ISSN 2148 - 4902
NORTHERN CLINICS OF ISTANBUL • İSTANBUL KUZEY KLİNİKLERİ
Vol. 4 • No. 1 • Year 2017
Indexed in ‘Web of Science’ Emerging Sources Citation Index
Journal abbreviation: North Clin Istanb Integrating personalized genomics into Turkish healthcare system • Echocardiographic epicardial fat thickness measurement • Is duodenal biopsy appropriate in areas endemic for Helicobacter pylori? • Association between serum vitamin B12 level and frailty
in older adults • The effects of training inpatients and their relatives about infection control measures and subsequent rate of infection • Neutrophil gelatinaseassociated lipocalin reflects the severity of anemia without iron deficiency and secondary hyperparathyroidism in
hemodialysis patients • Clinical features of the patient with multiple primary tumors • The effects of pre-obesity on quality of life, disease activity, and functional status in patients with ankylosing spondylitis • Is there any relationship between low PAPP-A levels
and measures of umbilical vein and placental thickness during first trimester of pregnancy? • Increased levels of red cell distribution width is correlated with presence of left atrial stasis in patients with nonvalvular atrial fibrillation • Acute biliary pancreatitis
in cholecystectomised patients • Giant neglected Bowen’s disease lesion treated successfully with topical 5-fluorouracil • Amyand’s hernia • Systemic juvenile idiopathic arthritis as a fever of unknown origin • Priapism associated with the addition of risperidone
to methylphenidate monotherapy • Intraarticular lipoma of the knee joint located in the posterior compartment • Foreign bodies in the rectum • Iatrogenic Cushing’s syndrome caused by intranasal steroid use • carbon monoxide poisoning in child, infant, and fetus
INDEXED IN WEB OF SCIENCE, EMERGING SOURCES CITATION INDEX, PUBMED, PUBMED CENTRAL, TUBITAK TR INDEX, AND TURKIYE CITATION INDEX.
NORTHERN CLINICS OF ISTANBUL İSTANBUL KUZEY KLİNİKLERİ Editor-in-Chief
Vıce Editors
Bekir Durmus, M.D.
Berna Terzioglu Bebitoglu, M.D. Levent Doganay, M.D. Yavuz Bastug, M.D. Derya Buyukkayhan, M.D. Metin Kement, M.D. Betül Sözeri, M.D. İlker Tekkeşin, M.D.
Scientıfıc Commıttee Abdullah Aydin, M.D.
Eren Ozek, M.D.
Kemal Memisoglu, M.D.
Recep Alp, M.D.
Adem Ozkan, M.D.
Eyup Gumus, M.D.
Kemal Nas, M.D.
Remzi Cevik, M.D.
Afitap Icagasioglu, M.D.
Fahri Ovali, M.D.
Kemalettin Koltka, M.D.
S. Tahir Eren, M.D.
Ahmet Gocmen, M.D.
Fatih Goktay, M.D.
Leyla Karadeniz Bilgin, M.D.
Sabahat Aksaray, M.D.
Alaattin Ozturk, M.D.
Fatih Saygili, M.D.
Lutfullah Orhan, M.D.
Sait Naderi, M.D.
Ali Ihsan Dokucu, M.D.
Fatma Eti Aslan, M.D.
Mahmut Durmuş, M.D.
Salih Boluk, M.D.
Ali Ozdemir, M.D.
Ferruh Isman, M.D.
Mehmet Ali Ozcan, M.D.
Salih Cetinkursun, M.D.
Ali Riza Cenk Celebi, M.D.
Filiz Akyuz, M.D.
Mehmet Doganay, M.D.
Sarenur Gokben, M.D.
Ali Riza Odabas, M.D.
Filiz Topaloglu Demir, M.D.
Mehmet Eren, M.D.
Sahin Senay, M.D.
Asiye Kanbay, M.D.
Fugen Aker, M.D.
Mehmet Kanbay, M.D.
Selcuk Mistik, M.D.
Atakan Yesil, M.D.
Fusun Mayda Domac, M.D.
Mehmet Selcuki, M.D.
Serhat Citak, M.D.
Ateş Kadioglu, M.D.
Gizem Dinler Doganay, M.D.
Mehmet Tayyar, M.D.
Seyhan Hidiroglu, M.D.
Atilla Polat, M.D.
Gozde Kir Cinar, M.D.
Mehmet Tunca, M.D.
Seyhun Kurşat, M.D.
Ayhan Verit, M.D.
Gulbahar Sarac, M.D.
Melek Celik, M.D.
Sibel Dogan, M.D.
Aysel Milanlioglu, M.D.
Gulendam Kocak, M.D.
Melek Gura, M.D.
Selami Sozubir, M.D.
Ayse Cikim Sertkaya, M.D.
Gulnur Tokuc, M.D.
Melih Atahan Guven, M.D.
Sema Yilmaz, M.D.
Ayse Serap Karadag, M.D.
H. Muammer Karakas, M.D.
Metin Akbulut, M.D.
Sevki Erdem, M.D.
Aysegul Gunduz, M.D.
Hakan Erdogan, M.D.
Metin Kapan, M.D.
Soner Sanioglu, M.D.
Aytekin Guven, M.D.
Hale Akbaylar, M.D.
Mine Hekimgil, M.D.
Sukran Kose, M.D.
Aytekin Oguz, M.D.
Haluk Vahaboglu, M.D.
Muhammed Fatih Onsuz, M.D. Tamer Okay, M.D.
Ayten Kadanali, M.D.
Hamit Okur, M.D.
Muhammet Tekin, M.D.
Tarik Sapci, M.D.
Baris Onder Pamuk, M.D.
H. Isin Ozisik Karaman, M.D.
Murat Acar, M.D.
Tayfun Kirazli, M.D.
Bekir Atik, M.D.
Hasan Bombaci, M.D.
Murat Muhcu, M.D.
Tongabay Cumurcu, M.D.
Beyhan Cengiz Ozyurt, M.D.
Hasan Borekci, M.D.
Mustafa Aldemir, M.D.
Tolga Baglan, M.D.
Birsen Yurugen, M.D.
Haydar Sur, M.D.
Mustafa Caliskan, M.D.
Tolga Canbak, M.D.
Canan Agalar, M.D.
Hilmi Ciftci, M.D.
Mustafa Girgin, M.D.
Tuba Tulay Koca, M.D.
Cevdet Ugur Kocogullari, M.D. Hulya Apaydin, M.D.
Nelgin Gerenli, M.D.
Tuba Yavuzsen, M.D.
Derya Buyukkayhan, M.D.
Huseyin Bayramlar, M.D.
Nezih Ozkan, M.D.
Turhan Caskurlu, M.D.
Destina Yalcin, M.D.
Ibrahim Akalin, M.D.
Nihat Aksakal, M.D.
Turkan Kudsioglu, M.D.
Didem Akcali, M.D.
Ibrahim Ali Ozemir, M.D.
Nilay Sahin, M.D.
Umut Kefeli, M.D.
Didem Korular Tez, M.D.
Ibrahim Ikizceli, M.D.
Nuri Aydin, M.D.
Veli Citisli, M.D.
Dilaver Tas, M.D.
Ihsan Karaman, M.D.
Nusret Acikgoz, M.D.
Volkan Ince, M.D.
Duygu Geler Kulcu, M.D.
Ihsan Metin Leblebici, M.D.
Onur S. Goksel, M.D.
Yasar Bukte, M.D.
Ebru Zemheri, M.D.
Ilknur Aktas, M.D.
Orhan Alimoglu, M.D.
Yesim Tuncok, M.D.
Emek Kocaturk Goncu, M.D.
Ismail Islek, M.D.
O. Emek Kocaturk Goncu, M.D. Yurdanur Kilinc, M.D.
Emin Evren Ozcan, M.D.
Kadriye Avci, M.D.
Ozge Ecmel Onur, M.D.
Yuksel Altintas, M.D.
Emine Samdanci, M.D.
Kamil Ozdil, M.D.
Ozlem Baysal, M.D.
Yuksel Ersoy, M.D.
Ercan Madenci, M.D.
Kaya Saribeyoglu, M.D.
Ozlem Guneysel, M.D.
Eren Gozke, M.D.
Kazim Capaci, M.D.
Ozlem Tanriover, M.D.
NORTHERN CLINICS OF ISTANBUL İSTANBUL KUZEY KLİNİKLERİ YEAR 2017 VOLUME 4 NUMBER 1
p-ISSN 2148 - 4902 e-ISSN 2536 - 4553
Ownership and Accountability for Contents on behalf of the Istanbul Northern Anatolian Association of Public Hospitals
Kamil Ozdil, M.D.
Publicatıon Manager
Bekir Durmus, M.D.
Publicatıon Coordinators
Neslihan Buyukmurat, M.D.
Umut Elmas
Executive Office
Istanbul Anadolu Kuzey Kamu Hastaneler Birligi Genel Sekreterligi E5 Karayolu Uzeri, 34752 Atasehir, Istanbul, Turkey Phone: +90 216 578 78 00 Fax: +90 216 577 40 48 http://www.kuzeyklinikleri.com e-mail: bilgi@kuzeyklinikleri.com
Issued by the Istanbul Northern Anatolian Association of Public Hospitals Indexed in WoS, Emerging Sources Citation Index, PubMed, PubMed Central, TUBITAK TR Index, Turkiye Citation Index.
Publisher
Press
KARE PUBLISHING Altayceşme Mah., Engin Sok., No: 3, Daire: 20 34843 Maltepe, Istanbul, Turkey Tel: +90 216 550 61 11 Fax: +90 216 550 61 12 http://www.kareyayincilik.com e-mail: kare@kareyayincilik.com
DESIGN
Ali Cangul kare@kareyayincilik.com
Info
YILDIRIM PRINTING HOUSE Yuzyil Mah., Massit Matbaacılar Sitesi, 1. Cad. No: 101, Bagcilar, Istanbul, Turkey Tel: +90 212 629 80 37 Fax: +90 212 629 80 39
Press date: April 2017 Circulation: 1100 Type of publication: Periodical
Turkısh to English Translatıon
Englısh Editıng
Gurkan Kazanci, M.D. PhD. Kazanci Medical Translation Office kazanci.g@gmail.com
KAREDITING www.karediting.com
Northern Clinics of Istanbul (NCI) is a peer-reviewed journal published triannually by the Istanbul Northern Anatolian Association of Public Hospitals. Materials published in the Journal is covered by copyright ©2017 NCI. All rights reserved. This publication is printed on paper that meets the international standard ISO 9706:1994. National Library of Medicine recommends the use of permanent, acid-free paper in the production of biomedical literature.
KARE PUBLISHIN G
CONTENTS Vol. 4 • No. 1 • Year 2017
INVITED E D I TO R I A L
V
EDITORIAL
VI
INSTRUCTIONS FOR THE AUTHORS
1–3
Integrating personalized genomics into Turkish healthcare system: A cancer-oriented pilot activity of Istanbul Northern Anatolian Public Hospitals with GLAB L. Doganay, K. Ozdil, K. Memisoglu, S. Katrinli, E. Karakoc, E. Nikerel, G. Dinler Doganay
ORIGINAL ARTICLES
4–12
Echocardiographic epicardial fat thickness measurement: A new screening test for subclinic atherosclerosis in patients with inflammatory bowel diseases K. Ozdil, Z. Caliskan, N. Keles, O. Ozturk, A. S. Tekin, R. Kahraman, L. Doganay, K. Demircioglu, Y. Yilmaz, M. Caliskan
13–21
Is duodenal biopsy appropriate in areas endemic for Helicobacter pylori? A. Sahin, G. Cihangiroglu, Y. Bilgic, T. Calhan, M. Cengiz
22–28
Association between serum vitamin B12 level and frailty in older adults O. Dokuzlar, P. Soysal, A. T. Isik
29–35
The effects of training inpatients and their relatives about infection control measures and subsequent rate of infection F. Ozturkan Erdek, C. Keles Gozutok, Y. Dogan Merih, A. Aliogulları
36–42
Neutrophil gelatinase-associated lipocalin reflects the severity of anemia without iron deficiency and secondary hyperparathyroidism in hemodialysis patients I. Pembegul Yigit, R. Ulu, N. Gozel, H. Taskapan, N. Ilhan, A. Dogukan
43–51
Clinical features of the patient with multiple primary tumors: Single center experience A. Gokyer, O. Kostek, M. B. Hacioglu, B. Erdogan, H. Kodaz, E. Turkmen, I. Hacibekiroglu, S. Uzunoglu, I. Cicin
52–59
The effects of pre-obesity on quality of life, disease activity, and functional status in patients with ankylosing spondylitis S. Toy, D. Ozbag, Z. Altay
60–65 66–72 73–76
Is there any relationship between low PAPP-A levels and measures of umbilical vein and placental thickness during first trimester of pregnancy? G. Uysal, S. Tutus, F. Cagli, C. Adiguzel Increased levels of red cell distribution width is correlated with presence of left atrial stasis in patients with non-valvular atrial fibrillation A. Kaya, C. Tukkan, A. T. Alper, B. Gungor, K. S. Ozcan, M. A. Tatlisu, A. I. Tekkesin, F. Ozpamuk Karadeniz, G. Gok, O. Kayapinar Acute biliary pancreatitis in cholecystectomised patients F. Ciftci, T. Anuk
CONTENTS Vol. 4 • No. 1 • Year 2017 Original Images
77
Giant neglected Bowen’s disease lesion treated successfully with topical 5-fluorouracil E. Ozlu, R. Ertas, K. Ozyurt, Y. Tekin, M. Atasoy
C A S E REPORTS
78–80
A condition that should be kept in mind in incarcerated hernia: Amyand’s hernia M. B. Bozan, F. M. Yazar, F. Erol, E. Gul, O. D. Alatas
81–84
Systemic juvenile idiopathic arthritis as a fever of unknown origin C. Hardal, M. Erguven, Z. A. Saglam
85–88
Priapism associated with the addition of risperidone to methylphenidate monotherapy: a case report H. Unver, N. Cakin Memik, E. Simsek
89–92
Intra-articular lipoma of the knee joint located in the posterior compartment: A rare location M. Bankaoglu, O. Yapici Ugurlar, M. Ugurlar, M. M. Sonmez, O. T. Eren
93–96
Foreign bodies in the rectum: 2 Case reports S. Zeren, Z. Bayhan, M. C. Algin, M. Mestan, U. Arslan
97–99
Iatrogenic Cushing’s syndrome caused by intranasal steroid use F. Dursun, H. Kirmizibekmez
100–107 Epidemiology, pathophysiology, clinical evaluation, and treatment of carbon monoxide poisoning in child, infant, and fetus A. A. Gozubuyuk, H. Dag, A. Kacar, Y. Karakurt, V. Arica
EDITORIAL
Dear NCI readers, This is the first issue of 2017 and our journal is now 4 years old. To begin our fourth year, we are very proud to announce that NCI has been accepted into the Web of Science scientific citation indexing service. This is an astonishing achievement of the editorial team, the publisher, the authors of the published articles, and the peer reviewers. We appreciate all the efforts of all parties. In this issue, you will find 10 original articles from surgical and medical colleagues of 9 different specialties. We hope that that NCI readers find the papers interesting and we look forward to your participation in upcoming issues. Bekir Durmus, M.D. Editor of NCI
INSTRUCTIONS FOR THE AUTHORS Northern Clinics of Istanbul
- NCI is a peer-reviewed, open-access, international journal published by the Istanbul Northern Anatolian Association of Public Hospitals (INAAPH). The NCI is printed 3 times a year. Free full-text articles in English are available at www. kuzeyklinikleri.com. The NCI is indexed in the Web of Science, Emerging Sources Citation Index, PubMed, PubMed Central, TUBITAK TR Index, Turkey Citation Index (Türkiye Atıf Dizini). The journal publishes research, interesting case reports, letters to the editor, review articles, editorial comments, medical news, and guidelines. The NCI accepts manuscripts written in Turkish and English. Opinions presented in published articles do not represent official endorsement of the INAAPH. Manuscripts should be prepared in accordance with the Uniform Requirements for Manuscripts Submitted to Biomedical Journals, which is regularly updated by the International Committee of Medical Journal Editors (ICMJE), and available at http://www.icmje.org. ARTICLE TYPES The NCI publishes the kinds of articles briefly described below.
Research Articles: These are articles on original clinical (conducted with healthy subjects or patients) or experimental (human, animal or in-vitro trials) research performed in all fields. Case Reports: This section contains reports on interesting, instructive or rarely seen cases. Review Articles: Reviews are usually written at the invitation of the editors. The NCI publishes clinical review articles related to the natural course of diseases, updated diagnostic and therapeutic approaches of concern to clinicians and specialists in basic sciences that encompass genetic, physiological, and pharmacological aspects of the underlying mechanisms of diseases, and reviews about state-of-the art treatment strategies, technological advancements, and newly approved drugs. Editorial Comments: This section contains editors’ comments, reviews, and other relevant items.
Letters to the Editor: These are comments, criticism and contributions in response to a paper published in the NCI. The author(s) of a criticized article has the right to reply. The article that is the subject of the comments should be listed in the references section. Letters must be sent to the editor within 4 weeks following publication of the subject article in the NCI. PREPARATION OF MANUSCRIPT General Format: All manuscripts should be typewritten on A4 white paper, and 2.5 cm-wide margins should be left on all sides. The references should be numbered consecutively in the order of their first mention in the text. All text material, including references, footnotes, and table and figure legends, should be typed using double-spacing in an 11 point font with left alignment and without hyphenated line breaks. The fonts Times New Roman or Arial should be used in the text, for symbols, and all other special characters. Please use the editing features of your word processing program to type bold or italic letters, mathematical symbols, Greek letters, subscript and superscript characters. Please take care not to confuse the letters O and I with the numerals 0 and 1. To set a left indent for a paragraph, click the TAB button once. Only the International System of Units (SI) should be used for units of measurement. Abbreviations and acronyms should be written in parentheses following the full name or an explanation of the usage should be provided just after the first appearance in the text. Please review the final version of the manuscript very carefully, especially for formatting and editing errors. All pages of the manuscript should be consecutively numbered starting from the title page (page 1, title page; page 2, Turkish abstract; page 3, English abstract, etc.). Page numbers should be indicated on the upper right-hand corner of each page. Final version of the manuscript should be in “.doc” or “.rtf” format. Manuscripts submitted in “.pdf” format will not be accepted.
Manuscript Sections: All research articles must contain the following sections: (1) Title page, (2) Abstract with keywords, (3) Introduction, (4) Methods, (5) Results, (6) Discussion, (7) Acknowledgements, (8) Conflict of interest, (9) Fund-
ing resources, (10) References, (11) Legends of the figures, (12) Tables, (13) Figures. In case of need, presentation of Methods, Results, and Discussion sections under subheadings is preferred. Case reports should be presented following abstract section, under headings of introduction, case presentation, and discussion. In review articles, appropriate headings can be used in accordance with the development of the manuscript. Sections of the manuscript in order of their appearance in the text with relevant explanations are listed below.
Title Page: The title page should contain the following information: (1) article title, (2) full name and academic title of all participating authors, (3) department and institution of all authors, including the city and country, (4) name, full mailing address, phone and fax numbers, and e-mail address of the corresponding author, and (5) word count (including title page, abstracts, explanatory notes for figures and tables). If the study was presented elsewhere, those details should be indicated on the title page. Abstract: The abstract should be written on a separate page. It should contain at most 250 words, and be structured as follows: (1) Objective, (2) Methods, (3) Results, and (4) Conclusion. Under these headings, briefly describe the subject of the article, methods used for the study, basic findings, and author’s conclusion. No subtitles may be used in the abstract of a case report. A minimal number of abbreviations and/or acronyms should be used. Abstracts should not contain any references. A maximum of 5 keywords should be included at the end of the abstract. The Medical Subject Headings (MeSH) prepared by the US National Library of Medicine (NLM) may be used as a reference for keywords. Introduction: State the specific purpose and available data relevant to the study. Methods: All methods used to select participants and conduct the study should be described in detail. Known methods should be cited. Novel or modified methods used should be described in detail. Doses, concentrations, routes, and duration of administration of drugs and chemical agents should be indicated. A concise report of all statistical methods used for summarizing available data and for test-
INSTRUCTIONS FOR THE AUTHORS ing the proposed hypothesis should be provided under a subtitle, including the p value criteria determined for statistically significant difference. Statistical evaluation conducted should be explained in detail. Standard statistical methods should be used as much as possible. If rarely employed or novel statistical methods were used, then the relevant references should be cited. When necessary, more detailed explanations about unusual, complex or new statistical methods can be provided in separate files for readers as online supplementary data. The commercial name and version number of any statistical software package program used should be provided. For statistical evaluation, the recommendations in the statistics section of the “Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical Publication” (http://www.ICMJE.org) should be taken into consideration.
Results: The study results should be presented in logical sequence and in detail. The findings should be supported by figures and tables. Information given in figures and tables should not be repeated in the text unless absolutely required. Discussion: Data relevant to the study subject matter should be examined, evaluated, and substantiated with references from domestic and international sources. General information irrelevant or superfluous to the report should not be included. Acknowledgement: The names of individuals who contributed to the study but who fail to meet the criteria of authorship should be mentioned in this section. The written consent of all individuals mentioned should be obtained. Conflict of Interest: All potential conflicts of interest should be declared under this heading. All affiliations with pharmaceutical firms, biomedical device manufacturers, and other service or product procurers relevant to the subject matter of the study should be explicitly indicated. If no conflict of interest exists, this should be stated as “none declared.” Declarations related to conflicts of interest should be placed at the bottom of a separate page after the acknowledgements and before the references. A Conflict of Interest Form will be sent to the authors of accepted papers.
Funding sources: The full name of any sponsoring foundation or institution should be provided. References: References should be listed consecutively in the order of their first appearance in the text. All sources the authors made direct use of should be included as references, excluding unpublished results and personal communications. During the preparation of the manuscript for publication, additional information regarding any unconfirmed references will be requested from the authors. Titles of journals should be abbreviated as indicated in the Index Medicus. If that is not possible, then the full name of the journal should be provided. In the references, a maximum of 6 authors should be cited for any 1 article with their full surname, and then the initial(s) of their first name. If more than 6 authors contributed to the cited article, then after the name of the sixth author, the abbreviation “et al.” should be added to indicate that there are additional authors. The notation and listing of references should comply with the following sample reference citations: 1. Journal: Balci NC, Sirvanci M, Tüfek I, Onat L, Duran C. Spontaneous retroperitoneal hemorrhage secondary to subcapsular renal hematoma: MRI findings. Magn Reson Imaging 2001;19:1145-8. 2. Articles in press: Roten L, Derval N, Sacher F, Pascale P, Wilton SB, Scherr D, et al. Ajmaline attenuates electrocardiogram characteristics of inferolateral early repolarization. Heart Rhythm 2011 Sep 19 [Epub ahead of print], doi:10.1016/j. hrthm.2011.09.013. 3. Book: Brown AM. Physiology of the liver. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2003. 4. Chapter in book: Anderson JL, Muhlestein JB. The role of infection. In: Theroux P, editor. Acute coronary syndromes: a companion to Braunwald’s Heart Disease. Philadelphia: W.B. Saunders; 2003. p. 88107. 5. Web page: Nainggolan L. New salt paper causes controversy. Heartwire. May 3, 2011. Available at: http:// www.theheart.org/article/1220043. do. Accessed: June 12, 2011.
Figure Legends: Explanatory notes for
each figure should be submitted on a separate page in order of their appearance in the text immediately after the references section under the heading “figure legends.” All abbreviations and symbols used in the figure should be defined in alphabetical order.
Figures: The manuscript will not be evaluated until all figures cited in the text are submitted. The number of figures provided should be in accordance with the content and data presented in the text, and table data should not be repeated in figures. All figures should be sent in individual electronic file format ready for publication with maximum dimensions of 125 cm x 180 cm. Illustrations in color should be in CMYK format and have a minimum resolution of 300 DPI suitable for publication. Figures depicted in gray scale should have a minimum resolution of 600 DPI, and the minimum resolution required for black and white illustrations is 1200 DPI. All figures should be in TIFF format. Figures must not disclose or imply the identity of a specific individual without the written consent of the individual in question. Tables: Each table should be typed or printed with double-spacing on a separate sheet of paper. Tables should be numbered consecutively in the order of their first citation in the text. The number and title of the table should be placed just above the table. Do not use vertical lines between columns. Horizontal lines should be used only above and below the headings of the columns, and at the bottom of the table. If required, explanatory notes regarding table data should be written in footnotes. All abbreviations and acronyms used in the table should also be explained in alphabetical order in footnotes. ETHICAL POLICY NCI follows the ethics flowcharts developed by the Committee on Publication Ethics (COPE) for dealing with cases of possible scientific misconduct and breaches of publication ethics. For detailed information please visit www.publicationethics.org. All submitted manuscripts are screened with plagiarism software (iThenticate) to detect instances of overlapping and similar text during the evaluation process.
INSTRUCTIONS FOR THE AUTHORS All manuscripts presenting data obtained from research involving human subjects must include a statement that the written informed consent of the participants was obtained and that the study was approved by an institutional review board or an equivalent body. This institutional approval should be submitted with the manuscript. Authors of case reports must submit the written informed consent of the subject(s) of the report or of the patient’s legal representative. Manuscripts with human and animal studies should describe the steps taken to eliminate pain and suffering. AUTHORSHIP All individuals listed as “author” in the submitted manuscript must make an adequate contribution to the study, meet the criteria of authorship, and take responsibility for their part of the manuscript. For the sake of the outcomes and the integrity of the study, at least one author should be responsible for each section of the manuscript. All authors mentioned in the cover letter must meet all of the following criteria: (1) substantial contribution to conception, design of the study, analysis, and interpretation of data, or all of these criteria; (2) significant contribution to the drafting of the article or revision of its scientific content; (3) approval of the final version of the article to be published. In multicentered studies, all individuals who are named as authors under the title of the article should meet all the above-mentioned requirements of authorship. Seeking or providing financial support for the study, and/or data collection do not satisfy the criteria of authorship per se, nor does general support or guidance provided to the study investigators. Individuals who contributed to the study in various ways but who fail to meet the criteria of authorship may be included in the acknowledgements with their written consent. Please refer to the ICMJE website for more information about authorship. Increasing the number of authors unnecessarily is not ethical conduct and to prevent any attempt to seek undue academic prestige or other unethical advantages, the editor may request a declaration from the authors of their individual contributions to the article and publish this information, if deemed appropriate. The sequence
of authors’ names should be based on a consensus reached by all the participating authors. Due to different specifications for the sequencing of authors, the order provided will be used unless otherwise stated. Authors may explain the rationale for a different sequence in a footnote. COVER LETTER Each manuscript should be sent with a cover letter that must contain the following explicit declarations: (1) all authors meet the criteria of authorship; (2) the submitted manuscript was not simultaneously sent to another journal and it is not presently being evaluated by another journal; (3) no part of the content of the manuscript has been previously published elsewhere; and (4) the manuscript has been read and approved of by all authors. The name, full address, phone and fax number(s), and e-mail address of the corresponding author to whom all editorial correspondence will be directed must be provided. A brief paragraph describing the scientific significance of the manuscript may also be included. SUBMISSION OF THE MANUSCRIPT All manuscripts should be submitted to the NCI via the online submission system. For questions or requests related to the submission and evaluation process of manuscripts, the editorial office may be contacted by e-mail at bilgi@ kuzeyklinikleri.com. In compliance with the journal’s publication rules, the current status of the manuscript will not be discussed on the phone prior to acceptance for publication. First-time users of the online submission system will need to register. A user name and a code specific to the user will be sent by e-mail. For further details please consult the online manuscript submission page. REVIEW OF MANUSCRIPTS In order for an article to be published in the journal it should not be published elsewhere, and must be deemed suitable for publication by the editorial board selected by the NCI Executive Committee. All responsibility for the manuscript belongs to the author(s). The evaluation process of the submitted manuscript will not begin until a document with the signed approval of all authors has been received. During typesetting and other
preparation of the manuscript for publication, a Copyright Transfer Form will be sent to the primary author(s) (“guarantors”) who will assume responsibility for the manuscript. All submitted manuscripts are first evaluated by the editorial board. At this stage, manuscripts not deemed suitable for publication in NCI, including those not complying with the requirements or without adequate scientific content, will be returned to the authors. Manuscripts found suitable for publication will be sent to reviewers for more detailed evaluation. Acceptability of manuscripts is dependent on originality, scientific content, and the subject of the study, in accordance with the publication protocol of the journal. All research articles deemed suitable for publication are subjected to a detailed statistical evaluation. The authors are informed of the editors’ decision on the acceptability of the manuscript via e-mail, usually within 6 weeks of its submission. The editors do not discuss their decision on the phone. All objections and requests should be communicated to the editors in a written format. If deemed necessary, the editorial board has the right to make modifications to the text without altering the main concept of the manuscript. An offprint of the manuscript will not be sent to the author(s). OPEN ACCESS NCI is a fully open access journal. All articles published in NCI are available on the internet to all users immediately upon publication. Non-commercial use and distribution in any medium is permitted, provided the author and the journal are properly credited. PUBLISHING FEE Manuscripts can be reached from the web page of journal without any fees. No additional fee is required from the authors for accepted manuscripts. ADDRESS OF CORRESPONDENCE Istanbul Anadolu Kuzey Kamu Hastaneler Birligi Genel Sekreterligi, E5 Karayolu Uzeri 34752 Atasehir, Istanbul, Turkey Tel: 0216 578 78 00 - 0216 578 78 50 Fax: 0216 577 40 48 E-mail: bilgi@kuzeyklinikleri.com
Invited editorial
GENETICS&MOLECULAR MEDICINE
North Clin Istanb 2017;4(1):1–3 doi: 10.14744/nci.2017.38980
Integrating personalized genomics into Turkish healthcare system: A cancer-oriented pilot activity of Istanbul Northern Anatolian Public Hospitals with GLAB Levent Doganay,1 Kamil Ozdil,2 Kemal Memisoglu,3 Seyma Katrinli,4 Emre Karakoc,5 Emrah Nikerel,6 Gizem Dinler Doganay4 Genomic Laboratory, Umraniye Training and Research Hospital, Istanbul, Turkey
1
Secretary General, Istanbul Association of Northern Anatolian Public Hospitals, Istanbul, Turkey
2
Director of Health, Health Directorate of Istanbul, Ministry of Health, Istanbul, Turkey
3
Genomic Laboratory, Istanbul Technical University, Istanbul, Turkey
4
Genomic Laboratory, Bioinformatics, Medipol University Faculty of Medicine, Istanbul, Turkey
5
Genomic Laboratory, Bioinformatics, Yeditepe University Faculty of Medicine, Istanbul, Turkey
6
C
ancer is a major health problem worldwide. The annual number of newly diagnosed cancer cases has reached approximately 14 million people, according to the World Health Organization [1]. The incidence rates are growing, and the estimated annual number of cancer cases in the next 20 years is 22 million. According to the World Cancer Report, 8.2 million people died due to cancer in 2012, and the annual number of deaths is expected to increase to 13 million within 20 years [1, 2]. In Turkey, cancer is the second leading cause of death after cardiovascular diseases. Data from the Turkish Statistical Institute revealed that 79,628 people lost their life as result of cancer in 2013 [3]. The cancer incidence rate in Turkey is around 200 for every 100,000 people according to the Cancer Department of the Public Health Institution of Turkey, and Istanbul has the most cancer-related deaths
with respect to entire population [4]. The most observed type of cancer in women is breast cancer, with an incidence rate of 40 cases for every 100,000 women. While the most diagnosed cancer types in men are respiratory system cancers, prostate, and colorectal cancers, with an incidence rate of 66, 26, and 21 cases, respectively, for every 100,000 males. There is inherited factor in 5% to 10% of breast and colorectal cancer cases [5]. When an accumulation of breast or colorectal cancer cases is observed in a family, the diagnosed patient should be screened for hereditary cancer gene mutations, and if the patient has a pathogenic mutation, family members who are at risk should also be screened. Cancer statistics of Turkey showed that only 47% of breast cancers and 29% of colorectal cancers have early diagnosis. In case of early diagnosis, the cure rate for breast and colorectal cancer is 90% and 80%, respectively.
Received: April 06, 2017 Accepted: April 19, 2017 Online: May 10, 2017 Correspondence: Dr. Levent DOGANAY. Umraniye Egitim ve Arastirma Hastanesi, Istanbul, Turkey. Tel: +90 216 - 632 18 18 e-mail: levent.doganay@ueh.gov.tr Š Copyright 2017 by Istanbul Northern Anatolian Association of Public Hospitals - Available online at www.kuzeyklinikleri.com
North Clin Istanb
2
Hereditary cancers are generally caused by mutations in genes that are related to a high probability of cancer development, vertical transmission from parents, and an association with other tumor types [6, 7]. Once an individual is suspected of carrying a risk for hereditary cancer, genetic counseling should be offered [8]. For example, in Istanbul, each year 6000 people are estimated to be diagnosed with breast or colorectal cancer. As many as 10% of these cancer patients, 600 cases, are expected to have a genetic background of predisposition for cancer. If these 600 patients have 3 siblings and 3 children, that estimation reveals 3600 healthy individuals that may have a cancer-predisposing mutation who are at risk of developing cancer. The current developments in molecular genetics, and especially nextgeneration sequencing (NGS) technologies, allow screening of multiple genes and multiple individuals very quickly, which in turn, greatly supports preventive medicine. To support this vital need for genomic screening of hereditary breast and colorectal cancers, Genomic Laboratory (GLAB) was founded in Istanbul under the constitution of the Istanbul Association of Northern Anatolian Public Hospitals with the cooperation of Istanbul Technical University with a grant from the Istanbul Development Agency in 2015. The main objective of GLAB is to use NGS to screen breast and colorectal cancer patients for hereditary cancer mutations, and if a patient has such a mutation, the other family members are screened to determine whether they have risk of developing hereditary cancer. Currently, the genes screened for are BRCA1/2 (breast cancer 1/2), TP53 (tumor protein p53), PTEN (phosphatase and tensin homolog), ATM (ataxia-telangiectasia mutated), PALB2 (partner and localizer of BRCA2), CDH1 (cadherin 1), RAD51C/D (RAD51 homolog C/D), BRIP1 (BRCA1-interacting protein 1), STK11 (serine/threonine kinase 11), and CHEK2 (checkpoint kinase 2). For colorectal cancer, MUTYH (mutY DNA glycosylase), EPCAM (epithelial cell adhesion molecule), MSH2/6 (DNA mismatch repair protein 2/6), MLH1 (MutL homolog 1, colon cancer, nonpolyposis type 2), APC (adenomatous polyposis coli), PMS2 (mismatch repair endonuclease PMS2), BMPR1A (bone morphogenetic protein receptor, type IA), PTEN (phosphatase and tensin homolog), ATM (ataxia-telangiectasia mu-
tated), BLM (Bloom syndrome protein), TP53 (tumor protein p53), SMAD4 (SMAD family member n°4), STK11 (serine/threonine kinase 11), and CHEK2 (checkpoint kinase 2). GLAB also gets further support for bioinformatics analysis from Yeditepe University and Medipol University. Currently, GLAB provides service to patients from Umraniye Teaching and Research Hospital and Goztepe Teaching and Research Hospital. The blood samples of breast and colorectal cancer patients are collected in these hospitals, and DNA isolation from the samples is performed in the GLAB laboratory located in Umraniye Teaching and Research Hospital. Isolated DNA samples are then transported to the GLAB laboratory located in ITU, with appropriate care to maintain the cold chain. Further NGS analysis is performed at this GLAB site, and the data generated are analyzed with bioinformatics tools. In this process, two different bioinformatics analysis pipelines are in use to minimize false positive and false negative results. Each observed variation is screened in multiple public databases for its phenotypic effect (i.e., whether the variation is benign, pathogenic, or of uncertain significance). In the end, a genetic report is created based on the recommendations of a medical genetics doctor that includes the patient’s genetic screening result indicating that the mutation profiles are uncertain significant, possibly pathogenic, or pathogenic variations, according to bioinformatics results. If a patient has a pathogenic variation and a risk of hereditary cancer, the patient may be offered a surgical option (prophylactic mastectomy, oophorectomy, colectomy etc.) in discussion with medical genetics doctor and surgical committee [8]. Moreover, family members of this patient are offered genetic screening and counseling. Umraniye Teaching and Research Hospital, which specializes in oncological genetic counseling, currently provides this service. As a result, GLAB is creating the foundation for preventive medicine in hereditary breast and colon cancer in Turkey, and is integrating personalized medicine into the Turkish health care system. The services provided by GLAB will prevent and detect cancer at early stages, thus reducing health care expenses and lowering cancer mortality rates. Conflict of Interest: None declared.
Doganay et al., Personalized medicine for cancer
Financial Disclosure: The authors declared that this study has received no financial support. Authorship contributions: Concept – L.D., K.O., K.M., S.K., E.K., E.N., G.D.; Litearature search – L.D., S.K., E.K., E.N., G.D.; Writing – L.D., S.K., G.D.; Critical review – L.D., K.O., K.M., S.K., E.K., E.N., GD.
REFERENCES 1. Forman D, Ferlay J. The Global and Regional Burden of Cancer. In: Stewart BW, Wild CP, editors. World Cancer Report. Lyon: IARCPress; 2014. p. 16–53. 2. GBD 2015 Mortality and Causes of Death Collaborators. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 2016;388:1459–544.
3 3. Türkiye İstatistik Kurumu. Ölüm İstatistikleri 2016. Available at: http://www.tuik.gov.tr/PreHaberBultenleri.do?id=21526. Accessed March 12, 2017. 4. Türkiye Halk Sağlığı Kurumu. Türkiye Kanser İstatistikleri 2017. Available at: http://kanser.gov.tr/Dosya/2017Haberler/2014RAPOR._uzun.pdf. Accessed March 12, 2017. 5. Thomas DM, James PA, Ballinger ML. Clinical implications of genomics for cancer risk genetics. Lancet Oncol 2015;16:e303– 8. 6. Lynch HT, Watson P, Conway TA, Lynch JF. Clinical/genetic features in hereditary breast cancer. Breast Cancer Res Treat 1990;15:63–71. 7. Garber JE, Offit K. Hereditary cancer predisposition syndromes. J Clin Oncol 2005;23:276–92. 8. Hartmann LC, Lindor NM. The role of risk-reducing surgery in hereditary breast and ovarian cancer. N Engl J Med 2016;374:454–68.
Orıgınal Article
CARDIOLOGY
North Clin Istanb 2017;4(1):4–12 doi: 10.14744/nci.2017.74508
Echocardiographic epicardial fat thickness measurement: A new screening test for subclinic atherosclerosis in patients with inflammatory bowel diseases Kamil Ozdil,1 Zuhal Caliskan,1 Nursen Keles,2 Oguzhan Ozturk,1 Ahmet Selami Tekin,2 Resul Kahraman,1 Levent Doganay,1 Kenan Demircioglu,2 Yusuf Yilmaz,2 Mustafa Caliskan2 Department of Gastroenterology, Saglık Bilimleri University Umraniye Training and Research Hospital, Istanbul,Turkey
1
Department of Cardiology, Istanbul Medeniyet University Goztepe Training and Research Hospital, Istanbul,Turkey
2
ABSTRACT OBJECTIVE: Inflammatory bowel diseases (IBD) consist of a number of chronic inflammatory diseases. Inflammatory process is known to be involved in all stages of atherosclerosis. Early atherosclerosis is reflected by increased levels of carotid artery intima media thickness (c-IMT) and high-sensitivity C-reactive protein (hs-CRP). Epicardial fat thickness (EFT) strongly influences both the formation and progression of atherosclerosis. Recent studies have demonstrated a relationship between c-IMT and hs-CRP levels and the risk of atherosclerosis in patients with IBD. However, no study has yet compared EFT between patients with IBD and the general healthy population. Hence, this study was designed to further evaluate whether patients with IBD have higher EFT values with increased c-IMT and hs-CRP levels compared to those in the healthy population. METHODS: A total of 110 patients with IBD and 105 healthy volunteers were enrolled into this study. EFT was evaluated by transthoracic echocardiography. c-IMT levels were measured using an ultrasound scanner with a linear probe. The plasma levels of hs-CRP were measured using a highly sensitive sandwich ELISA technique. RESULTS: The hs-CRP and c-IMT levels of patients with IBD were significantly higher than those of the control group. The EFT values of patients with IBD were significantly higher than those of the control group (0.54±0.13 vs. 0.49±0.09, p=0.002). CONCLUSION: Echocardiographic EFT measurements of patients with IBD were significantly higher than those of the normal population, which may be associated with an increased subclinical atherosclerosis risk in these patients. Keywords: Inflammatory bowel disease; atherosclerosis; carotid intima-media thickness; high-sensitivity C-reactive protein; epicardial fat thickness.
Received: March 08, 2017 Accepted: April 10, 2017 Online: May 10, 2017 Correspondence: Dr. Nursen KELES. Istanbul Medeniyet Universitesi, Goztepe Egitim ve Arastirma Hastanesi, Kardiyoloji Klinigi, Doktor Erkin Caddesi, Kadikoy, 81130 Istanbul, Turkey. Tel: +90 216 - 566 40 00 e-mail: drnursenkeles@yahoo.com.tr © Copyright 2017 by Istanbul Northern Anatolian Association of Public Hospitals–Available online at www.kuzeyklinikleri.com
Ozdil et al., Echocardiographic epicardial fat thickness measurement
I
nflammatory bowel diseases (IBD) consist of a number of chronic diseases that are subject to relapse. In IBD, as in Crohn’s disease and ulcerative colitis, an abnormal immune response occurs damaging the intestinal microvascular endothelial cells and resulting in chronic low-grade inflammation. Although IBD primarily influence the gastrointestinal system, they have been reported to affect other intestinal organs and tissues as well, including the cardiovascular (CV) system [1, 2]. It is a well-established fact that inflammatory pathway activation has an important role during the induction and progression of atherosclerosis. The inflammatory cascade is known to be involved in all stages of atherosclerosis, from the early phase of endothelial dysfunction to mature atheroma formation and its subsequent rupture or erosion [3, 4]. Several studies have shown that patients with IBD may have a higher risk of developing atherosclerosis [1, 2]. Early atherosclerosis is reflected by increased levels of carotid artery intima media thickness (cIMT). c-IMT is a result of cumulative atherogenetic processes and may predict CV events [5]. High-sensitivity C-reactive protein (hs-CRP) is a circulating acute-phase reactant that represents active systemic inflammation and has been reported to be a strong predictor of future CV events in large prospective trials [6]. Epicardial fat is a true visceral adipose tissue deposited in proximity to the atrium, the right ventricle’s free wall, and the left ventricular apex of the heart [7]. A recent study demonstrated that epicardial fat strongly influences both the formation and progression of coronary artery disease (CAD) [8]. Epicardial fat may also have a role in the screening of patients having intermediate CAD risk [9]. Recent studies have demonstrated an association between c-IMT and atherosclerotic risk in patients with IBD [10, 11]. However, there are no data regarding the comparison of epicardial fat thickness (EFT) between patients with IBD and the general healthy population. The relationships between c-IMT, hs-CRP, and EFT in patients with IBD are also not yet clear. Recently conducted trials have reported an increased risk of developing atherosclerosis in pa-
5
tients with IBD. We hypothesized that EFT may potentially be a novel early marker of atherosclerosis along with hs-CRP and c-IMT in patients with IBD. Therefore, this study was designed to further evaluate whether patients with IBD have higher EFT values with increased c-IMT and hs-CRP levels compared to those in the healthy control group. MATERIALS AND METHODS Study population Diagnoses of IBD were based on established criteria, namely, radiological, histological, clinical, and endoscopic evidence. The inclusion criterion was the patient’s age being between 18 and 60 years. Each patient was examined after at least a 15-day attackfree episode [Truelove–Witts Index (TWAS)] [12] <4 and Crohn’s Disease Activity Index (CDAI) [13] <150). Exclusion criteria were the presence of congenital or valvular heart disease; any signs indicating cardiac involvement; nonsinus cardiac rhythms; any prior myocardial infarctions; hyperthyroidism or hypothyroidism; cor pulmonale or chronic obstructive pulmonary disease; diabetes mellitus; inflammatory rheumatic diseases, including rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis; and systemic diseases such as collagenosis and hepatic, hemolytic, and renal diseases. Moreover, subjects who used vasoactive drugs, were smokers, had a history of CAD (previous NSTEMI or angina or revascularization) or any changes in ST segments or T waves reflecting myocardial ischemia, Q waves, or incidental left bundle branch block on their ECG were excluded from the study. Patients with triglyceride levels >4.56 mmol/L (400 mg/dL), body mass index (BMI) >35 kg/m2, or left ventricular mass index (LVMI) ≥125 g/m2 for men or 110 g/m2 for women were also excluded. A total of 110 patients with IBD fulfilled all the inclusion and exclusion criteria and were sequentially included into the study upon their admission to our gastroenterology outpatient clinic between January 2013 and March 2016. Of the 110 patients, 56 had Crohn’s disease and 54 had ulcerative colitis. For the control group, 105 healthy volunteers,
6
matched by sex and age, were recruited from volunteers and/or hospital staff. Gender, age, and BMI were recorded for each volunteer. All measurements of the patients were performed shortly after the first diagnosis of IBD. Biochemical assessments Levels of total serum cholesterol, low-density lipoprotein (LDL) cholesterol, triglyceride, high-density lipoprotein (HDL) cholesterol, and fasting blood glucose and erythrocyte sedimentation rate (ESR) were analyzed from blood samples of the study population. Serum hs-CRP levels were assessed by a highly sensitive sandwich ELISA technique. The study was conducted in accordance with the guidelines of the Declaration of Helsinki on biomedical research involving human subjects. Written informed consent was received from all study subjects, and the study protocol was approved by the institutional ethics committee. Echocardiographic evaluation Echocardiographic evaluation of the study population was performed by a GE VIVID 7 (Horten, Norway) transthoracic echocardiography (TTE) machine. M-mode, two-dimensional, and subsequently both standard and pulsed tissue Doppler echocardiographic evaluations were performed on the study population, with patients lying laterally in the decubitus position. The diastolic interventricular septal (IVS) and posterior wall (PW) thickness and the left ventricular end-systolic diameter (LVSD) and the left ventricular end-diastolic diameter (LVDD)were measured in the parasternal long-axis window. M-mode images were used to carry out all measurements [14]. The diastolic parameters, including the early diastolic peak flow velocity (E), the late diastolic peak flow velocity (A), the E/A ratio, and the E-wave deceleration time (DT), were obtained by transmitral pulsed Doppler above the tips of the mitral leaflets. The Doppler tissue-imaging (DTI) program was fixed in the pulsed-wave mode. Filters were used to exclude signals of high frequency, while the Nyquist limit conformed to the −15 to 20 cm/s ve-
North Clin Istanb
locity range. Minimized gains created a legible tissue signal with a minimum background noise. The tissue Doppler measurements, including myocardial early (Eʹ) and atrial (Aʹ) peak velocities (m/s) and isovolumic relaxation time (IVRTʹ), were achieved at the apical four-chamber aspect via positioning a 5-mm sample volume on the lateral side of the mitral annulus [14]. The IVRTʹ was defined as the time interval between myocardial systolic wave and the onset of Eʹ [14]. The recording of the velocities was noted for 10 cardiac cycles at a sweep speed of 100 mm/s. All tissue Doppler measurements were performed in the course of normal respiration. The same investigator completed the echocardiographic examination while blinded to subjects’ data, and two cardiologists blinded to subjects’ data investigated the echocardiogram recordings. Measurement of c-IMT c-IMT levels were measured by a linear probe of a Logiq 5 ultrasound scanner (General Electric Medical Systems, Wallingford, Connecticut, USA). One expert sonographer blinded to the study subjects’ data performed the sonographic evaluations, with the subjects lying in the supine position in a dark, quiet room. The left common carotid arteries (CCA) were investigated with the subject’s head positioned in the midline with a slight upward tilt. The probe was deployed about 1 cm proximally to the bifurcation of CCA, and the longitudinal plane was used to visualize the maximum lumen diameter. Distance between the media–adventitia interface and the lumen–intima interface was used to define c-IMT. Two parallel echogenic lines with an anechoic space between them can be scanned on the anterior wall of CCA [5]. Measurement of EFT EFT was evaluated by TTE using a GE VIVID 7 (Horten, Norway) machine. EFT was measured from the parasternal long-axis view on the right ventricle’s free wall at the end-diastole during three cardiac cycles. In the parasternal long-axis window, the hypoechoic space on the right ventricular free wall was defined as EFT. The largest perpendicular distance to the aortic annulus was achieved and averaged
Ozdil et al., Echocardiographic epicardial fat thickness measurement
7
Table 1. Demographic and biochemical properties of the study population
Crohn’s disease Ulcerative p1 IBD patients in remission Control group (n=56) colitis (n=54) value period (n=110) (n=105)
Age (years) 39.4±12.2 42.8±12.7 0.18 Male/female (n/n) 25/31 24/30 0.86 Body mass index 25.1±4.1 25.5±4.6 0.70 Fasting blood glucose (mg/dL) 92.4±8.9 94.1±13.4 0.46 Total cholesterol (mg/dL) 179.5± 34.1 183.1±36.4 0.66 Triglyceride (mg/dL) 117.3± 47.5 120.6±51.9 0.76 HDL cholesterol (mg/dL) 44.1±9.0 45.2±9.7 0.60 LDL cholesterol (mg/dL) 112.0±26.9 113.7±31.8 0.80 Hemoglobin (mg/dL) 13.7±1.5 13.3±1.6 0.21 Hs-CRP (mg/dL) 2.76±3.30 2.45±2.72 0.61 ESR (mm/h) 20.3±14.7 18.0±13.0 0.42 Systolic BP (mmHg) 119.7±13.2 123.4±16.0 0.23 Diastolic BP (mmHg) 74.7±6.6 75.9±8.6 0.44 Disease duration (years) 3.57±1.78 5.75±5.61 0.01 Disease activity score 61.6±20.2 3.49±0.72 (CDAI & TWAS)
41.1±12.6 40.8±5.7 49/61 59/56 25.2±4.4 26.7±2.56 93.1±11.3 93.3±7.0 181.8± 34.5 177.7±25.4 120.2± 49.0 117.5±47.9 44.6±9.1 45.4± 10.1 113.4±28.8 107.9±21.0 13.4±1.6 14.2±1.2 2.61±2.94 1.36±1.24 19.1±13.7 13.2±8.6 123.0±15.7 122.1±9.8 75.7±8.9 75.3±6.4 4.83±4.44 61.6±20.2 3.49±0.72
p2 value 0.83 0.33 0.06 0.84 0.35 0.70 0.53 0.13 <0.001 <0.001 0.001 0.56 0.73
HDL: High-density lipoprotein; LDL: Low-density lipoprotein; Hs-CRP: High-sensitivity C-reactive protein; BP: Blood pressure; ESR: Erythrocyte sedimentation rate; p1: Comparison between Crohn’s disease and ulcerative colitis; p2: Comparison between patients with IBD and control group.
over three cardiac cycles [15]. Intraclass correlation coefficient for echocardiographic EFT measurement was 0.94. Statistical analyses All analyses were performed using the statistical software package SPSS 16.0 for Windows (SPSS Inc. Chicago, IL). The variables were examined using analytic (Kolmogorov–Smirnov or Shapiro–Wilk’s test) and visual (histogram) methods by defining whether they are normally distributed. Descriptive statistics were used to summarize the data. Categorical variables were expressed as percentages, and continuous variables were expressed as mean±standard deviation. Differences between patients in normally and nonnormally distributed variables were evaluated by ANOVA and Kruskal–Wallis test, respectively, as appropriate. The Student’s t-test was used to compare the parameters between the groups. The correlation coefficients and their significance were calculated using the Spearman’s test. Kruskal–Wal-
lis tests were conducted to compare parameters between the groups. The Mann–Whitney U test was performed to examine the significance of pairwise differences using Bonferroni correction setting for multiple comparisons. The possible predictors identified by univariate analysis were further entered into multiple logistic regression analyses to determine the independent predictors. An overall 5% type I error level was used to infer statistical significance. RESULTS Study population The mean ages of patients with IBD (49 males and 61 females) and the healthy controls (59 males and 56 females) were 41.1±12.6 and 40.8±5.7 years, respectively, and there was no significant difference in age between the study groups (p=0.83). The differences in terms of sex, BMI, and systolic and diastolic blood pressures (BP) between the two groups were also not significantly different (Table 1).
8
North Clin Istanb
58
14.00 12.00
p<0.001
CRP
52 27 13
10.00 8.00 6.00 4.00
133 130 111 120 201
2.00 0.00 Control
Figure 1.
IBD
Comparison of hs-CRP levels of the study
groups.
Biochemical assessments Hs-CRP (2.61±2.94 vs. 1.36±1.24 mg/L, p<0.001) and ESR (19.1±13.7 vs. 13.2±8.6, p=0.001) (Figure 1) values of patients with IBD were significantly higher than those of the healthy controls. However, the hemoglobin levels of patients with IBD were significantly lower than those of the healthy controls (13.4±1.6 vs. 14.2±1.2, p<0.001). The other biochemical parameters of the patients with IBD were similar to those of the healthy controls (Table 1). Echocardiographic evaluation IVS and PW thickness, left ventricular ejection fraction (EF), LVDD, LVSD, and left atrium diameter of patients with IBD were similar to those of the control group (Table 2). Even though mitral E-wave was analogous among the groups, the differences in mitral A-wave, DT, and E/A ratio were significant between patients with IBD and the control group. Meanwhile, tissue Doppler parameters, including Eʹ, Aʹ, Eʹ/ Aʹ ratio, and IVRTʹ, were also significantly different between the study subjects (Table 2). The left ventricular diastolic function parameters of patients with IBD were significantly different compared to those of healthy controls. Measurement of c-IMT Patients with IBD had significantly higher c-IMT
Table 2. Echocardiographic and ultrasonographic assessment of study population IVS thickness (cm) PW thickness (cm) LVDD (cm) LVSD (cm) EF (%) LAD (cm) Mitral E-wave max (cm/s) Mitral A-wave max (cm/s) DT (ms) E/A ratio IVRT (ms) E’(cm/s) A’ (cm/s) IVRT’ (ms) E’/A’ ratio EFT (cm) CIMT (cm)
IBD patients in remission period (n=110)
Healthy controls (n=105)
p
0.91±0.13 0.95±0.7 4.60±0.30 2.90±0.31 66.5±5.5 3.10±0.46 79.0±17.8
0.93±0.09 0.91±0.08 4.45±0.31 2.88±0.22 66.2±2.6 3.10±0.30 79.3±12.4
0.31 0.50 0.14 0.06 0.62 0.65 0.87
72.1±15.1
62.80±10.7 <0.001
209.6±43.7 1.13±0.33 112.3±20.9 17.5±5.0 15.2±4.5 96.2±23.8 1.24±0.47 0.54±0.13 0.52±0.10
187.3±22.7 <0.001 1.31±0.21 0.001 107.8±9.6 0.06 19.6±3.5 0.01 13.7±3.0 0.004 90.7±11.4 0.03 1.48±0.39 <0.001 0.49±0.09 0.002 0.49±0.09 0.008
CIMT: Carotid intima-media thickness; DT: Deceleration time; EF: Ejection fraction; EFT: Epicardial fat thickness; IBD: Inflammatory bowel disease; IVS: Interventricular septum; IVRT: Isovolumetric relaxation time; LAD: Left atrial diameter; LVDD: Left ventricular end-diastolic diameter; LVSD: Left ventricular end-systolic diameter; PW: Posterior wall.
values than those of the control group (0.52±0.10 vs. 0.49±0.09, p=0.008) (Table 2, Figure 2). Among the patients with IBD, 13 had carotid plaques, whereas two among the control group had carotid plaques. The proportion of carotid plaques in patients with IBD was significantly higher than that in the control group (Table 3). Patients with IBD with carotid plaques had significantly higher EFT values than those of the control group (0.71±0.12 vs. 0.50±0.10, p<0.001). EFT measurement Patients with IBD had significantly higher EFT values than those of the control group (0.54±0.13 vs.0.49±0.09, p=0.002) (Figure 3). The EFT mea-
Ozdil et al., Echocardiographic epicardial fat thickness measurement
172
0.80
p=0.008
p=0.002
0.80
0.70 0.60 EFT
cIMT
9
0.60
0.50 0.40 0.40 0.20
0.30 Control
Figure 2.
IBD
Control
Comparison of c-IMT values of the study
groups.
Comparison of EFT values of the study
groups.
Table 3. Comparison of CIMT plaque presence in IBD patients and control group
Figure 3.
IBD
CIMT plaque Present
p
Absent
Control 2 103 IBD 13 97 Total 15 200
0.004
CIMT: Carotid intima-media thickness; IBD: Inflammatory bowel disease.
surements directly correlated with c-IMT and hsCRP levels (Figures 4 and 5) in the study population. The EFT values were independent of the diffuse involvement of the gastrointestinal tract in patients with IBD (Table 4). We also observed independent associations between EFT, hs-CRP, ESR, hemoglobin levels, and IBD via multiple logistic regression analysis (Table 5). DISCUSSION In the present study, we investigated whether echocardiographic EFT measurement may be used as a novel atherosclerosis predictor in patients with IBD with well-known predictors of atherosclerosis, including c-IMT and hs-CRP.
Studies have shown that inflammation plays a fundamental role in mediating all stages of atherosclerosis [4]. Chronic low-grade inflammation is involved in the pathogenesis of IBD remission period. Therefore, it is not surprising to observe that recent studies have reported that the risk of CV events increases in IBD, while the prevalence of factors traditionally associated with CV risk is lower than that in the general population [1, 2, 16]. The increased risk of developing atherosclerosis in patients with IBD has been demonstrated by investigating certain atherosclerotic predictors such as hs-CRP and c-IMT in some of those recent trials [17â&#x20AC;&#x201C;20]. Hs-CRP is defined as a systemic marker of inflammation. Recent prospective trials have shown that the pathogenesis of atherosclerosis is associated with a chronic low-grade inflammation, and an increased hs-CRP level is described as a risk factor for CAD [17, 18]. Maharshak et al. [17] found that patients with Crohnâ&#x20AC;&#x2122;s disease during the remission period have obviously elevated levels of inflammatory biomarkers, including hs-CRP and ESR. Caliskan et al. [18] also demonstrated that patients with IBD in remission have increased hs-CRP levels. We also found that hs-CRP levels in patients with IBD in the remission period were significantly higher than those in the normal population, which is consistent with previous studies.
10
North Clin Istanb
0.90
r=0.306; p=0.006
0.80
12.00
0.70
10.00 CRP
EFT
r=0.253; p=0.018
14.00
0.60
8.00 6.00
0.50 4.00 0.40
2.00 0.00
0.30 0.30
0.40
0.50
0.60
0.70
0.80
0.20
0.40
cIMT
Figure 4.
0.60 EFT
0.80
Figure 5. Correlation between EFT and hs-CRP of the
Correlation between EFT and c-IMT of the study population.
study population.
Table 4. The relationship between bowel segment involvement and lipids, CIMT, and EFT values of IBD patients
Terminal ileum
Ileocolic
Colic
p
Proctitis
Leftcolic
Diffusecolitis Pancolitis
p
Triglyceride 115 126 110 0.65 59 117 123 110 0.65 (74–143) (77–168) (84–155) (56–104) (87–151) (64–170) (102–125) HDL 44 44 46 0.82 47 46 42 42 0.82 (40–49) (38–48) (37–53) (46–48) (38–51) (38–45) (47–52) LDL 105 110 123 0.46 101 115 122 116 0.46 (96–133) (87–128) (114–150) (95–115) 102–126) (112–165) (106–131) EFT 0.50 0.56 0.60 0.17 0.57 0.52 0.63 0.58 0.17 (0.36–0.58) (0.50–0.64) (0.45–0.61) (0.41–0.59) (0.44–0.61) (0.58–0.70) (0.50–0.70) CIMT 2.3 2.1 2.5 0.13 2.5 2.2 2.1 2.5 0.13 (2.2–2.6) (1.9–2.4) (2.3–3.3) (2.4–2.6) (2.1–2.5) (1.9–2.4) (2.3–2.8) CIMT: Carotid intima-media thickness; EFT: Epicardial fat thickness; HDL: High density lipoprotein; LDL: Low density lipoprotein.
Gonzalez-Juanatey et al. [21] demonstrated that patients with rheumatoid arthritis, which is defined as a chronic inflammatory disease without evident CV disease, have a high frequency of left ventricular diastolic dysfunction. A previous study [18] identified LV diastolic dysfunction in patients with IBD during the remission period without having a higher burden of conventional atherosclerotic risk factors. We also found that the frequency of left ventricular diastolic dysfunction in patients with IBD is higher
than that in the normal population, in agreement with findings of previous studies. c-IMT is a measure of subclinical atherosclerosis associated with CV risk factors [6]. A meta-analysis reported that patients with rheumatoid arthritis have a statistically significantly higher c-IMT value [22]. Theocharidou et al. [11] also showed that cIMT was significantly greater in patients with IBD compared to that in healthy volunteers. Alkan et
Ozdil et al., Echocardiographic epicardial fat thickness measurement
Table 5. Results of multivariate logistic regression analy-
ses of potential predictors of inflammatory bowel disease EFT c-IMT Hs-CRP ESR Hb
Odds ratio
95% CI
p
63.268 14.096 1.416 0.720 1.039
1.602–2498.543 0.233–853.786 1.105–1.813 0.543–0.954 1.002–1.077
0.027 0.206 0.006 0.022 0.038
CI: Confidence interval; CIMT: Carotid intima-media thickness; EFT: Epicardial fat thickness; ESR: Erythrocyte sedimentation rate; Hb: Hemoglobin; Hs-CRP: High sensitivity C-reactive protein.
al. [10] also demonstrated higher values of c-IMT in patients with IBD. In the present study, we also found that c-IMT was significantly higher in patients with IBD compared to that in the healthy population, a finding in line with previous studies. Corrales et al. [23] determined the use of carotid ultrasonography for improving the stratification of the CV risk in rheumatoid arthritis. The modified EULAR systematic coronary risk evaluation (mSCORE) was used for CV risk calculation in that study. The investigators demonstrated that the presence of severe carotid US findings in patients with moderate mSCORE risk yielded high sensitivity for high/very high CV risk. Corrales et al. [24] also demonstrated in another study that carotid ultrasound is more sensitive than coronary artery calcification score for the evaluation of subclinical atherosclerosis in patients with rheumatoid arthritis. In our study, we also found that the ratio of carotid plaques in patients with IBD was significantly higher than that in the control group, and patients with IBD with carotid plaques had significantly higher EFT values. Several studies have shown that the risk of developing atherosclerosis is increased in IBD by exploring a variety of atherosclerotic predictors. However, EFT has not yet been investigated as an atherosclerotic predictor in IBD. Increased epicardial fat quantity is associated with incident CAD and major adverse CV outcomes [8]. These relationships occur independently
11
from BMI and other conventional risk factors. Epicardial fat tissue is actually one of the factors contributing to CAD compared to other visceral fat tissues [25]. Xu et al. [26] reported that both EFT and epicardial fat tissue volumes are significantly increased in patients with CAD compared to those in the healthy group in a recent meta-analysis of 2.872 patients. Bachar et al. [9] showed that EFT correlated strongly and positively with coronary atherosclerosis quantified by the computed tomography calcium score of 190 asymptomatic individuals with one or more factors of CV risk. A recent study demonstrated an independent relationship between arterial stiffness and EFT, suggesting that the use of echocardiographic EFT evaluation could be an easily quantifiable tool for the early determination of subclinical atherosclerosis [27]. We reported that the EFT values of patients with IBD were higher than those of the healthy control group. In the present study, the EFT measurements were independent of the diffuse involvement of the gastrointestinal tract in patients with IBD. This finding supports that low-grade chronic inflammation in IBD during remission affects the extraintestinal organs, including the CV system, independently from the gastrointestinal system involvement. In this study, we found that the EFT values of patients with IBD directly correlated with hs-CRP levels, and there were independent associations between EFT, hs-CRP, and IBD. On the other hand, a direct correlation was found between EFT and c-IMT values. Moreover, patients with IBD having carotid plaques had significantly higher EFT values compared to those of patients with IBD without carotid plaques. Conclusion We found that patients with IBD had higher echocardiographic EFT values than those of the control group, and the EFT values of patients with IBD were directly related with well-defined atherosclerosis predictors such as c-IMT and hs-CRP. An association was also found between carotid plaques
12
and higher EFT values. Therefore, all these findings suggest that echocardiographic EFT measurement may be used in the evaluation of CV risk along with hs-CRP and carotid ultrasound in patients with IBD. Conflict of Interest: None declared. Financial Disclosure: The authors declared that this study has received no financial support. Authorship contributions: Concept – K.O.; Design – Z.C.; Supervision – M.C.; Materials – L.D.; Data collection &/or processing – A.S.T., K.D., Y.Y.; Analysis and/or interpretation – O.O.; Literature search – R.K.; Writing – N.K.; Critical review – M.C.
REFERENCES 1. Hatoum OA, Gauthier KM, Binion DG, Miura H, Telford G, Otterson MF, et al. Novel mechanism of vasodilation in inflammatory bowel disease. Arterioscler Thromb Vasc Biol 2005;25:2355–61. 2. Hatoum OA, Binion DG, Otterson MF, Gutterman DD. Acquired microvascular dysfunction in inflammatory bowel disease: Loss of nitric oxide-mediated vasodilation. Gastroenterology 2003;125:58–69. 3. Ross R. Atherosclerosis-an inflammatory disease. N Engl J Med 1999;340:115–26. 4. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002;105:1135–43. 5. Yu H, Rifai N. High-sensitivity C-reactive protein and atherosclerosis: from theory to therapy. Clin Biochem 2000;33:601–10. 6. Persson J, Formgren J, Israelsson B, Berglund G. Ultrasounddetermined intima-media thickness and atherosclerosis. Direct and indirect validation. Arterioscler Thromb 1994;14:261–4. 7. Schejbal V. [Epicardial fatty tissue of the right ventricle--morphology, morphometry and functional significance]. Pneumologie 1989;43:490–9. 8. Verhagen SN, Visseren FL. Perivascular adipose tissue as a cause of atherosclerosis. Atherosclerosis 2011;214:3–10. 9. Bachar GN, Dicker D, Kornowski R, Atar E. Epicardial adipose tissue as a predictor of coronary artery disease in asymptomatic subjects. Am J Cardiol 2012;110:534–8. 10. Alkan E, Karakaş MS, Yıldırım B. Evaluation of increased subclinical atherosclerosis risk with carotid intima-media thickness and pulse wave velocity in inflamatory bowel disease. Turk J Gastroenterol 2014;25 Suppl 1:20–5. 11. Theocharidou E, Gossios TD, Griva T, Giouleme O, Douma S, Athyros VG, et al. Is there an association between inflammatory bowel diseases and carotid intima-media thickness? Preliminary data. Angiology 2014;65:543–50. 12. Truelove SC, Witts LJ. Cortisone in ulcerative colitis; final report on a therapeutic trial. Br Med J 1955;2:1041–8. 13. Best WR, Becktel JM, Singleton JW, Kern F Jr. Development of a Crohn’s disease activity index. National Cooperative Crohn’s
North Clin Istanb Disease Study. Gastroenterology 1976;70:439–44. 14. Sohn DW, Chai IH, Lee DJ, Kim HC, Kim HS, Oh BH, et al. Assessment of mitral annulus velocity by Doppler tissue imaging in the evaluation of left ventricular diastolic function. J Am Coll Cardiol 1997;30:474–80. 15. Iacobellis G, Ribaudo MC, Assael F, Vecci E, Tiberti C, Zappaterreno A, et al. Echocardiographic epicardial adipose tissue is related to anthropometric and clinical parameters of metabolic syndrome: a new indicator of cardiovascular risk. J Clin Endocrinol Metab 2003;88:5163–8. 16. Yarur AJ, Deshpande AR, Pechman DM, Tamariz L, Abreu MT, Sussman DA. Inflammatory bowel disease is associated with an increased incidence of cardiovascular events. Am J Gastroenterol 2011;106:741–7. 17. Maharshak N, Zilberman L, Arbel Y, Shapira I, Berliner S, Arber N, et al. Microinflammation in patients with Crohn’s disease in clinical remission. J Crohns Colitis 2008;2:310–4. 18. Caliskan Z, Gokturk HS, Caliskan M, Gullu H, Ciftci O, Ozgur GT, et al. Impaired coronary microvascular and left ventricular diastolic function in patients with inflammatory bowel disease. Microvasc Res 2015;97:25–30. 19. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000;342:836–43. 20. Blake GJ, Ridker PM. Novel clinical markers of vascular wall inflammation. Circ Res 2001;89:763–71. 21. Gonzalez-Juanatey C, Testa A, Garcia-Castelo A, Garcia-Porrua C, Llorca J, Ollier WE, et al. Echocardiographic and Doppler findings in long-term treated rheumatoid arthritis patients without clinically evident cardiovascular disease. Semin Arthritis Rheum 2004;33:231–8. 22. van Sijl AM, Peters MJ, Knol DK, de Vet HC, Gonzalez-Gay MA, Smulders YM, et al. Carotid intima media thickness in rheumatoid arthritis as compared to control subjects: a metaanalysis. Semin Arthritis Rheum 2011;40:389–97. 23. Corrales A, González-Juanatey C, Peiró ME, Blanco R, Llorca J, González-Gay MA. Carotid ultrasound is useful for the cardiovascular risk stratification of patients with rheumatoid arthritis: results of a population-based study. Ann Rheum Dis 2014;73:722–7. 24. Corrales A, Parra JA, González-Juanatey C, Rueda-Gotor J, Blanco R, Llorca J, et al. Cardiovascular risk stratification in rheumatic diseases: carotid ultrasound is more sensitive than Coronary Artery Calcification Score to detect subclinical atherosclerosis in patients with rheumatoid arthritis. Ann Rheum Dis 2013;72:1764–70. 25. Ding J, Hsu FC, Harris TB, Liu Y, Kritchevsky SB, Szklo M, et al. The association of pericardial fat with incident coronary heart disease: the Multi-Ethnic Study of Atherosclerosis (MESA). Am J Clin Nutr 2009;90:499–504. 26. Xu Y, Cheng X, Hong K, Huang C, Wan L. How to interpret epicardial adipose tissue as a cause of coronary artery disease: a meta-analysis. Coron Artery Dis 2012;23:227–33. 27. Kim BJ, Kim BS, Kang JH. Echocardiographic epicardial fat thickness is associated with arterial stiffness. Int J Cardiol 2013;167:2234–8.
Orıgınal Article
NEPHROLOGY
North Clin Istanb 2017;4(1):13–21 doi: 10.14744/nci.2017.85520
Is duodenal biopsy appropriate in areas endemic for Helicobacter pylori? Abdurrahman Sahin,1 Gulcin Cihangiroglu,2 Yilmaz Bilgic,1 Turan Calhan3, Mustafa Cengiz4 Department of Gastroenterology, Elazig Training and Research Hospital, Elazig, Turkey
1
Department of Pathology, Elazig Training and Research Hospital, Elazig, Turkey
2
Department of Gastroenterology, Private Turkey Hospital, Istanbul, Turkey
3
Department of Gastroenterology, Dr. Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital, Ankara, Turkey
4
ABSTRACT OBJECTIVE: The primary reason for obtaining duodenal biopsy sample is to diagnose celiac disease. Helicobacter
pylori (H. pylori) and drug injury are common causes of duodenitis. The aim of this retrospective study was to explore effects of H. pylori and drugs on duodenal mucosa. METHODS: Duodenal biopsy samples of patients who underwent upper gastrointestinal endoscopy (UGIE) between February 2014 and December 2014 were retrospectively examined. Clinical symptoms, referral indications, endoscopic findings, H. pylori status, and drug history were recorded. Duodenal biopsy findings were compared based on presence of H. pylori and drug history. RESULTS: Of 2389 patients who underwent UGIE, 206 had duodenal biopsy. Eight patients (3.9%) were diagnosed with celiac disease. After excluding cases with celiac disease, 76 patients of remaining 198 patients (36.9%) had duodenal histopathological abnormality. H. pylori was found in 95 (47.9%) patients. Drug usage was less common (42%). Of patients who had histopathological duodenitis, 59% were H. pylori-infected. Rate of duodenitis was higher in H. pylori (+) group than in H. pylori (-) group (45% vs 27.1%; odds ratio, 2.4; 95% confidence interval, 1.3–4.4; p=0.005). There was no difference between groups regarding drug use in terms of histopathological duodenitis. CONCLUSION: H. pylori is the major contributor to duodenitis in high prevalence regions. Serological testing may be more appropriate before performing duodenal biopsy in patients with suspected celiac disease. Keywords: Acetylsalicylic acid; celiac disease; duodenitis; Helicobacter pylori; nonsteroidal anti-inflammatory drugs.
U
pper gastrointestinal endoscopy (UGIE) is a common procedure to investigate dyspepsia, dysphagia, and other upper gastrointestinal (GI) symptoms [1]. Inspection of duodenum is one of the basic components of routine upper GI endoscopic examination. Duodenal endoscopic findings
give important clues for a wide range of disorders affecting upper GI tract. Duodenal biopsy sample is commonly obtained to investigate iron deficiency anemia, malabsorption, neoplasia, and infectious enteritis. However, various other disorders, such as infectious disease, inflam-
Received: February 19, 2017 Accepted: April 05, 2017 Online: May 10, 2017 Correspondence: Dr. Abdurrahman SAHIN. Elazig Egitim ve Arastirma Hastanesi, Gastroenteroloji Klinigi, Elazig, Turkey. Tel: +90 424 - 212 27 17 e-mail: arahmansmd@yahoo.com © Copyright 2017 by Istanbul Northern Anatolian Association of Public Hospitals - Available online at www.kuzeyklinikleri.com
14
North Clin Istanb
Table 1. Grading criteria of duodenal biopsies according to definitions of Serra et al. [5] Definition
Criteria
Number and site of biopsy specimens Villous height and architecture Ratio normal villous to crypt (V:C) Surface enterocytes Brush borders Presence of crypt hyperplasia Intraepithelial lymphocyte count (per 100 epithelial cells) Gastric metaplasia in chronic duodenitis Presence of microorganisms Neoplasia
Normal, broad, or blunted Range from 3:1 to 5:1 Normal, flattened, or damaged Preserved or lost Present/Absent Range from 1:5 to 5:5 Normal (1:5) / Increased (range from 2:5 to 5:5) Present/Absent Giardia, Cryptosporidium, Microsporidia, Isospora belli, Cyclospora, Mycobacterium avium-intracellulare, Cytomegalovirus, Cryptococcus neoformans Presence of benign or malignant tumor (adenoma or carcinoma, carcinoid, lymphoma)
matory disorder, toxic or physical reactions, may cause duodenal mucosal injury and result in appearance of duodenitis on endoscopic examination [2]. Determination of the cause of duodenitis is important, but histopathological findings do not always correlate with endoscopic findings. It is thought that Helicobacter pylori (H. pylori) and injury due to use of pharmaceutical drugs, including nonsteroidal anti-inflammatory drugs (NSAIDs), acetylsalicylic acid (ASA) and other antiplatelet drugs, are common cause of duodenitis [3, 4]. The aim of this retrospective study was to evaluate duodenal biopsy samples taken from patients who underwent endoscopic examination. Correlation of histopathological findings with H. pylori and drug toxicity was also assessed. MATERIALS AND METHODS
through December 2014 were examined for patients who had duodenal biopsy performed. Endoscopic duodenitis was detected according to presence of erythema, edema, or erosion. Endoscopic findings compatible with celiac disease, such as nodularity, mosaic pattern, and scalloping, were also recorded as endoscopic duodenitis. Demographic and medical data of patients were obtained from hospital databases. Drug prescription data for evaluation of patients in terms of drug usage, especially NSAIDs, ASA, or other antiplatelet drugs, were also obtained from hospital records. In patients who were diagnosed as celiac disease, serological markers, including IgA and IgG antibodies against tissue transglutaminase (tTG), endomysial antibodies (EMA), and gliadin antibodies (AGA), were also recorded. Patients who had inadequate demographic or clinical data or inadequate drug history were excluded.
Patient data This retrospective study was carried out using data of consecutive patients who underwent endoscopic examination for several indications, including dyspepsia, anemia, chronic diarrhea, epigastric pain, and reflux symptoms, in the gastroenterology department of Elazig Training and Research Hospital (Turkey). Endoscopy records from February 2014
Histopathological assessment Duodenal biopsy samples were assessed by one expert pathologist (GC) who was blinded to endoscopic findings. Histopathological findings were evaluated according to definition and classification of duodenal biopsy findings by Serra et al. to ensure objective criteria (Table 1) [5]. Diagnosis of H. pylori infection was based on results of rapid urease
Sahin et al., Effects of Helicobacter pylori on duodenal mucosa
15
2389 upper GI endoscopy
222 subjects had duodenal biopsy
12 subjects inadequate data 2 subjects inadequate sampling 2 subjects intestinal malignancy biopsy
206 subjects included
8 subjects with celiac disease
53 subjects Helicobacter pylori (+) Drug (-)
198 subjects in final assessment
42 subjects Helicobacter pylori (-) Drug (+)
42 subjects Helicobacter pylori (+) Drug (+)
53 subjects Helicobacter pylori (-) Drug (-)
GI: Gastrointestinal
Figure 1. Participation flowchart. Patients in final assessment were adjusted according to presence of Helicobacter pylori and drug usage. test or positive identification of the bacteria either on routine stains (Wright-Giemsa stain) or immunostain of gastric biopsies. Histological changes in patients diagnosed with celiac disease were classified according to Marsh classification [6]. Patients who had inadequate duodenal sampling were excluded. Patients diagnosed as malignancy with histopathological assessment of duodenal biopsy samples were also excluded. Statistical analysis Statistical analysis was performed using IBM SPSS Statistics for Windows, Version 21.0. (IBM Corp., Armonk, NY, USA) software. Quantitative data were expressed as meanÂąSD, while nominal data were expressed as number (percent). Chi-square test and simple odds ratio (OR) (95% confidence interval [CI]) were performed. P value <0.05 was considered significant.
RESULTS Total of 2389 upper GI endoscopy reports were screened. Among those, 222 patients (9.3%) had duodenal biopsy sampling performed. Clinical data of 12 patients were inadequate and those patients were excluded. Two patients were excluded because samples were either inadequately oriented or were distorted during processing. Two cases were diagnosed as intestinal malignancy (1 carcinoid tumor, 1 ampullary carcinoma). In all, 206 duodenal biopsy samples were accepted for final analysis (Figure 1). Duodenitis was found in 170 patients (82.5%) as endoscopic finding. Duodenal biopsy sample was taken from remaining 36 patients (17.5%) to investigate anemia (iron deficiency and/or vitamin B12 deficiency) in 26 (12.6%) and/or chronic diarrhea in 11 (5.3%), and intestinal lymphangiectasia in 8 patients. Demographic and clinical features, referral
16
North Clin Istanb
Table 2. Demographic characteristics, UGIE indications and endoscopic findings of the study population
Table 3. Histopathological findings of study population
Total (n=206)
n
n
%
Pathological abnormality Villous height and architecture Normal Broad Blunted Villous to crypt ratio (V:C) 3:1 4:1 5:1 Surface enterocytes Normal Flattened Damaged Presence of crypt hyperplasia Intraepithelial lymphocyte increase Gastric metaplasia in chronic duodenitis Presence of microorganisms
76
36.9
Age, years (mean±SD) Gender, female Helicobacter pylori presence Drugs‡ Referral indication Epigastric pain Dyspepsia Regurgitation Nausea/vomiting Weight loss Dysphagia Chronic diarrhea Abdominal pain Anemia Gastrointestinal bleeding Endoscopic findings LES relaxation Hiatal hernia Erythematous antral gastritis Erythematous pangastritis Erosive gastritis Gastric ulcer Duodenal ulcer
%
44.7±17.5 126 61.2 100 48.5 88 42.7 90 29 10 7 6 6 11 9 26 8
43.7 14.1 4.9 3.4 2.9 2.9 5.3 4.4 12.6 3.9
82 16 24 131 40 4 4
39.8 7.8 11.7 63.6 19.4 1.9 1.9
LES: Lower esophageal sphincter; UGIE: Upper gastrointestinal endoscopy. ‡Use of nonsteroidal anti-inflammatory drugs, acetylsalicylic acid, other antiplatelet drugs.
indications, and endoscopic findings are presented in Table 2. Pathological abnormalities were seen in 76 patients (36.9%). Most common pathological abnormality was increase in intraepithelial lymphocyte (IEL) count, detected in 33% (n=68) of patients. Second most frequent pathological finding was crypt hyperplasia, established in 54 cases (26.2%). No microorganism was detected in study population. Histopathological assessment of duodenal biopsies is provided in Table 3. Eight patients (3.9%) were diagnosed as celiac disease according to endoscopic, serological, and histopathological findings (Table 4). Six of them
Total (n=206)
187 90.8 11 5.3 8 3.9 4 1.9 37 18.0 163 79.1 186 9 11 54 68 18 0
90.3 4.4 5.3 26.2 33.0 8.7 0
(75%) were female. Mean age was 38.25±16.6 years. Referral indications were epigastric pain in 3 cases, dyspepsia in 1, diarrhea in 2, diarrhea with abdominal pain in 1, and anemia with vitamin B12 deficiency in 1 patient. H. pylori was present in 5 patients (67.5%). Duodenitis was prominent finding of endoscopic examination in all patients with celiac disease. Histopathological findings were consistent with Marsh III classification in 6 patients (75%). Duodenal biopsies of 2 patients (25%) were classified as Marsh II. After exclusion of cases with celiac disease, 198 patients were assessed for influence of H. pylori presence or drug use on development of duodenitis. Table 5 is a summary of histopathological findings with respect to H. pylori and drug usage. Unique difference was presence of pathological abnormality between groups (p=0.04). There was no difference between groups in subclassification of pathological abnormality (all p>0.05). In subgroup analysis, pathological abnormality was more common among patients who
Sahin et al., Effects of Helicobacter pylori on duodenal mucosa
17
Table 4. Demographic, clinical, and serological data, UGIE indications of patients with celiac disease, and histopathological findings according to Marsh classification
Age Sex Symptoms Endoscopic H. pylori Drug Serological findings status history positivity marker
Duodenal pathological findings
1 37 M Abdominal pain, diarrhea 2 33 F Anemia 3 24 F Diarrhea 4 66 F Diarrhea 5 24 F Epigastric pain 6 24 M Epigastric pain, regurgitation 7 61 F Epigastric pain 8 37 F Dyspepsia
Hiatal hernia, antral gastritis, duodenitis Duodenitis Pangastritis, duodenitis Pangastritis, duodenitis Antral gastritis, duodenitis Pangastritis, duodenitis Esophagitis, Gastric ulcer, duodenitis LES relaxation, duodenitis
+
+
AGA IgA, tTG IgA
Marsh IIIA
+ – + + – +
– – + – + +
tTG IgA EMA IgA EMA IgA AGA IgA, tTG IgA EMA IgA, tTG IgA EMA IgA, tTG IgA
Marsh IIIC Marsh II Marsh II Marsh IIIA Marsh IIIB Marsh IIIB
–
–
EMA IgG, tTG IgA Marsh IIIC
AGA: Anti-gliadin antibody; EMA: Endomysial antibody; F: Female; LES: Lower esophageal sphincter; M: Male; tTG: Tissue transglutaminase antibody; UGIE: Upper gastrointestinal endoscopy.
Table 5. Duodenal histopathological findings regarding Helicobacter pylori infection and drug usage
H. pylori (+) drug (-) (n=53)
H. pylori (-) drug (+) (n=42)
H. pylori (+) H. pylori (-) drug (+) Ddug (-) (n=42) (n=61)
n
n
n
%
%
%
n
p
%
Pathological abnormality 26 49.1 13 30.1 14 33.3 15 24.6 Villous height and architecture Normal 48 90.6 40 95.2 40 95.2 58 95.1 Broad 4 7.5 2 4.8 2 4.8 2 3.3 Blunted 1 1.9 0 0 0 0 1 1.6 Villous to crypt ratio (V:C) 3:1 1 1.9 1 2.4 0 0 1 1.6 4:1 12 22.6 4 9.5 9 21.4 8 13.1 5:1 40 75.5 37 88.1 33 78.6 52 58.2 Surface enterocytes Normal 46 86.8 40 95.2 40 95.2 58 95.1 Flattened 4 7.5 2 4.8 2 4.8 0 0 Damaged 3 5.7 0 0 0 0 3 4.9 Presence of crypt hyperplasia 18 34.0 11 26.2 10 23.8 12 19.7 Intraepithelial lymphocyte increase 23 43.4 13 30.9 11 26.2 14 22.9 Gastric metaplasia in chronic duodenitis 5 9.4 2 4.7 6 14.2 4 6.4
0.04 0.85
0.55
0.18
0.37 0.11 0.41
18
North Clin Istanb
Table 6. Duodenal histopathological findings with respect to the presence of Helicobacter pylori after excluding patients with celiac disease
H. pylori (+) (n=95)
n
%
H. pylori (-) (n=103) n
Odds ratio (95% CI)
p
%
Pathological abnormality 40 45 28 27.1 2.4 (1.3–4.4) Villous height and architecture Normal 88 92.6 98 95.1 Broad 6 6.3 4 3.9 Blunted 1 1.0 1 1.0 Villous to crypt ratio (V:C) 3:1 1 1.0 2 1.9 4:1 21 22.1 12 11.6 5:1 73 76.8 89 86.4 Presence of crypt hyperplasia 28 29.5 23 22.3 1.5 (0.8–2.8) Surface enterocytes Normal 86 90.5 98 95.1 Flattened 6 6.3 2 1.9 Damaged 3 3.2 3 2.9 Intraepithelial lymphocyte count 1.6 (0.9–2.9) Normal 61 64.2 76 73.8 Increased 34 35.8 27 26.2 Gastric metaplasia in chronic duodenitis 11 10 6 5.8 2.1 (0.8–5.9) Presence of microorganisms 0 0 0 0
0.005 0.61
0.13
0.25 0.27
0.14
0.15
CI: Confidence interval.
were infected with H. pylori and without drug use than in patients without H. pylori infection and with drug usage (49.1% vs 24.6%; OR, 2.9; 95% CI, 1.3– 6.5; p=0.007). In the same manner, rate of IEL increase was higher in patients who were only infected with H. pylori and without drug use than patients without H. pylori infection and drug usage (43.4% vs 22.9%; OR, 2.5; 95% CI, 1.1–5.7; p=0.02). In total, H. pylori was found in 95 (47.9%) cases. Histopathological duodenitis was more common among patients infected with H. pylori compared to H. pylori negative group (45% vs 27.1%; OR, 2.4; 95% CI, 1.3-4.4; p=0.005). Of those with histopathological duodenitis, 59% were H. pylori positive (Table 6). No difference was seen between groups according to IEL count, presence of crypt hyperplasia, villus atrophy, or gastric metaplasia (all p>0.05).
Total of 84 patients (42%) were taking NSAID or ASA. Among those patients, 61 (73%) were using proton pump inhibitor at time of UGIE and 42 (50%) showed H. pylori positivity. When cases were evaluated according to drug usage, mean age of patients taking NSAID or ASA was higher than mean age of non-users (51.5±16.5 years vs 40.6±16.6 years; p=<0.001). There was no difference between those taking NSAID or ASA and nonusers according to presence of duodenitis, IEL count, presence of crypt hyperplasia, villus atrophy, or gastric metaplasia (all p>0.05). DISCUSSION Histological findings of the small intestine are well defined. Investigations of abnormalities in histo-
Sahin et al., Effects of Helicobacter pylori on duodenal mucosa
logical findings have focused on celiac disease, in particular. Histopathological appearance of many diseases affecting duodenum is similar, so details in these findings are often not useful tools for diagnosis and management of diseases affecting the duodenal mucosa. In this study, we investigated duodenal biopsy findings. However, we found that only 9.3% of patients who underwent endoscopic examination had duodenal biopsy sampling. Reason for sampling in most cases was endoscopic appearance of duodenal mucosa compatible with duodenitis. Other reasons were investigation of anemia, diarrhea, weight loss in setting of normal-appearing mucosa, and presence of intestinal lymphangectasia. Ratio of duodenal biopsy sampling has been reported in the literature to be between 10% and 12% among adult cases undergoing UGIE [7]. Our findings were consistent with these results. Studies evaluating duodenal histopathological assessment generally focus on presence of celiac disease, and so most were conducted with patients who had normal-appearing mucosa. In a large series, it was found that duodenal biopsies were taken from normal-looking mucosa in 43% of patients who underwent UGIE due to anemia, diarrhea, or weight loss [8]. In nationwide study from the USA that was carried out on 103385 patients for 12-month period, duodenal biopsy sampling rate was 27.2% [9]. An interesting result of that study was that endoscopic appearance of duodenitis, scalloping or erosion/ulcer, were detected in only 5.6% of whole patient population and in 8.5% of patients who had duodenal biopsy. Moreover, 79.5% of duodenal biopsies in study were evaluated as normal histopathological findings. In our study, duodenal biopsies were performed mostly due to endoscopic findings of duodenitis, and only 12.5% of patients who had duodenal biopsy had normal-appearing duodenal mucosa. Endoscopic/histopathological consistency was seen in 36.9% of patients who had duodenal biopsy. Taking biopsy from patients who had endoscopic appearance of duodenitis is seen as more reliable compared with patients who had normal duodenal endoscopic findings. Diagnostic yield from biopsy
19
sample obtained from normal-appearing mucosa is lower than result of current study. It should also be kept in mind that, although endoscopic/histopathological concordance is well established in esophageal and gastric lesions, agreement between duodenal endoscopic findings and histopathological findings is poor. In clinical practice, main purpose of duodenal biopsy sampling is frequently to catch or to exclude silent or overt celiac disease. It is still diagnostic gold standard for celiac disease [10]. Eight patients (3.9%) were diagnosed with celiac disease in current study. All of these patients had endoscopic appearance compatible with celiac disease. Our result is consistent with a long-period study from Canada [11]. In that study, celiac disease prevalence was 2.4% among 9665 patients for over 30-year period. In another large-scale study conducted by Carmack and collagenous et al., celiac disease was detected in 1.2% of duodenal biopsy samples. Of patients who had clinical and endoscopic suspicion of celiac disease, 12% were diagnosed with the disease in histopathological assessment, and 64% of these patients had normal histopathological findings.[9]. In this study, celiac disease was diagnosed in 3.0% of those with diarrhea, weight loss, or anemia, and in 1.5% of patients with dyspepsia or gastroesophageal reflux disease. An interesting finding of our study was that referral indications for UGIE were gastrointestinal symptoms, such as epigastric pain and dyspepsia, in half of the patients diagnosed with celiac disease. Based on results of the above studies and our findings, patients with anemia, weight loss, or diarrhea would all have low probability of having celiac disease at initial clinical assessment. Moreover, endoscopic appearance of duodenitis is not sufficient to make decision on celiac disease. Given limitations of biopsy, including interindividual variability in interpretation and challenges of appropriate sample handling, preferred approach should be to evaluate serological markers prior to endoscopic examination for GI symptoms or other malabsorptionrelated symptoms (diarrhea, weight loss, anemia). Thus, unnecessary biopsy can be avoided. Current study demonstrated H. pylori positivity of 48% in study population, most of whom were
20
diagnosed endoscopically as duodenitis. H. pylori prevalence has been reported to range from 71.3% to 82.5% in studies from Turkey [12, 13]. Lower prevalence of H. pylori in current study population may have been due to high rate of drug usage and affect on gastric and duodenal mucosa. It is well known that NSAIDs and ASA are important causes of gastroduodenal lesions, especially in H. pylori (-) patients [14, 15]. Aside from NSAID-induced gastric mucosal damage, harmful effects of NSAIDs and ASA on intestinal mucosa are well established with widespread use of intestinal examination [16, 17]. A study evaluating patients with obscure GI bleeding showed that ulcerative lesions were due to chronic NSAID use, and mostly located in the ileum. ASA and other antiplatelet drugs cause erosions in all parts of small intestine (jejunum and ileum) [18]. Data about effect of NSAIDs on duodenal mucosa are conflicting. In 1 study, NSAIDs were found to be responsible for only 13% of H. pylori (-) duodenal ulcers [15]. Lewis et al. demonstrated that although NSAID drug use was associated with endoscopic appearance of duodenitis, impact of NSAIDs on histological inflammation was minimal [2]. Alternatively, histological changes were prominent in H. pyloriinfected patients who had normal endoscopic appearance. This explains why histological findings did not differ between groups taking NSAID/ASA and nonusers in current study. Mirbagheri et al. demonstrated that H. pylori infection had close association with histological duodenitis [3]. H. pylori presence was 67.3% in their study, and duodenitis was detected in 82.2% of patients infected with H. pylori. In an earlier study, histological duodenitis was found to be integral part of H. pylori gastritis [19]. Although we found lower presence of H. pylori (47.9%) when compared with mentioned studies, it is demonstrated in current study that H. pylori presence was major contributor to histopathological duodenitis, as 59% of those with histopathological duodenitis were infected with H. pylori. Gastric metaplasia develops in response to increased duodenal acid load, and has been found with high frequency in H. pylori-infected patients,
North Clin Istanb
at prevalence of 55% in duodenal ulcer patients and about 25% in those with distal gastric ulcer [1, 20]. High acid load is key event causing development of gastric metaplasia. Gastric metaplasia is considered adaptive event in response to high acid exposure [19]. Genta et al. demonstrated that H. pylori gastritis was lower in patients with gastric metaplasia without inflammation (6.3%) than in patients with normal duodenal histology (9.8%) [21]. They concluded that high rate of H. pylori negativity among patients with gastric metaplasia without inflammation would open role of H. pylori in development of gastric metaplasia to discussion. Contrary to that study, we found that although it did not reach statistical significance, gastric metaplasia was more prevalent among patients who had positive test for H. pylori. Most common pathogenic microorganism detected in duodenal biopsy is Giardia lamblia. In a study, Giardia lamblia was detected in 0.45% of 2000 patients undergoing UGIE [22]. Another study from Turkey reported that 2% of patients with iron deficiency anemia had Giardia lamblia detected in duodenal biopsies [23]. We found no microorganisms in duodenal biopsies of our unselected population. This might be due to small size of our study population. Major limitation of this study is its retrospective nature. Although duodenal biopsies were revaluated, presence of H. pylori was determined according to the pathology reports and endoscopy reports. To standardize pathological assessment, samples were evaluated according to single standard system by one expert pathologist. Clinical and demographic data, including drug usage, were obtained from hospital records and public health insurance system records. Non-prescription drug usage, especially nonprescription NSAIDs, could not be determined due to retrospective nature of this study and use might be underestimated. In this study, although pathological abnormality was more common in H. pyloriinfected patients, effect of H. pylori on abnormality subgroups did not reach statistical significance in our population. However, further studies are needed to evaluate effects of H. pylori on duodenal mucosa in terms of histopathological abnormality
Sahin et al., Effects of Helicobacter pylori on duodenal mucosa
subgroups. This study was a single center study conducted in eastern Turkey. Thus, our results cannot be accepted as having universal validity for Turkish population. In conclusion, duodenal biopsy endoscopic/histopathological concordance is lower than of esophageal and gastric cases. Although most common purpose of duodenal biopsy is diagnosis of celiac disease, histopathological findings rarely direct specific diagnosis. Biopsy of duodenum has low diagnostic yield. H. pylori is main cause of duodenitis in regions where it is prevalent. Routine duodenal biopsy for endoscopic appearance of duodenitis in areas endemic for H. pylori is not most reasonable approach. Checking serological markers before UGIE is more accurate method to manage appearance of endoscopic duodenitis. Conflict of Interest: None declared. Financial Disclosure: The authors declared that this study has received no financial support. Authorship contributions: Concept – A.S., G.C.; Design A.S., G.C.; Supervision – Y.B.; Materials – A.S., G.C., Y.B.; Data collection &/or proseccing – A.S., Y.B.; Analysis and/or interpretation – G.C., M.C.; Literature search; A.S., T.C.; Writing – A.S., Critical review – G.C., M.C., T.C.
REFERENCES 1. Walker MM, Talley NJ. Clinical value of duodenal biopsiesbeyond the diagnosis of coeliac disease. Pathol Res Pract 2011;207:538–44. 2. Lewis S, Stableforth W, Awasthi R, Awasthi A, Pitts N, Ottaway J, et al. An examination of the relationship between the endoscopic appearance of duodenitis and the histological findings in patients with epigastric pain. Int J Clin Exp Pathol 2012;5:581–7. 3. Mirbagheri SA, Khajavirad N, Rakhshani N, Ostovaneh MR, Hoseini SM, Hoseini V. Impact of Helicobacter pylori infection and microscopic duodenal histopathological changes on clinical symptoms of patients with functional dyspepsia. Dig Dis Sci 2012;57:967–72. 4. Kakar S, Nehra V, Murray JA, Dayharsh GA, Burgart LJ. Significance of intraepithelial lymphocytosis in small bowel biopsy samples with normal mucosal architecture. Am J Gastroenterol 2003;98:2027–33. 5. Serra S, Jani PA. An approach to duodenal biopsies. J Clin Pathol 2006;59:1133–50. 6. Marsh MN. Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity (‘celiac sprue’). Gastroenterology 1992;102:330–54.
21 7. Dubin SM, Kwong WT, Kalmaz D, Savides TJ. Low yield of routine duodenal biopsies for evaluation of abdominal pain. World J Gastroenterol. 2015;21:7495–9. 8. Lebwohl B, Tennyson CA, Holub JL, Lieberman DA, Neugut AI, Green PH. Sex and racial disparities in duodenal biopsy to evaluate for celiac disease. Gastrointest Endosc 2012;76:779–85. 9. Carmack SW, Genta RM. The diagnostic value of the duodenal biopsy: a clinico-pathologic analysis of 28,000 patients. Dig Liver Dis 2010;42:485–9. 10. Rubio-Tapia A, Hill ID, Kelly CP, Calderwood AH, Murray JA; American College of Gastroenterology. ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol 2013;108:656–76. 11. Freeman HJ. Detection of adult celiac disease with duodenal screening biopsies over a 30-year period. Can J Gastroenterol 2013;27:405–8. 12. Ozdil K, Sahin A, Kahraman R, Yuzbasioglu B, Demirdag H, Calhan T, et al. Current prevalence of intestinal metaplasia and Helicobacter pylori inf ection in dyspeptic adult patients from Turkey. Hepatogastroenterology 2010;57:1563–6. 13. Ozaydin N, Turkyilmaz SA, Cali S. Prevalence and risk factors of Helicobacter pylori in Turkey: a nationally-representative, crosssectional, screening with the ¹³C-Urea breath test. BMC Public Health 2 013;13:1215. 14. Gisbert JP, Calvet X. Review article: Helicobacter pylori-negative duodenal ulcer disease. Aliment Pharmacol Ther 2009;30:791– 815. 15. Chu KM, Kwok KF, Law S, Wong KH. Patients with Helicobacter pylori positive and negative duodenal ulcers have distinct clinical characteristics. World J Gastroenterol 2005;11:3518–22. 16. Graham DY, Opekun AR, Willingham FF, Qureshi WA. Visible small-intestinal mucosal injury in chronic NSAID users. Clin Gastroenterol Hepatol 2005;3:55–9. 17. Tsibouris P, Kalantzis C, Apostolopoulos P, Zalonis A, Isaacs PE, Hendrickse M, et al. Small bowel ulcerative lesions are common in elderly NSAIDs users with peptic ulcer bleeding. World J Gastrointest Endosc 2014;6:612–9. 18. Iwamoto J, Mizokami Y, Saito Y, Shimokobe K, Honda A, Ikegami T, et al. Small-bowel mucosal injuries in low-dose aspirin users with obscure gastrointestinal bleeding. World J Gastroenterol 2014;20:13133–8. 19. Caselli M, Gaudio M, Chiamenti CM, Trevisani L, Sartori S, Saragoni L, et al. Histologic findings and Helicobacter pylori in duodenal biopsies. J Clin Gastroenterol 1998;26:74–80. 20. Veijola L, Sankila A, Rautelin H, Kosunen TU, Sipponen P, Hyvärinen H, et al. Clinical significance of widespread gastric metaplasia in the duodenal bulb. J Clin Gastroenterol 2006;40:510–4. 21. Genta RM, Kinsey RS, Singhal A, Suterwala S. Gastric foveolar metaplasia and gastric heterotopia in the duodenum: no evidence of an etiologic role for. Hum Pathol 2010;41:1593–600. 22. Chew TS, Hopper AD, Sanders DS. Is there a role for routine duodenal biopsy in diagnosing giardiasis in a European population? Scand J Gastroenterol 2008;43:1219–23. 23. Gonen C, Yilmaz N, Yalcin M, Simsek I, Gonen O. Diagnostic yield of routine duodenal biopsies in iron deficiency anaemia: a study from Western Anatolia. Eur J Gastroenterol Hepatol 2007;19:37–41.
Orıgınal Article
GERIATRICS
North Clin Istanb 2017;4(1):22–28 doi: 10.14744/nci.2017.82787
Association between serum vitamin B12 level and frailty in older adults Ozge Dokuzlar,1 Pinar Soysal,2 Ahmet Turan Isik3 Department of Geriatric Medicine, Dokuz Eylul University Faculty of Medicine, Izmir, Turkey
1
Department of Geriatric Medicine, Kayseri Training and Research Hospital, Kayseri, Turkey
2
Center for Aging Brain and Dementia, Department of Geriatric Medicine, Dokuz Eylul University Faculty of Medicine, Izmir, Turkey
3
ABSTRACT OBJECTIVE: Frailty is associated with recurrent falls, fractures, limitation of daily living activities, cognitive impairment, increase in hospitalization, placement in nursing home, and mortality rate in older adults. Although malnutrition is one of the most important etiological factors, role of micronutrients is unclear. The aim of this study was to investigate association between frailty and vitamin B12, which has been demonstrated to be related to numerous geriatric syndromes. METHODS: Total of 335 patients who presented at geriatric outpatient clinic and underwent comprehensive geriatric assessment were included in this study. All patients were evaluated with both Fatigue, Resistance, Ambulation, Illnesses, and Loss of Weight (FRAIL) scale and Fried criteria for frailty. Vitamin B12 deficiency was defined as serum vitamin B12 level of less than 400 pg/mL. RESULTS: In total of 335 patients, 88 (26.3%) were assessed as frail, 156 (46.6%) were prefrail, and 91 (27.2%) were robust. When the 3 groups were compared, it was found that patients in frail group had highest average age and lowest education level (p<0.001) and that complaints of urinary incontinence, balance disorders, recurrent falls, sleep disorders, amnesia, chronic pain, and constipation were more frequent in this group (p<0.05). Albumin and 25-hydroxy vitamin D levels decreased as frailty level increased (p<0.05), but no association between vitamin B12 levels and frailty was found. Patients were divided into 2 groups: vitamin B12 level above and below 400 pg/ mL. Groups were then compared in terms of subparameters of both the FRAIL and Fried criteria, and no significant difference between groups was found (p>0.05). CONCLUSION: Results of this study determined no association between vitamin B12 level and frailty in geriatric population; however, longitudinal studies are needed to clarify relationship. Keywords: Frailty; micronutrient; older adult; vitamin B12.
F
railty is a geriatric syndrome, defined as medical syndrome with multiple causes and contributors that is characterized by diminished strength,
endurance, and reduced physiological function that increases an individual’s vulnerability for developing increased dependency and/or death [1]. Worldwide
Received: January 14, 2017 Accepted: March 31, 2017 Online: May 10, 2017 Correspondence: Dr. Ahmet Turan ISIK. Dokuz Eylul Universitesi Tip Fakultesi, Geriatri Bilim Dali, 35340 Izmir, Turkey. Tel: +90 232 - 412 43 41 e-mail: atisik@yahoo.com © Copyright 2017 by Istanbul Northern Anatolian Association of Public Hospitals–Available online at www.kuzeyklinikleri.com
Dokuzlar et al., Association between serum vitamin B12 level and frailty in older adults
prevalence of frailty and prefrailty among geriatric population is 13.9% and 48%, respectively [2]. Frailty is associated with falls from a height, fractures, restriction of daily living activities, decrease in mobility, loss of cognitive function, increase in frequency of hospitalization, placement in nursing homes, and mortality [3]. Therefore, recognition of factors causing frailty, identification of prefrail adults, and elimination of risk factors are very important issues. Numerous interrelated factors contribute to etiopathogenesis of frailty syndrome. Stimulation of hypothalamus-pituitary-adrenal axis with aging, inflammatory and oxidative stress pathways activated by existing comorbid diseases, anemia, senile anorexia and related deficient calorie and protein intake, in addition to decreased level of gonadotropin and insulin-like growth factor 1 have been evaluated in association with frailty [2, 4, 5]. Although factors leading to development of frailty affect each other in a vicious cycle, one of the basic causes seems to be malnutrition [6]. Significant quantity of evidence is available regarding relationship between insufficient protein and calorie intake with sarcopenia and frailty [7]. However, correlation between micronutrient deficiency and frailty is not clear. Incidence of vitamin B12 deficiency increases with age [8]. Vitamin B12 deficiency causes neuropathy, cognitive impairment, balance and gait disorders, recurrent falls, depression, orthostatic hypotension, and elevated homocysteine levels, and associated increase in cardiovascular risk [9, 10]. Very few studies have been performed to examine whether vitamin B12 deficiency, which is known to be related to many risk factors associated with frailty, has any direct effect on development of frailty [9]. The objective of this study was to investigate correlation between vitamin B12 and frailty. MATERIALS AND METHODS Patients Total of 335 patients who presented at geriatric polyclinics of a university hospital, met study inclusion criteria, and were treated between August 30 and December 1, 2016 on an inpatient basis, and provided written, informed consent were included
23
in this cross-sectional study. The study was initiated after receiving approval of the local ethics committee (date: March 10, 2016; decision no: 2016/07â&#x20AC;&#x201C;05). Exclusion criteria Patients who were unable to walk due to severe osteoarthritis or neuromuscular disease, immobile patients, patients presenting with delirium tremens during evaluation process, patients who had history of acute cerebrovascular events, gastrointestinal bleeding, sepsis, acute renal failure, acute coronary syndrome, acute hepatic failure, acute respiratory failure, or hospitalization in intensive care unit that might contribute to deterioration in health during follow-up period were excluded from the study. In addition, patients with mental disorders caused by substance or alcohol intoxication, withdrawal, or abuse; cases with vitamin B12 deficiency and concurrent malignancy or similar disease that might result in frailty; patients younger than 60 years of age; and patients who did not have detailed geriatric assessment performed were excluded from the study. All eligible patients who applied to geriatric polyclinic for any reason were included in the study. Patient characteristics Details of age, gender, education level, type of residence (home, nursing home), marital status, concomitant systemic diseases, and medications used were recorded. Patients were asked if they had fallen from a height within previous year. In addition, patients were asked if they had constipation, urinary incontinence, balance or gait difficulties, nocturia, sleep disorders, or pain. History of hypertension, diabetes mellitus, coronary artery disease, congestive heart failure, peripheral artery disease, chronic obstructive pulmonary disease, thyroid disease, osteoporosis, cerebrovascular disease, dementia, hyperlipidemia, depression, sarcopenia, dynapenia, cataracts, or hearing loss was examined. Detailed geriatric evaluation [11] The following scales, for which validation and reliability studies of Turkish version have been performed, were used for detailed neurocognitive
24
evaluation of the patients: Montreal Cognitive Assessment Scale (MOCA), Mini-Mental State Examination (MMSE) Cognitive State Test (COST) [12], Geriatric Depression Scale (GDS), Instrumental Activities of Daily Living (IADL), Basic Activities of Daily Living (BADL), Tinetti Performance Oriented Mobility Assessment (POMA) and Mini-Nutritional Assessment (MNA) were applied [13]. Laboratory test results Laboratory tests were performed to determine biochemical, metabolic, and nutritional state of the patients. Data related to complete blood count, fasting blood glucose, renal and hepatic function, cholesterol, albumin, thyroid stimulating hormone, HbA1c, vitamin D, vitamin B12, and folic acid were obtained. All biochemical tests were performed using Diagnostic Modular System autoanalyzer (E170 and P800; Roche Diagnostics, Basel, Switzerland). Serum 25-hydroxy-vitamin D [25(OH)D] level was measured using radioimmunoassay technique. Serum vitamin B12 level below 400 pg/mL was accepted as vitamin B12 deficiency [8]. Diagnosis of frailty To determine frailty, the patients were evaluated using both FRAIL scale and Fried criteria. FRAIL scale were developed by the International Academy of Nutrition and Aging (IANA) in 2008. Scale evaluates the following parameters: fatigue, resistance (inability to climb a flight of stairs), ambulation (difficulty walking more than 1 block), illness (≥5 comorbid diseases), and loss of weight (≥5% of actual weight) [14]. Fried criteria to identify frail individuals were developed by Fried et al. in 2001. Criteria are: shrinking (unintentional weight loss of 4.5 kg or >5% of baseline body weight), weakness (20% decrease in grip strength, adjusted for gender and body mass index), poor endurence (response to questions about essential activities), slowness (4 m walk >6–7 seconds, 20% slower than baseline value), low activity (weekly calories burned: men, <383 Kcal; women, <270 Kcal) [4].
North Clin Istanb
In both scales, 1 point is assigned for each criterion: 0 points, not frail; 1-2 points, prefrail; ≥3 points, frail. Individuals who scored 0 points on FRAIL and Fried criteria scales were accepted as control group. Statistical analysis To achieve 95% confidence level and 5% margin of error, sample size of 164 patients was required. Data were analyzed using SPSS for Windows, Version 15.0 (SPSS, Inc., Chicago, IL, USA) software. For descriptive statistics, measurable variables were evaluated using Kolmogorov-Smirnov Goodness-of-Fit test for normality of distribution. Variables with normal distribution were expressed as mean±SD, and variables with non-normal distribution were presented as median (minimummaximum). Numerical variables were displayed as number of cases, and percent distribution When only 2 groups were considered, significance of intergroup difference between means was examined using parametric t-tests, while significance of difference between medians was analyzed using nonparametric Mann-Whitney U test. When more than 2 groups were considered, significance of differences between means was evaluated using parametric analysis of variance test, while significance between median values was investigated using non parametric Kruskal-Wallis test. Numerical variables were evaluated using Pearson chi-square or Fisher’s exact test. P<0.05 was considered statistically significant. RESULTS Demographic characteristics of patients based on frailty status are summarized in Table 1. Total of 335 patients were included in the study: 88 (26.3%) frail patients, 156 (46.6%) who were prefrail, and 91 (27.2%) controls. Female patients were more numerous in the frailty group. When compared with control group, frail and prefrail patients had lower education level (p<0.001). Frailty was less frequently seen in married individuals and those living with partner, and more common among those living with caregiver (p<0.001) (Table 1). Frail and prefrail patients were compared with
Dokuzlar et al., Association between serum vitamin B12 level and frailty in older adults
25
Table 1. Comparison of patient characteristics based on frailty status
Control group n=91
Prefrail group n=156
Frail group n=88
p
Age (years) 70.33 72.64 77.50 <0.001 Gender (female/male) (%) 56.0/44.0 66.0/34.0 78.4/21.6 0.006 Level of education (%) 27/39.4/33.7% 51.3/31.6/17.1% 50.2/31.9/18.0% <0.001 0â&#x20AC;&#x201C;5/6â&#x20AC;&#x201C;11/>11years Marital status (%) 2.2/70.0/5.6/22.2% 1.9/63.6/6.5/27.9% 0.0/41.9/2.3/55.8% <0.001 (Single/married /divorced/widowed) Living environment (%) 17.6/61.5/16.5/0.0/4.4 16.9/60.4/18.2/0.6/3.9 15.1/36.0/44.2/1.2/3.5 0.001 (alone/with spouse/with relative/ with caregiver/in nursing home) Charlson Comorbidity Index 0.63 1.10 1.46 <0.001 Comorbid diseases (%) Hypertension 46.2 68.6 69.3 0.001 Coronary artery disease 8.8 16.7 18.2 0.149 Congestive heart failure 3.3 4.5 9.1 0.182 Peripheral artery disease 2.2 4.5 10.2 0.048 Chronic obstructive pulmonary disease 2.2 9.6 11.4 0.049 Thyroid disease 14.3 19.9 25.0 0.197 Osteoporosis 14.3 16.1 33.0 0.002 Cerebrovascular disease 4.4 5.8 10.2 0.249 Dementia 8.8 13.0 29.4 <0.001 Diabetes mellitus 15.4 31.4 29.5 0.017 Hyperlipidemia 23.1 26.3 21.6 0.684 Depression 24.2 35.1 50.0 0.001 Sarcopenia 0.0 30.8 40.9 <0.001 Laboratory parameters Glucose (mg/dL) 102.16 107.24 105.37 0.936 Albumin (g/dL) 4.27 4.20 4.04 <0.001 Folic acid (ng/dL) 8.86 8.68 8.11 0.389 Vitamin B12 (pg/mL) 408.28 429.78 402.07 0.452 Vitamin D (ng/mL) 27.96 25.90 22.44 0.002 TSH (IU/mL) 1.78 1.52 1.40 0.086 Geriatric assessments MMSE 27.51 25.49 21.75 <0.001 COST 26.50 25.33 18.15 0.038 MOCA 24.54 23.69 21.63 0.060 Geriatric Depression Scale 1.19 2.60 5.56 <0.001 Tinetti-balance 15.85 15.13 12.07 <0.001 Tinetti-gait 11.95 11.33 9.31 <0.001 Tinetti-total 27.79 26.46 21.38 <0.001 Timed Get Up and Go Test 9.22 11.37 20.05 <0.001 BADL 98.23 94.75 82.56 <0.001 IADL 21.32 19.29 13.34 <0.001 Mini-Nutritional Assessment 13.43 12.89 11.84 <0.001 COST: Cognitive State Test; BADL: Basic Activities of Daily Living; IADL: Instrumental Activities of Daily Living; MMSE: Mini-Mental State Examination; MOCA: Montreal Cognitive Assessment Scale; TSH: Thyroid stimulating hormone.
26
North Clin Istanb
Table 2. Comparison of FRAIL and Fried criteria based on vitamin B12 level Fatigue (FRAIL)* Resistance* Ambulation* Loss of weight* Illness* Poor endurance (Fried)** Shrinking** Weakness** Slowness** Low activity** FRAIL Robust/Prefrail/Frail Fried Robust/Prefrail/Frail
Vitamin B12 <400 pg/mL n=149
Vitamin B12 >400 pg/mL n=186
p
44.3 31.4 17.1 9.0 0.7 35.4 9.0 58.0 25.7 24.3
44.0 35.4 24.0 9.0 1.7 35.4 9.0 54.5 33.1 29.2
0.960 0.455 0.137 0.990 0.489 0.997 0.990 0.524 0.146 0.324
71.6/16.0/12.5
65.2/16.9/17.9
0.536
26.6/49.0/24.5
27.5/43.8/28.7
0.608
FRAIL: Fatigue, resistance, ambulation, illnesses, and loss of weight; *FRAIL criteria; **Fried criteria.
healthy individuals regarding complaints, and it was observed that urinary incontinence, balance disorders, recurrent falls, amnesia, chronic pain, and constipation increased with greater frailty (p<0.05). Comorbidities, such as hypertension, chronic obstructive pulmonary disease, osteoporosis, diabetes, dementia, depression, sarcopenia, and dynapenia, were also more frequently seen in frail and prefrail individuals (p<0.05). The 3 groups were compared with respect to detailed geriatric evaluation parameters, and lower MMSE, COST, MNA, POMA balance and gait test, BADL score and higher Timed Get Up and Go test and GDS scores were detected in the frailty group (p<0.05). Level of albumin and 25(OH)D decreased as severity of frailty increased (p<0.05); however, serum vitamin B12 level did not differ between groups (p>0.05). When groups were adjusted for age and education level, all differences persisted, with exception of MNA (p<0.05) (Table 2). No significant difference was seen in subparameters of FRAIL and Fried criteria between patient groups divided based on vitamin B12 level above or below 400 pg/mL or state of frailty (p>0.05) (Table 2).
DISCUSSION This study was examination of correlation between serum vitamin B12 level and frailty in geriatric cases and it was determined that vitamin B12 level could not be associated with frailty. In our study, frail and prefrail patients constituted 26.3% and 46.6% of the patient population, respectively. In meta-analysis of 23,910 patients performed by Soysal et al., researchers found incidence of frailty and prefrailty among the elderly of 13.9% and 48.9%, respectively [2]; However, Morley et al. indicated that frailty was seen at average rate of 9.9% among individuals older than 65 years [1]. Higher rate of frailty in our patients might be related to advanced age of our patients (median age: 77.5 years), and study population consists of patients admitted to hospital for any reason, not whole community. Education level of frail and prefrail patients was lower than that of control group in the present study. In the United Kingdom, twins were evaluated for frailty, and it was determined that even between twins, lower education level increased predisposition to frailty [15, 16]. Predisposition to frailty may be related to
Dokuzlar et al., Association between serum vitamin B12 level and frailty in older adults
influence of education level on bad habits [17], lower income level, decreased self-care, and aggravated cognitive deficiency. Consistent with literature findings, greater number of comorbidities (evaluated using Charlson Comorbidity Index) was detected among frail and prefrail individuals. Incidence of hypertension, diabetes mellitus, chronic obstructive pulmonary disease, osteoporosis, and sarcopenia was greater in frail and prefrail individuals [4, 18–20]. Frail, prefrail, and healthy individuals were compared in terms of predominant complaints and geriatric syndromes, and it was observed that balance disorder, depression, dementia, recurrent falls, sleep disorder, amnesia, and chronic pain increased with the severity of frailty [4, 21–23]. It is very important to detect risk factors that trigger development of frailty, as it could lead to greater number of complaints and complications. Relationship between vitamin B12 deficiency frequently seen in elderly population and associated with geriatric syndromes, such as cognitive deficiency, balance and gait disorders, recurrent falls, depression, and orthostatic hypotension, has been thought to be correlated with frailty [8–10]. However, comparison of vitamin B12 deficiency with subparameters of both FRAIL and Fried criteria and state of frailty yielded no intergroup difference. In the literature, very few studies have been conducted to investigate relationship between vitamin B12 level and frailty, and results are mixed. In a study performed in 2006, no correlation between vitamin B12 level and frailty was detected. As was the case with our study, vitamin D deficiency was reported to be possible etiological factor for frailty [9]. However, in another study conducted in 2010, correlation was demonstrated between different genetic variations affecting vitamin B12 transport mechanism and frailty. Authors hypothesized that vitamin B12 deficiency might induce development of frailty through mechanisms of increasing level of homocysteine and causing cellular damage via hypomethylation of DNA and RNA, leading to decrease in energy metabolism and possibly triggering activation of inflammatory pathways. However, in that study, probable correlation between genetic factors playing role in vitamin B12 metabolism rather than serum vitamin B12 levels was emphasized [24].
27
Strong points of our study include prospective design, adequate number of samples, and detailed evaluation of all patients. Limitations of the study include cross-sectional design, and evaluation of vitamin B12 deficiency based only on serum vitamin B12 level. Furthermore, methylmalonic acid and homocysteine levels were not measured, and patients with vitamin B12 replacement were included in the study. In addition, cognitive frailty was not investigated. In conclusion, in this cross-sectional analysis performed with large study population, correlation between frailty, which is frequently seen in geriatric cases with multiple adverse outcomes, and serum vitamin B12 level was not detected. Studies have concentrated on frailty for the last 20 years; however, further insight into correlation requires longitudinal studies to be performed in the future. Conflict of Interest: None declared. Financial Disclosure: The authors declared that this study has received no financial support. Authorship contributions: Concept – P.S., A.T.I.; Design – P.S., A.T.I.; Materials – P.S., A.T.I.; Data collection &/or processing – O.D.; Analysis and/or interpretation – P.S., A.T.I.; Literature search – O.D.; Writing – P.S., A.T.I., O.D.
REFERENCES 1. Morley JE, Vellas B, van Kan GA, Anker SD, Bauer JM, Bernabei R, et al. Frailty consensus: a call to action. J Am Med Dir Assoc 2013;14:392–7. 2. Soysal P, Stubbs B, Lucato P, Luchini C, Solmi M, Peluso R, et al. Inflammation and frailty in the elderly: A systematic review and meta-analysis. Ageing Res Rev 2016;31:1–8. 3. Vermeiren S, Vella-Azzopardi R, Beckwée D, Habbig AK, Scafoglieri A, Jansen B, et al; Gerontopole Brussels Study group. Frailty and the Prediction of Negative Health Outcomes: A Meta-Analysis. J Am Med Dir Assoc 2016;17:1163.e1–1163.e17. 4. Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, et al. Cardiovascular Health Study Collaborative Research Group. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 2001;56:M146–56. 5. Walston JD. Connecting Age-Related Biological Decline to Frailty and Late-Life Vulnerability. Nestle Nutr Inst Workshop Ser 2015;83:1–10. 6. Bonnefoy M, Berrut G, Lesourd B, Ferry M, Gilbert T, Guérin O, et al. Frailty and nutrition: searching for evidence. J Nutr Health Aging 2015;19:250–7.
28 7. Goisser S, Guyonnet S, Volkert D. The Role of Nutrition in Frailty: An Overview. J Frailty Aging 2016;5:74–7. 8. Bozoglu E, Isik AT, Doruk H, Kilic S. e e ects of early vitamin B12 replacement therapy on the cognitive and functional status of elderly subjects. Klinik Psikofarmakoloji Bülteni 2010;20:120–4. 9. Michelon E, Blaum C, Semba RD, Xue QL, Ricks MO, Fried LP. Vitamin and carotenoid status in older women: associations with the frailty syndrome. J Gerontol A Biol Sci Med Sci 2006;61:600–7. 10. Wahlqvist ML, Saviage GS. Interventions aimed at dietary and lifestyle changes to promote healthy aging. Eur J Clin Nutr 2000;54 Suppl 3:S148–56. 11. Soysal P, Isik AT, Buyukaydin B, Kazancioglu R. A comparison of end-stage renal disease and Alzheimer’s disease in the elderly through a comprehensive geriatric assessment. Int Urol Nephrol 2014;46:1627–32. 12. Babacan-Yildiz G, Isik AT, Ur E, Aydemir E, Ertas C, Cebi M, et al. COST: Cognitive State Test, a brief screening battery for Alzheimer disease in illiterate and literate patients. Int Psychogeriatr 2013;25:403–12. 13. Işık AT, Soysal P. Geriatri Pratiğinde Ölçekler. İstanbul Tıp Kitabevleri: İstanbul; 2016. 14. Woo J, Leung J, Morley JE. Comparison of frailty indicators based on clinical phenotype and the multiple deficit approach in predicting mortality and physical limitation. J Am Geriatr Soc 2012;60:1478–86. 15. Trevisan C, Veronese N, Maggi S, Baggio G, Toffanello ED, Zambon S, et al. Factors Influencing Transitions Between Frailty States in Elderly Adults: The Progetto Veneto Anziani Longitudinal Study. J Am Geriatr Soc 2017;65:179–184. 16. Young AC, Glaser K, Spector TD, Steves CJ. The Identification of Hereditary and Environmental Determinants of Frailty in a
North Clin Istanb Cohort of UK Twins. Twin Res Hum Genet 2016;19:600–9. 17. López-Sobaler AM, Rodríguez-Rodríguez E, Aranceta-Bartrina J, Gil Á, González-Gross M, Serra-Majem L, et al. General and Abdominal Obesity Is Related to Physical Activity, Smoking and Sleeping Behaviours and Mediated by the Educational Level: Findings from the ANIBES Study in Spain. PLoS One 2016;11:e0169027. 18. Ramsay SE, Arianayagam DS, Whincup PH, Lennon LT, Cryer J, Papacosta AO, et al. Cardiovascular risk profile and frailty in a population-based study of older British men. Heart 2015;101:616–22. 19. Liu LK, Lee WJ, Chen LY, Hwang AC, Lin MH, Peng LN, et al. Association between Frailty, Osteoporosis, Falls and Hip Fractures among Community-Dwelling People Aged 50 Years and Older in Taiwan: Results from I-Lan Longitudinal Aging Study. PLoS One 2015;10:e0136968. 20. Morley JE. Frailty and sarcopenia in elderly. Wien Klin Wochenschr 2016;128:439–45. 21. Ensrud KE, Blackwell TL, Ancoli-Israel S, Redline S, Cawthon PM, Paudel ML, et al. Sleep disturbances and risk of frailty and mortality in older men. Sleep Med 2012;13:1217–25. 22. Feng L, Zin Nyunt MS, Gao Q, Feng L, Yap KB, Ng TP. Cognitive Frailty and Adverse Health Outcomes: Findings From the Singapore Longitudinal Ageing Studies (SLAS). J Am Med Dir Assoc 2017;18:252–8. 23. Castañeda Morales VM, Jiménez Garduño AM, Escárcega MV, Sánchez Velázquez LD, Becerra Laparra I. Association between Chronic Pain and Frailty in Mexican Elders. J Frailty Aging 2016;5:59–61. 24. Matteini AM, Walston JD, Bandeen-Roche K, Arking DE, Allen RH, Fried LP, et al. Transcobalamin-II variants, decreased vitamin B12 availability and increased risk of frailty. J Nutr Health Aging 2010;14:73–7.
Orıgınal Article
NURSING SERVICES
North Clin Istanb 2017;4(1):29–35 doi: 10.14744/nci.2016.40316
The effects of training inpatients and their relatives about infection control measures and subsequent rate of infection Funda Ozturkan Erdek, Ciler Keles Gozutok, Yeliz Dogan Merih, Aysegul Aliogulları Zeynep Kamil Maternity and Children’s Diseases Training and Research Hospital, Istanbul, Turkey
ABSTRACT OBJECTIVE: Healthcare-associated infections are one of the most important problems of all health institutions. This study was conducted to evaluate results of training about infection control measures provided to patients treated and hospitalized in clinics of obstetrics and gynecology, and to their relatives, as well as subsequent effect on infection rate. METHODS: The study was conducted in clinics of obstetrics and gynecology of a state hospital. Study group comprised midwives and nursing staff, and inpatients and their relatives. Survey made up of 16 questions was administered to patients and relatives before and after training provided by infection nurses. Survey with 18 questions was administered to midwives/nurses to evaluate compliance of patients and relatives with infection control measures. Study data were analyzed using statistical analysis software and findings were evaluated as numbers and percentages using Student’s t-test. RESULTS: According to survey of patients and relatives, mean knowledge level score before and after training was 20.07±46.76 and 96.36±11.85, respectively. Results indicated that training about infection control measures was effective at increasing knowledge level and compliance of patients and their relatives (p<0.05). Of the total, 87.5% of midwives/nurses stated that educating patients and relatives about infection control measures facilitated treatment and healthcare processes. In all, 95.9% of midwives/nurses thought that such education contributed to observance of infection control measures by patients and relatives. CONCLUSION: It is thought that regular education about infection control measures provided to patients and relatives would have positive effect and reduce incidence rate of healthcare-associated infection. Keywords: Education; nosocomial infection; patients; relatives of patient.
H
ealthcare-associated infection is among the most important indicators of the quality of healthcare delivered during hospitalization period. These infections have great impact on mortality
and morbidity rates, threaten patient safety, prolong hospitalization, and increase healthcare expenses [1, 2]. Healthcare-associated infections are vital issue in monitoring and treatment processes of inpa-
Received: October 03, 2016 Accepted: December 28, 2016 Online: May 10, 2017 Correspondence: Dr. Funda OZTURKAN ERDEK. Saglik Bi̇ li̇ mleri̇ Uni̇ versi̇ tesi̇ , Zeynep Kami̇ l Kadin ve Cocuk Hastaliklari Egi̇ ti̇ m ve Arastirma Hastanesi̇ , Istanbul, Turkey. Tel: +90 216 - 391 06 80 e-mail: fundaerdek1982@gmail.com © Copyright 2017 by Istanbul Northern Anatolian Association of Public Hospitals–Available online at www.kuzeyklinikleri.com
30
tients in both developed and developing countries [3]. In a report released by the Centers for Disease Control and Prevention (CDC) in 2016, nosocomial infections were considered to be most important preventable healthcare problem [4]. This report indicated that nearly 4% of patients in the USA had suffered from hospital-acquired infection, and in studies performed in other countries, incidence rate has ranged between 3.1% and 14.1% [4–6]. It is possible to prevent healthcare-associated infection with effective infection control programs [7]. In a CDC report published in 2009, it was reported that if minimal infection control measures were implemented in institutions where healthcare services and treatment are offered, 6% of all healthcareassociated infections could be prevented, and 32% could be avoided with thorough infection control program [8]. In 2007, the World Health Organization (WHO) established international standards for infection control programs. These standards involve monitoring outcomes of follow-up; training of healthcare professionals, patients, and patient relatives; compliance with hand hygiene; use of protective equipment; prevention of sharp injuries; clean environment; waste sorting; and cleaning and disinfection of equipment [6, 9]. In our country, scope of infection control measures became more comprehensive with “The Regulations for Infection Control Measures to be Implemented in Inpatient Treatment Institutes,” published in the Official Gazette on August 11, 2015 (Issue #25903). This regulation mandated establishment of infection control committees in every hospital. Infection control committees are held responsible for preparation of infection control program that is to encompass basic tasks, such as preparation of written infection control standards, training of healthcare personnel, follow-up, and determination of effectiveness of infection control programs based on data [10]. Training programs aimed at providing more qualified and cost-effective healthcare services and preventing accidents and errors by ensuring safety of the patients in hospitals are available [11]. Implementation of effective infection control measures can be achieved with compliance of not just healthcare professionals, but also participation of patients
North Clin Istanb
and their relatives. Educational courses for patients and their relatives provided within the context of the quality standards for healthcare mandated by the Ministry of Health are to include infection control measures related to hand hygiene [12]. In a study performed by McGuckin et al., hygiene program with infection control measures was prepared and training was provided for healthcare professionals and patients. As a result, frequency of handwashing increased by at least 50% [13]. Terzi et al. indicated that 82.9% of healthcare professionals had received training on infection control measures, and 63.2% of them expressed wishes to receive further training on preventive measures [14]. Training in infection control measures is inexpensive, and it is possible to increase awareness, knowledge level, and compliance of healthcare professionals, patients, and patients’ relatives. Luby et al. reported that training in use of soap and other methods of hand hygiene decreased incidence of impetigo by 34%, diarrheic diseases by 53%, and pneumonia by 50% [15, 16]. Since healthcare professionals have incomplete knowledge of the patient, and because family will likely have effect on health behaviors, sustained educational programs according to knowledge and skill level of healthcare professionals and patients should be implemented. Ineffective application of training programs for inpatients plays important role in development of hospital-acquired infection. Healthcare professionals receive in-service training, and patients and their relatives receive individualized and disease-specific training. In departments with heavy patient circulation, occasionally implementation of this program may prove difficult. Patient training programs to protect and maintain wellbeing of individuals and to develop behavioral changes should be instituted using systematic, programmed approach [17]. This study was performed to evaluate effect of training provided to inpatients and their relatives concerning infection control measures and to assess subsequent rate of infection. MATERIALS AND METHODS Study was quasi-experimental research performed at the clinics of obstetrics and gynecology of a spe-
Ozturkan Erdek et al., The effects of training inpatients and their relatives about infection control measures
cial branch hospital between November 2015 and January 2016. Using guidelines on infection control measures published by the WHO and the CDC, a guide with visual and written content was prepared by researchers, the “Information Guide for Patients and their Relatives on Infection Control Measures.” First page of the guide contained definition of hospital-acquired infection, general infection control measures, and illustrations on handwashing technique. In detailed table on second page, waste materials were classified and proper waste sorting was explained in detail. Third and fourth pages explained importance of handwashing, general hygiene practices, use of protective equipment, and rules that should be followed by companions attending to patient and visitors. Total of 197 patients and relatives were included in the study. Data collection form comprising 16 questions to determine knowledge level of the participants was created in line with information in the guide. Another data collection form was prepared by researchers to ask 24 participating midwives and nurses 18 questions designed to assess compliance of the patients and their relatives with infection control measures following training. In the first phase of the study, preliminary test consisting of 16 questions was administered to patients hospitalized in the clinics of obstetrics and gynecology in order to evaluate their baseline knowledge level of infection control measures. Following pretest, infection control nurses provided one-to-one training for the patients using the “Information Guide for Patients and their Relatives on Infection Control Measures.” Participants were retested on same day to evaluate knowledge. After completion of training and testing, guideline materials were given to the patients. Midwives and nurses working in the clinics of obstetrics and gynecology were requested to observe compliance during treatment and visiting hours and record findings in data collection survey form. They were asked to evaluate hand hygiene, change in use of hand antiseptic, proper waste sorting, and compliance with measures to be followed by those attending to or visiting patient. Data analysis was performed with SPSS Statistics
31
Mean knowledge level of the patients and their relatives before and after training 150 96.36 100 50 0
20.07 Before training
After training
Figure 1.
Mean knowledge level of the patients and their relatives before and after training.
for Windows, Version 22.0 (IBM Corp., Armonk, NY, USA) software using numbers and percentages, and analyzed using Student’s t-test. Approval of the Zeynep Kamil Maternity and Children’s Diseases Training and Research Hospital ethics committee, and institutional approval of the hospital were obtained before beginning the research. Objective of the survey was explained to employees of the unit and patients, and written, informed consent was obtained. RESULTS Sociodemographic characteristics of the patients and their relatives were examined. Mean age was 32.89±9.92 years. In study group, 60% were primary school graduates, and 82% were unemployed. Fifty percent of participant nurses and midwives were in age group of 31-40 years. In all, 50% had bachelor’s degree, and 41.7% had work experience of ≥6 years. Average knowledge level score of the patients and their relatives determined before and after training based on questionnaire form is displayed in Figure 1. Correlation between training provided on infection control measures and knowledge level of participants (p<0.05) was calculated, and increase in post-training knowledge level was determined. Mean score before and after training was 20.07±46.76 and 96.36±11.85, respectively. Details of knowledge level of the patients and their relatives with respect to infection control measures before and after training are presented in Table 1. Increase in knowledge of infection control measures after training was demonstrated.
33
North Clin Istanb
Table 1. Participants’ knowledge of infection control measures
Before training After training
Yes No
No Yes No opinion
No opinion
n
%
n
%
n
%
n
%
n
%
n %
Do you know anything about hospital-acquired infection? Does hospital-acquired infection prolong hospital stay? Can hospital-acquired infection be prevented? During your hospital stay, should hands be washed with soap and water? During your hospital stay, should hand antiseptics be used? Do you know which waste material should be discarded in garbage bins containing red plastic bags? Do you know which waste materials should be discarded in garbage bins containing black plastic bags? Do you know which waste materials should be discarded in garbage bins containing blue plastic bags? Do you know which waste materials should be discarded in garbage bins containing yellow plastic bags? Do you know the precautions that should be taken by your hospital companion concerning infection control? Do you know the infection control measures that visitors should observe?
88
44.7
84
42.6
25
12.7
188
95.4
4
2.0
4 2.5
147
74.6
39
19.8
11
5.6
193
98
2
1.0
2 1.0
144
73.46
40
20.3
12
6.1
197
100
–
–
–
–
192
97.5
3
1.5
2
1.0
197
100
–
–
–
–
160
81.2
29
14.7
8
4.1
195
99
1
0.5
1 0.5
104
52.8
81
41.1
12
6.1
192
97.5
4
2.0
1 0.5
112
56.9
74
37.6
11
5.6
193
98
2
1.0
2 1.0
75
38.1
108
54.8
14
7.1
189
95.9
4
2.0
4 2.0
43
21.9
137
69.5
16
8.1
184
93.4
6
3.0
7 3.6
76
38.6
106
53.8
15
7.6
190
96.4
6
3.0
1 0.5
80
40.6
100
50.8
17
8.6
190
96.4
6
3.0
1 0.5
Most (95.8%) of the nurses and midwives working in obstetrics and gynecology clinics indicated that training was provided to patients, and 87.5% of the staff group stated that training on infection control measures facilitated treatment and healthcare procedures. Nurses also evaluated behavioral changes in patients observed after training on infection control measures, and 95.9% of them thought that the
training provided contributed favorably to compliance with infection control measures. According to staff working in the clinics of obstetrics and gynecology, increase in compliance with infection control measures was seen after training (Figure 2). Evaluation of postoperative healthcare-associated infection rate after training regarding infection control measures determined that there was
Ozturkan Erdek et al., The effects of training inpatients and their relatives about infection control measures
33
Evaluation by midwives and nurses of post-training compliance with infection control measures by the patients and their relatives 120 Yes No 100 80
%91.6
%95.8 %83.3
%75.9
%70.9
%91.7
%85.5
60 40
%29.2
20 0
%20.8 %8.3
Decrease in length of hospital stay
Decrease in material exchange
Increase in hand hygiene
%16.7 %4.2 Increase in use of equipment
Increase in compliance with isolation measures
%8.3 Increase in use of hand antiseptics
%12.5 Proper waste sorting
Figure 2. Compliance of the patients and their relatives with infection control measures. Rate of surgical site infection after cesarean section 1.5
1.05
1
0.77
0.5 0
SSI rate before training
SSI rate after training
Figure 3. Incidence rate of surgical site infection (SSI) before and after training of patients and their relatives.
decrease in infection rate. Incidence of surgical site infection when training was not uniformly provided was 1.05%, while rate between November 2015 and January 2016 when training using the “Information Guide for Patients and their Relatives on Infection Control Measures” was provided was 0.77% (Figure 3). DISCUSSION Training is one of the most important components of an infection control program [18]. Karakuş defined training as the process of acquiring knowledge, skills and attitudes required to develop behaviors that will make life easier [11]. According to this definition, informing patients and their relatives about healthcare-associated infection control measures will enable them to develop their knowledge and change their attitudes and behaviors to help prevent
infection. Uyar indicated that encouraging and providing opportunities for training patients and their relatives increases rate of compliance with infection control measures [18]. Particularly effective in the prevention of infection are observance of guidelines related to hand hygiene and proper waste sorting, visitor recognition of hospital rules, and prevention of sharing personal items between patients and with visitors. Greater knowledge of these issues increases compliance of patients and relatives with infection control measures [11]. Ocran and Tagoe reported that training for healthcare professionals and patients concerning prevention of healthcare-associated infection to encourage behavioral changes and compliance with recommended measures was related to educational level, and that greater level of formal education led to more positive contributions to preventive practices [19]. Uner et al. indicated that mean score of patients’ knowledge level and favorable attitudes about handwashing increased with greater schooling level [20]. In our study, however, 60% of the patients and their relatives were primary school graduates and increase in knowledge level of the patients relative to baseline was not correlated with level of formal education. Kurcer et al. demonstrated significant improvement in knowledge and attitudes of patients after training and counseling services were provided about how to live a healthy life [21]. Hanci et al.
34
isolated various microorganisms that can cause hospital-acquired infection from the hands of visitors to patients. They stated that providing information to visitors about infection control measures was effective in prevention of nosocomial infections [16]. In the present study, mean knowledge level score of patients before and after training was 20.07±46.76 and 96.36±11.85 points, respectively (Figure 1). Materials used to train the patients and their relatives included clear and easy to understand messages prepared to be suitable for individuals of every education level. It is thought that this aspect of the training was helpful to increase knowledge level of the participants. Avsar et al. indicated that training provided to patients should be easily comprehensible and age-appropriate [22]. Clear, simple language contributed favorably to the effectiveness of the training in the present study. Healthcare professionals are to provide patients with training on various subjects from the time of admission to the hospital. Guidelines released by the Ministry of Health concerning quality standards in healthcare services include training for patients and relatives about drugs to be used, issues related to patient’s care, use of equipment and medical devices, hand hygiene, nutrition and healthy diet, exercise, and procedure for referral to appropriate specialist [12]. In 2002, Yetkin et al. reported that 33% of nurses provided training for patients, 52.3% of those surveyed trained their patients from time to time, and 14.7% of them indicated that they did not train their patients at all [17]. Present study results revealed that 95.8% of the nursing staff reported training patients about infection control measures. High rate of training currently provided in hospitals is considered to be result of implementation of ministry quality standards beginning in 2007. Viewpoints of clinical nurses about development of behavioral changes in the patients concerning compliance with infection control measures and waste sorting after receiving training were evaluated, and it was determined that exchange of personal materials had decreased (75.9%), hand hygiene was more strictly observed (91.7%), use of hand antiseptic solutions increased (91.7%), and waste sorting also improved (85.5%) (Figure 2).
North Clin Istanb
Though surgical site infections have many etiological factors, application of effective infection control training may increase awareness of the patients and healthcare professionals, and literature studies have indicated that these programs are effective at reducing infection rate. In our study, reduction in incidence of surgical site infection following training using the “Information Guide for Patients and their Relatives on Infection Control Measures” from 1.05% at baseline to 0.77% was found (Figure 3). An informative report published by The Joint Commission in 2010 indicated that patient training contributed to a decrease in postsurgical infection rate from 3.61% to 1.83% [23]. Outcome of present study is supported by this report. Conclusion Observations of nursing staff at conclusion of the study with respect to effectiveness of educational course on prevention of healthcare-associated infection and infection control measures provided to patients and their relatives in easily understandable language were as follows: • Hospitalization period of the patients decreased, • Compliance of the patients and their relatives to hand hygiene was strengthened, • Visitors and companions attending to patients observed infection control measures more frequently, and • The patients and their relatives sorted domestic, medical, hazardous, and recyclable/glass waste more accurately. We conclude that providing regular training for inpatients and their relatives about infection control measures using written and visual educational material will decrease risk of hospital-acquired infection. Conflict of Interest: None declared. Financial Disclosure: The authors declared that this study has received no financial support. Authorship contributions: Concept – F.O.E., Y.D.M.; Design – F.O.E., Y.D.M.; Data collection &/or processing – F.O.E., C.K.G.; Analysis and/or interpretation – F.O.E., Y.D.M., A.A.; Writing – F.O.E., A.A.; Critical review – Y.D.M.
Ozturkan Erdek et al., The effects of training inpatients and their relatives about infection control measures
REFERENCES 1. Orucu M, Geyik MF. Yoğun bakım ünitesinde sık görülen enfeksiyonlar. Düzce Tıp Fakültesi Dergisi 2008;1:40–3. 2. Yüceer S, Demir SG. Yoğun bakım ünitesinde nozokomiyal enfeksiyonların önlenmesi ve hemşirelik uygulamaları. Dicle Tıp Dergisi 2009; 36: 226–32. 3. Asl HM, Nateghian A. Epidemiology of Nosocomial Infections in a Pediatric Intensive Care Unit (PICU). Archives of Clinical Infectious Diseases 2009;4:83-6. 4. National and state healthcare associated infections progress report, CDC 2016. https://www.cdc.gov/hai/pdfs/progressreport/hai-progress-report.pdf (access date: 3 April 2017). 5. Özçetin M, Saz EU, Karapınar B, Özen S, Aydemir Ş, Vardar F. Hastane enfeksiyonları; sıklığı ve risk faktörleri. J Pediatr Inf 2009;3: 49–53 6. Ağırbaş İ. Hastane enfeksiyonlari maliyet analizi, Ankara Üniversitesi Bilimsel Araştırma Projesi, 2013. http://acikarsiv.ankara.edu.tr/browse/24778/Enfeksiyon-maliyet-2013.pdf?show (access date: 11 April 2017). 7. Karahocagil MK, Yaman G, Göktaş U, Sünnetçioğlu M, Çıkman A, Bilici A, et al. Van Tıp Dergisi 2011;18:27–32. 8. Preventing Healthcare-Associated Infections. Council of State and Territorial Epidemiologists Sunday Workshop, June 7, 2009. https://www.cdc.gov/nhsn/ra/pdf/csteworkshopdhqp6709final.pdf (access date: 11 April 2017). 9. Standard precautions in health care, WHO 2007. http://www. who.int/csr/resources/publications/EPR_AM2_E7.pdf?ua=1 (access date: 3 April 2017). 10. T.C. Sağlık Bakanlığı Yataklı Tedavi Kurumları Enfeksiyon Kontrol Yönetmeliği. T.C. Resmi Gazete 2005;25903. http:// www.asm.gov.tr/UploadGenelDosyalar/Dosyalar/143/MEVZUAT/18_08_2010_12_59_33.pdf (access date: 3 April 2017). 11. Karakuş Z. Enfeksiyon Kontrol Hemşirelerinin Çalışma Alanında Yaşadığı Güçlükler ve Eğitimin Rolü. Marmara Üniversitesi Sağlık Bilimleri Enstitüsü Hemşirelik Öğretimi Anabilim Dalı Yüksek Lisans Tezi 2008. 12. T.C.Sağlık Bakanlığı Sağlık Hizmetleri Genel Müdürlüğü Sağlıkta Kalite ve Akreditasyon Daire Başkanlığı. Sağlıkta Kalite Standartları Hastane 2016;5. http://www.kalite.saglik.gov.tr/
35
Eklenti/3460,skshastanesetiv5r1pdf.pdf?0 (access date: 3 April 2017). 13. McGuckin M, Waterman R, Storr IJ, Bowler IC, Ashby M, Topley K, et al. Evaluation of a patient-empowering hand hygiene programme in the UK. J Hosp Infect 2001;48:222–7. 14. Terzi Ö, Aker S, Sünter AT, Pekşen Y. Hastane temizlik elemanları ve mesleki enfeksiyon riski: Bilgi ve davranışlar üzerine bir çalışma. İnönü Üniversitesi Tıp Fakültesi Dergisi 2009;16:7–12. 15. Luby SP, Agboatwalla M, Feikin DR, Painter J, Billhimer W, Altaf A, et al. Effect of handwashing on child health: a randomised controlled trial. Lancet 2005;366:225–33. 16. Hancı H, Ayyıldız A, Çelebi D. Hasta ziyaretleri için hastaneye gelen kişilerin ziyaret öncesi ve sonrası el floralarının karşılaştırılması. Atatürk Üniversitesi Veteriner Bilimleri Dergisi 2012;7:113–21. 17. Yetkin A. Hemşirelerin Hasta ve Ailesinin Eğitimi İle İlgili Görüş ve Uygulamaları. Atatürk Üniversitesi Hemşirelik Yüksekokulu Dergisi 2002;5:53–59. 18. Uyar Y. Hastane infeksiyonlarını önlemede personel sağlık kontrol çalışmaları ve eğitim stratejileri. IV. Ulusal Sterilizasyon Dezenfeksiyon Kongresi (Kongre Kitabı). Ankara 20 - 24 Nisan 2005;493–503. 19. Ocran I, Tagoe DNA. Knowledge and attitude of healthcare workers and patients on healthcare associated infections in a regional hospital in Ghana. Asian Pac J Trop Dis 2014;4: 135–39. 20. Üner S, Sevencan F, Başaran E, Balcı C, Bilaloğlu B. Bir sağlık ocağına başvuran kişilerin sosyal el yıkama ile ilgili bazı bilgi ve tutumların saptanması. TAF Prev Med Bull 2009;8:207–16. 21. Kurçer MA, Özbay A. Koroner arter hastalarında uygulanan yaşam tarzı eğitim ve danışmanlığının yaşam kalitesine etkisi. Anadolu Kardiyol Derg 2011;11:107–13. 22. Avşar G, Kaşıkcı M. Ülkemizde Hasta Eğitiminin Durumu. Atatürk Üniversitesi Hemşirelik Yüksekokulu Dergisi 2009;12:67–73. 23. Educating Patients About Surgical Site Infections: Complying with NPSG.07.05.01. The Joint Commission Perspectives on Patient Safety, December 2010. http://www.jcrinc.com/educating-patients-about-surgical-site-infections-complying-withnpsg-07-05-01/ (acces date: 3 April 2017).
Orıgınal Article
NEPHROLOGY
North Clin Istanb 2017;4(1):36–42 doi: 10.14744/nci.2017.59002
Neutrophil gelatinase-associated lipocalin reflects the severity of anemia without iron deficiency and secondary hyperparathyroidism in hemodialysis patients Irem Pembegul Yigit,1 Ramazan Ulu,2 Nevzat Gozel,3 Hulya Taskapan,4 Necip Ilhan,5 Ayhan Dogukan2 Department of Nephrology, Malatya Government Hospital, Malatya, Turkey
1
Department of Nephrology, Firat University Faculty of Medicine, Elazig, Turkey
2
Department of Internal Medicine, Firat University Faculty of Medicine, Elazig, Turkey
3
Department of Nephrology, Inonu University Faculty of Medicine, Malatya, Turkey
4
Department of Biochemistry, Firat University Faculty of Medicine, Elazig, Turkey
5
ABSTRACT OBJECTIVE: Secondary hyperparathyroidism (SHPT) and anemia are the primary and most common complications in patients receiving hemodialysis (HD). Neutrophil gelatinase-associated lipocalin (NGAL) is a new marker to assess iron deficiency and manage iron therapy for HD patients. The aim of this study was to determine any association between serum NGAL level and anemia without iron deficiency in patients with SHPT on chronic HD. METHODS: Total of 61 SHPT patients on chronic HD were enrolled in the study and divided into 3 groups: mild SHPT group (n=17), moderate SHPT group (n=21), and severe SHPT group (n=23). Hemogram, biochemical assays, and level of ferritin, high sensitivity C-reactive protein (hs-CRP), and NGAL were evaluated in all groups. RESULTS: Serum NGAL level was significantly higher and hemoglobin (Hb) level was significantly lower in severe SHPT patients compared with both mild and moderate SHPT patients. Furthermore, in severe SHPT group, serum NGAL level was significantly positively correlated with serum parathyroid hormone (r=0.79; p=0.00) and hs-CRP (r=0.52; p=0.01) level and negatively correlated with serum Hb (r=-0.56; p=0.00) level. CONCLUSION: SHPT was important factor affecting anemia in HD patients. Even when iron deficiency anemia is excluded in patients with SHPT, there was significant negative correlation between serum NGAL and Hb. Keywords: Anemia; hemodialysis; hyperparathyroidism; neutrophil gelatinase-associated lipocalin.
Received: November 11, 2016 Accepted: January 23, 2017 Online: May 10, 2017 Correspondence: Dr. Irem Pembegul YIGIT. Malatya Devlet Hastanesi, Nefroloji Klinigi, Malatya, Turkey. Tel: +90 422 - 211 20 48 e-mail: pembegulmd@yahoo.com © Copyright 2017 by Istanbul Northern Anatolian Association of Public Hospitals - Available online at www.kuzeyklinikleri.com
Yigit et al., Neutrophil gelatinase-associated lipocalin
C
hronic kidney disease (CKD) is defined as presence of kidney damage or decreased kidney function (estimated glomerular filtration rate <60 mL/min/1.73 m2) for 3 or more months, irrespective of cause. Prevalence and incidence of CKD continues to increase globally. Secondary hyperparathyroidism (SHPT) and anemia are the principal and most commonly seen complications in patients with CKD, and especially affect patients receiving hemodialysis (HD) [1]. Causes of SHPT include phosphate retention, decreased free calcium concentration, decreased 1,25-dihydroxyvitamin D (calcitriol) concentration, and increased fibroblast growth factor 23 concentrations, with reduced expression of vitamin D receptors, calcium-sensing receptors, fibroblast growth factor receptors, and klotho in the parathyroid glands. Most observational studies have reported associations between elevated parathyroid hormone (PTH) level and mortality [2–4]. Kidney Disease: Improving Global Outcomes guidelines suggest maintaining serum PTH value in HD patients in the range of 2 to 9 times upper reference limit for the assay due to technical differences in the laboratory [5]. Mechanism underlying anemia in patients on maintenance HD is attributed to several factors, including decreased erythropoietin (EPO) production, hyporesponsiveness to EPO, low iron stores, multiple instances of blood sampling, gastrointestinal bleeding, dietary restrictions, decreased intestinal absorption due to phosphate medication, dialysis inadequacy, SHPT, and chronic inflammation [6–8]. Among these, EPO deficiency is considered the most important cause. PTH acts directly or indirectly to increase intracellular calcium concentrations, and this leads to critical conclusions, including anemia, immune dysfunction, neurotoxicity, and impairment of vascular reactivity. At the same time, HD patients with SHPT suffer from excessive oxidative stress and inflammation [9, 10]. Neutrophil gelatinase-associated lipocalin (NGAL) is small 25 kDa glycoprotein, a member of lipocalin superfamily that is rapidly released from cells such as renal tubules, liver hepatocytes, endothelial, and smooth muscle cells in response to inflammation and ischemia [11, 12]. NGAL, iden-
37
tified as component of neutrophil granules, inhibits bacterial growth by depleting their intracellular iron stores. NGAL has also been shown to induce apoptosis of primary bone marrow cells, including erythroid progenitor cells, and to inhibit erythroid cell production, leading to anemia [13, 14]. Previous study demonstrated relationship between iron deficiency anemia and serum NGAL level in chronic HD patients [15]. The aim of present study was to test hypothesis whether NGAL might be correlated with severity of SHPT and anemia without iron deficiency. MATERIALS AND METHODS Patients Study was conducted with 61 chronic HD patients (mean age: 52.21±11.6 years; male/female: 29/32). All patients were anuric and were undergoing standard bicarbonate dialysis using standard biocompatible HD membrane 3 times a week for about 4 hours each session in the hemodialysis unit of Firat University. Blood flow rates were 250 to 300 mL/ min and dialysate flow rates were 500 mL/min. Ultrafiltration varied according to the patients’ actual weight. None had received intravenous iron or red cell blood transfusion in previous 2 months. Exclusion criteria of the study were as follows: patients who had been receiving HD for less than 6 months; age <18 or >70 years; serum PTH level <150 pg/ mL; presence of malignancy; presence or recent history of bleeding; B12 or folic-acid deficiency; iron deficiency anemia (transferring saturation value <20% and/or serum ferritin level <200 ng/mL); hemoglobinopathies; hemolytic anemias; liver, thyroid, or infectious disease; treatment with immunosuppressive drugs; and unwillingness to participate in the study. Causes of renal failure among HD patients were diabetic nephropathy in 25 (41%) patients, hypertension in 20 (32.8%), chronic glomerulonephritis in 4 (6.6%), polycystic kidney disease in 3 (4.9%), other cause in 4 (6.6%), and unknown cause in 5 (8.1%) patients. Mean duration of HD was 30.36±15.70 months (range: 6–68 months). Only 3 patients had permanent central venous catheters and the remainder (n=58) had arteriovenous
38
fistula. Although there is no precise cut-off level determining risk groups, as shown in the Dialysis Outcomes and Practice Patterns Study [10], patients with PTH over 600 have high risk of mortality; therefore, patients were divided into 3 groups based on PTH level: Group 1=150<PTH≤300 pg/mL, Group 2=301≤PTH≤600 pg/mL, and Group 3=601pg/mL≤PTH. The study was approved by the Local ethics committee and all patients provided written informed consent. All participants underwent detailed clinical examination. Demographic information and medical history of patients were obtained at baseline by interview with patients and review of medical records. Blood sampling and assay methods Blood samples were taken after an overnight fast at between 8:00 and 9:00 am before HD session. At the end of HD session, blood pump speed was reduced to <80 mL/min and blood samples was obtained at 2 minutes post dialysis from arterial dialysis tubing for calculation of adequacy of dialysis using (Kurea × Td) / Vurea for urea measurement. Laboratory analysis, including creatinin, serum iron (SI), total iron binding capacity (TIBC), albumin, calcium, phosphorus, alkaline phosphates (ALP), PTH, and hemoglobin (Hb) levels, was conducted using standard laboratory methods in central laboratory on the same day. For blood samples, complete blood count was assessed with Siemens Advia 2120i System (Siemens Healthineers, Erlangen, Germany), and biochemical parameters with Olympus AU 2700 autoanalyzer (Olympus Corp., Tokyo, Japan) using specific kits for devices. Ferritin level was determined with Siemens branded-eligible kits (Siemens Healthineers, Erlangen, Germany). PTH level was analyzed with Siemens Advia Centaur XP Immunoassay System (Siemens Healthineers, Erlangen, Germany) using specific kits. Serum and plasma samples were stored at -20ºC until measurement of NGAL and high sensitivity-C-reactive protein (hs-CRP). NGAL (Catalog No: EK0853) was examined using enzyme-linked immunosorbent assay method (Boster Biological Technology Co., Pleasanton, CA, USA; NGAL sensitivity 510 pg/mL). hs-CRP level was measured with Immulite
North Clin Istanb
2000 instruments using chemiluminescent method (detection range: 0.1–250 mg/L; intra assay precision: coefficient of variation [CV]% <10; inter assay precision: CV% <10) (Siemens Healthineers, Erlangen, Germany). Transferrin saturation was calculated using following formula: SI/TIBC x 100. Kt/V calculation was made online by submitting patient dialysis technique and test results to Hypertension Dialysis and Clinical Nephrology website (www.hdcn.com). Statistical analysis Statistical analyses were performed using SPSS for Windows, version 16.0 (SPSS Inc., Chicago, IL, USA). Descriptive analyses were presented as mean±SD. Normality of variables was assessed using Kolmogorov-Smirnov test. Kruskal-Wallis test was conducted to compare parameters between groups, and Mann-Whitney U-test was performed to test significance of pairwise differences for multiple comparisons. Pearson correlation analysis was employed to test correlations between NGAL and other variables considered in the study. Linear regression analysis employed Pearson coefficients as appropriate. Multiple regression analysis was used to determine independent factors affecting dependent variable (NGAL). Data were expressed as partial correlation coefficients (β) and p value. The results were considered significant if p value was <0.05. RESULTS All clinical and biochemical data are presented in Table 1. There was no significant difference between groups with respect to age, gender, HD duration, Kt/V, neutrophil count, or body mass index. NGAL level was significantly higher in severe SHPT group (p<0.05). Hb level was significantly lower in patients with severe SHPT compared with both mild and moderate SHPT patients. Although serum ferritin, calcium-phosphorus (CaxP) product, and ALP levels were higher in patients with
Yigit et al., Neutrophil gelatinase-associated lipocalin
39
Table 1. Clinical and biochemical data of patients on hemodialysis Age (years) Gender (F/M) DM (%) HD duration (months) Kt/V BMI (kg/m2) Neutrophil count (per mm3) Hb (g/dL) SI (µd/dL) Transferrin saturation (%) Ferritin (ng/mL) Ca (mg/dL) P (mg/dL) CaxP (mg2/dL2) Albumin (g/dL) ALP (IU/L) PTH (pg/mL) hs-CRP (ng/mL) NGAL (pg/mL)
Group 1 (mild) 150<PTH≤300
Group 2 (moderate) 301≤PTH≤600
Group 3 (severe) 601≤PTH
p
52.21±11.60 10/7 8 (47) 28.70±20.87 1.35±0.07 21.58±2.69 6348.26±1174.12 11.71±0.23 51.15±12.25 34.94±8.25 275.76±57.67 8.73±0.61 4.28±0.76 42.19±8.78 3.89±0.48 103.58±25.11 224.94±45.38 4620.65±1125.49 2870.29±464.72
51.33±13.53 9/12 8 (38) 27.66±16.06 1.34±0.08 22.73±2.46 6819.35±1326.12 11.13±0.34 54.48±11.09 32.23±3.91 299.19±77.46 8.96±0.78 4.31±0.69 46.91±9.02 3.64±0.39 97.86±31.06 439.52±85.72 5364.24±1866.82 3926.24±849.06
52.60±10.01 13/10 9 (39.11) 29.01±14.23 1.35±0.08 22.62±2.58 7129.42±1425.08 10.50±0.50 55.34±12.29 36.38±10.06 305.43±75.19 9.02±1.12 5.12±0.84 50.79±14.97 2.88±0.62 120.91±50.27 901.73±146.98 6763.48±1103.78 7995.09±771.34
NS NS NS NS NS NS NS a,b,c NS NS NS NS C NS b,c NS a,b,c b,c a,b,c
ALP: Alkaline phosphatase; BMI: Body mass index; Ca: Calcium; CaxP: Calcium x phosphorus; DM: Diabetes mellitus; F: Female; Kt/V: Kurea × Td/Vurea; M: Male; Hb: Hemoglobin; HD: Hemodialysis; hs-CRP: High-sensitivity C-reactive protein; NGAL: Neutrophil gelatinase-associated lipocalin; NS: Not significant; PTH: Parathyroid hormone; SI: Serum iron. Significant difference (p<0.05) between groups; a=Group 1:2; b=Group 2:3; c=Group 1:3.
severe SHPT, there was no significant difference between these groups. No significant difference was detected between mild and moderate SHPT groups in hs-CRP (p>0.05). Medical treatments of patients are presented in Table 2. There was no relationship between vitamin D treatment, NGAL, and Hb levels. Serum NGAL level was significantly positively correlated with serum PTH (r=0.79; p=0.00) and hs-CRP (r=0.52; p=0.01) levels, and negatively correlated with serum Hb (r=-0.56; p=0.00) level in all HD patients. All variables found to be significantly related to NGAL in univariate analysis were introduced in multivariate model using NGAL as dependent variable. After adjustment for other factors, significance was maintained for correlation between NGAL and serum Hb (β=-0.14; p=0.02) (Figure 1) and PTH (β=0.82; p=0.00) (Figure 2).
DISCUSSION PTH is uremic marker, and patients with SHPT may have higher prevalence of serum inflammatory cytokines and oxidative stress, which are associated with high all-cause and cardiovascular-specific mortality [9, 10]. Additionally, PTH has been identified as a possible factor in development of acquired immune dysfunction. Increases in intracellular calcium levels potentially lead to increase in cellular adenylate cyclase activity; this has been suggested as mechanism by which PTH influences neutrophils via impaired migration, reduced phagocytic activity, and inhibited granulocyte chemotaxis [16, 17]. In our study, neutrophil count was not associated with severity of SHPT. Both serum NGAL and hs-CRP levels were higher in severe SHPT group than mild or moder-
40
North Clin Istanb
Table 2. Medical treatments of patients
Group 1
n
%
Group 2
n
Phosphate binders Calcium-based 10 58.82 11 Non-calcium-based 3 17.65 8 Vitamin D, oral or intravenous 2 11.76 12 Paricalcitol – – 5 Cinacalcet – – –
Group 3
p
%
n
%
52.38 38.09 57.14 23.81 –
11 12 11 – 3
47.82 52.17 47.82 – 13.04
NS a,b,c a,c NA NA
NA: Not applicable NS: Not significant. Significant difference (p<0.05) between groups; a=Group 1:2; b=Group 2:3; c=Group 1:3.
12.00 1.250.00 11.50
PTH (pg/dL)
Hb (g/dL)
1.000.00 11.00
10.50
500.00
10.00
9.50 2.000.00
750.00
250.00
4.000.00 6.000.00 NGAL (pg/mL)
8.000.00
0.00 2.000.00
Figure 1. Correlation between serum NGAL and Hb lev-
Figure 2.
els.
levels.
ate SHPT groups in our study, a result that represents increased inflammation in severe SHPT patients. Additionally, correlation between NGAL and hs-CRP observed only in severe SHPT group suggests that inflammation is exacerbated with increase in PTH level. Furthermore, in a previous study, we reported that there was correlation between vascular access type and NGAL [18]. In the present study, only 3 patients had central venous permanent catheters, so we could comment on relationship between vascular access type and NGAL.
4.000.00 6.000.00 NGAL (pg/mL)
8.000.00
Correlation between serum NGAL and PTH
Anemia can lead to decreased quality of life (impairment of cardiac function, cognition, and exercise capacity) and increased mortality in HD patients. SHPT has been recognized as a cause of worsening anemia in normochromic and normocytic pattern. In the current study, we observed inverse association between PTH level and serum Hb concentration. This inverse relationship may be explained by elevated PTH level, which may cause resistance to EPO by increasing bone marrow fibrosis, increase osmotic fragility of red blood cells, leading to short-
Yigit et al., Neutrophil gelatinase-associated lipocalin
ened lifespan, or inhibit proliferation of erythroid precursors. Several studies have shown important relationships between refractory anemia and higher PTH level in HD patients, as well as improvement in anemia after parathyroidectomy or calcitriol treatment [19–22]. NGAL has recently emerged as an important factor in iron homeostasis and erythrocyte growth regulation that may contribute to anemia when chronically elevated [23]. Also, previous studies have shown that NGAL levels was higher in HD patients compared with healthy subjects, and high level closely reflected iron status and systemic inflammation in HD patients [15, 24, 25]. In another study, NGAL level was measured in blood and liver after experimental induction of different types of anemia, such as blood loss and hemolytic anemia. This study showed that NGAL upregulation is not exactly mediated only by increased iron demand occurring in anemia. These results led to hypothesis that increased NGAL production may be defense mechanism against general induced hypoxia and that increased synthesis of NGAL is independent of iron status [26]. Our study demonstrated that the patients with severe SHPT but without iron deficiency anemia had highest NGAL and lowest Hb levels. Correlation analyses indicated that NGAL positively correlated with PTH level and negatively with Hb level in both severe and moderate SHPT groups. These findings suggested that in case of SHPT, NGAL may correlate with anemia, regardless of iron reserve. Correlation of NGAL with hsCRP was observed only in severe SHPT group. As we did not include any other inflammation marker in our study, we cannot comment on contribution of inflammation to anemia observed in hyperparathyroid state, and with relatively small sample size of patients, and lack of bone marrow biopsies, constitutes important limitation in this cross-sectional study. In conclusion, SHPT may contribute to severity of anemia in HD patients. We concluded that even when iron deficiency anemia is excluded in patients with SHPT, there was significant negative correlation between serum NGAL and Hb.
41 Conflict of Interest: None declared. Financial Disclosure: The authors declared that this study has received no financial support. Authorship contributions: Concept – I.P.Y.; Design – I.P.Y.; Supervision – H.T., A.D.; Materials – I.P.Y.; Data collection &/ or processing – I.P.Y., R.U., N.G.; Analysis and/or interpretation – I.P.Y., N.I.; Literature search – I.P.Y.; Writing – I.P.Y.; Critical review – H.T., A.D.
REFERENCES 1. KDOQI; National Kidney Foundation. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. Am J Kidney Dis 2006;47(5 Suppl 3):S11–145. 2. Cunningham J, Locatelli F, Rodriguez M. Secondary hyperparathyroidism: pathogenesis, disease progression, and therapeutic options. Clin J Am Soc Nephrol 2011;6:913–21. 3. Block GA, Klassen PS, Lazarus JM, Ofsthun N, Lowrie EG, Chertow GM. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol 2004;15:2208–18. 4. Palmer SC, Hayen A, Macaskill P, Pellegrini F, Craig JC, Elder GJ, et al. Serum levels of phosphorus, parathyroid hormone, and calcium and risks of death and cardiovascular disease in individuals with chronic kidney disease: a systematic review and metaanalysis. JAMA 2011;305:1119–27. 5. Kidney Disease: Improving Global Outcomes (KDIGO) CKDMBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int Suppl. 2009;S1–130. 6. Babitt JL, Lin HY. Mechanisms of anemia in CKD. J Am Soc Nephrol 2012;23:1631–4. 7. Massry SG. Pathogenesis of the anemia of uremia: role of secondary hyperparathyroidism. Kidney Int Suppl 1983;16:S204– 7. 8. Nurko S. Anemia in chronic kidney disease: causes, diagnosis, treatment. Cleve Clin J Med 2006;73:289–97. 9. Lu KC, Tseng CF, Wu CC, Yeung LK, Chen JS, Chao TY, et al. Effects of calcitriol on type 5b tartrate-resistant acid phosphatase and interleukin-6 in secondary hyperparathyroidism. Blood Purif 2006;24:423–30. 10. Tentori F, Blayney MJ, Albert JM, Gillespie BW, Kerr PG, Bommer J, et al. Mortality risk for dialysis patients with different levels of serum calcium, phosphorus, and PTH: the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis 2008;52:519–30. 11. Xu S, Venge P. Lipocalins as biochemical markers of disease. Biochim Biophys Acta 2000;1482:298–307. 12. Cowland JB, Borregaard N. Molecular characterization and pattern of tissue expression of the gene for neutrophil gelatinaseassociated lipocalin from humans. Genomics 1997;45:17–23.
42 13. Goetz DH, Holmes MA, Borregaard N, Bluhm ME, Raymond KN, Strong RK. The neutrophil lipocalin NGAL is a bacteriostatic agent that interferes with siderophore-mediated iron acquisition. Mol Cell 2002;10:1033–43. 14. Miharada K, Hiroyama T, Sudo K, Danjo I, Nagasawa T, Nakamura Y. Lipocalin 2-mediated growth suppression is evident in human erythroid and monocyte/macrophage lineage cells. J Cell Physiol 2008;215:526–37. 15. Bolignano D, Coppolino G, Romeo A, De Paola L, Buemi A, Lacquaniti A, et al. Neutrophil gelatinase-associated lipocalin (NGAL) reflects iron status in haemodialysis patients. Nephrol Dial Transplant 2009;24:3398–403. 16. Geara AS, Castellanos MR, Bassil C, Schuller-Levis G, Park E, Smith M, et al. Effects of parathyroid hormone on immune function. Clin Dev Immunol 2010;2010. pii:418695. 17. Shurtz-Swirski R, Shkolnik T, Shasha SM. Parathyroid hormone and the cellular immune system. Nephron 1995;70:21–4. 18. Yigit IP, Celiker H, Dogukan A, Ilhan N, Gurel A, Ulu R, et al. Can serum NGAL levels be used as an inflammation marker on hemodialysis patients with permanent catheter? Ren Fail 2015;37:77–82. 19. Lin CL, Hung CC, Yang CT, Huang CC. Improved anemia and reduced erythropoietin need by medical or surgical intervention of secondary hyperparathyroidism in hemodialysis patients. Ren Fail 2004;26:289–95.
North Clin Istanb 20. Chen C, Wu H, Zhong L, Wang X, Xing ZJ, Gao BH. Impacts of parathyroidectomy on renal anemia and nutritional status of hemodialysis patients with secondary hyperparathyroidism. Int J Clin Exp Med 2015;8:9830–8. 21. Goicoechea M, Vazquez MI, Ruiz MA, Gomez-Campdera F, Perez-García R, Valderrábano F. Intravenous calcitriol improves anaemia and reduces the need for erythropoietin in haemodialysis patients. Nephron 1998;78:23–7. 22. Neves PL, Triviño J, Casaubon F, Santos V, Mendes P, Romão P, et al. Elderly patients on chronic hemodialysis with hyperparathyroidism: increase of hemoglobin level after intravenous calcitriol. Int Urol Nephrol 2006;38:175–7. 23. Yang J, Goetz D, Li JY, Wang W, Mori K, Setlik D, et al. An iron delivery pathway mediated by a lipocalin. Mol Cell 2002;10:1045–56. 24. Bolignano D, Lacquaniti A, Coppolino G, Donato V, Campo S, Fazio MR, et al. Neutrophil gelatinase-associated lipocalin (NGAL) and progression of chronic kidney disease. Clin J Am Soc Nephrol 2009;4:337–4. 25. Bolignano D, Coppolino G, Lombardi L, Buemi M. NGAL: a new missing link between inflammation and uremic anemia? Ren Fail 2009;31:622–3. 26. Jiang W, Constante M, Santos MM. Anemia upregulates lipocalin 2 in the liver and serum. Blood Cells Mol Dis 2008;41:169– 74.
Orıgınal Article
MEDICAL ONCOLOGY
North Clin Istanb 2017;4(1):43–51 doi: 10.14744/nci.2017.67044
Clinical features of the patient with multiple primary tumors: Single center experience Ali Gokyer,1 Osman Kostek,2 Muhammet Bekir Hacioglu,2 Bulent Erdogan,2 Hilmi Kodaz,2 Esma Turkmen,2 Ilhan Hacibekiroglu,2 Sernaz Uzunoglu,2 Irfan Cicin2 Department of Internal Medicine, Trakya University Faculty of Medicine, Edirne, Turkey
1
Division of Medical Oncology, Department of Internal Medicine, Trakya University, Balkan Oncology Hospital, Edirne, Turkey
2
ABSTRACT OBJECTIVE: Multiple primary tumors are the ones that develop in the same patient at the same or different times. They are usually examined under two groups. If the second tumor is diagnosed 6 months after the first tumor is diagnosed, it is named as metachronous tumor. If it is diagnosed in 6 months after the first diagnosis, it is called as synchronous tumor. The malignancy of tumors should be proved histologically. At least 2 cm of solid tissue should be present between two tumors. If they are at localized at the same place, a gap of at least 5 years should be present between them. Metastatic disease should be eliminated.This study aimedto review the clinical, demographic, and pathological features of multiple primary tumors, detect the prevalence, compare the results with literature findings, and evaluate and improve the approach to multiple primary tumors. METHODS: A total of 170 patients diagnosed with multiple primary tumors were included in this study. Patient data were obtained from pathology and medical reports of the patients. RESULTS: Most of the multiple primary tumors were metachronous. The number of male patients was more than that of female patients. The median time between double tumors was 3 monthsforsynchronous tumorsand 26 months for metachronous tumors. Synchronous tumors with the highest prevalence of comorbidity were lung–larynx and lung–colon, whereas metachronous tumors with the highest prevalence of comorbidity were lung–bladder, lung–larynx, breast–endometrium, and breast–colon. The history of smoking and alcohol was found to be higher in male patients andsynchronous tumors. CONCLUSION: The detection of the first tumor in the metastatic stage and an accompanying synchronous secondary tumor was found to be a poor prognostic factor. The treatment of the first tumor, smoking, squamous cell histology, and male gender were among the other factors negatively affecting survival,although they were not statistically significant. Keywords: Metachronous; multiple primary tumors; survival; synchronous.
M
ultiple primary tumors are the ones that develop in the same patient at the same or
different times,accounting for 0.7%–11% of all carcinomas [1, 2]. If the second tumor is diagnosed
Received: January 09, 2017 Accepted: April 05, 2017 Online: May 10, 2017 Correspondence: Dr. Osman KOSTEK. Trakya Universitesi, Ic Hastaliklari Anabilim Dali, Tıbbi Onkoloji Bilim Dali, Balkan Onkoloji Hastanesi, Edirne, Turkey. Tel: +90 284 - 235 76 41-1851 e-mail: osmankostek@hotmail.com © Copyright 2017 by Istanbul Northern Anatolian Association of Public Hospitals–Available online at www.kuzeyklinikleri.com
44
6 months after the first tumor is diagnosed, it is named as metachronous tumor, whereas if it is diagnosed in 6 months after the first diagnosis, it is called as synchronous tumor [3]. The formation of the second tumor occurs as a result of a series of complex interactions. The first tumor increases the risk of developing secondary tumor [4]. Also, smoking, alcohol intake, environmental factors, and genetic mutations increase the risk of developing secondary tumor. The chances of developing secondary tumorsare increased by additive and synergistic effect of the treatment with combined chemotherapy and radiotherapy applications. All patients should undergo special surveillance and should be followedup and treated with methods such as prophylactic surgery if necessary. This studyaimed to evaluate the clinical, demographic, and pathological features of multiple primary tumors,and compare the results with literature findings. The findings might contribute to future approaches to multiple primary tumors. MATERIALS AND METHODS Patient features This was a retrospective descriptive case series study, and all the cases with cancer diagnosis in the Trakya University medical oncology department between 2005 and 2015 were evaluated retrospectively. The medical recordsof 10,000 patients were analyzed before the study. The medical records of 180 patients with multiple primary tumors were included in the study. The patients with basal cell skin carcinoma as one of the tumors,out of 10 patients with multiple primary tumors, were excluded from the study (Figure 1). Study design The age and sex of the patients, history of smoking and alcohol use, age of first tumor diagnosis, first tumor organ, first tumor histology, first tumor site, first tumor stage, first tumor treatment, second tumor age, second tumor organ, second tumor histology, second tumor site, second tumor stage, second tumor treatment, synchronous and metachronous
North Clin Istanb
A total of 10.000 files related to patients with cancer diagnosis were evaluated 190 patients with multiple primary tumor 10 patients with BCC were excluded 180 subjects were included to the study 49 patients with Synchronous tumor
121 patients with Metachronous tumor
Figure 1. Method of selection of patient group. coexistence of double tumors and their fates, diagnosis date of the tumors, and difference between their diagnosis dates in months was recorded. Tumor stage was considered as metastatic disease and organ-limited disease. The smoking history of the patient was identified as having a cigarette story or not smoking. The tissue diagnoses in pathology reports were noted. Tumor treatment options were obtained from follow-up and treatment files. Treatment options were also categorized as curative and noncurative. If the secondtumor is diagnosed 6 months after the first tumor is diagnosed, it is named as metachronous tumor, whereas if it is diagnosed in 6 months after the first diagnosis, it is called as synchronous tumor. Also, each tumor with tissue biopsies was shown to be malignant with clinical and histological features, indicating that these tumors did not occur due to recurrence or metastasis of other tumors. The cases without tissue diagnosis or the ones with tissue diagnosis whose tumor could not be shown as malignant with immunohistological and/or histopathological staining were not included in this study. The fate of the patients was given as dead or being followedup. The present age of the patients who were being followedup was determined. The age on the death date and the death date were also determined for the dead patients. Based on the pathology reports, the
Gokyer et al., Clinical features of the patient with multiple primary tumors
exact diagnosis dates of the first and second tumors were recorded. The time between these two dates was recorded in months.Medical oncology records, hospital files, automation system, and pathology laboratory records were used during data collection. The information on the recent status of the patients who had at least 6 months over their last followup was provided by phone. The death records were obtained from the Ministry of Health death notification system. The date of diagnosis was taken as the time of the pathologic diagnosis or the time of surgery in patients without preoperative diagnosis. Statistical analysis Univariate and multivariate analyses were performed. Mean and median values of the patients were determined by descriptive statistics. Standard deviation (±) was used. The parametric variables were compared between groups using theindependent-samplet test. Nonparametric variables were evaluated using the chi-square test. Kaplan–Meier method was used for survival analyses. The confidence interval was considered as 95%, and a p value less than 0.05 was considered as statisticallysignificant. All data were entered in SPSS 20.0 for Windows (SPSS; Chicago, IL, USA). RESULTS Study group features The prevalence of multiple primary tumors was 1.9% in all patients. The patients were basically divided into two groups: ones with synchronous and metachronous tumors. Further, 49 patients (28%) hadsynchronous tumors and 121 patients (72%) hadmetachronous tumors (Figure 1). The clinical and demographic data of the patients areshown in Table 1. The rate of smoking was significantly higher in patients with synchronous tumorsthan in patients with metachronous tumors. Similarly, the rates of metastatic disease were higherin patients with synchronous tumors than in patients with metachronous tumors (Table 1). The prevalence order of the origin of primary tumor in the patients with synchronous tumorswas
45
colon (10), lung (9), larynx (6), prostate (4), skin (4), breast (3), bladder (3), endometrium (3), pancreas (2), stomach (2), thyroid (1), ovary (1), esophagus (1). Thirty-three (67.3%) of these tumors had adenocarcinoma histology, 14 (28.6%) had squamous cell carcinoma histology, 1had follicular carcinoma, and 1had melanoma histology. Twenty-one patients (42.9%) had metastatic disease, and 28 patients (57.1%) had organ-limited disease. The prevalence order of the origin of secondary tumorin the patients with synchronous tumor waslungs (15), colon (10), kidney (5), bladder (4), prostate (3), ovary(3), larynx (3), pancreas (2), endometrium (1), and stomach (1). Thirty-eight of these tumors (76.6%) had adenocarcinoma histology, and 11 tumors (22.4%) had squamous cell carcinoma histology. Twenty-two patients (44.9%) had metastatic disease, whereas27 patients (55.1%) had organ-limited disease. Twenty-nine (59.2%) of the patients with synchronous tumor died, and 20 patients (40.8%) carried on with their clinical follow-ups. When the co-occurrence of double tumors was analyzed in months, the mean was 2.63±1.56 (median 3; range 0–6). Co-occurrence was most frequently detected in five patients with colon–lung and fivepatients with lung–laryngeal (Table 2). One hundred and twenty-one patients with metachronous tumors were detected. Fortynine of these patients were female (40.5%) and 72male (59.5%). The mean age of the patients was 62±12.13 years (median 63 years; range 36–89 years). Thirty patients (24.8%)drank alcohol, and 91 patients (75.2%) did not drink alcohol. Of the patients, 61 (50.4%) had smoking history and 60 (49.6%) of them did notsmoke. The mean age of primary tumor in patients with metachronous tumors was 56±13.00 (median 57, range 20–88). According to the prevalence order of the tumor source, tumorswere detected in the breast (25), colon (16), larynx (16), bladder (12), prostate (9), skin (8), endometrium (8), lungs (7), kidney (6), ovary (5), testis (2), stomach (2), thyroid (1), nose (1), esophagus (1), liver (1), and cervix (1). Of these tumors, 89 had adenocarcinoma histology
46
North Clin Istanb
Table 1. Clinical and demographic characteristics of subjects Age, year Gender, M/F Smoking* Alcoholconsumption Histopathology of primarytumour, Adenocancer Squamouscellcancer Others** Stage of primarytumour** Localized Metastatic Histopathology of secondarytumour Adenocancer Squamouscellcancer Stage of secondarytumour Localized Metastatic Time intervalbetweensecondtumour (month)** Median (Interquartile range) Minimum- maximum Clinicaloutcome Death
Synchronous tumour (n=49) n
%
Metachronous tumour (n=121) n
%
33 13
64±12 11/38 67.3 26.5
61 30
50.4 24.8
33 14 2
67.3 28.6 4.1
89 29 3
73.5 24.0 2.5
28 21
57.1 42.9
97 24
80.2 19.8
38 11
76.6 22.4
94 26
77.6 21.4
27 21
55.1 44.9
69 52
57.1 42.9
3 (1–4) 0–6
62±12 49/72
26 (13–68) 7–312
29 59.2 61 50.4
*p<0.05; **Insynchronous tumours, 1 patient had tyroid follicular cancer and the other patient had malign melanoma. In metachronous group, 2 patients had pure seminoma, theother had thyroid follicular cancer.
(73%), 29 had squamous cell carcinoma histology (24%), 2 had seminoma histology (1.7%) and 1 had follicular cancer histology. Twenty-four patients (19.8%) had metastatic disease, whereas 97 patients (80.2%) had an organ-limited disease. The mean age of the secondary tumor in patients with metachronous tumors was 60±12.8 years (median 61; range 34–89). The tumors were classified according to the prevalence orderas lung (35), colon (21), breast (9), bladder (8), endometrium (8), prostate (7), kidney (6), larynx (6), pancreas (3), skin (3), stomach (2), tongue (2), thyroid (2), esophagus (1), biliary tract (1), and ureter (1) (Table 2). Ninety-four of these tumors had adeno-
carcinoma histology (77.7%), 26 had squamous cell carcinoma histology (21.5%), and 1 had follicular cancer histology. Sixty-nine patients (57%) had metastatic disease, and 52 patients (43%) had an organ-limited disease. Of patients with a metachronous disease, 61 patients (50.4%) died and 60 patients (49.6%) continued with their treatment in the outpatient clinic.The mean age of the co-occurrence of double tumors in months was 50±60.26 months (median 26months; range 7–312 months). In terms of tumor co-occurrence, 10 patients with lung–bladder, 10 patients with larynx–lung, 9 patients with breast–endometrium, 8 patients with breast–co-
Gokyer et al., Clinical features of the patient with multiple primary tumors
47
Table 2. Tumours location in patients with multiple primary tumours related to their organ involvement Synchronous
Colon, n (count) Lung Kidney Endometrium Colon Prostat Bladder Skin Larynx Ovary Stomach Lung, n (count) Larynx Pancreas Skin Bladder Kidney Stomach Breast Prostat Ovary Larynx, n (count) Lung Prostat Skin Bladder Pancreas Tongue Bladder, n (count) Lung Prostat Skin Larynx Colon Ovary, n (count) Breast Endometrium Colon Pancreas
tumour (n=49)
Metachronous tumour (n=49)
5 3 3 2 2 1 1 1 – –
4 1 2 – – 3 1 – 2 1
5 3 3 2 1 1 1 1 1
– – – 4 2 – – 1 –
– 1 1 1 – –
9 3 1 – 2 1
– 2 1 – –
6 2 – 2 2
2 1 – –
1 – 2 1
lon, 7 patients with colon–prostate, 6 patients with breast–ovary, 5 patients with lung–kidney, 5 pa-
Larynx Stomach, n (count) Pancreas Prostat Endometrium Tongue Kidney, n (count) Thyroid Lung Colon Skin Bladder Breast, n (count) Colon Endometrium Ovary Breast Kidney Thyroid Lung Endometrium, n (count) Breast Lung Colon Prostat, n (count) Colon Larynx Lung Skin, n (count) Lung Breast Colon Esophagus, n (count) Lung Thyroid, n (count) Kidney Testis, n (count) Lung Ureter
Synchronous
Metachronous
tumour (n=49)
tumour (n=49)
–
1
1 1 – –
– – 1 1
1 – – – –
– 3 1 1 1
– – – – – – –
7 5 4 3 2 2 2
– – –
4 3 2
– – –
6 2 1
– – –
5 1 1
–
1
–
1
– –
1 1
tients with skin–lung, and 4 patients with colon– lung were detected (Table 2).
48
North Clin Istanb
Table 3. Univariate variables evaluation for survival analysis
All
Synchronous
Median survival p (95% CI)
Median survival p (95% CI)
Median survival (95% CI)
p
22.1 (12.5–31.8) 0.64 24.9 (16.1–33.8)
5.1 (1.0–16.4) 0.45 8.9 (4.2–13.6)
34.4 (1.2–67.6) 35.9 (27.4–44.5)
0.83
21.5 (14.9–28.2) 0.17 39.8 (22.9–56.7)
7.9 (2.1–13.8) 0.59 10.7 (0.6–20.7)
34.2 (26.1–42.2) 44.7 (23.7–65.7)
0.56
21.5 (14.7–28.3) 0.42 33.4 (17.9–48.9)
7.9 (2.3–13.6) 0.87 10.7 (0.1–24.1)
34.8 (20.9–48.7) 35.9 (21.3–50.6)
0.62
24.9 (15.2–34.6) 0.45 22.1 (15.6–28.6)
6.1 (3.8–8.4) 0.93 8.9 (2.9–14.9)
48.9 (24.7–73.1) 34.4 (25.4–43.3)
0.23
86.2 (79.4–93.1) 0.004 19.3 (12.4–26.2) 22.1 (8.8–35.4) 22.2 (0.9–43.5) 3.9 (2.8–5.8)
– 0.05 8.9 (6.8–11.1) 30.7 (0.1–62.8) 2.1 (0.1–59) 3.9 (0.1–5.2)
86.2 (79.4–93.1) 28.7 (0.1–116.2) 22.1 (7.3–37.1) 34.2 (17.5–50.8) 20.7 (0.1–23.1)
0.03
24.9 (15.5–34.3) 0.98 22.2 (11.8–32.50) 13.5 (0.4–26.5)
6.6 (0.1–1.41) 0.96 8.9 (0.1–21.5) 5.3 (0.1–13.4)
34.4 (21.2–47.6) 34.8 (29.4–40.3) 48.9 (0.1–49.1)
0.43
29.6 (18.7–40.5) 0.001 15.7 (4.9–26.4)
12.1 (7.7–16.4) 0.01 5.3 (3.3–7.2)
41.1 (25.1–57.1) 28.7 (18.7–38.7)
0.09
13.7 (3.7–23.8) 0.005 30.7 (20.1–41.3)
5.1 (3.7–6.3) 0.001 16.1 (9.9–22.3)
26.4 (19.4–33.4) 41.1 (27.5–54.6)
0.36
Age, year <60 ≥60 Gender Male Female Smoking Yes No Alcohol Yes No Primarytumour site Breast Larynx Colon Lung Esophagus Primarytumour histology Adenocancer Squamouscell Others* Primarytumour stage Localized Metastatic Primarytumour treatment Non–curative Curative
Ninety of 180 patients with double primary tumors died. The median survival was calculated as 23.7 months [95% confidence interval (CI) 16.7– 30.7]. When the median survival was compared according to gender, it was detected as 21.5 months (95% CI 14.9–28.2) in males and 39.8 months (95% CI 22.9–56.7) in females (p=0.17). The median survival was calculated as 22.1 months in alcohol users (95% CI 15.6–28.6) (p=0.45), whereas it was 24.9 months (95% CI 15.2–34.6) in those who
Metachronous
did not use alcohol. Also, it was 21.5 months (95% CI 14.7–28.3) in smokers and 33.4 months (95% CI 17.9–48.9) (p=0.42) in nonsmokers. The median survival in those whose primary tumor organ was breast, colon, larynx, pancreas, and esophagus was calculated as 86.2, 22.2, 22.1, 19.3, 6.6, and 3.9 months, respectively. The survival rate of the patients with primary tumor histology as an adenocarcinoma and a squamous cell carcinoma was24.9 months (95% CI 15.5–34.3) and 22.3 months (95%
Gokyer et al., Clinical features of the patient with multiple primary tumors
Table 4. Multivariable analysis of prognostic factors for survival in patients with multiple primary tumours
RR
Age, ≥60 years Gender, male Primarytumour site Colon Lung Larynx Primarytumour stage Metastatic Primarytumour treatment Non-curative Multipleprimary status Synchronous
95% CI
p
0.561 0.226–1.392 0.320 0.059–1.736
0.21 0.19
2.451 0.649–9.258 2.710 0.876–8.377 2.163 0.669–6.995
0.18 0.08 0.19
2.837 1.075–7.490
0.03
0.850 0.236–3.064
0.81
4.582 2.085–10.070 <0.001
CI: Confidence interval; RR: Relative risk.
Synchronous Metachronous
1.0
Cumulative survial
0.8
0.6
0.2 p<0.001 0 50.0
100.0
30.7 months (95% CI 20.1–41.3) and 13.7 months (95% CI 3.7–23.8) in the patients who received a curative therapy and those who did not receive a curative therapy, respectively (p=0.005). The median survival of co-occurrenceof synchronous tumors and metachronous tumors was 8.9 months (95% CI 3.4–14.5) and 35.9 months (95% CI 27.6–44.3), respectively (p<0.001). Univariate analyses showed that the primary site, stage, and status of receiving curative therapy of the tumor could be used to predict patient survival (Table 3). Multivariate analysis showed that the presence of a synchronous tumor and a primary tumorat the metastatic stage wasassociated with poor prognosis and shorter survival in patients with two primary tumors (Table 4 and Figure 2). DISCUSSION
Survial
0
49
150.0 200.0 Months
250.0
300.0
Figure 2.
Survival rate of patients with synchronous and metachronous tumors.
CI 11.8–32.5), respectively (p=0.06). The median survival rate in the patients with a primary organlimited and metastatic tumors was29.7 months (95% CI 18.7–40.5) and 15.7 months (95% CI 4.9–26.4), respectively (p=0.001). The rate was
The prevalence of multiple primary tumors increases in relation to several factors such as increase in the number of treatment options, the fact that the progression of some cancer cells becomes similar with some chronic disease patterns, and increase in the use of cytotoxic agents and ionized radiation [5–7]. The number of patients with secondary tumorsmay also increase with the increase in the number of cancer patients in the following years. Therefore, extreme caution is required regarding the development of secondary tumors in the patients who are followed up and treated for primary tumors. Both having an accompanying synchronous tumor and the presence of a primary tumor at the metastatic stage were associated with bad prognosis in terms of survival in the present study. Studies on multiple primary tumors available in the literature are generally retrospective studies. They are especially based on the Warren and Gates criterion and conducted by classifying patients as synchronous and metachronous [8]. The prevalence of multiple primary tumors was reported as 0.73% in the study by Haddow et al. [9] conducted with 58,333 cancer patients in 1972, 3.97% in the study by Storm et al. [10] conducted with 379,941 cancer patients in 1985, and 1.03% in the study by Aydiner et al. [11] conducted with
50
26,000 cancer patients in 2000.This rate was 1.9% in the present study. This variation might be due to different strategies used in defining etiological causes and diagnoses of tumors. Smoking seems to be an important risk factor for the development of multiple primary tumors [12]. The statistically significant rate of smoking in the synchronous and metachronous groups was 47% and 34%, respectively, in the study by Aydiner et al. [11]. The rate of cigarette smokers in the synchronous and metachronous groups was 67% and 51%, respectively, in the present study. Hence, it can be concluded that smoking is an important risk factor for the development of synchronous tumors. Especially, a strong correlation exists between squamous cell carcinomas and cigarette smoking. The rate of smoking was found to be significantly high in tumors known to be related to smoking, such as lung, larynx, kidney, bladder, and pancreas. The patients who had a smoking history lived about 12 months less compared with nonsmokers, although the survival rate was not statistically significant. Alcohol use is a well-defined factor in the etiology of cancers such as liver, esophagus, breast, and colorectal [13]. The patient data about alcohol use could not be accessed due to registry failure in many studies about the development of multiple tumors., Alcohol use did not make a meaningful difference in terms of survival in the present study. However, since the amount of alcohol usedcould not be assessed clearly, this issue wasc onsidered as a weak point in data evaluation. When the data was analyzed for co-occurrence, head and neck–lung and colon–lung were the most relevant co-occurrences among synchronous tumors. The most frequent co-occurrences in the study by Feng Li et al. conducted with 175 lung cancer patients with double primary tumors, were lung–colon, lung–bladder, lung–breast, and lung– esophagus [14]. Therefore, if the same tumor is detected in these organs, the possibility of having a second primary tumor should be considered before the diagnosis of metastasis. Breast–endometrium co-occurrence may be the result of hormone therapy for breast cancer, due to
North Clin Istanb
the increased risk of endometrial cancer. Since the mutation analysis was not conducted, the assessment might not be accurate. Gene mutation screening might be useful in patients detected with tumor co-occurrence in the future. When all these data were analyzed, it was foundthat metachronous tumors were more likely to have higher survival rates, such as breast, prostate, and colon. The association between smoking and alcohol use was weaker in metachronous tumors than in synchronous tumors. As a result, the survival rate was significantly higher in metachronous tumors in the present study. Limited data are available in the literature on the progression and treatment of multiple primary tumors. In the study by Irimie et al. conducted with 62 cases with double primary tumors, it was found that curative surgery was applied to 40% of the first primary synchronous tumors, whereas it could only be applied to 30% of the secondary tumors [15]. In the same study, it was found that only 10% of metachronous tumors could undergo curative surgery. Further, 57% of the first primary synchronous tumors were detected at the organ-limited stage and curative treatments were applied to the all of them. However, the rate of treatment application to the first primary metachronous tumors was 80%. This result explained the difference between the survival rates of synchronous and metachronous tumors. The survival rate of patients with organ-limited primary tumor, who could undergo curative surgery, was significantly longer. The present study had some limitations such as a retrospective design, lack of gene mutation analyses, and homogeneity of the patient population. If quantitative data could have been presented (as number of pack-years of smoking) its prognostic effect would have been more accurately evaluated. In conclusion, the present study showed that synchronous and metastatic statuses of the disease are independent risk factors for mortality. In the light of this information, a secondary cancer followup may be informative, especially in the patients with malignancy.
Gokyer et al., Clinical features of the patient with multiple primary tumors
Conflict of Interest: None declared. Financial Disclosure: The authors declared that this study has received no financial support. Authorship contributions: Concept – A.G.; Design – O.K.; Supervision – I.C., S.U.; Material – I.C., O.K.; Data collection or processing – A.G., H.K., B.E., E.T., M.B.H., I.H., O.K.; Analysis – B.E., O.K.; Literature search – A.G.; Writing – A.G.; O.K.; Critical review – I.C., S.U., B.E.
REFERENCES 1. Tachimori Y. Cancer screening in patients with cancer. Jpn J Clin Oncol 2002;32:118–9. 2. Demandante CG, Troyer DA, Miles TP. Multiple primary malignant neoplasms: case report and a comprehensive review of the literature. Am J Clin Oncol 2003;26:79–83. 3. Suzuki T, Takahashi H, Yao K, Inagi K, Nakayama M, Makoshi T, et al. Multiple primary malignancies in the head and neck: a clinical review of 121 patients. Acta Otolaryngol Suppl 2002;88–92. 4. Ng AK, Kenney LB, Gilbert ES, Travis LB. Secondary malignancies across the age spectrum. Semin Radiat Oncol 2010;20:67–78. 5. Hemminki K, Boffetta P. Multiple primary cancers as clues to environmental and heritable causes of cancer and mechanisms of carcinogenesis. IARC Sci Publ 2004;289–97. 6. Carey TE. Field cancerization: are multiple primary cancers monoclonal or polyclonal? Ann Med 1996;28:183–8. 7. Wynder EL, Mushinski MH, Spivak JC. Tobacco and alcohol
51
consumption in relation to the development of multiple primary cancers. Cancer 1977;40:1872–8. 8. Warren S, Gates O. Multiple primary malignant tumors: a survey of the literature and statistical study. Am J Cancer 1932;16:1358–414. 9. Haddow AJ, Boyd JF, Graham AC. Multiple primary neoplasms in the Western Hospital Region, Scotland: a survey based on cancer registration data. Scott Med J 1972;17:143–52. 10. Storm HH, Jensen OM, Ewertz M, Lynge E, Olsen JH, Schou G, et al. Summary: multiple primary cancers in Denmark, 194380. Natl Cancer Inst Monogr 1985;68:411–30. 11. Aydiner A, Karadeniz A, Uygun K, Tas S, Tas F, Disci R, et al. Multiple primary neoplasms at a single institution: differences between synchronous and metachronous neoplasms. Am J Clin Oncol 2000;23:364–70. 12. Leon ME, Peruga A, McNeill A, Kralikova E, Guha N, Minozzi S, et al. European Code against Cancer, 4th Edition: Tobacco and cancer. Cancer Epidemiol 2015;39 Suppl 1:S20–33. 13. Williams LA, Olshan AF, Tse CK, Bell ME, Troester MA. Alcohol intake and invasive breast cancer risk by molecular subtype and race in the Carolina Breast Cancer Study. Cancer Causes Control 2016;27:259–69. 14. Li F, Zhong WZ, Niu FY, Zhao N, Yang JJ, Yan HH, et al. Multiple primary malignancies involving lung cancer. BMC Cancer 2015;15:696. 15. Irimie A, Achimas-Cadariu P, Burz C, Puscas E. Multiple primary malignancies--epidemiological analysis at a single tertiary institution. J Gastrointestin Liver Dis 2010;19:69–73.
Orıgınal Article
PT&R
North Clin Istanb 2017;4(1):52–59 doi: 10.14744/nci.2017.27122
The effects of pre-obesity on quality of life, disease activity, and functional status in patients with ankylosing spondylitis Seyma Toy,1 Davut Ozbag,2 Zuhal Altay1 Department of Physical Therapy and Rehabilitation, Inonu University Faculty of Medicine, Malatya, Turkey
1
Department of Anatomy, Inonu University Faculty of Medicine, Malatya, Turkey
2
ABSTRACT OBJECTIVE: This study was an investigation of effects of pre-obesity on clinical characteristics and quality of life in patients with ankylosing spondylitis (AS). METHODS: Total of 28 AS patients and 30 age- and sex-matched healthy controls were included in the study. Patients and controls with any systemic inflammatory disease and/or cognitive and mental problems were excluded. Disease activity and functional capacity were measured using the Bath Ankylosing Spondylitis Disease Activity Index and Bath Ankylosing Spondylitis Functional Index. For quality of life assessment, 36-Item Short Form Health Survey was used in both groups, and AS group also responded to Ankylosing Spondylitis Quality of Life questionnaire. RESULTS: There was no significant difference in sociodemographic characteristics between AS patients and healthy controls (p>0.05). Mean quality of life scores were significantly lower in the pre-obese AS patients compared with controls (p<0.05). Functional capacity was positively and significantly associated with body mass index (BMI) (p=0.024) and disease activity was significantly associated with female gender (p=0.011). CONCLUSION: Increased BMI in patients with AS is factor that affects quality of life, disease activity, and functional capacity. Multidisciplinary rehabilitation programs will support improved quality of life for pre-obese patients with AS. Keywords: Ankylosing spondylitis; body mass index; pre-obesity; quality of life.
A
nkylosing spondylitis (AS) is important autoimmune disease that is the prototype of spondyloarthritis group of diseases, and particularly affects the musculoskeletal system [1]. Anatomical changes resulting in vertebral ankylosis lead to
typical kyphotic deformity in patients with AS [2]. Kyphotic deformity causes reduced angle of vision and difficulty performing daily life activities, such as looking across the street while walking, communicating, driving a car, walking downhill, and main-
This study was presented as an oral presentation at the 16th National Congress of Anatomy held in Malatya in September 2014.
Received: August 15, 2016 Accepted: March 04, 2017 Online: May 10, 2017 Correspondence: Dr. Seyma TOY. Inonu Universitesi, Turgut Ozal Tip Merkezi, 44280 Malatya, Turkey. Tel: +90 422 - 341 06 60 e-mail: seymatoy44@gmail.com © Copyright 2017 by Istanbul Northern Anatolian Association of Public Hospitals–Available online at www.kuzeyklinikleri.com
Toy et al., The effects of preobesity on ankylosing spondylitis
taining personal hygiene [3, 4]. Numerous features of the course of AS, including pain, limitation of movement, functional loss, and deterioration of well-being, have negative effect on the patient’s quality of life [5]. As in many chronic diseases, there may also be social and economic consequences for patients with AS. Environmental factors are also of great importance to quality of life. Social support, family support, suitable work conditions, and minimizing fatigue are important for these patients. It is also known that there is connection between psychological condition and the course and clinical findings of AS. Deteriorating psychiatric condition causes AS to clinically progress more rapidly [6]. Among patients with AS, risk of permanent work disability is 3 times greater than those of similar age and gender in general population [7]. Role of adipose tissue in AS has not been widely investigated; however, some indirect results suggest that there is connection between excess adipose tissue and inflammation in AS [8]. Weakening of skeletal muscles and decreased muscular function and physical inactivity lead to change in body composition. Due to reduction in quantity of lean (non-fatty) tissue in AS, total fatty tissue is more prominent [9]. Fat deposit centers in the body cause center of gravity to shift toward the front in comparison with healthy-weighted individuals, which then adds mechanical strain and stress to structures behind the center of gravity [10]. Body mass index (BMI) is the most commonly used method of evaluating obesity. An individual’s weight in kilograms is divided by the square of height in meters [weight (kg) / height (m²)]. BMI correlation with quantity of body fat measured directly with densitometer is quite good [11]. In the literature, there are indirect prospective studies regarding relationship between BMI and AS; however, relationship to quality of life, disease activity, and functional condition has not been evaluated. For this reason, the main objective of this study was to assess quality of life, functional level, and disease activity of pre-obese patients with AS and compare results with healthy individuals.
53
MATERIALS AND METHODS Our case-control study sample consisted of 28 patients diagnosed with AS by specialist physicians according to the modified New York Criteria for AS (Group 1) and 30 healthy individuals (Group 2). Number of participants was determined as result of power analysis performed by department of biostatistics. Study was conducted in the Physical Therapy and Rehabilitation Unit of Turgut Ozal Medical Center, Inonu University, after receiving approval (number 2013/121) from the Human Ethics Committee of Inonu University. The patients and healthy controls were informed about the study and all study participants provided written informed consent. Criteria for participation for both groups were age in range of 25 to 55 years, BMI in range of 25 to 30 (pre-obese), and having no cognitive or mental problems. For Group 1, diagnosis of AS based on modified New York Criteria was criterion for inclusion in the study. Individuals who had undergone surgery related to AS and those with additional systemic disease, visual, or cognitive problems were excluded. Demographic data of participants were recorded. Measurement of height was performed with sensitivity of 0.1 cm using standard steel stadiometer while participants were barefoot. Measurement of weight was performed using Tanita BC-418 Segmental Body Composition Analyzer (Tanita Corp., Tokyo, Japan). World Health Organization BMI classification, Bath AS Disease Activity Index (BASDAI), and Bath AS Functional Index (BASFI) were employed to assess individuals according to study criteria. Both groups completed 36-Item Short Form Health Survey (SF-36) and patients with AS also responded to AS Quality of Life Questionnaire (ASQoL). Developed to evaluate disease activity, BASDAI is questionnaire consisting of 6 questions associated with 5 major symptoms of AS (fatigue, spinal pain, joint pain/swelling, localized sensitivity/susceptibility areas, and morning stiffness) [12– 15]. If BASDAI result is ≥4, it is then evaluated as high disease activity [16]. ASQoL questionnaire asks patients to answer 18 questions with “yes” or “no,” and number of affirmative responses is used to
54
North Clin Istanb
Table 1. Demographic characteristics of patients with ankylosing spondylitis and healthy controls Socio-demographic features
n
Group 1 Patient population (n=28) %
Mean±SD
n
Group 2 Control group (n=30) %
p
Mean±SD
Age (years) 40.64±11.4 43.8±9.4 0.251 Gender Female 8 28.6 12 40 Male 20 71.4 18 60 0.523 Body mass index 27±3.4 27.2±3.2 0.279 Educational status Primary school 8 28.6 8 26.7 High school 10 37.5 11 36.7 0.987 University 10 37.5 11 36.7 Occupational status Housewife/student/unemployed 7 25 9 30 Artisan/laborer 7 25 7 23.3 0.913 Civil servant 14 50 14 36.7 SD: Standard deviation.
calculate score between 0 and 18; lower scores suggest better quality of life [17]. The quality of life scale most frequently used in the field of medicine, SF-36 form, consists of 36 items that evaluate health in terms of physical and mental aspects in 8 scaled sections [18]. Statistical analysis Data were analyzed using IBM SPSS Statistics for Windows, Version 22.0. software (IBM Corp., Armonk, NY, USA). In group comparisons, MannWhitney U-test and Kruskal-Wallis test were used. Following Kruskal-Wallis test, Conover method was used for paired comparison. In group comparisons of categorical data, chi-square test with Yates correction and Fisher’s exact test were used. Significance level was determined to be p<0.05. RESULTS Demographic characteristics of Group 1 and Group 2 are provided in Table 1.
Table 2. BASDAI, BASFI, and ASQoL scores of the patients with ankylosing spondylitis Tests BASDAI BASFI ASQoL
Mean±SD
Value range
4.78±2.1 4.87±2.8 10.5±5.095
1.6–6.7 0–6.2 0–18
ASQoL: Ankylosing Spondylitis Quality of Life questionnaire; BASDAI: Bath Ankylosing Spondylitis Disease Activity Index; BASFI: Bath Ankylosing Spondylitis Functional Index; SD: Standard deviation.
BASFI, BASDAI, and ASQoL score data can be seen in Table 2. Mean BASFI value of group with BMI of 25 to 27 was 2.9±1.1, whereas mean BASFI of the group with BMI of 27.1 to 29.9 was 6.45±2.3 (p=0.024) (Table 3). ASQoL results revealed only 39.3% of patients had score of 9 or less (Figure 1). When the patients with AS were evaluated in terms of gender, a statistically significant difference was seen in women’s BASDAI values
Toy et al., The effects of preobesity on ankylosing spondylitis
Table 3. Comparison of BASFI, BASDAI, and ASQoL
scores of the patients with AS according to BMI group Tests BASFI BASDAI ASQoL
BMI 25–27 (n=14) Mean±SD
BMI 27.1–29.9 (n=14) Mean±SD
p
2.9±1.1 3.75±1.7 8.5±2.5
6.45±2.3 5.65±1.9 13.5±6.1
0.024 0.265 0.114
AS: Ankylosing spondylitis; ASQoL: Ankylosing Spondylitis Quality of Life questionnaire; BASDAI: Bath Ankylosing Spondylitis Disease Activity Index; BASFI: Bath Ankylosing Spondylitis Functional Index; BMI: Body mass index; SD: Standard deviation.
ASQoL≤9 61%
39%
ASQoL>10
Figure 1. ASQoL scores in patients with AS. (p=0.011) (Table 4). Results indicated that healthy individuals had significantly higher score in all of the quality of life criteria in comparison with the pre-obese patients with AS (Table 5). Although the SF-36 test results revealed better quality of life in the patients whose BMI was in range of 25 to 27 compared with those whose BMI was between 27.1 and 29.9, no statistically significant relationship was observed (Table 6). DISCUSSION AS is chronic inflammatory disease with broad clinical spectrum and unknown etiology. It primar-
55
Table 4. Comparison of BASFI, BASDAI, and ASQoL scores of the patients with AS according to gender Tests BASFI BASDAI ASQoL
Female
Male
p
7.3±2.6 6.35±2. 13.5±6.1
3.6±1.5 3.75±1.6 10±5.5
0.182 0.011 0.469
AS: Ankylosing spondylitis; ASQoL: Ankylosing Spondylitis Quality of Life questionnaire; BASDAI: Bath Ankylosing Spondylitis Disease Activity Index; BASFI: Bath Ankylosing Spondylitis Functional Index.
ily affects young men, and is characterized by apparent inflammation in the spinal joints and neighboring structures, causing progressive bone fusion in the vertebrae [19, 20]. The disease leads to serious impairment in at least one-third of cases. Influences on psychological state, such as pain in the vertebrae and joints, reduced physical activity and spinal mobility, joint stiffness/involvement, fatigue, and depression may worsen physical findings [21]. Our study was designed to evaluate effect of preobesity in patients with AS on quality of life, disease activity, and functional condition/status. Since 33.7% of society (38.2% of males and 29.3% of females) is pre-obese, according to 2014 data of the Turkish Statistical Institute, and as we were of the opinion that obesity and morbid obesity would already have reduced quality of life, we incorporated pre-obese patient population into our study [22]. Based on study results, we came to conclusion that pre-obesity led to increase in disease activity of AS patients, deterioration of functional condition, and significant decline in quality of life compared with healthy individuals. Studies have reported that age, gender, and duration of disease affect the course of the disease as well as metrological indices [23]. Review of the literature yielded mean age of AS patients in 1 study [24] of 37.0±9.7 years, and another study reported 67% of the patients were male with mean age of 38±13 years [25]. Mean age of the patients with AS in our study proved to be 40.64±11.4 years; 28.6% of our participants were female and 71.4% of them were male. In recent
56
North Clin Istanb
Table 5. Evaluation of SF-36 test results of the AS patients and control group Sub-groups
AS patients (n=28) Mean±SD
Control group (n=30) Mean±SD
p
Value range
Physical function Difficulty in physical role Pain General health Vitality Difficulty in social role Difficulty in emotional role Psychological health
35.07±11.5 34.11±8.6 36.42±7.8 37.04±8.1 43.07±7.04 37.22±11.5 34.37±10.6 41.4±9.1
50.12±7.3 48.01±8.9 46.81±6.7 48.76±7.3 48.61±4.6 49.6±7.6 47.21±9.3 50.4±7.8
<0.0005 <0.0005 <0.0005 <0.0005 0.02 <0.0005 <0.01 <0.0005
10–100 0–100 10–100 20–97 25–100 0–100 0–100 0–80
SD: Standard deviation.
Table 6. Comparison of SF-36 test results in the AS group according to BMI categories Physical function Difficulty in physical role Pain General health Vitality Difficulty in social role Difficulty in emotional role Psychological health
Group
n
Mean±SD
p
Value range
BMI 25–27 BMI 27.1–29.9 BMI 25–27 BMI 27.1–29.9 BMI 25–27 BMI 27.1-29.9 BMI 25–27 BMI 27.1–29.9 BMI 25–27 BMI 27.1–29.9 BMI 25–27 BMI 27.1–29.9 BMI 25–27 BMI 27.1–29.9 BMI 25–27 BMI 27.1–29.9
14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14
37.25±6.1 28.85±4.9 35±6 28±4.9 37.5±6.5 35.55±6.3 37.05±7.1 33.6±6.5 44.35±8.5 42.15±8.3 35.4±6.9 30.8±5.1 34.55±6.8 24.75±4.9 41.4±7.5 34.5±6.3
0.194
10–100
0.164
0–100
0.603
10–100
0.210
20–97
0.734
25–100
0.603
0–100
0.77
0–100
0.62
0–80
AS: Ankylosing spondylitis; BMI: Body mass index; SD: Standard deviation.
studies, female/male ratio reported has ranged between 1/10 and 1/3 [26]. In the present study, female/male ratio was determined to be 2/5. Patient population in the present study was consistent with the literature in terms of age and gender.
When AS symptoms are evaluated in terms of gender, in female patients this disease courses more insidiously; it progresses slowly and more moderately, starting in the form of peripheral joint involvement [27]. In our study, as in the literature [27],
Toy et al., The effects of preobesity on ankylosing spondylitis
BASDAI score of women was significantly higher than that of men (p=0.011). We are of the opinion that disease activity in women was higher due to fact that most of the women who participated in our study were housewives and had been exposed to more physical strains and stresses at home. Separately, we must also consider influences such as hormonal changes in women due to their menstrual cycle, the fact that women are more susceptible to trauma, and that they are often more able to express their complaints as factors in higher scores. In their study in which 101 patients with AS responded to SF-36 quality of life survey, Ozgul et al. reported that subsections affected most were difficulty in physical role, evaluation of general health, and pain [28]. Turan et al. stated that SF-36 subgroups most affected by AS were physical function, physical role, and emotional role in a study they conducted [29]. Ward et al. [30] evaluated 175 patients diagnosed with AS and found that quality of life of those whose educational level was low was worse in 7 out of 8 fields of SF-36. In our study, there was significant decrease in quality of life in all subsections of SF-36 in the preobese patients with AS when compared with the healthy controls. We believe this could be explained by the fact that it is outcome of mechanical factor that increases along with obesity. Yilmaz et al. [31] reported in their study that high BASDAI, BASFI, and BASMI scores had caused all subgroup scores of SF-36 to decline, while causing ASQoL scores to rise significantly. ASQoL is valuable tool in evaluating effect of interventions performed on patients with AS. In our study, unlike several studies in the literature, we used ASQoL index to evaluate quality of life of patients with AS. ASQoL score of pre-obese patients with AS revealed that quality of life was poor for 60.3% of our patients. When we compared ASQoL scores in 2 subgroups based on BMI and sub-groups of female and male patients, we found no significant difference. While in the literature there are numerous evidence-based studies conducted for the purpose of minimizing pain, spinal stiffness, fatigue, and re-
57
striction in joint movement, which are among the symptoms of AS, as well as to increase functioning, there is very limited number of studies that examine BMI and AS. There are studies [32, 33] regarding the fact that visceral adiposity increase in AS raises cardiovascular risks, and it was reported that during 1- or 2-year period following tumor necrosis factor (TNF) alpha therapy, early abdominal obesity increased visceral adipose tissue in patients with AS [32]. It was also reported that in patients who received TNF alpha therapy there was significant correlation between visceral adipose tissue and body fat and disease activity [34]. In studies in which body composition in AS was evaluated, changes within fat and muscle mass compared with normal controls were identified [35]. Another study reported that epicardial fat thickness was significantly increased in patients with AS compared with healthy controls [36]. Retrospective European study of spondyloarthropathy in 155 individuals who were treated with infliximab (Remicade; Janssen Biotech, Inc., Horsham, PA, USA) evaluated the patients in groups defined as normal, pre-obese, and obese according to BMI, and results of 6-month infliximab treatment revealed significant difference between groups in terms of visual analogue scale responses, though no significant difference was observed in their BASDAI scores [37]. Durcan et al. [38] reported in a study conducted with 46 patients with AS that BASFI score within group with mean BMI of 27.4 (67.5%) proved to be 4.7, whereas BASFI score in group with normal mean BMI was 2.5. BASDAI score in group with mean BMI of 27.4 was 4.8, while in the other group it was found to be 2.9. In another study, significant correlation was found between body fat and BMI and BASMI. In a study conducted in Turkey [39], quantity of central/peripheral fat and quantity of upper/lower-half body fat in patients with AS were found to be significantly high, and anthropometric measurements of the AS patients were reported to be different from those of healthy individuals. In contrast, Rubio et al. reported that BMI and ASDAS score were not related [40]. In our study, we separated the patients into 2
58
subgroups with mean BMI of 25 to 27 and 27.1 to 29.9, and we found that BASFI results within group with greater BMI were significantly higher (p=0.024). Separately, since BASDAI in our preobese AS patients was ≥4 (4.78±2.1), this score suggests severe disease activity. Even though BMI increase in patients with AS is identified with medical treatments and mobility restriction stemming from pain, more remains to be clarified; however, we can assume that greater BMI will lead to additional physical complaints over time. Our study suggests that while specifying treatment strategies for patients with AS, taking BMI into consideration, trying to bring it to normal level, and implementing specially planned, extensive, and multidisciplinary rehabilitation program for patients will promote improved quality of life for patients with AS. Conflict of Interest: None declared. Financial Disclosure: The authors declared that this study has received no financial support. Authorship contributions: Concept – S.T.; Design – S.T.; Supervision – D.O.; Materials – Z.A.; Data collection &/or processing – S.T.; Analysis and/or interpretation – Z.A.; Literature search – D.O.; Writing – S.T.; Critical review:- D.O.
REFERENCES 1. Kaya T, Karatepe GA, Günaydın R, Ürper S. Ankilozanspondilit’li olgularda hastalık aktivitesinin fonksiyonel durum ve yaşam kalitesini belirlemedeki rolü. Archieves of Rheumatology, 2006;21:9-12 2. Vergara ME, O’Shea FD, Inman RD, Gage WH. Postural control is altered in patients with ankylosing spondylitis. Clin Biomech (Bristol, Avon) 2012;27:334–40. 3. Aydog E, Depedibi R, Bal A, Eksioglu E, Unlü E, Cakci A. Dynamic postural balance in ankylosing spondylitis patients. Rheumatology (Oxford) 2006;45:445–8. 4. Bostan EE, Borman P, Bodur H, Barça N. Functional disability and quality of life in patients with ankylosing spondylitis. Rheumatol Int 2003;23:121–6. 5. Russel AS. Ankylosing spondylitis: history. In: Klippel JH, Dieppe PA, editors. 2nd ed. Rheumatology. St Louis: Mosby;1994. p. 14:1–2. 6. Barlow JH, Macey SJ, Struthers GR. Gender, depression, and ankylosing spondylitis. Arthritis Care Res 1993;6:45–51. 7. Boonen A, Chorus A, Miedema H, van der Heijde D, Landewé R, Schouten H, et al. Withdrawal from labour force due to work
North Clin Istanb disability in patients with ankylosing spondylitis. Ann Rheum Dis 2001;60:1033-9. 8. Briot K, Gossec L, Kolta S, Dougados M, Roux C. Prospective assessment of body weight, body composition, and bone density changes in patients with spondyloarthropathy receiving anti-tumor necrosis factor-alpha treatment. J Rheumatol 2008;35:855– 61. 9. Toussirot E, Grandclément E, Gaugler B, Michel F, Wendling D, Saas P, et al. Serum adipokines and adipose tissue distribution in rheumatoid arthritis and ankylosing spondylitis. A comparative study. Front Immunol 2013;4:453. 10. Corbeil P, Simoneau M, Rancourt D, Tremblay A, Teasdale N. Increased risk for falling associated with obesity: mathematical modeling of postural control. IEEE Trans Neural Syst Rehabil Eng 2001;9:126–36. 11. Garrow JS, Webster J. Quetelet’s index (W/H2) as a measure of fatness. Int J Obes 1985;9:147–53. 12. Sieper J, Rudwaleit M, Baraliakos X, Brandt J, Braun J, BurgosVargas R, et al. The Assessment of SpondyloArthritis international Society (ASAS) handbook: a guide to assess spondyloarthritis. Ann Rheum Dis 2009;68 Suppl 2:ii1–44. 13. Ahmadi K, Wilson C, Tiwana H, Binder A, Ebringer A. Antibodies to Klebsiella pneumoniae lipopolysaccharide in patients with ankylosing spondylitis. Br J Rheumatol 1998;37:1330–3. 14. Haywood KL, Garratt AM, Jordan K, Dziedzic K, Dawes PT. Spinal mobility in ankylosing spondylitis: reliability, validity and responsiveness. Rheumatology (Oxford) 2004;43:750–7. 15. Machado P, Landewé R, Lie E, Kvien TK, Braun J, Baker D, et al. Ankylosing Spondylitis Disease Activity Score (ASDAS): defining cut-off values for disease activity states and improvement scores. Ann Rheum Dis. 2011;70:47–53. 16. Garrett S, Jenkinson T, Kennedy LG, Whitelock H, Gaisford P, Calin A. A new approach to defining disease status in ankylosing spondylitis: the Bath Ankylosing Spondylitis Disease Activity Index. J Rheumatol 1994;21:2286–91. 17. Doward LC, Spoorenberg A, Cook SA, Whalley D, Helliwell PS, Kay LJ, et al. Development of the ASQoL: a quality of life instrument specific to ankylosing spondylitis. Ann Rheum Dis 2003;62:20–6. 18. Sieper J, Braun J, Rudwaleit M, Boonen A, Zink A. Ankylosing spondylitis: an overview. Ann Rheum Dis 2002;61 Suppl 3:iii8– 18. 19. Van Der Linden S, Van Der Heijde D, Braun J. Ankylosing spondylitis. In: Haris ED, Budd RC, Firestein GS, Genovese MC, editors. Kelley’s textbook of rheumatology. 7th ed. Philadelphia: Elsevier/ Saunders;2005: p.1125–39. 20. Arnett FC. Ankylosing spondylitis. In: Koopman WJ. Editor. Arthritis and Allied Conditions: A Textbook of Rheumatology. 13th ed. Baltimore : Williams & Wilkins; 1997. p. 1197–208. 21. Lim HJ, Moon YI, Lee MS. Effects of home-based daily exercise therapy on joint mobility, daily activity, pain, and depression in patients with ankylosing spondylitis. Rheumatol Int 2005;25:225–9.
Toy et al., The effects of preobesity on ankylosing spondylitis
22. http://www.tuik.gov.tr/PreHaberBultenleri.do?id=18854 (access date: 5 April 2017). 23. Will R, Edmunds L, Elswood J, Calin A. Is there sexual inequality in ankylosing spondylitis? A study of 498 women and 1202 men. J Rheumatol 1990;17:1649–52. 24. Ozdemir O. Quality of life in patients with ankylosing spondylitis: relationships with spinal mobility, disease activity and functional status. Rheumatol Int 2011;31:605–10. 25. Ibn Yacoub Y, Amine B, Laatiris A, Abouqal R, Hajjaj-Hassouni N. Health-related quality of life in Moroccan patients with ankylosing spondylitis. Clin Rheumatol 2011;30:673–7. 26. Feldtkeller E, Khan MA, van der Heijde D, van der Linden S, Braun J. Age at disease onset and diagnosis delay in HLA-B27 negative vs. positive patients with ankylosing spondylitis. Rheumatol Int 2003;23:61–6. 27. Roussou E, Sultana S. Spondyloarthritis in women: differences in disease onset, clinical presentation, and Bath Ankylosing Spondylitis Disease Activity and Functional indices (BASDAI and BASFI) between men and women with spondyloarthritides. Clin Rheumatol 2011;30:121–7. 28. Ozgül A, Peker F, Taskaynatan MA, Tan AK, Dinçer K, Kalyon TA. Effect of ankylosing spondylitis on health-related quality of life and different aspects of social life in young patients. Clin Rheumatol 2006;25:168–74. 29. Turan Y, Duruöz MT, Cerrahoglu L. Quality of life in patients with ankylosing spondylitis: a pilot study. Rheumatol Int 2007;27:895–9. 30. Ward MM. Health-related quality of life in ankylosing spondylitis: a survey of 175 patients. Arthritis Care Res 1999;12:247– 55. 31. Yılmaz O, Tutoğlu A, Garip Y, Ozcan E, Bodur H. Healthrelated quality of life in Turkish patients with ankylosing spondylitis: impact of peripheral involvement on quality of life in terms of disease activity, functional status, severity of pain, and social and emotional functioning. Rheumatol Int
59 2013;33:1159–63. 32. Hmamouchi I, Roux C, Paternotte S, Kolta S, Dougados M, Briot K. Early increase of abdominal adiposity in patients with spondyloarthritis receiving anti-tumor necrosis factor-α treatment. J Rheumatol 2014;41:1112–7. 33. Sari I, Demir T, Kozaci LD, Akar S, Kavak T, Birlik M, et al. Body composition, insulin, and leptin levels in patients with ankylosing spondylitis. Clin Rheumatol 2007;26:1427–32. 34. Aydin M, Aydin F, Yuksel M, Yildiz A, Polat N, Akil MA, et al. Visceral fat reflects disease activity in patients with ankylosing spondylitis. Clin Invest Med 2014;37:E186. 35. Briot K, Gossec L, Kolta S, Dougados M, Roux C. Prospective assessment of body weight, body composition, and bone density changes in patients with spondyloarthropathy receiving anti-tumor necrosis factor-alpha treatment. J Rheumatol 2008;35:855– 61. 36. Üstün N, Kurt M, Atcı N, Yağız E, Güler H, Turhanoğlu A. Increased Epicardial Fat Tissue Is a Marker of Subclinic Atherosclerosis in Ankylosing Spondylitis. Arch Rheumatol 2014;29:267–72 37. Ottaviani S, Allanore Y, Tubach F, Forien M, Gardette A, Pasquet B, et al. Body mass index influences the response to infliximab in ankylosing spondylitis. Arthritis Res Ther 2012;14:R115. 38. Durcan L, Wilson F, Conway R, Cunnane G, O’Shea FD. Increased body mass index in ankylosing spondylitis is associated with greater burden of symptoms and poor perceptions of the benefits of exercise. J Rheumatol 2012;39:2310–4. 39. Okçu MZ, Yardımcı S, Çomoğlu S. Body fat percent and fat distribution parameters in rheumatic diseases. J Back Musculoskelet Rehabil 2002;16:57–61. 40. Rubio Vargas R, van den Berg R, van Lunteren M, Ez-Zaitouni Z, Bakker PA, Dagfinrud H, et al. Does body mass index (BMI) influence the Ankylosing Spondylitis Disease Activity Score in axial spondyloarthritis?: Data from the SPACE cohort. RMD Open 2016;2:e000283.
Orıgınal Article
OBSTETRICS&GYNECOLOGY
North Clin Istanb 2017;4(1):60–65 doi: 10.14744/nci.2017.26121
Is there any relationship between low PAPP-A levels and measures of umbilical vein and placental thickness during first trimester of pregnancy? Gulsum Uysal,1 Sadan Tutus,2 Fulya Cagli,3 Cevdet Adiguzel1 Department of Obstetrics and Gynecology, Adana Numune Training and Research Hospital, Adana, Turkey
1
Department of Radiology, Kayseri Training and Research Hospital, Kayseri, Turkey
2
Department of Obstetrics and Gynecology, Kayseri Training and Research Hospital, Kayseri, Turkey
3
ABSTRACT OBJECTIVE: Low pregnancy-associated plasma protein A (PAPP-A) level is associated with adverse perinatal outcomes. The purpose of this study was to evaluate relationship between umbilical cord diameter (UCD), umbilical vein and artery diameters (UVD, UAD), placental thickness, and PAPP-A level at gestational age of between 11 and 14 weeks. METHODS: UCD, UVD, UAD, and placental thickness of 246 women were assessed during ultrasound examination at between 11 and 14 weeks of gestation, as well as measurement of nuchal translucency (NT) and crownrump length (CRL). Patients were divided into 2 groups according to PAPP-A percentile. Group 1 comprised 23 patients who had low PAPP-A (<0.44 multiple of medians [MoM], <10th percentile) and Group 2 was made up of 223 patients with PAPP-A of >0.44 MoM, >10th percentile. Calipers used for measurement were placed inner edge to inner edge of echogenic boundaries of the vessel. Largest sections of all vessels (UV and both arteries) were evaluated. Thickest part of the placenta was used for placental thickness measurement. RESULTS: Narrow UCD (<4.5±0.6 mm) was associated with low PAPP-A level (p=0.02). There was no significant difference in UVD, UAD, or placental thickness between groups. There was no significant difference in gestational age, CRL, or NT between groups. Fetal birth weight was significantly lower in Group 1 (p=0.03). CONCLUSION: Closer attention to women with low-risk, healthy pregnancies and low PAPP-A level in first trimester screening results is recommended. They should be routinely screened for background medical risk factors and umbilical cord morphology in first trimester scan. Keywords: First trimester; placental thickness; pregnancy-associated plasma protein A; umbilical cord; umbilical vein.
Received: January 04, 2017 Accepted: March 20, 2017 Online: May 10, 2017 Correspondence: Dr. Gulsum UYSAL. Adana Numune Egitim ve Arastirma Hastanesi, 00170 Adana, Turkey. Tel: +90 322 - 355 00 00 e-mail: gulsumaykut@yahoo.com © Copyright 2017 by Istanbul Northern Anatolian Association of Public Hospitals–Available online at www.kuzeyklinikleri.com
Uysal et al., Relationship between low PAPP-A levels and measures of umbilical vein and placental thickness
61
T
he umbilical cord is a bridge organ between mother and fetus, and can be easily measured in the first trimester with improvements made to ultrasound probes used in imaging. Although we dispose of the umbilical cord at birth, it plays a unique role in fetal-placental unit. There are 2 arteries and single vein in the Wartonâ&#x20AC;&#x2122;s jelly of standard umbilical cord [1]. Morphology of umbilical cord structure alters in presence of various pathological conditions, such as hypertensive disorders [2], gestational diabetes [3], fetal distress [4], and growth restriction [5]. Moreover, umbilical cords with single artery [6], lean cords [4], and short cords [7] have been reported in cases with chromosomal defects and genetic syndromes. However, sonographic size of the umbilical cord in first trimester during routine prenatal sonographic scan receives little attention. Pregnancy-associated plasma protein A (PAPPA), which is encoded by the PAPPA gene in humans, is a protein. Low plasma level of PAPP-A has been recommended as biochemical marker for pregnancy with aneuploid fetus [8]. Moreover, low level has been observed in situations such as intrauterine growth restriction (IUGR) [9], preeclampsia [10], placental abruption, premature birth, fetus that is small for gestational age (SGA), and fetal death [11]. The aim of this study was to evaluate relationship between umbilical cord thickness, umbilical vein and artery diameter, placental thickness, and PAPP-A level at gestational age of between 11 and 14 weeks. MATERIALS AND METHODS This prospective study was conducted at Kayseri Education and Research Hospital, a tertiary teaching hospital in Kayseri, Turkey. Ethics approval for the study was obtained from Erciyes University Hospital (protocol number: 2014/290). Total of 246 consecutive women with singleton pregnancy who presented spontaneously for combined first trimester screening between April and December 2014 were included in the study. Patients with multiple pregnancy or pregnancy with
Figure 1. Umbilical vein diameter was measured at the widest distance between the opposing walls of the vein. structural fetal anomaly were excluded. The present study was conducted according to the recommendations of the Declaration of Helsinki on Biomedical Research Involving Human Subjects. Written informed consent was obtained from all patients. Umbilical cord diameter (UCD), umbilical vein and artery diameters (UVD, UAD), and placental thickness were assessed during detailed ultrasound examination at between 11 and 14 weeks of gestation, as well as nuchal translucency (NT) and crown-rump length (CRL) measurements. All ultrasound examinations were carried out with Xario device (Toshiba Medical Systems Corp., Otawarashi, Tochigi, Japan) equipped with 2.8â&#x20AC;&#x201C;7 MHz transducer. Scans were performed transabdominally by a single radiologist (S.T.). Maternal age, gravida, parity, and gestational age were recorded. Gestational age was calculated from first day of last period and confirmed ultrasonographically at first trimester scan. Data of gestational age and fetal birth weight after delivery were also recorded. During ultrasound examination, a free loop of umbilical cord was identified and magnified to obtain an appropriate image for measurement. UCD was measured from outer edge to outer edge. Diameter of UVD was measured at widest distance between opposing walls of the vein (Figure 1). Calipers for measurement were placed on echogenic boundary of the vessel from inner edge to in-
62
North Clin Istanb
Table 1. Basal characteristics of patient groups
Figure 2.
Placental thickness measurement was recorded at the thickest part of the placenta.
ner edge. Largest sections of all vessels (UV and both arteries) were evaluated. Average of both vessels was calculated for UAD. Thickest part of the placenta was used for placental thickness measurement, as shown in Figure 2. Fetal CRL and NT were measured in all women according to recommendations of the Fetal Medicine Foundation [12]. PAPP-A measurement was conducted using UniCel Dxl 800 Access immunoassay system analyzer (Beckman Coulter, Inc., Brea, CA, USA), which is used for routine first trimester prenatal screening program. PAPP-A values were converted to gestation-specific multiple of medians (MoM), using Prisca software program (Siemens Healthcare Diagnostics, Erlangen, Germany). Patients were divided into 2 groups according to PAPP-A value. Those below 10th percentile in MoM of PAPP-A were classified as Group 1, and those above 10th percentile were classified as Group 2. All analyses were performed using PASW Statistics for Windows, Version 18.0 (SPSS, Inc., Chicago, IL, USA). Quantitative variables were expressed as mean value±SD for parametric variables and median and minimum-maximum levels for nonparametric variables. Continuous variables were analyzed for normal distribution using Kolmogorov-Smirnov test. A 2-tailed p< 0.05 was considered significant. Differences in continuous variables between 2 groups were determined by
Age (years) Gravida (n) Median (min-max) Parity (n) (mean) Gestational age (weeks) CRL (mm) NT (mm) Fetal birth weight (gr) Gestational age at delivery (week)
Group 1 Group 2 p PAPP-A <%10 PAPP-A >%10 (<0.05) (<0.44 MoM) (>0.44 MoM) 29.0±6.2
26.4±5.7
0.04
3 (1–6) 2 (0–4) 12.4±0.5
2 (1–8) 1 (0–4) 12.3±0.5
0.001 0.002 0.4
66.6±8.0 1.6±0.2 2945±522
65.1±7.5 1.5±0.2 3237±546
0.38 0.4 0.01
37.2±3.0
38.2±3.0
0.1
CRL: Fetal crown-rump length; MoM: Multiple of medians; NT: Nuchal translucency; PAPP-A: Pregnancy-associated plasma protein-A.
Student’s t-test or Mann-Whitney U test. Logistic regression analysis using the enter method was performed for multivariate analysis of independent predictors. Significant parameters (p<0.05) were entered into multivariate analysis. RESULTS Total of 246 umbilical cords of healthy pregnancies were evaluated in the study. Scans of umbilical cord vessels and placental thickness were successfully examined in all cases. There were 23 patients in Group 1, defined as below the 10th percentile in MoM of PAPP-A (<0.44MoM) and 223 patients in Group 2, above the 10th percentile in MoM of PAPP-A (>0.44 MoM). Characteristics of the patients by group and measurement of CRL, NT, and fetal weight are presented in Table 1. Maternal age, gravida, and parity were significantly higher in Group 1 (PAPP-A <0.44MoM) compared with Group 2. Mean maternal age was 29±6.2 in Group 1 and 26±5.7 in Group 2. There was no significant difference in gestational age, gestational
Uysal et al., Relationship between low PAPP-A levels and measures of umbilical vein and placental thickness
DISCUSSION
Table 2. Relationship between groups and umbilical
vessel diameter and placental thickness UCD (mm) UVD (mm) UAD (mm) Placental thickness (mm)
Group 1 Group 2 p PAPP-A <%10 PAPP-A >%10 (<0.05) (<0.44 MoM) (>0.44 MoM) 4.5±0.6 1.6±0.2 1.2±0.2 16.8±2.9
4.8±0.5 1.6±0.2 1.2±0.1 16.9±3.3
0.02 0.9 0.5 0.8
MoM: Multiple of medians; PAPP-A: Pregnancy associated plasma proteinA; UAD: Umbilical artery diameter; UCD: Umbilical cord diameter; UVD: Umbilical vein diameter.
Table 3. Multivariate analysis Age Gravida Parity Fetal birth weight UCD
63
Multivariate odds ratio
95% CI
p
0.959 0.820 0.691 1.001 2.638
0.875–1.052 0.466–1.442 0.292–1.637 1.000–1.002 1.140–6.103
0.38 0.49 0.40 0.031 0.023
CI: Confidence interval; UCD: Umbilical cord diameter.
age at delivery, CRL, or NT between groups. Fetal birth weight was significantly lower in Group 1. Values for diameter of umbilical cords, vessels, and placental thickness are provided in Table 2. There was no difference in UVD, UAD, or placental thickness between groups. UCD was significantly greater in Group 2. Significant parameters of univariate analysis (p<0.05) were entered into multivariate analysis (age, gravida, parity, fetal birth weight, UCD). UCD was found to be an independent predictor of low PAPP-A level (odds ratio [OR], 2.638; 95% confidence interval [CI], 1.140–6.103; p=0.023), together with fetal birth weight (OR, 1.001; 95% CI, 1.000–1.002; p=0.031) (Table 3).
Major finding of our study was that there is relationship between diameter of umbilical cord and PAPPA, one of the first trimester biochemical markers. Low PAPP-A level in first trimester appeared to be associated with narrow UCD (<4.5±0.6 mm). UCD or umbilical cord morphology evaluation is not routine scan during first trimester ultrasound. In a recent study it was reported that UCD in first trimester was related to growth of the embryo, and may be used as ultrasonographic measurement to detect risks to fetus, such as spontaneous abortion or preeclampsia [2]. Furthermore, Ghezzi et al. indicated that more than half of cases with fetal demise that occurred early in second trimester had thinner umbilical cord (diameter <2 SD) compared with UCD scan in first trimester [2]. We know that low PAPP-A level is associated with poor perinatal outcomes, including fetus that is SGA, preterm delivery, hypertensive disorders of pregnancy, and stillbirth [13]. In a recent study, Wells et al. concluded that PAPP-A can be used as new biomarker for maternal diabetes [14]. They also reported that markedly decreased PAPP-A level was associated with severe gestational diabetes. Therefore, it may predict risk of gestational diabetes [14]. The questions is, what is the cause of low PAPPA level and adverse perinatal outcome? Abnormal placentation has been suspected in recent studies [15, 16]. Actually, they suggested that women who had low PAPP-A level in first trimester with normal first trimester aneuploidy screening results should be screened routinely for risk factors related to abnormal placentation. Avsar et al. evaluated relationship between first trimester PAPP-A level and intrapartum fetal distress results. They revealed that PAPP-A level was lower (<0.5 MoM) in cases with intrapartum fetal distress [17]. Additionally, in another study, patients who had cord insertion on the lower segment of the uterus had lower maternal serum PAPP-A level [18]. In our study, narrower UCD (<4.5±0.6 mm) was associated with low PAPP-A level (<0.44MoM) in aneuploidy screening results of first trimester. We have also reported
64
that there was no relationship between low PAPPA level (<0.44MoM) and UVD, UAD, or placental thickness. This is the first study to evaluate association between UVD, UAD, placental thickness, and PAPP-A. We think that changing role of Wharton’s jelly, which increases as gestation advances, may explain insignificant relationship between low PAPPA level and UVD, UAD, and placental thickness. Umbilical cord is part of fetal metabolism and it has been suggested that thickness of umbilical cord may be related to mechanism of fetal nutrition [19]. Both thick and thin umbilical cords might be dependent on quantity of Warton’s jelly and/or changing size of umbilical cord vessels in cross-sectional area [20]. Further larger studies are needed to explain probable relationship between umbilical cord, morphology of Warton’s jelly, and fetal outcome in early pregnancy. In our study, low PAPP-A value in first trimester combined test in low-risk healthy pregnancy was associated with lower fetal birth weight at term. Studies in the literature report relationship between low PAPP-A level and SGA infant. It has been demonstrated that there was statistically significant relationship between PAPP-A level below fifth percentile or less than 0.4 MoM and SGA or IUGR [9, 21]. Abnormal placentation may be behind low level of PAPP-A and adverse outcomes. Larger studies should be helpful to bring focus to pathogenesis. On the other hand, in another study, Saruhan et al. found that PAPP-A level below 10th percentile was not significantly associated with SGA [22]. Current consensus on association between PAPP-A level below 10th percentile and SGA remains mixed. Our data indicated that as maternal age and gravida increase, frequency of low PAPP-A level (<0.44MoM) increases in low-risk, healthy pregnancies in first trimester scan. It might be explained by placental damage, which can be greater with advanced maternal age and complex obstetric history. There are several limitations to our study. Our study protocol did not include longitudinal followup cord anatomy through gestation in second or third trimester. We did not have a high-risk, first trimester pregnancy group; therefore, we could not perform measurement of diameter of umbilical cord
North Clin Istanb
and vessels in high-risk group. Major limitation of our study was relatively small patient population. Studies involving larger number of participants should be conducted to verify and further advance our findings. Also, we could not include pregnancy outcome (e.g., diabetes, preeclamsia, or growth retardation) other than fetal birth weight. In conclusion, our data revealed that UCD was independent predictor of low PAPP-A level. Although there is debate about cut-off of low PAPP-A level (under 10th or 5th percentile), it would seem to be worthwhile to pay attention to low PAPP-A level. We suggest closer attention be paid to performing umbilical cord measurements in first trimester scan. Larger prospective studies need to be performed to further investigation of UCD and cord vessel evaluations in first trimester of gestation. There are many questions that remain to be solved about potential role of umbilical cord morphology in fetal outcome. Conflict of Interest: None declared. Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent: Informed consent was obtained from all patients who were included in our study. Financial Disclosure: The authors declared that this study has received no financial support. Authorship contributions: Concept – G.U.; Design – G.U.; Supervision – C.A., F.U.; Materials – S.T.; Data collection and/ or processing – F.C., G.U.; Literature earch – S.T., F.C.; Writing – G.U.; Critical review – C.A.
REFERENCES 1. Wu MH, Chang FM, Shen MR, Yao BL, Chang CH, Yu CH, et al. Prenatal sonographic diagnosis of single umbilical artery. J Clin Ultrasound 1997;25:425–30. 2. Ghezzi F, Raio L, Di Naro E, Franchi M, Brühwiler H, D’Addario V, et al. First-trimester sonographic umbilical cord diameter and the growth of the human embryo. Ultrasound Obstet Gynecol 2001;18:348–51. 3. Weissman A, Jakobi P. Sonographic measurements of the umbilical cord in pregnancies complicated by gestational diabetes. J Ultrasound Med 1997;16:691–4. 4. Raio L, Ghezzi F, Di Naro E, Franchi M, Maymon E, Mueller MD, et al. Prenatal diagnosis of a lean umbilical cord: a simple
Uysal et al., Relationship between low PAPP-A levels and measures of umbilical vein and placental thickness
marker for the fetus at risk of being small for gestational age at birth. Ultrasound Obstet Gynecol 1999;13:176–80. 5. Bruch JF, Sibony O, Benali K, Challier JC, Blot P, Nessmann C. Computerized microscope morphometry of umbilical vessels from pregnancies with intrauterine growth retardation and abnormal umbilical artery Doppler. Hum Pathol 1997;28:1139–45. 6. Persutte WH, Hobbins J. Single umbilical artery: a clinical enigma in modern prenatal diagnosis. Ultrasound Obstet Gynecol 1995;6:216–29. 7. Gilbert-Barness E, Drut RM, Drut R, Grange DK, Opitz JM. Developmental abnormalities resulting in short umbilical cord. Birth Defects Orig Artic Ser 1993;29:113–40. 8. Chitayat D, Langlois S, Wilson RD; Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada; Prenatal Diagnosis Committee of the Canadian College of Medical Geneticists. Prenatal screening for fetal aneuploidy in singleton pregnancies. J Obstet Gynaecol Can 2011;33:736–50. 9. Carbone JF, Tuuli MG, Bradshaw R, Liebsch J, Odibo AO. Efficiency of first-trimester growth restriction and low pregnancyassociated plasma protein-A in predicting small for gestational age at delivery. Prenat Diagn 2012;32:724–9. 10. Poon LC, Maiz N, Valencia C, Plasencia W, Nicolaides KH. First-trimester maternal serum pregnancy-associated plasma protein-A and pre-eclampsia. Ultrasound Obstet Gynecol 2009;33:23–33. 11. Marttala J, Peuhkurinen S, Laitinen P, Gissler M, Nieminen P, Ryynanen M. Low maternal PAPP-A is associated with smallfor-gestational age newborns and stillbirths. Acta Obstet Gynecol Scand 2010;89:1226–8. 12. Nicolaides KH. Nuchal translucency and other first-trimester sonographic markers of chromosomal abnormalities. Am J Obstet Gynecol 2004;191:45–67. 13. Balcı S. Predictive values of maternal serum PAPP-A level, uterine artery Doppler velocimetry, and fetal biometric measurements for poor pregnancy and poor neonatal outcomes in pregnant women. J Turk Ger Gynecol Assoc 2016;17:143–9. 14. Wells G, Bleicher K, Han X, McShane M, Chan YF, Bartlett A,
65
et al. Maternal Diabetes, Large-for-Gestational-Age Births, and First Trimester Pregnancy-Associated Plasma Protein-A. J Clin Endocrinol Metab 2015;100:2372–9. 15. Proctor LK, Toal M, Keating S, Chitayat D, Okun N, Windrim RC, et al. Placental size and the prediction of severe early-onset intrauterine growth restriction in women with low pregnancyassociated plasma protein-A. Ultrasound Obstet Gynecol 2009;34:274–82. 16. Rizzo G, Silvestri E, Capponi A, Servadei F, Pietrolucci ME, Capece A, et al. Histomorphometric characteristics of first trimester chorionic villi in pregnancies with low serum pregnancyassociated plasma protein-A levels: relationship with placental three-dimensional power doppler ultrasonographic vascularization. J Matern Fetal Neonatal Med 2011;24:253–7. 17. Avşar AF, Seçen Eİ, Akçay GF, Keskin HL, Taş EE, Dalgacı AF. The relationship between first-trimester pregnancy-associated plasma protein-A levels and intrapartum fetal distress development. J Turk Ger Gynecol Assoc 2016;17:139–42. 18. Hasegawa J, Farina A, Simonazzi G, Bisulli M, Puccetti C, Pilu G, et al. Umbilical cord insertion into the lower segment of the uterus at 11 to 13 weeks’ gestation is associated with maternal serum PAPP-A. Prenat Diagn 2011;31:434–8. 19. Raio L, Ghezzi F, Di Naro E, Gomez R, Franchi M, Mazor M, et al. Sonographic measurement of the umbilical cord and fetal anthropometric parameters. Eur J Obstet Gynecol Reprod Biol 1999;83:131–5. 20. Ghezzi F, Raio L, Günter Duwe D, Cromi A, Karousou E, Dürig P. Sonographic umbilical vessel morphometry and perinatal outcome of fetuses with a lean umbilical cord. J Clin Ultrasound 2005;33:18–23. 21. Marttala J, Peuhkurinen S, Laitinen P, Gissler M, Nieminen P, Ryynanen M. Low maternal PAPP-A is associated with smallfor-gestational age newborns and stillbirths. Acta Obstet Gynecol Scand 2010;89:1226–8. 22. Saruhan Z, Ozekinci M, Simsek M, Mendilcioglu I. Association of first trimester low PAPP-A levels with adverse pregnancy outcomes. Clin Exp Obstet Gynecol 2012;39:225–8.
Orıgınal Article
CARDIOLOGY
North Clin Istanb 2017;4(1):66–72 doi: 10.14744/nci.2017.72324
Increased levels of red cell distribution width is correlated with presence of left atrial stasis in patients with non-valvular atrial fibrillation Adnan Kaya,1 Ceyhan Tukkan,2 Ahmet Taha Alper,2 Baris Gungor,2 Kazim Serhan Ozcan,3 Mustafa Adem Tatlisu,2 Ahmet Ilker Tekkesin,2 Fatma Ozpamuk Karadeniz,4 Gulay Gok,2 Osman Kayapinar1 Department of Cardiology, Duzce University Faculty of Medicine, Duzce, Turkey
1
Department of Cardiology, Dr. Siyami Ersek Cardiovacular Surgery Hospital, Istanbul, Turkey
2
Department of Cardiology, Derince Training and Research Hospital, Kocaeli, Turkey
3
Department of Cardiology, Erzurum Training and Research Hospital, Erzurum, Turkey
4
ABSTRACT OBJECTIVE: Red cell distribution width (RDW) and neutrophil to lymphocyte ratio (NLR) have been found to be associated with non-valvular atrial fibrillation (AF) and cardiovascular diseases. However, correlation of these parameters with presence of left atrial (LA) thrombus and/or spontaneous echo contrast (SEC) in patients with non-valvular AF has not been clarified. This study was an investigation of correlation of RDW, NLR, and clinical risk factors with LA thrombus and dense SEC in patients with non-valvular AF in the Turkish population. METHODS: The demographic, laboratory, and echocardiographic properties of 619 non-valvular AF patients who underwent transesophageal echocardiography (TEE) examination before direct current cardioversion (DCCV) or AF ablation treatment were retrospectively investigated. Complete blood count (CBC) and biochemical parameters were studied 6 to 12 hours before TEE examination. Left atrial stasis (LAS) markers were noted as presence of left atrial/left atrial appendage (LA/LAA) thrombus or dense spontaneous echo contrast (DSEC). RESULTS: Total of 325 (52%) patients with LAS were compared with 294 patients (48%) without LAS. In the LAS group, there were 274 (84%) patients with LA/LAA thrombus and 51 (16%) patients with DSEC. LAS (+) group, values for RDW (14.85±1.48 vs. 13.77±1.30; p<0.01), NLR (2.38 [1.58], vs. 2.10 [1.35]; p<0.01) and C-reactive protein (0.95 [0.61] vs. 0.88 [0.60] mg/L; p<0.01) were significantly higher than seen in LAS (-) group. In multivariate regression analysis, increased level of RDW, age, male gender, heart failure, duration of AF >6 months, and international normalized ratio <2 were independently correlated with presence of LAS. CONCLUSION: Our study indicated that increased level of RDW is independently correlated with higher risk for development of LAS in patients with non-valvular AF. Keywords: Left atrial thrombus; non-valvular atrial fibrillation; red cell distribution width.
Received: February 21, 2017 Accepted: April 12, 2017 Online: May 10, 2017 Correspondence: Dr. Adnan KAYA. Duzce Universitesi Tip Fakultesi, Kardiyoloji Anabilim Dali, Duzce, Turkey. Tel: +90 380 - 542 14 16 e-mail: adnankaya@ymail.com © Copyright 2017 by Istanbul Northern Anatolian Association of Public Hospitals–Available online at www.kuzeyklinikleri.com
Kaya et al., RDW is increased in left atrial stasis
A
trial fibrillation (AF) is the most common cardiac arrhythmia and is associated with increased cardiovascular risks [1]. The major complication of AF is formation of thrombus in the left atrium (LA) and/or left atrial appendage (LAA) causing thromboembolism. Abnormal flow dynamics in the LA and LAA cause blood stasis, endothelial damage, and thrombus formation, even in the absence of valvular disease [2]. The inflammatory process is important in pathogenesis of AF, which is associated with the stimulation of coagulation cascade and thrombus formation [3]. Recently, correlation of red cell distribution width (RDW) and neutrophil to lymphocyte ratio (NLR) with inflammatory status has been demonstrated [4]. In addition, prognostic importance of these parameters in various cardiovascular diseases, including non-valvular AF, has been found [5, 6]. Transesophageal echocardiography (TEE) is the criterion standard for detection of LA/LAA thrombus and dense spontaneous echo contrast (DSEC). These findings indicate left atrial stasis (LAS), and are correlated with higher risk of thromboembolism during electrical cardioversion and AF ablation procedures [7â&#x20AC;&#x201C;9]. The aim of this study was to investigate the correlation of pre-procedural RDW, NLR, and clinical risk factors with presence of LAS in patients with non-valvular AF who had undergone TEE examination. MATERIALS AND METHODS
Patient selection This study was a retrospective, cross-sectional study conducted between January 2009 and June 2014 at our tertiary cardiovascular hospital. Study consisted of 325 consecutive LAS (+) patients who had undergone TEE between January 2009 and June 2014 and randomly selected 294 LAS (-) patients from the same time interval before electrical cardioversion or AF ablation treatment. Patients older than 80 years of age, with valvular AF, post-operative AF, recent acute coronary syndrome, anemia (for men hemoglobin <13 gr/ dL, for women hemoglobin <12gr/dL), acute or
67
chronic inflammatory disease, renal failure, hepatic failure, malignancy, or with other indication of chronic anticoagulation or history of blood transfusion within 3 months were excluded. All patient risk factors, clinical information, laboratory and demographic data were obtained from hospital records. Echocardiography examination Transesophageal echocardiography was performed with GE Vivid 7 device (GE Healthcare, Inc. Chicago, IL, USA) and 6T phased array multiplane transesophageal (2.9 to 7.0 MHz) probe. All examinations were performed after administration of local anesthesia of hypopharynx with lidocaine spray and sedation with 2 to 5 mg intravenous administration of midazolam. LA and LAA were investigated for presence of thrombus and DSEC in different tomographic planes of TEE. LA/LAA thrombus was defined as (1) masses adhering to LA wall or LAA, (2) masses moving independently from the LAA wall, (3) masses of different echogenicity density from LAA wall, and (4) confirmation of mass in more than 1 imaging plane. Special efforts were made to discriminate pectinate muscles from thrombi. In case of doubt, images were re-evaluated until consensus was reached. Spontaneous echo contrast (SEC) scoring was done from 1+ to 4+ as described by Fatkin et al. [10]. Patients with 3+ and 4+ SEC were defined as DSEC. Patients with thrombus of LA/LAA and/or DSEC formed study group [LAS (+) group] and patients who did not have these findings formed control group [LAS (-) group]. Congestive heart failure (CHF) was defined as having diagnosis of ejection fraction preserved heart failure and/or heart failure with systolic dysfunction (ejection fraction less than 49%) and use of heart failure medication. In addition, Congestive Heart Failure, Hypertension, Age, Diabetes Mellitus, Stroke (CHADS2) score and Congestive Heart Failure, Hypertension, Age, Diabetes Mellitus, Stroke, Vascular Disease, Sex (CHA2DS2-VASc) score were calculated for each patient in order to evaluate risk of thromboembolism and stroke [11]. The study was approved by the local ethics committee of the hospital.
68
Laboratory analysis Fasting blood samples were drawn according to hospital protocol from antecubital vein puncture into ethylenediaminetetraacetic acid-treated or plain tubes on day of admission 6 to 12 hours before TEE examination. Complete blood count (CBC) testing utilized clinical laboratory methods (Coulter LH 780 Hematology Analyzer; Beckman Coulter Inc., Brea, CA) for hemoglobin, total white blood cell (WBC) count, platelet count and RDW. Baseline NLR was calculated by dividing neutrophil count by lymphocyte count. High-sensitivity C-reactive protein (CRP) level was measured with Cobas Integra analyzer (Roche Diagnostics, Basel, Switzerland) using turbidimetric method. Statistical analysis Statistical analyses were performed using SPSS for Windows, Version 15.0 (SPSS Inc., Chicago, IL, USA) software. Continuous variables were checked for normal distribution assumption using Kolmogorov-Smirnov test and were reported as mean±SD or median (interquartile range). Differences between LAS (+) and (-) groups were evaluated using Student’s t-test or Mann-Whitney U test. Categorical variables were tested with Pearson’s chisquared test and Fisher’s exact test. Receiver operating curves (ROC) were generated to define cut-off values (upper left corner of ROC as point of maximum sensitivity and specificity) of RDW for presence of LAS in the study population. In addition, univariate and multivariate binary logistic regression analysis was performed to investigate independent correlates of LAS. Variables with p<0.10 in univariate analysis were included in multivariate regression analysis. All p values were two-sided and p value <0.05 was considered statistically significant. RESULTS The study included 325 patients with LAS and 294 patients without LAS. In the LAS (+) group, there were 274 (84%) patients with LA/LAA thrombus and 51 (16%) patients with DSEC. Clinical and demographic properties of the study population are summarized in Table 1. Study patients were older
North Clin Istanb
(62.8±12.5 vs. 54.5±13.9; p=0.01), and frequency of male gender was higher (63% vs. 54%; p=0.03) compared with control group. Frequency of patients with hypertension, diabetes mellitus, CHF, and vascular diseases was higher and duration of AF was longer in LAS (+) group. Mean CHADS2 score (1.90±1.16 vs. 1.08±1.01; p<0.01) and mean CHA2DS2-VASc score (2.43±1.40 vs. 1.58±1.19; p<0.01) were significantly higher in LAS (+) group. In addition, percentage of patients with CHADS2≥3, CHA2DS2-VASc ≥3 was significantly higher in LAS (+) group compared with LAS (-) group. In total, 370 patients had warfarin treatment and rate of warfarin use was significantly higher in the LAS (+) group (82% vs. 36%; p<0.01). When only patients with warfarin treatment were considered, rate of LA/LAA thrombus was 66%. Frequency of patients with optimal anticoagulation (international normalized ratio between 2–3) at time of TEE examination was 78%. Only patients without LAS had undergone electrical cardioversion or AF ablation procedure and none of the treated patients had thromboembolic complication. Hematological and biochemical parameters of study groups are compared in Table 2. Statistically significant difference was observed between creatinine levels, whereas hemoglobin level and WBC, platelet, neutrophil, and lymphocyte counts were not different between groups. In LAS (+) group, NLR (2.38 [1.58] vs. 2.10 [1.35]; p<0.01), RDW (14.85±1.48 vs. 13.77±1.30; p<0.01), and CRP (0.95 [0.61] vs. 0.88 [0.60] mg/L; p<0.01) levels were significantly higher compared with control group. In subgroup analysis, when patients with LA/LAA thrombus were compared with patients with DSEC, RDW (14.84±1.56 vs. 14.34±0.93; p=0.32), NLR (2.25 [1.62] vs. 2.32 [0.93]; p=0.32), and CRP (0.96 [0.60] vs. 0.95 [0.51] mg/L; p=0.91) levels were not significantly different (Figure 1). In ROC curve analysis, area under curve (AUC) of RDW was significantly higher compared with AUC of NLR and CRP for discrimination of LAS in the study population (0.732 vs. 0.579 vs. 0.584, respectively; p<0.01) (Figure 2). Cut-off level of
Kaya et al., RDW is increased in left atrial stasis
69
Table 1. Demographic characteristics and risk factor identification for left atrial stasis (+) and (-) groups
LAS (+) (n=325)
n
Age, years Male sex Hypertension Diabetes mellitus Stroke Congestive heart failure Vascular disease AF duration >6 months LA/LAA thrombus DSEC CHADS2 score CHADS2 score>3 CHA2DS2-VASc score CHA2DS2-VASc>3 Treatment Warfarin Acetylsalicylic acid No treatment
LAS (-) (n=294)
%
n
p
%
62.8±12.5 54.5±13.9 <0.01 206 63 161 54 0.03 247 76 164 55 <0.01 49 15 23 8 <0.01 24 7 14 5 0.24 59 18 12 4 <0.01 57 17 19 6 <0.01 278 85 143 49 <0.01 274 84 – – – 51 16 – – – 1.90±1.16 1.08±1.01 <0.01 85 26 28 10 <0.01 2.43±1.40 1.58±1.19 <0.01 148 45 59 20 <0.01 265 50 10
82 15 3
105 148 41
36 50 14
<0.01 <0.01
Table 2. Comparison of hematological parameters between left atrial stasis (+) and (-) groups
LAS (+) (n=325)
LAS (-) (n=294)
p
Creatinine, mg/dL 0.93±0.25 0.87±0.24 <0.01 Hemoglobin, g/dL 13.8±1.5 14.0±1.3 0.21 3 Platelet, 10 /µL 246±75 249±77 0.56 WBC, 103/µL 7.92±1.85 7.91±2.23 0.77 Neutrophil, 103/µL 5.03±1.65 4.79±1.79 0.09 Lymphocyte, 103/µL 2.12± 1.12 2.26±0.91 0.10 NLR 2.38 [1.58] 2.10 [1.35] <0.01 RDW, % 14.85±1.48 13.77±1.30 <0.01 CRP, mg/L* 0.95 [0.61] 0.88 [0.60] <0.01 CRP: C-reactive protein; NLR: Neutrophil to lymphocyte ratio; RDW: Red cell distribution width; WBC: White blood cell. *CRP level could be obtained in only 524 patients.
Red cell distribution width (%)
AF: Atrial fibrillation; LA: Left atrium; LAA: Left atrial appendage; DSEC: Dense spontaneous echo contrast; CHADS2: Congestive Heart Failure, Hypertension, Age, Diabetes Mellitus, Stroke; CHA2DS2-VASc: Congestive Heart Failure, Hypertension, Age, Diabetes Mellitus, Stroke, Vascular Disease, Sex.
20.00
p<0.01
p=0.32
18.00 16.00 14.00 12.00 10.00
Figure 1.
LAS (-)
LAS (+)
DSEC
LA/LAA thrombus
Box-plot graph demonstrating comparison of red cell distribution width level between the study groups. DSEC: Dense spontaneous echo contrast; LA: Left atrium; LAA: Left atrial appendage; LAS: Left atrial stasis.
70
North Clin Istanb
pendent correlates of LAS in the study population. In multivariable model, age, male gender, heart failure, AF duration >6 months, and increased RDW level (odds ratio, 1.67; 95% confidence interval, 1.44-1.94; p<0.01) were found to be independently correlated with presence of LAS (Table 3).
1.0
Sensitivity
0.8 0.6 0.4 Red cell distribution width (%) C-reactive protein Neutrophil to lymphocyte ratio Reference line
0.2 0.0
0.0
0.2
0.4 0.6 1-Specificity
0.8
1.0
Figure 2.
Receiver operating characteristic curve analysis of red cell distribution width, neutrophil to lymphocyte ratio, and high sensitivity C-reactive protein level for prediction of left atrial stasis in the study population.
RDW >13.7% predicted presence of LAS with sensitivity of 78.1% and specificity of 58.5%. In patients with RDW >13.7%, rate of LAS (+) was 68.9%, which was significantly higher than in patients with RDW ≤13.7% (30.6%) (p<0.01). Univariate and multivariate binary logistic regression analysis was performed to investigate inde-
DISCUSSION In this study, we determined correlation between increased RDW level and increased risk for LA/LAA thrombus formation and DSEC in Turkish patients with non-valvular AF. In multivariate binary logistic regression analysis, older age, male gender, heart failure, AF duration >6 months, and increased RDW level were found to be independently correlated with presence of LAS. NLR was determined to be significantly higher in study group, but it was not an independent predictor when combined with clinical risk factors. To the best of our knowledge, this is the first study in which RDW independently predicted LAS. AF is the most common sustained tachyarrhythmia and is associated with increased cardiovascular morbidity, mortality, and preventable stroke, accounting for approximately one-third of cardiac hospitalizations for cardiac rhythm disturbances [12].
Table 3. Univariate and multivariate regression analysis for predictors of left atrial stasis in the study population Variables Age Male gender Hypertension Heart failure Diabetes mellitus AF duration >6 months Creatinine CRP* Hemoglobin RDW NLR
Unadjusted OR (95% CI)
p
1.05 (1.03–1.06) 1.42 (1.03–1.96) 2.52 (1.79–3.56) 5.30 (2.79–10.1) 2.09 (1.23–3.51) 6.29 (4.28–9.24) 2.80 (1.44–5.48) 1.32 (1.024–1.69) 0.91 (0.81–1.01) 1.81 (1.57–2.08) 1.08 (0.99–1.17)
<0.01 0.03 <0.01 <0.01 <0.01 <0.01 <0.01 0.03 0.11 <0.01 0.06
Adjusted OR (95% CI) 1.03 1.53 0.98 3.59 1.09 3.25 1.41
(1.01–1.05) (1.05–2.31) (0.61–1.58) (1.68–6.86) (0.59–2.11) (2.08–5.12) (0.63–3.45) – – 1.67 (1.44–1.94) 0.98 (0.89–1.07)
p <0.01 0.04 0.92 <0.01 0.77 <0.01 0.75 – – <0.01 0.61
AF: Atrial fibrillation; CI: Confidence interval; CRP: C-reactive protein; INR: International normalized ratio; OR: Odds ratio; RDW: Red cell distribution width; NLR: Neutrophil to lymphocyte ratio. *CRP level was not included in the multivariable model because this parameter could be obtained in only 524 patients.
Kaya et al., RDW is increased in left atrial stasis
Left atrial stasis, dyssynchrony, and compromised contraction and relaxation are the underlying pathologies in AF that cause SEC, sludge, and thrombus in LA/LAA. Consequently, any thrombus migration from LA/LAA interrupts blood flow of the organ it occludes, and associated disabilities occur. There may be some concerns about the number and ratio of patients with LAS in our study (325/619), which is unlike 2 previously published papers. There were 88 patients with LAS of 247 patients who underwent TEE in study conducted by Providencia et al. [13]. The other study included 24 patients with LAS of 90 patients who had undergone TEE [14]. Both studies compromised all consecutive TEE patients, while we selected 325 consecutive patients with LAS and matched them with 294 consecutive patients without LAS. In our study, we found that patients with LAS were older, as well as more often hypertensive, and diabetic. Similarly, they had CHF, vascular disease and persistent AF more often than control group. CHADS2 score, CHA2DS2-VASc score, and warfarin usage were also higher than seen in controls. These demographic properties of the groups were compatible with current literature. However, there were no statistical differences in previous stroke, despite high rate of warfarin use in LAS (+) group. We think patients under warfarin treatment may not have had enough time in therapeutic range, which means ineffective treatment. Zhao et al. [14] found increased warfarin usage in LAS group, as seen in our study, but found that previous stroke was also higher in LAS group, unlike our results. RDW, which has institutionally been used for differential diagnosis of anemia, is a quantitative measure of variability in the size of circulating erythrocytes, and is now accepted as prognostic index for cardiovascular diseases. It is associated with increased mortality in patients with stroke, CHF, and myocardial infarction; however, there is no clear pathophysiological mechanism yet for this association. Chronic inflammation and oxidative stress, which are present in both development and persistence of AF, may reduce number of red blood cells, which in turn increases erythropoietin production and leads to increase in RDW. Higher RDW level
71
was associated with high level of CRP, erythropoietin, interleukin-6, tumor necrosis factor (TNF) alpha, and TNF receptor I/II in systolic heart failure patients [15], which revealed association of chronic inflammation with RDW level. Association of RDW and non-valvular AF has recently been reported [16]. There are 2 studies that investigated association of RDW and LAS in nonvalvular AF, and both failed to show independent correlation of RDW with LAS. The study conducted by Providencia et al. [13] indicated that RDW and mean corpuscular volume (MCV) add incremental value to each other, but when clinical risk factors were added, MCV remains independent predictor. Zhao et al. [14] also reported association of RDW with LAS, but when clinical risk factors were added, low hemoglobin and persistence of AF remained independent predictors. In our study, even after adding clinical risk factors, RDW was independent predictor of LAS. Increased neutrophil count is consistent with subclinical inflammation, while decreased lymphocyte count shows physiological stress and poor general health [17]. This means NLR could be used as a monitor for inflammatory status and stress response. In this study, even though NLR was higher in LAS (+) group, we did not observe independent correlation between NLR and presence of LAS (+) when RDW levels and clinical factors were included in multivariable regression model. Chronic inflammation could have a role in development of AF. It generates electrical and structural remodeling, forming substrate for development and persistence of arrhythmia. Ongoing rhythm disturbance with atrial endothelial destruction due to inflammation results in thrombus formation in LAA. In other words, severity of inflammatory status in LA may be correlated with risk of LA/LAA thrombus formation. Limitations There are some potential limitations with the present study. First of all, this was a retrospective study and demonstrates association of variables rather than cause-effect relationship. In addition, our findings do not describe clinical use of CBC parameters
72
in prediction of future thromboembolic events in patients with AF. Lack of parameters, especially iron/ferritin level, can be accepted as a limitation. Lack of parameters demonstrating inflammation other than CRP could also be considered a limitation of our study. Rate of LA/LAA thrombus formation was higher than seen in previous studies13,14. This finding may suggest that effectiveness and duration of anticoagulation was not adequate for resolution of thrombi at time of TEE examination. For further investigation of this topic, multicenter, prospective studies are warranted. Conclusion RDW is independent predictor of LAS in non-valvular AF in Turkish population. Larger prospective studies may reveal clinical use of CBC parameters, and especially RDW level, for defining cases with higher risk of LAS, embolization, and cerebrovascular events. Conflict of Interest: None declared. Financial Disclosure: The authors declared that this study has received no financial support. Authorship contributions: Concept – A.K., A.T.A., C.T., A.I.T; Design – A.K., B.G., K.S.O., M.A.T., O.K.; Supervision – O.K., G.G., F.O.K., M.A.T.; Materials – B.G., A.K., G.G., M.A.T., C.T., A.I.T., F.O.K.; Data collection &/or processing – A.K., C.T., A.I.T., A.T.A., F.O.K., G.G.; Analysis and/or interpretation – G.G., O.K., B.G., K.S.O., A.I.T.; Literature search – K.S.O., M.A.T., G.G., F.O.K., A.T.A., C.T.; Writing – A.K., B.G.; Critical review – A.T.A., B.G., A.I.T., O.K., K.S.O.
REFERENCES 1. Morady F, Zipes DP. Atrial fibrillation: clinical features, mechanisms and management. In: Braunwald E, Libby P, Bonow RO, Mann DL, Zipes DP, editors. Braunwald’s heart disease. A textbook of cardiovascular medicine. 9th ed. Philadelphia, PA: WB Saunders Company; 2012. p. 825–84. 2. Khoo CW, Krishnamoorthy S, Lim HS, Lip GY. Atrial fibrillation, arrhythmia burden and thrombogenesis. Int J Cardiol 2012;157:318–23. 3. Watson T, Shantsila E, Lip GY. Mechanisms of thrombogenesis in atrial fibrillation: Virchow’s triad revisited. Lancet 2009;373:155–66. 4. Lappé JM, Horne BD, Shah SH, May HT, Muhlestein JB, Lappé DL, et al. Red cell distribution width, C-reactive protein, the complete blood count, and mortality in patients with coronary disease and a normal comparison population. Clin Chim Acta
North Clin Istanb 2011;412:2094–9. 5. Felker GM, Allen LA, Pocock SJ, Shaw LK, McMurray JJ, Pfeffer MA, et al; CHARM Investigators. Red cell distribution width as a novel prognostic marker in heart failure: data from the CHARM Program and the Duke Databank. J Am Coll Cardiol 2007;50:40–7. 6. Tonelli M, Sacks F, Arnold M, Moye L, Davis B, Pfeffer M; for the Cholesterol and Recurrent Events (CARE) Trial Investigators. Relation Between Red Blood Cell Distribution Width and Cardiovascular Event Rate in People With Coronary Disease. Circulation 2008;117:163–8. 7. Klein AL, Grimm RA, Murray RD, Apperson-Hansen C, Asinger RW, Black IW, et al; Assessment of Cardioversion Using Transesophageal Echocardiography Investigators. Use of transesophageal echocardiography to guide cardioversion in patients with atrial fibrillation. N Engl J Med 2001;344:1411–20. 8. Scherr D, Dalal D, Chilukuri K, Dong J, Spragg D, Henrikson CA, et al. Incidence and predictors of left atrial thrombus prior to catheter ablation of atrial fibrillation. J Cardiovasc Electrophysiol 2009;20:379–84. 9. Kerut EK, Hanawalt C, McKinnie J. Transesophageal echocardiography during pulmonary vein cryoballoon ablation for atrial fibrillation. Echocardiography 2015;32:281–90. 10. Fatkin D, Loupas T, Jacobs N, Feneley MP. Quantification of blood echogenicity: evaluation of a semiquantitative method of grading spontaneous echo contrast. Ultrasound Med Biol 1995;21:1191–8. 11. Olesen JB, Lip GY, Hansen ML, Hansen PR, Tolstrup JS, Lindhardsen J, et al. Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study. BMJ 2011;342:d124. 12. Griffin BP. Manual of cardiovascular medicine. 13 th edition. Philadelphia PA: Lippincott Williams and Wilkins; 2013. p. 424. 13. Providência R, Ferreira MJ, Gonçalves L, Faustino A, Paiva L, Fernandes A, et al. Mean corpuscular volume and red cell distribution width as predictors of left atrial stasis in patients with non-valvular atrial fibrillation. Am J Cardiovasc Dis 2013;3:91– 102. 14. Zhao J, Liu T, Korantzopoulos P, Fu H, Shao Q, Suo Y, et al. Red blood cell distribution width and left atrial thrombus or spontaneous echo contrast in patients with non-valvular atrial fibrillation. Int J Cardiol 2015;180:63–5. 15. Förhécz Z, Gombos T, Borgulya G, Pozsonyi Z, Prohászka Z, Jánoskuti L. Red cell distribution width in heart failure: prediction of clinical events and relationship with markers of ineffective erythropoiesis, inflammation, renal function, and nutritional state. Am Heart J 2009;158:659–66. 16. Güngör B, Özcan KS, Erdinler İ, Ekmekçi A, Alper AT, Osmonov D, et al. Elevated levels of RDW is associated with nonvalvular atrial fibrillation. J Thromb Thrombolysis 2014;37:404– 10. 17. Canpolat U, Aytemir K, Yorgun H, Şahiner L, Kaya EB, Kabakçı G, et al. Role of preablation neutrophil/lymphocyte ratio on outcomes of cryoballoon-based atrial fibrillation ablation. Am J Cardiol 2013;112:513–9.
Orıgınal Article
GENERAL SURGERY
North Clin Istanb 2017;4(1):73–76 doi: 10.14744/nci.2017.08108
Acute biliary pancreatitis in cholecystectomised patients Fatih Ciftci,1 Turgut Anuk2 Department of General Surgery, Vocational School of Health Services, Istanbul Gelisim University, Istanbul, Turkey
1
Department of General Surgery, Kafkas University Faculty of Medicine, Kars, Turkey
2
ABSTRACT OBJECTIVE: The present study is an evaluation of cases of acute biliary pancreatitis that developed subsequent to cholecystectomy. METHODS: Total of 44 patients were assessed in this retrospective study. Demographic characteristics, severity of illness, time elapsed between cholecystectomy and development of pancreatitis, whether endoscopic sphincterotomy (ES) was performed, surgical procedure used, duration of hospitalization, and mortality data were recorded. RESULTS: Mean age of all patients was 60.14±16.4 years (range: 20–85 years), and female:male ratio was 28:16. Mean length of time elapsed between cholecystectomy and development of acute pancreatitis was 80.6 months (range: 5–230 months). Gallstones and biliary sand were found in the choledochi of 36 patients upon endoscopic retrograde cholangiopancreatography (ERCP), but not observed in the remaining 8 patients. ES was performed and material was extracted in 32 of the 36 patients, but stone extraction was unsuccessful in 4 cases; 3 patients underwent open surgery with choledochus exploration and 1 patient died. Excluding this patient, mean duration of hospitalization was 7.5±2.5 days. CONCLUSION: Stones in bile ducts may remain asymptomatic for long periods after cholecystectomy. However, some stones trigger acute pancreatitis months or years after cholecystectomy, causing risk of mortality. ERCP and ES are the standard treatments. If these are unsuccessful, the choledochus may be explored via open or laparoscopic surgery. Keywords: Acute biliary pancreatitis; cholecystectomy; endoscopic retrograde cholangiopancreatography; endoscopic sphincterotomy.
A
n international consensus conference defined acute pancreatitis (AP) as inflammation of pancreatic tissue affecting both adjacent and distant organ systems to varying degrees [1]. Gallbladder and bile duct stones cause 35% to 65% of all cases
of AP [2, 3]. Prevalence of stones in the choledochus of cholecystectomized patients is 2% to 15% [4, 5]. Incidence of acute biliary pancreatitis (ABP) has been well studied. In the present study, ABP patients who had previously undergone cholecystec-
Received: September 10, 2016 Accepted: February 10, 2017 Online: May 10, 2017 Correspondence: Dr. Fatih CIFTCI. Istanbul Gelisim Universitesi, Saglik Hizmetleri Meslek Yuksekokulu, 34306 Avcilar, Istanbul, Turkey. Tel: +90 212 - 422 70 00 e-mail: oprdrfatihciftci@gmail.com © Copyright 2017 by Istanbul Northern Anatolian Association of Public Hospitals–Available online at www.kuzeyklinikleri.com
74
tomy were evaluated and our clinical experience is described. MATERIALS AND METHODS Data of 44 patients with history of cholecystectomy who were diagnosed with ABP between September 2001 and December 2014 were retrospectively evaluated. Most of the patients had undergone cholecystectomy at our clinic; 4 had surgery in another clinic. During this time period, total of 4744 cholecystectomies were performed due to symptomatic cholelithiasis in our general surgery department. No choledocholithiasis or acute pancreatitis was detected at time of surgery. There was no history of biliary intervention prior to surgery. Four patients who had surgery at another clinic also had no history of intervention or pancreatitis. Among these 4744 patients, 3 cases with bile duct injury were managed via primary repair and T-tube placement. AP presentation included specific abdominal pain with increase in serum amylase level 3 times greater than reference range [6]. Ranson criteria were used to describe severity of illness; score below 3 reflects mild illness, while higher scores indicate severe disease [7]. Demographic characteristics, severity of illness, time elapsed between cholecystectomy and development of pancreatitis, whether endoscopic sphincterotomy (ES) was performed, surgical procedure used, duration of hospitalization, and mortality data were recorded. Etiological cause was determined by evaluating anamnesis, physical findings, and laboratory test results. ABP was diagnosed when AP was associated with laboratory findings of cholecystitis and concomitant radiological evidence of stones in the bile ducts [2]. Patients with extrabiliary causes of cholestatic jaundice and those who did not undergo cholecystectomy were excluded. Patients who developed AP within 3 months of cholecystectomy were also excluded due to possibility that AP was caused by stones overlooked during cholecystectomy [2]. Statistical analysis SPSS for Windows, Version 15.0 software (SPSS Inc., Chicago, IL, USA) was used to analyze de-
North Clin Istanb
Table 1. Demographic features Age (years) Gender (female/male) Time to development of pancreatitis after cholecystitis (days) ERCP + ES, n (%) Laparotomy + exploration of the choledochus, n (%) Mortality Hospitalization duration (days)* Mean amylase level (units/L) Mean choledochal diameter (mm)
60.14±16.4 (range: 20–85) 28/16 80.6 (5–230) 36 (81.8) 3 (6.8) 1 (2.2) 7.5±2.5 749±387 14.29±3.89
ERCP: Endoscopic retrograde cholangiopancreatography; ES: Endoscopic sphincterotomy. Mean±SD. *Excluding the patient who died.
scriptive statistics. Continuous variables are presented as mean±SD and categorical variables as percentages and numbers. RESULTS Mean patient age (44 patients) was 60.14±16.4 years (range: 20-85 years), and female:ratio was 28: 16. Based on Ranson criteria, 36 patients had mild AP and 8 cases were severe. Demographic characteristics, time elapsed between cholecystectomy and pancreatitis, duration of hospitalization, mortality rate, and treatment methods are provided in Table 1. Mean time elapsed from cholecystectomy to AP development was 80.6 months (range: 5–230 months). Mean amylase level was 749±387 U/L and mean choledochal diameter 14.29±3.89 mm. Stones and sand were found in the bile ducts of 24 patients using magnetic resonance cholangiopancreatography and/or in 20 on ultrasonography image. ERCP was performed in all patients. ES and stone extraction were successful in 32 of the 36 patients in whom the choledochus contained stones and sand. Two patients had impacted stones in the distal choledochus, and ERCP was unsuccessful. ES could not be performed in 2 other patients with large (>2 cm in diameter) stones in the choledochus and duodenal diverticula close to the papilla. Stones
Ciftci et al., Acute biliary pancreatitis in cholecystectomised patients
were not found in the remaining 8 patients, but their choledochi were wider than normal on ERCP. In 4 patients with no indications of periampullar tumor on ERCP or radiologically, it was thought stones might have fallen into the intestinal lumen and ES was performed. Laparotomy with insertion of T-tube was performed to explore the choledochus and clean the bile duct in 7 patients with stones that were not extracted during ERCP. One patient with impacted stones developed necrotizing pancreatitis. Necrosectomy with concomitant choledochal exploration, bile duct cleansing, and Ttube insertion was performed; however, the patient died from multiple organ failure associated with sepsis on day 48 of hospitalization after completion of scheduled re-laparotomy and peritoneal lavage. Excluding this patient, mean duration of hospitalization was 7.5±2.5 days. DISCUSSION Data on prevalence and severity of ABP in patients who have undergone cholecystectomy are limited. In published studies, 2% to 15% of patients had bile duct stones after open and laparoscopic cholecystectomies [4, 5, 8, 9]. Some stones remain asymptomatic, but others trigger potentially fatal AP months, or even years, after cholecystectomy. One study found that rate of symptomatic choledochus stones was 2.5% [4]. Another study of 278 AP patients found that 10% developed ABP subsequent to cholecystectomy; illness tended to be severe, and the patients required referral to tertiary medical care center [2]. The cited authors reported mean of 4 years between cholecystectomy and ABP [2]. In the present study, mean elapsed time was 80.6 months (range: 5–230 months). An earlier study at another clinic followed annual average of 100 AP cases [10]. In the 13-year period of the current study, 44 cases of postcholecystectomy ABP constituted 2% of all AP cases. ERCP and ES are standard approaches used for treatment of patients with choledochal stones subsequent to cholecystectomy. However, some authors have reported that these techniques are unsuccessful approximately 10% of the time [4, 10–13].
75
When ERCP and ES fail, laparoscopic or open surgery and choledochal exploration is the approach of choice [4, 11]. In our study, ERCP and ES were unsuccessful in 9.1% of cases. This rate is similar to that of previous reports. These patients underwent open surgery with choledochus exploration and T-tube insertion. Duodenal diverticula have been reported to be significant trigger of recurrent ABP subsequent to cholecystectomy. One study found that 15-year frequency of bile disease in cases with duodenal diverticula was 10.2% [14]. Gloor et al. reported ABP recurrence frequency of 8% in postcholecystectomy patients with duodenal diverticula [2]. In our series, prevalence of such diverticula was 4.5%. A previous study found that ABP was more frequent after cholecystectomy in patients with choledochal diameter greater than 10 mm [15–19]. In our series, choledochal diameter of all patients was greater than normal. Presentation of ABP following cholecystectomy ranges from mild edematous pancreatitis to clinically severe necrotizing pancreatitis; rate of severe disease was reported to be 61.5% [2, 20, 21]. In one study, rate of pancreatic necrosis among those with severe pancreatitis was 50% and mortality was 8%. Severe pancreatitis was evident in 4 patients (9.1%) in our study. One patient developed pancreatic necrosis (25%) and ultimately died of sepsis and multiple organ failure. In conclusion, stones in the bile ducts should be considered possible cause of AP developing after cholecystectomy. Although some stones remain asymptomatic for a long period after cholecystectomy, others may predispose patients to potentially fatal AP. In such cases, ERCP and ES are standard treatment approaches. If these techniques are unsuccessful, laparoscopic or open surgery with choledochus exploration may be subsequent alternative. Conflict of Interest: None declared. Financial Disclosure: The authors declared that this study has received no financial support. Authorship contributions: Concept – F.C.; Design – F.C.; Supervision – F.C.; Materials; F.C., T.A.; Data collection/or processing – F.A., T.A.; Analysis and/or interpretation – F.C., T.A.; Literature search – F.C.; Writing – F.C.; Critical review – F.C.
76
REFERENCES 1. Bradley EL 3rd. A clinically based classification system for acute pancreatitis. Summary of the International Symposium on Acute Pancreatitis, Atlanta, Ga, September 11 through 13, 1992. Arch Surg 1993;128:586–90. 2. Gloor B, Stahel PF, Müller CA, Worni M, Büchler MW, Uhl W. Incidence and management of biliary pancreatitis in cholecystectomized patients. Results of a 7-year study. J Gastrointest Surg 2003;7:372–7. 3. Gül M, Aliosmanoğlu, Türkoğlu A, Uçmak F, Ülger BV, Oğuz A, et al. Kolesistektomili hastalarda akut biliyer pankreatit. 2012; 28:186–8 4. Alexakis N, Lombard M, Raraty M, Ghaneh P, Smart HL, Gilmore I, et al. When is pancreatitis considered to be of biliary origin and what are the implications for management? Pancreatology 2007;7:131–41. 5. Cox MR, Budge JP, Eslick GD. Timing and nature of presentation of unsuspected retained common bile duct stones after laparoscopic cholecystectomy: a retrospective study. Surg Endosc 2015;29:2033–8. 6. Potter MW, Shah SA, McEnaney P, Chari RS, Callery MP. A critical appraisal of laparoscopic staging in hepatobiliary and pancreatic malignancy. Surg Oncol 2000;9:103–10. 7. Toouli J, Brooke-Smith M, Bassi C, Carr-Locke D, Telford J, Freeny P, et al. Guidelines for the management of acute pancreatitis. J Gastroenterol Hepatol 2002;17 Suppl:S15–39. 8. Yanar F, Alış H. Akut pankreatitlerin prognozunun belirlenmesinde skorlama sistemlerinin rolü. Turkiye Klinikleri J Gen Surg-Special Topics 2011;4: 43–7. 9. Rogers AL, Farha GJ, Beamer RL, Chang FC. Incidence and associated mortality of retained common bile duct stones. Am J Surg 1985;150:690–3. 10. Braghetto I, Debandi A, Korn O, Bastias J. Long-term follow-up after laparoscopic cholecystectomy without routine intraoperative cholangiography. Surg Laparosc Endosc 1998;8:349–52.
North Clin Istanb 11. Anwar S, Rahim R, Agwunobi A, Bancewicz J. The role of ERCP in management of retained bile duct stones after laparoscopic cholecystectomy. N Z Med J 2004;117:U1102. 12. Chiappetta Porras LT, Nápoli ED, Canullán CM, Quesada BM, Petracchi JE, Oría AS. Laparoscopic bile duct reexploration for retained duct stones. J Gastrointest Surg 2008;12:1518–20. 13. Leese T, Neoptolemos JP, Carr-Locke DL. Successes, failures, early complications and their management following endoscopic sphincterotomy: results in 394 consecutive patients from a single centre. Br J Surg 1985;72:215–9. 14. Williams EJ, Green J, Beckingham I, Parks R, Martin D, Lombard M; British Society of Gastroenterology. Guidelines on the management of common bile duct stones (CBDS). Gut 2008;57:1004–21. 15. Mackenzie ME, Davies WT, Farnell MB, Weaver AL, Ilstrup DM. Risk of recurrent biliary tract disease after cholecystectomy in patients with duodenal diverticula. Arch Surg 1996;131:1083–5. 16. Grönroos JM, Haapamäki MM, Gullichsen R. Effect of the diameter of the common bile duct on the incidence of bile duct stones in patients with recurrent attacks of right epigastric pain after cholecystectomy. Eur J Surg 2001;167:767–9. 17. Billi P, Barakat B, D’Imperio N, Pezzilli R. Relapses of biliary acute pancreatitis in patients with previous attack of biliary pancreatitis and gallbladder in situ. Dig Liver Dis 2003;35:653–5. 18. Scheurer U. Acute pancreatitis--ERCP/endoscopic papillotomy (EPT) yes or no? Swiss Surg 2000;6:246–8. 19. Peterlejtner T, Szewczyk T, Firkowski P, Zdrojewski M. Endoscopic treatment of the choledocholithiasis--effectiveness, safety and limitations of the method. Pol Przegl Chir 2012;84:333–40. 20. Kohut M, Nowak A, Nowakowska-Duiawa E, Marek T. Presence and density of common bile duct microlithiasis in acute biliary pancreatitis. World J Gastroenterol 2002;8:558–61. 21. Singh VK, Moran RA, Afghani E, de-Madaria E. Treating acute pancreatitis: what’s new? Expert Rev Gastroenterol Hepatol 2015;9:901–11.
Original Images
DERMATOLOGY
North Clin Istanb 2017;4(1):77 doi: 10.14744/nci.2017.77598
Giant neglected Bowen’s disease lesion treated successfully with topical 5-fluorouracil Emin Ozlu,1 Ragıp Ertas,1 Kemal Ozyurt,1 Yucel Tekin,2 Mustafa Atasoy1 Department of Dermatology, Kayseri Training and Research Hospital, Istanbul, Turkey
1
Department of Pathology, Kayseri Training and Research Hospital, Kayseri, Turkey
2
A
B
C
D
Figure 1.
(A) Pretreatment appearance of giant plaque lesion. (B) Full thickness atypia in the epidermis, a loss of polarity, dyskeratotic cells (HE x200). (C) Posttreatment appearance of giant plaque lesion. (D) Disappearance of atypia and mild chronic inflammation (HE x10).
Bowen’s disease is in situ squamous carcinoma of the skin, mostly affecting sun-exposed areas of the body. There are many options in the treatment of Bowen’s disease, with varying success rates. Five-fluorouracil (5-FU) inhibits DNA synthesis and causes death of tumor cells by targeting rapidly proliferating cells. Topical 5-FU has been used effectively in the treatment of Bowen’s disease. The current report describes case of giant neglected Bowen’s disease lesion in a male patient, which was successfully treated with 5-fluorouracil therapy. A 62-year-old male patient presented at our clinic complaining of erythema and scaling. The patient had lesion that had enlarged over course of 7 years. Dermatological examination revealed infiltrative red-brown plaque with oval-round shape and welldefined and irregular margins on left lateral side of the body, measuring 13x13 cm in size with patchy crust and scaling (Figure 1A). Histopathological examination of punch biopsy material demonstrated
disruption of polarity in all layers of epidermis, mildmoderate atypia, multiple dyskeratotic cells, increased mitotic activity, and moderate-severe mononuclear infiltration in the upper layer of dermis. Integrity of basement membrane was preserved without invasion (Figure 1B). The patient was diagnosed with Bowen’s disease and treatment with topical 5-FU 5% applied twice daily was initiated. Skin ulcer developed at the site of plaque lesion 1 month after initiation of therapy, and therefore therapy was discontinued. Two months after cessation of therapy, infiltrated plaque had disappeared and lesion showed near-complete regression (Figure 1C). Skin biopsy materials obtained from 3 different areas at the site of plaque lesion 1 year after therapy indicated that epidermal atypia had completely disappeared, polarity had been restored, and there was no finding in favor of Bowen’s disease (Figure 1D). Clinicians should not overlook effective nonsurgical treatment methods, such as topical 5-FU, in cases of Bowen’s disease.
Received: January 31, 2017 Accepted: March 09, 2017 Online: May 10, 2017 Correspondence: Dr. Emin OZLU. Kayseri Egitim ve Arastirma Hastanesi, Dermatoloji Klinigi, Kayseri, Turkey. Tel: +90 352 - 336 88 88 e-mail: dermatologg@gmail.com © Copyright 2017 by Istanbul Northern Anatolian Association of Public Hospitals - Available online at www.kuzeyklinikleri.com
Case Report
GENERAL SURGERY
North Clin Istanb 2017;4(1):78–80 doi: 10.14744/nci.2015.87609
A condition that should be kept in mind in incarcerated hernia: Amyand’s hernia Mehmet Bugra Bozan,1 Fatih Mehmet Yazar,1 Fatih Erol,1 Evrim Gul,2 Omer Dogan Alatas2 Department of General Surgery, Elazig Training and Research Hospital, Elazig, Turkey
1
Department of Emergency Clinic, Elazig Training and Research Hospital, Elazig, Turkey
2
ABSTRACT As a complication of inguinal hernia, incarcerations are often seen in emergency services. Incarceration is an acute complication of inguinal hernia presenting as surgical emergency. The sac of inguinal hernia most frequently contains omentum and intestine but sometimes organs such as appendix and Meckel’s diverticulum can also be seen in the hernial sac. We present a case of Amyand’s hernia containing appendix in the incarcerated herniated sac. Keywords: Amyand’s hernia; groin hernia; incarseration.
E
mergency cases are an important aspect of surgical practice. Hernia is displacement of intraabdominal tissues and organs through a weak point in the abdominal wall [1]. Incarceration is an acute complication of inguinal hernias. Most common contents of hernial sac include omentum, and intestines but. Cladius Amyand was first to described the presence of an appendix in the hernia sac, a condition coined after him. Amyand’s hernia is not very commonly seen condition representing 0.07–0.13% of all inguinal hernias [2, 3]. In this paper we describe a case of appendix present in incarcerated inguinal hernia. CASE REPORT A 35-year-old patient who presented at the emergency room with complaints of pain localized to
the right inguinal region, nausea, and vomiting for 3 days with no bowel complaints. On physical examination a painful, irreducible swelling was noted on the right inguinal region. Examination of other systems yielded normal results. His lab results showed leucocytosis (13290/mm3). With no other abnormal finding. Plain abdominal radiograms obtained in the standing position did not reveal any pathology. Superficial tissue ultrasound of the inguinal region obtained under emergency conditions detected a hernia sac containing mesenterium, intestinal loopsand a blind-ended tubular structure with a diameter of 6 mm which was ruled in favor of an appendix. The patient was operated in emergency preoperatively a single dose of 1 g cefazolin was administered IV. A right inguinal oblique incision was
This case report was presented at the International Critical Care and Emergency Medicine Congress, held at Istanbul, 06–08 November 2013.
Received: October 11, 2014 Accepted: September 01, 2015 Online: May 10, 2017 Correspondence: Dr. Mehmet Bugra BOZAN. Elazig Egitim ve Arastirma Hastanesi, Genel Cerrahi Klinigi, 23100 Elazig, Turkey. Tel: +90 424 - 238 10 00 e-mail: bbozan@yahoo.com © Copyright 2017 by Istanbul Northern Anatolian Association of Public Hospitals - Available online at www.kuzeyklinikleri.com
Bozan et al., A condition that should be kept in mind in incarcerated hernia: Amyand’s hernia
79
sac was repaired and Lichtenstein herniorraphy was performed using prolene mesh. The postoperative period was uneventful was patient was discharged in good health. DISCUSSION
Figure 1. Appendix in the hernia sac (white arrow, hernia sac; yellow arrow, appendiceal tissue). used to isolate the hernia sac. On opening the sac mesentery of appendix was found adherent to the hernia sac along with herniation of appendix and intestinal loops (Figure 1). Appendix was intact (Figure 1). Appendectomy was performed, hernial
Incareceration as an acute complication of inguinal hernia is often seen as surgical emergency. Omentum and intestine are common present in the hernia sac but different organs can also be seen in hernia sac (e.g., appendix, Meckel’s diverticulum) [4]. Cladius Amyand was first to described the presence of appendix in the inguinal hernia sac, a condition named after him as Amyand’s hernia. It is a rare condition constituting 1% of all types of inguinal hernias and presence of inflamed appendiceal tissue is not a prerequisite for its diagnosis [2, 3]. In our case also appendiceal tissue was herniated, but not inflammed. Adhesions formed in the hernia sac causes the appendix to remain in the hernia sac [5]. In our case, herniation of appendiceal tissue was due to retraction of appendiceal mesentery by adhesion formation which pulled the appendix in the sac. As all inguinal hernias, Amyand’s hernia is more frequently observed in males [3, 5], our case was also a 35-year-old male patient. Though definitive diagnosis is generally made during intraoperative period, ultrasound, and abdominal computed tomography can aid in diagnosis preoperatively, as the case presented here [5].
Table 1. Types of Amyand’s hernia according to Losanoff and Basson, and their treatment [5] Classification
Definition
Type 1 Intact appendix in inguinal hernia sac Type 2 Acute appendicitis in inguinal hernia sac without abdominal sepsis Type3 Acute appendicitis in inguinal hernia sac and abdominal wall or peritoneal sepsis Type4 Acute appendicitis in inguinal hernia sac, and presence of related or unrelaated abdominal pathology
Surgical Approach Reduction of inguinal hernia; hernia repair using mesh; appendectomy in young patients Appendectomy through inguinal hernia repair site; primary repair of the hernia without using mesh Laparatomy, appendectomy, primary hernia repair without using mesh Apply treatment plans recommended for Type1-3; in case of need apply any other necessary treatment modality
80
The differential diagnosis of Amyand’s hernia and inguinal hernias includes testicular torsion, acute epididymitis, acute hydrocele, and inguinal lymphadenitis. Treatment options are based on the severity of appendiceal inflammation. Generally, if the appendix is not inflamed, hernia repair can be performed using synthetic mesh. If inflammation is present hernia repair is performed without using synthetic meshes through inguinal or other abdominal incisions as per the recommendations. With this approach, it is thought that potential complications of surgical site infection (SSI), mesh infections, and fistula formation can be prevented. Thus, appendectomy is performed in the presence of inflammation, while in cases without inflammation, appendectomy is debatable. According to Losanof ve Basson if appendiceal inflammation is not present, then reduction of the hernia sac, and in young patients, appendectomy, and hernia repair with synthetic mesh are recommended. Table 1 in our case, since the patient was young, appendectomy was performed despite benign nature of the appendix [5]. Inflammation was not observed herniorrhaphy using mesh was performed. Conclusion Incarcerated inguinal hernias which can confront us in emergency services are among conditions which
North Clin Istanb
should be carefully considered. As was seen especially in this case, physician practicing in emergency services, and general surgeons should not overlook the potential presence of different organs such as appendix in incarcerated hernial sac. Conflict of Interest: None declared. Financial Disclosure: The authors declared that this study has received no financial support. Authorship contributions: Concept – M.B.B., F.M.Y., F.E.; Design – M.B.B., F.E.; Supervision – E.G., O.D.A.; Materials – M.B.B.; Data collection &/or processing – M.B.B., E.G.; Analysis and/or interperation: M.B.B., F.E.; Literature search – M.B.B.; Writing – M.B.B.; Critical review – M.B.B., F.M.Y.
REFERENCES 1. Ersoy E, Tekin E, Condon R. Karın Duvarı Fıtıkları. In: Sayek İ (Ed.) Temel Cerrahi. 4. Baskı. Güneş Tıp Kitabevleri: Ankara; 2013: s. 1803–24. 2. Sharma H, Gupta A, Shekhawat NS, Memon B, Memon MA. Amyand’s hernia: a report of 18 consecutive patients over a 15year period. Hernia 2007;11:31–5. 3. Milanchi S, Allins AD. Amyand’s hernia: history, imaging, and management. Hernia 2008;12:321–2. 4. Bendavid R. The unified theory of hernia formation. Hernia 2004;8:171–6. 5. Singal R, Gupta S. “Amyand’s Hernia” - Pathophysiology, Role of Investigations and Treatment. Maedica (Buchar) 2011;6:321–7.
Case Report
FAMILY MEDICINE
North Clin Istanb 2017;4(1):81â&#x20AC;&#x201C;84 doi: 10.14744/nci.2016.07769
Systemic juvenile idiopathic arthritis as a fever of unknown origin Cigdem Hardal,1 Muferet Erguven,2 Zuhal Aydan Saglam1 Department of Family Medicine, Istanbul Medeniyet University Goztepe Training and Research Hospital, Istanbul, Turkey
1
Department of Pediatrics, Istanbul Medeniyet University Goztepe Training and Research Hospital, Istanbul, Turkey
2
ABSTRACT Juvenile idiopathic arthritis (JIA) is a rare inflammation with still unidentified cause. It can also be cause of fever of unknown origin. Diagnosis is made by eliminating infection, malignancy, and rheumatological diseases. In this report, case of a 5-year-old patient with symptoms of intermittent fever, areas of rash on the body, itching, and swelling, redness, and pain in the right and left ankle is described. Serological test results were negative for infectious agents, and malignancy was excluded. Patient was diagnosed with systemic JIA associated with intermittent fever, negative rheumatological markers and negative serology test results. Treatment with methylprednisolone and methotrexate yielded positive clinical response. Diagnosis of systemic JIA can be challenging, and must be made by eliminating other diseases. Keywords: Arthritis; cause of fever of an unknown orgin; systemic JIA.
S
ystemic JIA is a rarely seen inflammatory disease of unknown etiology characterized by high fever and extraarticular findings. Diagnosis is made by eliminating malignancy and other rheumatological diseases [1]. Incidence of systemic JIA varies from country to country [2, 3]. Average incidence and prevalence rates detected range between 0.92 to 2.5/100.000 and 1.2 to 11.3/100.000, respectively. Systemic JIA has no pathognomonic sign; diagnosis is made by ruling out etiological factors such as collagenous tissue disease and infection. Though its
etiopathogenesis is not precisely known, 2 primary etiologies have been emphasized: immunological predisposition and environmental factors. Among environmental influences, infection is most frequently thought to be significant, but stress and trauma are also considered to have important roles in etiology [1]. Presently described is case of a 5 year-old patient with symptoms including swelling, redness and pain in the right and left ankles. Following tests and clinical follow-up, patient was diagnosed as systemic JIA.
Received: June 23, 2015 Accepted: May 07, 2016 Online: May 10, 2017 Correspondence: Dr. Cigdem HARDAL. Medeniyet Universitesi Goztepe Egitim ve Arastirma Hastanesi, Aile Hekimligi Klinigi, Istanbul, Turkey. Tel: +90 216 - 566 40 00 e-mail: drhardal@gmail.com Š Copyright 2017 by Istanbul Northern Anatolian Association of Public Hospitals - Available online at www.kuzeyklinikleri.com
North Clin Istanb
82
CASE REPORT A 5-year-old female child was brought to outpatient clinic with complaints of rash and itching on her body, and swelling, redness, and pain in both ankles. Detailed anamnesis revealed that itching and redness on her elbows and knees had appeared 3 weeks earlier and she had received treatment for allergy at another medical facility. For 3 weeks she had periods of fever, during which rash had spread all over her body. Right and left ankles then became red and swollen. The patient was admitted to investigate etiology of fever of unknown origin. Vital signs were: body temperature, 36.5°C; pulse rate, 80/bpm; respiratory rate, 17/min; arterial blood pressure, 90/60 mmHg. On physical examination, rash and swelling on both ankles and maculopapullary skin eruptions all over the body, and particularly on extremities, were observed (Figure 1). Biochemical parameters of the patient included: white blood cell count (WBC), 10.8x103/uL; hemoglobin (Hb), 9.8 gr/dL; platelets, 521x103/uL; aspartate transaminase, 21 U/L; alanine transaminase, 8 U/L; erythrocyte sedimentation rate (ESR), 103 mm/h; C-reactive protein (CRP), 7.82 mg/ dL (<0.5); ferritin, 382 ng/mL; fibrinogen, 644.92 mg/dL (200–400); D-dimer, 1.88 mg/mL (0–0.5); and prothrombin time, 14.7 s (11–14). To rule out malignancy, bone marrow aspiration was performed. Malignancy was not detected, and histopathology was reported as infection or collagenase. No pathogenetic agent was detected in urine or blood cultures. Serological tests yielded negative results for mycoplasm, chlamydia, toxoplasm, rubella, and collagen tissue disease markers (anti-double strand DNA, anti-smooth muscle antibody, antimitochondrial antibody, anti-Sjogren’s syndrome A and B, and anti-Sm antibody). Rheumatoid factor (RF) was 9.94 IU/mL (<19). Following all tests, diagnosis of juvenile idiopathic arthritis was made based on consideration of available anamnesis and clinical and laboratory findings. Steroid treatment at daily dose of 30 mg/kg was initiated. After 3 days of pulsed methylprednisolone treatment, steroid maintenance treatment (methylprednisolone) at daily dose of 2 mg/kg was initiated. The patient did not experience febrile episode after initiation of steroid therapy. On sixth day of treatment, painful rash appeared on right and left ankles. Methotrex-
Figure 1.
Rash was observed on upper extremity of the patient.
ate at dose of 10 mg/m2 was added to the treatment. On 10th day, some notable hematological parameters were as follows: Hb, 10 gr/dL; platelet count, 713x103/uL; CRP, 1.61; and ferritin 51 ng/mL. Biochemical parameters were within normal limits. On 14th day of treatment, her body temperature rose and her state of general health deteriorated. CRP level increased to 6.78 mg/dL. Pulsed steroid (methylprednisolone) treatment at daily dose of 30 mg/kg was repeated for 3 more days followed by maintenance treatment at daily dose of 2 mg/kg. During follow-up, CRP was measured at 0.33 mg/ dL, and ESR regressed to 20 mm/hr. General state of the patient improved and she was discharged, with treatment to be maintained on ambulatory basis. At third month, treatment of 8 mg/d methylprednisolone and methotrexate at weekly dose of 10 mg/m2 continued. DISCUSSION In developed countries, 10% to 20% of patients with JIA develop systemic JIA; in our country, it is the largest JIA subgroup. It is characterized by intermittent high fever and other extraarticular symptoms. No gender difference has been reported. Although children may be affected at any age, generally they are younger than 4 years of age. Characteristic feature is fever of up to 39.5°C occurring once or twice a day before returning to normal or even below normal level [4]. In these patients, as was the
Hardal et al., Systemic juvenile idiopathic arthritis as a fever of unknown origin
case with our patient, temperature frequently peaks once in the morning and once at night. In most patients, pink-colored, occasionally itchy, and typically macular eruptions with pale center measuring less than 1 cm appear on the body, most often on the trunk and proximal part of the extremities, and then spontaneously resolve with drop in body temperature [4]. Rash may lead to misdiagnosis of allergy. Febrile peaks may not be typical at onset of disease and may occur after onset of treatment. In our patient, interval between onset of fever and establishment of diagnosis of systemic JIA was approximately 3 weeks, during which time fever was not under control and was therefore evaluated as fever of unknown origin [4]. Other systemic findings include fatigue, somnolence, irritability, and muscle pain. These symptoms are generally seen during episodes of fever and resolve with decrease in body temperature. In many patients, marked myalgia, arthralgia, or transient arthritis may be seen, especially during febrile episodes. These signs also regress with drop in body temperature [5]. As in present case, most often knee, elbow, ankle, wrist, or hip joints are affected; however, any small joint may be involved [4, 5]. Occasionally, the disease can recur as attacks without any clinical manifestation (fever, rash) apart from systemic symptoms. Less frequently, the disease can include tenosynovitis, synovial cyst, peritonitis, valvulitis with or without myocarditis, pulmonary parenchymal disease, central nervous system or renal involvement, stridor due to involvement of cricoarytenoid joint, or lymphedema. In nearly one-third of patients, significant lymphadenopathy and/or hepatosplenomegaly is seen [4]. In our patient, lymphadenopathy and hepatosplenomegaly were not detected. Depending on the inflammatory process, mild increase in hepatic enzymes may occur during active period of the disease. In nearly 50% of the patients with pleurisy, and especially those with pericarditis, level of hepatic enzymes is increased. However, most patients are asymptomatic. Pericarditis and myocarditis respond very rapidly to steroid treatment. Arthritis may accompany these symptoms or manifest weeks or months later and may complicate diagnosis [6, 7]. In patients with systemic JIA, marked leukocytosis with left shift may be seen. WBC count may exceed 100.000/mm3 [4].
83
In our patient, count was 10.800/mm3. As was the case with presently described patient, elevation of CRP, ferritin, C3, and C4 levels, and pronounced normocytic-normochromic or microcytic-hypochromic chronic anemia may be present. In 40% of patients, significant anemia is seen. Anemia may be related to iron deficiency, inadequate nutrition, or gastrointestinal loses due to medications [6]. In almost all cases of systemic-onset JIA, anti-nuclear antibody and RF are negative [4, 7]. ESR increases markedly, and in most cases, exceeds 100 mm/h. Consumptive coagulopathy and serious deterioration of hepatic functions may be seen. Ferritin level, which is acute phase marker, may increase significantly. Increased sedimentation rate with other signs of chronic inflammation, and normal or low platelet count should suggest alternative diagnosis (leukemia, sepsis) or JIA complicated by consumptive coagulopathy. Moderate degree of coagulopathy is frequently observed in patients with systemic arthritis. In small number of patients, macrophage activation syndrome (MAS), or hemophagocytic syndrome, may develop. MAS is a life-threatening disease [1, 6]. It has also been reported in patients with polyarthritis, and it has been suggested that development may be due to use of nonsteroidal anti-inflammatory drugs (NSAIDs), intramuscular gold preparations, or sulphasalazine. Patient need not be in typical systemic-onset period for MAS to be observed. These patientsâ&#x20AC;&#x2122; symptoms include chronic fever, hepatosplenomegaly, lymphadenopathy, and encephalopathy. Definitive diagnosis is made based on bone marrow aspiration findings and demonstration of hemophagocytosis in tissue cultures [6, 7]. Generally, uveitis is not seen in patients with systemic JIA. Secondary AA-type amyloidosis is an important potential complication of the disease. Although it is rarely seen in the USA, it is reportedly observed in 5% of patients in Europe [1]. As indicated in a study conducted by Ozdogan et al., in our country, incidence of uveitis decreased from 10% to 5% due to greater use of therapeutic agents and closer monitoring of patients [8]. In our case, inability to detect any etiological agent in serological or microbiological examination, negative collagenous tissue markers, exclusion of malignancy, and finally, response elicited by steroid
North Clin Istanb
84
therapy established diagnosis of systemic JIA. Previously, pyramid approach had been recommended in treatment planning. As first-line treatment, aspirin or NSAIDs were used, followed months later by antimalarials, gold salts, or Dpenicillamine [4]. Now, however, this treatment approach has been abandoned. Current treatment strategy inverts previous pyramid: • Corticosteroid treatment 1–2 mg/kg/d • Intense, high dose steroid (30 mg/kg/dose) • Methotrexate (10–20 mg/m2/wk) • If increased dose does not generate treatment response, then etanercept and infliximab are added to treatment [1]. In conclusion, though rarely seen, systemic JIA is an important disease to be considered in patients who present with fever of unknown origin, multisystem involvement, and joint complaints, in particular. Better understanding of this disease will enable us to detect new cases more easily. Conflict of Interest: None declared. Financial Disclosure: The authors declared that this study has received no financial support.
Authorship contributions: Concept – C.H., M.E.; Design – C.H., M.E., ZAS; Supervision – ME; Materials – ME; Data collection &/or processing – C.H., ZAS; Analysis and/or interpretation – C.H., M.E., Z.A.S; Literature search – ZAS; Writing – C.H., ZAS; Critical review – M.E, Z.A.S.
REFERENCES 1. Petyy RE, Cassidy JT, Chronic arthritis. In: Cassidy JT, Petty RE. editors. Textbook of Pediatrik Rheumatology. 5th ed. Elsevier Saunders; 2005: p. 206–341. 2. Fink CW, Fernandez-Vina M, Stastny P. Clinical and genetic evidence that juvenile arthritis is not a single disease. Pediatr Clin North Am 1995;42:1155–69. 3. Graham TB, Glass DN. Juvenile rheumatoid arthritis: ethnic differences in diagnostic types. J Rheumatol 1997;24:1677–9. 4. Neyzi O, Ertuğrul T. Pediatri. 2. Baskı. Nobel Tıp Kitabevleri: İstanbul; 1993. s. 329–35. 5. Isenberg D, Maddison P, Woo P, Glass D, Breedveld F. editors. Oxford Textbook of Rheumatology. 3th ed. Oxford University Press: London; 2004. 6. Woo P, Laxer RM, Shery DD. Klinik Uygulamada Pediyatrik Romatoloji. Kasapçopur Ö. çeviri ed. Deomed Yayıncılık: İstanbul; 2009. 7. Kasapçopur Ö, Özdoğan H. Jüvenil idyopatik artrit. Türkiye Klinikleri J Pediatr Sci 2008;4:31–42 8. Ozdogan H, Kasapçopur O, Dede H, Arisoy N, Beceren T, Yurdakul S, et al. Juvenile chronic arthritis in a Turkish population. Clin Exp Rheumatol 1991;9:431–5.
Case Report
PSYCHIATRY
North Clin Istanb 2017;4(1):85–88 doi: 10.14744/nci.2015.82574
Priapism associated with the addition of risperidone to methylphenidate monotherapy: a case report Hatice Unver,1 Nursu Cakin Memik,1 Emrah Simsek2 Department of Child and Adolescent Psychiatry, Kocaeli University Faculty of Medicine, Kocaeli, Turkey
1
Department of Urology, Kocaeli University Faculty of Medicine, Kocaeli, Turkey
2
ABSTRACT Priapism is a state of prolonged and unwanted erection without sexual stimulation or desire. Priapism may occur with a variety of diseases or as a side effect of medication. Immediate diagnosis and treatment is essential, as ischemia of cavernous tissues results in erectile dysfunction. Described in the present report is a 12-year-old male with priapism associated with the addition of risperidone to methylphenidate monotherapy. Priapism decreased and disappeared following discontinuation of drug therapy and implementation of cavernous drainage. To our knowledge, the present is the first report to describe priapism associated with the addition of risperidone to methylphenidate monotherapy. It is hoped that attention will be drawn to the risk of priapism caused by the combination of these psychopharmacologic agents. Key words: Methylphenidate; priapism; risperidone.
P
riapism is defined as persistent, painful, abnormal tumescence that occurs without sexual stimulation and does not subside after sexual intercourse or masturbation [1]. The condition was named after Priapus, a mythical hero known as the god of fertility, the son of Aphrodite and Dionysus, whose oversized, permanent erection was viewed as a symbol of masculinity and power [2]. Priapism can occur at any age. Sickle cell anemia, malignancy, and perineal trauma are the most common causes of priapism in children and adolescents [3]. Priapism can lead to permanent and irre-
versible erectile dysfunction, urinary retention, and gangrene [1, 3], as well as impotence in 40–50% of patients, due to ischemia and fibrosis developing in the corpus cavernosum [4]. A large and increasing number of drugs reportedly cause the condition, including anticoagulants, antihypertensives, antidepressants, anxiolytics, antipsychotics, intracavernous drugs, alcohol, and narcotics such as cocaine and marijuana [1, 3–6]. Priapism is connected to the mechanism of alpha-1 receptor blockade. Traditional alpha-1 receptor blockers such as prazosin are known to cause
This article was presented as a poster at the 5th International Congress on Psychopharmacology in 2013.
Received: March 23, 2015 Accepted: August 02, 2015 Online: May 10, 2017 Correspondence: Dr. Hatice UNVER. Kocaeli Universitesi Tip Fakultesi, Cocuk ve Ergen Psikiyatrisi Anabilim Dali, Kocaeli, Turkey. Tel: +90 262 - 303 87 02 e-mail: drhaticeunver@gmail.com © Copyright 2017 by Istanbul Northern Anatolian Association of Public Hospitals - Available online at www.kuzeyklinikleri.com
North Clin Istanb
86
priapism. Trazodone is the psychotropic medication most commonly associated with priapism, with an incidence of 1 in 6000 [7]. To our knowledge, the present is the first report to describe priapism associated with methylphenidate and risperidone treatment, though 7 cases of priapism in adolescents taking psychotropic medications have been reported. The condition has occurred in adolescents taking risperidone and paroxetine, risperidone and lithium, olanzapine and methylphenidate, risperidone monotherapy, oxcarbazepine in combination with aripiprazole and lithium, osmotic controlled-release methylphenidate hydrochloride, and immediate-release methylphenidate [5â&#x20AC;&#x201C;13]. The case of a 12-year-old patient who developed priapism after using methylphenidate and risperidone is described in the present report. CASE REPORT Four years prior to the submission of the present report, the patient, then 8 years old, was diagnosed with attention deficit-hyperactivity disorder and treatment of OROS methylphenidate 18 mg/day was initiated, taken in the morning. Dosage was increased to 27, 36, and 54 mg due to unsatisfactory clinical response, and dosage of 54 mg/day has been taken for the past 1.5 years. Risperidone 0.5 mg/day was added due to the development of symptoms of behavioral disorder. A week after the addition, dosage of risperidone was increased to 2 x 0.5 mg/day due to unsatisfactory clinical response. Drugs were taken consistently. On the 22nd day of treatment, the patient developed a painful erection upon waking, without sexual stimulation. Three hours later, the patient was admitted by emergency services and underwent cavernous drainage, after which slow infusion of 10% diluted epinephrine was injected into the corpus cavernosum to reduce pain and erection. Blood flow improved, however, the patient experienced a second erection while still in the hospital, and drainage was repeated, after which the erection improved. Though a third erection did occur, blood flow was normal, and surgical intervention was not necessary. Shunt surgery was not attempted, due to the age of the patient. Medical treatment was terminated after hospital admis-
sion. The patient was discharged the day after the procedure with a 50% improvement in his erection. However, when the patient was admitted for control on the 3rd and 5th day after discharge, an erection of 50% was present. The erection disappeared on the 7th day after initial discharge. Upon investigation, the patient was found to have taken no illicit drug or unprescribed medical agent, and to have no medical condition associated with priapism, including the hemoglobinopathies, sickle cell anemia, or chronic myeloid leukemia. Upon detailed medical examination, methylphenidate and risperidone treatment was suspected as the cause of priapism. After discontinuation of psychostimulant and antipsychotic treatment, 50 mg/day atomoxetine treatment was initiated due to increase in symptoms of attention deficit-hyperactivity disorder. Symptoms improved, and prolonged erection was not repeated. The patient and his parents were provided with detailed information regarding the present report and signed a detailed written consent form. DISCUSSION Priapism is a condition that requires immediate attention, as it can lead to devastating long-term consequences, including impotence, urinary retention, and gangrene [11, 12]. Penile erection is a result of neural and vascular factors, involving an increased sacral parasympathetic tone that leads to increased blood flow into the arterioles and sinusoids, at which point the veins are compressed. Priapism results from alpha-1-adrenergic blockade in the corpora cavernosum, leading to parasympathetic, mediated arterial dilation and the inhibition of the sympathetic system. The result is intracavernosal stasis due to inadequate venous outflow caused by obstruction of the subtunical venules, causing hypoxia, acidosis, and pain [5]. The cause of priapism may be primary, secondary, or idiopathic. Priapism with primary etiology is not accompanied by a disorder of physical or psychological origin responsible for the prolonged erection. Secondary priapism is induced by factors directly or indirectly affecting the erection, such as traumatic, neoplastic, hematologic, surgical, neurologic, toxic, allergic, infective, or pharmacologic complications [1, 14]. Arterial high- and low-flow priapism occur. High-flow priapism leads to retention of well-oxy-
Unver et al., Priapism associated with the addition of risperidone to methylphenidate monotherapy
genated blood in the corpus cavernosum. The etiology remains unclear, though pharmacological, traumatic, and neurologic diseases have been proposed. High-flow priapism is painless and does not cause ischemia, as opposed to low-flow or veno-occlusive priapism, which results in hypoxia and tissue ischemia. If the blockade continues, it will lead to irreversible changes and permanent damage. Priapism caused by antipsychotics is usually low-flow, typically lasting more than 4â&#x20AC;&#x201C;6 hours, and is associated with a much higher likelihood of irreversible impotence [5, 15]. The present patient suffered from lowflow priapism. Blood flow returned to normal and pain decreased after drainage. Various therapeutic options exist, including mechanical (sustained perineal compression and ice packs), pharmacological (intracavernous, venous, or oral drug therapy), radiological (selective transcatheter embolization therapy), and surgical options (arterial ligation or arteriovenous shunts). Less invasive procedures are being conducted with increasing rates of success, and the need for surgical intervention is decreasing [16]. The present patient suffered from pain associated with tissue hypoxia and acidosis, requiring urgent therapeutic intervention of irrigation and corporeal blood aspiration of up to 150â&#x20AC;&#x201C;200 ml. Priapism may occur at any time during course of treatment involving psychotropic drugs and may occur without change of dose. Priapism can be considered an idiosyncratic reaction, as it is correlated neither with dosage nor duration of psychotropic drug use [5]. The effects of multiple neurotransmitters, particularly those affecting dopamine reuptake and release in the striatum, form the mechanism of priapism following OROS methylphenidate treatment. OROS methylphenidate hydrochloride is an osmotic, controlled-release delivery system designed for once-daily oral dosing. Following usage, a gradual increase in mean methylphenidate plasma concentration peaks at 6â&#x20AC;&#x201C;8 hours in an event lasting an average of 12 hours. It has been demonstrated that common adverse effects of methylphenidate are insomnia, decreased appetite, weight loss, abdominal pain, headache, anxiety, tendency to cry, and irritability. Increases in systolic and diastolic blood pressure, as well as heart rate have been reported and
87
may be related to dose [17, 18, 19]. While priapism is not a common side effect, it has been reported with use of osmotic, controlled- and immediate-release methylphenidate [8, 10, 13, 20]. In the present case, priapism developed only after addition of risperidone to OROS methylphenidate monotherapy. Priapism has been reported in patients with unusual susceptibility to side effects taking multiple antipsychotics. The mechanism of priapism associated with atypical antipsychotics such as risperidone is not clear, but is thought to be related to alpha-adrenergic blockage mediated by the alpha receptors in the corpora cavernosum [12]. Risperidone has nearly the highest affinity for the alpha-adrenergic receptor among atypical antipsychotics, and has been associated with priapism in 20 cases. Priapism can occur soon after initiation of risperidone treatment, after stable doses of risperidone have been taken for long periods of time, after a change in dose, or after the addition of another medication, including other antipsychotics, lithium, or serotonin-specific reuptake inhibitors [5, 7, 12]. It has been proposed that psychopharmacologic agents affect sexuality in 3 steps, either positively or negatively, and that the effects of dopaminergic agents are especially prevalent on the 1st and 2nd. In the first step, the libido is raised by amphetamine and methylphenidate, causing dopamine discharge. Sexual stimulation, the second step, may be triggered by certain dopaminergic agents [21]. As a result, in the present case, the addition of risperidone to OROS methylphenidate monotherapy caused prolonged erection. It is suggested that the risk of priapism may increase when risperidone is added to methylphenidate treatment. As priapism can lead to permanent and irreversible erectile dysfunction, clinicians should be aware of this side effect and counsel children or adolescent patients and their families accordingly, in order to improve the adaptation of the treatment. Education of patients and families would increase awareness, promote early reporting, and help reduce long-term consequences, including impotence and gangrene. Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study has received no financial support.
88 Authorship contributions: Concept – H.U.; Design – H.U.; Supervision – N.C.M.; Data collection &/or processing – H.U., E.S.; Analysis and/or interpretation – N.C.M.; Literature search – H.U.; Writing – H.U.; Critical review – N.C.M.
REFERENCES 1. Van der Horst C, Stuebinger H, Seif C, Melchior D, Martínez-Portillo FJ, Juenemann KP. Priapism - etiology, pathophysiology and management. Int Braz J Urol 2003;29:391– 400. 2. Papadopoulos I, Kelâmi A. Priapus and priapism. From mythology to medicine. Urology. 1988;32:385–6. 3. Pryor J, Akkus E, Alter G, Jordan G, Lebret T, Levine L, et al. Priapism. J Sex Med 2004;1:116–20. 4. Muneer A, Minhas S, Arya M, Ralph DJ. Stuttering priapism--a review of the therapeutic options. Int J Clin Pract 2008;62:1265– 70. 5. Sood S, James W, Bailon MJ. Priapism associated with atypical antipsychotic medications: a review. Int Clin Psychopharmacol 2008;23:9–17. 6. Munarriz R, Hwang J, Goldstein I, Traish AM, Kim NN. Cocaine and ephedrine-induced priapism: case reports and investigation of potential adrenergic mechanisms. Urology 2003;62:187–92. 7. Compton MT, Miller AH. Priapism associated with conventional and atypical antipsychotic medications: a review. J Clin Psychiatry 2001;62:362–6. 8. Husár M, Zerhau P. Priapism in childhood--case report of 14-year-old boy. [Article in Czech] Rozhl Chir 2006;85:329– 30. [Abstract] 9. Prabhuswamy M, Srinath S, Girimaji S, Seshadri S. Risperidone-induced priapism in a 12-year-old boy with schizophrenia. J Child Adolesc Psychopharmacol 2007;17:539–40. 10. Schwartz RH, Rushton HG. Stuttering priapism associated with withdrawal from sustained-release methylphenidate. J Pe-
North Clin Istanb diatr 2004;144:675–6. 11. Negin B, Murphy TK. Priapism associated with oxcarbazepine, aripiprazole, and lithium. J Am Acad Child Adolesc Psychiatry 2005;44:1223–4. 12. Patel AG, Mukherji K, Lee A. Priapism associated with psychotropic drugs. Br J Hosp Med 1996;55:315–9. 13. Çakın Memik N, Yıldız Ö, Şişmanlar Ş, Karakaya I, Ağaoğlu B. Metilfenidat kullanımı ile meydana gelen priapizm: bir olgu sunumu. Türk Pediatri Dergisi 2010;52:435–9. 14. Shantha TR, Finnerty DP, Rodriquez AP. Treatment of persistent penile erection and priapism using terbutaline. J Urol 1989;141:1427–9. 15. Witt MA, Goldstein I, Saenz de Tejada I, Greenfield A, Krane RJ. Traumatic laceration of intracavernosal arteries: the pathophysiology of nonischemic, high flow, arterial priapism. J Urol 1990;143:129–32. 16. Bastuba MD, Saenz de Tejada I, Dinlenc CZ, Sarazen A, Krane RJ, Goldstein I. Arterial priapism: diagnosis, treatment and longterm followup. J Urol 1994;151:1231–7. 17. Kimko HC, Cross JT, Abernethy DR. Pharmacokinetics and clinical effectiveness of methylphenidate. Clin Pharmacokinet 1999;37:457–70. 18. Heal DJ, Cheetham SC, Smith SL. The neuropharmacology of ADHD drugs in vivo: insights on efficacy and safety. Neuropharmacology 2009;57:608–18. 19. Özcan T, Toros F, Pekdemir H, Çiçek D, Çamsarı A, Yurttaş M, et al. The Effect of Methylphenidate on Time Domain Heart Rate Variability in the Treatment of Attention Deficit and Hyperactivity Disorder. Çocuk ve Gençlik Ruh Sağlığı Dergisi 2004;11:117–22. 20. Coskun M, Zoroglu S. A report of two cases of sexual side effects with OROS methylphenidate. J Child Adolesc Psychopharmacol 2009;19:477–9. 21. Stahl SM. Cinsiyete özgü ve cinsel işlevle ilgili psikofarmakoloji. Temel psikofarmakoloji içinde (Çev. Taneli B, Taneli Y) İstanbul: Yelkovan yayıncılık 2003;539–69.
CASE REPORT
ORTHOPAEDICS
North Clin Istanb 2017;4(1):89–92 doi: 10.14744/nci.2016.03016
Intra-articular lipoma of the knee joint located in the posterior compartment: A rare location Mujdat Bankaoglu,1 Ozge Yapici Ugurlar,2 Meric Ugurlar,3 Mesut Mehmet Sonmez,3 Osman Tugrul Eren3 Department of Radiology, Sisli Hamidiye Etfal Training and Research Hospital, Istanbul, Turkey
1
Department of Radiology, Trakya University Faculty of Medicine, Edirne, Turkey
2
Department of Orthopedics and Traumatology, Sisli Hamidiye Etfal Training and Research Hospital, Istanbul, Turkey
3
ABSTRACT This report presents the case of a 51-year-old woman with intermittent left knee pain, especially during full flexion of the knee, which had been ongoing for 1 year. Magnetic resonance imaging (MRI) showed mild effusion and round mass at the posterior compartment without synovial changes. Computerized tomography (CT) indicated mass had homogeneous low attenuation and density measurement of -99.4±62.3 Hounsfield units (HU), correlated with a lipomatous lesion. Keywords: Computerized tomography; CT; intra-articular lipoma; knee joint.
L
ipomas are the most common soft-tissue tumors[1]. Intra-articular occurrence of true lipomas has been rarely reported in the literature, and they are mostly noted in the anterior aspect of the knee joint, especially on the Hoffa’s fat pad and suprapatellar pouch [2–5]. The posterior compartment is an unusual location for solitary mass lesions of the knee joint [6]. According to our research of the literature, this article presents the first reported case of an intra-articular lipoma located in the posterior compartment, behind the posterior cruciate ligament. CASE REPORT A51-year-old woman presented with intermittent
left knee pain, especially during flexion of the knee, which had been ongoing for 1 year. There was no history of trauma related to the knee joint, but there was a limitation of the knee during flexion. Physical examination revealed no swelling, palpable mass, erythema, or local heating. There was no instability of the joint. McMurray and Lachman tests, as well as anterior and posterior drawer test results were negative. Blood tests revealed a normal leukocyte count. Other laboratory tests were also unremarkable. Radiography of the knee showed only mild osteodegenerative changes (Figure 1). Magnetic resonance imaging (MRI) showed medial meniscus degenerative changes, grade 2 chondral lesions
Received: December 07, 2015 Accepted: January 01, 2016 Online: May 02, 2016 Correspondence: Dr. Meric UGURLAR. Sisli Hamidiye Etfal Egitim ve Arastirma Hastanesi, Istanbul, Turkey. Tel: +90 212 - 373 50 00 e-mail: mugurlar@yahoo.com © Copyright 2017 by Istanbul Northern Anatolian Association of Public Hospitals - Available online at www.kuzeyklinikleri.com
90
North Clin Istanb
at the medial femoral and tibial condyles, mild effusion, and round mass at posterior compartment without synovial changes (Figures 2Aâ&#x20AC;&#x201C;C). A computerized tomography (CT) scan indicated the mass showed a well-defined, homogeneously low attenuated, hypodense nodular lesion at the posterior aspect of lateral femoral condyle. The density measurement of the mass on CT was -99,4Âą62,3 Hounsfield units (HU), correlated with a lipomatous lesion (Figure 3). No biopsy was performed before the operation. Arthroscopic evaluation confirmed medial meniscus degeneration, and chondral lesions, as well as a yellowish synovial mass behind the posterior cruciate ligament. Mass was excised and referred for histopathological examination, which determined mass was adipose tissue and synovial tissue, confirming diagnosis of a synovial lipoma. DISCUSSION Though intra-articular lipomatous lesions are infrequent [3], there are two different benign types: the true lipoma and the more common lipoma arborescens [2]. Lipoma arborescens should be differentiated from true lipoma. Intra-articular true lipoma is defined as a solitary round or ovoid mass of fatty tissue contained in a thin, fibrous capsule and without synovial changes [7], while lipoma arborescens A
B
Figure 1. Lateral radiograph of the knee showed only mild osteodegenerative changes.
is characterized by a diffuse subsynovial deposit of fat and a villous appearance, associated with joint effusion and synovial cyst, and bone erosion [7]. C
Figure 2. (A) In the sagittal fat-saturated T2-weighted MR image, there is round, nodular lesion behind the posterior cruciate ligament with distinct, regular margins isointense to the subcutaneous fatty tissue. (B) The sagittal fat-saturated T2-weighted MR image shows a thin, subtle, hypointense rim surrounding the lesion, consistent with a fibrous capsule. (C) In the sagittal T1-weighted MR image of the left knee, the lesion shows isointensity to subcutaneous fatty tissue.
Bankaoglu et al., Intra-articular lipoma of the knee joint located in the posterior compartment
Figure 3. In the axial CT image of the left knee joint, at posterior aspect of lateral femoral condyle, there is round, homogenously hypodense nodular lesion with a density of -99,4±62,3 HU, consistent with a lipoma. Both intra-articular true lipoma and lipoma arborescens most commonly involve the knee joint [4], but lipoma arborescens is a synovial disorder that affects particularly the suprapatellar pouch [7]. True lipomas are mostly noted in anterior aspect of the knee joint, especially on the Hoffa’s fat pad and suprapatellar pouch [2–5]. In the present case, the lesion did not arise within the synovium and did not fill the subsynovium as a lipoma arborescens does. Neither was there synovial overgrowth or villous, frond-like tissues, which are characteristics of lipoma arborescence. Unlike other intra-articular lipoma cases, the lesion in this case was located at the posterior aspect of the knee joint, neighboring the posterior cruciate ligament (Figure 2A). The lesion had no obvious fibrous septa but it contained a fibrous capsule, which can be seen with a true lipoma (Figure 2B). Ultrasonography (USG), CT and MRI are principal modalities used in radiological assessment of soft tissue tumors. The role of plain radiographs is limited in evaluation of lipomas but infrequently, the lesion may be identified as a low density, soft
91
tissue mass. Lipomas close to the bone may cause osseous changes, such as hyperostosis, periostal reaction, remodeling or bony erosions and cartilaginous or osseous matrix within the masses [8]. In the present case, there were no osseous changes detected in plain radiographs (Figure 1). While USG can be used for diagnosis, the lipoma in this case was diagnosed solely with MRI. This is the major limitation of the report. High resolution CT scan imaging is often diagnostic, even though MRI shows better soft tissue definition. On CT, lipomas generally appear as well-defined homogenous lesions. Benign lipomas have a homogeneous low attenuation on CT, with measurement of between -65 and -120 HU [9]. Although the HU value varies by specific body location, direct comparison with the attenuation of surrounding normal fat is often helpful [10]. In the present patient, measurement of the mass was in fat density (-99.4 HU), correlated with the lipomatous lesion. Posterior compartment is an unusual location for solitary mass lesions of the knee joint [6]. According to our research of the literature, there are two reported cases of solitary, intra-articular lipoma occurring in the femoral intercondylar notch [4, 5]. Thus, according to the radiological work- up, we diagnosed this lesion as lipoma. Learning points 1. Intra-articular occurrence of lipomas is rare. 2. They are usually reported in the anterior aspect of the knee joint. 3. It should be kept in mind by radiologists and orthopedic surgeons that they can be found in the posterior aspect. 4. True lipoma and lipoma arborescens are benign lipomatous lesions of the knee joint. 5. Lipoma arborescens should be differentiated from true lipoma. 6. High resolution CT scan imaging is often diagnostic. 7. MRI shows better soft tissue definition.
92 Conflict of Interest: None declared. Financial Disclosure: The authors declared that this study has received no financial support. Authorship contributions: Concept, M.U.; Design, M.U.; Supervision, M.M.S.; Materials, M.B.; Data collection and/ or processing, M.B., Ö.Y.U.; Analysis and/or interpretation, Ö.Y.U.; Literature search, M.M.S.; Writing, M.U.; Critical review, O.T.E.
REFERENCES 1. Rydholm A, Berg NO. Size, site and clinical incidence of lipoma. Factors in the differential diagnosis of lipoma and sarcoma. Acta Orthop Scand 1983;54:929–34. 2. Lee F, Keel SB, Gebhardt MC, Rosenthal DI. Intra-articular lipoma with osteochondroid metaplasia in the knee joint. Skeletal Radiol 2001;30:230–3. 3. Matsumoto K, Okabe H, Ishizawa M, Hiraoka S. Intra-articular lipoma of the knee joint. A case report. J Bone Joint Surg Am 2001;83-A:101–5. 4. Yamaguchi S, Yamamoto T, Matsushima S, Yoshiya S, Matsub-
North Clin Istanb ara N, Matsumoto T. Solitary intraarticular lipoma causing sudden locking of the knee: a case report and review of the literature. Am J Sports Med 2003;31:297–9. 5. Motsis E, Vasiliadis HS, Xenakis TA. Intraarticular synovial lipoma of the knee located in the intercondylar notch, between ACL and PCL: a case report and review of the literature. Knee Surg Sports Traumatol Arthrosc 2005;13:683–8. 6. Ozalay M, Tandoğan RN, Akpinar S, Cesur N, Hersekli MA, Ozkoç G, et al. Arthroscopic treatment of solitary benign intraarticular lesions of the knee that cause mechanical symptoms. Arthroscopy 2005;21:12–8. 7. Ryu KN, Jaovisidha S, Schweitzer M, Motta AO, Resnick D. MR imaging of lipoma arborescens of the knee joint. AJR Am J Roentgenol 1996;167:1229–32. 8. Knapp EL, Kransdorf MJ, Letson GD. Diagnostic imaging update: soft tissue sarcomas. Cancer Control 2005;12:22–6. 9. Munk PL, Lee MJ, Janzen DL, Connell DG, Logan PM, Poon PY, et al. Lipoma and liposarcoma: evaluation using CT and MR imaging. AJR Am J Roentgenol 1997;169:589–94. 10. Murphey MD, Carroll JF, Flemming DJ, Pope TL, Gannon FH, Kransdorf MJ. From the archives of the AFIP: benign musculoskeletal lipomatous lesions. Radiographics 2004;24:1433–66.
CASE REPORT
GENERAL SURGERY
North Clin Istanb 2017;4(1):93–96 doi: 10.14744/nci.2015.30592
Foreign bodies in the rectum: 2 Case reports Sezgin Zeren,1 Zulfu Bayhan,1 Mustafa Cem Algin,1 Metin Mestan,2 Ufuk Arslan3 Department of General Surgery, Dumlupinar University Faculty of Medicine, Kutahya, Turkey
1
Department of General Surgery, Evliya Celebi Training and Research Hospital, Kutahya, Turkey
2
Department of General Surgery, Bahcelievler State Hospital, Istanbul, Turkey
3
ABSTRACT Encountering a foreign object in the rectum is rare; however, the incidence has greatly increased in recent years. Treatment of these patients requires a multidisciplinary approach because this condition may have serious complications. Presently described is management of 2 cases of rectal foreign body treated in the clinic. Keywords: Complication; foreign body; perforation; rectum.
F
oreign objects are most often encountered in upper gastrointestinal system; very rarely, foreign bodies are seen in lower gastrointestinal system or rectum. Foreign objects may be inserted into rectum accidentally, for sexual satisfaction, or to inflict harm. Embarrassment of patient and inability to obtain satisfactory anamnesis complicate treatment process [1, 2]. Various kinds of foreign object may be observed in the rectum, including sharp instruments that may pierce rectum, colon, or create visceral organ injuries. In addition, factors such as delayed treatment have prevented formulation of a standard guideline for these circumstances [2]. Removal of intrarectal foreign object is a complicated issue for surgeons. Locating and extracting the item is an emergency procedure that can have serious complications [3]. Therefore, review of diagnosis and treatment process in 2 cases of intrarectal foreign object is presented.
CASE REPORT Case 1 — A 52-year-old male patient contacted emergency services with abdominal and anal pain that had gradually increased over nearly 6 hours. Detailed medical history of patient revealed that he had inserted a foreign object into rectum and that he had occasionally done so to achieve sexual satisfaction over period of nearly 2 years. Patient stated that he had placed glass mineral water bottle in a glove and covered it with lubricating gel before inserting it into his rectum, but this time he couldn’t remove it. On physical examination, abdomen was relaxed and natural. Complete blood cell count (CBC) and biochemical parameters were within normal range. On digital rectal examination, base of bottle was palpated as solid object 5-6 cm proximal to anus. Standing abdominal radiographs of patient were obtained in emergency department for differential
Received: May 02, 2015 Accepted: August 07, 2015 Online: May 10, 2017 Correspondence: Dr. Sezgin ZEREN. Dumlupinar Universitesi Tip Fakultesi, Genel Cerrahi Anabilim Dali, Evliya Celebi Yerleskesi, Tavsanli Yolu 10. km, 43100 Kutahya, Turkey. Tel: +90 274 - 265 22 86 e-mail: sezginzeren@gmail.com © Copyright 2017 by Istanbul Northern Anatolian Association of Public Hospitals - Available online at www.kuzeyklinikleri.com
94
Figure 1. Intrarectal glass bottle detected on erect abdominal radiograph of Case 1.
diagnosis, and showed bottle in the rectum without any evidence of free air or air-fluid levels. (Figure 1). Anal canal was dilated under sedation anesthesia; however, foreign body could not be extracted. Retroscopy under general anesthesia revealed base of bottle had completely occluded the lumen, and procedure was unsuccessful. Infraumbilical incision was performed and during exploration, foreign object was palpated in the colon. Manual effort to eject object from the outside also failed. Colotomy was then performed, and bottle was extracted in its entirety and without breakage (Figure 2). Colon was closed and there was no indication of intra-abdominal fluid or perforation. Postoperative period was uneventful. Psychiatric consultation and follow-up at outpatient clinics of psychiatry and general surgery were recommended prior to hospital discharge. Case 2 â&#x20AC;&#x201D; A 40-year-old male patient consulted emergency services with complaints of abdominal pain and constipation lasting for 4 hours. From patientâ&#x20AC;&#x2122;s medical history, it was learned that he had been occasionally inserting foreign objects into his rectum for sexual satisfaction for nearly 1 year. He had no known history of chronic disease, and reported no drug use or substance abuse. He stated that this time he had inserted a deodorant container into his rectum but was unable to remove it. Physical examination revealed bilateral tenderness of
North Clin Istanb
Figure 2. Image of deodorant bottle seen on erect abdominal radiograph of Case 2.
lower abdominal quadrants. CBC and biochemical parameters were within normal limits. During digital rectal examination a solid object was palpated
Figure 3. Surgically extracted rectal foreign object seen in Figure 1.
Zeren et al., Foreign bodies in the rectum
and erect view abdominal radiograph was taken. There was no indication of air-fluid levels or intraabdominal free air. Intrapelvic deodorant container was observed (Figure 3). Digital rectal examination was repeated under sedation anesthesia; however, foreign object could not be extracted. Patient was transferred to operating room, anal canal was dilated under general anesthesia, and object was removed manually. Postoperative period was uneventful. Patient was discharged with recommendation of psychiatric follow-up in outpatient clinic. Personal information of patients has not been disclosed, and written informed consent of both patients was obtained. DISCUSSION Management and treatment of patients who contact emergency services with intrarectal foreign body is truly very complex and challenging for surgeons. Generally, patient has inserted the object body into own rectum; rarely it may happen accidentally, or it may be the result of a criminal act. In the present cases, both patients had inserted foreign objects into their rectum seeking sexual satisfaction [4]. The objects used are things such as a drinking glass, a bottle, a deodorant container, a wooden stick, a sex toy, or various other household items [1]. In the first case presently described, a glass mineral water bottle nearly 15 cm long was removed, and in the second, a deodorant bottle measuring 12 cm was extracted. Most of the time, the objects can be removed by the patients themselves, though 20% of cases require endoscopic intervention. Only 1% involve surgical intervention [5]. Both of present patients indicated that they had previously been able to remove inserted foreign objects; however, when last attempt failed, they contacted emergency services. Review of literature provides descriptions of various methods to extract foreign objects. Principal methods have been performed under sedation or general anesthesia, and include manual transanal extraction, endoscopic transanal extraction using Kocher clamp, laparoscopic transanal extraction, and laparotomy through a single incision. In the
95
first case described presently, laparotomy followed by colostomy was required to remove the object, while in second case, manual extraction was performed under general anesthesia [1, 6, 7]. Glass objects broken during manual extraction can cause injuries to colon mucosa or hand of the surgeon, and may lead to sphincteric dysfunction [8]. Meticulous care should be exercised during extraction. Though generally no complications are seen, rarely very serious complications have occurred. In the literature there are reports of rectal perforations and bleeding, gas-fecal incontinence, bladder injuries, iliac vessel injuries, and migration of intrarectal foreign body to chest wall, leading to extensive injury. In such cases, diversion procedures have occasionally been performed [3]. In present cases, possible presence of perforation or peritonitis was considered in physical examination in order to detect acute abdomen, and abdominal radiographs were examined for signs of intra-abdominal free air. Based on absence of any perforation or peritonitis, abdominopelvic computed tomography (CT) was not considered necessary; however, it would have been requested if signs of acute abdomen were present or if diagnoses were delayed. Both physicians and patients were very lucky that no complications developed in the presently described cases. Hospital stay and duration of treatment were reduced. BuluĹ&#x; et al. did not perform diversion procedures because of fecal contamination, perforation, fear of injuring other intra-abdominal organs, lack of stable vital signs, and need for early intervention [2]. In the present cases, lack of peritoneal irritation, abdominal contamination or perforation eliminated need for diversion procedures. In conclusion, a general approach is available for foreign bodies detected in upper gastrointestinal system; however, clear guidelines for removal of intrarectal foreign objects have not yet been determined [9]. Approach to these cases and treatment process is still a complex issue. Varying characteristics of objects such as perforating or cutting qualities, size, hardness, and depth of insertion are determinative factors for surgical procedure and post-treatment follow-up of the patient. Referral of these patients
96
to psychiatry outpatient clinics for treatment of any underlying issues may be beneficial. Conflict of Interest: None declared. Financial Disclosure: The authors declared that this study has received no financial support. Authorship contributions: Concept – M.C.A; Design – S.Z.; Supervision – M.M; Funding – U.A; Materials – S.Z.; Data collection and/or processing –M.M; Analysis and/or interpretation –Z.B.; Literature search –U.A; Writing –S.Z, Z.B; Critical review – M.C.A.
REFERENCES 1. Cologne KG, Ault GT. Rectal foreign bodies: what is the current standard? Clin Colon Rectal Surg 2012;25:214–8. 2. Buluş H, Aydın A, Koyuncu A, Sugüneş T, Akpınar A, Coşkun A. Case of unusual foreign body in the rectum. Turk J Colorectal Dis 2010;20:185–7.
North Clin Istanb 3. Thomas VP. A rare case of penetrating rectal injury. Indian J Surg 2013;75:242–4. 4. Caliskan C, Makay O, Firat O, Can Karaca A, Akgun E, Korkut MA. Foreign bodies in the rectum: an analysis of 30 patients. Surg Today 2011;41:795–800. 5. Anderson KL, Dean AJ. Foreign bodies in the gastrointestinal tract and anorectal emergencies. Emerg Med Clin North Am 2011;29:369–400. 6. Elias B, Debs T, Hage S, Bassile B, Hanna P, Saint Eve P. Single incision laparoscopic surgery technique for transanal removal of rectal foreign body. J Surg Case Rep 2014;20:1–3. 7. Yılmaz B, Ozmete S, Altınbas A, Aktaş B, Ekiz F. Successful removal of an unusual rectal foreign body with a Kocher clamp. Endoscopy 2014;46 Suppl 1 UCTN:E549. 8. Şahin A, Çapa T, Javadi M. Rektal yabancı cisimler. Kolon Rektum Hastalıkları Dergisi 1995;5:12–4. 9. Yıldız İ, Yıldız İ, Yıldız ÖÖ, Bayır H, Genç A. Evolving with chicken bones Partial Airway Obstruction: A Case Repor. Abant Medical Journal 2015;4:290–2.
CASE REPORT
PEDIATRICS
North Clin Istanb 2017;4(1):97–99 doi: 10.14744/nci.2016.38981
Iatrogenic Cushing’s syndrome caused by intranasal steroid use Fatma Dursun, Heves Kirmizibekmez Umraniye Training and Research Hospital, Istanbul, Turkey
ABSTRACT Cushing’s syndrome (CS) is common after oral steroid use and has also been reported following topical or inhaled use, but it is extremely uncommon after intranasal administration. This is the case of a 6-year-old child who developed Cushing’s syndrome after intranasal application of dexamethasone sodium phosphate for a period of 6 months. Pediatricians and other clinical practitioners should be aware that high-dose and long-term nasal steroid administration may cause iatrogenic Cushing’s syndrome characterized by complications of glucocorticoid excess as well as serious and even life-threatening complications of adrenal insufficiency. Keywords: Children; iatrogenic Cushing’s syndrome; nasal steroid.
C
ushing’s syndrome (CS) is defined as high glucocorticoid level due to any cause and is classified as adrenocorticotropic hormone (ACTH) dependent or independent. CS commonly occurs due to exogenous systemic glucocorticoid administrations for treatment [1]. CS following use of inhaled or nasal steroid is rare and has been primarily reported in AIDS patients on ritonavir (a potent inhibitor of hepatic cytochrome P450) who were simultaneously taking inhaled steroids such as fluticasone for reactive airway disease [2, 3]. The authors seek to emphasize that patients and caregivers should be informed about posology, method, and duration of administration of steroids before treatment is initiated. This report is the case of a child who developed iatrogenic CS following intranasal use of dexamethasone.
CASE REPORT A 6-year and 3-month-old boy was admitted to pediatric endocrinology because of excessive weight gain and hypertrichosis. He had been diagnosed with allergic rhinitis 6 months prior, and was receiving a mixture prepared with Onadron® ampule (dexamethasone sodium phosphate) and physiological serum by nasal route. The mixture had been prescribed in a dose of 3 drops, twice a day. This was about 0.4 mg/day of dexamethasone and was administered regularly for six months. Physical examination revealed moon face, hypertrichosis on skin of face, arms, and upper back, and purple striae on the skin of thighs (Figure 1). Weight was 30 kg (+2 SDS), height was 120 cm (+0.6 SDS) and body mass index (BMI) was 20.8 (+2 SDS). Blood
Received: August 18, 2015 Accepted: January 24, 2016 Online: April 04, 2016 Correspondence: Dr. Fatma DURSUN. Merdivenkoy Mah., Yekta Sok., No: 2, A Blok, Goztepe, Istanbul, Turkey. Tel: +90 216 - 632 18 18 e-mail: fatmadursun54@yahoo.com © Copyright 2017 by Istanbul Northern Anatolian Association of Public Hospitals - Available online at www.kuzeyklinikleri.com
98
North Clin Istanb
Figure 2. Moon face began to regress after the cessation of dexamethasone drops.
Figure 1. Physical appearance of the patient after using nasal steroid.
pressure and other findings of systemic inspection were normal. Early morning cortisol level was 2.1 mcg/dL, and serum transaminase levels were increased, while glucose, insulin, lipid profile and thyroid functions were normal. Low-dose ACTH stimulation test with 1 mcg Synacthene was performed and stimulated cortisol level was found to be 3.4 mcg/dL, suggesting hypothalamic-pituitaryadrenal (HPA) axis suppression. Hydrocortisone was prescribed with a dose of 10 mg/m2/day for physiological replacement. Weight gain had ended, moon face was regressing and transaminase levels were in normal ranges 1 month after cessation of dexamethasone drops (Figure 2). Low-dose ACTH test was repeated at the end of 3 months, following a suspension of hydrocortisone replacement for 48 hours. HPA axis was still suppressed, so physiological hydrocortisone replacement was continued. The stimulated level of cortisol was normal at the end of 6 months.
DISCUSSION CS following use of intranasal steroids is rare [2, 4, 5]. Perry et al. [6] presented a series of 9 children with CS following use of steroid nasal drops (betamethasone, beclomethasone, fluticasone and flunisolide) for ear, nose and throat problems. Seven of the patients had received intranasal betamethasone, which was replaced with flunisolide in one. The other two patients were given budesonide and beclomethasone [6]. The present patient had received dexamethasone drops. CS following intranasal administration of dexamethasone for allergic rhinitis has also been reported previously [7]. Absorption through nasal mucosa and partly through intestinal mucosa after a portion of the dose is swallowed is the mechanism of systemic effect. Treatment consists of discontinuation of intranasal steroid preparation and tapering doses of hydrocortisone to account for secondary adrenal insufficiency until the axis recovers [7]. Normal daily cortisol production in the body ranges from 8 to 15 mg/day [8]. Wilkins and coworkers observed more than 40 years ago [9] that prednisone and dexamethasone are, respectively, 10- and 80-fold more
Dursun et al., Iatrogenic Cushing’s syndrome caused by intranasal steroid use
potent than hydrocortisone in suppressing adrenal androgen production. The present patient had received 0.4 mg/day dexamethasone, equal to approximately 32 mg/day hydrocortisone. The stimulated level of cortisol became normal at the end of sixth month of the follow-up period. When adrenal suppression from intranasal steroids is suspected, the most appropriate and widely available test is low-dose stimulation test with synthetic ACTH. HPA axis suppression was confirmed with low-dose ACTH test in the present patient. A non-invasive alternative is measurement of cortisol in salivary profiles, but currently, this assay is not routinely available [6]. If patients are treated with glucocorticoids at higher doses than the physiological dose for longer than 4 weeks, secondary adrenal cortex atrophy may develop as a result of inhibition of corticotropin-releasing hormone (CRH) and ACTH secretions. Average 6-week period is needed to restore the gland secretory function after discontinuation of the drug [1]. However, the current patient required physiological glucocorticoid replacement for 6 months to prevent adrenal insufficiency due to HPA suppression. In conclusion, pediatricians and other clinical practitioners should be aware that high-dose and long-term nasal steroid administration may cause iatrogenic CS. Iatrogenic CS is characterized by complications of glucocorticoid excess, as well as serious and even life-threatening complications of adrenal insufficiency. Conflict of Interest: None declared. Financial Disclosure: The authors declared that this study
99
has received no financial support. Authorship contributions: Concept, F.D.; Design, F.D.; Supervision, F.D., H.K.; Materials, F.D.; Data collection and/ or processing, F.D.; Analysis and/or interpretation, F.D., H.K.; Literature search, F.D., H.K.; Writing, F.D., H.K.; Critical review, F.D., H.K.
REFERENCES 1. Baş VN, Cetinkaya S, Aycan Z. Iatrogenic Cushing syndrome due to nasal steroid drops. Eur J Pediatr 2012;171:735–6. 2. Dutta D, Shivaprasad KS, Ghosh S, Mukhopadhyay S, Chowdhury S. Iatrogenic Cushing’s syndrome following short-term intranasal steroid use. J Clin Res Pediatr Endocrinol 2012;4:157– 9. 3. Mahlab-Guri K, Asher I, Gradstein S, Zung A, Radian-Sade S, Elbirt D, et al. Inhaled fluticasone causes iatrogenic cushing’s syndrome in patients treated with Ritonavir. J Asthma 2011;48:860–3. 4. Fuchs M, Wetzig H, Kertscher F, Täschner R, Keller E. Iatrogenic Cushing syndrome and mutatio tarda caused by dexamethasone containing nose drops. [Article in German] HNO 1999;47:647–50. [Abstract] 5. Oluwayemi IO, Oduwole AO, Oyenusi E, Onyiriuka AN, Abdullahi M, Fakeye-Udeogu OB, et al. Iatrogenic Cushing’s syndrome in children following nasal steroid. Pan Afr Med J 2014;17:237. 6. Perry RJ, Findlay CA, Donaldson MD. Cushing’s syndrome, growth impairment, and occult adrenal suppression associated with intranasal steroids. Arch Dis Child 2002;87:45–8. 7. Kimmerle R, Rolla AR. Iatrogenic Cushing’s syndrome due to dexamethasone nasal drops. Am J Med 1985;79:535–7. 8. Esteban NV, Loughlin T, Yergey AL, Zawadzki JK, Booth JD, Winterer JC, et al. Daily cortisol production rate in man determined by stable isotope dilution/mass spectrometry. J Clin Endocrinol Metab 1991;72:39–45. 9. Wilkins W, Thomas CC, Springfield, Ill. The diagnosis and treatment of Endocrine. Disorders in childhood 1950.
Invited Review
CHILD HEALTH AND DISEASES
North Clin Istanb 2017;4(1):100–107 doi: 10.14744/nci.2017.49368
Epidemiology, pathophysiology, clinical evaluation, and treatment of carbon monoxide poisoning in child, infant, and fetus Atilla Alp Gozubuyuk, Huseyin Dag, Alper Kacar, Yakup Karakurt, Vefik Arica Department of Pediatrics, Okmeydani Training and Research Hospital, Istanbul, Turkey
ABSTRACT Carbon monoxide (CO) poisoning is one of the most common types of poisoning causing death worldwide. In our country, it occurs particularly during winter as a result of leak from stove or water heater, or as result of inhalation during a fire. Although most poisonings occur accidentally, some cases are suicide attempt. As CO is a substance that is not visible and has no taste or smell and is therefore difficult to detect, the gas can be a “silent killer” that is not noticed until effects develop. CO reacts with oxygen, creating carboxy hemoglobin (COHb), which leads to tissue hypoxia. In addition, it has direct effect of causing cellular damage. Although symptoms of acute poisoning are most commonly observed in patients admitted to emergency rooms, effects of chronic exposure to CO can also seen. Clinically, although it affects all organ systems, involvement of central nervous system (CNS) and cardiovascular system is predominant. Most common poisoning symptoms are weakness, dizziness, headache, nausea, and nonspecific flu-like symptoms, like vomiting. Depending on severity of exposure, seizures, syncope, and arrhythmia may also be observed. In pregnant women, fetus can be harmed with relatively low level of COHb. Poisoning in infants has a more severe course than seen in other age groups. Symptoms must be associated with cause of poisoning, and careful anamnesis and treatment must be conducted quickly. Oxygen is the antidote for CO. It is administered through a mask in the form of normobaric oxygen therapy or through specific devices in the form of hyperbaric oxygen therapy. In this review, clinical data and current diagnostic and therapeutic approaches concerning CO poisoning are discussed. Keywords: Carbon monoxide; child; fetus; hyperbaric oxygen; infant; poisoning, pregnant.
C
O is a colorless, odorless, tasteless, non-irritating gas present in the environment even when there is no fire or smoke. It has been reported to be the most frequent cause of fatal poisoning, with an incidence rate of 31%. Average of 4% to 10% of all cases of poisoning occur during childhood, and
58% to 75% of deaths due to poisoning are caused by CO inhalation. In cases of poisoning by industrial chemicals, CO is the most common (11%) after inhalation of thinner (31%). In our country, CO poisoning is most frequently seen during winter months, especially during windy weather, as
Received: October 12, 2016 Accepted: January 26, 2017 Online: May 10, 2017 Correspondence: Dr. Vefik ARICA. Okmeydani Egitim ve Arastirma Hastanesi, 31100 Istanbul, Turkey. Tel: +90 212 - 314 55 55 e-mail: vefikarica@hotmail.com © Copyright 2017 by Istanbul Northern Anatolian Association of Public Hospitals - Available online at www.kuzeyklinikleri.com
Gozubuyuk et al., Clinical evaluation, and treatment of carbon monoxide poisoning in child
accident in the home due to inappropriate heating methods [1–3]. In the USA, third most frequent cause of accidental death is CO poisoning, most of which (57%) were due to inhalation of exhaust gases [4, 5]. Sources of CO 1) Endogenous production: CO is produced endogenously as result of human metabolism of hemoglobin. It functions as neurotransmitter, and it is produced at very low (0–5%) levels in every individual. In infants (3–7%), smokers, and patients with hemolytic anemia (5–10%), level is higher. Under physiological conditions, it saturates approximately 0.5% of hemoglobin, and it is known as COHb [6]. 2) Hydrocarbons: CO is produced as result of incomplete burning of compounds with carbon component, such as coal, wood, petroleum, fertilizers, dried dung, and natural gas. Concentration in the atmosphere is generally less than 0.001%; however, when there is incomplete combustion of hydrocarbons, ratio in the atmosphere increases. Such pollution is greater in air of urban environment [7]. 3) Exhaust Gases: Exhaust gases emitted from motor vehicles are major deadly source of CO. Exposure to gases released in closed garage may lead to fatal blood level of CO within 10 minutes. Potentially fatal exposure may also occur in semi-closed garage or areas adjacent to garage [7, 8] 4) Fire: CO is liberated in burning of any material [7]. 5) propane and methane: Incomplete combustion of gases generates CO. Leaks from poorly maintained or improperly used heating systems can be a source, as well as petrochemical industry use of natural gas and crude oil [7]. 6) methylene chloride: Vapor of methylene chloride, component of thinners and other solvents, penetrates the skin, is inhaled through the lungs, and transported to the liver via blood circulation, where it is metabolized, resulting in release of CO [7]. 7) cigarette smoke: Cigarette smoke is 4% CO. Baseline COHb level in smokers and nonsmokers living in metropolitan cities have been detected at 10% and 2%, respectively [6, 8].
101
Pathophysiology of co poisoning CO gas is readily absorbed and is unchanged by the lungs. After absorption, it largely (90%) binds to hemoglobin, and rarely (10%), to myoglobin and cytochrome C-oxidase. Less than 1% is dissolved in plasma, and less than 1% of CO is oxidized to carbon dioxide. Cardiac injury has been associated with hypoxia in human and animal studies, and it has been reported that neurological and perivascular injuries were hypoxic as result of oxidative stress (reoxygenation) secondary to CO exposure. Damage to central nervous system (CNS) as result of hypoxia may lead to cardiovascular insufficiency, and effect of high doses of CO on smooth muscle may result in hypotension [7, 9, 10]. How does CO induce cellular injury? A. It impairs both oxygen carrying capacity of blood and oxygen diffusion. 1. CO diffuses into hemoglobin. CO demonstrates 200-fold stronger affinity for hemoglobin compared with oxygen. In event of poisoning, CO and oxygen compete to bind to hemoglobin, and CO wins the contest. Therefore, even small increase in CO level may cause poisoning (Haldane effect) [7]. 2. It prevents delivery of oxygen to tissues via hemoglobin. Since CO binds to hemoglobin with higher affinity than oxygen, a shift occurs in oxygen-hemoglobin dissociation curve, making it a hyperbola. With this shift, capacity of hemoglobin to deliver oxygen to tissues decreases, with resultant development of tissue hypoxia [6]. B. CO has direct effect of causing tissue injury. Binding of CO to hemoglobin does not explain all pathophysiological effects seen in CO poisoning. Observations in various animal studies suggest that direct effect of CO on cells is more important than decrease in oxygen carrying capacity of hemoglobin [11]. 1. CO impairs normal respiratory function of cells. CO irreversibly binds to hemeproteins (cytochrome a-3 and myoglobin), which carry oxygen within the cell, resulting in cellular respiratory dysfunction. As a consequence, there is mitochondrial deterioration in CNS and heart cells, which require higher level of energy, cellular damage, and eventually tissue damage. Though mito-
102
chondrial functions improve with oxygen therapy, cellular damage cannot be recovered [6, 12]. 2. CO causes myocardial injury by binding to cardiac myoglobin. CO binds to myoglobin with an affinity 60 times stronger than that of oxygen. Binding of CO to cardiac myoglobin induces myocardial depression, hypotension, and arrhythmias. Cardiac dysfunction developing secondary to CO poisoning further aggravates tissue hypoxia in a vicious cycle [7, 13]. 3. CO induces re-oxygenation injury in CNS [9]. 4. CO promotes formation of oxygen free radicals. CO causes hypoxia, which induces production of oxygen free radicals, resulting in reversible demyelinization in brain [7, 14, 15]. Clinical findings in co poisoning Fetus, infant, children, the elderly, patients with cardiovascular disease, anemia, pulmonary disease, and pregnant women are at higher risk in event of CO poisoning compared with other patients. Clinical severity of CO poisoning depends on amount of CO in the inhaled air, duration of exposure to CO, and general state of health of the affected individual. Although CO poisoning is harmful for all systems, most frequently CNS and cardiovascular systems are affected. Neurological findings are clearly defined; however, data related to cardiac pathologies, especially in children, are limited in number, and such pathology can be difficult to recognize. Myocardial injury may develop without any systemic symptom. Most frequent cause of death in CO poisoning is cardiac arrest secondary to ventricular arrhythmia. Clinical findings differ between cases of acute and chronic poisoning [8, 12, 16, 17]. Symptoms of poisoning based on cohb level [18] • 10–20%: Nausea, fatigue, tachypnea, emotionality, confusion, clumsiness • 21–30%: Headache, exertional dyspnea, angina, visual impairment, some insufficiency in adaptation to environment, inadequate reaction to danger, slight muscular weakness, and decreased sensory perception • 31–40%: Dizziness, confusion, nausea, vomiting, visual impairment, problematic decisionmaking
North Clin Istanb
• 41–50%: Fainting, changes in state of consciousness, amnesia, tachycardia, tachypnea • 51–60%: Seizures, coma, severe acidosis • ≥60%: Death Symptoms of acute poisoning: Fatigue, severe headache, dizziness, nausea, vomiting, chest pain, palpitations, exertional dyspnea, attention deficit, imbalance, numbness, seizures, coma, respiratory arrest [19]. Findings of late-term poisoning: Rhabdomyolysis, non-cardiogenic pulmonary edema, multiorgan failure, disseminated intravascular coagulation, acute tubular necrosis, incontinence, mutism, mask-like face, and delayed neuropsychiatric manifestations [20]. In 30% of cases with nonspecific symptoms of CO poisoning, diagnosis is overlooked. Patients may be misdiagnosed with flu, gastroenteritis, or infantile colic [7]. In moderately severe acute CO poisoning, nonspecific symptoms, such as tachycardia, tachypnea, headache, nausea, vomiting, and lethargy, may be confused with viral infections [16]. It becomes even more difficult to make distinction during winter months. Thorough anamnesis may reveal exposure to CO; however, many mild cases of poisoning go undiagnosed, and late-term deaths can occur due to CO poisoning [12]. In patients who are chronically exposed to low dose of CO, headache, lassitude, thought disorders, dizziness, paresthesia, chest pain, palpitation, visual impairment, nausea, diarrhea, and abdominal pain may be noticed. In children, school performance may worsen, and these symptoms may be frequently confused with those of other diseases. In cases of chronic poisoning, it should be remembered that clinical picture may worsen, and signs and symptoms of acute phase may develop [8, 12]. After resolution of symptoms of acute poisoning, delayed neuropsychiatric syndrome manifests in nearly 20% of patients within 3 to 240 days (frequently within first month). In these patients, neuropsychiatric disorders, such as dementia; memory deficit; personality changes; learning difficulties; behavioral, attention, and concentration disorders; psychosis; parkinsonism; paralysis; chorea; apraxia; peripheral neuropathy; or incontinence may be observed [7]. No clinical or biochemical markers can
Gozubuyuk et al., Clinical evaluation, and treatment of carbon monoxide poisoning in child
determine the patients at risk for this syndrome; however, symptoms of 60% of patients with delayed neuropsychiatric syndrome regress within 1 year. This condition is more frequently seen in adults [21]. Diagnosis and clinical evaluation in co poisoning History: Clinical suspicion is the most important step in the diagnosis. Environmental conditions, heating systems, defects in heating systems, maintenance of system, extent of fire (if any), duration and intensity of exposure to CO, number of individuals affected, presence (if any) of sick animals exposed to CO, extent of exposed area, and time of admission or referral to hospital should be investigated during anamnesis [7, 12]. Relatives of unconscious children should be questioned for differential diagnosis, and information about any comorbid systemic disease (especially cardiopulmonary and hematological diseases) of the patient should be obtained. All of this information is important to determine diagnosis and prognosis [5]. Physical examination: Vital signs and symptoms should be evaluated first. Tachycardia, tachypnea, slight increase in blood pressure, and hyperthermia may be seen, and as severity of poisoning increases, bradycardia, hypotension, and hypothermia may occur. Complete systemic examination should be performed. Findings related to differential diagnosis should be investigated, and after stabilization of the patient, detailed neurological examination should be performed. If possible, the patient should be requested to walk to determine balance disorder. Cherry-red color of skin and mucosal layers, suggested as classic pathognomonic sign of CO poisoning, has no diagnostic value, as it is only seen post mortem. Bullae, vesicles, and erythematous spots may, however, be seen on skin surface. Cardiac auscultation should include exploration for dysrhythmia, and pulmonary examination should include signs of respiratory distress and pulmonary edema [7, 8, 12, 22]. Fundoscopic examination: In severe cases of CO poisoning, papilledema, optic atrophy, flame-shaped hemorrhage in retina, bright red veins (early sign), and enlargement of retinal veins may be detected. Visual field defects (central scotoma, homonymous hemianopsia, blindness, and retrobulbar neuritis) should be evaluated.
103
Laboratory: Biochemical analyses: Abnormal renal or and hepatic function test results, hyperglycemia, elevated anion gap, hypokalemia, or elevated levels of creatinine kinase, and cardiac enzymes, such as troponin-I and creatinine kinase-MB, may be seen. Hemogram may reveal slight degree of leukocytosis, and thrombocytopenia or prolongation of coagulation time may also be detected. PaO2 remains at normal level. In mild degree of poisoning, respiratory alkalosis may be observed, and in case of severe poisoning, metabolic acidosis or lactic acidosis may be seen. Even if COHb values are within normal limits, increased serum lactate level is better indicator of tissue hypoxia. Complete urinalysis may reveal proteinuria or glucosuria. Severe poisoning may lead to myoglobinuria, albuminuria, oliguric or non-oliguric renal failure. As part of differential diagnosis, toxicological analysis for other poisons should be also performed [7, 9, 12, 23, 24]. Diagnosis: Diagnosis is based on percentage of COHb in the blood. Unconscious children presented with suspected undiagnosed CO poisoning should have COHb measured as soon as possible. In assessment of COHb, it should be remembered that baseline level in smokers is higher, and that if the patient was brought to the emergency service late and received even small quantity of oxygen during transport, COHb level may be underestimated. Clinical data should constitute basis of diagnosis. Strong correlation between severity of poisoning and COHb level does not exist; however, COHb percentage can be used to monitor treatment. Elevated level is important for diagnosis and monitoring, but lower level does not rule out diagnosis. Venous or arterial blood sample may be used to gauge level of COHb; however, arterial blood is preferred. COHb level below 10% is normal. Diagnosis of CO poisoning can be made if it is above 10% [7, 12, 17, 25]. In cases of CO poisoning, although blood oxygen levels are below normal, PaO2 in blood gas remains within normal limits. If PaO2 is below normal, then it is associated with â&#x20AC;&#x153;concomitant pulmonary dysfunction.â&#x20AC;? Oxygen saturation is monitored with pulse oxymeter. However, since pulse oxymeter will absorb oxyhemoglobin and COHb in equal proportions, measured value represents sum. It should not be forgotten that falsely normal concentration may be displayed. Increased level of serum lactate, which should be measured in patients with metabolic aci-
104
dosis, indicates long-term exposure to CO [12, 26]. Electrocardiogram (EKG): EKG should be obtained for all cases. Though inadequate data are available for children, in nearly 35% of patients, signs of CO poisoning are observed on EKG. Frequently, myocardial lesions are observed; however, these lesions are fatal in less than 5% of patients. Ischemic changes, such as ST depression or ST elevation may be present on EKG. If ST elevation is seen, thrombolytic treatment is not suitable, since cause of cardiac ischemia is not thrombotic occlusion of coronary arteries, but instead, related to myocardial injury caused by direct effect of CO. Although arrhythmias that affect hemodynamic status are rarely seen, dysrhythmias, including ventricular extrasystoles and ventricular fibrillation can be detected [27, 28]. Chest X-ray: Aspiration pneumonia, pulmonary edema, and acute respiratory distress syndrome may be observed [19]. Computed tomography (CT) and magnetic resonance (MR) imaging: Cerebral CT should be performed in acute case for differential diagnosis of impaired consciousness. It is not used for diagnosis of CO poisoning. Normal cerebral CT may be associated with favorable clinical entity, though signs detected on CT may not be consistent with clinical findings [7]. Most frequently observed signs on CT within the first 6 hours include low-density lesions on the globus pallidus and deep white matter lesions secondary to damaging effects of CO mediated by oxygen free radicals [29, 30]. Similarly, as more sensitive imaging modality, MR image may be used. In delayed neuropsychiatric disease, bilateral necrosis of the globus pallidus and involvement of the cerebral cortex, hippocampus, and susbstantia nigra have frequently been demonstrated on CT and MR images [7, 30]. When to use CT/MR imaging [29â&#x20AC;&#x201C;31]: 1. In differential diagnosis of acute loss of consciousness 2. In patients who have not recovered completely following hyperbaric oxygen (HBO) therapy 3. In cases of delayed neuropsychiatric disease 4. In infant EKG: Slow, diffuse, low-voltage waves may be detected [23].
North Clin Istanb
Differential diagnosis in co poisoning In the differential diagnosis of CO poisoning, viral infections of the upper respiratory tract, hypoxic encephalopathy, encephalitis, meningitis, intracranial CNS pathologies, gastroenteritis, drug overdose (sedatives, hypnotics, salicylates), ethanol or methanol intoxication, cyanide intoxication, methemoglobinemia due to opiate use, migraine, hypertension headache, trauma, depression, and other psychiatric disorders should be taken into consideration [32]. Hospitalization criteria Signs and symptoms persisting up to 4 hours after initiation of treatment, COHb level of more than 25%, signs demonstrating myocardial involvement, pregnancy, treatment-refractory metabolic acidosis, seizures, syncope, rhabdomyolysis [17, 32]. Criteria for home discharge after first aid In the absence of hospitalization criteria, or if there is resolution or lack of complaints or signs after 4 hours of observation, child may be sent home. If consultation with pediatric psychiatry has ruled out possibility of suicide attempt, child may be discharged [17, 33]. At time of discharge, the patient should be informed about long-term effects of poisoning, and bed rest should be recommended to decrease oxygen consumption. In addition, any activity that may trigger anxiety should be avoided. Furthermore, patients should be warned against smoking and being in areas where others are smoking [17, 33]. Co poisoning in pregnant women and effect on fetus Pregnant women poisoned with CO should be hospitalized and fetal monitoring should be provided. Affinity of CO to hemoglobin is stronger in fetus compared with other age groups. In event of CO poisoning, fetal COHb level will be higher than that of mother, and clearance is 5 times slower [34, 35]. Fetal COHb value returns to normal level 40 hours after COHb level normalizes in mother [7, 12]. It should not be forgotten that fetal involvement can occur even if maternal CO level is not toxic. Therefore, when compared with other cases of CO poisoning, HBO treatment is initiated at lower maternal CO level in pregnant women, and
Gozubuyuk et al., Clinical evaluation, and treatment of carbon monoxide poisoning in child
is more aggressive and longer lasting in order to protect the fetus. No correlation has been determined between fetal death and maternal COHb level [27]. Nonetheless, CO exposure may have teratogenic effects of physical deformity, psychomotor disability, or miscarriage. Despite administration of HBO, in cases of CO poisoning during third trimester, adverse effects on fetal brain have been reported [18, 35]. Co poisoning in infants Data are scarce concerning the application of HBO treatment for fetuses, infants, and pediatric patients [14]. In the literature, CO poisoning in neonates is usually reported in case where mother has also been exposed [36]. In infants, normal CO level is 4%. Immature CNS, higher affinity of CO to fetal hemoglobin compared with adult hemoglobin, longer half-life of fetal COHb, and greater consumption of oxygen increase risks of CO poisoning in infants [37]. American Academy of Pediatrics reported that use of CO detectors is useful to prevent exposure to CO in areas where there is cigarette smoke and where scented candles or incense are burned [38]. In the very few studies available, case reports have emphasized that oxygen treatment lowers COHb level more slowly in infants than in other age groups [39, 40]. Treatment of co poisoning First goal in treatment of CO poisoning is to remove the patient from toxic environment and to deliver oxygen therapy to reverse cellular metabolic dysfunction. Vital functions should be ensured, vascular access should be established, and continuous cardiopulmonary monitoring should be performed. Treatment for tissue hypoxia and hypovolemia should be initiated, and if necessary, HBO therapy should be administered. If present, complications should be treated [12]. Rapid intervention and delivery of appropriate dose of oxygen constitutes basis of treatment since there is competition with oxygen to bind with hemoglobin, and because binding of CO to hemoglobin is reversible [27]. Half-life of CO is approximately 5 hours in room air, and 1½ hours in 100% oxygen environment, and 25 minutes during HBO treatment under 3 bar pressure. In other words, oxygen shortens half-life of CO.
105
This has important implications for cardiac functions [40]. Oxygen treatment delivered with mask under normal pressure (normobaric oxygen therapy): Oxygen should be delivered with airtight mask that closely adheres to the face at rate of 10–15 L/min until clinical symptoms resolve or COHb level drop below 5% (in case with cardiovascular or pulmonary symptoms <2%), typically average of approximately 4 to 6 hours. If the patient is unconscious or rescued from a fire, endotracheal intubation or mechanical ventilation may be required. Need for HBO should be evaluated [12, 27, 40]. Since lactic acidosis facilitates penetration of oxygen through tissues, it should not be corrected unless pH drops below 7.15 [7, 8]. Hyperbaric oxygen therapy: HBO therapy shortens half-life of COHb, reduces production and level of oxygen free radicals, inhibits lipid peroxidation, and improves impaired mitochondrial functions and platelet aggregation in capillaries. HBO therapy offers shortened symptom recovery time, decreased mortality rate, and development of fewer neuropsychiatric symptoms in the long term in comparison with use of normobaric oxygen. If patient has stable clinical status and is conscious but has history of loss of consciousness before admission, HBO therapy can be administered once. As indicated in the literature, these patients have higher risk of experiencing neuropsychiatric symptoms in long term, and HBO therapy decreases this risk. Beneficial effects of HBO therapy have been demonstrated even after 3 weeks in patients with persistent neuropsychiatric symptoms who didn’t receive HBO therapy at baseline. However, since CO induces hypoxia and because there is direct cell injury as well, results of HBO therapy as far as late-term sequelae and mortality should be discussed further [8, 10, 12, 21]. If possible, HBO therapy should be performed within first 6 hours of poisoning. If after HBO therapy, loss of consciousness persists, therapy should be repeated within 6 to 8 hours. Prognosis improves after repeated applications. Delivery of 100% oxygen for 30 to 90 minutes under 2.7 to 3 ATA is recommended. Then, pressure is decreased, and 100% oxygen is delivered under 2.2 ATA for 90 minutes. HBO therapy may be repeated for patients whose symptoms do not regress [10, 17].
106
HBO indications in CO poisoning [7]: 1. Loss of consciousness (even transient) 2. Visual impairment 3. Every patient, at any age, if COHb >25–40% 4. In patients with ischemic heart disease, if COHb >20% 5. In infants, children, and pregnant women, if COHb >15% 6. Signs of cardiac ischemia or arrhythmia on EKG 7. Any clinical finding persisting for more than 3 weeks 8. Persistence of clinical symptoms despite normobaric oxygen therapy for 4 hours Conditions where HBO therapy is contraindicated: Untreated pneumothorax is considered absolute contraindication for HBO treatment. HBO is not preferred for patients who received prolonged cardiopulmonary resuscitation, hemodynamically unstable patients, or patients with emphysema and/ or chronic bronchitis [9, 24]. Possible side effects of HBO therapy: Rupture of tympanic membrane, ear discomfort, tension pneumothorax, hypotension, dysrhythmia, seizure, and oxygen toxicity may occur, and there is risk associated with transportation of unstable patient to therapy location [9, 24]. Other treatment modalities: In hypotensive patients, first hydration is performed, and if vasopressor is required, dopamine is usually preferred. If refractory hypotension is present, then noradrenaline is added to treatment [25]. For seizures, initially, benzodiazepines are administered. If the patient does not respond to treatment or if there is recurrence, other antiepileptics may be added, such as phenobarbital. If hemoglobin level is less than 10 g/dL, supportive treatment to correct anemia may be considered. Bed rest and reduced consumption of oxygen are advised; any anxiety-inducing activity should be avoided. Urine excretion rate should be 1 mL/kg/h. Some publications have indicated that hypothermia delays cortical cell damage, or even precludes neuronal injury and it may be used in treatment of CO poisoning [41–43]. Preventing co poisoning Especially during winter months, public service
North Clin Istanb
messages broadcast in mainstream media should emphasize dangers associated with CO and advise about proper heating procedures for home and workplace, exhaust gases, petrochemicals, thinners, and fire. Greater regulation and oversight of employee health and safety is also needed. Efforts should be made to include Syrian war refugees currently residing in Turkey in these awareness-raising campaigns. CO poisoning can be prevented with proper installation and use of home and workplace heating systems, especially those using gas, adequate ventilation, and routine maintenance. CO levels in exhaust gases can be reduced with regular maintenance and use of catalytic converters [12, 8]. Finally, although CO sensors do not register low levels of CO, they are still recommended for capacity to provide warning. Conflict of Interest: None declared. Financial Disclosure: The authors declared that this study has received no financial support. Authorship contributions: Concept – A.A.G.; Design – H.D.; Supervision – V.A.; Materials – A.K., A.A.G., H.D.; Data collection &/or processing – A.K., H.D.; Analysis and/or interpretation – A.A.G., H.D., V.A., A.K.; Literature search – Y.K., V.A., A.K.; Writing – A.A.G., H.D.; Critical review – V.A.
REFERENCES 1. Uysalol M, Uysalol EP, Saraçoğlu GV, Kayaoğlu S. A Retrospective Analysis of Pediatric Patients Admitted to the Pediatric Emergency Service for Carbon Monoxide Intoxication. Balkan Med J 2011; 28:237–43. 2. Başar L. Türkiye’de zehirlenmelere bağlı ölüm olgularının profile. Adalet Bakanlığı Adli Tıp Kurumu Başkanlığı Uzmanlık Tezi. İstanbul: 2000. 3. Özcan N, İkincioğulları D. Ulusal Zehir Danışma Merkezi Çalışma Raporu Özeti 2008. http://www.journalagent.com/ turkhijyen/pdfs/THDBD_66_3_29_58.pdf (access date: 11 April 2017). 4. Geehr EC, Salluzzo R, Bosco S, Braaten J, Wahl T, Wallenkampf V. Emergency health impact of a severe storm. Am J Emerg Med 1989;7:598–604. 5. Wolf SJ, Lavonas EJ, Sloan EP, Jagoda AS; American College of Emergency Physicians. Clinical policy: Critical issues in the management of adult patients presenting to the emergency department with acute carbon monoxide poisoning. Ann Emerg Med 2008;51:138–52. 6. Blumenthal I. Carbon monoxide poisoning. J R Soc Med 2001;94:270–2. 7. Ernst A, Zibrak JD. Carbon monoxide poisoning. N Engl J Med
Gozubuyuk et al., Clinical evaluation, and treatment of carbon monoxide poisoning in child
1998;339:1603–8. 8. Meredith T, Vale A. Carbon monoxide poisoning. Br Med J (Clin Res Ed) 1988;296:77–9. 9. Tomaszewski C. Carbon monokside. In: Goldfrank LR, Flomenbaum NE, Lewin NA, Weisman RS, Howland MA, Hoffman A editors. Goldfrank’s Toxicologic Emergencies. 5th ed. Norwalk, Connecticut: Appleton & Lange; 1999: p. 1199–210. 10. Hampson NB. editor. Hyperbaric Oxygen Therapy: 1999 Committee Report. Kensington MD: Undersea & Hyperbaric Medical Society 1999. 11. Goldbaum LR, Orellano T, Dergal E. Mechanism of the toxic action of carbon monoxide. Ann Clin Lab Sci 1976;6:372–6. 12. Turner M, Hamilton-Farrell MR, Clark RJ. Carbon monoxide poisoning: an update. J Accid Emerg Med 1999;16:92–6. 13. Zhang J, Piantadosi CA. Mitochondrial oxidative stress after carbon monoxide hypoxia in the rat brain. J Clin Invest 1992;90:1193–9. 14. Thom SR. Carbon monoxide-mediated brain lipid peroxidation in the rat. J Appl Physiol 1990;68:997–1003. 15. Chang KH, Han MH, Kim HS, Wie BA, Han MC. Delayed encephalopathy after acute carbon monoxide intoxication: MR imaging features and distribution of cerebral white matter lesions. Radiology 1992;184:117–22. 16. Satran D, Henry CR, Adkinson C, Nicholson CI, Bracha Y, Henry TD. Cardiovascular manifestations of moderate to severe carbon monoxide poisoning. J Am Coll Cardiol 2005;45:1513–6. 17. http://www.turktox.org.tr/index.php/tr/ana-sayfa/36bulten-38/guencel-ve-son-haberler/119-karbon-monoksit-zehirlenmesi (access date: 11 April 2017). 18. Keith W, Van Meter. Carbon monoxide Poisoning. In: Tintinalli JE, Kelen GD, Stapczynski JS editors. Emergency Medicine A Comprehensive Study Guide. New York: McGraw-Hill; 2000: p. 1302-6. 19. Clardy P, Manaker S. Carbon mononoxide poisoning. In: UpToDate, Rose BD, editor. UpToDate: Waltham, MA; 2006. 20. Phin N. Carbon monoxide poisoning (acute). Clin Evid 2005;1732–43. 21. Weaver LK, Hopkins RO, Chan KJ, Churchill S, Elliott CG, Clemmer TP, et al. Hyperbaric oxygen for acute carbon monoxide poisoning. N Engl J Med 2002;347:1057–67. 22. Buckley NA, Isbister GK, Stokes B, Juurlink DN. Hyperbaric oxygen for carbon monoxide poisoning: a systematic review and critical analysis of the evidence. Toxicol Rev 2005;24:75–92. 23. Olson KR. Carbon monoxide. In: Olson KR. editor. Poisoning & Drug Overdose. 4th ed. Mc Graw Hill; 2004. p. 151–4. 24. Gussow L. Carbon Monoxide, Poisoning. In: Schaider JJ, Hayden SR, Wolfe RE, Barkin RM, Rosen P., editors. Rosen & Barkin’s 5-Minute Emergency Medicine Consult. 2nd ed. Lippincott Williams & Wilkins; 2003. p. 178–9 25. Ferri FF, Marx JA, Heikki EN, Runyon MS. Carbon mononoxide poisoning. In: Ferri FF. editor. First Consult. Elsevier; 2006. 26. Turner M, Esaw M, Clark RJ. Carbon monoxide poisoning treated with hyperbaric oxygen: metabolic acidosis as a predictor of treatment requirements. J Accid Emerg Med 1999;16:96–8. 27. Levasseur L, Galliot-Guilley M, Richter F, Scherrmann JM,
107
Baud FJ. Effects of mode of inhalation of carbon monoxide and of normobaric oxygen administration on carbon monoxide elimination from the blood. Hum Exp Toxicol 1996;15:898–903. 28. McMeekin JD, Finegan BA. Reversible myocardial dysfunction following carbon monoxide poisoning. Can J Cardiol 1987;3:118–21. 29. Tom T, Abedon S, Clark RI, Wong W. Neuroimaging characteristics in carbon monoxide toxicity. J Neuroimaging 1996;6:161–6. 30. Pracyk JB, Stolp BW, Fife CE, Gray L, Piantadosi CA. Brain computerized tomography after hyperbaric oxygen therapy for carbon monoxide poisoning. Undersea Hyperb Med 1995;22:1–7. 31. Horowitz AL, Kaplan R, Sarpel G. Carbon monoxide toxicity: MR imaging in the brain. Radiology 1987;162:787–8. 32. Philips SD, Dart RC. Carbon monoxide. In: Dart RC, editor. 5-Minute Toxicology Consult, 1st ed. Lippincott Williams & Wilkins; 2000. p.304–7 33. Leikin JB, Paloucek FP. Poisoning & Toxicology Compendium with Symptoms Index. Hudson (Cleveland), Ohio:Lexi-Comp Inc;1998. p. 932 34. Caravati EM, Adams CJ, Joyce SM, Schafer NC. Fetal toxicity associated with maternal carbon monoxide poisoning. Ann Emerg Med 1988;17:714–7. 35. Meter VK. Carbonmonoxide poisoning. In: Tintinalli J, Kelen E. editors. Emergency Medicine. 5th ed. USA: The Mc Graw-Hill; 2000: p. 1302–6. 36. Salam MT, Millstein J, Li YF, Lurmann FW, Margolis HG, Gilliland FD. Birth outcomes and prenatal exposure to ozone, carbon monoxide, and particulate matter: results from the Children’s Health Study. Environ Health Perspect 2005;113:1638–44. 37. Chou KJ, Fisher JL, Silver EJ. Characteristics and outcome of children with carbon monoxide poisoning with and without smoke exposure referred for hyperbaric oxygen therapy. Pediatr Emerg Care 2000;16:151–5. 38. Knight L, Levin A, Mendenhall C. Candles and Incense as Potential Sources of Indoor Air Pollution: Market Analysis and Literature. VA: National Technical Information Service 2001. https://nepis.epa.gov/Exe/ZyPDF.cgi?Dockey=P1009BZL. txt (access date: 11 April 2017). 39. Bolat F, Uslu S, Bülbül A, Cömert S, Can E, Nuhoğlu A. Yenidoğan Döneminde Karbonmonoksit İntoksikasyonu: Vaka Sunumu. Çocuk Dergisi 2010:10:47–50. 40. Burney RE, Wu SC, Nemiroff MJ. Mass carbon monoxide poisoning: clinical effects and results of treatment in 184 victims. Ann Emerg Med 1982;11:394–9. 41. Uemura K, Hoshino S, Uchida K, Tsuruta R, Maekawa T, Yoshida K. Hypothermia attenuates delayed cortical cell death and ROS generation following CO inhalation. Toxicol Lett 2003;145:101–6. 42. Penney DG. Chronic carbon monoxide poisoning: a case series. In: PenneyDG. editor. Carbon monoxide poisoning. Boca Raton, FL: CRC Press; 2008: p. 551–67. 43. Gorman DF, Clayton D, Gilligan JE, Webb RK. A longitudinal study of 100 consecutive admissions for carbon monoxide poisoning to the Royal Adelaide Hospital. Anaesth Intensive Care 1992;20:311–6.