;193:431-438.

25. Bettelli E, Korn T, Oukka M, Kuchroo VK. Induction and effector func-tions of T(H)17 cells. Nature. 2008;453:1051-1057.

26. Yang Y, Torchinsky MB, Gobert M, Xiong H, Xu M, Linehan JL, AlonzoF, Ng C, Chen A, Lin X, Sczesnak A, Liao JJ, Torres VJ, Jenkins MK,Lafaille JJ, Littman DR. Focused specificity of intestinal TH17 cells to-wards commensal bacterial antigens. Nature. 2014;510:152-156.

27. Liang Y, Pan HF, Ye DQ. Tc17 cells in immunity and systemic autoim-munity. Int Rev Immunol. 2014;34:318-331.

28. Kim JM, Rasmussen JP, Rudensky AY. Regulatory T cells prevent cat-astrophic autoimmunity throughout the lifespan of mice. Nat Im-munol. 2007;8:191-197.

29. Lan Q, Fan H, Quesniaux V, Ryffel B, Liu Z, Zheng SG. Induced Foxp3(+)regulatory T cells: a potential new weapon to treat autoimmune andinflammatory diseases? J Mol Cell Biol. 2012;4:22-28.

30. Goto Y, Panea C, Nakato G, Cebula A, Lee C, Diez MG, Laufer TM, Ig-natowicz L, Ivanov II. Segmented filamentous bacteria antigens pre-sented by intestinal dendritic cells drive mucosal Th17 celldifferentiation. Immunity. 2014;40:594-607.

31. Marwaha AK, Crome SQ, Panagiotopoulos C, Berg KB, Qin H,Ouyang Q, Xu L, Priatel JJ, Levings MK, Tan R. Cutting edge: increasedIL-7-secreting T cells in children with new-onset type 1 diabetes. J Im-munol. 2010;185:3814-3818.

32. Hansen CH, Krych L, Buschard K, Metzdorff SB, Nellemann C, HansenLH, Nielsen DS, Frøkiær H, Skov S, Hansen AK. A maternal gluten-freediet reduces inflammation and diabetes incidence in the offspring ofNOD mice. Diabetes. 2014;63:2821-2832.

33. Sofi MH, Gudi R, Karumuthil-Melethil S, Perez N, Johnson BM, Vasu C.pH of drinking water influences the composition of gut microbiomeand type 1 diabetes incidence. Diabetes. 2014;63:632-644.

34. Bonder MJ, Tigchelaar EF, Cai X, Trynka G, Cenit MC, HrdlIckova B,Zhong H, Vatanen T, Gevers D, Wijmenga C, Wang Y, Zhernakova A.The influence of a short-term gluten-free diet on the human gut mi-crobiome. Genome Med. 2016;8:45.

35. Pastore MR, Bazzigaluppi E, Belloni C, Arcovio C, Bonifacio E, Bosi E.Six months of gluten-free diet do not influence autoantibody titers,but improve insulin secretion in subjects at high risk for type 1 dia-betes. J Clin Endocrinol Metab. 2003;88:162-165.

36. De Palma G, Nadal I, Collado MC, Sanz Y. Effects of a gluten-free dieton gut microbiota and immune function in healthy adult human sub-jects. Br J Nutr. 2009;102:1154-1160.

Çakır et al. Turk J Endocrinol MetabGluten-Free Diet and Intestinal Microbiota in Diabetes Development 2017;21:127-130

130

Introduction

Hepatomegaly and elevated liver enzymes in diabetic patientsmust be looked for in an orderly manner. Although the most com-mon cause of elevated liver enzymes in diabetic patients is ‘non-al-coholic fatty liver disease (NAFLD)’, glycogenic hepatopathy is oneof the other causes. Glycogenic hepatopathy may either exist aloneor in combination with other features, as a part of Mauriac Syn-

drome. A case of Mauriac Syndrome in a patient with poorly con-trolled type 1 diabetes mellitus (DM) has been presented in the fol-lowing case report.

Case

A 20-year-old male with type 1 DM was referred to the hospitalwith complaints of diarrhea, nausea, and vomiting since a few

131

MMaauurriiaacc SSyynnddrroommee:: CCaassee RReeppoorrtt aanndd RReevviieeww ooff tthhee LLiitteerraattuurreeMMaauurriiaacc SSeennddrroommuu:: OOllgguu SSuunnuummuu vvee LLiitteerraattüürrüünn GGöözzddeenn GGeeççiirriillmmeessii

İnönü University Faculty of Medicine, Department of Endocrinology and Metabolic Diseases, Malatya, Turkey *Tepecik Research and Training Hospital, Department of Internal Medicine, İzmir, Turkey

**Recep Tayyip Erdoğan University Faculty of Medicine, Department of Internal Medicine, Rize, Turkey

This is a case report of a young male with poorly controlled type 1 diabetes mellitus who presented with the clinical features of diabetic ke-toacidosis. Once the patient was stabilized, he was examined for hepatomegaly and elevated liver enzymes. Along with the other clinicalfeatures, the patient was diagnosed as a case of Mauriac Syndrome. Mauriac Syndrome, initially described by Mauriac in 1930, is one ofthe causes of hepatomegaly and elevated liver enzymes in poorly controlled diabetic patients. However, hepatomegaly, growth retarda-tion and other clinical features of the syndrome have been found to be reversible with optimization of insulin therapy. In patients with po-orly controlled diabetes, Type 1 diabetic patients must be closely observed for sexual maturation and growth. After optimal therapy hasbeen given, close follow-up is essential to observe the regression of clinical features.Keywords: Mauriac syndrome, hepatic glycogenosis, type 1 diabetes mellitus.

Diyabetik ketoasidozun klinik bulgularıyla prezente olan kötü kontrollü tip 1 diabetes mellitus tanılı genç bir erkek hastayı sunuyoruz. Hastastabilize edildikten sonra, hepatomegali ve artmış karaciğer enzimleri açısından incelendi. Diğer klinik bulgular eşliğinde, hastaya Mau-riac sendromu tanısı koyuldu. Mauriac sendromu ilk olarak 1930’da Mauriac tarafından tanımlanmıştır ve kötü kontrollü diyabetik hasta-lardaki hepatomegali ve karaciğer enzim yüksekliği sebeplerinden biridir. Hepatomegali, büyüme geriliği ve sendromun diğer klinikbulgularının insulin tedavisinin optimizasyonu ile geri dönebildiği bilinmektedir. Kötü kontrollü diyabet hastalarında, hastalar cinsel matü-rasyon ve büyüme gelişme açısından yakından izlenmelidir. Optimal tedavi verildikten sonra, klinik bulguların regresyonunu izlemek açı-sından yakın takip elzemdir.Anahtar kelimeler: Mauriac sendromu, hepatik glikogenoz, Tip 1 diabetes mellitus

Address for Correspondence: Ömercan Topaloğlu, Inonu University Faculty of Medicine, Department of Endocrinology and Metabolic Diseases, Malatya, Turkey

Phone: 90 422 341 06 60 E-mail: [email protected] Received: 20.01.2016 Accepted: 27.03.2017


131Case ReportDOI: 10.25179/tjem.2017-56496Turk J Endocrinol Metab 2017;21:131-135

days. The stool of the patient was brownish and did not containmucus or blood. Fever, weakness, and anorexia were some of theother symptoms. The patient also complained of morning fastinghypoglycemia episodes for a long time. The patient was diagnosedwith type 1 DM in childhood and had suffered from the same sincelast 11 years; he also presented with diabetic ketoacidotic coma.The patient has been on intensive insulin regimen since the time hewas diagnosed with DM. No other autoimmune diseases or com-plications of diabetes could be seen in the patient. The patient wasnot on any other medication.Physical examination revealed that the patient had body temper-ature 37.6 °C, pulse rate was found to be 138 beats/min, bloodpressure was noted to be 86/40 mmHg, body weight was 45 kgand height was 155 cm. He had protuberant abdomen, moon face,and diminished beard. The liver was non-tender, has smooth mar-gins and was palpable at 12 cm from the right costal margin at themidclavicular line. Splenomegaly and ascites were not found. Nopalmar erythema, spider angiomata, leg edema, petechia or pur-pura were found. Examinations of the other systems did not revealany remarkable findings.Laboratory analysis showed that venous plasma glucose was 348mg/dL, urine ketone was moderately positive; arterial blood gasanalysis was observed to be compatible with metabolic and lacticacidosis. Biochemical analysis revealed increased ALT (184 U/L),AST (167 U/L), gamma-GT (180 U/L) and ALP (140 U/L) levels (Table1). The patient was diagnosed with diabetic ketoacidosis and ap-propriate fluid, electrolyte, and insulin protocol were followed. In-tensive insulin regimen and diet therapy were initiated once thepatient was stable. During the follow up of the patient, serum cal-cium, and phosphorous levels were found to be more than theupper limits of normal. The reason for these increments could notbe detected and the patient was followed up further.Ultrasonography of the abdomen revealed hepatomegaly (verticallength 175 millimeters) and increased liver parenchymalechogenicity compatible with grade 1 steatosis; the kidneys werefound to be normal in terms of size and echogenicity. Serologicalfindings (positive anti-HBs 922.07 mIU/mL, and anti-HBc; negativeHBs) suggested recovery from hepatitis B infection. Other viral andparasitic markers were found to be negative (anti-HAV, anti-HCV,anti-HIV 1, anti-HIV 2, anti-rubella IgM, anti-CMV IgM, EBV VCA IgM,parvovirus B19 IgM, anti-toxoplasma IgM and IgG). Autoimmunehepatitis markers such as antinuclear antibody, anti-smooth-muscle antibody, anti-liver-kidney-muscle, antimitochondrial anti-body were negative. Thus, any possible infectious hepatitis,autoimmune hepatitis, and primary biliary cirrhosis were excluded.Ophthalmological examination revealed no findings of Kayser-Fleischer ring or diabetic retinopathy. Ferritin (90 ng/mL) andalpha1-antitrypsin (1.1 g/L; normal range 0.9–2) were found to bein the normal range. No corresponding signs or symptoms of amy-loid organ infiltration or Gaucher disease were seen.Possible diagnoses included nonalcoholic steatohepatitis, primary(congenital) glycogen storage disease, and secondary glycogenstorage disease. To demonstrate hepatic glycogen or fat deposi-tion, liver biopsy was performed. The liver biopsy revealed PAS-positive granules in enlarged hepatocytes, indicating the presence

of glycogen deposition. The presence of combined clinical findingssuch as hepatomegaly, elevated liver enzymes, hepatic glycogendeposition, hyperlipidemia, Cushingoid features, and short statureled to the diagnosis of Mauriac syndrome probable. On the basisof this diagnosis, the hormonal analysis was also performed. Totaltestosterone was found to be 126 ng/dL (262 to 1593), LH was 0.86mIU/mL (0.8 to 7.6), FSH was 2.99 mIU/mL (0.7 to 11.1), IGF–1 was120 ng/mL (182 to 780), cortisol was 30.2 mcg/dL (5.0 to 25) andACTH was observed to be 21.7 pg/mL (0 to 46). Radiographical ex-amination of the left wrist revealed that the bone age was 14. Thelaboratory and radiological findings demonstrated hypogo-nadotropic hypogonadism and growth retardation, suggestingMauriac syndrome. Genetic analysis was also performed to ex-clude congenital glycogen storage disease type 1 (GSD–1). Het-erozygote mutation (17q21, p.R83C) in glucose-6-phosphatasegene was found in the patient. Although it is known that the carri-ers of GSD–1 are asymptomatic, the existence of GSD–1 carrier sta-tus may contribute to hepatic glycogen deposition in a patient withMauriac syndrome.

Discussion

Glycogenic hepatopathy was first described by Mauriac (1) in 1930as “hepatic glycogenosis”, in children affected with brittle diabetes,

Topaloğlu et al. Turk J Endocrinol MetabMauriac Syndrome: Case Report 2017;21:131-135

132

Test On admission 1 day later 12 days later Reference value

Glucose 292 57 276 74–106 mg/dL

Urea 44 7 39 17–43 mg/dL

Creatinine 1.3 0.6 0.7 0.8–1.3 mg/dL

Uric acid 3.6 4.7 3.5–7.2 mg/dL

Cholesterol 217 302 110–199 mg/dL

Triglyceride 208 268 30–199 mg/dL

HDL-cholesterol 34 52 40–85 mg/dL

LDL-cholesterol 141 196 62–129 mg/dL

AST 167 160 55 1.0–35 U/L

ALT 184 132 64 0–45 U/L

ALP 180 221 30–120 U/L

Gamma-GT 140 120 0–55 U/L

LDH 264 239 0–248 U/L

CK 27 33 21 0–171 U/L

T.Bilirubin 0.5 0.5 0.32 0.3–1.2 mg/dL

D.Bilirubin 0.1 0.1 0.06 0.0–0.2 mg/dL

Protein 5.77 7.4 6.6–8.3 g/dL

Albumin 3.6 4.5 3.5–5.2 g/dL

Globulin 2.17 2.9 2.3–3.5 g/dL

Na 138 138 137 136–145 mmol/L

K 3.7 3.8 4.64 3.6–5.1 mmol/L

Cl 95 102 95 96–110 mmol/L

Ca 9.9 9.1 10.9 8.8–10.6 mg/dL

P 3.1 5.4 2.5–4.5 mg/dL

Ferritin 90 10–160 ng/mL

HbA1c 10.34 4–6%

Table 1. Biochemical test results of the patient.

Cushingoid features, poor growth, and hyperlipidemia. Hence thesyndrome was named as Mauriac syndrome. Later then, the re-ports showed the presence of hepatic glycogenosis without otherfeatures of the syndrome (2).The pathophysiologic process of glycogenic hepatopathy involvestwo components: hyperglycemia and overinsulinization.2 In pa-tients with poorly controlled type 1 DM, hyperglycemia increasesthe need for insulin. When insulin is administered to the patient inhigher amounts, more quantities of active glycogen synthase areactivated by the insulin. Increased activation of enzyme promoteshepatic glycogen storage by conversion of glucose-1-phosphate toglycogen. Because the entry of glucose into the liver via GLUT–2mechanism is insulin independent, hyperglycemia itself also initi-ates glycogen synthesis. In some instances, glycogen could alsobe stored in kidneys causing nephromegaly. Although the mostwell-known cause of acquired glycogenic hepatopathy is uncon-trolled type 1 DM, uncontrolled type 2 DM and use of corticosteroidsmay also cause this type of glycogenic hepatopathy. In glycogenichepatopathy, hypercortisolism also contributes to glycogen stor-age in the liver (3), as was evident in this patient. Hypercortisolismalso causes delay in sexual maturation and growth in patients withMauriac syndrome (3).Glycemic fluctuations may also cause hepatic glycogenosis, dueto the discrepancy between insulin and glucose levels in the blood.The most common cause of these fluctuations is uncontrolled dia-betes mellitus. This patient also exhibited glycemic excursions inthe hospital. These two clinical features caused the glycogenic he-patopathy in the patient. Resnick et al. reported Dumping syn-drome as a cause of acquired glycogenic hepatopathy, in a2-year-old male patient who had undergone fundoplication andwas fed by gastrostomy; he presented no evidence of congenitalglycogen storage disease, diabetes mellitus, or corticosteroid use(4). From the point of view that glycemic oscillations in Dumpingsyndrome could lead to glycogenic hepatopathy, the authors sup-pose that glycemic undulations in diabetic gastroparesis could alsoresult in glycogenic hepatopathy. There are no studies in the liter-ature depicting the relationship between diabetic gastroparesisand acquired glycogenic hepatopathy in diabetic patients.It is important to distinguish Nonalcoholic Steatohepatitis (NASH)from glycogenic hepatopathy. NASH warrants weight loss, correc-tion of hyperglycemia, improvement of hypertriglyceridemia andtherapy using insulin-sensitizing agents and ursodeoxycholic acid(5). However, in glycogenic hepatopathy, glycemic control by ad-equate intensive insulin regimen reverses the condition of glyco-gen deposition and hepatomegaly. Although glycogenichepatopathy does not progress to cirrhosis (6-8). NASH is an es-tablished cause of cirrhosis and is frequently diagnosed worldwide(5). The chief means of distinguishing between NASH and glyco-genic hepatopathy is a liver biopsy. However, in case glycogenichepatopathy is highly suspected, the empirical therapy for regu-lation of glycemic control could be initiated and biopsy may not bea necessity. However, both, glycogenosis and steatosis may existsimultaneously in the same patient as reported in some cases (9).Whenever a type 1 DM patient presents with hepatomegaly or el-evated serum liver enzymes, the differential diagnosis should in-

clude the classic causes of liver damage and hepatomegaly. How-ever, insulin-reversible hepatic glycogenosis should be thought inpriority, especially in the patients with uncontrolled type 1 diabetes.Insulin-reversible hepatic glycogenosis is the most common causeof hepatomegaly and raised serum liver aminotransferase levels inchildren and adolescents with type 1 DM (10). Nevertheless, ele-vated liver enzymes do not predict the presence or the extent ofglycogenosis (6). The other major cause of hepatomegaly in dia-betic patients is steatosis, and thus the distinction between steato-sis and glycogenosis is important and obligatory. Ultrasonographicexamination cannot reliably distinguish between these two condi-tions, as is evident in the present patient, where ultrasonographyof abdomen showed increased echogenicity compatible withgrade 1 steatosis, but a liver biopsy revealed only glycogen stor-age. For this reason, the distinction between steatosis andglycogenosis in a patient with uncontrolled diabetes and he-patomegaly obligates liver biopsy (6). However, according to someauthors liver biopsy should be reserved for patients with persist-ently elevated liver enzymes despite metabolic control (11).In patients with Mauriac syndrome, all the clinical features regresswith optimum insulin therapy and strict control of blood glucoselevels. During follow up, in patients with glycogenic hepatopathy,,hepatomegaly and elevated liver enzymes generally return to nor-mal with tight metabolic control of four weeks (10,12). In this pa-tient, hepatomegaly and elevated liver enzymes returned to normalafter four weeks of discharge. In a patient with type 1 DM, if he-patomegaly persists for a period longer than four weeks, other rea-sons must be investigated (12). In another case report it was seenthat with optimum insulin therapy, the clinical and biochemicalmanifestations of three patients with glycogenic hepatopathy re-versed within two weeks (3).Other features of the syndrome also regress with insulin treatment,though it takes more time. One of the signs of Mauriac syndromeis growth failure. Mauras et al. investigated the mechanisms in-volved in growth failure in two patients with Mauriac syndrome (13).No hypothalamic-pituitary dysfunction was observed in them.However, in the patient involved in the present study, both de-creased IGF–1 levels and hypercortisolism led to growth failure.Growth failure also regresses with adequate insulin treatment inpatients with Mauriac syndrome (14). For this reason, growth andpubertal maturation in patients with type 1 DM must be monitoredclosely, with optimal therapy.Pubertal delay in Mauriac syndrome can also be reversed by pro-viding optimal insulin therapy. Traisman et al. followed up a femalepatient diagnosed with Mauriac syndrome for 22 years and foundthat although delayed sexual development was present shedemonstrated two successful pregnancies (15). The laboratory re-sults of the patient involved in the present case revealed hypogo-nadotropic hypogonadism. An aggressive treatment with insulinmay result in the deterioration of retinopathy and nephropathy inpatients with Mauriac syndrome (14).In type 1 DM patients indicated for pancreatic transplantation,transplantation has been found to improve glycemic control andreduce diabetic complications; although a number of complica-tions belonging to transplantation itself may ensue. Whether or not

Turk J Endocrinol Metab Topaloğlu et al.2017;21:131-135 Mauriac Syndrome: Case Report 133

the pancreatic transplantation is efficient in Mauriac syndrome hasnot yet been well established. Maia et al. reported that the clinicaland biochemical derangements of a patient with Mauriac syn-drome had improved after pancreatic transplantation (16). Hence,pancreatic transplantation may be considered as an option for pa-tients with Mauriac syndrome.The pathophysiological process could ensue at any time after di-agnosis of type 1 DM (6,17). In the present patient, hepaticglycogenosis was determined 11 years after the diagnosis of type1 DM. However, a case report of two patients with type 1 DM re-vealed a clinical picture of hepatic glycogenosis with the presen-tation of type 1 DM, after supraphysiological doses of insulin wereadministered (17). Though hepatic glycogenosis has classicallybeen described in patients with type 1 DM, it may also be diag-nosed in type 2 diabetic patients who are using higher quantitiesof insulin or are incompatible with diet. Another case report ofglycogenic hepatopathy in a patient with type 2 diabetes mellituswas published (18).In cases of glycogenic hepatopathy, serum liver enzymes are mildto moderately elevated. In the patient involved in the present casereport, alanine aminotransferase and aspartate aminotransferaselevels were elevated four and a half times the upper limit of normal.Torbenson et al. showed that in patients with glycogenic he-patopathy, the level of liver transaminases could be dramatically el-evated, up to ten times the upper limit of normal (7). Liver syntheticfunction is generally preserved in patients with glycogenic he-patopathy as was event in the patient involved in the present casereport (6).Hypoglycemia may occur in patients with type 1 DM, because ofthe course of diabetes, aggressive treatment, or blunted counter-regulatory hormone response. When the episodes of hypo-glycemia are observed in a patient with type 1 DM andhepatomegaly, congenital glycogen storage diseases(GSD) shouldalso be considered as differential diagnoses. In this patient, GSD1awas considered as a differential diagnosis, owing to the existenceof hypoglycemic episodes, hepatomegaly, lactic acidosis, growthretardation, hyperlipidemia, and hepatic glycogenosis. Lei et al.showed that most frequent mutations of G6P gene are R83C (37%)and Q347X (22%) as observed in 70 patients previously diagnosedas GSD1a by the lack or greatly reduced activity of G6Pase activityin liver biopsy specimens. Including other less common mutationsin that study, 11 of 70 patients carried only one mutant allele;; oneof the Jewish patients was heterozygous for R83C mutation (19).Accordingly, in the patient, in the present case report, whether het-erozygous R83C mutation would contribute to hepatic glycogeno-sis and other clinical features is debatable. The authors agree thatthe clinical features of the patient in the present case report werecompatible with Mauriac syndrome and associated secondary he-patic glycogenosis owing to hepatomegaly, lactic acidosis and thelack of neonatal history of hypoglycemia and initiation of clinicalfeatures with puberty.Tomihira et al. reported the occurrence of hepatic glycogenosis ina female with type 1 DM admitted with diabetic ketoacidosis (20).Due to recurrence of marked hepatomegaly and elevated livertransaminases with the concurrence of hypoglycemic episodes,

they supposed the partial deficiency of liver glycogen phosphory-lase activity and analyzed the PYGL gene. The nucleotide se-quence of the gene was observed to be heterozygous forsubstitutions at positions Asp339 on exon 9 and Ala703 on exon17. They concluded that the structure of PYGL coding sequence inthat patient was unlikely to cause liver glycogenosis. Therefore, inpatients with diabetes and hepatic glycogenosis, the clinical deci-sion of whether the glycogenosis is primary or secondary must bedone at first. This could be followed by genetic analysis in case,the history supports congenital glycogen storage disease and clin-ical suspicion is high.

Conclusion

As soon as hepatomegaly and elevated liver enzymes are detectedin diabetic patients, detailed history and physical examination mustbe carried out. Glycogenic hepatopathy should be considered, es-pecially in patients with poorly controlled type 1 DM. If other clini-cal features accompany, Mauriac syndrome may be suspected.In a diabetic patient with glycogenic hepatopathy or Mauriac syn-drome, the clinical features regress with optimization of insulintherapy, and the follow-up of the patient in regard to glycemic con-trol and other clinical features is obligatory. In patients with type 1DM, growth and pubertal maturation should be closely monitored,as growth failure and pubertal maturation delay could be the pre-senting features of Mauriac Syndrome.Hence, as in all diabetic patients, patient education is essential, es-pecially for the reversibility of clinical features with optimal insulintherapy, so is in Mauriac Syndrome.


Concept: Ömercan Topaloğlu, Design: Sibel Demiral Sezer, Data Col-lection or Processing: Derya Akarken, Analysis or Interpretation: Ömer-can Topaloğlu, Literature Search: Ömercan Topaloğlu, Writing:Ömercan Topaloğlu. Conflict of Interest: No conflict of interest is declared by the authors. Financial Disclosure: The authors declared that this study received nofinancial support.

RReeffeerreenncceess

1. Mauriac P. Gros ventre, hepatomegalie, troubles de la croissancechez les enfants diabetiques traites depuis plusieurs annes par l’in-suline. Gaz Hebd Med Bourdeaux. 1930;26:402-410.

2. Rogal SS, Ukomadu C, Levy BD, Loscalzo J. Clinical problem-solving.A sweet source of abdominal pain. N Engl J Med. 2011;364:1762-1767.

3. Flotats Bastardas M, Miserachs Barba M, Ricart Cumeras A,Clemente León M, Gussinyer Canadell M, Yeste Fernández D, AlbisuAparicio MA, Carrascosa Lezcano A. [Hepatomegaly due to glyco-gen storage disease and type 1 diabetes mellitus]. An Pediatr (Barc).2007;67:157-160.

4. Resnick JM, Zador I, Fish DL. Dumping syndrome, a cause of acquiredglycogenic hepatopathy. Pediatr Dev Pathol. 2011;144:318-321.

5. Smith BW, Adams LA. Nonalcoholic fatty liver disease and diabetesmellitus: pathogenesis and treatment. Nat Rev Endocrinol.2011;78:456-465.

6. Chatila R, West AB. Hepatomegaly and abnormal liver tests due toglycogenosis in adults with diabetes. Medicine (Baltimore).1996;75:327-333.

Topaloğlu et al. Turk J Endocrinol MetabMauriac Syndrome: Case Report 2017;21:131-135

134

7. Torbenson M, Chen YY, Brunt E, Cummings OW, Gottfried M, JakateS, Liu YC, Yeh MM, Ferrell L. Glycogenic hepatopathy: an underrec-ognized hepatic complication of diabetes mellitus. Am J Surg Pathol.2006;30:508-513.

8. von Sengbusch A, Tannapfel A, Klein HH, Hering S. [Hepatomegalyund elevated transaminases in a 24 year-old with type 1 diabetesmellitus]. Internist (Berl). 2010;51:84-87.

9. Shrivastava MS, Palkar AV, Padwal NJ, Moulick N. Reversible steato-hepatosis in a young boy with brittle type 1 diabetes mellitus: mau-riac syndrome. BMJ Case Rep. 2011;2011. pii: bcr0320113975.

10. Munns CF, McCrossin RB, Thomsett MJ, Batch J. Hepatic glycogeno-sis: reversible hepatomegaly in type 1 diabetes. J Paediatr ChildHealth. 2000;36:449-452.

11. Dios Fuentes E, Serrano Romero M, García García-Doncel L, GonzálezDuarte D. Hepatic involvement in a teenager with type 1 diabetes andpoor metabolic control. Endocrinol Nutr. 2008;55:230-233.

12. Abaci A, Bekem O, Unuvar T, Ozer E, Bober E, Arslan N, Ozturk Y,Buyukgebiz A. Hepatic glycogenosis: a rare cause of hepatomegaly intype 1 diabetes mellitus. J Diabetes Complications. 2008;225:325-328.

13. Mauras N, Merimee T, Rogol AD. Function of the growth hormone-insulin-ike growth factor 1 axis in the profoundly growth-retarded di-abetic child: evidence for defective target organ responsiveness inthe Mauriac syndrome. Metabolism. 1991;4010:1106-1111.

14. Kim MS, Quintos JB. Mauriac syndrome: growth failure and type 1 di-abetes mellitus. Pediatr Endocrinol Rev. 2008;5:989-993.

15. Traisman HS, Traisman ES. Mauriac’s syndrome revisited. Eur J Pedi-atr. 1984;142:296-297.

16. Maia FF, Araújo LR. [Pancreas transplantation in Mauriac syndrome:clinical and biochemical parameters after one year follow up]. ArqBras Endocrinol Metabol. 2005;49:455-459.

17. Carcione L, Lombardo F, Messina MF, Rosano M, De Luca F. Liverglycogenosis as early manifestation in type 1 diabetes mellitus. Dia-betes Nutr Metab. 2003;163:182-184.

18. Nakamuta M, Ohashi M, Goto K, Tanabe Y, Hiroshige K, Nawata H.Diabetes mellitus-associated glycogen storage hepatomegaly: re-port of a case and review of the Japanese literature. Fukuoka IgakuZasshi. 1993;84:354-358.

19. Lei KJ, Chen YT, Chen H, Wong LJ, Liu JL, McConkie-Rosell A, Van HoveJL, Ou HC, Yeh NJ, Pan LY. Genetic basis of glycogen storage diseasetype 1a: prevalent mutations at the glucose-6-phosphatase locus. AmJ Hum Genet. 1995;57:766-771.

20. Tomihira M, Kawasaki E, Nakajima H, Imamura Y, Sato Y, Sata M,Kage M, Sugie H, Nunoi K. Intermittent and recurrent hepatomegalydue to glycogen storage in a patient with type 1 diabetes: geneticanalysis of the liver glycogen phosphorylase gene (PYGL). DiabetesRes Clin Pract. 2004;65:175-182.

Turk J Endocrinol Metab Topaloğlu et al.2017;21:131-135 Mauriac Syndrome: Case Report 135

136

Introduction

Acromegaly is a rarely occurring disease that is caused due to ex-cessive secretion of the growth hormone (GH), usually by a benignpituitary tumor. Fertility is commonly impaired in the patients withacromegaly as a result of the following: hypopituitarism and a re-duced gonadotropin reserve, either due to the destruction of go-nadotropic cells or due to the compression of gonadotropic cellsand the pituitary stalk, which results in hypothalamic-pituitary-

ovarian axis dysfunction; co-secretion of prolactin and growth hor-mone by a mixed GH-prolactin (PRL) adenoma; or excessive GH/in-sulin-like growth factor 1 (IGF-1) secretion, sensitizing the ovaries togonadotropin stimulation (1, 2).Multiple treatment options are available for acromegaly, includingsurgery, radiotherapy and medical treatment. Pregnancy inacromegalic patients will become more frequent with the im-provement in treatment modalities. There are limited data avail-able regarding the pregnancies in acromegalic patients; although,

AAccrroommeeggaallyy aanndd PPrreeggnnaannccyy:: FFiivvee NNeeww CCaasseessAAkkrroommeeggaallii vvee GGeebbeelliikk:: BBeeşş YYeennii VVaakkaa

Düzce University Faculty of Medicine, Department of Endocrinology and Metabolism, Düzce, Turkey*Dicle University Faculty of Medicine, Department of Endocrinology and Metabolism, Diyarbakır, Turkey

**Atatürk University Faculty of Medicine, Department of Endocrinology and Metabolism, Erzurum, Turkey

Pregnancy is a rare occurrence in acromegalic patients because of impaired fertility due to the disease. There are limited data availableregarding pregnancy in acromegalic patients; although, it appears that the patients are usually able to carry their pregnancies to full term.In addition, certain metabolic effects of acromegaly need to be considered as they can be harmful to both mother and fetus. The discon-tinuation of the medical treatment is usually recommended as the effects of medical treatment are unclear. Herein, we report ve new casesof pregnancies in acromegalic patients who had undergone surgery and medical treatment for macroadenoma, before the onset of preg-nancy, from different centers. Two of them had received radiotherapy after the surgery. None of the patients in our study were treated forpregnancy; however, two of them were receiving octreotide when the diagnosis of pregnancy was established. The medical treatment ofthese two patients was discontinued at the beginning of pregnancy. Four patients delivered healthy babies, and therapeutic abortion wasperformed at the sixth week of pregnancy to one of the patients who was being treated with octreotide before the pregnancy. Out of theve patients in our study, two had pregestational diabetes and one had hypertension. As a conclusion, it can be said that pregnancy inacromegalic patients is usually uneventful without any treatment throughout the pregnancy. Keywords: Acromegaly; pregnancy; medical therapy

Gebelik, akromegalik hastalarda bozulmuş fertilite nedeni ile nadir görülür. Gebelik sırasında akromegaliye yaklaşım konusunda sınırlısayıda veri olmasına rağmen genellikle hastaların gebeliklerinin term doğumla sonuçlandığı görülmektedir. Ek olarak akromegalinin farklımetabolik etkileri, anne ve fetusa zarar verebileceğinden, göz önünde bulundurulmalıdır. Medikal tedavinin etkileri net olmadığından sık-lıkla tedavinin kesilmesi önerilir. Burada farklı merkezlerden elde edilen veriler ile gebelik öncesi makroadenom nedeni ile cerrahi ve me-dikal tedavi uygulanmış 5 akromegalik hastada yeni gebelik vakaları sunduk. Bunlardan iki hastaya operasyon sonrası radyoterapiuygulanmıştı. Hastalarımızdan hiçbirine gebelik için tedavi uygulanmamıştı, fakat iki tanesi gebelik saptandığında oktreotid tedavisi al-maktaydı. Bu iki hastanın medikal tedavisi gebelik başlangıcında kesildi. Dört hasta sağlıklı bebekler doğurdu ve oktreotid tedavisi alan has-talardan birine altıncı haftada terapötik abortus uygulandı. Beş hastamızdan iki tanesinde pregestasyonel diyabet, bir tanesinde ayrıcahipertansiyon saptandı. Sonuç olarak akromegalik gebelerde hiçbir medikal tedavi uygulanmaksızın komplikasyonsuz gebelik gerçekle-şebileceği söylenebilir.Anahtar kelimeler: Akromegali; gebelik; medikal tedavi

Address for Correspondence: Tuba Soysal, Düzce University Faculty of Medicine, Department of Endocrinology and Metabolism, Düzce, Turkey

Phone: +90 533 7277212 E-mail: [email protected] Received: 22.01.2016 Accepted: 22.05.2016


Case ReportDOI: 10.25179/tjem.2017-56497


it appears that the patients are usually able to carry their preg-nancies to full term. On the other hand, the reported data have re-vealed that GH-secreting tumors may enlarge symptomaticallyduring pregnancy (3). In addition, GH and IGF-1 levels change con-troversially during the pregnancy; however, in the majority of thecases, tumor growth is not observed (3-6). Certain metabolic effects of acromegaly, such as diabetes mellitusand hypertension due to the elevated levels of GH and IGF-1, needto be considered as they can be harmful to both mother and fetus.Limited data are available regarding the management ofacromegaly during pregnancy. Therefore, the effects of medicaltreatment are unclear. Here, we report five new cases of preg-nancies in acromegalic patients and share our observations re-garding pregnancy in acromegalic patients.

Case Reports

CCaassee 11

A 28-year-old female patient was diagnosed with acromegaly atage 22. She underwent transsphenoidal surgery for macroadenomathree times and received postoperative pituitary gamma knife ra-diotherapy. She was treated with octreotide and cabergoline. Sixyears later, she became pregnant. Her treatment drugs were thendiscontinued. She did not receive any treatment for pregnancy. Inher obstetric history, there had been a live birth. In addition, she hadbeen diagnosed with diabetes mellitus and hypothyroidism in herpast medical history. Before pregnancy, her serum GH was 4.26ng/mL, and IGF-1 was 472 ng/mL (normal range: 117-329 ng/mL).She had pregestational diabetes; however, she did not develop ar-terial hypertension and visual field abnormality during the preg-nancy. She delivered a normal, healthy infant by cesarean sectionat 38 weeks of pregnancy. The weight of the baby was 3.1 kg, andhe did not have any congenital anomaly. Postpartum first-month GHand IGF-1 levels were 1.67 ng/mL and 381 ng/mL, respectively.

CCaassee 22

A 31-year-old female patient was operated by transsphenoidal ap-proach for a macroadenoma that measured 32 mm in diameter,four years ago. She received octreotide and cabergoline. She hada diagnosis of pregnancy, following which the medical treatmentfor acromegaly was discontinued. She did not receive any treat-ment for pregnancy. Before pregnancy, the serum GH level was3.58 ng/mL, and the IGF-1 level was 370 ng/mL (normal range: 117-329 ng/mL). At 11, 22 and 30 weeks of pregnancy, the GH levelswere 3.71, 3.36 and 3.09 ng/mL, respectively; and the IGF-1 levelswere 240, 165 and 165 ng/mL, respectively. Her pregnancy wasuncomplicated. She did not develop hypertension or gestationaldiabetes, and her visual field examination results were normal. Shedelivered a normal, full-term infant by cesarean section. The babywas healthy and her weight was 2.9 kg.

CCaassee 33

A 40-year-old female patient, who had previously given birth tothree healthy children, was diagnosed with acromegaly five yearsago. She underwent transsphenoidal resection of macroadenomatwice; the first surgery was performed in 2009, and the second one

in 2011. Pituitary magnetic resonance imaging (MRI) revealed a re-current adenoma, 12x10x10 millimeter in size. She received post-operative gamma knife radiation. She also received lanreotide andcabergoline. She was diagnosed with pregnancy without any treat-ment and the drugs were discontinued. The mean serum-GH levelwas 8.01 ng/mL, and the mean IGF-1 level was 279 ng/mL (normalrange: 117-329 ng/mL), between 32 and 36 weeks of pregnancy.She had been diagnosed with diabetes mellitus, hypertension, andhypothyroidism in her past medical history. She had pregestationaldiabetes and her visual field examination results were normalthroughout the pregnancy. She underwent a cesarean section at37.5 weeks of pregnancy and delivered a healthy, 2.9 kg baby.Postpartum first-month GH and IGF-1 levels were 28.5 ng/mL and1380 ng/mL, respectively. MRI revealed a recurrent adenoma,14x11x10 millimeter in size.

CCaassee 44

A 43-year-old female patient, the mother of two children, was di-agnosed with acromegaly at age 38. A pituitary MRI revealed amacroadenoma, 11x10 millimeter in size. She underwent transsphe-noidal surgery. Octreotide was prescribed to her as the medicaltreatment for acromegaly. Postoperative MRI revealed a residualadenoma, 6 � 4 millimeter in size. She became pregnant and hermedical treatment was discontinued. Before pregnancy, the serumGH level was 0.4 ng/mL, and the IGF-1 level was 100 ng/mL (normalrange: 117-329 ng/mL). In the sixth week of pregnancy, therapeuticabortion was performed to the patient with her consent.

CCaassee 55

A 28-year-old female patient was diagnosed with acromegaly,and adenoidectomy was performed for a 14x10 millimetermacroadenoma by the transsphenoidal approach, four years ago.After the surgery, she was treated with octreotide, at a dose of 10mg. She became pregnant while she was being treated with oc-treotide. She did not receive any treatment for pregnancy and oc-treotide was discontinued for the rest of the pregnancy. Beforepregnancy, the serum GH level was 9.3 ng/mL, and the IGF-1 levelwas 177 ng/mL (normal range: 117-329 ng/mL). At six months ofpregnancy, the serum GH level was 3 ng/mL, and the IGF-1 con-centration was 265 ng/mL. The pregnancy period was uneventfuland the patient did not develop arterial hypertension or glucoseabnormalities. Her visual field examination results were also nor-mal. She delivered, vaginally, a normal, healthy, full-term infant at40 weeks of pregnancy. The weight of the baby was 3.2 kg and hedid not have any congenital anomaly.

Discussion

The retrospective study of five women, who underwent surgery andthe treatment for macroadenoma from different centers beforepregnancy, allowed us to analyze maternal outcomes in acrome-galic patients. These five women, who were followed for a meanduration of five years, were aged between 28 and 43 years. Onlytwo of them had received radiotherapy after the surgery.None of these five patients were treated for pregnancy; however,two of them were receiving octreotide while they received the di-

Turk J Endocrinol Metab Önder et al.2017;21:136-139 Acromegaly and Pregnancy 137

Önder et al. Turk J Endocrinol MetabAcromegaly and Pregnancy 2017;21:136-139

138

agnosis of pregnancy. If the tumor mass or the treatments do notdestroy the gonadotropin lineage, the reproductive potential is pre-served; however, fertility in patients with acromegaly is generallyknown to be impaired (7). Conceptions (spontaneous as well as in-duced) have been reported in less than 150 cases in the literaturetill date, achieved with and without treatment (4, 5, 7, 8). GH and IGF-1 levels were not measured routinely in the patients inour study. Maternal GH was obtained from pituitary as well as pla-centa during the pregnancy, depending on the trimester. The pla-cental GH binds to GH receptors and acts as a GH agonist. Theincrease in the IGF-1 levels due to placental GH secretion appearsto result in a negative feedback to the hypothalamus and pituitaryduring normal pregnancy, causing suppression of pituitary GH se-cretion. Nevertheless, in acromegalic patients, this feedback inhi-bition is rendered ineffective and the pituitary GH secretion persiststhroughout the pregnancy (9). Even though the additional placental GH is present during the preg-nancy, a reduction in the IGF-1 levels during pregnancy in the pa-tients with acromegaly is usually seen even without medicaltreatment (7, 10, 11). It has been presumed that this improvement inthe IGF-1 levels could be due to the effect of the marked increase inthe estrogen levels during pregnancy (12). However, the impact ofpregnancy on the GH and IGF-1 levels in acromegalic patients is lim-ited to sporadic cases (3, 7, 13, 14). Therefore, monitoring of GH andIGF-1 levels in the pregnant acromegalic patients is not necessary. A major concern during pregnancy in acromegalics is the tumorgrowth. Although theoretically, adenoma enlargement may be ex-pected in the acromegalic patients because of the estrogen expo-sure (3), in the majority of the patients, tumor enlargement is notobserved (4, 5, 7, 13, 15). In a normal pregnancy, this has little clin-ical significance; however, in patients with residual tumor or unre-sected tumors, an increase in the gland size can cause visual fielddefects, headaches, and potentially, pituitary apoplexy (16-18). Inthe five cases mentioned here, we did not observe any visual field

impairment, pituitary apoplexy, or exacerbation of acromegaly dur-ing pregnancy; although, a routine visual field examination wasnot performed during the pregnancy period.There are limited data regarding the medical treatment ofacromegaly during pregnancy. In a study by Cheng et al.,dopamine agonists (DA) and somatostatin analogs (SA) appear toexhibit a reduced incidence of side effects in the mothers and thefetuses (5). In addition, pregnancies have been reported to be un-eventful in the acromegalic women treated with dopamine ago-nists, as observed in a much larger number of women withprolactinomas (13). However, since both bromocriptine and caber-goline can cross the placenta, it has been recommended to limittheir usage throughout pregnancy (19).Although SA, octreotide, and lanreotide are more efficacious thanDA for the treatment of acromegaly, these agents have not beencommonly used during pregnancy (4). Uneventful pregnancieshave been reported in which SA was continued during the preg-nancy without any side effects (13, 20, 21). Besides, medical treat-ment with SA during pregnancy was associated with low birthweight. It has been reported that octreotide crosses placenta (21,22), and therefore, it may potentially affect the fetal outcome. Nev-ertheless, based on the lack of sufficient data on the safety of SAsduring pregnancy, it is generally recommended to limit their usageduring pregnancy in symptomatic patients (4). None of the five pa-tients in our study were treated during pregnancy; while only twoof them were receiving octreotide when they received the diagno-sis of pregnancy, following which their medical treatment was dis-continued. Out of the five pregnancies mentioned in this study, fourdelivered normal, full-term babies; and the therapeutic abortionwas performed at the sixth week of pregnancy, to the patient whoreceived octreotide before the pregnancy (Table 1). Another important concern during pregnancy in patients withacromegaly is the effect of excess GH/IGF-1 levels on the motherand the fetus. Further, theoretically, women with acromegaly are at

Patient 1 (H.Z) Patient 2 (S.A) Patient 3 (N.Y) Patient 4 (B.T) Patient 5 (S.A)

Age (years) 28 31 40 43 28

Duration of acromegaly six years four years ve years ve years four years

Adenoma type before surgery Macroadenoma Macroadenoma Macroadenoma Macroadenoma Macroadenoma

Radiotherapy Gamma knife No Gamma knife No No

Medical treatment before pregnancy Octreotide Octreotide Lanreotide Octreotide Octreotide

Cabergoline Cabergoline Cabergoline

Treatment for pregnancy No No No No No

Treatment during pregnancy No No No Octreotide 10 mg* Octreotide 10 mg**

Gestational diabetes during pregnancy Pregestational diabetes No Pregestational diabetes No No

Gestational hypertension during pregnancy No No Yes No No

Gestational age/Type of delivery 38. weeks 38. weeks 37. weeks 6. weeks 40. weeks

C/S C/S C/S curettage

Birth weight 3100 gram 2900 gram 2900 gram - 3200 gram

Congenital anomaly No No No - No

* Therapeutic abortion was performed to a patient with her wish who received octreotide before the pregnancy

** Patient received octreotide before pregnancy, the drug was stopped when the patient was found to be pregnant.

Table 1. Demographic results of acromegalic patients who got pregnant.

Turk J Endocrinol Metab Önder et al.2017;21:136-139 Acromegaly and Pregnancy 139

a higher risk for glucose intolerance or hyperglycemia as the preg-nancy itself is an insulin-resistant state (13). Despite the limited data,the follow-up to check for the occurrence of gestational diabetes,coronary artery disease, hypertension, and dyslipidemia is stronglyrecommended (16, 23, 24). Acromegaly can potentially affect thefetus; however, there are limited data supporting this, as most ofthe studies have reported normal, healthy infants. (3, 7, 13). It isknown that the disease can be associated with miscarriage, pre-mature births, abnormal birth weight, and growth retardation (21).Among the five patients in our study, two had pregestational dia-betes; one of them had hypertension and had been diagnosed withdiabetes and hypertension in her past medical history. Four patientsin our study delivered healthy, full-term infants; and therapeuticabortion was performed to one of the five patients.In conclusion, according to our results together with the limiteddata, acromegalic female patients can conceive without receivingany treatment for pregnancy, even after treating acromegaly withsurgery, radiotherapy, and medical treatment. Most pregnancies inthe acromegalic patients are uneventful and the infants remain un-affected. Somatostatin analogs have been reported to be safe forusage throughout the pregnancy; however, further studies areneeded to establish their safety.


Concept: Elif Önder, Yusuf Aydın, Tuba Soysal. Design: Yusuf Aydın,Tuba Soysal. Data Collection or Processing: Elif Önder, Yusuf Aydın,Mazhar Tuna, Adem Güngör. Analysis or Interpretation: YusufAydın, Tuba Soysal, Elif Önder. Literature Search: Yusuf Aydın, TubaSoysal. Writing: Tuba Soysal, Yusuf Aydın. Conflict of Interest: No conflict of interest was declared by the au-thors. Financial Disclosure: The authors declared that this study receivedno financial support.

References1. Hsu CJ, Hammond JM. Concomitant effects of growth hormone

on secretion of insulin-like growth factor I and progesterone by cultured porcine granulosa cells. Endocrinology. 1987;121:1343-1348.

2. Kaltsas GA, Androulakis II, Tziveriotis K, Papadogias D, Tsikini A,Makras P, Dimitriou K, Stathopoulou A, Piaditis G. Polycystic ovariesand the polycystic ovary syndrome phenotype in women with activeacromegaly. Clin Endocrinol (Oxf). 2007;67:917-922.

3. Herman-Bonert V, Seliverstov M, Melmed S. Pregnancy inacromegaly: successful therapeutic outcome. J Clin Endocrinol Metab.1998;83:727-731.

4. Cheng V, Faiman C, Kennedy L, Khoury F, Hatipoglu B, Weil R, Ham-rahian A. Pregnancy and acromegaly: a review. Pituitary. 2012;15:59-63.

5. Cheng S, Grasso L, Martinez-Orozco JA, Al-Agha R, Pivonello R, ColaoA, Ezzat S. Pregnancy in acromegaly: experience from two referralcenters and systematic review of the literature. Clin Endocrinol (Oxf).2012;76:264-271.

6. Shimatsu A, Usui T, Tagami T, Kuzuya H, Takahashi JA. Suppressedlevels of growth hormone and insulin-like growth factor-1 during suc-cessful pregnancy in persistent acromegaly. Endocr J. 2010;57:551-553.

7. Cozzi R, Attanasio R, Barausse M. Pregnancy in acromegaly: a one-center experience. Eur J Endocrinol. 2006;155:279-284.

8. Esfandiari N, Gotlieb L, Casper RF. Live birth of healthy triplets after invitro fertilization and embryo transfer in an acromegalic woman withelevated growth hormone. Fertil Steril 2005;83:1041.

9. Beckers A, Stevenaert A, Foidart JM, Hennen G, Frankenne F. Placen-tal and pituitary growth hormone secretion during pregnancy inacromegalic women. J Clin Endocrinol Metab. 1990;71:725-731.

10. Lau SL, McGrath S, Evain-Brion D, Smith R. Clinical and biochemicalimprovement in acromegaly during pregnancy. Endocrinol Invest.2008;31:255-261.

11. Colao A, Merola B, Ferone D, Lombardi G. Acromegaly. J Clin En-docrinol Metab. 1997;82:2777-2781.

12. Leung KC, Johannsson G, Leong GM, Ho KK. Estrogen regulation ofgrowth hormone action. Endocr Rev. 2004;25:693-721.

13. Caron P, Broussaud S, Bertherat J, Borson-Chazot F, Brue T, Cortet-Rudelli C, Chanson P. Acromegaly and pregnancy: a retrospectivemulticenter study of 59 pregnancies in 46 women. J Clin EndocrinolMetab. 2010;95:4680-4687.

14. Verhaeghe J. Does the physiological acromegaly of pregnancy benefitthe fetus? Gynecol Obstet Invest. 2008;66:217-226.

15. Caron P. Acromegaly and pregnancy. Ann Endocrinol (Paris).2011;72:282-286.

16. Atmaca A, Dagdelen S, Erbas T. Follow-up of pregnancy in acrome-galic women: different presentations and outcomes. Exp Clin En-docrinol Diabetes. 2006;114:135-139.

17. Kasuki L, Neto LV, Takiya CM, Gadelha MR. Growth of an aggressivetumor during pregnancy in an acromegalic patient. Endocr J.2012;59:313-319.

18. Mikhail N. Octreotide treatment of acromegaly during pregnancy.Mayo Clin Proc. 2002;77:297-298.

19. Molitch ME. Pituitary disorders during pregnancy. Endocrinol MetabClin North Am. 2006;35:99-116.

20. Takano T, Saito J, Soyama A, Ito H, Iizuka T, Yoshida T, Nishikawa T.Normal delivery following an uneventful pregnancy in a Japaneseacromegalic patient after discontinuation of octreotide long actingrelease formulation at an early phase of pregnancy. Endocr J.2006;53:209-212.

21. Fassnacht M, Capeller B, Arlt W, Steck T, Allolio B. Octreotide LAR treat-ment throughout pregnancy in an acromegalic woman. Clin En-docrinol (Oxf). 2001;55:411-415.

22. Maffei P, Tamagno G, Nardelli GB, Videau C, Menegazzo C, Milan G,Calcagno A, Martini C, Vettor R, Epelbaum J, Sicolo N. Effects of oc-treotide exposure during pregnancy in acromegaly. Clin Endocrinol(Oxf). 2010;72:668-677.

23. Neal JM. Successful pregnancy in a woman with acromegaly treatedwith octreotide. Endocr Pract. 2000;6:148-150.

24. Molitch ME. Pituitary tumors and pregnancy. Growth Horm IGF Res.2003;13:S38-44.

140

Introduction

Obesity, defined as a body mass index (BMI) ≥30 kg/m2, is a sig-nificant public health concern worldwide. In the United States and

Turkey, more than 35% of the adults are obese (1-3). Obesity is aserious medical condition associated with several comorbidities in-cluding type 2 diabetes, cardiovascular and cerebrovascular dis-eases, digestive, locomotor and respiratory disorders, cancers

SSuummmmaarryy ooff BBaarriiaattrriicc SSuurrggeerryy GGuuiiddeelliinnee ooff tthhee SSoocciieettyy ooffEEnnddooccrriinnoollooggyy aanndd MMeettaabboolliissmm ooff TTuurrkkeeyyTTüürrkkiiyyee EEnnddookkrriinnoolloojjii vvee MMeettaabboolliizzmmaa DDeerrnneeğğii BBaarriiaattrriikk CCeerrrraahhii KKııllaavvuuzzuu ÖÖzzeettii

Harran University Medical Faculty, Department of Endocrinology and Metabolism, Sanlıurfa, Turkey*University of Health Sciences, Yüksek Ihtisas Training and Research Hospital, Department of Endocrinology and Metabolism, Bursa, Turkey

**University of Health Sciences, Fatih Sultan Mehmet Training and Research Hospital, Department of Endocrinology and Metabolism, Istanbul, Turkey***University of Health Sciences, Gülhane Training and Research Hospital, Department of Endocrinology and Metabolism, Ankara, Turkey

****Trakya University Medical Faculty, Department of Endocrinology and Metabolism, Edirne, Turkey*****Gaziosmanpaşa University Medical Faculty, Department of Endocrinology and Metabolism, Tokat, Turkey

******İnönü University Medical Faculty, Department of Endocrinology and Metabolism, Malatya, Turkey*******Reyap Sağlık Grubu, Department of Endocrinology and Metabolism, Çorlu, Istanbul, Turkey

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

Obesity is a common condition affecting approximately one-third of the adult population worldwide. Obesity results in a number of medical,psychosocial and economical problems, in many patients, it is usually difcult to achieve the desired weight loss with medical therapies, severalsurgical approaches for weight loss have been developed in the recent years and are described as bariatric or metabolic surgery. Though bariat-ric surgery promotes dramatic and reliable improvement in obesity and related complications, yet proper patient selection and careful selectionof the bariatric method along with good pre- and post-operative management is very important for a successful therapy. Therefore, the authorsaim to present a short review on the Bariatric Surgery Guideline of the Society of Endocrinology and Metabolism of Turkey. The indications and con-traindications for bariatric surgery, description of commonly used bariatric surgical methods, preoperative preparation of obese patients prior tothe surgery, early and late postoperative management and follow-up of the patients have been summarized in this review. This review has beenwritten in accordance with the opinions and recommendations of the Hypertension, Lipid Metabolism and Obesity Study Group of the Society ofEndocrinology and Metabolism of Turkey.Keywords: Obesity; bariatric surgery; metabolic surgery; indications; contraindications; preoperative evaluation; postoperative following

Obezite, dünyadaki yetişkin nüfusun yaklaşık üçte birini etkileyen yaygın bir hastalık olup pek çok tıbbi, psikososyal ve ekonomik problemlere neden ol-maktadır. Birçok hastada tıbbi tedaviler ile istenilen kilo kaybının sağlanamaması nedeniyle obezitenin tedavisi için günümüzde çeşitli cerrahi yaklaşımlargeliştirilmiş olup bunlar bariyatrik veya metabolik cerrahi olarak adlandırılmaktadır. Bariyatrik cerrahi sonuçları, obezite ve ilgili komplikasyonlarda çar-pıcı ve uzun süreli iyileşmeyi desteklese de, uygun hastanın ve bariyatrik yöntemin seçimi, ameliyat öncesi ve sonrası değerlendirme ile takip, bariyat-rik cerrahinin başarısı için çok önemlidir. Bu nedenle, Türkiye Endokrinoloji ve Metabolizma Derneği Bariyatrik Cerrahi Kılavuzunun kısa bir derlemesiniyapmayı amaçladık. Bu derlemede, bariyatrik cerrahi endikasyon ve kontraendikasyonları, obez hastanın preoperatif dönemde hazırlanması, yaygınolarak kullanılan bariyatrik cerrahi yöntemler ve postoperatif dönemde hastanın takip ve tedavisi özetlenmiş olup Türkiye Endokrinoloji ve MetabolizmaDerneği, Hipertansiyon, Lipid Metabolizması ve Obezite Çalışma Grubu görüş ve önerileri doğrultusunda hazırlanmıştır.Anahtar kelimeler: Obezite; bariyatrik cerrahi; metabolik cerrahi; endikasyonlar; kontrendikasyonlar; preoperative değerlendirme; postoperatif takip

Address for Correspondence: Sinem KIYICI, University of Health Sciences, Yuksek Ihtisas Training and Research Hospital, Department of Endocrinology and Metabolism, Bursa, Turkey

Phone: 0224 295 50 00 E-mail: [email protected] Received: 26/07/2017 Accepted: 03/08/2017


Invited ReviewDOI: 10.25179/tjem.2017-57388


(e.g., colon, breast, and uterine) and psychosocial complications.Obesity also poses severe economic impact (4, 5). The cost of obe-sity complications and their treatment in the United States isroughly 200 billion US dollars, which accounted for over 20% of theUS’s entire healthcare spending in 2005 (6). The global economicimpact of obesity was determined to be 2.0 trillion dollars in 2014(5). Many studies have shown that weight loss reduces the risk ofdeveloping complications and may also improve the establishedconditions (7). Treatment options for obesity include surgical treat-ment [bariatric surgery (BS)] and non-surgical treatment. The non-surgical management usually comprises of dietary changes,physical exercise, and behavioral therapy aimed at reducing en-ergy intake and increasing energy expenditure, in addition to var-ious pharmacotherapies. Unfortunately, non-surgical approachesmay be ineffective in achieving or sustaining weight loss in manyobese patients. Therefore, the use of bariatric or metabolic surgi-cal methods is increasing worldwide. According to the reports ofthe International Federation for the Surgery of Obesity and Meta-bolic Diseases (IFSO), a total number of 468,609 bariatric proce-dures were performed worldwide in 2013, out of which, 95.7%were laparoscopic procedures. Sleeve gastrectomy (SG) was themethod that was most commonly used in the USA/Canada and inthe Asia/Pacific regions; while in the Europe and Latin/South Amer-ica regions, it was the second most commonly used method afterRoux-en-Y Gastric Bypass (RYGB) (8). In Turkey, approximately10,000 obese patients underwent bariatric surgery in 2016 (9).At present, the long term outcomes of weight loss, after BS, havebeen found to be up to 20 years. Several randomized controlledstudies have reported a weight loss of 17.3% to 33.8% in the sur-gical intervention groups at a period of 2-5 years after BS. In con-trast, the control groups showed lower weight loss (1.4% to 10.2%)(10). In a recently conducted retrospective study, Maciejewski et al.(11) reported that patients undergoing RYGB lost 21% more of theirbaseline weight at 10 years as compared to their nonsurgical con-trols. Though some patients who underwent BS, regained weight,at 10 years after surgery; yet, 72% of the patients still showed aweight loss of more than 20%. In contrast, at 10 years follow-up,less than 10% of the nonsurgical subjects exhibited a weight loss of20% or more. It was concluded from the Swedish Obese Subjects(SOS) study data that mean changes in body weight after 2 and20 years were -23% and -18% in the surgical group and 0% and -1% in the control group, respectively. Patients who underwentbariatric surgery showed a long-term reduction in overall mortal-ity [hazard ratio (HR)=0.71; p=0.01] as well as decreased incidencesof diabetes (HR=0.17; p<0.001), myocardial infarction (HR=0.71;p=0.02), stroke (HR=0.66; p=0.008) and cancer (for women:HR=0.58; p=0.0008; for men: n.s.] as compared to the usual caregroup (12). The remission of diabetes mellitus is seen in 60% to 80%of the patients 1 to 2 years after BS while it still persists in approxi-mately 30% of patients at 15 years (13).

Ignored issues for bariatric surgery in the present studies

Although all studies on BS suggest that surgical procedures canhelp achieve significant weight loss, the long term success rateshave shown a decline (14). Modifiable risk factors associated with

poor outcome include open surgery and the type of bariatric sur-gery performed; the non-modifiable risk factors include male gen-der, older age, super obesity (BMI ≥50 kg/m2) with a history ofcongestive heart failure, prior coronary intervention, peripheral vas-cular disease, deep venous thrombosis (DVT), pulmonary em-bolism (PE), obstructive sleep apnea (OSA), chronic use ofcorticosteroids, impaired functional status, and chronic renal failure(15-17). Therefore, further studies utilizing new clinical risk-stratifi-cation systems for optimizing patient selection criteria and conse-quently, patient outcomes, are required. The individuals, especiallyfemales, undergoing gastric bypass surgery at ages younger than35 years lack mortality benefit (18). Moreover, the suicide rate in-creases after surgery in patients, particularly in females more than35 years of age. Hence, preoperative psychiatric analysis of pa-tients in this population is extremely important (19). The antidiabeticbenefits of surgery often wane over time. In 35-50% patients oreven more, in whom remission of diabetes is eventually seen,eventually experience recurrence at later years. The highest dis-ease-free period is seen in individuals undergoing RYGB (medianduration: 8.3 years). Baseline duration of diabetes (e.g., >8 years),use of insulin, and poorer glycemic control are associated withlower rates of diabetes remission and a higher risk of relapse (20).Almost all trials reporting BS outcomes were designed retrospec-tively, except for SOS which was a prospective study. Although SOSstudy reported a lower incidence of cancer in the BS group, ascompared to the control group, this result was evident only in thefemales and not in the males (21). Moreover, the reported reduc-tion in risk was only for cancers likely known to be associated withobesity, and not for non-obesity-related cancers (22). Therefore,well-designed randomized prospective trials are required to aid inproper patient selection for BS. The authors suggest the use of mul-tidisciplinary approach in order to achieve maximum benefits fromBS.

Cost effectiveness of bariatric surgery

Although BS is known to have striking results in the managementof obesity, the financial benefits of BS for healthcare systems havenot yet been clearly demonstrated. The SOS study showed that, inthe first 6 years after surgery, costs were higher for the BS patientsas compared to their controls, but not thereafter. Drug costs werelower for the surgical group at the period of 7-20 years (23).

Indications for Bariatric Surgery

The careful selection of patients is crucial in obtaining successful re-sults from BS. All patients must be followed at least 3 to 6 monthsahead of the surgery in an endocrinology department and shouldbe encouraged to lose weight prior to the surgery because even asmall reduction in weight can reduce surgical complications whileincreasing the success of the surgery. This period can also predictwhich patient would benefit from the surgical procedure. If it is clearthat an adequate weight loss cannot be achieved despite appro-priate nonsurgical therapy, then only a BS should be opted for. Insome candidates, nonsurgical therapy can result in a decrease inthe patient’s BMI to the extent that the patient no longer meets theBS indication. Though a majority of surgeons suggest that such a

Turk J Endocrinol Metab Sabuncu et al.2017;21:140-147 Summary of Bariatric Surgery Guideline 141

Sabuncu et al. Turk J Endocrinol MetabSummary of Bariatric Surgery Guideline 2017;21:140-147

142

decrease in BMI should not stop the candidate from surgery, in thissituation the patient’s choice should be taken into consideration.BS indications for nondiabetic and diabetic patients are shown inTables 1 and 2 (24-26).

Issues need to be taken into consideration in patients withdiabetes

1- Antidiabetic therapy: insulin secretagogues, thiazolidinediones,and insulin can often result in weight gain. Therefore, weight lossor weight neutral antidiabetic drugs (e.g., metformin, alpha glu-cosidase inhibitors, DPP-4 inhibitors, GLP-1 agonists and SGLT 2 in-hibitors) must be preferred for treating diabetic patients wheneverpossible (24).2- Patients must be enquired about their concomitant medicationspossibly promoting weight gain (e.g., anticholinergics, antihista-mines, antidepressants, antipsychotics, anticonvulsants includinggabapentin, glucocorticoids, and oral contraceptives containingprogestins) and, whenever possible, they must either be stoppedor changed with alternatives or their use must be minimized (24).3- Younger age, shorter duration of diabetes, non-use of insulin,and better glycemic control are consistently associated with higherrates of remission of diabetes and/or lower risk of recurrence (20). 4- It has been reported that bariatric surgery improves the meta-bolic profiles and daily insulin requirements of morbidly obese pa-tients with type 1 diabetes; however, more long term studies arerequired to establish the role of bariatric surgery in such patients(27).

Contraindications for Bariatric SurgeryBS should not be used only for controlling hyperglycemia or for pre-venting cardiovascular risk in non-obese patients. Absolute or rel-ative contraindications of BS are shown in Table 3 (25, 26, 28-30).

Concerns and Suggestions for Bariatric Surgery

Bariatric surgery is costly and poses several potential health risks.Potential risks associated with the surgical procedure include gen-eral surgical complications such as bleeding, infection, a numberof systemic problems and death. Long term risks include dumpingsyndrome, vitamin and mineral deficiencies, anemia, hernia, bowelobstruction, gallstones, osteoporosis, and, rarely severe hypo-glycemia resulting from hypersecretion of insulin and death (31).Long-term nutritional and micronutrient deficiencies occur with avaried frequency depending on the type of surgery. Postprandialhypoglycemia most frequently occurs with RYGB. In a study, hypo-glycemia occurred in 11% of the 450 patients who underwent RYGBor vertical sleeve gastrectomy (32). Patients undergoing BS may beat an increased risk for substance abuse (i.e., tobacco, alcohol, andillicit drug use) (33). Patients who undergo BS also show increasedrates of depression and other major psychiatric disorders (34, 35).Hence, patients having a history of alcohol or substance abuse,significant depression, suicidal ideation, or other mental healthconditions must be assessed by an experienced psychiatrist formanagement of obesity prior to their consideration for surgery. Pa-tients with any preoperative psychopathology must be followed upat regular intervals after BS for the optimization of management.

BMI categories (kg/m2 ) Patient situation

>40 Patients without coexisting illness and for whom bariatric surgery would not be associated with excessive risk

35.0-39.9 Patients with at least one severe obesity-related comorbidity, including but not limited to T2DM, hypertension,

hyperlipidemia, OSA, OHS, NAFLD or NASH, pseudotumor cerebri, GERD, asthma, venous stasis disease,

severe urinary incontinence, debilitating arthritis, or considerably impaired quality of life

30.0-34.9 Patients with T2DM, metabolic syndrome, and the Asian origin may be considered for bariatric surgery*

<30 There is no evidence to support recommending a bariatric surgical procedure for the management of T2DM alone*

GERD: Gastroesophageal reux disease; OHS: Obesity-hypoventilation syndrome; OSA: Obstructive sleep apnea; NAFLD: Nonalcoholic fatty liver disease; NASH: Nonal-

coholic steatohepatitis; T2D: Type 2 diabetes mellitus.

* See Table 2.

Table 1. The candidates for bariatric surgery.

Table 2. Treatment modalities of overweight and obese type 2 diabetic patients.

BBMMII ccaatteeggoorriieess ((kkgg//mm22))

TTrreeaattmmeenntt mmooddaalliittiieess 25.0–26.9 27.0–29.9 30.0–34.9 35.0–39.9 >40

Diet, exercise, and behavioral therapy + + + + +

Drug therapy* + + + +

Metabolic surgery** +a +b +c

* Potential benets must be weighed against the potential risks of the drugs. If there is an absence of drug tolerance, safety or effectivity (<5% weight loss after 3 months), drugtherapy should be stopped.** Only for selected and motivated patients. a It is considered for patients whose diabetes cannot be regulated.b It is recommended for patients whose diabetes cannot be regulated.c It is recommended for all patients regardless of glycemic regulation.


Preparation of Patients for Bariatric Surgery

All candidates must undergo medical, psychological and anes-thetic risk assessment prior to bariatric surgery. A multidisciplinaryteam including an endocrinologist, a dietician, a psychiatrist, anurse specialist and an experienced surgeon is required for over-all assessment, success, and support of the patient considered fora bariatric surgical procedure. Medical assessment should includea complete history, physical examination and several laboratorytests (Table 4) (20, 25, and 26). Patients with upper gastrointestinalsymptoms such as dysphagia, reflux, and pain must be evaluatedusing an esophagogastroduodenoscopy and an ultrasonographyto detect any H. pylori infection, anatomical abnormalities such asa hiatal hernia and other pathologies like ulcers, polyps, masses,nonalcoholic fatty liver disease or gallstones.

Surgical Procedures

The surgical treatment of obesity was initially developed from theobservation of weight loss associated with the procedures of re-moval of stomachs or small intestines (36). Since the last decade,the number of bariatric surgical procedures has greatly increasedbecause of the increase in the prevalence of obesity and the recog-nition of benefits associated with surgery (10). The exploration ofthe BS began with the resection of one-meter small bowel by Hen-riksson et al. (37). Around the beginning of the year 2000, RYGBand gastric banding were the most commonly used proceduresfor BS (8). At the present time, sleeve gastrectomy, RYGB, gastricbanding, and biliopancreatic diversion with a duodenal switch arethe most common bariatric procedures, respectively (38). Thebariatric surgical procedures are classified into three main cate-gories: malabsorptive procedures, restrictive volume procedures,

and mixed procedures. In general, laparoscopic bariatric proce-dures are preferred over open bariatric procedures due to thelower risk of early postoperative morbidity and mortality.

Malabsorptive procedures

A. Biliopancreatic diversion with duodenal switch

Biliopancreatic diversion is primarily a malabsorptive and a par-tially reversible procedure. Addition of duodenal switch to the bil-iopancreatic diversion is an adaptation of the standard procedure.It is a complex procedure and is associated with high rates of com-plications such as gastrointestinal side effects and vitamins andprotein deficiencies. Therefore biliopancreatic diversion with duo-denal switch is likely to be used only in patients with ’super obesity’(BMI above 50 kg/m2) (39, 40).

B. Restrictive volume procedures

Sleeve gastrectomy

Sleeve gastrectomy is believed to be the most commonly per-formed procedure worldwide (41). In this procedure, the stomachis vertically divided to reduce its size to about 25%. It is an irre-versible procedure. It has relatively fewer risks of complications dueto the relatively quick operating time and the protection of anatom-ical configuration (40).

Gastric banding

In this procedure, an adjustable band is placed around the proxi-mal part of the stomach to form a small pouch (9). Though it haslower rates of morbidity and mortality, yet it exhibits less beneficialeffects than the other procedures. It is associated with a higher riskof need for reoperation and weight regain (42, 43).

Extreme ages ( <18 and >65 years)a,b

BMI < 40, 35 or 30c

Untreated endocrinological disorders (e.g., Cushing, hypothyroidism, insulinoma)

Untreated eating disorders (e.g., bulimia nervosa)

Untreated major depression or psychosis

Severe coagulopathy

Severe cardiac disease restraining anesthesia

Current drug and alcohol abuse

Inability to adhere to nutritional recommendations (e.g., life-long vitamin replacement)

Pregnancyd

Portal hypertension

Neoplasia

Several digestive system disorders (e.g., chronic pancreatitise, severe GERDf, Crohne,h)

GERD: gastroesophageal reux disease a Patients with diabetes, hypertension or other severe comorbidities in the extreme age categories may be considered appropriate surgical candidates. b Functional age is more important than chronological age.c See Table 1. d Candidates for BS should avoid pregnancy before and 18 months after surgery.e for gastric band, f for sleeve gastrectomy, h for RYGB and biliopancreatic diversion.

Table 3. Contraindications for bariatric surgery.


144

Mixed procedures

Roux-en-Y gastric bypass

RYGB is the gold standard for bariatric surgery and was the mostcommonly performed procedure until recently. However, currently,it has become the second most common bariatric surgical proce-dure (40, 44). Effects of this procedure include a reduction in stom-ach capacity, decreased absorption by the digestive tract, andalterations in gut hormone levels (45).

Early Postoperative Management

Postoperative care should involve a multidisciplinary team includ-ing a surgeon, an endocrinologist, a psychiatrist, a dietitian and anurse specialized in bariatric surgical treatment. Evaluation of com-plete blood count, electrolyte level, renal and liver functions mustbe followed up every 12 h during the next 48 h and then every dayfor the next 3 days. Patients at a high risk of coronary artery dis-ease should be monitored by telemetry within the first 24 h aftersurgery. Respiratory problems are common early postoperativecomplications following BS. Patients with significant comorbiditiessuch as neuromuscular, pulmonary or cardiac problems are at ahigher risk for respiratory complications; however, hypoxemia maydevelop in any patient (26, 46). Adequate hydration must be main-tained; usually, 1.5 L of fluids must be administered per day eitherintravenously or orally (38). Pneumatic compression devices withsubcutaneous unfractionated or low molecular weight heparinmay be used for the prophylaxis of venous thromboembolism (47).Nausea and vomiting may occur and are directly correlated to thecomplexity of the procedure. Prophylaxis with antiemetic drugs sig-nificantly decreases the incidence of nausea and vomiting aftersurgery (46). In case rhabdomyolysis is suspected, serum creatinekinase level must be measured. Serum glucose levels should be

monitored postoperatively in type 2 diabetic patients and hypo-glycemia should be avoided in such patients (26).As a rule, a low-sugar, clear liquid meal program can be initiatedin the first 24 h, independent of the bariatric procedure performedunless an anastomotic leak occurs (46, 26). A dietician specializedin the bariatric diet should be consulted for postoperative meal ini-tiation and progression (26). Generally, patients are dischargedfrom the hospital at fourth to sixth days with full liquid diet. Theamount of liquid intake and urine output must be self-monitoredafter discharge (46). A gradual diet program is implemented sothat a solid diet can be tolerated by these patients at the end of 1-2 months (48). After the clear liquid diet period, the diet program isgradually progressed to full liquid diet for 10-14 days, followed bypuree food for the next 10-14 days, to soft food for next 14 days andfinally to regular food (Table 5) (49). Patients should follow certain rules in staged meal progression dietprogram, which includes (26):

eating three small meals during the day and chewing small bitesof food thoroughly before swallowing,

adhering to the principles of healthy eating (e.g., at least 5 dailyservings of fresh fruits and vegetables),

protein intake should be individualized according to age, genderand weight (minimal 60 gram/day protein intake and up to 1.5gram/kg ideal body weight per day),

the patient must keep away from concentrated sweets to reducecaloric intake, especially after RYGB to minimize the symptoms ofdumping syndrome.Nutritional follow-up is essential to obtain maximum weight losswhile also avoiding macro- and micronutrient deficiencies andweight regain. Long-term vitamin and mineral supplementationmust be considered to prevent micronutrient deficiencies. In allpatients, vitamin and mineral supplementations consisting of a

Complete H & P (obesity-related comorbidities, causes of obesity, BMI, weight loss history, commitment, and exclusions related to surgical risk)

Routine labs (FPG, lipid prole, kidney function, liver prole, urine analysis, prothrombin time/INR, blood type, CBC)

Nutrient screening (ferritin, B12, folic acid, and 25-vitamin D)

Cardiopulmonary evaluation (ECG, CXR, echocardiography if cardiac disease or pulmonary hypertension suspected. DVT evaluation if clinically indicated.

Pulmonary function test for OSA patients.)

Sleep apnea screening (with one of the questionnaire-based methods such as STOP-Bang. Conrmatory tests, such as polysomnography only for those

who are at high risk of having OSA based upon the initial screen)

Gastrointestinal evaluation (H. pylori screening in high-prevalence areas, liver, and gallbladder evaluation and upper endoscopy if indicated)

Endocrine evaluation (TSH for all patients; androgens with PCOS suspicion; exclusion of Cushing’s syndrome; diagnosing type of diabetes, screening for

diabetes complications, measurement of insulin reserve and A1c for diabetics)

Clinical nutrition evaluation by dietitian

Psychosocial-behavioral evaluation by psychiatrist

Documentation of medical necessity for bariatric surgery

Maintaining efforts for preoperative weight loss

Optimizing glycemic control

Pregnancy counseling

Smoking cessation counseling

CBC: Complete Blood Count; CXR: Chest X-Ray; DVT: Deep Venous Thrombosis; ECG: Electrocardiography; FPG: Fasting Plasma Glucose; H & P: History and Physical ex-

amination.

Table 4.Preoperative medical assessment.


daily dose of multivitamin should be initiated within the first month(50, 51). Recommended vitamin and mineral supplementationafter BS is summarized in Table 6. Many patients may require ad-ditional micronutrient supplementation in addition to the recom-mended dosages. The extent and severity of micronutrientdeficiency are associated with the extent and severity of disruptionof normal gastrointestinal anatomy and physiology. Iron deficiencyis the most common micronutrient deficiency following BS, espe-cially in malabsorptive procedures. Vitamin D, vitamin B12, vitaminA, thiamine, and zinc are also some of the other micronutrientswhose deficiencies may occur following malabsorptive surgeries.Protein malnutrition is the major macronutrient deficiency relatedto BS. Adequate protein intake must be provided (26, 38) to thepatients.

Longterm Follow-Up

In patients with BS, lifelong follow-up visits are required. Most con-ditions associated with obesity (e.g., type 2 diabetes mellitus, hy-pertension, dyslipidemia, sleep apnea, arthritis, gastroesophagealreflux disease, and non-alcoholic fatty liver disease) either improveor resolve after surgery (38). Furthermore, various complicationssuch as dumping syndrome, ulcers, cholelithiasis, nephrolithiasis,depression, stenosis, nutritional deficiencies and weight regainmay arise in the long time (51, 52). Therefore, patients must be fol-lowed up regularly in terms of conditions associated with obesityor those that are likely to occur after BS. The frequency of follow-up depends on the performed BS. The interval of visits and pa-rameters to be evaluated during follow are given in Table 7 (26). The following conditions must be evaluated in cases of inadequateweight loss or weight regain (26);

decreased patient adherence to lifestyle modification,use of medications likely to cause weight gain, development of maladaptive eating behaviors,psychological conditions,complications that may cause inadequacy of BS (e.g., pouch en-

largement, anastomotic dilation, the formation of fistula in RYGBor inadequate band restriction in gastric banding).To conclude, BS is an important treatment modality for obese pa-tients. However, detailed preoperative assessment, appropriatepostoperative management, and follow-up are essential for longterm safety and success of the surgery.

Meal Time

Low-sugar clear liquid meal Usually, begin within rst 24 h.

Continue to hospital discharge (4–6 days)

Full liquid diet 10–14 days

Puree food 10–14 days

Soft food 14 days

Regular food Usually, begin at the end of 1-1.5 month

Table 5. Gradual diet program and its timing.

Supplement GB SG RYGB BPD-DS

Mutivitamin plus minerals each containing iron, folic acid and thiamine (number of tablets) 1 2 2 2

Calcium citrate 1200–1500 mg/day or

Calcium carbonate 2000 mg/day + + + +

Vitamin D at least 3000 IU titrate to >30 ng/dL + + + +

Vitamin B12 1000 µg/1–3 month im, 350–1000 µg/day oral + + + +

Iron 45–60 mg/day via multivitamin - + + +

GB: Gastric banding; SG: Sleeve gastrectomy; RYGB: Roux-en-Y gastric bypass; BPD/DS: Biliopancreatic diversion with duodenal switch.

Table 6. Recommended nutritional supplements after bariatric surgery.

GB SG RYGB BPD/DS

Visits (initial/interval) (month)* 1/1–2 1/3–6 1/3–6 1/3

Complete blood count (at each visit) + + + +

Lipid prole (every 6-12 months based on risk and therapy) + + + +

Urine calcium excretion (at 6 and 12. month) + + + +

Vitamin B12 (annually) + + + +

Iron studies, folic acid, vitamin D, PTH - - + +

Vitamin A (initially and annually) - - optional +

Copper, zinc, and selenium (if specic ndings occur) - - + +

Thiamine (if specic ndings occur) + + + +

DXA (at the second year) - - + +

GB: Gastric banding; SG: Sleeve gastrectomy; RYGB: Roux-en-Y gastric bypass; BPD/DS: Biliopancreatic diversion with duodenal switch; PTH: parathyroid hormone; DXA:

Dual-energy X-ray absorptiometry,* annually after the rst year.

Table 7. Long-term follow up of bariatric surgery patients.

Author ContributionsConcept: all authors, Design: all authors, Data Collection or Pro-cessing: all authors, Analysis or Interpretation: all authors, Litera-ture Search: all authors, Writing: all authors.Conflict of Interest: No conflict of interest was declared by the authors.Financial Disclosure: The authors declared that this study receivedno financial support.

References1. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of childhood and

adult obesity in the United States, 2011-2012. JAMA. 2014;311:806-814.

2. Gundogan K, Bayram F, Gedik V, Kaya A, Karaman A, Demir O,Sabuncu T, Kocer D, Coskun R. Metabolic syndrome prevalence ac-cording to ATP III and IDF criteria and related factors in Turkish adults.Arch Med Sci. 2013;9:243-253.

3. Satman I, Omer B, Tutuncu Y, Kalaca S, Gedik S, Dinccag N, KarsidagK, Genc S, Telci A, Canbaz B, Turker F, Yilmaz T, Cakir B, Tuomilehto J.Twelve-year trends in the prevalence and risk factors of diabetes andprediabetes in Turkish adults. Eur J Epidemiol. 2013;28:169-180.

4. Pi-Sunyer X. The medical risks of obesity. Postgrad Med. 2009;121:21-33.

5. Tremmel M, Gerdtham UG, Nilsson PM, Saha S. Economic burden ofobesity: a systematic literature review. Int J Environ Res Public Health.2017;14.

6. Cawley J, Meyerhoefer C. The medical care costs of obesity: an in-strumental variables approach. J Health Econ. 2012;31:219-230.

7. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM,Walker EA, Nathan DM; Diabetes Prevention Program ResearchGroup. Reduction in the incidence of type 2 diabetes with lifestyle in-tervention or metformin. N Engl J Med. 2002;346:393-403.

8. Angrisani L, Santonicola A, Iovino P, Formisano G, Buchwald H,Scopinaro N. Bariatric Surgery Worldwide 2013. Obes Surg.2015;25:1822-1832.

9. Kıyıcı S. Bariyatrik Cerrahi Kılavuzunda Neyi, Neden Değiştirdik? 39.Türkiye Endokrinoloji ve Metabolizma Hastalıkları Kongresi, KongreKitabı. 2017:44-47.

10. Vidal J, Corcelles R, Jiménez A, Flores L, Lacy AM. Metabolic andbariatric surgery for obesity. Gastroenterology. 2017;152:1780-1790.

11. Maciejewski ML, Arterburn DE, Van Scoyoc L, Smith VA, Yancy WS Jr,Weidenbacher HJ, Livingston EH, Olsen MK. Bariatric surgery andlong-term durability of weight loss. JAMA Surg. 2016;151:1046-1055.

12. Sjöström L. Review of the key results from the Swedish Obese Subjects(SOS) trial-a prospective controlled intervention study of bariatric sur-gery. J Intern Med. 2013;273:219-34.

13. Panteliou E, Miras AD. What is the role of bariatric surgery in the man-agement of obesity? Climacteric. 2017;20:97-102.

14. Cooper TC, Simmons EB, Webb K, Burns JL, Kushner RF. Trends inweight regain following Roux-en-Y Gastric Bypass (RYGB) bariatricsurgery. Obes Surg. 2015;25:1474-1481.

15. Nguyen NT, Masoomi H, Laugenour K, Sanaiha Y, Reavis KM, Mills SD, Stamos MJ. Predictive factors of mortality in bariatric surgery:data from the Nationwide Inpatient Sample. Surgery. 2011;150:347-351.

16. Ramanan B, Gupta PK, Gupta H, Fang X, Forse RA. Development andvalidation of a bariatric surgery mortality risk calculator. J Am CollSurg. 2012;214:892-900.

17. Khan MA, Grinberg R, Johnson S, Afthinos JN, Gibbs KE. Periopera-tive risk factors for 30-day mortality after bariatric surgery: is func-tional status important? Surg Endosc. 2013;27:1772-1777.

18. Davidson LE, Adams TD, Kim J, Jones JL, Hashibe M, Taylor D, MehtaT, McKinlay R, Simper SC, Smith SC, Hunt SC. Association of patientage at gastric bypass surgery with long-term all-cause and cause-specific mortality. JAMA Surg. 2016;151:631-637.

19. Bhatti JA, Nathens AB, Thiruchelvam D, Grantcharov T, Goldstein BI,Redelmeier DA. Self-harm emergencies after bariatric surgery: a pop-ulation-based cohort study. JAMA Surg. 2016;151:226-232.

20. Rubino F, Nathan DM, Eckel RH, Schauer PR, Alberti KG, Zimmet PZ,Del Prato S, Ji L, Sadikot SM, Herman WH, Amiel SA, Kaplan LM,Taroncher-Oldenburg G, Cummings DE. Metabolic surgery in thetreatment algorithm for type 2 diabetes: a Joint Statement by Inter-national Diabetes Organizations. Diabetes Care. 2016;39:861-877.

21. Sjöström L, Gummesson A, Sjöström CD, Narbro K, Peltonen M,Wedel H, Bengtsson C, Bouchard C, Carlsson B, Dahlgren S, Jacob-son P, Karason K, Karlsson J, Larsson B, Lindroos AK, Lönroth H, Näs-lund I, Olbers T, Stenlöf K, Torgerson J, Carlsson LM. Effects of bariatricsurgery on cancer incidence in obese patients in Sweden (SwedishObese Subjects Study): a prospective, controlled intervention trial.Lancet Oncol. 2009;10:653-662.

22. Adams TD, Stroup AM, Gress RE, Adams KF, Calle EE, Smith SC,Halverson RC, Simper SC, Hopkins PN, Hunt SC. Cancer incidenceand mortality after gastric bypass surgery. Obesity (Silver Spring).2009;17:796-802.

23. Neovius M, Narbro K, Keating C, Peltonen M, Sjöholm K, Agren G,Sjöström L, Carlsson L. Health care use during 20 years followingbariatric surgery. JAMA. 2012;308:1132-1141.

24. American Diabetes Association. Obesity management for the treat-ment of type 2 diabetes. Diabetes Care. 2017;40:S57-63.

25. Lim RB (author), Jones D (section editor), Chen W (deputy editor).Bariatric operations for management of obesity: indications and pre-operative preparation. www.uptodate.com/contents/bariatric-oper-ations-for-management-of-obesity-indications-and-preoperative-preparation 2017.

26. Mechanick JI, Youdim A, Jones DB, Garvey WT, Hurley DL, McMahonMM, Heinberg LJ, Kushner R, Adams TD, Shikora S, Dixon JB,Brethauer S. Clinical practice guidelines for the perioperative nutri-tional, metabolic, and nonsurgical support of the bariatric surgerypatient--2013 update: cosponsored by American Association of Clin-ical Endocrinologists, the Obesity Society, and American Society forMetabolic & Bariatric Surgery. Endocr Pract. 2013;19:337-372.

27. Kirwan JP, Aminian A, Kashyap SR, Burguera B, Brethauer SA, SchauerPR. Bariatric surgery in obese patients with type 1 diabetes. DiabetesCare. 2016;39:941-948.

28. Food and Drug Administration. Summary of safety and effectivenessdata. REALIZE™ adjustable gastric band (model 2200-X), 2017:34.www.accessdata.fda.gov/cdrh_docs/pdf7/P070009b.pdf

29. Yermilov I, McGory ML, Shekelle PW, Ko CY, Maggard MA. Appropri-ateness criteria for bariatric surgery: beyond the NIH guidelines. Obe-sity (Silver Spring). 2009;17:1521-1527.

30. Gagner M, Hutchinson C, Rosenthal R. Fifth International ConsensusConference: current status of sleeve gastrectomy. Surg Obes RelatDis. 2016;12:750-756.

31. Service GJ, Thompson GB, Service FJ, Andrews JC, Collazo-Clavell ML,Lloyd RV. Hyperinsulinemic hypoglycemia with nesidioblastosis aftergastric-bypass surgery. N Engl J Med. 2005;353:249-254.

32. Lee CJ, Clark JM, Schweitzer M, Magnuson T, Steele K, Koerner O,Brown TT. Prevalence of and risk factors for hypoglycemic symptomsafter gastric bypass and sleeve gastrectomy. Obesity (Silver Spring).2015;23:1079-1084.

33. Li L, Wu LT. Substance use after bariatric surgery: a review. J Psychi-atr Res. 2016;76:16-29.

34. Kalarchian MA, Marcus MD, Levine MD, Courcoulas AP, Pilkonis PA,Ringham RM, Soulakova JN, Weissfeld LA, Rofey DL. Psychiatric dis-orders among bariatric surgery candidates: relationship to obesityand functional health status. Am J Psychiatry. 2007;164:328-334.

35. Zhao G, Ford ES, Dhingra S, Li C, Strine TW, Mokdad AH. Depressionand anxiety among US adults: associations with body mass index. IntJ Obes (Lond). 2009;33:257-266.

36. Griffen WO Jr, Bivins BA, Bell RM. The decline and fall of jejunoilealbypass. Surg Gynecol Obstet 1983;157:301-308.


146


37. Henrikson V. [Kan tuntarnresektion forsvaras som terapi mot fettsot?].Nordisk Med 1952;47:744-747.

38. Hanipah ZN, Schauer PR. Surgical treatment of obesity and diabetes.Gastrointest Endosc Clin N Am. 2017;27:191-211.

39. Moshiri M, Osman S, Robinson TJ, Khandelwal S, Bhargava P,Rohrmann CA. Evolution of bariatric surgery: a historical perspective.AJR Am J Roentgenol 2013;201:W40-48.

40. Colquitt JL, Pickett K, Loveman E, Frampton GK. Surgery for weightloss in adults. Cochrane Database Syst Rev. 2014;8:CD003641.

41. Khorgami Z, Shoar S, Andalib A, Aminian A, Brethauer SA, SchauerPR. Trends in utilization of bariatric surgery, 2010-2014: sleeve gas-trectomy dominates. Surg Obes Relat Dis. 2017;13:774-778.

42. Azim S, Kashyap SR. Bariatric surgery: pathophysiology and out-comes. Endocrinol Metab Clin North Am. 2016;45:905-921.

43. Parikh MS, Fielding GA, Ren CJ. U.S. experience with 749 laparoscopicadjustable gastric bands: intermediate outcomes. Surg Endosc.2005;19:1631-1635.

44. American Society for Metabolic and Bariatric Surgery. Bariatric sur-gery procedures. Gainesville (FL): American Society for Metabolic andBariatric Surgery (ASMBS); 2016. Available at: https://asmbs.org/pa-tients/bariatric-surgery-procedures. Accessed February 13, 2016.

45. Neylan CJ, Kannan U, Dempsey DT, Williams NN, Dumon KR. The sur-

gical management of obesity. Gastroenterol Clin North Am.2016;45:689-703.

46. Elrazek AE, Elbanna AE, Bilasy SE. Medical management of patientsafter bariatric surgery: principles and guidelines. World J Gastroin-test Surg. 2014;6:220-228.

47. Wu EC, Barba CA. Current practices in the prophylaxis of venousthromboembolism in bariatric surgery. Obes Surg. 2000;10:7-14.

48. Bosnic G. Nutritional requirements after bariatric surgery. Crit CareNurs Clin North Am. 2014;26:255-262.

49. Marcotte E, Chand B. Management and prevention of surgical andnutritional complications after bariatric surgery. Surg Clin North Am.2016;96:843-856.

50. Colossi FG, Casagrande DS, Chatkin R, Moretto M, Barhouch AS,Repetto G, Padoin AV, Mottin CC. Need for multivitamin use in thepostoperative period of gastric bypass. Obes Surg. 2008;18:187-191.

51. Hamad G (author), Jones D (section editor), Chen W (deputy editor).Bariatric surgery: postoperative and long-term management of theuncomplicated patient https://www.uptodate.com/contents/bariatric-surgery-postoperative-and-long-term-management-of-the-uncomplicated-patient.

52. Thibault R, Pichard C. Overview on nutritional issues in bariatric sur-gery. Curr Opin Clin Nutr Metab Care. 2016;19:484-490.

Documents

Honorary Board · Murat Faik Erdoğan, Ankara, Turkey Associate Editors Hasan Ali Altunbaş, Antalya, Turkey Dilek Gogas Yavuz , İstanbul, Turkey Serkan Yener , İzmir, Turkey Statistical