Northern Clinics of Istanbul - NCI by KAREPUBLISHING

P ISSN 2148–4902 E ISSN 2536–4553

NORTHERN CLINICS OF ISTANBUL • İSTANBUL KUZEY KLİNİKLERİ NORTHERN CLINICS OF ISTANBUL • İSTANBUL KUZEY KLİNİKLERİ

Vol. 6 • No. 3 • Year 2019

INDEXED IN WEB OF SCIENCE, EMERGING SOURCES CITATION INDEX, PUBMED, PUBMED CENTRAL, EUROPE PMC, EBSCO, DOAJ, TUBITAK TR INDEX, AND TURKIYE CITATION INDEX.

Journal Abbreviation: North Clin Istanb

Vol. 6 • No. 3 • Year 2019

KARE

The hepatoprotective effect of Aloe vera on ischemiareperfusion injury in rats • The role of thiol levels in predicting contrast-induced nephropathy in patients with ST-segment elevation myocardial infarction who underwent primary percutaneous coronary intervention • Relationship between brain computed tomography findings and

bispectral index score in patients presenting with head trauma • The frequency of alopecia and quality of life in high-school students in rural areas (Sivrihisar, Mahmudiye, Alpu, and Beylikova) of Eskisehir • Echocardiographic assessment of children participating in regular sports training • Lipid profile, atherogenic indices, and their relationship with epicardial

coexistence frequency • The prevalence of thyroid dysfunction and its relationship with perinatal outcomes in pregnant women in the third trimester • How successful is “pleural sound sign” in the identification of pneumothorax? • Comparison of intraoperative ultrasonography guidance with an open surgical method for venous port catheter

fat thickness and carotid intima–media thickness in celiac disease • Factors associated with diverticular bleeding and re-bleeding: A United States hospital study • Nephrolithiasis in ankylosing spondylitis and its relationship with disease assessment scales • Investigation of C5–C6 radiculopathy and shoulder rotator cuff lesions

placement in chemotherapy • Otorhinolaryngological symptoms among smokeless tobacco (Maras powder) users • Evaluation of the predictive power of laboratory markers in the diagnosis of acute appendicitis in the elderly • Ascariasis-associated perforated appendicitis: Computed tomography findings • Unusual combined cause of Takotsubo cardiomyopathy:

Hyponatremia and seizure • 46 XX male syndrome with hypogonadotropic hypogonadism: A case report • Subperiosteal hemorrhage due to a distal femoral physeal fracture in a neonate • Lansoprazole as an uncommon cause of anaphylaxis: What to give next? • History of establishment and evaluation of Ottoman-Turkish urology inside the surgical science

NORTHERN CLINICS OF ISTANBUL İSTANBUL KUZEY KLİNİKLERİ Editor Levent Doganay, M.D.

Associate Editors

Publıcatıon Coordınators

Berna Terzioglu Bebitoglu, M.D. Bekir Durmus, M.D.

Beril Tekay Umut Elmas

Betul Sozeri, M.D.

Asistant to the Edıtor

Managing Editor

Aysenur Aydin

Neslihan Buyukmurat, M.D.

Scientıfıc Commıttee* Didem Tuba Akcali, M.D.

Mehmet Zafer Goren, M.D.

Sait Naderi, M.D.

Ilknur Aktas, M.D.

Aysegul Gunduz, M.D.

Kemal Nas, M.D.

Mustafa Aldag, M.D.

Ozlem Guneysel, M.D.

Cagatay Nuhoglu, M.D.

Mustafa Aldemir, M.D.

Melek Gura Celik, M.D.

Tamer Okay, M.D.

Orhan Alimoglu, M.D.

Melih Atahan Guven, M.D.

Muhammed Fatih Onsuz, M.D.

Nuri Aydin, M.D.

Mert Ilker Hayiroglu, M.D.

Melike Ozcelik, M.D.

Ozlem Baysal, M.D.

Mine Hekimgil, M.D.

Kamil Ozdil, M.D.

Basak Bilir Kaya, M.D.

Seyhan Hidiroglu, M.D.

H. Isin Ozisik Karaman, M.D.

Hasan Bombaci, M.D.

Afitap Icagasioglu, M.D.

Necdet Saglam, M.D.

Derya Buyukkayhan, M.D.

Ates Kadioglu, M.D.

Abdurrahman Sahin, M.D.

Mustafa Caliskan, M.D.

Atila Karaalp, M.D.

Tarik Sapci, M.D.

Kazim Capaci, M.D.

Ayse Serap Karadag, M.D.

Ayse Banu Sarifakioglu, M.D.

Turhan Caskurlu, M.D.

Ihsan Muhammet Karaman, M.D.

Fatih Saygili, M.D.

Ali Riza Cenk Celebi, M.D.

Semra Kayatas Eser, M.D.

Mehmet Selcuki, M.D.

Beyhan Cengiz Ozyurt, M.D.

Umut Kefeli, M.D.

Ozlem Tanriover, M.D.

Tongabay Cumurcu, M.D.

Tayfun Kirazli, M.D.

Gulnur Tokuc, M.D.

Gizem Dinler Doganay, M.D.

Gurkan Kiran, M.D.

Filiz Topaloglu Demir, M.D.

Sibel Dogan, M.D.

Cemal Kocaaslan, M.D.

Ismail Turkmen, M.D.

Mehmet Doganay, M.D.

O. Emek Kocaturk Goncu, M.D.

Sezgin Vatansever, M.D.

Dilek Erdogan Ari, M.D.

Sukran Kose, M.D.

Ayhan Verit, M.D.

Yuksel Ersoy, M.D.

Turkan Kudsioglu, M.D.

Destina Yalcin, M.D.

Duygu Geler Kulcu, M.D.

Kemal Memisoglu, M.D.

Tuba Yavuzsen, M.D.

Kaan Gideroglu, M.D.

Aysel Milanlioglu, M.D.

Sema Yilmaz, M.D.

Ahmet Gocmen, M.D.

Murat Muhcu, M.D.

Ebru Zemheri, M.D.

*The editorial board list is sorted alphabetically by surname.

NORTHERN CLINICS OF ISTANBUL İSTANBUL KUZEY KLİNİKLERİ YEAR 2019 VOLUME 6 NUMBER 3

p ISSN 2148 - 4902 e ISSN 2536 - 4553

Ownership and Accountability for Contents on behalf of The Istanbul Health Directorate Kemal Tekesin, M.D.

Publicatıon Manager Kemal Memisoglu, M.D.

Publicatıon Coordinators Beril Tekay Umut Elmas

Executive Office Umraniye Teaching and Research Hospital Elmalikent Mah., Adem Yavuz Cad. No: 1, 34764 Umraniye, Istanbul-Turkey Phone: +90 216 632 18 18 Fax: +90 216 632 71 24 http://www.kuzeyklinikleri.com e-mail: bilgi@kuzeyklinikleri.com Indexed in Web of Science, Emerging Sources Citation Index, PubMed, PubMed Central, Europe PMC, DOAJ, TUBITAK TR Index, CINAHL and Turkiye Citation Index.

Publisher KARE PUBLISHING Dumlupinar Mah., Cihan Sok., No: 15, B Blok Da: 162 Kadikoy, Istanbul, Turkey Tel: +90 216 550 61 11 Fax: +90 216 550 61 12 http://www.kareyayincilik.com e-mail: kare@kareyayincilik.com

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Northern Clinics of Istanbul (NCI) is a peer-reviewed journal published 4 issues in a year. Materials published in the Journal is covered by copyright ©2019 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.

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Press date: September 2019 Circulation: 1000 Type of publication: Periodical

CONTENTS Vol. 6 • No. 3 • Year 2019 IV

Instructions for the authors

O R I G I N A L A RT I C LE S 203–209 The hepatoprotective effect of Aloe vera on ischemia-reperfusion injury in rats M. H. Sehitoglu, I. Karaboga, A. Kiraz, H. A. Kiraz 210–218 The role of thiol levels in predicting contrast-induced nephropathy in patients with ST-segment elevation myocardial infarction who underwent primary percutaneous coronary intervention A. Korkmaz, B. Ozyazgan, A. Kosem, O. Ucar Elalmis, U. Guray, M. Ileri, S. Neselioglu, O. Erel 219–225 Relationship between brain computed tomography findings and bispectral index score in patients presenting with head trauma O. Kusken, T. Cimilli Ozturk, A. Hunuk, E. Unal Akoglu, R. Ak, C. Arslan Turan, O. E. Onur 226–235 The frequency of alopecia and quality of life in high-school students in rural areas (Sivrihisar, Mahmudiye, Alpu, and Beylikova) of Eskisehir O. Ozay, D. Arslantas, A. Unsal, I. Bulur 236–241 Echocardiographic assessment of children participating in regular sports training S. Kayali, F. T. Yildirim 242–247 Lipid profile, atherogenic indices, and their relationship with epicardial fat thickness and carotid intima–media thickness in celiac disease Z. Caliskan, K. Demircioglu, S. Sayar, R. Kahraman, O. Caklili, F. B. Ozcan, O. Kostek, O. F. Baycan, H. L. Doganay, M. Caliskan 248–253 Factors associated with diverticular bleeding and re-bleeding: A United States hospital study A. Abdel Jalil, R. Gorski, S. Abdel Jalil, R. Cronin, M. Comianos, M. Mann, H. Rajagopalan, A. Abdel Jalil, V. Tahan 254–259 Nephrolithiasis in ankylosing spondylitis and its relationship with disease assessment scales A. Rezvani, I. Aktas, N. Tastekin, R. Celiker, S. Sarikaya, E. Dursun, S. Ozdolap, N. Dursun, C. Zateri, L. Altan, M. Birtane, K. Akgun, N. Sut 260–266 Investigation of C5–C6 radiculopathy and shoulder rotator cuff lesions coexistence frequency C. Arifoglu Karaman, B. Oz, A. Sari 267–272 The prevalence of thyroid dysfunction and its relationship with perinatal outcomes in pregnant women in the third trimester H. Dulek, F. Vural, N. Aka, S. Zengin 273–278 How successful is “pleural sound sign” in the identification of pneumothorax? S. Goknil Calik, M. Calik, S. Girisgin, O. Karaoglan, Z. D. Dundar, M. Ergin 279–283 Comparison of intraoperative ultrasonography guidance with an open surgical method for venous port catheter placement in chemotherapy O. O. Balkanay, S. Demiryas 284–292 Otorhinolaryngological symptoms among smokeless tobacco (Maras powder) users S. Sagiroglu, A. Erdogan, A. Doganer, R. A. Okyay 293–301 Evaluation of the predictive power of laboratory markers in the diagnosis of acute appendicitis in the elderly S. Bayrak, C. Tatar, E. Cakar, S. Colak, M. E. Gunes, K. Tekesin, B. Gurbulak, E. Kinaci, M. M. Sevinc

O RI G I N A L I M A G E 302–303 Ascariasis-associated perforated appendicitis: Computed tomography findings S. Aslan, M. S. Nural

C A SE RE PO RTS 304–307 Unusual combined cause of Takotsubo cardiomyopathy: Hyponatremia and seizure E. C. Simsek, S. V. Emren, O. Ozdogan 308–311 46 XX male syndrome with hypogonadotropic hypogonadism: A case report M. M. Yalcin, C. Ozkan, M. Akturk, F. E. Percin, A. Altinova, A. Karakoc, G. Ayvaz, N. Cakir 312–314 Subperiosteal hemorrhage due to a distal femoral physeal fracture in a neonate M. Ozturk, A. Yurtbay, D. Keskin, A. V. Polat, M. B. Selcuk 315–316 Lansoprazole as an uncommon cause of anaphylaxis: What to give next? A. A. Aydin, S. Bilge, T. Duzenli, H. Aslan, G. Aydin

REVIEW 317–319 History of establishment and evaluation of Ottoman-Turkish urology inside the surgical science A. Verit, A. Urkmez, S. Tellaloglu

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Orıgınal Article

BIOCHEMISTRY

North Clin Istanb 2019;6(3):203–209 doi: 10.14744/nci.2018.82957

The hepatoprotective effect of Aloe vera on ischemia-reperfusion injury in rats Muserref Hilal Sehitoglu,1

Ihsan Karaboga,2

Asli Kiraz,3

Hasan Ali Kiraz4

Department of Medical Biochemistry, Canakkale Onsekiz Mart University Faculty of Medicine, Canakkale, Turkey

Emergency and Disaster Management, Namik Kemal University School of Health, Tekirdag, Turkey

Department of Medical Microbiology, Canakkale Onsekiz Mart University Faculty of Medicine, Canakkale, Turkey

Department of Anesthesiology and Reanimation, Canakkale Onsekiz Mart University Faculty of Medicine, Canakkale, Turkey

ABSTRACT OBJECTIVE: Aloe vera is known for its antioxidant properties. In this experimental study, we aimed to investigate the efficacy of Aloe vera in ischemia-reperfusion (I/R) liver injury in rats. METHODS: Male Wistar Albino rats were divided into three groups, where the sham group (n=7) underwent no medication or surgical procedures, the I/R group (n=7) was the control group that received 45 minutes of applied abdominal aorta ischemia and rats were sacrificed 24 hours after reperfusion, and the I/R+AV group (n=7) was the treatment group that was given Aloe vera (30 mg/kg) every day followed by gastric lavage for a month before applying ischemia and performing sacrifice as in the previous group. Before sacrifice, all the liver tissues were removed. Tissues were examined for histopathological investigation, iNOS immunoreactivity and tissue biochemistry, malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) activities. RESULTS: The SOD, CAT, and GSH-Px levels of the I/R+AV group were not significantly different from the sham group (p>0.05) but were significantly higher when compared to the I/R group. MDA levels of liver tissues were significantly lower (p<0.05) in the I/R+AV group as compared to the I/R group. Disrupted hepatic cords, sinusoidal dilatation, hemorrhage, cytoplasmic vacuolization of hepatocytes, and intensive iNOS immunoreactivity were detected in the I/R group. Decreased histopathological change score and iNOS immunoreactivity score were noticed in the I/R+AV group as compared to the I/R group. CONCLUSION: It was found that Aloe vera showed a hepatoprotective effect against I/R injury. Further research is required to determine the effective dose, administration method, and effects of Aloe vera for liver transplantation. Keywords: Aloe vera; hepatoprotective; ischemia-reperfusion; rat.

Cite this article as: Sehitoglu MH, Karaboga I, Kiraz A, Kiraz HA. The hepatoprotective effect of Aloe vera on ischemia-reperfusion injury in rats. North Clin Istanb 2019;6(3):203–209.

rgan damage due to reperfusion after temporary ischemia is related to many clinical tableaux. I/R injury occurs during a variety of surgical interventions like organ transplants and coronary bypasses and due to diseases, such as stroke, shock, and cardiac infarcts. The destructive effects of I/R injury result in direct tissue damage due to a variety of events with harmful effects

at the cellular level and linked inflammation, the formation of acute reactive oxygen radicals (ROS) following re-oxygenation, cell death, and organ failure [1–3]. I/R injury in the liver causes a biphasic response in the form of acute and subacute phases. The acute phase is observed 3– 6 hours after reperfusion and is characterized by free radical formation and activation of

Received: March 23, 2018 Accepted: October 02, 2018 Online: October 10, 2018 Correspondence: Dr. Muserref Hilal SEHITOGLU. Canakkale Onseki̇ z Mart Uni̇ versi̇ tesi̇ Tip Fakultesi, Dekanlik Binasi, 17100 Canakkale, Turkey. Tel: +90 286 218 00 18 - 2103 e-mail: hill_al@hotmail.com © Copyright 2019 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

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T-lymphocytes and Kupffer cells. The response in the subacute phase is intense neutrophil infiltration and is observed 18–24 hours after reperfusion [2]. When examined histopathologically, I/R injury causes cellular swelling, vacuolization, destruction of endothelial cells, and polymorphonuclear cell infiltration [4]. The nitric oxide (NO) synthase family forms a range of enzymes causing oxidative deamination of L-arginine and NO formation. Induced NO-synthase (iNOS) is one of these enzymes, which causes increased levels of NO during inflammatory events by contributing to NO synthesis. iNOS testing is possible in tissues by immunohistochemical staining [5]. In organisms, ROS are natural products that occur as a result of oxygen metabolism. They have a small molecular structure that has a destructive effect on other cells when they are produced in quantities above the antioxidant capacity of the body. Reperfusion of the ischemic liver involves exposure to high levels of ROS, and I/R injury is one of the best examples of this situation. When the balance between ROS and antioxidants is disrupted, oxidative stress occurs. The leading enzymes with protective effects against ROS are superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px). When the levels of these types of protective enzymes and molecules reduce, ROS increases and forms a critical situation. Malondialdehyde (MDA) is a toxic metabolite formed by lipid peroxidation that develops after ischemia and reperfusion and is the most important marker of lipid peroxidation [6–8]. Preventing I/R injury to the liver carries great importance for healing after liver transplants and treatment of severe liver disease. This is because patients with I/R injury are more liable to suffer from mortal complications due to the development of a variety of pathophysiological processes that cause Kupffer cell activation and increase the levels of ROS, inflammatory mediators, and cytokines [9, 10]. There are a variety of studies proving that antioxidants are beneficial for I/R injury [3, 6, 11–13]. Aloe vera (AV) is a semi-tropical plant from the Liliaceae family with a broad range of application in traditional medications [14]. It has been shown that AV has strong antioxidant and antimicrobial properties due to the phenolic compounds it contains. AV gel has almost two hundred bioactive ingredients such as minerals, vitamins, proteins, lipids, amino acids, and polysaccharides [15, 16]. It has proven to be an effective treatment agent

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in many diseases ranging from asthma and ulcers to wound healing and cancer [17]. We have shown that AV is effective against different tissue ischemia-reperfusion injuries in various studies that we have conducted previously [18, 19]. Although AV has some healing effects on liver damage, no study has been done to date to determine whether it can prevent liver from ischemia-reperfusion damage, especially following organ transplantation. This study researched whether AV, known for its antioxidant and antiinflammatory effects, has a protective effect on I/R injury induced in rats. MATERIALS AND METHODS After receiving permission from the Çanakkale Onsekiz Mart University Animal Experiments Local Ethics Committee (decision no: 2014/13-1) a total of 21 male Wistar Albino rats, aged 8–12 weeks and weighing 250– 300 g, were enrolled in the study. During the study, the rats were housed in special cages with appropriate feeding conditions and under controlled temperature (23°C –25°C) and lighting (12 hours light, 12 hours dark), with ad libitum access to food and water. Rats were randomly divided into three groups of seven individuals: Sham group (n=7): Underwent laparotomy and observation only (No I/R and no treatment) to neutralize the effects of surgery and anesthesia. I/R group (n=7): Control group; underwent laparotomy and liver I/R, but AV was not given. I/R+AV group (n=7): Treatment group; underwent laparotomy and liver I/R and AV was given. AV was obtained from Herbalife Turkish distributor (Herbalife Inc, Istanbul, Turkey). It is used by many people as food supplements. Dosage: In this study, we decided the dose of Aloe vera as 30 mg/kg body weight on the basis of studies that used 10–120 mg/kg/day doses to reveal the therapeutic effects of AV [18–24]. Since we have previously demonstrated the efficacy of AV at a dose of 30 mg/kg, a singledose trial was deemed appropriate for use in this study. Experimental Procedure Anesthesia for all groups used xylazine (Bayer, Istanbul, Turkey) 5 mg/kg and ketamine hydrochloride (Parke Davis, Istanbul, Turkey) 50 mg/kg, with spontaneous respiration at room temperature. The rats were placed in the supine position on the operating table under sterile

Sehitoglu et al., The hepatoprotective effect of Aloe vera on ischemia-reperfusion injury in rats

conditions and a skin and subdermal midline incision was opened. Intestines were pushed to the right and the abdominal aorta was accessed via the midline incision. In groups with induced ischemia, the abdominal aorta and inferior vena cava were carefully dissected and separated from each other. The abdominal aorta was clamped from the lower section of the renal artery that turns immediately above the bifurcation. After 45 minutes of clamping, the clamps were removed, and reperfusion ensued. The abdomen was closed appropriately. Rats in all groups were sacrificed 24 hours later by administration of a high dose anesthetic, Ketamine (50 mg/kg). Immediately before the sacrifice, all liver tissues were fully removed. Half of the tissue was stored in formaldehyde. Histopathological investigations, iNOS immunoreactivity and malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) tissue biochemistry tests exposed to ischemia were performed as stated below. Biochemical Investigations of Rat Liver Tissues After macroscopic analysis, rat tissues were kept at − 80 °C. Tissues for biochemical analysis were homogenized in the appropriate buffer separately for each method and supernatants were removed. Superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) activities, and malondialdehyde (MDA) levels of rat liver tissues were duplicated and measured with highly sensitive ELISA spectrophotometry. The protein concentrations were indicated by the Bradford method using Bradford reagent (Sigma Aldrich, Bradford reagent-B6916-1KT, USA). All the data was defined as the mean±standard deviation (SD) based on each milligram of protein. Tissue SOD activities were measured with the SOD assay kit (Biovision-K335-100; Milpitas, CA95035, USA) using highly sensitive ELISA spectrophotometry. The IC50 (50% inhibition activity of SOD) values were determined by this colorimetric method under 450 nm. The results were expressed as U/mL SOD per milligram protein (U/mL.mg protein). CAT activity of rat liver tissues was determined with a commercial colorimetric kit, the S-341 Cell Biolabs’ OxiselectTM Catalase Activity Assay Kit. The results, measured using highly sensitive ELISA spectrophotometry, were expressed as U/mL CAT per milligram protein (U/mL.mg protein). Liver tissue GPx activities were measured with a commercial Glutathione Peroxidase Activity Colorimet-

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ric Assay Kit (Biovision-K762-100; Milpitas, CA95035, USA) using highly sensitive ELISA spectrophotometry. The results were expressed as U/mL GPx per milligram protein (mU/mL.mg protein). Lipid peroxidation was determined by the reaction of malondialdehyde (MDA) with thiobarbituric acid (TBA) to form a colorimetric (532 nm) product, proportional to the MDA present. The Lipid Peroxidation Colorimetric/Fluorometric Assay Kit (BiovisionK739-100; Milpitas, CA95035, USA) was used to determine MDA levels. The results were expressed as nmole MDA per milligram tissues (nmole/mg tissue). Statistical Analysis Results were subjected to a one-way analysis of variance (ANOVA) using SPSS 21.0 software (SPSS Inc., USA). Differences among the groups were obtained using Turkey’s test. Statistical significance was accepted as p<0.05. All the data was expressed as mean ± SD in each group. Histopathological Examination For histopathological examination, liver tissues were fixed in 4% formaldehyde for 48 hours. After fixation, tissues were embedded in paraffin and cut into 5 µm sections by a microtome (Slee, 5061). Paraffin sections were stained with hematoxylin and eosin (H&E). H&E-stained sections were examined under a light microscope (Olympus CX41) by two histopathologists blind to the grouping of the animals, who used different magnifications to detect liver injury. Histopathological changes of sinusoidal dilatation, hemorrhage, and vacuolization were assessed in the liver tissue. Tissue damage was graded and scored as follows; 0: normal histological appearance, 1: mild, 2: moderate, and 3: severe. Immunohistochemical Examination For examination of iNOS immunoreactivity in liver tissue, paraffin-embedded liver tissue was cut into 5 µm segments and deparaffinized in xylene, following which it was rehydrated in graded series by ethanol. Sections were washed in phosphate buffer saline and boiled in a citrate buffer using a microwave oven at 90°C–100°C for 10 minutes. Endogenous peroxidase activity was blocked with H2O2 and sections were transferred to normal goat serum to block nonspecific binding. Then sections were incubated with primary antibody (Anti-iNOS, ab15323)

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Table 1. Superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activities, and levels of malondialdehyde (MDA) of rat liver tissues

Groups SOD CAT GPx MDA (U/ml.mg protein) (U/ml.mg protein) (U/ml.mg protein) (nmol/mg tissue) Mean±SD Mean±SD Mean±SD Mean±SD Liver Sham group 24.03±5.11 32.36±5.41 36.10±3.59 4.99±0.29 I/R 0.57±0.42* 10.40±3.35* 16.43±3.26* 18.30±1.46* I/R+AV 17.97±1.99ß 29.60±2.28ß 31.14±4.65ß 7.70±2.30ß SD: Standard deviation; I/R: Ischemia reperfusion; AV: Aloe vera. The notations * and ß are significantly different with respect to the One-way ANOVA-Tukey’s test in each column (p<0.05).

RESULTS The mean and SD values of SOD, CAT, GPx, and MDA in all groups are shown in Table 1 and Figure 1. SOD, CAT, and GPX levels of I/R group (0.57±0.42, 10.40±3.35, and 16.43±3.26 U/ml.mg protein, respectively) were found to be lower as compared to the other groups, and this was statistically significant (p<0.05). SOD, CAT, and GPX levels of I/R+AV group (17.97±1.99, 29.60±2.28, and 31.14±4.65 U/ ml.mg protein, respectively) were not significantly dif-

U.mL-1.mg protein-1

Sham

I/R+AV

I/R

40.00

30.00 b

20.00 10.00 0.00

CAT activity

SOD activity Sham

mU.mL-1.mg protein-1

Statistical Analysis Data was analyzed using the SPSS 16.0 statistical software package for Windows (SPSS Inc, Chicago, USA). The results were reported as mean±SD. Groups were compared using the nonparametric Kruskal-Wallis test. The Mann-Whitney U test was used for binary comparisons. The Spearman correlation test was used to evaluate the relationship between the variables histologically. A pvalue of less than 0.05 was considered significant.

I/R

I/R+AV

60.00 b

40.00 20.00 0.00

GPx activity Sham

I/R

I/R+AV

30.00 nmol/mg

in a humidified chamber at room temperature for 1 hour. After incubation of anti-iNOS, the sections were incubated with biotinylated secondary antibody and streptavidin peroxidase (Ultra Vision Detection System-HRP kit, Thermo Scientific/Lab Vision) at room temperature for 10 minutes, respectively. Chromogen 3-amino-9-ethyl-carbazole (AEC Substrate System, Thermo Scientific/ Lab Vision) was applied, and the sections were counterstained with hematoxylin. Anti-iNOS immunoreactivity was examined and scored semi-quantitatively from 0 to 3 as follows; 0: none, 1: weak, 2: moderate, and 3: intense for each liver tissue.

20.00

10.00 0.00

MDA levels

Figure 1. The effects of aloe vera therapy on superoxide dismutase (SOD) and catalase (CAT) (A), glutathione peroxidase (GPX) (B) activities and levels of malondialdehyde (MDA) (C) of rat liver tissues. Aloe vera therapy groups are significantly different compared to the ischemia groups (p<0.05).

ferent from the sham group (p>0.05) but were significantly higher when compared to the I/R group. In the same way, MDA levels of liver tissues were

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Figure 2. Hematoxylin & eosin (H&E) staining of liver tissue. (A) Sham group showing normal histological appearance, (B) I/R group showing disrupted hepatic cord and vacuolization, and (c) I/R+AV showing minimal sinusoidal dilation and vacuolization (H&E, 200X, arrow; cytoplasmic vacuolization, star; disrupted hepatic cords, arrowhead; hemorrhage).

Table 2. Comparison of histopathological changes and iNOS immunoreactivity scores of groups Group

Sinusoidal Hemorrhage Cytoplasmic iNOS dilatation vacuolization immunoreactivity Mean±SD Mean±SD Mean±SD Mean±SD

Sham group 0 0 0 0.7±0.4 I/R 2.7±0.4a 2.4±0.5a 2.3±0.4a 2.8±0.4a I/R+AV 1.5±0.5a,b 1.2±0.6a,b 1.5±0.5a,b 1.2±0.4a,b iNOS: Induced NO-synthase; SD: Standard deviation; I/R: Ischemia reperfusion; AV: Aloe Vera; aCompared with Control group (p<0.05); bCompared with I/R group (p<0.05).

Figure 3. Immunohistochemical staining of liver tissue with Anti-iNOS. (A) Sham, (B) I/R, (C) I/R+AV. AV-treated groups showing decreased iNOS immunoreactivity. (Hematoxylin counterstain, 200X, arrow; iNOS positive cells).

significantly lower (p<0.05) in the I/R+AV group (7.70±2.30 nmol/mg tissue) as compared to the I/R group (18.30±1.46 nmol/mg tissue). As revealed in Figure 2, normal liver architecture was observed in the sham group. Disrupted hepatic cords, sinusoidal dilatation, hemorrhage, cytoplasmic vacuolization of hepatocytes, and intensive iNOS im-

munoreactivity was detected in the I/R group. Decreased histopathological change score and iNOS immunoreactivity score was noticed in the I/R+AV group (Table 2, p<0.05). iNOS immunoreactivity was clearly decreased in I/R+AV group as compared to the I/R group (p<0.05). Immunohistochemical findings of the groups are presented in Figure 3.

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DISCUSSION Liver transplantation is a commonly used treatment method for congenital and acquired disorders of the liver [2]. I/R injury in liver transplantation is closely related to nonfunctional or dysfunctional graft development and may result in graft rejection. ROS and reactive nitrogen radicals (RNS) play an important role during I/R injury by intracellular calcium overload and many cellular factors. In this situation, the consumption of endogenous antioxidants due to the release of ROS and RNS causes apoptotic and necrotic cell death. Among endogenous intracellular antioxidants, catalase, superoxide dismutase, glutathione peroxidase, and allopurinol are the most well-known. iNOS is released by endothelial cells, hepatocytes, and Kupffer cells and is an enzyme that is active independent of calcium. iNOS has protective and toxic effects on the effect linked to the type of stimulus, iNOS expression levels, and duration [6, 25]. Many extracellular antioxidant agents have been shown to have beneficial effects for treatment of liver I/R injury. Examples of these include α-tocopherol, ascorbate, coenzyme Q, pentoxifylline, lipoic acid, quercetin, cyanidin, green tea extract, N-acetylcysteine, catalase derivatives, allopurinol, and aminoguanidine. Many clinical and experimental studies on these types of antioxidants have produced different results, which may be linked to the type of subjects used in the study, the method of administration, duration and dose of the antioxidant agent used, duration of ischemia, and many other factors [6]. Currently, AV is used widely in food and drinks, pharmaceutical material, and cosmetics. Aloe species are generally used worldwide due to its anti-tumor, antiinflammatory, antioxidant, and laxative effects [14, 26]. An experimental study on rats showed that AV had a neuroprotective effect on the sciatic nerve in I/R injury [27]. To date, though many studies have used Aloe vera, there is no study that investigated the protective effect of AV on I/R injury in the liver. In a study of the effects of AV gel against oxidative stress-induced liver damage, it was determined that AV reduced the formation of lipid peroxidation [28]. Also, when the effects of AV were examined on nephrotoxicity in rabbits, it was determined to have increased the total antioxidant status, reduced the total oxidant status, and increased serum catalase levels due to increased doses of AV [29]. AV has favorable effects on the antioxidant enzyme levels of streptozotocin-induced diabetes in rats. When superoxide dismutase, glutathione peroxidase,

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catalase, and glutathione s-transferase enzyme levels of rats administered with AV were compared to rats given glibenclamide as a reference antidiabetic drug, the results were not significantly different. AV was effective on enzyme levels similar to glibenclamide and the antioxidant enzyme levels were increased as compared to diabetic rats [30]. In this study, it was found that catalase, superoxide dismutase, and glutathione peroxidase enzyme levels in rats administered with AV were significantly greater than in rats in the I/R group. The MDA levels in the AV group were significantly lower than in the I/R group. Our results suggest that AV’s antioxidant levels are beneficial for I/R injury of the liver. It was seen that the iNOS expression levels are decreased in the AV-treated rats in the liver injury induced by carbon tetrachloride [31]. Also, in our previous study, we have shown by histopathological examination that the increase in the level of nNOS with damage caused by cerebral ischemia was decreased by AV effect. nNOS levels of the I/R+AV group (36.71±5.15) were found to be lower as compared to the I/R group (62.71±11.91) [19]. Histopathological investigation revealed that the negative effects linked to I/R injury in the AV group were improved by the administration of a certain amount of AV. iNOS immunoreactivity was significantly lower in the AV group as compared to the I/R group, which supports the hepatoprotective effect of AV on I/R injury. When we consider that oxidative stress plays a role in countless diseases, it becomes important to determine a direct and in vivo effect on oxidative damage. Currently, oxidative stress is shown by new biological markers, and of these, allantoin measured in urine is promising [32]. In our study, the newly discovered oxidative stress markers were not examined, and this was a limiting factor. There is a need to develop new agents with fewer side effects to replace these medications. We believe that more studies will be beneficial to patients and clinicians in determining the administration dose, method, and possible effects of herbal material with proven antioxidant activity like AV. Ethics Committee Approval: Canakkale Onsekiz Mart University, Animal Experiments Local Ethics Committee (Decision no: 2014/13-1) Conflict of Interest: There is no conflict of interests. Financial Disclosure: The authors declared that this study has received no financial support. Authorship Contributions: Concept – MHS; Design – MHS, HAK; Supervision – MHS; Materials – MHS, HAK, IK, AK; Data collection and/or processing – MHS, IK; Analysis and/or interpretation – MHS, IK; Writing – MHS, AK; Critical review – MHS, AK, HAK.

Sehitoglu et al., The hepatoprotective effect of Aloe vera on ischemia-reperfusion injury in rats

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Orıgınal Article

CARDIOLOGY

North Clin Istanb 2019;6(3):210–218 doi: 10.14744/nci.2018.72335

The role of thiol levels in predicting contrast-induced nephropathy in patients with ST-segment elevation myocardial infarction who underwent primary percutaneous coronary intervention Ahmet Korkmaz,1 Mehmet Ileri,

Burcu Ozyazgan,1 Salim Neselioglu,

Arzu Kosem,2

Ozgul Ucar Elalmis,1

Umit Guray,1

Ozcan Erel

Department of Cardiology, Ankara Numune Training and Research Hospital, Ankara, Turkey

Department of Clinical Biochemistry, Ankara Numune Training and Research Hospital, Ankara, Turkey

Department of Clinical Biochemistry, Yildirim Beyazit University Faculty of Medicine, Ankara, Turkey

ABSTRACT OBJECTIVE: Contrast-induced nephropathy (CIN) is a common complication of diagnostic or interventional procedures that may arise from administration of intravascular contrast media. Recent studies have reported the thiol-disulfide ratio as a novel oxidative stress marker. Therefore, we investigated the role of thiol levels in predicting CIN in patients with ST-segment elevation myocardial infarction (STEMI) who had undergone primary percutaneous coronary intervention (PCI). METHODS: A total of 302 patients were enrolled in the study. CIN was defined as an increase in serum creatinine concentration ≥0.5 mg/dL compared with the admission value or a >25% relative rise during the first 48–72 hours after the procedure. To evaluate the relationship between thiol levels and CIN, the patients were divided into a CIN group and a non-CIN group. RESULTS: CIN occurred in 44 (15%) patients. Native thiol (274.8±84.7 μmol/L vs. 220.8±97.1 μmol/L, p=0.001) and total thiol (305.4±89.7 μmol/L vs. 260.1±102.1 μmol/L, p=0.009) levels were higher in patients within the non-CIN group. Disulfide (15.8±6.6 μmol/L vs. 19.6±8.4 μmol/L, p=0.002) levels, and mean disulfide/total thiol ratios (8.4±3.7 vs. 5.9±3.1, p=0.001) were higher in patients with CIN (+) group. In univariate analysis, the initial native thiol, total thiol, disulfide levels, and disulfide/total thiol ratio were found to have prognostic significance in the development of CIN. In the multivariate regression analysis, only the disulfide/total thiol ratio (OR=1.190; 95% CI: 1.090–1.300; p=0.001) was significantly and independently associated with CIN. The cutoff value of the disulfide/total thiol ratio to predict CIN on admission in patients with STEMI who underwent primary PCI was 7, with a sensitivity of 68.2% and a specificity of 79.8%. CONCLUSION: Our results suggest that thiol/disulfide homeostasis could be a good biochemical risk marker for CIN in STEMI patients who underwent primary PCI. Keywords: Acute myocardial infarction; contrast-induced nephropathy; thiol levels.

Cite this article as: Korkmaz A, Ozyazgan B, Kosem A, Ucar Elalmis O, Guray U, Ileri M, et al. The role of thiol levels in predicting contrast-induced nephropathy in patients with ST-segment elevation myocardial infarction who underwent primary percutaneous coronary intervention. North Clin Istanb 2019;6(3):210–218.

Received: December 27, 2017 Accepted: September 24, 2018 Online: August 26, 2019 Correspondence: Dr. Ahmet KORKMAZ. Ankara Numune Egitim ve Arastirma Hastanesi, Kardiyoloji Klinigi, Ankara, Turkey. Tel: +90 505 913 53 80 e-mail: drahmtkrkmz07@gmail.com © Copyright 2019 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

Korkmaz et al., Thiol levels and contrast-induced nephropathy in patients with STEMI

ontrast-induced nephropathy (CIN) is a common complication of diagnostic or interventional procedures that may arise from administration of intravascular contrast media. It is defined as an increase in baseline serum creatinine level by ≥25% or an absolute increase of ≥0.5 mg/dL within 48–72 hours after contrast media administration [1]. CIN has become the third leading cause of hospital-acquired acute kidney injury following surgery and nephrotoxic drug damage, accounting for 11% of observed cases [2]. The reported incidence of CIN ranges between 5%–50% depending on the previous risk of the investigated patient population [3]. Pre-existing renal dysfunction and diabetes mellitus (DM) are major patient-related risk factors [3]. CIN is closely associated with prolonged hospitalization, increased costs, a risk of end-stage renal failure, repeated revascularization, and increased morbidity and mortality in the short- and long-term [1, 4, 5]. Thiols are organosulfuric compounds that contain carbon-bonded sulfhydryl groups (-SH). They are mostly present in the cytosol and mitochondria [6], with lower concentrations in plasma. They are composed of human plasma albumin and to a lesser extent by low-molecular-weight thiols such as cysteinylglycine, cysteine (Cys), homocysteine, glutathione, and γ-glutamylcysteine [7]. Thiols may undergo oxidative reactions that yield various products. One such process is the thiol-disulfide exchange reaction [8]. When oxidative stress increases, oxidation of Cys residues lead to the reversible formation of mixed disulfides between low-molecular-mass thiols and protein thiol groups. These disulfide bonds can be reduced back to thiol groups, thus maintaining a thiol/ disulfide homeostasis [9]. Therefore, thiols constitute a substantial proportion of the total level of antioxidants and play an important role in the defense mechanisms against radical oxygen species (ROS) [10]. In recent studies, the thiol-disulfide ratio has been reported to be a novel oxidative stress marker. Although there is a confirmed association of oxidative stress with acute myocardial infarction (AMI) and CIN [11–14], to our knowledge, there are no studies to date that address thiol levels and thiol/disulfide homeostasis in CIN. Therefore, we investigated the role of thiol levels in predicting CIN in patients with ST-segment elevation myocardial infarction (STEMI) who underwent primary percutaneous coronary intervention (PCI). MATERIALS AND METHODS The Local Ethics Committee approved of the study

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protocol and all participants provided their written informed consents. From November 2016 to September 2017, we prospectively collected in-hospital data from consecutive patients who underwent emergency primary PCI for AMI within 12 hours of the onset of symptoms. The diagnosis of STEMI was established according to contemporary guidelines [15]. We excluded patients who were on chronic peritoneal or hemodialysis treatment, those who had undergone renal transplantation, or those who had been exposed to a contrast injection within 2 weeks before PCI. Patients with an active infection or chronic inflammatory disease, a significant systemic disease, severe hepatic dysfunction, known malignancy, or major surgery in the previous month were also excluded, as were patients who presented with cardiogenic shock or died during the first 72 hours of their hospital stay or during revascularization. During the study, 302 patients who met the above-mentioned criteria were enrolled. To evaluate the possible relationship between thiol levels and CIN, the study patients were divided into two groups according to the development of CIN, i.e., CIN (+) group and CIN (-) group. The patients’ baseline characteristics were recorded along with their respective in-hospital and followup data. In all patients, a detailed medical history was recorded, including the presence and management of hypertension, hypercholesterolemia, diabetes mellitus, family history of coronary artery disease, and smoking status. Patients who had an average blood pressure level of ≥140/90 mmHg or were under antihypertensive medication were considered hypertensive. DM was diagnosed if the patient had fasting glucose levels of ≥126 mg/dl measured twice during the follow-up or was on an antidiabetic prescription before the AMI incident [16]. Patients who smoked at least one cigarette per day were deemed active smokers. All primary PCIs were performed via the femoral or radial artery by an experienced interventional cardiologist using the appropriate equipment (Siemens Axiom Artis Z Angiography System, Germany). Nonionic low osmolality contrast medium (Omnipaque 350 MG/ml; GE Healthcare, Cork, Ireland) was used for these procedures. Total contrast medium volume used during primary PCI was recorded in all patients. All patients were administered 300 mg acetylsalicylic acid (ASA) with a loading dose of 60 mg prasugrel or 180 mg ticagrelor before the procedure. A dose of 70–100 U/kg unfractionated heparin was administered after

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visualizing the arterial anatomy. The use of bare metal or drug-eluting stents and glycoprotein IIb/IIIa was left to the discretion of the physician. All patients received intravenous hydration with isotonic saline. All patients were transferred to the intensive care unit after the procedure, where treatment was continued with 100 mg ASA and 10 mg prasugrel or 90 mg ticagrelor twice a day. The decision for concurrent use of statins, angiotensin-converting enzyme inhibitors, and beta-blockers was made according to the recommendations in the guidelines. After the coronary intervention, transthoracic echocardiography assessments were performed at the coronary intensive care unit using Vivid 7 (GE Medical System, Horten, Norway) with a 3.5 MHz transducer. On admission, venous blood samples were obtained before the administration of any medication. Serum creatinine concentration was measured in all patients at admission and at 24 hours, 48 hours, and 72 hours after primary PCI. After the serum samples for thiol were collected, they were centrifuged at 1500 g for 10 minutes and the separated samples were stored in plain tubes at − 80 0C until the analysis. CIN was defined as an increase in serum creatinine concentration by ≥0.5 mg/dL as compared to the admission value or a >25% relative rise during the first 48–72 hours after the procedure. Serum glucose, creatinine, blood urea nitrogen, alanine-amino transferase, total cholesterol, low-density lipoprotein (calculated with Friedewald Formula: Total cholesterol-(HDLc)-TG/5), high-density lipoprotein, and triglyceride values were measured by an automatic biochemistry analyzer (Roche Diagnostics, Indianapolis, IN, USA). Hematological parameters were measured from citrate-based anticoagulated tubes by the Sysmex K-1000 autoanalyzer (Block Scientific, Bohemia, N.Y., USA) within 30 minutes of sampling. Thiol/disulfide homeostasis was measured according to the procedure defined by Erel et al. [17]. Subsequently, the reducible disulfide bonds were reduced to form free functional thiol groups. Sodium borohydride was used as reductant the and unused reductant was extracted with formaldehyde. All thiol groups containing native and reduced bonds were determined after a reaction with 5, 5′-dithiobis-(2-nitrobenzoic) acid. Half of the difference between native and total thiols ensured the dynamic disulfide quantity (−S-S). After determining the amounts of native thiol (−SH) and disulfide (−S-S), the ratio of disulfide to native thiol (−S-S−/−SH) was calculated [17].

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Statistical Analysis For baseline characteristics, the Kolmogorov-Smirnov test was used to test the normality of distribution. Quantitative variables with a normal distribution were specified as mean±standard deviation, while variables with nonnormal distribution were shown as median (interquartile range) and categorical variables were shown as number and percentage values. For continuous variables with a normal distribution, the Student’s t-test was used to compare groups, while the Mann–Whitney U test was used when the distribution was not normal. Categorical variables were compared with Chi-square and Fisher’s Exact Chi-square tests. To determine the independent predictors of CIN, parameters with a significance level of 0.1 or less on the univariate analysis were investigated using the univariate and multivariate logistic regression model. The receiver operating characteristics (ROC) curve was used to show the sensitivity and specificity of disulfide/total thiol ratio, which is the optimal cutoff value for predicting CIN. Differences were considered significant at the 2-sided P-value of <0.05. All statistical analyses were carried out using the SPSS for Windows version 22 (IBM SPSS Inc., Chicago, IL). RESULTS Demographic, clinical, and laboratory characteristics of the patients are summarized in Table 1. The study population consisted of 302 patients with a mean age of 60.2±12.7 years. Of the 302 patients, 130 (43%) were female and 44 (15%) developed CIN. In the CIN group, the baseline creatinine was higher as compared to the non-CIN group. There were no differences in the other parameters between the CIN (+) and CIN (-) groups (p>0.05) (Table 2). Native thiol (274.8±84.7 μmol/L vs. 220.8±97.1 μmol/L, p=0.001) and total thiol (305.4±89.7 μmol/L vs. 260.1±102.1 μmol/L, p=0.009) levels were higher in patients in the non-CIN group. Disulfide levels (15.8±6.6 μmol/L vs. 19.6±8.4 μmol/L, p=0.002) and mean disulfide/total thiol ratios (8.4±3.7 vs. 5.9±3.1, p=0.001) were higher in patients with CIN (+) group (Table 3). The relationship between the disulfide/total thiol ratio levels with CIN in patients with AMI is shown in Figure 1. The results of the univariate and multivariate regression analysis for CIN are listed in Table 4. In the univariate analysis, the initial native thiol, total thiol, disulfide levels, and disulfide/total thiol ratio were found to have

Korkmaz et al., Thiol levels and contrast-induced nephropathy in patients with STEMI

Table 1. Baseline clinical, demographic, and laboratory characteristics of the study population Age (Med., Mean±SD, Min.-Max.)

59.0 / 60.2±12.7 / 33.0–81.0

Gender (Male / Female) 172 (57%) / 130 (43%) DM, n (%)

106 (35%)

HT, n (%)

131 (43%)

CAD, n (%)

87 (29%)

CABG, n (%)

32 (11%)

TIA/Stroke, n (%)

22 (7%)

AMI localization Anterior / Non-anterior 176 (58%) / 126 (42%) Access site Femoral / Radial 184 (61%) / 118 (39%) Smoking, n (%)

180 (60%)

Median Mean±SD Min.-Max.

Glucose (mg/dL)

124.5 150.3±81.2 68–533

Serum creatinine (mg/dL)

1.05 1.122±0.677 0.63–1.8

Hemoglobin (g/L)

13.9

WBC count (x1000/mm3)

12.3

11.5±4.1 5.8–23.7

Platelet count (x1000/mm3)

231

240.3±87.5 110–626

Total cholesterol (mg/dL)

191

188.5±45.6 77–387

LDL (mg/dL)

126

117.4±38.6 51–245

HDL (mg/dL)

37.6

39.7±10.1

16–70

Triglycerides (mg/dL)

116

147±92

35–617

48.1±11

20–64

LVEF (%)

Contrast medium volume (mL)

220

13.7±1.6

9.6–16.5

210.1±50.2 90–400

Min.: Minimum; Max.: Maximum; SD: Standard deviation; AMI: Acute myocardial infarction; CABG: Coronary artery bypass graft; CAD: Coronary artery disease; DM: Diabetes mellitus; HDL: High-density lipoprotein; HT: Hypertension; LDL: Low-density lipoprotein; LVEF: Left ventricular ejection fraction; TIA: Transient ischemic attack; WBC: White blood cell.

prognostic significance in the development of CIN. In the multivariate regression analysis, only the disulfide/total thiol ratio (OR=1.190; 95% CI=1.090–1.300; p=0.001) was significantly and independently associated with CIN. Finally, the ROC analysis was performed to determine the cutoff value of disulfide/total thiol ratio for predicting CIN. The cutoff value of disulfide/total thiol ratio on admission to predict CIN in patients with STEMI who underwent primary PCI was 7, with a sensitivity of 68.2% and a specificity of 79.8% (AUC=0.740 (0.655– 0.825), p<0.001) (Fig. 2). DISCUSSION The primary finding of this study is that among patients

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with AMI who underwent primary PCI (in STEMI), the pre-procedural thiol levels that were assessed at admission served as an independent predictor of the development of post-procedural CIN. To our knowledge, this is the first study that investigated thiol/disulfide homeostasis as a novel marker for the relation between oxidative stress and CIN in patients with STEMI. Our findings demonstrated that a high level of disulfide/total thiol was significantly associated with CIN. Thiols are important antioxidant agents in human beings. The importance of disulfide/thiol homeostasis has been shown in a number of recent studies. Kundi et al. reported that the disulfide/thiol ratio increased in AMI and they asserted that this ratio might be an indicator for detecting acute myocardial damage [13]. Topuz et al. showed that thiol/disulfide homeostasis could be altered during acute pulmonary thromboembolism and could also be associated with worsened hemodynamic parameters [18]. They also suggested that this homeostasis may be used as a prognostic marker for hospital mortality. Some studies indicate that low thiol concentrations and an imbalance in the thiol/disulfide ratio may play a pathogenic role in the formation of coronary artery ectasia (CAE), atherosclerosis, and chemotherapy-induced cardiac toxicity [19–21]. In all these studies, the authors hypothesized that oxidative stress might contribute to the main mechanism of pathogenesis. New emerging risk factors such oxidative stress, hs-CRP, N-terminal probrain natriuretic peptide, serum uric acid levels, lower bilirubin concentrations, and gamma-glutamyl transferase (GGT) were found to be relevant to CIN development [22–27]. The novel oxidative stress marker in our study, thiol/disulfide ratio, has also been linked to CIN development in patients with acute STEMI undergoing primary PCI. CIN represents a significant adverse event during administration of contrast medium that leads to worse clinical outcomes despite successful early coronary revascularization. The pathogenesis of CIN is complex and multifactorial and the underlying biological mechanisms have not yet been fully elucidated. Several potential factors have been postulated, such as intrarenal vasoconstriction, reduced renal blood flow, medullary hypoxia, oxidative stress, inflammation, thrombosis, endothelial dysfunction, generation of reactive oxygen species (ROS), and direct tubular epithelial cell injury by contrast media [6, 7, 28]. In certain trials, the pathophysiology of CIN appears to be based on the formation

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Table 2. Baseline clinical, demographic, and laboratory characteristics of patients with and without contrast-induced nephropathy

CIN (-) CIN (+)

Mean±SD

Age

60.1±12.4

Median 59.0

Mean±SD

60.9±14.1

Median

58.5

0.724m

Sex Male 155 60 27 61 0.810X² 103 40 17 39

Female DM

Yes

170

18 41

0.382X²

HT No 144 56 27 61 0.492X² 114 44 17 39

Yes Smoking

No 104 40 18 41 0.675X² 154 60 26 59

Yes CAD

Yes

185

14 32

232

0.633X²

CABG

Yes

0.478X²

TIA/Stroke No 237 92 43 98 0.166X² Yes 21 8 1 2 AMI localization Anterior 148 57 28 64 0.435X² 110 43 16 36

Non-anterior Access site

Femoral 158 61 26 59 0.511X² 100 39 18 41

Radial Glucose (mg/dL)

146±76

124

160±86

125

0.424m

Serum creatinine (mg/dL)

1.08±0.32

1.01

1.13±0.28

1.16

0.036m

Hemoglobin(g/L)

13.8±1.8

13.8

13.7±1.6

13.5

0.594m

11.4±3.8

11.1

12.0±4.7

11.5

0.422m

Platelet count (x1000/mm3)

239±78

231

247±74

243

0.367m

Total cholesterol (mg/dL)

187±45

190

199±49

199

0.095m

LDL, (mg/dL)

116±38

111

126±37

122

0.082m

HDL, (mg/dL)

39±11

40±10

0.383m

Triglycerides (mg/dL)

142±89

132

154±95

148

0.082m

LVEF,(%)

48±10

46±12

0.455m

Contrast medium volume (mL)

210±50

212

217±60

223

0.105m

WBC count (x1000/mm ) 3

CIN: Contrast-induced nephropathy; SD: Standard deviation; AMI: Acute myocardial infarction; CABG: Coronary artery bypass graft; CAD: Coronary artery disease; DM: Diabetes mellitus; HDL: High-density lipoprotein; HT: Hypertension; LDL: Low-density lipoprotein; LVEF: Left ventricular ejection fraction; TIA: Transient ischemic attack; WBC: White blood cell. mMann–Whitney U Test; X²Chi Square (χ2) Test.

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Table 3. The level of native thiol, total thiol, disulfide, and disulfide/total thiol ratio between the patients with and without contrast-induced nephropathy (CIN)

CIN (-)

Total thiol, (μmol/L) Native thiol (μmol/L) Disulfide (μmol/L) Disulfide/Total thiol %, x100

CIN (+)

Mean±SD

Median

Mean±SD

Median

305.4±89.7 274.8±84.7 15.8±6.6 5.9±3.1

302.8 282.5 15.2 5.3

260.1±102.1 220.8±97.1 19.6±8.4 8.4±3.7

263.3 229.1 18.4 8

0.009m <0.001m 0.002m <0.001m

SD: Standard deviation; CIN: Contrast-induced nephropathy; mMann–Whitney U Test.

Disulphide/Total thiol ratio

0 CIN (-)

CIN (+)

Figure 1.

Relationship between disulfide total thiol ratio levels with contrast-induced nephropathy in patients with acute myocardial infarction.

of ROS and tubular cell toxicity [29, 30]. The plasma thiol/disulfide homeostasis shows a synergistic effect with the contrast media and increases acute kidney injury incidence by increasing ROS levels. Common findings in recent studies on thiol/disulfide levels include decreased native thiol level, increased disulfide level, and increased disulfide/total thiol ratio due to excess oxidative stress [13, 14, 18]. Consistent with previous studies, we found that patients in the CIN (+) group had lower native thiol but a higher disulfide level and disulfide/total thiol ratio as compared to the CIN (-) group. CIN is closely associated with prolonged hospitalization, increased costs, and increased short- and longterm morbidity and mortality [1]. Various strategies are hence being employed to prevent the incidence of CIN. Recently, increasing evidence has suggested that statins may, aside from their lipid-lowering effect, also play a protective role for the kidneys in the prevention of CIN due to their pleiotropic effects that include anti-inflammatory and antioxidant actions and the enhancement of endothelial nitric oxide production [31,

Table 4. Univariate and multivariate logistic regression analysis of contrast-induced nephropathy (CIN) Univariate Multivariate Native thiol Total thiol Disulfide Disulfide/Total thiol ratio

%95 CI

0.993 0.995 1.077 1.199

0.989–0.997 0.991–0.998 1.030–1.126 1.098–1.310

<0.001 0.003 0.001 <0.001

1.190

1.090–1.300

<0.001

CIN: Contrast-induced nephropathy; OR: Odd ratios; CI: Confidence interval.

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Sensitivity (%)

100

100 100

40 60 1–Specificity

0 100

Figure 2. Receiver operator characteristic (ROC) curve analysis showing that at a cut-off of 7, the value of disulfide total thiol ratio exhibited 68.2 sensitivity and 79.8 specificity for predicting contrast-induced nephropathy.

32]. In other studies involving N-acetylcysteine (NAC), it was demonstrated that the inhibition of reactive oxygen species (ROS) may represent a key mechanism of the nephroprotective effect of NAC [33, 34]. Based on these findings, we can speculate a relationship between thiol/disulfide homeostasis and CIN. We suggest that the lower native thiol and higher disulfide level in AMI patients are probably due to an increase in thiol oxidation due to the excess oxidative status during AMI. During the acute phase in AMI, the oxidative response may affect the baseline cardiorenal reserves of the patients. Addition of thiol levels to the current risk models derived from clinical, angiographic, and laboratory-based variables and to the previously validated Mehran risk score [35] may result in significant improvement in the prediction of CIN. This suggests that measurement of thiols improves the evaluation of risk for CIN in patients with STEMI who are undergoing primary PCI. Study Limitations Our study had several limitations. First of all, it included a relatively small number of CIN patients who were admitted to a single center. Secondly, blood

samples were obtained at the time of admission, and we did not observe the serial changes in thiols concentration after primary PCI. Thirdly, several novel renal biomarkers, including neutrophil gelatinaseassociated lipocalin, cystatin C, urinary Kim-1, and interleukin 18, were not measured during the study [36, 37]. Fourthly, because all patients in the present study underwent emergency PCI, the total fluid volume and net fluid balance were not quantified. Moreover, thiols are nonspecific inflammatory and oxidative stress biomarkers that are influenced by cardiac and extra-cardiac conditions. The study group included some patients with diabetes mellitus and potential renal dysfunction, which was another limitation of this study. Finally, the deterioration of renal function after primary PCI may have been caused by multiple other contributing factors, including hemodynamic alterations, neurohormonal activation, and administration of nephrotoxic drugs. Conclusion Our results suggest that thiol/disulfide homeostasis could be a good biochemical risk marker for CIN in STEMI patients who have undergone primary PCI. Considering its clinical significance, thiol/disulfide homeostasis may help in identifying high-risk candidates of CIN in AMI. We believe that larger prospective studies are needed in the future to confirm the pathophysiological role of thiol/disulfide homeostasis in CIN and to provide valuable insights into the relevant literature. Ethics Committee Approval: The Ethics Committee of SBU Ankara Numune Egitim ve Arastirma Hastanesi provided the ethics committee approval for this study (Date: 22.02.2017 Number: E-16-1096). Conflict of Interest: The authors have no conflicts of interest to disclose. Financial Disclosure: The authors declared that this study has received no financial support. Authorship Contributions: Concept – AKork.; Design – AKork.; Supervision – AKork., AK; Materials – BO, AKork., AK; Data collection and/ or processing – AKork., BO; Analysis and/or interpretation – AKork., UG, MI, OUE; Writing – AKork.; Critical review – UG, SN, OE, OUE, AKork.

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218 N-acetylcysteine for the prevention of contrast-induced nephropathy. Am J Med 2009;122:874.e9–15. 34. Kang X, Hu DY, Li CB, Ai ZS, Peng A. N-acetylcysteine for the prevention of contrast-induced nephropathy in patients with pre-existing renal insufficiency or diabetes: a systematic review and meta-analysis. Ren Fail 2015;37:297–303. 35. Mehran R, Aymong ED, Nikolsky E, Lasic Z, Iakovou I, Fahy M, et al. A simple risk score for prediction of contrast-induced nephropathy after percutaneous coronary intervention: development and initial vali-

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Orıgınal Article

EMERGENCY MEDICINE

North Clin Istanb 2019;6(3):219–225 doi: 10.14744/nci.2018.89266

Relationship between brain computed tomography findings and bispectral index score in patients presenting with head trauma Ozlem Kusken,1

Tuba Cimilli Ozturk,2

Cansu Arslan Turan,2

Aysel Hunuk,3

Ebru Unal Akoglu,2

Rohat Ak,2

Ozge Ecmel Onur2

1Department of Emergency Medicine, Istanbul Medeniyet University, Goztepe Training and Research Hospital, Istanbul, Turkey Department of Emergency Medicine, University of Health Sciences, Fatih Sultan Mehmet Training and Research Hospital, Istanbul, Turkey

Department of Emergency Medicine, Kartal Yavuz Selim State Hospital, Istanbul, Turkey

ABSTRACT OBJECTIVE: Head trauma is one of the most important emergency health problems both in the world and in our country. The objective in our study is to (i) state the correlation between the findings of bispectral index score (BIS) and computed tomography (CT), which are used to evaluate the level of consciousness of patients with isolated head trauma, and (ii) investigate objective results about the patient’s level of consiousness/alertness according to the CT modality, which is used frequently. METHODS: This prospective study was carried out between 03.01.2014 and 09.01.2014 in the emergency department of Fatih Sultan Mehmet Education and Research Hospital. The average BIS scores were correlated with the Glasgow Coma Scale (GCS) point, the Canadian CT Head Rule major and minor criteria, and the pathologic findings in CT imaging. The patients’ demographic features, vital signs at admission, and arrival times at the hospital were investigated. RESULTS: In our study, 64 (31.7%) patients were female, and 138 (68.3%) patients were male. The mean BIS scores were 84.99±11.20 (86.05) and 93.78±3.80 (95.05) in patients with and without CT pathologies, respectively. The correlation between CT pathology and BIS scores was statistically significant: BIS scores were lower in patients with CT pathologies (p=0.001; p<0.01). There was a statistically significant positive correlation between the BIS and GCS scores (45.6%) (p<0.05). CONCLUSION: We showed that most head traumas occur after dangerous accidents, and according to the results, we can predict that males are more frequently affected than females.There was a statistically significant positive correlation between BIS scores and GCS points. In our study, the BIS scores were statistically significantly lower in patients with CT pathology than in patients without. We can predict that if the BIS score of the patient is low, then there will be the presence of pathology on CT imaging. Keywords: Canadian CT criteria for head trauma; bispectral index score; brain computed tomograpy; head trauma.

Cite this article as: Kusken O, Cimilli Ozturk T, Hunuk A, Akoglu EU, Ak R, Arslan Turan C, et al. Relationship between brain computed tomography findings and bispectral index score in patients presenting with head trauma. North Clin Istanb 2019;6(3):219–225.

ead trauma is one of the most important emergency health problems both in the world and in our country [1]. Computed tomography (CT) is the most important imaging modality in patients with head

trauma. However, CT has some disadvantages such as radiation exposure and cost [2, 3]. To date, several studies have been conducted to determine patients with head trauma who would benefit from brain CT, and a number

Received: August 16, 2017 Accepted: September 12, 2018 Online: August 25, 2019 Correspondence: Dr. Rohat AK. Istanbul Fatih Sultan Mehmet Egitim ve Arastirma Hastanesi, Acil Tip Klinigi, Istanbul, Turkey. Tel: +90 0506 821 31 36 e-mail: rohatakmd@gmail.com © Copyright 2019 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

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of clinical decision-making rules have been developed. One of these is the Canadian CT Head Rule (CCHR) [3, 4]. Within the framework of CCHR criteria, patients with head trauma who should be screened are determined, and some patients are monitored according to observation and clinical progress. One of these clinical follow-up parameters is the state of consciousness, and monitoring with the Glasgow Coma Scale (GCS) is recommended. It is not always possible to monitor and objectively measure instantaneous changes in consciousness in clinical practice. One measurable and objective parameter is the bispectral index (BIS). A BIS monitoring device that has been developed on the basis of monitoring electroencephalography (EEG) signals is preferred when monitoring the consciousness of critical patients (e.g., patients with acute brain injury) because it is easily applicable, yields numerical results, and allows continuous monitoring [5]. No study showing (i) the relationship among severity of head trauma, underlying pathology, and BIS values and (ii) the relationship between CT scanning indications and BIS levels has been seen in the literature thus far. Our primary aim in this study was to determine (i) the BIS values of patients with moderate or mild head trauma who underwent brain CT and (ii) whether there was any relationship between the presence of pathology on brain CT and BIS levels. Our secondary aim was to investigate the effect of each criterion of CCHR on BIS levels. MATERIALS AND METHODS This study was conducted prospectively at Fatih Sultan Mehmet Training and Research Hospital Emergency Medicine Clinic between 03.01.2014 and 09.01.2014 after approval of the ethics committee. All adult patients admitted to the emergency department with isolated head trauma between the dates mentioned above were evaluated according to the study criteria, and eligible patients were included in the study. CTs were routinely performed for all patients with GCS scores <13 who presented to the emergency department with head trauma and were aged over 18 years as recommended in the guidelines. Patients with minor head trauma (GCS scores 14 and 15) were evaluated according to CCHR criteria. All patients who were considered to be undergoing CT scans by the clinician or who planned to undergo CT scans according to CCHR criteria and

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who agreed to participate in the study were included. Pregnant patients under 18 years of age, sedative drug users, patients who had been operated upon under general anesthesia within the last 72 h, cases with cerebrovascular events, known brain tumors, or cranial pathology/space-occupying lesions, patients with a previous history of epilepsy or anti-epileptic drug users, patients whose consciousness was blurred for other reasons, patients who needed resuscitation and recording procedures (which would probably delay intervention), patients with incomplete data, patients whose BIS electrodes could not be placed appropriately, and multiple trauma patients were not included. Maximum 15-min data of the patients who were followed up with BIS measurements were collected, and the brain CT images and BIS levels were compared. For BIS monitoring, the patient was in the supine position before the BIS electrode was placed, and the temple was wiped with an alcohol swab. After the conductive gel was applied, a ring was placed in the middle of the forehead about 2â&#x20AC;&#x201C;3 cm above the root of the nose. Another ring was attached between the lateral part of the eyebrow and the hair line, and two other rings were glued onto the eyebrow. Approximately 5 s of hand pressure was applied to each ring. A relationship was established between the skin and the sensor, and at least 15 min of recording was performed. The mean value was calculated. If the patientâ&#x20AC;&#x2122;s condition was unstable or there was an urgent need to take sedatives, recordings were performed for as long as possible before the medication was administered. No change was made in patient intervention and treatment. BIS monitoring was performed with the COVIDIEN complete monitoring system PN/185-0151, which we currently use in the emergency department (Fig. 1). After approval of the signal quality index, which is one of the pop-up windows on the monitor, BIS monitoring was provided, and the GCS and BIS values were recorded simultaneously. Arterial blood pressure, pulse rate, weight, and height were also measured. The mean BIS values and GCS scores were compared with the CCHR major and minor criteria and the presence of pathology (if any) on CT. In addition, demographic characteristics, vital signs at admission, and duration of hospitalization were examined. On evaluating the findings obtained in this study, the IBM SPSS Statistics 22 for statistical analysis (SPSS IBM, Turkey) program was used. While evaluating the

Kusken et al., Relationship between brain computed tomography findings and bispectral index score

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Table 1. Evaluation of the distributions of major and minor criteria of Canadian CT Head Rules Major criteria GCS score <15 at 2 h after trauma Any sign of skull fracture Suspected open or depressed skull fracture Vomiting >2 episodes Age ≥65 years Minor criteria Amnesia before impact ≥30 min. Dangerous mechanism

1 – 1 2 40

0.5 – 0.5 1.0 19.8

53 121

26.2 59.9

GCS: Glasgow Coma Scale.

Figure 1. BIS device. study data, the fitness of the parameters to normal distribution was evaluated by the Shapiro–Wilks test. It was found that the parameters were not distributed normally. Descriptive statistical methods (mean, standard deviation, and frequency) as well as quantitative data were compared with the Mann–Whitney U test. For the comparison of qualitative data, the chi-square test, Fisher’s exact chi-square test, and the Yates continuity correction test were used. Spearman’s rho correlation analysis was used to examine the relationships among the parameters, and statistical significance was evaluated at p<0.05. RESULTS A total of 587 patients older than 18 years with isolated head trauma were admitted to the emergency department during our study. Fifty-eight patients had severe head trauma and were excluded from the study. Cranial CT was not requested in 285 of the remaining 529 patients, and these patients were excluded from the study. The study population consisted of 244 patients. Fortytwo patients whose records could not be taken due to intensity were excluded from the study, and a total of 202 patients (64 (31.7%) female and 138 (68.3%) male) were included. The ages of the patients ranged from 18 to 90 years, with a mean of 45.48±19.47 years. The mean GCS was 14.92±0.548–15 (range: 8–15 pts), and BIS was 93.17±5.15 (range: 56.9–98 pts). In our study, men were found to be significantly more populous. A little more than half of the patients (50.5%) were

admitted to the hospital within the first 30 min after the trauma, and the majority (97.5%) of them presented to the emergency department within the first 90 min. Among the vital signs of the patients at admission, the median systolic arterial blood pressure (136.85 mmHg), diastolic arterial blood pressure (78.85 mmHg), and pulse rates (81.02/min) were measured. All patients with GCS scores <13 admitted to the emergency department with head trauma over the age of 18 years underwent a routine CT scan as recommended in the guidelines. Patients with minor head trauma (GCS scores 14 and 15) were evaluated according to CCHR criteria. The distribution of the major criteria of CCHR gave the following results: one (0.5%) patient had a GCS score <15, one (0.5%) patient had suspected open or depressed skull fracture, and two (1%) patients had vomiting episodes (GCS score >2) at 2 h after the trauma. None of the patients had a skull base fracture. Forty patients (19.8%) were 65 years or older. The distribution of the minor criteria gave the following results: retrograde amnesia was seen in 53 (26.2%) patients and dangerous mechanism in 121 (59.9%) patients. The distribution of cases according to the CCHR criteria is shown in Table 1. A total of 14 patients had CT pathology. Two of the 14 cases were older than 65 years.The patients had retrograde amnesia (n=1), suspected open or depressed skull fractures (n=1), and 10 of them had been exposed to dangerous traumatic mechanisms. When the BIS values of the cases and the major and minor CCHR criteria

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North Clin Istanb BIS 120 100 Mean±SD

GCS

14.00

12.00

80 60 40 20 0

10.00

Yes

No Abnomal CT findings

Figure 3. Correlation between abnomal CT findings and BIS.

0.00 50.00

60.00

70.00

80.00

90.00

100.00

SD: Standard deviation; CT: Computed tomography; BIS: Bispectral Index.

BIS

Figure 2.

Relationship between GCS score and BIS value. GCS: Glasgow Coma Scale; BIS: Bispectral Index.

were compared, it was observed that CT was performed with indications of being older than 65 years (n=40). In our study, the other major criteria included GCS scores <15 (n=1), head fracture findings (n=0), suspected depressed skull fracture (n=1), and more than two vomiting episodes (n=2) detected at 2 h after the trauma; however, they were not sufficient for statistical calculations. The BIS values of major criteria of being over 65 years, minor criteria of having a history of retrograde amnesia longer than 30 min (n=53), and exposure to dangerous traumatic mechanisms (n=121) were compared. However, no statistical significance was found in any of them. The BIS values were in the range 41–65 in only 1 (0.5%) case, 66–85 in 14 (6.9%) cases, and 86–100 in 187 (92.6%) cases. The BIS values were compared according to sex, age, GCS scores, and CT findings. They did not differ significantly when compared by sex (p>0.05). When the BIS value and GCS scores were analyzed by Spearman’s rho correlation analysis, a positive and statistically significant correlation was found at a level of 45.6% (p<0.05) (Fig. 2). In our study, the mean BIS value of patients who had abnormal CT findings was 84.99±11.20 (86.05), and the mean BIS value of those without abnormal CT findings was 93.78±3.80 (95.05). A statistically significant correlation between CT pathology and BIS values was found, and those with CT pathology had lower BIS values (p=0.001; p<0.01) (Fig. 3). Our 173 patients (85.6%) were discharged, and 29 patients (14.4%) were hospitalized.

DISCUSSION In our study, a statistically significant correlation was found between BIS values, which can give a numerical value in the measurement of consciousness level in patients presenting to the emergency department with head trauma, and pathologic findings detected in patients with brain CT. In these patients, lower BIS values were found. Therefore, it can be concluded that patients who presented to the emergency department with head trauma and whose BIS values were low are eligible candidates for imaging by brain tomography. In our study, the GCS levels and BIS values were found to be correlated. Moreover, it was concluded that in a head trauma patient whose GCS status could not be evaluated precisely, BIS values that quantitatively and objectively assessed head trauma could be used. Brain injury due to head trauma, which is one of the most important health problems of our time (and especially seen in young people), is a lethal, disabling pathologic condition requiring long-term treatment and care [6]. It has been reported that head trauma occurs every 15 s and a patient dies from head trauma every 12 min, and it accounts for 50% of all trauma-related deaths [7]. The early detection and proper management of this clinical condition, whose contribution to mortality is indisputable, is therefore critical. Of 202 adult patients over 18 years, 138 (68.3%) were male and 64 (31.7%) were female. The mean age was 45.48±19.47 years. Our patient group was found to be compatible with similar studies performed in adult patients in terms of sex and age distribution [6, 8]. In most studies, young adult males have been reported to be the most traumatized age group. The higher number of traumatized men than women can be explained by the

Kusken et al., Relationship between brain computed tomography findings and bispectral index score

fact that men lead a more active life in our society; as a result, they are more exposed to trauma [9]. Indeed, the incidence of dangerous mechanisms was found to be statistically significantly higher in our male (65.2%) than in our female (48.4%) patients. Early detection and intervention is of crucial importance in traumatic brain injury. When the general statistics about traffic accidents are examined, 10% of deaths occur within the first 5 min, 50% within the first 30 min, and 80% within 1 h after the accident [10]. In this sense, the arrival time at the hospital is crucial for the wounded. In this study, the arrival times of the patients were investigated. It was found that 50.5% of the cases were brought to the emergency department within the first 30 min and 37.1% within the first hour after the accident. When other studies on the subject were examined, our results were found to be acceptable and even better than the others. In the study by Işık H.S. on 954 people, 34.1% of the cases came within the first 2 h and 43.6% of them within 2–6 h after the incident. In the study by Beyaztas et al. (Sivas), Altıntop et al., 44.52% and 24% of the patients presented to the hospital within the first hour after the incident [11, 12].This situation may be related to the fact that our hospital is easily accessible, and the ambulance services have improved considerably. Brain CT is the most commonly used method in emergency departments to detect the severity of trauma and to make early surgical decisions. However, radiation exposure and high costs are still important factors limiting its use. Research has shown that it is not necessary to perform a brain CT scan for every patient with head trauma, and studies have focused on the development of various guidelines for imaging with the correct indications. GCS is actually the main determinant for these rules. One of the most commonly used criteria are the CCHR rules. In almost all these guidelines, the processes that should be followed in head trauma, which are considered mild according to GCS criteria, are mostly based on clinical status and anamnesis, and no objective data are included in these rules. Moreover, consciousness and GCS measurements of the patients are subjective data based on the clinician’s observation and examination. BIS has recently been used in emergency services as a monitoring method to determine patients’ awareness and monitor patients during treatment with sedative drugs. The numerical expression of consciousness is important.

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However, there are not enough data about whether it can be a guide in cases of head trauma. In our study, CTs were routinely performed for all patients over 18 years with GCS scores <13 who presented to the emergency department with head trauma as recommended in the guidelines. Patients with minor head trauma (GCS scores 14 and 15) were evaluated according to CCHR criteria. As one of the major criteria of CCHR, being 65 years or older was detected in 40 (19.8%) cases. Other criteria included more than two episodes of vomiting in 2 (1%) patients, GCS scores <15 in 1 (0.5%) patient, and suspected open or depressed skull fracture criteria in 1 (0.5%) patient within 2 h after trauma. No sign of skull base fracture was seen in any of the cases. Age is an important parameter in almost every study. In some studies, 65 years of age, and in some studies 60 years of age were taken as the limit, and the intracranial pathology rate was reported to be higher in elderly patients when compared with those under this age limit [13]. Hsiang et al. reported that headache, nausea, and vomiting were among the most common complaints after head trauma of all patients who died among mild head trauma patients with a GCS score of 15 [14]. Several studies have also examined whether these complaints make sense as a risk factor. Some studies have reported that they are insignificant, and yet there are studies showing otherwise. In some reports, intracranial lesions were found to be higher in patients with this type of complaint [13, 14]. In our study, no significant difference was found when cranial pathology was compared in patients with and without such complaints. When the distribution of minor criteria is examined, 53 (26.2%) of the cases had amnesia and 121 (59.9%) had been the victims of dangerous accidents. Loss of consciousness after trauma has been accepted as an important parameter for several years [15]. However, although the majority of patients experience loss of consciousness, the definition of fainting, blackout, and such loss of consciousness reduces the reliability of this important parameter [13]. In this study, while taking the anamnesis, other people who were present with the patient were consulted, and thus it was possible to obtain more satisfactory data on the loss of consciousness. Boran et al. found a higher rate of intracranial pathology in patients experiencing loss of consciousness after trauma [16]. In our study, amnesia plays an important role in CT ordering rules. Although the pathology detection rate on CT was statistically insignificant, it was significant among indications for CT.

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One of the most important issues in the follow-up and treatment of critical disorders that result in consciousness disorder is to closely monitor the state of consciousness. The close monitoring of changes in the brain function of these patients is very important in terms of prognosis and management of treatment. Clinical monitoring methods are frequently used to monitor the level of consciousness, and it is possible that measurements made using monitorized medical devices have been utilized more recently [5]. Although the clinical follow-up scales of the users are short and easily applicable, they may not always give real results because of the different results obtained by the practitioners. Therefore, it is generally believed that measurements with automatic devices give more accurate and reliable results in the evaluation of sedation and consciousness level, and studies are hence focused on this issue. BIS, power spectral measurement, and auditory excitable potentials are the most commonly used device-dependent methods [17]. BIS, which is a user-independent method based on objective measurement, is preferred for its practical use. BIS is a method of interpretation that quantifies the degree of the acute phase between the components of EEG signals [5]. BIS was first developed to determine the depth of anesthesia [5, 17] and is currently used in (i) the follow-up of sedation in intensive care patients, (ii) the follow-up of consciousness in critically ill patients with severe brain injury, and (iii) patients resuscitated after cardiac arrest. Moreover, research in this direction is increasing day by day. There are different results in studies investigating the relationship between GCS and BIS. Haug et al. investigated the BIS and GCS values in patients who were followed up in the emergency unit due to head trauma and examined the rates of survival and neurologic sequelae according to the BIS and GCS values [18]. They reported that the BIS values obtained after the administration of sedative drugs following trauma are useful in predicting traumatic brain injury and also in evaluating the neurologic outcomes of patients at the time of discharge. Gill et al. compared the BIS and GCS values in a study on patients presenting to the emergency unit with a decrease in consciousness level and found that there was no correlation between them [19]. BIS was found to be in the ranges 47–98 and 56–98 for GCS scores 3–5 and 12–14, respectively. Gill et al. found a correlation between BIS values and GCS scores in a clinical study; however, small changes in GCS scores in assessing the impairment of consciousness corresponded to a wider range in BIS measurements. Therefore, they

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concluded that BIS was inadequate in assessing the deterioration in consciousness. Xifeng et al., in their study on 189 patients with severe brain injury due to head trauma, concluded that the BIS values of patients were significant in predicting the detection and follow-up of consciousness [20]. In a study conducted by Paul et al. on 29 patients with severe and moderate brain injury due to a mass-occupying lesion, a statistically significant difference was found between GCS scores and BIS values. It was concluded that there was a relationship between the BIS values and GCS scores of coma patients [21]. According to our results, when the GCS and BIS values were compared, a statistically significant positive correlation and concordance was found. Because it was known that the BIS value was especially affected by sedation and muscle relaxants, patients who were treated with these drugs were excluded. Therefore, there is no group of patients with severe head trauma in our study population. In addition, patients with low GCS on admission and requiring medication due to agitation were excluded from the study. This is also an important limitation of our study. In our study, any pathologic condition due to trauma was not recorded on CT scans according to CCHR criteria, and the findings were retrospectively compared with the BIS values of the patients. The mean BIS values of patients with and without abnormal CT findings were 84.99±11.20 (86.5) and 93.78±3.80 (95.05), respectively. When the two groups were compared, the BIS values of patients without CT were found to be statistically significantly higher. According to this result, it can be predicted that patients with low BIS values may have pathology on brain CT. However, to determine the limit value for this finding, it is necessary to conduct studies in large patient groups. One of the most important limitations of our study is that the number of patients was not sufficient to arrive at a conclusion, because the BIS values could not be determined. BIS requires at least 15 min of recording; however, patients in a critical condition cannot wait and should be sedated for early intubation. Therefore, our study does not provide sufficient information about the values in severe head trauma. Another limitation of our study is that indications of CT scans in our patient group were not evenly distributed; therefore, all the CCHR major and minor criteria could not be compared with BIS. We believe that each criterion can be evaluated separately in larger patient groups. In our study, the BIS values of

Kusken et al., Relationship between brain computed tomography findings and bispectral index score

patients with CT pathology were found to be low; however, the clinical significance of this could not be evaluated owing to the small number of pathologic CTs obtained. Conclusion From the results of our study, it is possible to say that head traumas are often caused by dangerous accidents and affect men more severely. It was observed that patients arrived at our hospital relatively quickly and were evaluated in an earlier stage. In comparisons made with the measured BIS values, a statistically significant positive correlation was found between the GCS and BIS values. However, no statistically significant difference was found between the sex of the patients and significantly, and frequently observed CCHR criteria as being <65 or >65 years of age the presence of dangerous mechanism and history of amnesia. Another important result of our study was that the BIS values of patients with traumatic pathology on CT were significantly lower than those with normal CT. Although low BIS values cannot be determined precisely owing to the limited number of subjects in our study, we believe that low values indicate that it is appropriate to perform CT. In continuation of this study, we will increase the number of subjects, and numerically more important cutoff values of BIS will be determined. Ethics Committee Approval: This study was conducted prospectively at Fatih Sultan Mehmet Training and Research Hospital Emergency Medicine Clinic between 03.01.2014 and 09.01.2014 after approval of the ethics committee (Date: 3.03.2014, number: FSMEAH-KAEK 2014/11) 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. Authorship Contributions: Concept – OK, OEO; Design – TCO, OEO; Supervision – TCO, OEO; Materials – CAT, RA, OK; Data collection and/or processing – OK, CAT, RA; Analysis and/or interpretation – OK, AH, EUA; Writing – OK, RA, OEO; Critical review – TCO, RA, EUA, AH.

REFERENCES 1. Silav G, Uğur HÇ, Tun K, Attar A, Egemen N. The Systemic Effects of Head Traumas. Ankara Üniversitesi Tıp Fakültesi Mecmuası 2000;53:293–7. 2. Franco-Koehrlen CA, Iglesias-Leboreiro J, Bernárdez-Zapata I, Rendón-Macías ME. Clinical decision to perform cranial computed tomography in children with non-severe head injury. [Article in Spanish].

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Bol Med Hosp Infant Mex 2015;72:169–73. 3. Yurtseven A, Altıntop İ, Bayram MK, Kaynak MF, Danlı N. Are We Overuse Computerized Tomography In Emergency Department? Journal of Anatolian Medical Research 2016;1:1-6. 4. Stiell IG, Clement CM, Rowe BH, Schull MJ, Brison R, Cass D, et al. Comparison of the Canadian CT Head Rule and the New Orleans Criteria in patients with minor head injury. JAMA 2005;294:1511–8. 5. Bombacı E, Boztepe A, Çizen A, Çevik Z, Çolakoğlu S, Yollu Atakan T. Bilinci kapalı yoğun bakım hastalarında bispektral indeks monitörizasyonu ile modifiye Glasgow koma ve Ramsay sedasyon skala puanları arasındaki ilişki. Bakırköy Tıp Dergisi 2005:1. 6. Sharp AL, Nagaraj G, Rippberger EJ, Shen E, Swap CJ, Silver MA, et al. Computed Tomography Use for Adults With Head Injury: Describing Likely AvoidableEmergency Department Imaging Based on the Canadian CT Head Rule. Acad Emerg Med 2017;24:22–30. 7. Alewander RH, Proctor HJ. Head Travma. In: Advanced Travma Life Support. 3th ed. Chicago, USA: Americen Collage of Surgeons; 1993. p. 159–83. 8. Saiki RL. Current and evolving management of traumatic brain injury. Crit Care Nurs Clin North Am 2009;21:549–59. 9. Paşaoğlu A. Erişkinde Kafa Travmaları. In: Temel Nöroşirürji Cilt I. Ankara: Türk Nöroşirürji Derneği Yayınları; 2005. p. 316–23. 10. Sabuncuoğlu H. Trafik kazaları ve istatistiklerle Türkiye gerçeği. Nörotravma ve Yoğun Bakım 2009;4:11–5. 11. Beyaztaş FY, Alagözlü H. The Evaluation Of The Traffic Accident Cases Applying To The Emergency Department Of The Hospital Of The Cumhuriyet Unıversity In 1998. Ulus Travma Derg 2002;8:29– 33. 12. Altıntop L, Güven H, Doğanay Z, ve arkadaşları. Ondokuz Mayıs Üniversitesi Tıp Fakültesi acil servis trafik kazası hastalarının değerlendirilmesi. Samsun: Trafik 2000 Sempozyumu; 22–23 Mayıs 2000. 13. Servadei F, Merry GS. Mild head injury in adults. In: Winn HR, editor. Youmans Neurological Surgery. 5th ed. Philadelphia: Saunders; 2004. p. 5065–81. 14. Hsiang JN, Yeung T, Yu AL, Poon WS. High-risk mild head injury. J Neurosurg 1997;87:234–8. 15. Dikmen SS, Levin HS. Methodological issues in thestudy of mild head injury. J Head Trauma Rehabil 1993;8:30–7 16. Boran BO, Barut N, Akgün C, Çelikoğlu E, Bozbuğa M. Indications for computed tomography in patients with mild head injuries. Ulus Travma Acil Cerrahi Derg 2005;11:218–24. 17. Némethy M, Paroli L, Williams-Russo PG, Blanck TJ. Assessing sedation with regional anesthesia: inter-rater agreement on a modified Wilson sedation scale. Anesth Analg 2002;94:723–8. 18. Haug E, Miner J, Dannehy M, Seigel T, Biros M. Bispectral electroencephalographic analysis of head-injured patients in the emergency department. Acad Emerg Med 2004;11:349–52. 19. Gill M, Haycock K, Green SM, Krauss B. Can the bispectral index monitor the sedation adequacy of intubated ED adults? Am J Emerg Med 2004;22:76–82. 20. Xifeng W, Lianshuang Z, Dawei W. Prediction of neurological outcome using bispectral index in patients with severe acute brain injury. Turk J Med Sci 2013;43:718–25. 21. Paul DB, Umamaheswara Rao GS. Correlation of Bispectral Index with Glasgow Coma Score in mild and moderate head injuries. J Clin Monit Comput 2006;20:399–404.

Orıgınal Article

PUBLIC HEALTH

North Clin Istanb 2019;6(3):226–235 doi: 10.14744/nci.2018.59365

The frequency of alopecia and quality of life in high-school students in rural areas (Sivrihisar, Mahmudiye, Alpu, and Beylikova) of Eskisehir Ozkan Ozay,1

Didem Arslantas,2

Alaeettin Unsal,2

Isil Bulur3

Ercis Community Health Center, Van, Turkey

Department of Public Health, Eskisehir Osmangazi University Faculty of Medicine, Eskisehir, Turkey

Department of Dermatology, Memorial Atasehir Hospital, Istanbul, Turkey

ABSTRACT OBJECTIVE: The aim of the present study was to determine the incidence of alopecia and related factors and the healthrelated quality of life (HRQoL) in high-school students in rural areas of Eskisehir. This was a cross-sectional study. METHODS: The study was performed between March 2, 2015 and April 30, 2015. A total of 1662 (74.9%) students were included in the study. The questionnaire performed for the purpose and consisted of four sections was filled out by the students themselves under supervision. The HRQoL was evaluated by Short Form—36 (SF-36). Students’ hair and scalps were examined by a dermatologist. The acquired data were analyzed by SPSS 20 statistical package program. Chi-square test, Mann–Whitney U test, and logistic regression analyses were used for statistical analyses. A p value ≤0.05 was accepted as statistically significant. RESULTS: In the present study, the incidence of alopecia was found to be 37.4% (n=622). Alopecia was more frequently seen in male students who have complaints about their scalps and those with a fatty scalp. In the study group, students with alopecia had poor HRQoL in general health perception, vitality, and mental health of SF-36. CONCLUSION: There is a need to provide early diagnosis and treatment to decrease the incidence of alopecia and to improve the quality of life. Health education studies must be performed to increase the awareness of students about alopecia. Integrating hair and scalp examination into school health screening studies, steering the students who have alopecia to the dermatologists, and suggesting students who have fatty scalp regular hair washing will be appropriate. Keywords: Adolescent; alopecia; Eskisehir; quality of life.

Cite this article as: Ozay O, Arslantas D, Unsal A, Bulur I. The frequency of alopecia and quality of life in high-school students in rural areas (Sivrihisar, Mahmudiye, Alpu, and Beylikova) of Eskisehir. North Clin Istanb 2019;6(3):226–235.

dolescent (adolescence) period is a process in which rapid physical, biological, psychological, and emotional changes are experienced during transition from childhood to adulthood. The World Health Organization (WHO) defines the 10–19 age group as the adolescent period, and this period may vary from person to person; it is difficult to confine the adolescent period

strictly within a certain age group because of the sociocultural and socioeconomic characteristics of the societies, geographic, and seasonal features of the living place and dietary habits of the communities [1–4]. According to the WHO’s definition of adolescent, it is reported that 1 out of 5 people worldwide is in the adolescent age group, meaning approximately 1.2 billion

Received: Januarl 26, 2018 Accepted: April 30, 2018 Online: June 12, 2019 Correspondence: Dr. Ozkan OZAY. Ercis Toplum Sagligi Merkezi, Ercis, 65400 Van, Turkey. Tel: +90 506 953 02 50 e-mail: ozkanozay33@gmail.com © Copyright 2019 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

Ozay et al., The frequency of alopecia and quality of life in high-school students in rural areas of Eskisehir

people. Globally, 85% of adolescents live in developing countries. In most countries, adolescents account for 20%–25% of the population, whereas the adolescent age group accounts for 16.8% of Turkey’s population [4–7] While hormonal changes in the adolescent period cause physical growth and pubertal changes, significant psychosocial changes are also seen. This change, which begins in the second decade of life, varies according to gender, person, and society [4]. Adolescent period is a special period where both hair problems and other dermatological disorders are seen frequently because of the hormonal changes in human life and the intense life conditions of collective life as is seen in schools or dormitories. Hair problems lead to depression and anxiety in adolescents and young adults and may affect their health-related quality of life (HRQoL) adversely. Changes in the appearance and quality of hair as wearing, splitting, thinning of hair strands or vice versa, and hypertrichosis (excessive growth of hair) may be defined as hair problems [1, 4, 8]. As generally known, congenital, infectious, autoimmune, genetic, and environmental factors are responsible for hair loss (alopecia). The known risk factors for alopecia are chronic endocrine or allergic diseases, surgery, regular drug use, nutrition, gynecological diseases, and stressful lifestyle [8, 9]. Physicians should identify the problem or any other underlying disease that causes hair loss accurately because of the lack of self-confidence and the quality of life caused by hair loss. Although it is important to evaluate alopecia in primary health care services, it is known that many physicians fail to evaluate and diagnose alopecia [10, 11]. Alopecia is categorized into two groups as those with and without scar, and most of them are cases with scarless alopecia. Androgenetic alopecia (AGA), telogen effluvium (TE), alopecia areata (AA), traction alopecia, and tinea capitis are grouped under the category of scarless alopecia, whereas discoid lupus erythematosus, lichen planus, infection (e.g., bacterial, viral, and fungal)induced alopecia, and alopecia secondary to trauma or burns are also grouped under the category of scarred alopecia. According to the amount of hair loss, alopecia is also classified as diffuse alopecia and focal alopecia. The most common subtypes of alopecia in adolescents are AGA and TE [9, 10, 12, 13]. The prevalence of alopecia in adolescents worldwide varies widely between 15.5% and 38.5% because of the diversity of societies with respect to their genetic, eth-

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nic, and lifestyle characteristics [14–17]. A field research related to the prevalence of alopecia has not been performed in Turkey. The present study was conducted to determine the prevalence of alopecia among high-school students studying in the rural settlement of Eskisehir, to investigate the presumably related factors, and to evaluate the HRQoL of the study participants. MATERIALS AND METHODS This was a cross-sectional study on high-school students who were receiving education and training in high schools in four districts (Sivrihisar, Mahmudiye, Alpu, and Beylikova) situated at the center of Eskisehir province between March 2, 2015 and April 30, 2015. The total population of the research region is 46,869 people. The region is at a medium socioeconomic level, and generally, the livelihood of the people is agriculture and animal husbandry [18, 19]. The study constituted of high-school students grades 9–12 living and receiving education and training in the schools situated in the center of the districts of Sivrihisar, Mahmudiye, Alpu, and Beylikova. A total of 14 high schools were situated in the district centers, and a total of 2220 students were receiving education and training in these high schools. In our study, any sampling was not performed, and it was aimed to reach all students. The study was approved by the ethics committee, and necessary permissions and appointments were received from the Provincial Directorate of National Education and High Schools. The students were allowed to attend and gather in the classes during the day and hours of the appointment. Students were informed about the subject and purpose of the study. Oral informed consent was obtained from the students who agreed to participate in the study. The previously prepared questionnaire forms were filled up by the students themselves under surveillance in accordance with the purpose of the study. The questionnaire form consisted of four sections. Questions about some of the sociodemographic characteristics of the students were included in the first section. Some factors that are thought to be related to the presence of alopecia comprised the second section. Results of hair and scalp examination were recorded in the third section. The fourth section consisted of questions about Short Form—36 (SF-36) scale items. After completing the questionnaire survey, the height and body weights of the students were

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measured by the researchers. Then, the students’ hair and scalp were examined by a dermatologist. The presence and severity of alopecia were assessed by examination. The severity of hair loss among those with alopecia was grouped as mild, moderate, and severe. To make the diagnosis of TE, which is one of the subtypes of alopecia, skin pull test was performed [20– 22]. According to the dermoscopic examination of hair strands, students having hair strands with a diameter of ≤39 μm, 40–79 μm, and ≥80 μm were evaluated as those with thin, normal, and thick hair strands, respectively [23]. In the present study, the criteria in the Declaration of Helsinki have been complied with. In our study, SF-36 was used in the evaluation of HRQoL. This scale was developed by Ware et al. in 1992, and its validity and reliability study in Turkey was performed by Kocyigit et al. in 1999 [24, 25]. The SF36 is a self-evaluation scale, and the status of individuals within the last 4 weeks is taken as a basis. There are eight subdomains of the scale, including physical functioning, physical role, pain, general health, vitality, social functioning, mental role, and mental health. The higher the score from each subdomain, the higher the HRQoL of that subdomain [26, 27]. Data obtained were evaluated using the IBM SPSS statistical package program (International Business Machines for Social Sciences version 20.0; SPSS Inc., Chicago, IL, USA). Chi-square test and Mann–Whitney U test were used for data analysis. Backward Stepwise (Wald) Logistic Regression Analysis was performed with some variables found to be related to the presence of alopecia. A p value ≤0.05 was accepted as statistically significant. RESULTS A total of 2220 students were attending the high schools in the research area. Of the 2220 students, 463 could not be found in schools during the study period, and 95 were excluded from the study because they did not accept hair and scalp examination. The study group was composed of 1662 (74.9%) students. The ages of the students ranged from 14 to 19 years, and the average age was 16.2±1.1 years. In our study, the prevalence of alopecia was 37.4% (n=622). The study group consisted of 906 (54.5%) male and 756 (45.5%) female students, and 493 (29.6%) students were aged ≤15 years. Of the 1662 students, 349 (21.0%)

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were smokers, and 179 (10.8%) were drinking alcohol. A total of 262 (15.8%) students had physician-diagnosed chronic diseases. Table 1 shows the distribution of alopecia in the study group according to some sociodemographic characteristics. Of the 1662 students, 1422 (85.6%) had been living in a core family, and 240 (14.4%) had been living in a large family. More than half of the students reported that their family was at a moderate income level. Mothers of 250 (15.0%) and fathers of 1256 (75.6%) students were employed. Mothers of 1147 (69.0%) students had received primary education (or lower level). However, fathers of 856 (51.2%) students were secondary and high-school graduates, and 927 (55.8%) students were living with their families. Table 2 shows the distribution of alopecia among the study groups according to some parental characteristics. In the study group, 419 (25.2%) students were complaining of burning, stinging, and itching sensations on the scalp, whereas 835 (50.2%) students were using hair dryer after shower/bath, and 409 (24.6%) students were using chemical hair styling products. Table 3 shows the distribution of alopecia in the study group according to some factors related to hair health. According to the results of scalp examination, 938 (56.4%) students had thin, 633 (38.1%) had thick, and 91 (5.5%) had normal hair strands. According to the results of scalp examination, 780 (46.9%) students had natural, 563 (33.9%) had greasy, 253 (15.2%) had dry, and 66 (4.0%) had moist hair. Table 4 presents the distribution of hair strand thickness and scalp type in patients with and without alopecia. Among the students with alopecia, 385 (23.2%) had AGA, 171 (10.3%) had TE, 40 (2.4%) had triangular (TAA), 37 (2.2%) had traction, 17 (1.0%) had scleral, and 4 (0.2%) had androgenic alopecia. In the study group, the distribution of students with alopecia according to alopecia subtypes is given in Figure 1. In the study group, the results of logistic regression analysis that is performed with the variables (sex, age group, smoking status, presence of complaint in the scalp, hair thickness, and scalp type) found to be related to the presence of alopecia are given in Table 5. In our study, according to the results of logistic regression analysis, gender, presence of scalp, and type of scalp were found to be risk factors for the incidence of alopecia.

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Table 1. Distribution of study participants with and without alopecia according to their sociodemographic characteristics Some sociodemographic characteristics Gender Male Female Age group ≤15 years 16 years 17 years ≥18 years Smoking status Smoker Nonsmoker Alcohol consumption Yes No Presence of physician-diagnosed chronic disease Yes No Total

Alopecia

Yes

Test value

Total

n %* n %* n %**

X2; p

378 41.7 528 58.3 906 54.5 15.704; 0.001 244 32.3 512 67.7 756 45.5 172 34.9 321 65.1 493 165 34.4 314 65.6 479 192 40.2 286 59.8 478 93 43.9 119 56.1 212

29.6 28.8 8.462; 0.037 28.8 12.8

155 44.4 194 55.6 349 21.0 9.211; 0.002 467 35.6 846 64.4 1313 79.0 78 43.6 101 56.4 179 10.8 3.241; 0.072 544 36.7 939 63.3 1483 89.2 101 38.5 161 61.5 262 15.8 521 37.2 879 62.8 1400 84.2 0.168; 0.682 622 37.4 1040 62.6 1662 100.0

*Percentage of the row; **Percentage of the column.

In the study group, there were no differences in the scores obtained in the subdomains other than the general health, vitality, and mental health subdomains. Table 6 presents the distribution of the median scores obtained from the subdomains of the SF-36 scale in the study group. DISCUSSION Alopecia, which can be seen in men and women of all ages, is a dermatological problem observed in approximately half of the people throughout their lives. Although alopecia is not a life-threatening condition, hair loss can often lead to adverse social and psychological consequences due to the fact that hair is an important social communication tool, and hair loss adversely affects selfconfidence and the quality of life of individuals [10, 11]. Owing to the increase in androgenic hormonal activity and psychosocial changes, the incidence of alopecia in adolescence has increased significantly [4, 28, 29]. In

our study, the incidence of alopecia was 37.4%. In studies conducted in various countries, the incidence of alopecia in adolescents has been reported to range from 15.5% to 38.5% [14–17]. The reasons of the different results reported in various studies may be considered as the differences in sociodemographic, ethnic, genetic, and lifestyle characteristics of the societies in which the studies are conducted and the differences in the diagnostic methods used. AGA is the most common alopecia subtype in adolescence and afterwards. Androgenic hormones trigger alopecia by miniaturizing strong terminal hairs, and as a result, alopecia is expected to be more common in men [29–31]. In our study, the incidence of alopecia was higher in male than in female students (p≤0.05, odds ratio (OR)=1.367). Paik et al. and Xu et al. reported similar results [32, 33]. Agirgol et al. reported that there is no relationship between the frequency of alopecia and gender [34]. There was no correlation between the frequency of alopecia and age group in the study group (p>0.05).

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Table 2. Distribution of study participants with and without alopecia according to some parental characteristics Some parental characteristics Family type Core Large Income level of the family Poor Moderate Good Employment status of the mother Employed Unemployed Employment status of the father Employed Unemployed Educational level of the mothers Primary school and lower Secondary school and higher Educational level of the fathers Primary school and lower Secondary school and higher Place of residence With his family Dormitory Total

Alopecia

Yes

Test value

Total

n %* n %* n %**

X2; p

533 37.5 889 62.5 1422 85.6 0.014; 0.906 89 37.1 151 62.9 240 14.4 36 42.9 48 57.1 84 5.1 438 38.1 713 61.9 1151 69.3 2.646; 0.266 148 34.7 279 65.3 427 25.7 95 38.0 155 62.0 250 15.0 0.042; 0.838 527 37.3 885 62.7 1412 85.0 471 37.5 785 62.5 1256 75.6 0.012; 0.911 151 37.2 255 62.8 405 24.4 430 192

37.5 37.3

717 323

62.5 62.79

1147 515

69.0 31.0

0.007; 0.936

319 303

39.3 35.6

492 548

60.7 64.4

811 851

48.8 51.2

2.466; 0.116

361 38.9 566 61.1 927 55.8 261 35.5 474 64.5 735 44.2 2.063; 0.151 622 37.4 1040 62.6 1662 100.0

*Percentage of the row; **Percentage of the column.

Kyriakis et al. reported results similar to our study [35]. Price et al. reported an increase in the incidence of alopecia with aging [36]. Kim et al. reported that the incidence of alopecia in the 14â&#x20AC;&#x201C;18 age group is higher than that in the 10â&#x20AC;&#x201C;14 age group [37]. In our study, the relationship between the age group and the incidence of alopecia could not be determined due to the fact that the age groups were very close to each other. The poor socioeconomic status of the family and the poor environmental characteristics of the living place are risk factors that increase the incidence of alopecia [38]. In our study, there was no relationship between the incidence of alopecia and family type, family income level, parental working status, parental education level, and place of residence (p>0.05, for each). Similar studies

have reported the lack of any correlation between the socioeconomic characteristics, such as family type, family income, and parental education, and the incidence of alopecia [39, 40]. Since the schools included in the study were in rural areas and the individuals living there had similar socioeconomic and environmental characteristics, any correlation between the parental characteristics and the incidence of alopecia could not be found. The chemical substances contained in the cigarette can cause free radicals to break down the capillary structure, reduce the blood supply, and impair nutrition of the hair follicles. Alcohol consumption can also damage the hair follicles by increasing oxidative stress and reducing protein synthesis. Smoking and alcohol consumption may cause alopecia due to these reasons [41â&#x20AC;&#x201C;44]. Simi-

Ozay et al., The frequency of alopecia and quality of life in high-school students in rural areas of Eskisehir

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Table 3. Distribution of study participants with and without alopecia according to some factors related to hair health Some factors related to hair health Complaints related to the scalp Yes No Use of hair dryer Users Non-users Use of hair styling products Users Non-users Total

Alopecia

Yes

Test value

Total

n %* n %* n %**

X2; p

174 41.5 245 58.5 419 25.2 4.027; 0.045 448 36.0 795 64.0 1243 74.8 311 37.2 524 62.8 835 50.2 0.023; 0.879 311 37.6 516 62.8 827 49.8 144 35.2 265 64.8 409 24.6 478 38.1 775 61.9 1253 75.4 1.139; 0.286 622 37.4 1040 62.6 1662 100.0

*Percentage of the row; **Percentage of the column.

Table 4. Distribution of students with and without alopecia according to hair strand thickness and scalp type Hair strand thickness and scalp type Thickness of the hair strand Thin Normal Thick Scalp type Natural Dry Moist Fatty Total

Alopecia

Yes

Test value

Total

n %* n %* n %**

X2; p

356 38.0 582 62.0 938 56.4 22 24.2 69 75.8 91 5.5 7.273; 0.026 244 38.5 389 61.5 633 38.1 251 32.2 529 67.8 780 46.9 97 38.3 156 61.7 253 15.2 24 36.4 42 63.6 66 4.0 20.999; <0.001 250 44.4 313 55.6 563 33.9 622 37.4 1040 62.6 1662 100.0

*Percentage of the row; **Percentage of the column.

lar studies have also reported the lack of any relationship between smoking and alcohol consumption and the incidence of alopecia [43â&#x20AC;&#x201C;46]. Mosley et al. reported that the incidence of alopecia is higher in smokers [47]. Severi et al. reported that the incidence of alopecia is higher in alcohol consuming individuals, and that alcohol consumption is associated with AGA, especially involv-

ing the forehead and vertex, and not related to the other types of alopecia [43]. Owing to the smaller age of the students in the study group and the time required for the observation of the cumulative effects of cigarette and alcohol on alopecia did not pass, the relationship between smoking and alcohol consumption and the frequency of alopecia might not be found in our study.

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Table 5. Results of logistic regression analysis performed using variables detected to be related to alopecia Variables

Gender (reference: female students) Male students 0.313 0.113 Complaints related to the scalp (reference: none) Yes 0.265 0.121 Scalp types (reference: natural) Dry Moist Fatty Constant – 1.441

95% CI

0.005 1.367 1.097–1.705 0.028 1.303 1.029–1.650 0.486 0.100 0.001 0.381

1.210 1.294 1.586 0.000

0.708–2.066 0.952–1.759 1.257–2.001 – –

SE: Standard error; OR: Odds ratio; CI: Confidence interval.

Table 6. Distribution of median scores obtained by study participants with and without alopecia from SF-36 scale subdomains SF-36 subdomains

Alopecia

Test value

Yes Median (Min.–Max.)

No Median (Min.–Max.)

z; p

90.0 (0.0–100.0) 75.0 (0.0–100.0) 80.0 (0.0–100.0) 60.0 (0.0–100.0) 60.0 (0.0–100.0) 75.0 (0.0–100.0) 66.7 (0.0–100.0) 56.0 (0.0–100.0)

95.0 (0.0–100.0) 100.0 (0.0–100.0) 87.5 (0.0–100.0) 65.0 (0.0–100.0) 65.0 (0.0–100.0) 75.0 (0.0–100.0) 66.7 (0.0–100.0) 60.0 (0.0–100.0)

1.370; 0.171 1.755; 0.079 1.785; 0.074 1.968; 0.049 2.326; 0.020 1.397; 0.162 1.396; 0.163 3.007; 0.003

Physical functioning Physical role Pain General health Vitality Social functioning Mental role Mental health Min.: Minimum; Max.: Maximum.

Alopecia subtypes (n) 450 400 350 300 250 200 150 100 50 0

Tri. A

Tra. A

Alo. A

AA: Androgenetic alopecia; TE: Telogen effluvium; Tri. A: Triangular alopecia; Tra. A: Traction alopecia; SA: Scarred alopecia; Alo. A: Alopecia areata.

Figure 1. In the study group, the distribution of students with alopecia according to alopecia subtypes.

Chronic diseases, such as hypothyroidism, hyperthyroidism, thyroiditis, hypertension, and diabetes, cardiovascular diseases, anemia, vascular structure, and autoimmune diseases cause T lymphocyte-mediated hair follicle damage and increase the risk of the development of alopecia [48–51]. There was no significant difference in the prevalence of alopecia among patients with physician-diagnosed chronic disease (p>0.05). Similar results have been reported in various studies [28, 52, 53]. Akbas et al. emphasized that the incidence of AA is found to be higher in patients with autoimmune thyroid diseases, atopic dermatitis, vitiligo, pernicious anemia, and chronic AA [19]. In the present study, the reasons of not

Ozay et al., The frequency of alopecia and quality of life in high-school students in rural areas of Eskisehir

finding a relationship between the presence of chronic disease and the incidence of alopecia can be related to the small age of the students, the onset of chronic illnesses in general in advanced ages, and the cumulative emergence of the alopecic effects of chronic diseases. Burning, stinging, and itching sensations felt on the scalp can be caused by scalp lesions, and these lesions may lead to impaired nutrition oxygenation, and integrity of the scalp. In addition, the presence of a complaint or lesion involving the scalp can cause mechanical trauma because of the continuous playing with the hair and scratching of the scalp. It is expected that the presence of complaints related to the scalp will increase the incidence of alopecia due to these effects [19]. In the study group, the frequency of alopecia was higher in those with complaints related to the scalp than in those without (p≤0.05, OR=1.303). It has been reported that the incidence of alopecia is higher in patients with symptoms, such as pruritus, burning, and stinging sensations, felt on the scalp and those with sensitive scalp skin [19, 54, 55]. The use of a hair dryer, especially at high temperatures, is known to induce alopecia by causing deformities and fractures in the hair shaft. The use of a hair dryer at high temperatures to shape hair causes the hair follicles to burn, creating a special type of alopecia called “hot comb alopecia” [56, 57]. In the study group, there was no difference in the frequency of alopecia between the hair dryer users and non-users (p>0.05). Whiting et al. and Jan et al. reported that the use of a hair dryer at high temperatures causes alopecia due to its traumatic effect [58, 59]. Since the students participating in the study group used a hair dryer at low temperatures to dry their hair after a bath/shower, not for the purpose of hot combing, we did not find any difference in the incidence of alopecia between users and non-users of hair dryers. Chemical hair styling products, such as jelly, grease, and hairspray, can lead to alopecia by causing irritation and allergic reaction on the scalp and destroying keratin protein, an important component of the hair strand [60, 61]. In our study, no difference was found in the incidence of alopecia among those who used and did not use chemical hair styling products (p>0.05). Similar results were reported in the study by Gummer et al. [62]. Draelos et al. and Zviak et al. reported higher incidence of alopecia among users of chemical hair styling products [63, 64]. In the present study, the reasons of not finding a difference in the frequency of alopecia between users and non-users of chemical hair styling products may be re-

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lated to our study group being composed of adolescents. In addition, owing to the shorter follow-up period, we could not observe the side effects of these products, and our study population living in rural areas could not afford for these products due to economic concerns. Thin hair strand is a sign of miniaturization in the hair follicle, causing the hair to become more fragile, and may lead to alopecia. The development of alopecia is facilitated with greater volume of hair loss with aging in people with thick hair [65, 66]. In the present study, there was no relationship between the thickness of hair follicle and the frequency of alopecia (p>0.05). Several studies have reported that the incidence of alopecia is higher in those with thin hair strands [67, 68]. Courtois et al. and Barman et al. reported that alopecia is more frequently detected in patients with thicker hairs [65, 69]. Different results obtained in various studies may be due to the difference in examination methods. The sebum, which is produced by the sebaceous glands in the scalp, has a rich fat content and protects the scalp from mechanical trauma as it acts as a physical barrier by providing the lubrication of the scalp. In case of excessive secretion of the sebum, the hair follicles may become clogged, and the oxygenation and blood supply of the hair may be reduced with the potential increase in the risk of alopecia [70, 71]. In the study group, the incidence of alopecia was higher in patients with oily/greasy hair (p≤0.05, OR=1.586). Ronny et al. and Pireard et al. reported that alopecia is more common in those with oily-haired skin [72, 73]. Banka et al. reported that any correlation is not found between the incidence of scalp type and alopecia [74]. Owing to the increased activation of androgenic hormones during puberty, terminal hairs in hair follicles can turn into miniature hairs and induce the development of AGA. It is known that changes in thyroid and androgenic hormone metabolism play an important role in TE etiology. The most common alopecia subtypes due to hormonal changes occurring during and after adolescence are AGA and TE [28, 30, 75, 76]. In the present study, the incidence rates of AGA and AA were 23.2% and 10.3%, respectively. In some studies, the incidence rates of AGA and TE have been reported to range between 13.1 and 24.5% [32, 36, 77] and 1.6 and 59.7%, respectively [19, 78]. The reasons of the different results reported in various studies may be due to the sociodemographic and ethnic characteristics, lifestyles of the study populations investigated, and different diagnostic methods used in these studies.

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Since the body’s perception of people is negatively affected by alopecia, their self-esteem decreases, which is known to affect the quality of life adversely leading to psychological and social problems [11, 79]. In the study group, the SF-36 scale scores indicated the presence of a worse quality of life in the general health, vitality, and mental health subdomains of patients with alopecia (p≤0.05, for each). In the other subdomains of the scale, no difference was found with respect to the quality of life among those who were not identified with alopecia (p>0.05, for each). Gulec et al. reported poorer quality of life in the subdomains of vitality and mental health in those with alopecia [80]. Hollanda et al. reported that patients with alopecia are found to have poorer quality of life in the mental health, mental role, social function, and pain subdomains [81]. Conclusion In the present study, owing to the high prevalence of alopecia, we deemed it appropriate to conduct health education studies, to integrate hair and scalp examinations into school screening programs, to direct students with alopecia to the dermatologists, to make students with fatty scalp to wash their hair regularly to improve the quality of life of the students in the research region, and to increase the awareness of students so as to increase the rates of early diagnosis and treatment. Conflict of Interest: The authors declare no conflict of interest. Financial Disclosure: The authors have no proprietary or financial interest in any products used in this study. Authorship Contributions: Concept – OO, DA, AU, IB; Design – OO, DA; Supervision – OO, DA; Materials – OO, DA, AU, IB; Data collection and/or processing – OO, IB; Analysis and/or interpretation – OO, DA, AU; Writing – OO, DA; Critical review – OO, DA, AU.

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Orıgınal Article

PEDIATRICS

North Clin Istanb 2019;6(3):236–241 doi: 10.14744/nci.2018.40360

Echocardiographic assessment of children participating in regular sports training Seyma Kayali,1

Fatma Tuba Yildirim2

Department of Pediatric Cardiology, University of Health Sciences, Kecioren Training and Research Hospital, Ankara, Turkey

Department of Pediatrics, Sorgun State Hospital, Yozgat, Turkey

ABSTRACT OBJECTIVE: The aim of the present study was to determine the effects of a well-controlled endurance training program on cardiac functions and structures in healthy children and to define whether training hours per week and type of sports affect the training-induced cardiovascular response. METHODS: Echocardiographic recordings were obtained in 126 children who systematically participated in sports training for at least 1 year (study group), and the results were compared with the values obtained in 62 normal children who did not actively engage in any sports activity (control group). The two groups were comparable for age, sex, and body mass index. Study group participants were divided into two groups according to the duration of physical activity (training hours per week, <8 h and >8 h) and five groups according to the cardiovascular demand of sports type. Clinical examination, resting electrocardiogram, two-dimensional, M-mode, and Doppler echocardiography were obtained in all participants. RESULTS: Left ventricle wall dimensions, left atrial diameters, and aortic measurements were significantly higher in the study group. The mean mitral E/A ratio was also significantly higher in the training group than in untrained subjects (p<0.001). Echocardiographic measurements were similar between different sports type participants in the study group. However, aortic root diameter, left atrial diameter, and left ventricle posterior wall diastolic thickness were higher in children training >8 h/ week than in children training <8 h/week in the study group. CONCLUSION: The present study showed that the echocardiographic parameters of children participating in regular sports training activities statistically significantly exceeded the parameters of untrained controls. These parameters were mostly dependent on the duration of training hours per week. Keywords: Athlete’s heart; children; echocardiography; sports activity.

Cite this article as: Kayali S, Yildirim FT. Echocardiographic assessment of children participating in regular sports training. North Clin Istanb 2019;6(3):236–241.

“A

thlete’s heart” is known as myocardial hypertrophy due to regular and intensive physical exercises. This condition is physiological, adaptive, and reversible [1]. It is also well documented that myocardial remodeling is related to the intensity and kind of sports practiced [2]. The relationship between different sports types and cardiac structures especially in adults has been investigated in many previous studies [3, 4]. However, there are

few studies in children and adolescents about the effects of sports training on cardiac functions and structures [5]. Short-term training sessions have been shown to result in significant structural and functional cardiac adaptations including increases in left ventricular posterior wall (PW) diameter and interventricular septum (IVS) thickness in children [6]. Very recently, Zdravkovic et al. investigated the electrocardiographic changes in pread-

Received: February 08, 2018 Accepted: August 29, 2018 Online: September 03, 2018 Correspondence: Dr. Seyma KAYALI. Saglik Bilimleri Universitesi, Kecioren Egitim ve Arastirma Hastanesi, Cocuk Kardiyolojisi Klinigi, Ankara, Turkey. Tel: +90 312 356 90 00 e-mail: ak-seyma@hotmail.com © Copyright 2019 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

olescent footballers and reported significant differences between the footballers and control group regarding P-wave, S-wave, and R-wave voltages; wave duration; and QTc interval duration that were considered as the electrocardiogram (ECG) pattern of left ventricle (LV) remodeling since those athletes did not develop any adverse cardiac events in the 6-year follow-up [7]. In that aspect, it is important to determine the impact of regular exercise and the remodeling period on children’s heart that is still in the maturation period. The aim of the present study was to determine the effects of regular exercise on the child’s heart and to define whether training hours per week or type of sports affects the training-induced cardiovascular response in training children. MATERIALS AND METHODS This was a prospective, case–control study conducted from February 2016 to December 2016 on 126 children who systematically participated in sports training for at least 1 year (study group) and 62 normal children who did not actively engage in sports (control group). Children with congenital heart disease and arrhythmia-associated chronic diseases (e.g., obesity, hypertension, and diabetes mellitus) and children who were under regular medications were excluded from the study. Study group participants were divided into two groups according to the duration of physical activity (training hours per week, <8 h and >8 h) and five groups according to the cardiovascular demand of sports type (2). This classification allows classifying sports type according to cardiovascular demand. The lowest total cardiovascular demands (cardiac output and blood pressure) are shown in green and the highest in red; blue, yellow, and orange depict low moderate, moderate, and high moderate total cardiovascular demands (2) (Fig. 1). All participants had clinical examination, resting ECG, two-dimensional (2D), M-mode, and Doppler echocardiography. Echocardiographic Examination Echocardiography was performed using the Vivid 3 (General Electric, USA) echocardiography by the aid of 3 MHz probes. All echocardiographic examinations were performed by one experienced pediatric cardiologist who was blinded to the training status of the participants to avoid inter-observer variability, from the long

Increasing cardiovascular demand

Kayali et al., Echocardiographic assessment of children participating in regular sports training

Low

Billiards, bowling, cricket, curling, golf

Low moderate

Diving, table tennis, volleyball, motorcycling

Moderate

Gymnastics,weight lifting, synchronized swimming, orienteering, running, tennis

High moderate

Bodybuilding, wrestling, basketball, snowboarding, team handball

High

Boxing, cycling, decathlon, rowing

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Figure 1. Classification of sports according to cardiovascular demand.

axis view and following the American Heart Association echo guidelines [8]. The standard LV 2D parameters were obtained at rest. The basal 2D systo-diastolic and Doppler parameters; IVS and PW thickness; LV end-diastolic diameter (LVEDd), LV end-systolic diameter (LVESd), left atrium (LA), aortic root (AR), and ascending aorta (AA) dimensions; pulse wave Doppler transmitral flow E-wave and A-wave (E/A ratio) were recorded. Mitral E/A ratio was used as a diastolic index of the LV. The assessment of the systolic function of the myocardium was made by the measurement of the ejection fraction (EF%) that was obtained according to the formula [(LVEDd)3−(LVESd)3/(LVEDd)3]*100 and the percentage of the shortening of the LV (FS%) (LVEDd−LVESd/LVEDd*100). Statistical Analyses Statistical analyses were performed by the SPSS 22 for Windows software (IBM SPSS Statistics for Windows, Version 22.0. Armonk, NY,USA). All data were expressed as mean±SD. The echocardiographic variables were compared between the study and control groups by the Student’s t-test and Mann–Whitney U test. The study group comparison according to sports type was performed by Kruskal–Wallis variance analysis test. A p value <0.05 was regarded as statistically significant. Ethical Approval All study procedures were approved by the ethics committee of a tertiary center (2012-KAEK-15/1322) according to the Declaration of Helsinki. Written informed consent was obtained from all subjects and their parents.

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groups

Study group (n=126)

Control group (n=62)

Age (months) Height (cm) Weight (kg) BMI(kg/m2) SBP (mmHg) DBP (mmHg) HR (bpm)

162.3±31.9 160.7±16.4 53.4±16.9 20.1±3.6 113.6±10.4 63.2±8.2 83.9±13.3

162.3±31.1 157.4±13.3 50.3±12.5 20±3.18 112.1±10.3 65±7.4 91.8±14.2

0.99 0.16 0.20 0.80 0.36 0.15 0.01

20 15

BMI: Body mass index; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; HR: Heart rate.

Table 2. Comparison of echocardiographic parameters among the groups

AR mm AA mm LAD mm EF % FS% LVEDd mm LVESd mm IVSD mm IVSS mm LPWd mm LPWs mm Mitral E/A

Control group (n=62)

Study group (n=126)

Table 1. Comparison of demographic characterics among

Study group (n=126)

Control group (n=62)

22.6±3.5 21.1±2.8 27.2±4.1 71.8±5.6 41±4.8 43±5.7 25.3±4.4 10.5±2.2 13.5±2.4 9.6±2.2 15.3±3.1 1.9±0.2

21.5±2.6 20.3±2.1 25.2±3.4 71.2±6.2 40.5±5.2 42.8±4 25.1±3.9 9.2±2.1 12.1±2.1 7.8±1.7 13.3±3.7 1.6±0.2

0.02 0.03 0.01 0.49 0.55 0.77 0.79 0.01 0.01 0.01 0.01 0.01

AR: Aortic root; AA: Asendan aorta; LAD: Left atrial diameter; EF: Ejection fraction; FS: Shortening fraction; LVEDd: Left ventricle end diastolic diameter; LVESd: Left ventricle end sistolic diameter; IVSD: Interventriculer septum in diastole; IVSS: Interventriculer septum in systole; LPWD: left ventricle posterior wall thickness in diastole; LPWs: left ventricle posterior wall thickness in systole.

RESULTS Demographic and general characteristics of the study participants are defined in Table 1. There were no statistically significant differences between the study and control groups regarding age, gender, height, weight, and body mass index (BMI). Resting systolic and diastolic blood pressures were also similar. Heart rate was lower

10 5

LPWS

LPWDL

IVSS

IVSD

LAD mm

AA mm

AR mm

Figure 2. Alterations in some echocardiographic parameters among the two groups. AR: Aortic root; AA: Asendan aorta; IVSD: Interventriculer septum diameter in diastole; IVSS: Interventriculer septum diameter in systole; LPWD: Left ventricle posterior wall diameter in diastole; LPWS: Left ventricle posterior wall diameter in systole. in the study group (p=0.01) (Table 1). The echocardiographic measurements of aortic dimensions (AR and AA) were significantly higher in the study group (p=0.02 and p=0.03, respectively). Echocardiographic analyses of the left heart showed that the values of the LA, LV PW thickness in diastole (LVPWd), and LV PW thickness in systole (LVPWs) were statistically significantly increased in the study group (p=0.01) (Table 2, Fig. 2). The values of interventricular septum diameter in systole (IVSs), interventricular septum diameter in diastole (IVSd), and mitral E/A ratio were also found to be higher in the study group (p=0.01). Contractibility parameters (EF% and FS%) and LVEDd and LVESd were higher in the study group, but the differences between the two groups were not statistically significant. When the study group was assessed according to training hours per week, all echocardiographic measurements were higher in the group training >8 h. However, only measurements of LVPWd, LA, and AR were statistically significantly higher in the subgroup training >8 h than in the study subgroup training <8 h (p=0.01) (Table 3). When the study group participants were assessed according to sports type classification, there were 5 participants in green, 7 in blue, 56 in yellow, 15 in orange, and 43 in red areas. Any statistically significant differences

Kayali et al., Echocardiographic assessment of children participating in regular sports training

Table 3. Echocardiographic measurements of groups according to training hours per week AR mm AA mm LAD mm EF % FS% LVEDd mm LVESd mm IVSD mm IVSS mm LPWd mm LPWs mm Mitral E/A

Control group Less than More than (n=62) 8 hours a week 8 hours a week 21.5±2.6 20.3±2.1 25.2±3.4 71.2±6.2 40.5±5.2 42.8±4.0 25.1±3.9 9.2±2.1 12.1±2.1 7.8±1.7 13.3±3.7 1.6±0.2

22.1±3.4 21.0±2.9 26.8±3.8 71.8±5.3 41.1±4.5 43.3±5.5 25.2±4.4 10.3±2.3 13.3±2.5 9.3±1.9 15.2±2.7 1.9±0.2

24.0±3.5 21.7±2.4 29.0±4.4 71.9±6.5 41.7±5.8 43.4±6.8 25.5±4.6 10.8±2.1 14.3±2.5 10.5±2.8 15.7±3.9 1.9±0.2

AR: Aortic root; AA: Asendan aorta; LAD: Left atrial diameter; EF: Ejection fraction; FS: Shortening fraction; LVEDd: Left ventricle end diastolic diameter; LVESd: Left ventricle end sistolic diameter; IVSD: Interventriculer septum in diastole; IVSS: Interventriculer septum in systole; LPWD: Left ventricle posterior wall thickness in diastole; LPWs: Left ventricle posterior wall thickness in systole.

regarding echocardiographic parameters were not determined between these subgroups (p>0.05). DISCUSSION Currently, the adaptation of the heart to training has been largely studied in adults. However, there are still limited data about the adaptation of children’s heart to training that is still in the maturation period. In the present study, we determined that regular exercise training induces cardiovascular changes in children. First, in the present study, heart rate was determined to be statistically significantly lower in the study group. It is a well-known fact that long term endurance training is associated with cardiac neural remodeling in favor of cardioprotective vagal mechanisms, resulting in resting bradycardia [9]. Different pediatric and adult studies showed that athletes were having significantly greater prevalence of sinus bradycardia than non-athletes [5, 10]. Similarly, Sharma et al. evaluated the electrocardiographic alterations in 1000 junior athletes with a mean age of 15.7 years and reported that athletes have a significantly higher prevalence of sinus bradycardia and sinus arrhythmia than non-athletes with significantly prolonged PR interval and QRS and QT durations [11]. Although we did not

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evaluate the electrocardiographic changes, we also determined that regular training in children is associated with lower heart rates. We believe that this alteration is associated with increased vagal tone and increased cardiac size as reported in previous studies [11]. Cardiac output increases up to 30 L/min to 40 L/ min with a positive linear relationship to the intensity of the activity during exercise in trained subjects [12]. However, it may eventually lead to increased hemodynamic insult and mechanical stress on the great vascular structures and cardiac chambers. Associated with increased blood flow, hemodynamic insult, or increased shear stress during exercise, dilatation of AR and AA could be observed due to medial degeneration of the vessel layer [12]. Ventricular systolic EF was also determined to be increased in training children [6]. Second, in the present study, the echocardiographic measurements of aortic dimensions (AR and AA) were significantly higher in the study group (p=0.02 and p=0.03, respectively). Similarly, it was reported recently that aortic dilation and subsequently, thoracic aorta aneurysms may be an occupational disease due to the nature of some professions including athletes [13]. The compensation procedure for this elevated cardiac output and overload of the flowing blood results in the increase of not only the diameter of the aorta but also the diameter of cardiac chambers and relative wall thickness [14, 15]. Third, in the present study, LVPWd, LVPWs, IVSd, and IVSs were statistically significantly higher in the study group, whereas there were no differences in LVEDd and LVESd measurements. However, an increase in the left ventricular end-diastolic diameter associated with an improvement in diastolic function after training compared with the resting data was previously reported [16]. The two main types of an athlete’s heart were described according to the type of exercise as dynamic or static: Eccentric hypertrophy (increase in cavity diameter and wall thickness) and concentric hypertrophy (increase in wall diameter without any change on cavity size). [17]. Therefore, individuals with an athlete’s heart could exhibit further cardiac adaptation in response to different trainings [18, 19]. In that aspect in the evaluation of different results reported in the literature about the effects of training on cardiac functions, the type of training should be considered. Our findings are due to heterogeneity of the study group and also support further cardiac adaptation ac-

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cording to sports type. Similarly, Venkunas et al. did not observe any significant differences in the end-diastolic diameter between the athletic and control groups [20]. Fourth, one of the significant findings to be discussed was greater left atrial diameter measurement in the study group than that in the control group. The increase of the LA is common in athletes due to increased pressure in the cavity during exercise. Toufan et al. recently reported that LA diameters are increased as a left atrial remodeling in response to prolonged duration of regular endurance sports [19]. Fifth, regarding the diastolic function, there was a significant increase of the E/A ratio in the study group. In several studies related to diastolic function in athletes, an increase in E-wave velocity and an increase in the E/A ratio have been observed from different sports [20, 21]. These findings are suggestive of a supernormal diastolic function mediated by a combination of improved initial ventricular relaxation and increased left ventricular compliance. When the study group was examined in itself according to training hours, statistically significant increases in LVPWd, LA, and AR were detected in participants training >8 h/week. Similarly, a study in which participants were divided into groups according to training hours per week reported that IVS thickness, end-diastolic diameter, and left ventricular mass were significantly higher in athletes whose training exceeded 8 h/ week than in controls [22]. Agrebi et al. reported that among children who were having a regular training for handball, LVEDd, LVESd, LA, AR, and LV mass are all significantly lower in younger children than in older ones and adults [23]. This finding was suggested to be associated with the duration of prior practice and early cardiac remodeling. We did not subgroup the patients regarding their ages, but this data also supports our finding that with an increase in training time, LVEDd, LVESd, LA, AR, and LV mass were increasing. It is a well-known fact that cardiovascular response to sports is associated with the type and duration of exercise [24, 25]. Since, our study group was so heterogeneous when classified according to sports type, no difference could be determined between the groups regarding echocardiographic parameters. We did not determine any significant alterations in systolic blood pressure between the study and control groups. In a recent study, Tan et al. [26] reported a decrease in both systolic blood pressure and heart rate of obese children with exercise training. We did not deter-

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mine the BMIs of children in the present study, which may be the topic of future investigations. There are some limitations of the present study that should be defined. First is the low number of study participants, and second is the assessment of only shortterm records. Moreover, in a recent study, D’Ascenzi et al. determined an increase in right ventricle size after 5 months of intensive training in children without an alteration in its functions that was suggested as a part of the remodeling period [27]. Conclusion The principal aspect of the present study is the confirmation of the presence of sports-related cardiovascular changes in children similar to adults. These parameters were mostly dependent on the duration of training hours per week. Further prospective, larger, long-term follow-up studies are warranted to understand the importance of especially sports type on cardiovascular response. Ethics Committee Approval: This study was approved by the ethic committe of Health Sciences University Kecioren Training and Research Hospital (Number: 2012-KAEK-15/1322). Conflict of Interest: The authors declare no conflict of interest. Financial Disclosure: The authors declared that this study has received no financial support. Authorship Contributions: Concept – SK; Design – SK; Supervision – SK; Materials – SK, FTY; Data collection and/or processing – SK, FTY; Analysis and/or interpretation – SK, FTY; Writing – SK; Critical review – SK, FTY.

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Scand J Med Sci Sports 2014;24 Suppl 1:4–9. 7. Zdravkovic M, Milovanovic B, Hinic S, Soldatovic I, Durmic T, Koracevic G, et al. Correlation between ECG changes and early left ventricular remodeling in preadolescent footballers. Physiol Int 2017;104:42–51. 8. Bonow RO, Carabello BA, Chatterjee K, de Leon AC Jr, Faxon DP, Freed MD, et al. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Forceon Practice Guidelines (writing Committee to Revise the 1998 guidelines for the management of patients with valvular heart disease) developed in collaboration with the Society of Cardiovascular Anesthesiologists endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. J Am Coll Cardiol 2006;48:e1–148. 9. Sala R, Malacarne M, Tosi F, Benzi M, Solaro N, Tamorri S, et al. May a unitary autonomic index help assess autonomic cardiac regulation in elite athletes? Preliminary observations on the national Italian Olympic committee team. J Sports Med Phys Fitness 2017;57:1702–10. 10. Stanley J, Peake JM, Buchheit M. Cardiac parasympathetic reactivation following exercise: implications for trainingprescription. Sports Med 2013;43:1259–77. 11. Sharma S, Whyte G, Elliott P, Padula M, Kaushal R, Mahon N, et al. Electrocardiographic changes in 1000 highly trained junior elite athletes. Br J Sports Med 1999;33:319–24. 12. Warburton DE, Haykowsky MJ, Quinney HA, Blackmore D, Teo KK, Humen DP. Myocardial response to incremental exercise in endurancetrained athletes: influence of heart rate, contractility and the Frank-Starling effect. Exp Physiol 2002;87:613–22. 13. Okamoto RJ, Xu H, Kouchoukos NT, Moon MR, Sundt TM 3rd. The influence of mechanical properties on wall stress and distensibility of the dilated ascending aorta. J Thorac Cardiovasc Surg 2003;126:842– 50. 14. Aparci M, Erdal M, Isilak Z, Yalcin M, Uz O, Arslan Z, et al. Enlargement of the aorta: An occupational disease? Exp Clin Cardiol 2013;18:93–7. 15. Pluim BM, Zwinderman AH, van der Laarse A, van der Wall EE. The athlete’s heart. A meta-analysis of cardiac structure and function. Circulation 2000;101:336–44. 16. Obert P, Mandigouts S, Nottin S, Vinet A, N’Guyen LD, Lecoq AM.

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Cardiovascular responses to endurance training in children: effect of gender. Eur J Clin Invest 2003;33:199–208. 17. Morganroth J, Maron BJ, Henry WL, Epstein SE. Comparative left ventricular dimensions in trained athletes. Ann Intern Med 1975;82:521– 4. 18. Naylor LH, George K, O’Driscoll G, Green DJ. The athlete’s heart: a contemporary appraisal of the ‘Morganroth hypothesis’. Sports Med 2008;38:69–90. 19. Toufan M, Kazemi B, Akbarzadeh F, Ataei A, Khalili M. Assessment of electrocardiography, echocardiography, and heart rate variability in dynamic and static type athletes. Int J Gen Med 2012;5:655–60. 20. Venckunas T, Lionikas A, Marcinkeviciene JE, Raugaliene R, Alekrinskis A, Stasiulis A. Echocardiographic parameters in athletes of different sports. J Sports Sci Med 2008;7:151–6. 21. Moro AS, Okoshi MP, Padovani CR, Okoshi K. Doppler echocardiography in athletes from different sports. Med Sci Monit 2013;19:187– 93. 22. Bartkeviciene A, Dalia B. Changes in morphometric parameters and function of left ventricle in child and adolescent athletes. Medicina (Kaunas) 2007;43:251–8. 23. Agrebi B, Tkatchuk V, Hlila N, Mouelhi E, Belhani A. Impact of specific training and competition on myocardial structure and function in different age ranges of male handball players. PLoS One 2015;10:e0143609. 24. Prakken NH, Velthuis BK, Teske AJ, Mosterd A, Mali WP, Cramer MJ. Cardiac MRI reference values for athletes and nonathletes corrected for body surface area, training hours/week and sex. Eur J Cardiovasc Prev Rehabil 2010;17:198–203. 25. Galanti G, Stefani L, Mascherini G, Di Tante V, Toncelli L. Left ventricular remodeling and the athlete’s heart, irrespective of quality load training. Cardiovasc Ultrasound 2016;14:46. 26. Tan S, Chen C, Sui M, Xue L, Wang J. Exercise Training Improved Body Composition,Cardiovascular Function, and Physical Fitness of 5-Year-Old Children With Obesity or Normal Body Mass. Pediatr Exerc Sci 2017;29:245–53. 27. D’Ascenzi F, Pelliccia A, Valentini F, Malandrino A, Natali BM, Barbati R, et al. Training-induced right ventricular remodelling in pre-adolescent endurance athletes: The athlete’s heart in children. Int J Cardiol 2017;236:270–5.

Orıgınal Article

GASTROENTEROLOGY

North Clin Istanb

2019;6(3):242–247 doi: 10.14744/nci.2019.54936

Lipid profile, atherogenic indices, and their relationship with epicardial fat thickness and carotid intima–media thickness in celiac disease Zuhal Caliskan,1

Kenan Demircioglu,2

Fatma Betul Ozcan,2

Osman Kostek,3

Suleyman Sayar,1

Resul Kahraman,1

Omer Faruk Baycan,2

Ozge Caklili,2

Hamdi Levent Doganay,1

Mustafa Caliskan

Department of Gastoenterology, Saglik Bilimleri University, Umraniye Training and Reaserch Hospital, Istanbul, Turkey

Department of Cardiology and Internal Medicine, Istanbul Medeniyet University, Goztepe Training and Reaserch Hospital, Istanbul, Turkey

Department of Oncology, Trakya University, Edirne, Turkey

ABSTRACT OBJECTIVE: In this study, we aimed to investigate the presence of subclinical atherosclerosis by measuring epicardial fat thickness (EFT) and carotid intima–media thickness (cIMT), evaluate low-level inflammation with high-sensitivity C-reactive protein (hsCRP), and evaluate whether there is a relationship among lipid profile, atherogenic indices, and hsCRP with these subclinical atherosclerosis markers in patients with celiac disease (CD). METHODS: After exclusion and inclusion criteria were applied, 31 patients with CD (24 female, mean age: 39.4±12.3 years) and 32 healthy controls (21 female, mean age: 39.5±4.4 years), totally 63 cases, were recruited. Subclinical atherosclerosis was evaluated with EFT by transthoracic echocardiography and cIMT by ultrasonography. Inflammatory markers including erythrocyte sedimentation rate (ESR), hsCRP, and lipid profile were recorded. Also, atherogenic indices were calculated: Castelli risk index I and II (TG/HDL-c and LDL-c/HDL-c, respectively), atherogenic index of plasma (AIP; logarithm TG/HDL-c), non-HDL-c (TG-HDL-c), and atherogenic coefficient (AC; non-HDL-c/HDL-c). RESULTS: EFT was significantly higher in the CD group (0.49±0.10 vs. 0.49±0.09; p-value: 0.02). Although cIMT was higher in the patient group, it did not reach statistical significance (0.51±0.08, 0.47±0.08; p-value: 0.10). HDL cholesterol level was found to be significantly lower (42.0±8.8 vs. 50.0±13.7; p-value: 0.01), and the plasma atherogenic index was found to be significantly higher in the patient group (0.98±0.50 vs. 0.62±0.64; p-value: 0.02). hsCRP (3.51±3.18 vs. 1.92±1.40; p-value: 0.02) and ESR (17.2±12.8 with 9.7±3.1; p-value: 0.01) were found to be significantly higher in the CD group. Although there was a significant positive correlation between EFT and hsCRP (r: 0.453; p-value: 0.01), there was a significant negative correlation between cIMT and HDL-cholesterol (−0.339; p-value: 0.05), and a significant positive correlation with the other components of the atherogenic index was found. CONCLUSION: The risk of atherosclerosis has been increased in patients with CD. Chronic inflammation may be responsible for this increase along with atherogenic indices. Keywords: Atherogenic dyslipidemia; celiac disease; cIMT; epicardial fat thickness.

Cite this article as: Caliskan Z, Demircioglu K, Sayar S, Kahraman R, Caklili O, Ozcan FB, et al. Lipid profile, atherogenic indices, and their relationship with epicardial fat thickness and carotid intima–media thickness in celiac disease. North Clin Istanb 2019;6(3):242–247.

Received: November 02, 2018 Accepted: January 09, 2019 Online: September 02, 2019 Correspondence: Dr. Zuhal CALISKAN. Saglik Bilimleri Universitesi, Umraniye Egitim ve Arastirma Hastanesi, Gastroenteroloji Klinigi, Istanbul, Turkey. Tel: +90 507 838 53 05 e-mail: caliskanzuhal@gmail.com © Copyright 2019 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

Caliskan et al., Atherogenic indeces and their relation of EFT and cIMT in celiac disease

therosclerotic heart disease is the leading cause of morbidity in Western population [1]. Recently due to altering nutritional conditions and dietary habits of developing countries, an increase in cardiovascular mortality has been observed in Turkey as well [1, 2]. A novel study has reported a multifactorial interaction between inflammation and development, and progression and rupture of plaque in atherosclerotic lesions [3]. In this context, it is assumed that atherosclerosis is an immuneinflammatory disease [3, 4]. Also, in most of the patients with acute coronary syndrome, there is an increase in high-sensitivity C-reactive protein (hsCRP), which is a marker of inflammation, and it is reported that hsCRP is a prognostic marker for future cardiovascular events [5]. There is an increase in cardiovascular disease in chronic inflammatory diseases such as ankylosing spondylitis, rheumatoid arthritis, and inflammatory bowel diseases. Subclinical inflammation was held responsible for increase of cardiovascular diseases in these immune-inflammatory conditions, which do not possess conventional cardiovascular risk factors [6–8]. Celiac disease (CD) is an autoimmune disease in which genetically susceptible persons develop antibodies against gluten (gliadin) protein [9]. The disease is characterized with chronic inflammation of proximal segment of small intestine [9]. It also affects other organs and tissues. Some recent studies have reported that CD causes endothelial damage and susceptibility to atherosclerosis [10, 11]. However, in these studies, there are no data to explain the pathogenesis of cardiovascular heart disease risk. Epicardial fat tissue is an active visceral fat tissue which itself is an endocrine organ. It is well known that epicardial fat tissue thickness (EFT) measured with echocardiography has a significant association with low level of inflammation and subclinical atherosclerosis [12]. Also, carotid intima–media thickness (cIMT) assessed with ultrasound is a marker of early-stage atherosclerotic disease [7]. Atherogenic lipid profile is defined as an increase in serum total cholesterol, low-density lipoprotein cholesterol (LDL-c), and triglycerides (TG), and a decrease in high-density level (HDL-c) cholesterol [13]. Some studies have stated that HDL cholesterol levels are lower in patients with CD compared to healthy controls. Other studies have suggested that Castelli risk index I and II (TG/HDL-c and LDL-c/HDL-c, respectively), plasma atherogenic index (PAI; logarithm TG/ HDL-c), non-HDL-c (TG-HDL-c), and atherogenic coefficient (AC; non-HDL-c/HDL-c) indices are more

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sensitive in predicting atherosclerotic cardiovascular heart disease risk [13–15]. In this study, we aimed to investigate the presence of subclinical atherosclerosis by measuring EFT and cIMT, evaluate low-level inflammation with hsCRP, and evaluate whether there is a relationship between atherogenic indices and hsCRP with these subclinical atherosclerosis markers in patients with CD. MATERIALS AND METHODS Study population The study was conducted in compliance with Helsinki declaration 1967. Patient consents were obtained from each subject. Inclusion criteria of the study included positive serologic testing for CD (anti-tissue transglutaminase (dTG) or anti-endomysium antibody (EMA)) and confirmation of the diagnosis with endoscopic biopsy (MARSH score) was required. Patients who fulfilled these criteria were advanced to cardiovascular examination and medical history with 12-derivative standard EKG workup. Patients with angina pectoris were evaluated using a treadmill test and patients with positive test results were excluded. Other exclusion criteria were: active smoking, morbid obesity (body mass index >35 kg/m2), pregnancy, diabetes, another immune or inflammatory diseases besides CD and hypertension (patients under hypertensive treatment or with blood pressure >140/90 mmHg). Patients with liver disease, renal disease, cardiovascular, or cerebrovascular disease history (myocardial infarction, transient ischemic attack, or stroke) were also excluded. After exclusion criteria and inclusion criteria were applied, 31 patients with CD (24 female, mean age: 39.4±12.3 years) and 32 healthy controls (21 female, mean age: 39.5±4.4 years), totally 63 cases, were recruited. Age, sex, body mass index (BMI), heart rate, and blood pressure of the patients were recorded. Sedimentation, hsCRP, complete blood count, renal function tests, and immune disease diagnostic tests were evaluated. Blood lipid profile and blood glucose levels of all subjects were assessed after 12-hours fasting. Atherogenic indices were calculated as previously described [15]. Written informed consents were obtained from each subject. The institutional ethics committee approved the study protocol. Imaging Techniques Echocardiographic evaluations (EFT measurement) Echocardiographic evaluation was performed by a clin-

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ical data-blind, experienced cardiologist with a ‘S5-1 probe Philips EPIQ/G, Bothell, WA’ device. EFT was defined as non-echogenic spaces between epicardial layers in two-dimensional imaging. EFT was recorded from parasternal long- and short-axis windows, free wall of right ventricle, end diastolic, and through three cardiac cycles. Maximal measurements from each site were recorded and their mean was calculated. Ultrasonographic evaluation (carotid intima–media measurement) cIMT was measured with a high-resolution 7.5 MHz linear ultrasound probe (Hitachi EUB 6500, Osaka, Japan, device compatible). Measurements were performed with two-dimensional ultrasound imaging from internal carotid artery and 10 mm far from carotid artery bifurcation. To minimize the effect of arterial compliance on results, measurements were performed with EKFG monitorization and with peak-R wave match (to correlate with the stage of cardiac cycle) [7, 16]. In every session, measurements were made from three sites. Mean cIMT is defined as the mean of six measurements in two different sessions. To test the repeatability coefficient of EFT and cIMT, measurements of 10 subjects from the control group were repeated. Coefficients were found as 0.920 for EFT and 0.952 for cIMT. Statistical Analysis All analyses were performed with SPSS 9.0 (SPSS for Windows 9.0, Chicago, IL). Variables were expressed as mean±standard deviation. Student’s t-test was used for comparison of two groups. Pearson correlation analysis was used to test the relationship between EFT and cIMT. Multivariate linear regression model was used to test independent predictors of EFT. RESULTS Clinical Characteristics of the Study Population Clinical features and laboratory results of the patient and control groups are summarized in Table 1. Age, gender, BMI, systolic and diastolic blood pressures, heart rate, fasting blood glucose, serum urea nitrogen, and creatinine levels were similar between groups. There was no significant difference between groups in terms of lipid panel, which includes total cholesterol, triglycerides, LDL cholesterol, non-HDL cholesterol, Castelli risk index I, II, and atherogenic coefficient,

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Table 1. Demographic and biochemical characteristics of patients with celiac disease and control subjects

Celiac Control p disease group (n=31) (n=32)

Age (years) 39.4±12.3 39.5±4.4 0.84 Gender female/male (n/n) 24/7 21/11 0.30 Body mass index (kg/m2) 24.8±4.2 24.7±4.3 0.97 Systolic BP (mmHg) 119.7±9.1 118.7±8.7 0.64 Diastolic BP (mmHg) 75.5±5.2 77.0±5.7 0.26 Heart rate (beat/minute) 72.9±3.7 74.1±10.9 0.54 Fasting plasma glucose (mg/dl) 93.1±6.7 90.9±6.0 0.18 BUN (mg/dl) 19.9±7.1 18.3±4.9 0.30 Creatinine (mg/dl) 0.67±0.19 0.64±0.14 0.44 Total cholesterol (mg/dl) 180.4±24.6 186.4±31.2 0.40 Triglycerides (mg/dl) 119.1±44.8 108.4±51.1 0.14 HDL cholesterol (mg/dl) 42.7±8.8 50.0±13.7 0.01 LDL cholesterol (mg/dl) 113.0±20.9 115.7±27.3 0.65 Non-HDL cholesterol (mg/dl) 76.3±49.5 50.8±57.5 0.06 Castelli risk index I 3.00±1.54 2.26±1.54 0.06 Castelli risk index II 2.76±0.83 2.46±0.86 0.17 Atherogenic index of plasma 0.98±0.50 0.62±0.64 0.02 Atherogenic coefficient 1.20±1.22 1.27±1.54 0.85 Hemoglobin (mg/dl) 13.1±1.1 14.0±1.1 0.22 hsCRP (mg/l) 3.51±3.18 1.92±1.40 0.02 ESR (mm/h) 17.2±12.8 9.7±3.1 0.01 Disease duration (years) 5.1±5.4 n/a n/a EFT (cm) 0.49±0.10 0.43±0.09 0.02 cIMT (cm) 0.51±0.08 0.47±0.08 0.10* *Non-parametric test (Mann–Whitney U). BP: Blood pressure; BUN: Blood urea nitrogen; HDL: High-density lipoprotein; LDL: Low-density lipoprotein; hsCRP: High-sensitivity C-reactive protein; ESR: Erythrocyte sedimentation rate; EFT: Epicardial fat thickness; cIMT: Carotid intima–media thickness; atherogenic coefficient: non-HDL-c/HDL-c; atherogenic index of plasma: log TG/HDL-c; Castelli risk index I: TC/HDL-c; Castelli risk index II: LDLc/HDL-c; non-HDL-c: TC-HDL-c.

whereas HDL cholesterol was found to be significantly lower (42.7±8.8 vs. 50.0±13.7; p-value: 0.01) and plasma atherogenic index was significantly found to be higher (0.98±0.50 vs. 0.62±0.64; p-value: 0.02) in the patient group. hsCRP (3.51±3.18 vs. 1.92±1.40; p-value: 0.02) and ESR (17.2±12.8 with 9.7±3.1; pvalue: 0.01) were found to be significantly higher in the CD group and EFT was significantly higher in the CD group (0.49±0.10 vs. 0.49±0.09; p-value: 0.02). Although cIMT was higher in the patient group, it did not reach statistically significant levels (0.51±0.08 vs. 0.47±0.08; p-value: 0.10).

Caliskan et al., Atherogenic indeces and their relation of EFT and cIMT in celiac disease

Table 2. Correlations between EFT and cIMT and other study variables Age (years) Systolic BP (mmHg) Diastolic BP (mmHg) hsCRP (mg/dl) HDL- cholesterol (mg/dl) LDL- cholesterol (mg/dl) Triglyceride (mg/dl) Triglyceride/HDL-c ratio LDL-c/HDL-c ratio Log Triglyceride/HDL-c ratio Non-HDL-c (mg/dl) Non-HD-c/LDL-c ratio

EFT

cIMT

r p r p -0.096 0.61 0.016 0.93 -0.189 0.31 -0.242 0.19 -0.111 0.55 -0.108 0.56 0.453 0.01 -0.068 0.71 0.179 0.33 -0.339 0.05 -0.124 0.50 0.362 0.04 -0.119 0.52 0.506 0.004 -0.082 0.66 0.473 0.007 -0.162 0.38 0.444 0.01 -0.082 0.66 0.473 0.007 -0.097 0.60 0.504 0.004 0.117 0.53 0.187 0.31

EFT: Epicardial fat thickness; cIMT: Carotid intima–media thickness; BP: Blood pressure; hsCRP: High-sensitivity C-reactive protein; HDL-c: High-density lipoprotein cholesterol; LDL-c: Low-density lipoprotein cholesterol; ESR: Erythrocyte sedimentation rate; atherogenic coefficient: non-HDL-c/HDL-c; atherogenic index of plasma: log TG/HDL-c; Castelli risk index I: TC/HDL-c; Castelli risk index II: LDL-c/HDL-c; non-HDL-c: total cholesterol-HDL-c.

Correlation Analysis Between cIMT and EFT and Other Variables While there was a significant positive correlation between EFT and hsCRP (r: 0.453; p-value: 0.01), no relation was found between EFT and other variables. On the other hand, there was a negative correlation between cIMT and HDL-cholesterol (−0.339; p-value: 0.05) and a positive correlation with the other components of the atherogenic indices (Table 2). Multiple regression analysis was performed to determine the independent predictors of the increase in EFT. When EFT was taken as an independent variable and for diagnosis of CD, hsCRP, BMI, triglycerides, LDL, and HDL-cholesterol values were considered as dependent variables, and the presence of CD was determined as an independent predictor for the increase in EFT (β: 0.060; p=0.03; Table 3). DISCUSSION This study showed that in patients with CD and without coronary heart disease risk factors, (i) EFT has increased statistically; however, although cIMT has shown

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Table 3. Multivariate predictors of increased EFT in the study population Intercept Celiac disease HsCRP (mg/dl) Body mass index (kg/m²) Triglyceride (mg/dl) LDL-c (mg/dl) HDL-c(mg/dl)

SE (B)

0.310 0.157 0.001 0.060 0.028 0.03 0.014 0.001 0.17 0.001 0.004 0.25 0.001 0.001 0.41 0.001 0.001 0.66 0.002 0.001 0.24

hsCRP: High-sensitivity C-reactive protein; LDL-c: Low-density lipoprotein cholesterol; HDL-c: High-density lipoprotein cholesterol.

an increase, it is not statistically significant, (ii) there is an increase in atherogenic indices of patients with CD including lipid parameters, ESR, and hsCRP compared to controls, and (iii) there is a close relationship between subclinical atherosclerosis markers, such as EFT and cIMT, and inflammatory markers. It has been reported that in immune diseases, the atherosclerotic process progresses [6–8, 11]. Among coronary risk factors, chronic systemic inflammation itself can be the main culprit [11]. A recent study by Baena-Díez JM et al. has reported that in immuno-inflammatory diseases, the risk of cardiovascular events increases significantly [17]. Yarur et al. observed that the risk of ischemic heart disease increases in inflammatory bowel diseases [18]. CD is a chronic autoimmune enteropathy, which is induced by gluten containing diet in genetically susceptible persons [9, 11]. The proximal segment of small intestine is the primary target organ [9]. Nevertheless, the autoimmune nature of CD has targeted other organ systems including the cardiovascular system [10, 11, 19]. Gluten enteropathy is characterized with villus atrophy, crypt hyperplasia, and increased lymphocyte infiltration [19]. The intestinal epithelial layer is infiltrated by CD 8+ T cells intensely and triggers enterocyte apoptosis in epithelial tissues [19, 20]. Exposure to gluten-containing foods activates CD8 T lymphocytes in peripheral circulation and clusterization in intestinal tissues [21]. For gliadin protein to be recognized by CD 8+ lymphocytes, it has to be presented by epithelial tissues. In this process, CD8+ T lymphocytes secrete interferon (IFN) gamma [22]. Also, intestinal microbiota contributes to activation of CD8+ T cells [23]. It has been proved that IFN gamma increases intestinal per-

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meability and plays an important role in the inflammatory process by increasing gluten peptide translocation [24]. This inflammatory process is responsible for pathogenesis of the disease and it can also be related to the atherosclerotic process. Recent studies have pronounced the relationship between atherosclerosis and inflammation more strongly. EFT and cIMT have been designed as non-invasive, easily repeatable and applicable, cost-efficient methods to assess atherosclerosis. This is the first study to evaluate cardiovascular risk assessment with EFT in patients with CD. Along with its mechanic-shield effect, epicardial fat tissue has paracrine and metabolic features, which play a role in the development of atherosclerosis [25, 26]. This tissue is the production site for various proinflammatory cytokines including interleukin 6, TNF alpha, and leptin. This tissue is adjacent to coronary arteries and this neighborhood can initiate a paracrine inflammatory effect to enhance the development of atherosclerosis. Also secretion of inflammatory cytokines can also cause a systemic inflammatory effect [25, 26]. In this study, although we have not assessed inflammatory mediators such as interleukin 6 and TNF alpha, the close relationship between hsCRP and EFT supports our hypothesis, which underlines the role of inflammation in atherosclerosis. In our study, another important finding was the statistically insignificant increase of cIMT in patients compared to controls, decrease in HDL cholesterol, and increase in TG/HDL cholesterol levels, which can be expressed as an atherogenic index. A close relationship between cIMT and atherogenic indices was observed. Ciacci et al. reported hypercholesterolemia in newly diagnosed gluten-unrestricted patients, but this has not been proven with other studies (probably due to recruitment of more subclinical patients with CD) [27, 28]. On the contrary, it has been proposed that low HDL cholesterol can be a manifestation of CD [29]. In our study, HDL cholesterol levels were significantly lower in patient cohort, compatible with the current literature. These changes can be attributed to malabsorption of lipids and/or decrease in Apo A1 secretion [27–29]. cIMT and EFT are important subclinical markers of atherosclerosis and represent early-stage cardiovascular disease [7, 12, 16]. HDL cholesterol has a strong antioxidant capacity as well as an ability to transfer cholesterol molecules to tissues for degradation [30]. Oxidative modification of LDL cholesterol has a key role in pathogenesis of atherosclerosis. Oxidized LDL can initiate the

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atherosclerotic process and speed disease progression [31]. Along with low HDL cholesterol levels, the oxidative stress caused by CD causes imbalance between oxidants and anti-oxidants, thus causing lipid membrane oxidation. This situation can also cause direct toxic effects on endothelial and smooth muscle cells [32]. In this context, some studies have reported that gliadin protein can have particles which can trigger oxidative stress as well as proinflammatory cytokine release [32, 33]. It has been observed that some gliadin peptides can accumulate in lysosomes [31–33] and increase free radical levels [34, 35]. Another cause for increased atherosclerosis risk in CD can be oxidative modification of LDL cholesterol by gliadin peptides. Conclusions This study shows that CD causes predisposition to subclinical atherosclerosis by increasing EFT and cIMT. The fact that there is a close relationship between the increase in ET and cIMT suggests that in these patients, inflammation of the disease may have a role in the atherosclerotic process. Along with conventional lipid panels, evaluation of atherosclerotic index can help identify atherosclerosis risk. Ethics Committee Approval: The Ethics Committee of Istanbul Medeniyet University provided the ethics committee approval for this study (Date: 12.09.2018 Number: 2018/0343). Conflict of Interest: Each and every author does not have any personal or financial relationships that have any potential to inappropriately influence (bias) his or her actions or manuscript. Financial Disclosure: No financial or other potential conflicts of interest exist (includes involvement with any organization with a direct financial, intellectual, or other interest in the subject of the manuscript) regarding the manuscript. In addition, there are no any grants and sources of financial support related to the topic or topics of the manuscript. Authorship Contributions: Concept – ZC, MC; Design – ZC, MC, SS; Supervision – HLD; Materials – KD, RK; Data collection and/or processing – FBO, OK, OFB; Analysis and/or interpretation – OK, OC, HLD; Writing – OC, MC; Critical review – HLD, RK.

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Orıgınal Article

GASTROENTEROLOGY

North Clin Istanb

2019;6(3):248–253 doi: 10.14744/nci.2018.23540

Factors associated with diverticular bleeding and re-bleeding: A United States hospital study Ala Abdel Jalil,1 Moss Mann,6

Robyn Gorski,2 Hari Rajagopalan,7

Salah Abdel Jalil,3 Asem Abdel Jalil,8

Ryan Cronin,4

Michael Comianos,5

Veysel Tahan1

Department of Gastroenterology & Hepatology, University of Missouri-Columbia, Columbia, Missouri, USA

Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA

Department of General Surgery, Grand Strand Medical Center, Myrtle Beach, South Carolina, USA

Department of General Surgery, East Tennessee State University, Johnson City, Tennessee, USA

Department of Internal Medicine, Ohio Health Riverside Methodist Hospital, Columbus, Ohio, USA

Department of Gastroenterology, Carolinas Medical Center, Florence, South Carolina, USA

School of Business, Francis Marion University, Florence, South Carolina, USA

Department of Pulmonary, Critical Care and Sleep Medicine, University of Missouri, Kansas, Missouri, USA

ABSTRACT OBJECTIVE: Diverticular bleeding is the most common cause of lower gastrointestinal bleeding. Arteriovascular disease, metabolic syndromes, non-steroidal anti-inflammatory drugs (NSAIDs), anti-thrombotics, and anticoagulants have been suggested as risk factors. There is a paucity of studies addressing factors associated with diverticular re-bleeding, especially in the United States. The aim of this study is to evaluate factors associated with colonic diverticular bleeding and re-bleeding in a US community-based hospital. METHODS: We conducted a retrospective case-control study to analyze the factors associated with diverticular bleeding. Between January 2010 and July 2011, 93 patients were admitted to our hospital with a primary diagnosis of acute diverticular bleeding. We compared them to 152 patients who were admitted with a primary diagnosis of diverticulitis in the same period. We collected data from the medical records of each patient in relation to the demographics, comorbidities, medications, social habits, location of diverticulosis, length of stay in the hospital, and re-bleeding rate within 2 years of the first bleeding episode. RESULTS: Factors such as cerebrovascular accident (p=0.009), coronary artery disease (p=0.037), diabetes mellitus (p=0.046), obstructive sleep apnea (p=0.033), NSAIDs (p=0.038), use of anti-thrombotics (p=0.001), anticoagulants (p=0.002) or calcium channel blockers (p=0.009), and bilateral diverticulosis (p=0.001) were significantly associated with diverticular bleeding as compared to diverticulitis. Recurrence of bleeding was noted in 26 out of 93 patients (28%) within 2 years of the first bleeding episode (p=0.001). Bilateral colonic involvement, anticoagulants, and elderly age (≥65 years) were found to have a closer relationship to diverticular re-bleeding, although it was not statistically significant. CONCLUSION: This study reveals that arteriovascular disease, diabetes mellitus, NSAIDs, the use of anti-thrombotics, anticoagulants or calcium channel blockers, and obstructive sleep apnea are factors that are significantly associated with diverticular bleeding. It also shows that bilateral colonic involvement, elderly age, and anticoagulants have a closer relationship to diverticular re-bleeding. More prospective studies in patients with diverticular bleeding should be conducted to shed light on the causality of these factors and the prevalence of diverticulitis. Keywords: Bleeding; community; diverticula; diverticulum; factor; outcome.

Cite this article as: Abdel-jalil A, Gorski R, Abdel Jalil S, Cronin R, Comianos M, Mann M, et al. Factors associated with diverticular bleeding and re-bleeding: A United States hospital study. North Clin Istanb 2019;6(3):248–253.

Received: December 19, 2017 Accepted: August 06, 2018 Online: September 05, 2018 Correspondence: Dr. Ala ABDEL JALIL. One Hospital Dr., CE 041 65212 Columbia, United States. Tel: +1573-884-6044 e-mail: ala79md@gmail.com © Copyright 2019 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

Abdel Jalil et al., Factors associated with diverticular bleeding

iverticular disease accounts for 312,000 admissions and 1.5 million days of inpatient care annually in the United States, with costs of care exceeding 2.6 billion dollars [1]. Diverticular disease of the gastrointestinal tract is more common in developed countries and occurs more often in older individuals. Prevalence of diverticular disease increases from 50% to 66% in patients older than 80 years [1], and is equally seen in both men and women [2]. Many patients diagnosed with diverticulosis remain asymptomatic, while approximately 10%â&#x20AC;&#x201C;20% of patients eventually develop symptoms such as diverticular hemorrhage [3]. Although the patients with diverticulosis usually remain asymptomatic, symptomatic patients suffer from various symptoms ranging from irritable bowel syndrome (IBS)-type symptoms to disabling recurrent abdominal pain [4]. Diverticular hemorrhage can become severe with substantial morbidity and a mortality rate of 10%â&#x20AC;&#x201C;20% [5]. The pathogenesis of diverticular bleeding is not completely understood but one common theory is that it originates over time because of repetitive injury to the vasa recta due to muscle contraction. Approximately 70%â&#x20AC;&#x201C; 80% of diverticular bleedings resolve spontaneously, with re-bleeding occurring in up to 38% of patients [6]. Patients with uncomplicated diverticulitis generally respond well to outpatient conservative treatment, such as oral antibiotics. However, surgical treatment may be required for patients with recurrent diverticular bleeding and for diverticulitis complicated by a large abscess formation, perforation, intestinal obstruction, or fistula formation [7]. While some studies have assessed the factors associated with diverticular hemorrhage, there is a paucity of studies evaluating the factors associated with diverticulitis, diverticular bleeding, and diverticular rebleeding, most notably in the United States. Factors that have been postulated to be associated with an increased risk for diverticular bleeding include arteriovascular disease, metabolic syndrome, non-steroidal anti-inflammatory drugs (NSAIDS), anti-thrombotics, and anticoagulants. NSAIDs and aspirin have been identified to increase the risk for acute lower gastrointestinal bleeding, including acute diverticular bleeding and re-bleeding. Other factors associated with diverticular bleeding include a large number of diverticula, hypertension, and arteriosclerotic diseases including ischemic heart disease and chronic renal failure [8]. Patients with chronic kidney disease have been noted to display radiologic findings consistent with divertic-

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ular disease, yet remain asymptomatic [9]. The use of calcium channel blockers has also been suggested as a factor associated with a higher incidence of diverticular bleeding [10]. The purpose of this study was to evaluate the factors associated with colonic diverticular bleeding and re-bleeding (defined as a hospital admission within two years of a previous diverticular bleeding) in a United States hospital. MATERIALS AND METHODS In this study, we utilized a case-control approach to analyze factors associated with diverticular bleeding and re-bleeding. Between January 2010 and July 2011, 93 patients were admitted to our hospital with a primary diagnosis of acute diverticular bleeding based on clinical presentation and colonoscopic and radiographic examinations conducted during the hospital stay. Diverticular bleeding was defined as lower gastrointestinal bleeding manifested by painless hematochezia in presence of active bleeding or stigmata of bleeding from affected diverticula during the colonoscopic exam, without the presence of another identifiable bleeding source. To analyze the factors associated with diverticular hemorrhage, a control group consisting of 152 patients was used. All the patients were admitted within the same time period with a primary diagnosis of acute diverticulitis based on clinical presentation and radiologic evidence of diverticulitis on computed tomography. We used diverticulitis as the control group since this condition is one of the major complications of diverticular disease and patients generally require hospital admission. The medical records of each patient in the case and control groups were screened for information regarding demographics, comorbidities, medications, findings of colonoscopy, location of diverticulosis, outcome of admission, complications including surgical intervention, hemoglobin level at time of presentation, and re-bleeding rate within 2 years of the first bleeding episode. We excluded patients who were pregnant, patients who had a concomitant severe active medical illness (including sepsis, myocardial infarction, or stroke), patients with end-stage renal disease or terminal cancer, and patients who were admitted for other medical or surgical reasons but developed gastrointestinal bleeding during their admission. Informed consent was obtained from all the participants. This study was approved by each institutional review board involved in the study.

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Table 1. Demographics and characteristics of patients and comparison of different variables between diverticulosis and diverticulitis groups

Diverticulosis (case group)

Diverticulitis (control group)

Age (years), mean±SD 73.3±12.1 Gender (M/F) 1.4:1 Race (W/B) 1:1 Length of stay (days) 5.85±1.41 Hemoglobin level at admission (g/dL), mean±SD 10.2±2.46 BMI, mean±SD 32.2±5.0 Hypertension, % 74.1 Cerebrovascular accident, % 13.9 Coronary artery disease, % 32.2 Diabetes mellitus, % 35.4 Chronic kidney disease, % 23.6 Obstructive sleep apnea, % 7.5 Gout, % 11.8 Alcohol use, % 12.9 Smoking, % 15 NSAIDs use, % 18.2 Aspirin/anti-thrombotics, % 48.3 Warfarin/anticoagulants, % 15.0 Proton pump inhibitor, % 25.8 ACEI/ ARB, % 49.4 Beta blocker, % 46.2 Calcium channel blockers, % 37.6

59.2±13.1 <0.001 1.8:1 0.37 1.7:1 0.035* 6.11±0.71 >0.05 12.6±2.0 <0.001 31.2±10.8 0.068 75 0.88 4.6 0.009 20.3 0.04 23.6 0.046 15.7 0.12 1.9 0.03 8.5 0.40 7.2 0.14 18.4 0.49 9.2 0.03 23.6 0.001 2.6 0.002 32.2 0.28 49.3 0.98 34.2 0.06 22.3 0.01

*Was more significant in black patients. BMI: Body mass index; NSAIDs: Non-steroidal anti-inflammatory drugs; ACEI: Angiotensin-converting enzyme inhibitor; ARB: Angiotensin receptor blocker.

Statistical Analysis Descriptive methods utilizing mean and standard deviation were employed. To examine the differences in the distribution among case and control groups, the Student’s t-test, Pearson Chi-Square, or Fischer’s Exact Test were used when appropriate. Logistic regression analysis was used to examine the interaction between different factors. An alpha level of significance was set at <0.05. RESULTS Forty-three (46%) patients included in the case group had diverticular disease in the left colon, 5 (5%) in the right, and 37 (40%) presented with bilateral diverticular disease. Eight patients (9%) did not have a colonoscopy for various reasons, including advanced age. In the control group, 94% of the participants had diverticular disease in the left colon. The mean age

for case and control groups was 73.3±12.1 years and 59.2±13.1 years, respectively. There was no significant difference between the two groups with regard to gender, body mass index (BMI) (32.2±5.0 and 31.2±10.8, respectively), or length of stay (5.85±1.41 days and 6.11±0.71 days, respectively). African American patients were found to have a higher association with diverticular bleeding as compared to diverticulitis (white: black ratio = 1:1 and 1.7:1, respectively for diverticular bleeding and diverticulitis; p=0.035). Table 1 shows the demographics and characteristics of patients and the comparison of different variables between the case and control groups. Hypertension was not found to be significantly associated with either diverticular bleeding or re-bleeding, whereas cerebrovascular accident (CVA) was found to be significantly associated with diverticular bleeding (p=0.009) but not re-bleeding. This pattern of asso-

Abdel Jalil et al., Factors associated with diverticular bleeding

ciation with diverticular bleeding but not re-bleeding was also seen with coronary artery disease (CAD) (p=0.037), diabetes mellitus (p=0.046), and obstructive sleep apnea (OSA) (p=0.033). Chronic kidney disease (defined as GFR <60 ml/min/1.73 m2 for >3 months) was not shown to be significantly associated with diverticular bleeding or re-bleeding. Multiple logistic regression analysis showed no significant interaction between these variables that indicated an increase in the risk of diverticular bleeding or re-bleeding. Diverticular bleeding, but not re-bleeding, was shown to increase in patients who used NSAIDs or aspirin and calcium channel blockers (CCBs). In contrast, proton pump inhibitors (PPIs) showed no difference in relation to diverticular bleeding or re-bleeding. In patients taking both NSAIDs and a PPI, no interaction effect was seen with respect to an increase in the risk of bleeding or re-bleeding. Anticoagulants such as warfarin and anti-thrombotic drugs such as aspirin and Plavix showed a higher association with diverticular bleeding, however, they were not statistically significant for diverticular re-bleeding (p=0.11 for anticoagulant use; p=0.5 for aspirin/anti-thrombotic use). Alcohol use (defined as >2 drinks/day for males and >1 drink/ day for females) among the case group was not found to be significantly associated with either diverticular bleeding or re-bleeding as compared to the diverticulitis group. Gender differences were not significant between groups with respect to the rates of bleeding and re-bleeding. In our study, patients were divided into four groups on the basis of age: very elderly (≥80 years), elderly (65– 79 years), middle age (45–64 years), and young (≤44 years). The older a patient, the higher the association with diverticular bleeding; we found that 27 of 35 (77%) very elderly patients, 39 of 81 (48%) of elderly patients, 26 of 105 (25%) middle-aged patients, and only 4% of young patients in the case group developed diverticular hemorrhage. The very elderly patients were the closest of the four groups to being statistically significant for rebleeding (p=0.08). Patients were grouped based on BMI as: normal (BMI 18–25), overweight (BMI 25–29.9), and obese (BMI ≥30); this factor was not significantly different between the two groups for either bleeding or re-bleeding. Left-sided bleeding occurred more commonly out of the three groups and right-sided bleeding occurred least commonly. Bilateral diverticulosis was signifi-

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cantly associated with diverticular bleeding (p=0.001). Recurrence of bleeding was noted in 26 of 93 (28%) case group patients within 2 years of the first bleeding episode (p=0.001). While there are a myriad of outcomes for patients presenting to the hospital with diverticular bleeding, death as an outcome was not shown to be more prevalent among those patients hospitalized with diverticular bleeding versus diverticulitis. The length of stay in the hospital and the risk for re-bleeding were independent of each other in this study; no significant correlation was found. As was expected, at the time of admission, the patients presenting with diverticular bleeding had significantly lower levels of hemoglobin than those with diverticulitis (p≤0.01). DISCUSSION Diverticular bleeding accounts for many hospitalizations throughout the world, yet few studies have identified specific factors leading to an increased risk of bleeding. Our study confirms that certain comorbidities are more associated with diverticular bleeding, including cardiovascular diseases (CVA, CAD) and diabetes mellitus. The association between OSA and diverticular hemorrhage is the first of its kind to be mentioned in the literature. Such an association could be explained by the higher prevalence of sleep apnea among patients with cardiovascular disease, who in turn have a higher risk for diverticular hemorrhage. A previous study noted that apart from NSAIDs and anticoagulants, arterial hypertension had been shown to be an independent risk factor for colonic diverticular bleeding [11]. This indicates that arteriosclerosis and associated diseases such as metabolic syndrome could, therefore, play an important role in the pathogenesis of acute diverticular bleeding. However, our study did not show that hypertension is associated with a higher risk for diverticular bleeding. The high prevalence of hypertension and metabolic syndrome in our study population might be the reason for this nonsignificant association. In our study, the African American and elderly patients were shown to have a higher association with diverticular bleeding, while gender had no bearing on the risks of bleeding or re-bleeding, as has been previously stated in the literature. Although approximately 70%– 80% of diverticular bleeding resolves spontaneously, rebleeding occurs in up to 38% of patients, thus making it a pertinent factor to explore. In our study, we found a very

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Table 2. Factors with close significance for diverticular rebleeding Bilateral colonic involvement Anticoagulant use Very elderly age (â&#x2030;Ľ80)

Table 3. Outcome of admission, surgical intervention, complications, and re-bleeding rate

p 0.10 0.11 0.08

elderly age (â&#x2030;Ľ80) to be an important factor for re-bleeding, close to reaching statistical significance (p=0.08). The location of the bleed was also examined and bilateral disease was a significant factor for diverticular bleeding, (bilateral: 9/39, left/sigmoid: 23/186, and right-sided disease: 2/12 in both groups). Bilateral involvement was close to reaching statistical significance for diverticular re-bleeding (p=0.10). Table 2 shows the factors with close significance for diverticular re-bleeding. Table 3 reveals a staggering difference in rates of rebleeding within 2 years of the first bleeding episode between the patients with diverticulosis versus those with diverticulitis, with the former resulting in significantly more re-bleeding incidences (27.9% vs. 7.2%). While the difference in death as an outcome between the two groups was shown to be insignificant, surgical intervention and complications (abscess or fistula formation, intestinal obstruction, peritonitis, sepsis, perforation, or the need for colonic resection or laparotomy) were higher in the diverticulitis group (p<0.001). Our study verifies that certain medications, including NSAIDs, aspirin, anticoagulants, and CCBs are associated with a higher rate of diverticular hemorrhage. The strong association between diverticular bleeding and the use of NSAIDs as evaluated by our study agrees with the current literature, however, unlike a previous study on diverticular bleeding in Japan [12] our study showed no increased risk of diverticular re-bleeding after NSAID use. This was also true for aspirin with respect to the risk of diverticular bleeding and re-bleeding. Anticoagulants such as warfarin and other anti-thrombotic drugs such as clopidogrel have been mentioned in the literature to increase the risk of diverticular bleeding, which our results concur with. On delving further into the effect of anticoagulants on re-bleeding, no association was found between any of the drugs and diverticular re-bleeding. The use of PPIs exhibited no increased diverticular bleeding or

Diverticulosis Diverticulitis (case group) (control group) % %

Outcome (death) Surgical intervention Complications** Re-bleeding within 2 years

3.2 5.3 10.7 27.9

1.3 26 33.5

0.3 <0.001* <0.001*

7.2 0.001

*Was more significant in the diverticulitis group. **Complications include abscess or fistula formation, intestinal obstruction, peritonitis, sepsis, perforation or need for colonic resection or laparotomy.

re-bleeding risk among patients. Our study also verifies that CCBs are associated with diverticular bleeding, an observation that has been described in a European study, but up to this point had yet to reveal itself in a US-based study. This study used a retrospective case-control approach to identify factors associated with diverticular hemorrhage and delineate the common and distinctive factors associated with diverticular bleeding and re-bleeding. This approach may have led to selection bias. To address this issue, we selected patients who were admitted with a primary diagnosis of diverticulitis as the control group (contrary to other matching groups) since non-bleeding diverticulosis patients may not necessarily get admitted to the hospital. Other limitations include the possibility of the patients getting treated at other facilities for their illness (diverticular bleeding or re-bleeding), which may have led to an underestimation of the prevalence of rebleeding. Reviewing the patient population and demographics showed that a majority of the patients received their medical care at our facility, as it is the main hospital in the region. Our findings may show some overestimation due to higher prevalence of metabolic syndrome in our region. Conclusion This case-control study reveals that cardiovascular disease, diabetes mellitus, NSAIDs, anti-thrombotics, anticoagulants, CCBs, and OSA are significant risk factors associated with diverticular bleeding. It also suggests that bilateral colonic involvement increases the risk for diver-

Abdel Jalil et al., Factors associated with diverticular bleeding

ticular bleeding. Bilateral involvement, anticoagulant use, and elderly age (≥65 years) were factors that had a closer relationship to diverticular re-bleeding, although it was not statistically significant. This is the first study to introduce OSA as a possible risk factor associated with diverticular bleeding, which may have been mediated by the high prevalence of cardiovascular disease and metabolic syndromes in the study population. Advanced age, especially in very elderly patients (≥80 years old) had a strong association with diverticular bleeding. CCBs have been described in a German study as a risk factor associated with diverticular hemorrhage; our study confirms this observation in a United States hospital. Interestingly, obesity was not shown to be a significant risk factor for diverticular bleeding in our study. This may be due to the high prevalence of obesity in the region where the study was conducted. As a significant contributor to hospital admissions, diverticular bleeding, and re-bleeding, risk factors are prime targets for investigations in order to prevent or decrease the number of hospital admissions and to improve morbidity from the disease. Further investigation into the causality of these risk factors for diverticular bleeding and re-bleeding through prospectively designed studies is required. Ethics Committee Approval: Study was approved by McLeod Regional Medical Center’s IRB & Ethics committee on May 16th, 2013. Acknowledgement: The authors acknowledge Dr. Hari Rajagopalan from the School of Business at Francis Marion University in Florence, South Carolina for the valuable statistical help he provided for the study. Conflict of Interest: The authors declare no conflict of interest. Financial Disclosure: The authors declared that this study has received no financial support.

253 Authorship Contributions: Concept – AAJ, MM, RG; Supervision – AAJ, VT, MM, HR; Materials – AAJ, RC, MC, RG, SAJ; Data collection and/or processing – RG, RC, MC, SAJ; Analysis and/or interpretation – AAJ, MM, HR, AAJ, VT; Writing – RG, AAJ, SAJ; Critical review – AAJ, VT, HR, AAJ.

REFERENCES 1. Matrana MR, Margolin DA. Epidemiology and pathophysiology of diverticular disease. Clin Colon Rectal Surg 2009;22:141–6. 2. McConnell EJ, Tessier DJ, Wolff BG. Population-based incidence of complicated diverticular disease of the sigmoid colonbased on gender and age. Dis Colon Rectum 2003;46:1110–4. 3. Stollman NH, Raskin JB. Diverticular disease of the colon. J Clin Gastroenterol 1999;29:241–52. 4. Lee KM, Paik CN, Chung WC, Jung SH, Chang UI, Yang JM. Clinical significance of colonic diverticulosis associated with bowel symptoms and colon polyp. J Korean Med Sci 2010;25:1323–9. 5. Chait MM. Lower gastrointestinal bleeding in the elderly. World J Gastrointest Endosc 2010;2:147–54. 6. Raphaeli T, Menon R. Current treatment of lower gastrointestinal hemorrhage. Clin Colon Rectal Surg 2012;25:219–27. 7. Oh HK, Han EC, Ha HK, Choe EK, Moon SH, Ryoo SB, et al. Surgical management of colonic diverticular disease: discrepancy between rightand left-sided diseases. World J Gastroenterol 2014;20:10115–20. 8. Niikura R, Nagata N, Akiyama J, Shimbo T, Uemura N. Hypertension and concomitant arteriosclerotic diseases are risk factors for colonicdiverticular bleeding: a case-control study. Int J Colorectal Dis 2012;27:1137–43. 9. Galbraith P, Bagg MN, Schabel SI, Rajagopalan PR. Diverticular complications of renal failure. Gastrointest Radiol 1990;15:259–62. 10. Kaplan RC, Heckbert SR, Koepsell TD, Rosendaal FR, Psaty BM. Use of calcium channel blockers and risk of hospitalized gastrointestinal tract bleeding. Arch Intern Med 2000;160:1849–55. 11. Yamada A, Sugimoto T, Kondo S, Ohta M, Watabe H, Maeda S, et al. Assessment of the risk factors for colonic diverticular hemorrhage. Dis Colon Rectum 2008;51:116–20. 12. Tsuruoka N, Iwakiri R, Hara M, Shirahama N, Sakata Y, Miyahara K, et al. NSAIDs are a significant risk factor for colonic diverticular hemorrhage in elder patients: evaluation by a case-control study. J Gastroenterol Hepatol 2011;26:1047–52.

Orıgınal Article

PM&R

North Clin Istanb

2019;6(3):254–259 doi: 10.14744/nci.2018.58219

Nephrolithiasis in ankylosing spondylitis and its relationship with disease assessment scales Aylin Rezvani,1

Ilknur Aktas,2

Erbil Dursun,6

Senay Ozdolap,5

Murat Birtane,

Nurettin Tastekin,3

Kenan Akgun,

Nigar Dursun,6

Reyhan Celiker,4 Coskun Zateri,7

Selda Sarikaya,5

Lale Altan,8

Necdet Sut

Department of Physical Medicine and Rehabilitation, Bezmialem Vakif University, Istanbul, Turkey

Department of Physical Medicine and Rehabilitation, Health Science University Fatih Sultan Mehmet Training and Research Hospital,

Istanbul, Turkey Department of Physical Medicine and Rehabilitation, Trakya University Faculty of Medicine, Edirne, Turkey

Department of Physical Medicine and Rehabilitation, Acibadem University Faculty of Medicine, Istanbul, Turkey

Department of Physical Medicine and Rehabilitation, Bulent Ecevit University Faculty of Medicine, Zonguldak, Turkey

Department of Physical Medicine and Rehabilitation, Kocaeli University Faculty of Medicine, Izmit, Turkey

Department of Physical Medicine and Rehabilitation, Canakkale Onsekiz Mart University Faculty of Medicine, Canakkale, Turkey

Department of Physical Medicine and Rehabilitation, Uludag University Faculty of Medicine, Bursa, Turkey

Department of Physical Medicine and Rehabilitation, Istanbul University Cerrahpasa Faculty of Medicine, Istanbul, Turkey

Department of Biostatistics, Trakya University Faculty of Medicine, Edirne, Turkey

ABSTRACT OBJECTIVE: The aim of this study was to investigate the frequency of renal calculi in patients with ankylosing spondylitis (AS) and to determine its relationship with disease assessment variables. METHODS: The study was designed retrospectively, and it included a cohort of 320 patients with AS diagnosed using the Modified New York Criteria. A total of 119 patients who underwent renal ultrasonography (USG), in who the erythrocyte sedimentation rate, C-reactive protein, blood calcium, phosphorus, Vitamin D, parathormone, and urinary calcium excretion were measured, and who also had lateral cervical and lumbar radiography in the same time period were extracted from the cohort. All patients’ demographic characteristics and the results of blood and urine tests were recorded. The Ankylosing Spondylitis Disease Activity Index (BASDAI), Ankylosing Spondylitis Functional Index (BASFI), Ankylosing Spondylitis Mobility Index (BASMI), and Modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) were evaluated in all patients. RESULTS: Thirteen of the 119 patients had renal calculi confirmed by USG data. The frequency of nephrolithiasis detected by USG was 10.9% in patients with AS. The disease lasted significantly longer in patients with renal calculi ([nephrolithiasis (+): 18.39±8.72 years; nephrolithiasis (−): 12.02±8.43 years, p=0.01]). The BASMI total score was significantly higher in the group of patients with renal calculi. There was not any significant difference in terms of blood samples, HLA-B27, BASDAI, BASFI, and mSASSS between groups. CONCLUSION: The frequency of renal stones is increased in patients with AS compared to healthy population. Especially patients who had AS for a long time and higher BASMI values are more susceptible to renal calculi. It is important to point out that the results of this type of studies would be more reliable if the study is conducted on large patient groups and population-based prevalence. Keywords: Ankylosing spondylitis; BASDAI; BASFI; BASMI; mSASSS; nephroilitasiz; urolithiasis.

Cite this article as: Rezvani A. Aktas I, Tastekin N, Celiker R, Sarikaya S, Dursun E, et al. Nephrolithiasis in ankylosing spondylitis and its relationship with disease assessment scales. North Clin Istanb 2019;6(3):254–259.

Received: March 26, 2018 Accepted: May 12, 2018 Online: August 08, 2018 Correspondence: Dr. Aylin REZVANI. Bezmialem Vakif Universitesi Tip Fakultesi, Fiziksel Tip ve Rehabilitasyon Anabilim Dali, Istanbul, Turkey. Tel: +90 212 453 17 00 e-mail: rezvani.aylin@gmail.com © Copyright 2019 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

Rezvani et al., Nephrolithiasis in ankylosing spondylitis and its relationship with disease assessment scales

nkylosing spondylitis (AS) is a chronic inflammatory disease with the predilection for the spine and sacroiliac joints, thus causing back pain and post-inactivity stiffness [1]. In addition, AS can manifest itself as peripheral arthritis and enthesitis, and it can also have extra-articular involvement such as the eye, lung, kidney, and heart [1]. The prevalence of AS is generally believed to be 0.1%–1.4%, and the gender disparity is reported as the male-to-female ratio of around 2:1 [2]. IgA nephropathy, secondary amyloidosis, and analgesic nephropathy represent the most common renal involvement seen in AS [3]. However, the incidence of renal calculi has been shown to be higher in these patients than in normal populations [4]. The prevalence of urolithiasis ranges from 2% to 20% throughout the world, based on different population characteristics [5]. With a prevalence of 11.1%, urinary calculi disease is considered endemic in Turkey, and it shows a specific geographical distribution, where the south-eastern Anatolian and Aegean regions have the highest prevalence [6]. Several studies showing an increased incidence of renal calculi in patients with AS have been published [7–13]. Jacobsen et al. found the risk of nephrolithiasis in patients with AS to be more than twofold compared to the general population. The authors described nephrolithiasis as an extra-articular manifestation in AS and factors such as the male gender, history of inflammatory bowel disease, and previous history of kidney stones were significant and clinical important predictors of nephrolithiasis in patients with AS [12]. Furthermore, a recently published study from Taiwan with a large patient number assessed the risk of nephrolithiasis among patients with AS compared to matched general population. The percentages of newly diagnosed nephrolithiasis were 5.76% in AS and 4.58% in the non-AS patients. The results showed that patients with AS were more likely to be associated with nephrolithiasis than non-AS patients [14]. Although its etiology is unknown, the formation of calculi requires a complex integration of numerous factors, such as high blood calcium and phosphate saturation, high levels of urinary calcium, the formation, retention, and accumulation of crystals, urinary pH, and abnormalities in crystallization inhibitors [15]. In addition to an increased level of cytokines, bone resorption, and increased bone turnover, a prolonged use of anti-inflammatory drugs and accompanied intestinal problems also play a role in calculi formation in AS [16].

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In the light of the information provided, the aim of this study was to investigate the frequency of detected renal calculi by ultrasonography (USG) and its relationship with disease assessment scales in our patients with AS. MATERIALS AND METHODS The study was designed retrospectively. A total of 320 patients with AS being followed by the “Activity Platform” were included in the study. The Activity Platform is comprised of 11 physiatrists from nine different centers in Turkey, showing a special interest in spondyloarthritis and rheumatoid arthritis, who have received a standardized training that included examination, an assessment of the questionnaire forms, and radiological grading performance of patients with AS. A total of 119 patients who had renal USG, erythrocyte sedimentation rate, Creactive protein, blood level of calcium, phosphorus, Vitamin D, parathormone, and urinary calcium levels, and also lateral cervical and lumbar conventional radiography in the same time period were extracted from the cohort. All of the AS cases were diagnosed according to the Modified New York Criteria [17]. The sociodemographic characteristics (age, gender, and disease duration), clinical features, and comorbidities were recorded. Patients who had a history of hypertension, diabetes, and cardiovascular disease were excluded. Patients were identified as “renal calculi positive” with calculi-compatible images and “renal calculi negative” if they were calculi incompatible. A written informed consent was obtained from each patient. The patients were assessed using the Assessment of SpondyloArthritis International Society recommendations for core outcome domains in the AS assessment [18]. Turkish versions of Bath AS Disease Activity Index (BASDAI) [19], Turkish version of Bath AS Functional Index (BASFI) [20], and Bath AS Metrology Index (BASMI) [21] were evaluated for disease activity, functional status, and mobility, respectively. The BASMI subscale was calculated using the chest expansion, cervical rotation, lumbar flexion, lumbar lateral flexion, and intermalleolar distance evaluations. A Modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) [22] was used for the radiological assessment of structural damage. For this reason, lateral views of the lumbar and cervical spine of 119 patients also having renal ultrasonographic evaluation in the same time period were scored by the same researcher (R.Ç.) experienced in grading the mSASSS

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Table 1. Demographic characteristics of as patients with and without nephrolithiasis Characteristics Age (years) Male gender Disease duration (years) HLA B27 (+)

Nephrolithiasis (-)

Nephrolithiasis (+)

40.42±10.59 %61 12.02±8.43 93/106

45.69±10.10 %84.6 18.39±8.72 13/13

0.91 0.13 0.01* 0.33

*p<0.05.

Table 2. Laboratory results of patients in the same time period of ultrasonographic evaluation Characteristics Calcium (mg/dl) Phosphorus (mg/dl) Vitamin D (ng/ml) Parathormon (pg/ml) Urine calcium (24 h)

Nephrolithiasis (-)

Nephrolithiasis (+)

10.11±8.24 3.30± 0.58 29.36±33.92 55.79±31.01 145.04±84.97

9.42±0.36 3.19±0.53 23.87±10.06 57.03±41.59 238.91±403.70

0.45 0.59 0.89 0.55 0.76

[22]. The frequency of nephrolithiasis in our patients was assessed by comparing it to Turkish population nephrolithiasis data. Statistics We used a chi-squared and/or Fisher’s exact test to compare categorical variables such as nephrolithiasis between the patients with AS and normal population. An independent two-samples t-test was used to compare continuous variables such as mSASSS, BASFI, BASMI, an BASDAI scores between the patients with AS with and without nephrolithiasis. In each case, a p-value <0.05 was considered to be statistically significant. A data analysis was performed using the SPSS version 18. RESULTS Thirteen of 119 patients included in the study had renal calculi confirmed by USG data. The prevalence of nephrolithiasis detected by USG was 10.9% in our patients with AS. One hundred and six patients had no history of renal calculi and no compatible renal calculi in USG. There was no difference in age, gender, and the HLA-B27 positivity between AS patients with

and without renal calculi (p>0.05). Disease duration was significantly higher in patients with renal calculi (nephrolithiasis [+]: 18.39±8.72 years, nephrolithiasis [−]: 12.02±8.43 years, p=0.01). Demographic characteristics of the patients are presented in Table 1. There was no significant difference in the serum calcium, phosphorus, Vitamin D, parathormone, and urinary calcium excretion results obtained on the same date of USG evaluation in patients from both groups (>0.05) (Table 2). There was no significant difference in terms of BASFI between the two groups (Table 3). The BASMI total score was significantly higher in the group of renal calculi positive patients. Although no significant difference was observed between the two groups in terms of chest expansion, lateral spinal flexion, a modified Schober test, and intermalleolar distance in the BASMI subscale, the tragus-wall distance was significantly increased, and cervical rotation values were significantly decreased in patients with renal calculi. The mSASS values were 39.08±22.72 in patients with renal calculi and 32.09±16.76 in the other group. There was no significant difference in terms of mSASS between the two groups (p=0.244) (Table 4).

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Table 3. The relationship between nephrolithiasis and BASMI subscale Nephrolithiasis (-) Nephrolithiasis (+) p

Chest expantion (cm)

Cervical rotation (degree)

3.79± 1.71 3.04±1.68 0.156

61.09±22.41 42.04±27.30 0.01*

Tragus to wall distance (cm)

Lateral spinal flexion (cm)

Modified schober test (cm)

Intermalleolar distance (cm)

16.23±5.58 11.24±6.26 4.13±2.06 93.47±19.13 19.68±5.94 7.83±5.05 3.29±1.80 90.88±25.12 0.02* 0.07 0.20 0.86

BASMI: Ankylosing Spondylitis Mobility Index; *p<0.05.

Table 4. The relation of nephrolithiasis with BASMI, BASFI, BASDAI, and mSASS Nephrolithiasis (-) Nephrolithiasis (+) p

BASMI 3.50±2.45 5.17±2.44 0.02*

BASFI 3.11±2.30 3.28±2.77 0.93

BASDAI 3.69±2.34 3.17±2.75 0.40

mSASS 32.08±16.76 39.08±22.72 0.24

BASMI: Ankylosing Spondylitis Mobility Index; BASFI: Ankylosing Spondylitis Functional Index; BASDAI: Ankylosing spondylitis disease activity Index; mSASS: Modified Stoke Ankylosing Spondylitis Spinal Score; *p<0.05.

DISCUSSION Considering the results of our study in general, the frequency of renal calculi was found to be 10.9% in our patients with AS. The presence of renal calculi was correlated with mobility indices (BASMI) and were more common in AS patients with a longer disease duration. An extra-articular involvement is common in inflammatory diseases. Although renal involvement has been shown in many studies on AS, the number of studies investigating the coexistence of renal calculi in AS is very limited [7–13]. The frequency of renal calculi in our patients with AS was 10.9%. Our results were compatible with other studies. A significantly higher prevalence of urolithiasis in patients with AS (11.7%) versus normal population (5.7%) was reported by Fallahi et al. [13]. Korkmaz et al. reported that renal calculi were more common in patients with AS (20%) than with Behçet’s disease (5.5%) and healthy controls (3.3%) [4]. They found renal calculi to be more common in their patients who had AS for a longer time. Canales et al. reported the increased frequency of renal stones in patients with spondyloarthropathies (29%) versus rheumatoid arthritis (12%) [23].

On the contrary, Incel et al. reported no difference in the frequency of renal calculi in patients with AS and normal population. It may be related with the low number of patients in their study [24]. Many factors such as spinal immobilization, the presence of inflammatory cytokines, new bone formation, and a prolonged use of nonsteroidal anti-inflammatory agents has been associated with alterations in calcium metabolism [15]. On the other hand, there are many factors that contribute to the process of calculi formation in as duration of the disease, the effect of conditions such as the immobility and treatment process, urinary tract infection, changes in urinary pH, urostasis, metabolic diseases, congenital abnormalities, heredity, dietary, climate, and occupation [25]. Although of unknown etiology, the formation of calculi requires a complex integration of numerous factors. Resorlu et al. reported that 80%–90% of the renal calculi in patients with AS were calcium-based calculi supporting the possibility of problem primarily due to calcium metabolism [10]. It is stated that osteopenia associated with calcium metabolism impairment in AS increases the frequency of calcium-induced renal calculi. Here with the pathologi-

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cal process of resorption, the predominance of formation phase in the bone cycle could also affect the formation of renal calculi [24]. In a recent prospective study, Gonullu et al. found a significantly higher level of blood calcium at the baseline in AS patients with compared to AS patients without renal calculi [11]. Although this study did not reach statistical significance, the authors also found high urinary calcium levels compared to patients who did not have calculi. They concluded that a subgroup of AS patients tend to have high blood and urinary calcium and that these biochemical abnormalities and other factors might be responsible for the development of urolithiasis [11]. Our study was not in line with their trial as we could not find any significant difference in the blood level of calcium, phosphorus, Vitamin D, parathormone, and urinary calcium excretion. Lui et al. found a functional disability (BASFI) and disease activity (BASDAI) to be greater in AS patients with renal calculi, but no significant differences were detected in the mobility index (BASMI) [8]. They found a significant association with Crohn’s disease in AS patients with urolithiasis [8]. Similarly, Fallahi et al. found a significantly higher BASFI, BASMI, and BASDAI in their AS patients with urolithiasis [13]. There was not any significant difference in terms of BASFI and BASDAI in our study, but on contrary, BASMI showed to be significantly worse in patients with AS who had renal calculi. It has been stated that renal calculi do not occur in AS patients with long disease duration. Our results confirm this piece of information, as in our study, the frequency of renal calculi was found to be significantly higher in both AS patients with long disease duration and with low BASMI values, which do occur in established patients. The absence of difference in the intermalleolar distance may be related to the fact that osteoproliferation is more intense in the spine than in the hips. Although there are apparent differences, the statistical insignificance in the chest expansion and the Schober test may be related to the late involvement of costochondral and costovertebral joints. In contrast to general expectation in believing that renal calculi accompanies AS cases with more severe radiographic damages and a presumably poor prognosis, Lui et al. found no significant difference in terms of mSASSS in their AS patients with a history of renal calculi [8]. Although there was a higher radiological score, Cansu et al. also did not report any significant differences

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in AS patients with urolithiasis [9]. Our study was compatible with these two studies. Interestingly, at the molecular level, an increased amount of bone-related proteins such as osteonectin, osteoprotegerin, bone sialoprotein, and transcription factors evolving in bone ossification have been found in the epithelial kidney cell, which can differentiate into an osteoblastic phenotype in the pathogenesis of renal calculi formation [26]. Although common features are involved in the pathogenesis of bone ossification and renal stone formation, the inconsistency of results suggests the other unknown factors and pathways should be researched in the future. There were some limitations to our study. One of them was its retrospective design. Nevertheless, despite the retrospective study, we found an increased frequency of renal calculi in patients with AS parallel with the literature, showing the presence of urolithiasis in these patients, which should be taken into consideration. The second one was the evaluation of mSASSS, which could have been more valid if it had been done by two of our investigators instead of one. Finally, the third limitation were the patients’ treatment data, which were not included in our study. Conclusion Evaluating all these data, we can easily conclude that the frequency of renal calculi is increased in patients with AS. Especially, patients who had AS for a long time and higher BASMI scores are more susceptible to renal calculi, and the evaluation of nephrolithiasis should not be forgotten in such patients. It is important to point out that the results of this type of studies are more reliable if the study includes large patient groups and populationbased prevalence. Conflict of Interest: The authors declare no conflict of interest. Financial Disclosure: The authors declared that this study has received no financial support. Authorship Contributions: Concept – AR, IA, NT, RC, SS, ED, SO, ND, CZ, LA, MB, KA; Supervision – IA, RC, ED, ND, LA, MB, KA; Materials – AR, IA, NT, RC, SS, ED, SO, ND, CZ, LA, MB, KA; Data collection and/or processing – AR, IA, NT, RC, SS, ED, SO, ND, CZ, LA, MB, KA; Analysis and/or interpretation – AR, NS; Writing – AR; Critical review – IA, NT, RC, SS, ED, SO, ND, CZ, LA, MB, KA.

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Rezvani et al., Nephrolithiasis in ankylosing spondylitis and its relationship with disease assessment scales

2. Dean LE, Jones GT, MacDonald AG, Downham C, Sturrock RD, Macfarlane GJ. Global prevalence of ankylosing spondylitis. Rheumatology (Oxford) 2014;53:650–7. 3. Vilar MJ, Cury SE, Ferraz MB, Sesso R, Atra E. Renal abnormalities in ankylosing spondylitis. Scand J Rheumatol 1997;26:19–23. 4. Korkmaz C, Ozcan A, Akçar N. Increased frequency of ultrasonographic findings suggestive of renal stones in patients with ankylosing spondylitis. Clin Exp Rheumatol 2005;23:389–92. 5. Otunctemur A, Ozbek E, Cakir SS, Dursun M, Polat EC, Ozcan L, et al. Urolithiasis is associated with low serum testosterone levels in men. Arch Ital Urol Androl 2015;87:83–6. 6. Muslumanoglu AY, Binbay M, Yuruk E, Akman T, Tepeler A, Esen T, et al. Updated epidemiologic study of urolithiasis in Turkey. I: Changing characteristics of urolithiasis. Urol Res 2011;39:309–14. 7. Singh G, Kumari N, Aggarwal A, Krishnani N, Misra R. Prevalence of subclinical amyloidosis in ankylosing spondylitis. J Rheumatol 2007;34:371–3. 8. Lui NL, Carty A, Haroon N, Shen H, Cook RJ, Inman RD. Clinical correlates of urolithiasis in ankylosing spondylitis. J Rheumatol 2011;38:1953–6. 9. Cansu DU, Calışır C, Savaş Yavaş U, Kaşifoğlu T, Korkmaz C. Predictors of radiographic severity and functional disability in Turkish patients with ankylosing spondylitis. Clin Rheumatol 2011;30:557–62. 10. Resorlu M, Gokmen F, Resorlu H, Adam G, Aylanc N, Akbal A, et al. Prospective evaluation of the renal morphology and vascular resistance in patients with ankylosing spondylitis. Med Ultrason 2015;17:180–4. 11. Gönüllü E, Bilge NŞY, Cansu DU, Bekmez M, Musmul A, Akçar N, et al. Risk factors for urolithiasis in patients with ankylosing spondylitis: a prospectivecase-control study. Urolithiasis 2017;45:353–7. 12. Jakobsen AK, Jacobsson LT, Patschan O, Askling J, Kristensen LE. Is nephrolithiasis an unrecognized extra-articular manifestation in ankylosing spondylitis? A prospective population-based Swedish national cohort study with matched general population comparator subjects. PLoS One 2014;9:e113602. 13. Fallahi S, Jamshidi AR, Gharibdoost F, Mahmoud MI, Paragomi P, Nicknam MH, et al. Urolithiasis in ankylosing spondylitis: Correlation with Bath ankylosing spondylitis disease activity index (BASDAI), Bath ankylosing spondylitis functional index (BASFI) and Bath ankylosing spondylitis metrology index (BASMI). Caspian J Intern Med

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2012;3:508–13. 14. Shih MT, Tang SH, Cha TL, Wu ST, Chiang JH, Chen WC. The Risk of Nephrolithiasis Among Patients With Ankylosing Spondylitis: a Population-Based Cohort Study. Arch Rheumatol 2016;31:346–52. 15. Khan SR. Reactive oxygen species, inflammation and calcium oxalate nephrolithiasis. Transl Androl Urol 2014;3:256–76. 16. Toussirot E, Wendling D. Osteoporosis in ankylosing spondylitis. [Article in French]. Presse Med 1996;25:720–4. 17. van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum 1984;27:361–8. 18. van der Heijde D, Calin A, Dougados M, Khan MA, van der Linden S, Bellamy N. Selection of instruments in the core set for DC-ART, SMARD, physical therapy, and clinical record keeping in ankylosing spondylitis. Progress report of the ASASWorking Group. Assessments in Ankylosing Spondylitis. J Rheumatol 1999;26:951–4. 19. Akkoc Y, Karatepe AG, Akar S, Kirazli Y, Akkoc N. A Turkish version of the Bath Ankylosing Spondylitis Disease Activity Index: reliability and validity. Rheumatol Int 2005;25:280–4. 20. Karatepe AG, Akkoc Y, Akar S, Kirazli Y, Akkoc N. The Turkish versions of the Bath Ankylosing Spondylitis and Dougados Functional Indices: reliability and validity. Rheumatol Int 2005;25:612–8. 21. Jenkinson TR, Mallorie PA, Whitelock HC, Kennedy LG, Garrett SL, Calin A. Defining spinal mobility in ankylosing spondylitis (AS). The Bath AS Metrology Index. J Rheumatol 1994;21:1694–8. 22. Creemers MC, Franssen MJ, van’t Hof MA, Gribnau FW, van de Putte LB, van Riel PL. Assessment of outcome in ankylosing spondylitis: an extended radiographic scoring system. Ann Rheum Dis 2005;64:127–9. 23. Canales BK, Leonard SM, Singh JA, Orzano IM, Zimmermann B, Weiland D, et al. Spondyloarthropathy: an independent risk factor for kidney stones. J Endourol 2006;20:542–6. 24. Incel NA, Gökoğlu F, Nacir B, Incel N. Bone and stone in ankylosing spondylitis: osteoporosis and urolithiasis. Clin Rheumatol 2006;25:667–70. 25. Drach GW. Urinary lithiasis. In: Campbell’s urology, vol II. Saunders, Philadelphia; 1986; p. 1094. 26. Gambaro G, Fabris A, Abaterusso C, Cosaro A, Ceol M, Mezzabotta F, et al. Pathogenesis of nephrolithiasis: recent insight from cell biology and renal pathology. Clin Cases Miner Bone Metab 2008;5:107–9.

Orıgınal Article

PT&R

North Clin Istanb

2019;6(3):260–266 doi: 10.14744/nci.2018.04796

Investigation of C5–C6 radiculopathy and shoulder rotator cuff lesions coexistence frequency Cigdem Arifoglu Karaman,1

Bengi Oz,2

Aylin Sari1

Department of Physical Medicine and Rehabilitation, Erenkoy Physical Therapy and Rehabilitation Hospital, Istanbul, Turkey

Department of Physical Medicine and Rehabilitation, Katip Celebi University Ataturk Training and Research Hospital, Izmir, Turkey

ABSTRACT OBJECTIVE: The aim of this study was to evaluate the coexistence of C5 and/or C6 root compression with rotator cuff pathologies and its effect on pain and disability. METHODS: A total of 65 patients with pain radiating from neck to shoulder were retrospectively evaluated on the basis of demographic data, duration of symptoms, overhead activities, and physical examination. The visual numerical scale (VNS), Quick DASH (Disabilities of the Arm, Shoulder, and Hand), and Shoulder Pain and Disability Index (SPADI) were also used. Cervical magnetic resonance imaging (MRI) was used to evaluate C5–C6 root compression, which was separated into two groups as patients with or without upper trunk root compression (UTRC). These groups were compared according to the MRI findings of patients with rotator cuff pathologies. RESULTS: According to our results, C5 root compression (12.3%), C6 root compression (41.5%), UTRC (44.6%) were detected. There was no difference between the groups regarding the Hawkins and Neer tests. The Yergason and Jobe tests were statistically higher in patients without UTRC. In the shoulder MRIs, the rate of subscapular muscle tear was significantly higher in patients with UTRC. Other shoulder MRI findings were not different between the groups. VNS-neck and SPADI-pain scores were significantly higher in patients without UTRC. There was no difference between the groups in the scores of VNSshoulder, Quick DASH, SPADI-disability, and SPADI-total. CONCLUSION: Radiating pain from neck to shoulder that is caused by C5–C6 root compression does not create a predisposition for clinical, radiologic, and functional pathologies in shoulder joint. It seems difficult to diagnose the exact origin of pain in patients who present with neck pain radiating to shoulder based on the findings of cervical or shoulder MRI alone. Keywords: Cervical radiculopathy; C5 root compression; C6 root compression; impingement syndrome; rotator cuff lesion.

Cite this article as: Arifoglu Karaman C, Oz B, Sari A. Investigation of C5–C6 radiculopathy and shoulder rotator cuff lesions coexistence frequency. North Clin Istanb 2019;6(3):260–266.

ne out of every three people in society complains of neck pain due to various reasons at some point in their lives [1]. Shoulder pain is the third most common musculoskeletal pathology [2]. The primary pathology of pain in the shoulder region may not always be related to rotator cuff lesions. Cervical region pathologies can also cause pain complaints on the shoulder and arm [3– 5]. Cervical pain, which is among the causes of shoulder pain, is seen at a significant frequency of 5% [6]. When

the frequency of neck-shoulder intersection syndrome was examined, a low degree of concomitancy was found between them [7]. However, it should be kept in mind that the cause of shoulder pain may be related to cervical nerve root irritation [8]. Cervical radiculopathy is a pathological process that progresses with increasing neurophysiological dysfunction of the nerve root. Acute disk herniations that occur in pathological compression conditions affect the

Received: August 16, 2017 Accepted: May 14, 2018 Online: November 16, 2018 Correspondence: Dr. Cigdem ARIFOGLU KARAMAN. Erenkoy Fizik Tedavi ve Rehabilitasyon Hastanesi, Istanbul, Turkey. Tel: +90 216 411 80 11 – 1179 e-mail: dr.cigdemarifoglu@gmail.com © Copyright 2019 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

Arifoglu Karaman et al., Investigation of C5–C6 radiculopathy and shoulder rotator cuff lesions coexistence frequency

nerve roots, such as degenerative neural foramen stenosis, trauma, and tumor. The pain due to these conditions may spread to the back, anterior chest wall, arm, and forearm. It has been reported that cervical radiculopathy may occur along with arm pain in 99% of patients, sensory changes in 85%, and neck pain in 80% of cases [9]. In C5–C6 radiculopathy, the pain usually radiates to the upper trapezoidal area, the deltoid region, and the lateral portion of the arm [10, 11]. The rotator cuff muscles, which play an important role in the functioning of the shoulder, are innervated with the nerves arising from the C5 and C6 nerve roots. Radiculopathy that affects the C5 and C6 roots is thought to cause atrophy and weakness in shoulder rotator cuff muscles and deltoid muscle, as well as pain and sensory changes [12]. In particular, it has been argued that C5 radiculopathy may mimic rotator cuff lesions and that the pain is localized to the shoulder, which may cause weakness of the shoulder during abduction and external rotation [13]. Although there is no randomized or cohort study in the literature on this subject, it is thought that the muscles of the shoulder girdle may be affected in cases where the C5 and C6 nerve roots are compressed. There may also be conditions affecting the functionality of the neck and shoulder and the upper extremities. The socio-economic problems caused by neck and shoulder pain in humans are seen very frequently and may cause a significant decrease in their quality of life [14]. In this study, we aimed to investigate the frequency of the C5 and C6 spinal roots compression, which is a common etiologic problem in neck-shoulder pain, and rotator cuff lesions coexistence. We also aimed to assess the pain and disability level of affected shoulders in conjunction with clinical and magnetic resonance imaging (MRI) findings. MATERIALS AND METHODS Patients aged 18–70 years who applied to our outpatient clinic from December 2014 to April 2015 with the complaint of pain radiating from the neck to shoulder and had cervical and shoulder MRI examinations were included in our study. Patients with a history of pregnancy, chronic alcoholism, myocardial infarction within the past 6 months, diabetes mellitus, malignancy, cervical surgery, shoulder trauma, and vascular, inflammatory, infectious or neurological diseases were excluded from the study. The study protocol was approved by the İzmir Kâtip

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Çelebi University Atatürk Training and Research Hospital Ethics Committee. Cervical MRI examinations of the patients were evaluated for the presence of C5 and C6 root compression. According to the presence of compression on the C5 and/or C6 root(s), a total of 65 patients were divided into two groups: with and without upper truncus root compression (UTRC). Age, gender, occupation, working status requiring overhead activities, and duration of neck and shoulder pain were recorded. The positivity of the following tests was recorded: scapular winging, atrophy of shoulder muscles, limited range of motion (ROM) of the shoulder, impingement tests (Hawkins, Neer, and painful arc test), the Speed and Yergason tests for biceps pathology, the Jobe, drop arm test, external rotation resistance, trumpet sign, lift-off, and abdominal compression tests for rotator cuff muscle strength. ROM of the shoulder joint was considered to be normal if the angles of flexion and abduction were 180° and the internal rotation (IR) and external rotation (ER) anges were 90°. The lower values were recorded as “decreased” ROM. The positivity of the Hawkins and/or Neer test was recorded as “impingement tests positive”, and if both of them were negative, it was recorded as “impingement tests negative”. A diagnosis of clinical impingement was made based on these tests. The neurological examination consisted of evaluating motor and sensory examinations, deep tendon reflexes (DTR), and pathological reflexes. During the motor examination, those with myotomal muscle strength of 5/5 were grouped as “normal” and the lower values were recorded as “decreased myotomal strength”. In the sensory examination, the superficial and pain sensations were evaluated and grouped as “normal” and “diminished. Deep tendon reflexes (DTRs) were grouped as “normal” and “decreased”. Pathological reflexes were evaluated by the Babinski and Hoffman tests. The visual numerical scale (VNS) is a simple method that can be used to assess the severity of subjective pain. This test is easy to understand by both the patient and the practitioner, and positively correlates with other measurement methods [15]. In our study, VNS measurements for neck and shoulder pain in the patient records were evaluated using scores between 0 and 10. The shortened forms of disabilities of arm, shoulder, and hand (Quick DASH) questionnaire is frequently used to evaluate the physical functions and symptoms of upper extremity. It is an abridged version of the 30-ques-

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tion DASH questionnaire and can be effectively used instead of DASH [16–18]. In this study, the results of the Quick DASH questionnaire were evaluated, which were included in the patients’ medical records and had scores between 0–100. The Shoulder Pain and Disability Index (SPADI) is used to measure the level of pain and disability associated with shoulder pathologies and to assess shoulder functionality. It consists of a total of two sections and 13 questions, 5 of which assess pain and 8 of which assess disability. The total SPADI score is calculated by averaging the scores of two sections. The total score can be between 0 and 100, and a higher score indicates a worsened disability. In the present study, the Turkish version of the SPADI, which has been proven to be valid and reliable, was used [19]. Previous medical records were used in the evaluation of the cervical and shoulder MRI examinations of the patients included in our study. These records had been reported by a radiologist and loaded in the computer database of our hospital. Foraminal constriction and root compression at C4–C5 and C5–C6 vertebral levels were evaluated on the cervical MRI. Patients were classified according to the presence of upper trunk nerve root compression (UTRC) if there was C5 and/or C6 root compression. MRIs of the shoulders where the neck pain had radiated were evaluated. The stages of impingement detected on the shoulder MRI, rupture and atrophy of the supraspinatus, infraspinatus and subscapularis muscles, pathologies of the biceps muscle (tendinitis, tendinosis, rupture), acromioclavicular joint (ACE) hypertrophy, signs of adhesive capsulitis, changes in humeral head, and labrum rupture were recorded. Impingement (subacromial impingement) syndrome was evaluated in four stages as recommended by Zlatkin et al. [20] and the other findings were recorded as “present” or “absent”. Statistical Analysis The SPSS for Windows 16.0 statistical package program was used to evaluate the data. The demographic data of the patients were evaluated by descriptive analysis. Evaluations from Pearson’s Chi-square or Fisher’s Exact test were used to compare categorical variables between the groups. The Mann-Whitney U test was used to compare continuous variables between groups because the data did not show normal distribution. The level of statistical significance was considered at p<0.05.

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RESULTS A total of 54 (83.1%) female and 11 (16.9%) male patients with a mean age of 46.23±9.33 years who presented with complaints of neck-to-shoulder pain were included in the study. When the cervical MRI examinations of the patients were examined, no cervical pathology was detected in 4.6% of the patients, while the remaining patients had cervical pathologies such as spondylosis, disc hernia, and narrow canals. Eight (12.3%) patients had C5 root compression and 27 (41.5%) had C6 root compression. Upper trunk root compression (C5 and/or C6) was detected in only 29 (44.6%) patients, while in 36 (55.4%) UTRC wasn’t detected. In 20.7% (n=6) of the patients with UTRC, C5 and C6 root compression were observed simultaneously. The mean age of patients with UTRC was statistically significantly higher than those without UTRC (p=0,011). No statistically significant difference was found between the two groups in terms of sex, neck and shoulder pain duration, overhead activity, and paresthesia (p>0.05). The VNS-neck pain scores were higher in patients without UTRC and there was a statistically significant difference between the two groups (p=0.048). However, no statistically significant difference was found between the groups in terms of VNS-shoulder pain scores (p>0.05). Rate of patients with clinical impingement syndrome was 86.2% in with-UTRC group and 91.7% in withoutUTRC group. No significant intergroup difference was detected (p>0.05) (Table 1) in this case. When the physical examination findings of the patients’ shoulders were compared (Table 1), the Yergeason test scores were found to be higher in patients without UTRC (p=0.041). The Neer, Hawkins and Speed tests did not show any statistically significant difference between the groups (p>0.05). The Jobe test evaluated the continuity and muscle strength of the rotator cuff muscles to be highly positive in non-UTRC patients, and this intergroup difference was statistically significant (p=0.025). There was no statistically significant difference between the groups in terms of painful arc, drop arm, ER resistance, lift-off, abdominal compression tests, and trumpet sign (p>0.05). Among these tests, the drop arm test and trumpet sign were not positive in any of the patients in the UTRC group. There was no statistically significant difference in the ROM of the shoulder between patients with and without UTRC (p>0.05) (Table 1). There was no significant difference between the

Arifoglu Karaman et al., Investigation of C5–C6 radiculopathy and shoulder rotator cuff lesions coexistence frequency

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Table 1. Comparison of the patient groups as for demographic data, pain, and physical examination findings n=65 Age (years) Gender Female Male Duration of neck pain (months) Duration of shoulder pain (months) Overhead activity + – VNS-neck (0–10) VNS-shoulder (0–10) Paresthesia + – Clinical impingement + – Hawkins test + – Neer test + – Speed test + – Yergason test + – Painful arc test + – Jobe test + – Drop arm test and trumpet sign + – ER resistance test + – Lift- off test + – Abdominal compression test + – Superficial sensation N Decreased Pain sensation N Decreased C5 muscle strength N Decreased Shoulder flexion, and abduction, and ER N Decreased Shoulder IR N Decreased

UTRC (+) (n=29)

UTRC (−) (n=36)

n % n % 49.86±8.06

43.30±9.36

0.011*

22 75.9 32 88.9 0.196† 7 24.1 4 11.1 34.82±35.47 31.33±33.80 0.497* 28.03±36.08 14.15±18.83 0.057* 17 58.6 18 50 12 41.4 18 50.0 6.58±2.16 7.63±2.11 7.44±2.24 8.19±2.31

0.488‡ 0.048* 0.083*

17 58.6 26 72.2 0.249‡ 12 41.4 10 27.8 25 4

86.2 13.8

33 3

91.7 8.3

0.691†

21 8

72.4 27.6

33 3

91.7 8.3

0.051†

20 69.0 25 69.4 0.967‡ 9 31.0 11 30.6 19 65.5 31 86.1 0.050‡ 10 34.5 5 13.9 12 41.4 24 66.7 17 58.6 12 33.3

0.041‡

16 55.2 27 75.0 0.093‡ 13 44.8 9 25.0 18 62.1 31 86.1 0.025‡ 11 37.9 5 13.9 0 29

0 100

2 34

5.6 94.4

0.498†

16 55.2 26 72.2 0.153‡ 13 44.8 10 27.8 11 37.9 18 50 18 62.1 18 50.0

0.331‡

1 3.4 3 8.3 0.622† 28 96.6 33 91.7 23 6

79.3 20.7

28 8

77.8 22.2

0.881‡

26 3

89.7 10.3

30 6

83.3 16.7

0.720†

29 0

100 0

35 1

97.2 2.8

1.00†

29 0

100 0

32 4

88.9 11.1

0.122

29 0

100 0

33 3

91.7 8.3

0.247

† Fisher’s Exact test; *Mann-Whitney U test; ‡Pearson chi-square test; UTRC: Upper trunk root compression; VNS: Visual numerical scale; ER: External rotation; N: Normal; IR: Internal Rotation.

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Table 2. Comparison of the radiological findings of the patient

groups n=65

UTRC (+) UTRC (-) (n=29) (n=36)

n % n %

Impingement Stage 0 Stage 1 Stage 2 Stage 3 m.supraspinatus tear + – m.infraspinatus tear + – m.subscapularis tear + – Biceps pathology + – Adhesive capsulitis + – Changes in humeral bone + – Labrum pathology + – Atrophy of m.supraspinatus + – Atrophy of m.infraspinatus + – Atrophy of m.subscapularis + – Bursitis + –

2 6.9 2 5.6 7 24.1 10 27.8 16 55.2 18 50.0 4 13.8 6 16.7

0.961

15 51.7 23 63.9 ‡ 14 48.3 13 36.1 0.323 12 41.4 9 25.0 ‡ 17 58.6 27 75.0 0.160 12 41.4 5 13.9 ‡ 17 58.6 31 86.1 0.012 11 37.9 16 44.4 ‡ 18 62.1 20 55.6 0.596 5 17.2 5 13.9 † 24 82.8 31 86.1 0.742 16 55.2 15 41.7 ‡ 13 44.8 21 58.3 0.279 7 24.1 7 19.4 ‡ 22 75.9 29 80.6 0.647 11 37.9 14 38.9 ‡ 18 62.1 22 61.1 0.937 11 37.9 11 30.6 ‡ 18 62.1 25 69.4 0.532 10 34.5 9 25.0 ‡ 19 65.5 27 75.0 0.403 5 17.2 10 27.8 ‡ 24 82.8 26 72.2 0.316

Fisher’s Exact test; ‡Pearson Chi-square test; UTRC: Upper trunk root compression.

†

groups in terms of the superficial sensory and pain examinations and the motor examination tests of the elbow flexor muscles (m.biceps and m.brachialis) performed for the evaluation of the C5 spinal nerve (p>0.05) (Table 1). In the motor examination of the wrist extensor muscles (m.extensor carpi radialis longus and brevis), the DTRs were not pathologic in any patient. Therefore, these parameters were excluded from the evaluation. There was no statistically significant difference between patients in terms of impingement staging according to the shoulder MRI (p>0.05) (Table 2). Stage 2 im-

Table 3. Comparison of shoulder pain and disability scales of the patient groups n=65 Quick DASH SPADI (pain) (%) SPADI (disability) (%) SPADI (total) (%)

UTRC (+) (n=29) 49.53±15.70 70.27±22.02 47.97±22.51 59.12±20.23

UTRC (-) (n=36)

56.35±20.0 80.27±17.76 59.06±27.83 69.66±21.63

0.124 0.033 0.092 0.057

*Mann-Whitney U test; UTRC: Upper trunk root compression; Quick DASH: Shortened form of disabilities of arm, shoulder, and hand, SPADI: Shoulder Pain and Disability Index.

pingement syndrome was the most common radiological finding in both groups. Shoulder MRI examinations revealed supraspinatus (n=38:58.5%), infraspinatus (n=21; 32.3%), subscapularis (n=17:26.2%;) muscle ruptures and bicipital pathologies (n=27: 41.5%) in the respective number of patients. Supraspinatus (n=25; 38.5%), infraspinatus (n=33.8%) (n=22), and subscapularis (n=19; 29.2%) muscle atrophies were detected in the respective number of patients. Subscapularis muscle rupture was found to be statistically higher in patients with UTRC (p=0.012). No statistically significant difference was found between the groups in terms of rupture of supraspinatus and infraspinatus muscles, atrophy of the supraspinatus, infraspinatus and subscapularis muscles, pathologies of the biceps, findings of adhesive capsulitis, bony changes in the humeral head, and labrum and bursa pathologies (p>0.05) (Table 2). Quick DASH and SPADI questionnaires evaluating shoulder pain and disability were compared between the groups. SPADI-pain scores were relatively higher in the non-UTRC group (p=0.033). There was no significant difference between the groups in terms of Quick DASH, SPADI-disability, and SPADI-total scores (p>0.05) (Table 3). DISCUSSION It is well known that cervical pathologies can cause neck pain as well as shoulder and arm pain. In cervical radiculopathy, which is one of the most important causes of neck-to-shoulder pain, the involvement of the C6 root is most commonly observed, followed by involvement of both C5 and C6 roots, and then only the C5 root [21, 22]. The involvement of C5 and C6 roots is also significant for shoulder girdle muscles.

Arifoglu Karaman et al., Investigation of C5–C6 radiculopathy and shoulder rotator cuff lesions coexistence frequency

In the brachial plexus, the suprascapular nerve originating from the upper trunk (formed by the combination of C5 and C6 roots) innervates the supraspinatus and infraspinatus muscles. In addition, the subscapular nerve arising from the posterior fasciculus (formed by the posterior branch of the upper trunk) innervates the subscapular muscle. The axillary nerve innervates the deltoid and teres minor muscles. Therefore, this study was planned considering that the innervation of the rotator cuff muscles may be impaired, and as a result, rotator cuff activity and shoulder joint function may be affected if the C5 and C6 nerve roots are compressed. In our study, we evaluated the relationship between C5 and C6 radiculopathy and shoulder lesions by clinical and MRI findings. We detected that upper trunk root compression may constitute a risk for only subscapularis muscle rupture, but otherwise does not predispose to any clinical, radiological, and functional pathology in shoulder. When the literature is examined, the number of studies involving both shoulder and cervical region pathologies is quite limited. In the few studies that have been performed, additional pathologies, such as cervical radiculopathy, were investigated with different tests (mainly EMG) in the patients with shoulder pathology. MRI findings for cervical radiculopathy have not been evaluated in the previous studies; our study is unique because all of our patients were examined with MRI findings in addition to clinical findings. In a study in which 191 patients with suspected cervical radiculopathy were evaluated for myofascial pain, impingement syndrome, lateral epicondylitis, and deQuervain tenosynovitis; cervical radiculopathy was seen in 9% of the patients with shoulder impingement syndrome. In the same study, impingement syndrome was found to be significantly less frequent in the group with cervical radiculopathy [23]. Vad et al. [24] detected neurological findings in 28% of EMG examinations of 25 patients with full-thickness rotator cuff tears and severe atrophy of the shoulder muscles. C6 radiculopathy was detected in 14.2% of the patients, upper truncus or axillary neuropathy in 57.1%, and suprascapular neuropathies were found in 28.5% of the patients [24]. In another study, cervical radiculopathy was shown in only one of 26 patients with rotator cuff tears [25]. In a study of 33 patients diagnosed with shoulder impingement syndrome, confirmed C5–C6 radiculopathy was detected in 5.3% of patients and possible cervical radiculopathy was seen in 23.7% of the patients. It was recom-

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mended that cervical radiculopathy be kept in mind as a possible source of pain in the evaluation of patients with shoulder pain [26]. When all these studies are evaluated, it should be considered that those nerve injuries that cause shoulder pathologies can occur not only at the root level but also at other levels of the brachial plexus. The incidence of cervical radiculopathy increases with age. It has the highest incidence rates between the ages of 50–54 years, and its frequency decreases over the age of 60 years [21]. In the literature, cervical radiculopathy has been shown to be more common in men [9, 21, 27, 28]. In our study, the majority of patients presenting with neck-to-shoulder pain were female, and the mean age of pain occurence (49.86±8.06 years) was statistically higher in patients with C5–C6 root compression. In the Quick DASH and SPADI questionnaires, we evaluated the reflection of the clinical and radiological data on pain and disability. The SPADI-pain scores were significantly higher in the non-C5–C6 root compression group, while no statistically significant intergroup difference was detected for the Quick DASH and SPADI-disability and SPADI-total scores. The VNS-neck values were lower in patients with C5–C6 root compression than in those without. In the literature, we did not find any other study that used the VNS, Quick DASH, and SPADI questionnaires in the presence of C5–C6 root compression The higher VNSneck value in patients without the compression may be due to the fact that C5–C6 root compression is not the only cause of neck pain and other pathologies may have caused neck pain in our patients. In patients without C5–C6 root compression, higher SPADI-pain scores could be associated with isolated shoulder pathology or involvement of more distal levels of the brachial plexus. The most important limitations of our study were, firstly, the limited number of patients available for enrollment, and secondly, the radicular involvement that occurred because of root compression could not be supported by EMG findings. These limitations may cause the result that compression of the upper trunk root only poses a risk for subscapularis muscle rupture but otherwise does not predispose to a clinical, radiological, or functional pathology in the shoulder. Therefore, in our daily practice, for patients with neck and shoulder pain, it may be a more accurate approach to evaluate the patient with a cervical MRI when making differential diagnosis of radicular pain and then confirm it with an EMG if necessary.

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However, as in previous studies, only EMG-mediated diagnoses may not be sufficient for optimal evaluation. Prospective studies with long-term follow-ups and sample sizes comprising larger populations are needed. In conclusion, neck pain radiating to the shoulder may be associated with cervical radiculopathy. It should be kept in mind that the underlying cervical pathology may affect the rotator cuff muscles and that the primary pathology may be caused by factors that do not involve the rotator cuff in patients presenting with shoulder pain. Due to the socio-economic problems and poor quality of life caused by neck and shoulder pain, it is important to determine the main source of pain and arrange treatment accordingly. Ethics Committee Approval: The study protocol was approved by the Izmir Katip Celebi University, Ataturk Training and Research Hospital Ethics Committee (11.12.2014/255). 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. Authorship Contributions: Concept – BO; Design – BO, CAK; Supervision – BO; Materials – CAK; Data collection and/or processing – CAK; Analysis and/or interpretation – BO, CAK; Writing – CAK; Critical review – BO, AS.

REFERENCES 1. Zhuang L. Twenty one cases of vertebral-artery-type cervical spondylosis treated with acupuncture and moxibustion. J Tradit Chin Med 2000;20:280–1. 2. Urwin M, Symmons D, Allison T, Brammah T, Busby H, Roxby M, et al. Estimating the burden of musculoskeletal disorders in the community: the comparative prevalence of symptoms at different anatomical sites, and the relation to social deprivation. Ann Rheum Dis 1998;57:649–55. 3. De Palma AF. Surgery of the Shoulder. 3rd ed. Philadelphia: Lippincott Williams&Wilkins; 1983. p. 571–80. 4. Hawkins RJ. Cervical spine and the shoulder. Instr Course Lect 1985;34:191–5. 5. Bateman JE. Neurologic painful conditions affecting the shoulder. Clin Orthop Relat Res 1983:44–54. 6. Sarpel T. Omuz Ağrısı Nedenleri ve Muayenesi. In: Beyazova M, Gökçe Kutsal Y, editors. Fiziksel Tıp ve Rehabilitasyon. 2nd ed. Ankara: Güneş Tıp Kitabevleri; 2011. p. 1995–2018. 7. Sembrano JN, Yson SC, Kanu OC, Braman JP, Santos ER, Harrison AK, et al. Neck-shoulder crossover: how often do neck and shoulder pathology masquerade as each other? Am J Orthop (Belle Mead NJ) 2013;42:E76–80. 8. Coventry MB. Problem of painful shoulder. J Am Med Assoc 1953;151:177–85. 9. Henderson CM, Hennessy RG, Shuey HM Jr, Shackelford EG. Poste-

North Clin Istanb rior-lateral foraminotomy as an exclusive operative technique for cervical radiculopathy: a review of 846 consecutively operated cases. Neurosurgery 1983;13:504–12. 10. Ellenberg MR, Honet JC, Treanor WJ. Cervical radiculopathy. Arch Phys Med Rehabil 1994;75:342–52. 11. Slipman CW, Plastaras CT, Palmitier RA, Huston CW, Sterenfeld EB. Symptom provocation of fluoroscopically guided cervical nerve root stimulation. Are dynatomal maps identical to dermatomal maps? Spine (Phila Pa 1976) 1998;23:2235–42. 12. Manifold SG, McCann PD. Cervical radiculitis and shoulder disorders. Clin Orthop Relat Res 1999:105–13. 13. Carette S, Fehlings MG. Clinical practice. Cervical radiculopathy. N Engl J Med 2005;353:392–9. 14. Lundberg G, Gerdle B. Tender point scores and their relations to signs of mobility, symptoms, and disability in female home care personnel and the prevalence of fibromyalgia syndrome. J Rheumatol 2002;29:603– 13. 15. Erdine S. Ağrının derecelendirilmesi ve ağrı ölçümleri. In: Erdine S, editor. Ağrı. 1st ed. İstanbul: Nobel Tıp Kitabevleri; 2000. p. 98–100. 16. Beaton DE, Wright JG, Katz JN; Upper Extremity Collaborative Group. Development of the QuickDASH: comparison of three itemreduction approaches. J Bone Joint Surg Am 2005;87:1038–46. 17. Gummesson C, Ward MM, Atroshi I. The shortened disabilities of the arm, shoulder and hand questionnaire (QuickDASH): validity and reliability based on responses within the full-length DASH. BMC Musculoskelet Disord 2006;7:44. 18. The Quick DASH Türkçe. Available at: http://www.dash.iwh.on.ca/ sites/dash/public/translations/QuickDASH_Turkish_2012.pdf. Accessed 2006. 19. Bumin G, Tuzun EH, Tonga E. The Shoulder Pain and Disability Index (SPADI): cross-cultural adaptation, reliability, and validity of the Turkish version. J Back Musculoskelet Rehabil 2008;21:57–62. 20. Zlatkin MB, Iannotti JP, Roberts MC, Esterhai JL, Dalinka MK, Kressel HY, et al. Rotator cuff tears: diagnostic performance of MR imaging. Radiology 1989;172:223–9. 21. Radhakrishnan K, Litchy WJ, O’Fallon WM, Kurland LT. Epidemiology of cervical radiculopathy. A population-based study from Rochester, Minnesota, 1976 through 1990. Brain 1994;117:325–35. 22. Lunsford LD, Bissonette DJ, Jannetta PJ, Sheptak PE, Zorub DS. Anterior surgery for cervical disc disease. Part 1: Treatment of lateral cervical disc herniation in 253 cases. J Neurosurg 1980;53:1–11. 23. Cannon DE, Dillingham TR, Miao H, Andary MT, Pezzin LE. Musculoskeletal disorders in referrals for suspected cervical radiculopathy. Arch Phys Med Rehabil 2007;88:1256–9. 24. Vad VB, Southern D, Warren RF, Altchek DW, Dines D. Prevalence of peripheral neurologic injuries in rotator cuff tears with atrophy. J Shoulder Elbow Surg 2003;12:333–6. 25. Costouros JG, Porramatikul M, Lie DT, Warner JJ. Reversal of suprascapular neuropathy following arthroscopic repair of massive supraspinatus and infraspinatus rotator cuff tears. Arthroscopy 2007;23:1152–61. 26. Date ES, Gray LA. Electrodiagnostic evidence for cervical radiculopathy and suprascapular neuropathy in shoulder pain. Electromyogr Clin Neurophysiol 1996;36:333–9. 27. Yoss RE, Corbin KB, Maccarthy CS, Love JG. Significance of symptoms and signs in localization of involved root in cervical disk protrusion. Neurology 1957;7:673–83. 28. Kelsey JL, Githens PB, Walter SD, Southwick WO, Weil U, Holford TR, et al. An epidemiological study of acute prolapsed cervical intervertebral disc. J Bone Joint Surg Am 1984;66:907–14.

Orıgınal Article

GYNECOLOGY&OBSTETRICS

North Clin Istanb

2019;6(3):267–272 doi: 10.14744/nci.2018.51422

The prevalence of thyroid dysfunction and its relationship with perinatal outcomes in pregnant women in the third trimester Hatice Dulek,1

Fisun Vural,2

Nurettin Aka,2

Sergul Zengin3

Department of Family Medicine, Bilecik Golpazarı State Hospital, Bilecik, Turkey

Department of Obstetrics and Gynecology, Haydarpasa Numune Training and Research Hospital, Istanbul, Turkey

Department of Family Medicine, Haydarpasa Numune Training and Research Hospital, Istanbul, Turkey

ABSTRACT OBJECTIVE: In this study, we aimed to investigate the prevalence of thyroid dysfunction in pregnant women in their third trimester and assess its relationship with perinatal outcomes. METHODS: A total of 796 women who delivered babies at the Haydarpaşa Numune Training and Research Hospital between January 2014 and January 2015 were evaluated retrospectively. Women with complete data and relevant results from thyroid functions tests were included in the study (n=573). Serum levels of thyroid stimulating hormone (TSH), free triiodothyronine (T3), free thyroxine (T4) were studied for all patients. Patients were classified according to thyroid function test results as having hypothyroidism, subclinical hypothyroidism, hyperthyroidism, or euthyroid state. The perinatal outcomes (Apgar score, birth type and birth weight) were compared. RESULTS: A total of 86.7% of pregnant woman (492/573) showed normal thyroid function tests. Out of the remaining participants,0.5% had hypothyroidism, 8.9% had subclinical hypothyroidism, and 2.8% had hyperthyroidism. TSH levels correlated with maternal age. The perinatal outcomes were insignificant between groups. CONCLUSION: The prevalence of thyroid dysfunction was 13.2% in our population. Subclinical hypothyroidism and hyperthyroidism had no adverse effects on birth weight, cesarean section rates, and Apgar scores. Keywords: Hypothyroidsm; perinatal outcome; thyroid.

Cite this article as: Dulek H, Vural F, Aka N, Zengin S. The prevalence of thyroid dysfunction and its relationship with perinatal outcomes in pregnant women in the third trimester. North Clin Istanb 2019;6(3):267–272.

hyroid hormone is necessary for fetal development and maturation. Until the fetus synthesizes its own thyroid hormones, it is dependent on the T4 hormone that passes through the placenta from the mother [1, 2]. The need for iodine increases during pregnancy because of increased maternal-fetal metabolism and glomerular filtration rate [3]. To meet the increased metabolic needs of the mother and the fetus during pregnancy, physiological changes take place in the thyroid gland. These

changes should be considered when evaluating thyroid function tests during pregnancy [4, 5]. Thyroid diseases are the second most common endocrine disorders affecting women in the reproductive period [1]. Women are likely to experience thyroid-related problems during pregnancy. Early diagnosis and treatment of thyroid diseases before and during pregnancy is important for maintaining the health of the mother and the baby [5].

Received: November 29, 2016 Accepted: July 02, 2018 Online: September 02, 2019 Correspondence: Dr. Fisun VURAL. Haydarpasa Numune Egitim ve Arastirma Hastanesi, Kadin Hastaliklari ve Dogum Klinigi, Istanbul, Turkey. Tel: +90 532 361 36 46 e-mail: fisunvural@yahoo.com.tr © Copyright 2019 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

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At least 2%–3% of pregnant women are affected by thyroid dysfunction. Hyperthyroidism occurs in 0.2%–0.4% of pregnant women and is most commonly associated with Grave’s disease. The incidence of hypothyroidism in pregnancy is between 0.5%–3.5%. Hashimoto’s thyroiditis is its most common cause, but it is also seen in regions with iodine deficiency [6]. Thyroid dysfunction in pregnancy may be accompanied by both maternal and fetal complications. Hypothyroidism in pregnancy is associated with premature birth, fetal cardiac complications, low birth weight, increased frequency of cesarean delivery, placental complications, preeclampsia and gestational hypertension, perinatal morbidity-mortality, and cognitive dysfunction. In hyperthyroidism during pregnancy, complications such as stillbirth, abortion, premature birth, preeclampsia, heart failure and thyroid storm may develop [6–9]. Subclinical hypothyroidism is associated with increased TSH levels and normal fT4 values and is more common than overt hypothyroidism. Although it has been suggested to be associated with preterm labor and fetal loss, its relationship with pregnancy complications is controversial [8]. As the harmful effects of thyroid diseases for both mother and baby have started to come into prominence, the need for screening thyroid during pregnancy has also been discussed. Although literature shows that screening for subclinical hypothyroidism is cost-effective, the number of studies showing the results and benefits of screening has not yet reached a sufficient level [10–14]. The prevalence of thyroid dysfunction in pregnancy should be known in order to perform community-based screenings in a healthy way. The aim of this study was to investigate the frequency of thyroid dysfunction and its relationship with perinatal outcomes in pregnant women in their 3rd trimester, who applied to our education and research hospital.

Patients with a diagnosis of hyperemesis gravidarum, those who had undergone thyroid surgery previously, had undergone lithium or amiodarone therapy or head and neck radiotherapy, were infertile, and had type 1diabetes were excluded from the study. Out of the 796 screened births, those who did not meet the inclusion criteria were excluded and the study was conducted with 573 patients. Evaluation of TFTs: The diagnosis of hypothyroidism, hyperthyroidism, and subclinical hypothyroidism was based on the American Thyroid Association (ATA) guidelines [15]. According to these, the normal values are 0.1–2.5 μ/L in the 1st trimester, 0.2–3.0 μ/L in the 2nd trimester, and 0.3–3.0 μ/L in the 3rd trimester. If TSH was >10 μ/L, a diagnosis of overt hypothyroidism was made, and if it was between 3–10 μ/L, a diagnosis of subclinical hypothyroidism was made. Since the participants were in their >24 gestational week, the 3rd trimester values were taken as reference. Perinatal results of the patients were obtained from their computerized records and files. The levels of TSH (thyroid stimulating hormone), T4 (thyroxine), T3 (triiodothyronine), and anti-TPO (antithyroid peroxidase) antibody were studied as part of the TFTs. The results were recorded by the Abbot Architect 1600 Chemiluminescence method.

MATERIALS AND METHODS

RESULTS

Between January 2014 and January 2015, the thyroid function tests (TFT) of 573 pregnant women who had given birth in our hospital were included in the study. The study was designed retrospectively and approval from the ethical committee was obtained. Patient Selection: Patients who gave birth at our clinic and who underwent TFT after 24 weeks of gestation were included in the study. These patients had not undergone TFTs during the 1st and 2nd trimesters and had not experienced any thyroid problems previously.

The patients’ age range was 18-45 years (mean±SD =27.8±5.7). A total of 258 (45%) patients delivered by the vaginal route and 315 patients opted for cesarean sections (55%). Table 1 presents the general characteristics of the patients who participated in the study. Of the 573 pregnant women, 492 (86.7%) had normal TFT results and 76 patients (13.2%) had abnormal results. According to the results of screening tests of thyroid function, the prevalence rates of overt hypothyroidism (n=3, 0.5%), subclinical hypothyroidism (n=51, 8.9%), and hyperthy-

Statistical Analysis Data were analyzed by the two-way method and within a 95% confidence interval. The SPSS 18 program was used for data analysis (SPSS Inc., Chicago, IL, USA). In addition to descriptive statistical analysis (percentage, minimum, maximum, mean, standard deviation), the intergroup comparisons were done according to the distribution of the data. The Student’s t-test, Chi-square test, and Mann Whitney-U test were used. A value of p<0.05 was considered statistically significant.

Dulek et al., The prevalence of thyroid dysfunction and its relationship with perinatal outcomes in pregnant women

Maximum

Mean±SD

14 1 0 0 0

45 9 6 5 6

27.8±5.7 2.5±1.4 1.1±1.0 0.2±0.6 1.1±1.0

Age Gravida Parity Abortus Survived SD: Standard deviation.

roidism were as indicated. Figure 1 shows the distribution of thyroid dysfunction during pregnancy. Correlation analysis was performed for TSH elevation using some parameters. Correlation analyses were performed between TSH values and parameters such as, maternal age (r=0.085, p=0.04), anti-TPO (r=0.347, p=0.09), and birth weight (r=-0.07, p=0.873). An increase in TSH correlated positively with maternal age. Although there is a positive correlation with anti-TPO, the number of patients with anti-TPO was limited, because of which statistically significant data could not be found. TSH was found to increase with age. There was no significant correlation between TSH increase and birth weight. Patients with and without anti-TPO antibodies were compared in terms of birth weight and Apgar scores, but no significant difference was found. Patients with normal thyroid function were compared with cases of subclinical hypothyroidism and hyperthyroidism to evaluate some obstetric and perinatal

0.5

8.9

2.8 Hypothyroidism

Minimum

Subclinical hyperthyroidism

86.7

Overt subclinical

in the study (n=573)

100 90 80 70 60 50 40 30 20 10 0

Normal TFT

Table 1. General characteristics of the patients participating

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Figure 1. Prevalence rates of hyperthyroidism, hypothyroidism, and subclinical hypothyroidism. outcomes (Table 2). Cesarean delivery rates of patients with normal TFT and overt hypo- and hyperthyroidism were similar (p>0.05). The subclinical hypothyroidism group had lower C/S rates (p=0.03). In the overt hypothyroidism group, the 1- and 5-minute Apgar scores were lower, but the variance distribution was not homogeneous, so the statistical significance could not be obtained. The groups were similar in terms of Apgar scores and birth weights (p>0.05). DISCUSSION Normally functioning thyroid glands are able to meet the increasing need for hormones during pregnancy and keep thyroid hormone levels within normal limits. Ex-

Table 2. Comparison of some obstetric and perinatal outcomes of patients with normal thyroid functions or subclinical hypothyroidism

Parameters Age Gravida Parity Abortus Cesarean delivery rate Birth weight (g) Apgar 1. min Apgar 5. min

Hypothyroidism

Subclinical hypothyroidism

Hyperthyroidism

Normal TFT value

0.714 3.0±0.0 1.5±0.7 0.5±0.7 %100 2814±161 2.5±3.5 4.0±5.6

27.7±5.4 2.1±1.4 0.8±0.9 0.2±0.8 %43* 3322±489 7.4±1.5 8.8±1.5

28.0±5.2 2.4±1.1 1.2±1.1 0.09±0.2 %54 3125±410 8.1±0.7 8.8±1.5

28.3±5.7 2.6±1.3 1.2±1.0 0.2 ±0.6 % 59 3360±1278 7.7±1.2 9.0±0.9

ns ns ns ns s ns ns ns

*p<0.05; s: Significant; ns: Nonsignificant.

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Table 3. Domestic studies demonstrating the prevalence rates of thyroid dysfunction in Turkey Author Temur et al. [16] Karakurt et al. [17] Bostanci et al. [18] Guzel et al. [19] Donmez et al. [20] Our study

City

Year

Hypothyroidism

Hyperthyroidism

TSH reference values

Istanbul Ankara Elazig Istanbul Istanbul Istanbul

2012 2007 2011 2015 2005 2016

%3.6 %2.8 %2.84 %5.38 %1.6 %6.8

%1 %0.6 %0.68 %15.8 %4 %2.8

0.34–5.6 MU/L – 0.3–4.5 MU/L 0.1–3 MU/L* 0.6–3.42 MU/L 0.3-3 MU/L*

TSH cut-off values determined by ATA according to the trimesters of pregnancy were taken into consideration.

cessive or deficient maternal thyroid hormone levels are known to have serious effects on the fetal and maternal outcomes at every stage of a pregnancy [9]. However, the performance of screening tests for evaluating thyroid function during routine pregnancies is still controversial. Maternal hypothyroidism is the most common thyroid dysfunction in pregnancy. In our study, the prevalence of overt hypothyroidism was 0.5% (n=3), which was consistent with the literature. In both new and previously diagnosed cases with overt hypothyroidism, the initiation of a full dose of L-thyroxine is considered necessary to prevent complications related to hypothyroidism [4, 10]. To determine the optimum dose, the trimester-specific intervals for TSH and the total and free thyroid hormone levels should be determined correctly. Reference values may vary in regions where iodine deficiency is common [11]. Iodine deficiency, which is an important public health issue, causes serious problems in different periods of life, starting as early as the intrauterine period. The daily iodine requirement increases 1.5 times in pregnant women and up to 2 times in breastfeeding mothers. Adequate levels of maternal iodine intake should be ensured in regions with iodine deficiency. Its recommended daily average dose is 200 μg [12]. The rate of iodine deficiency in Istanbul has been reported as 46.2% [13]. Severe levels of iodine deficiencies can cause fetal neural developmental disorders, as they can lead to maternal and fetal iodine deficiencies. For normal fetal brain and cognitive development, maternal thyroid functions should remain at normal levels. If this is not treated, hypothyroidism may cause premature births and fetal losses. In a 3-year follow-up study, Pop et al. detected significantly lower mental and motor scores in babies aged

1–2 years, born to pregnant women who had hypothyroidism in the first trimester [10]. In this study, the Apgar scores were lower in the overt hypothyroid group, but this did not have any statistical significance. Since our cases with hypothyroidism were limited in number, we were not able to comment on its relationship with perinatal outcomes. The incidence of hyperthyroidism in pregnant women is 0.2%. However, in our study, the incidence of hyperthyroidism was 2.8% (n=31). It has been stated that the most common cause of hyperthyroidism in pregnancy is gestational transient thyrotoxicosis (GTT), which is 10 times more frequent than Graves’ disease. GTT is not an autoimmune condition and may occur during a normal pregnancy as well. This condition is more frequently encountered in twin pregnancies and it is typically associated with hyperemesis gravidarum. Herein, hyperthyroidism is less dominant than Graves’ disease and is more common in the 1st trimester [14]. Antithyroid drugs are used to treat hyperthyroidism during pregnancy [11]. In this study, perinatal outcomes of cases with hyperthyroidism were similar to the other groups. The rate of cesarean sections was largely similar between the groups; it was lower only in the subclinical hypothyroid group. Since our clinic is a reference center, higher rates of cesarean delivery were also detected in the normal group. As a consensus, screening for thyroid dysfunction in pregnancy is performed during the follow-up of high risk women by assessing symptomatic thyroid dysfunction or recording a history of thyroid disease, autoimmune disease [2], pregnant women carrying high risk for thyroid diseases, and for the diagnosis of subclinical thyroid diseases, [15]. In our study, the TSH elevation was found to

Dulek et al., The prevalence of thyroid dysfunction and its relationship with perinatal outcomes in pregnant women

be positively correlated with maternal age (p<0.05). This finding is consistent with the literature. According to the Association of Endocrine Metabolism Thyroid Diseases Diagnosis and Treatment Guidelines [15], it is recommended that women older than 35 years be screened for TSH every 5 years. We have seen that the results of the studies on this subject in our country vary [16–19]. In their studies including the 1st and 2nd trimesters, Temur et al. [16] detected the upper limit of TSH as 5.6 mμ/L and the frequency of hypothyroidism as 3.6%. In these studies, any difference between pregnant women with and without the risk factors for thyroid dysfunction. They also insistently emphasized the need for screening all pregnant women. The prevalence of hypo- and hyperthyroidism according to some studies and regions of our country is given in Table 3 [16–19]. According to these results, in our country, we see that the cut-off values are not standardized in the diagnosis of hypo- and hyperthyroidism. Similar cut-off values were used in a study by Guzel et al. [19] in Istanbul. Although the prevalence of hypothyroidism among their patients was similar to our study, the prevalence of hyperthyroidism in their study was higher. However, these researchers included all the pregnancy trimesters in the study. In our study, thyroid dysfunction was found in 76 patients (13.2%) and the prevalence of hyperthyroidism was 2.8%. Similar to our study, Donmez et al. performed the study in the 3rd trimester in the metropolitan city of Istanbul, but their reference range of normal thyroid values were different from ours [20]. When we look at the studies performed in our country, we see that different cut-off values were used for TFTs, and they were performed during different gestational weeks. In the light of all these results, we think that countrywide prospective studies where standard cut-off values are used will give more valuable results about the prevalence and perinatal outcomes of thyroid diseases during pregnancy. The imitations of this study include its retrospective design, the evaluation of TFTs in the last trimester, and the missing anti-TPO data in some pregnant women. In addition, TFTs were requested from pregnant women in primary care. Since all pregnant women are registered in family medicine, we think that it is more appropriate to include primary care data when conducting prevalence studies. In conclusion, thyroid diseases that develop during pregnancy can be treated if a diagnosis is made, and the

271

treatment may yield satisfactory results. Otherwise, it is highly probable that this disease may have serious health consequences for both the mother and the newborn. According to our findings; the prevalence of thyroid dysfunction in the third trimester was 13.2% in the pregnant population. No adverse effects of subclinical hypothyroidism and hyperthyroidism were detected on the perinatal outcomes. Since TSH increase is correlated with age, we can recommend routine screening, especially for pregnant women over 35 years of age. Regarding the participation of those under the age of 35 and those who do not carry risk factors, we believe that a healthy outcome can be achieved after large-scale data is collected. Ethics Committee Approval: Haydarpasa Numune Training and Research Hospital Clinical Research Ethics Committee HNEAH-KAEK 2016/79 (HNEAH KAEK 2016/KK/79) date: 27.09.2016, decision number: 2479. 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. Authorship Contributions: Concept – HD, FV; Design – FV; Supervision – FV; Materials – HD; Data collection and/or processing – HD, SZ; Analysis and/or interpretation – FV; Writing – HD; Critical review – NA.

REFERENCES 1. Negro R, Mestman JH. Thyroid disease in pregnancy. Best Pract Res Clin Endocrinol Metab 2011;25:927–43. 2. American College of Obstetrics and Gynecology. ACOG practice bulletin. Thyroid disease in pregnancy. Number 37, August 2002. American College of Obstetrics and Gynecology. Int J Gynaecol Obstet 2002;79:171–80. 3. Soldin OP, Tractenberg RE, Hollowell JG, Jonklaas J, Janicic N, Soldin SJ. Trimester-specific changes in maternal thyroid hormone, thyrotropin, and thyroglobulin concentrations during gestation: trends and associations across trimesters in iodine sufficiency. Thyroid 2004;14:1084–90. 4. Stagnaro-Green A, Abalovich M, Alexander E, Azizi F, Mestman J, Negro R, et al; American Thyroid Association Taskforce on Thyroid Disease During Pregnancy and Postpartum. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid 2011;21:1081– 125. 5. Haddow JE, McClain MR, Lambert-Messerlian G, Palomaki GE, Canick JA, Cleary-Goldman J, et al; First and Second Trimester Evaluation of Risk for Fetal Aneuploidy Research Consortium. Variability in thyroid-stimulating hormone suppression by human chorionic [corrected] gonadotropin during early pregnancy. J Clin Endocrinol Metab 2008;93:3341–7. 6. Baloch Z, Carayon P, Conte-Devolx B, Demers LM, Feldt-Rasmussen U, Henry JF, et al; Guidelines Committee, National Academy of Clin-

272 ical Biochemistry. Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid 2003;13:3–126. 7. Susan J, Mandel SC, David SC. The use of antithyroid drugs in pregnancy and lactation. J Clin Endocrinol Metab 2001;86(6):2354–9. 8. Tekin Bayoğlu Y, Güven Güvendağ E. Thyroid Disease in Pregnancy and Neonatal Outcome. Jinekoloji-Obstetrik ve Neonatoloji Tıp Dergisi 2014;4:150–3. 9. Casey BM, Leveno KJ. Thyroid disease in pregnancy. Obstet Gynecol 2006;108:1283–92. 10. Pop VJ, Brouwers EP, Vader HL, Vulsma T, van Baar AL, de Vijlder JJ. Maternal hypothyroxinaemia during early pregnancy and subsequent child development: a 3-year follow-up study. Clin Endocrinol (Oxf ) 2003;59:282–8. 11. Soldin OP. Thyroid function testing in pregnancy and thyroid disease: trimester-specific referenceintervals. Ther Drug Monit 2006;28:8–11. 12. Lao TT. Thyroid disorders in pregnancy. Curr Opin Obstet Gynecol 2005;17:123–7. 13. Gür E, Ercan O, Can G, Akkuş S, Güzelöz S, Ciftcili S, et al. Prevalence and risk factors of iodine deficiency among schoolchildren. J Trop Pedi-

North Clin Istanb atr 2003;49:168–71. 14. Glinoer D. Management of hypo- and hyperthyroidism during pregnancy. Growth Horm IGF Res 2003;13 Suppl A:S45–54. 15. American Thyroid Association. Consensus Statement #2: American Thyroid Association statement on early maternal thyroidal insufficiency: recognition, clinical management and research directions. Thyroid 2005;15:77–9. 16. Temur M, Cengiz H, Arıcı B, Yaşar L, Özdemir İA. Detection of Thyroid Dysfunction in Early Pregnancy. Gazi Med J 2012;23:6–9. 17. Karakurt F, Gümüş İnegöl İ, Kargılı A, Uz B, Keskin E, Köroğlu M. Gebe Hastalarımızda Tiroid Fonksiyon Testleri. Yeni Tıp Dergisi 2007;24:54 18. Bostancı MS, Taşkesen F. Thyroid dysfunction during pregnancy and evaluation of its results. J Clin Exp Invest 2011;2:196–201. 19. Güzel E, Sivri Aydın D, Çilesiz Göksedef B, Boran Birtan A. The incidence of thyroid dysfunction in pregnant women. Perinatal Journal 2015;23:96–100 20. Dönmez Kesim M, Aydın Y, Atış A, Şişli T. Thyroid function disturbances in third trimester pregnancy. Turkiye Klinikleri J Gynecol Obst 2005;15:132–6.

Orıgınal Article

EMERGENCY MEDICINE

North Clin Istanb

2019;6(3):273–278 doi: 10.14744/nci.2018.46548

How successful is “pleural sound sign” in the identification of pneumothorax? Saniye Goknil Calik,1 Zerrin Defne Dundar,3

Mustafa Calik,2

Sadik Girisgin,3

Osman Karaoglan,4

Mehmet Ergin3

Department of Emergency and First Aid, KTO Karatay University Institute of Medical Sciences, Konya, Turkey

Department of Thoracic Surgery, Health Sciences University, Konya Training and Research Hospital, Konya, Turkey

Department of Emergency Medicine, Necmettin Erbakan University Meram Faculty of Medicine, Konya, Turkey

Department of Emergency Medicine, Konya Numune State Hospital, Konya, Turkey

ABSTRACT OBJECTIVE: In the present study, in thorax ultrasonography (USG) Doppler images obtained from cases with occult pneumothorax, we investigated the status of pulsatile pleural sounds over the pleural line and called these as the pleural sound sign (PSS). The purpose of the present study was to identify the efficacy of the proposed PSS in diagnosing pneumothorax and to compare it with the other USG findings including the sliding lung sign (SLS) and seashore sign (SSS). METHODS: The present study included 66 consecutive patients who were referred to the emergency unit with a blunt trauma from October 2009 to January 2010 at a tertiary university hospital. RESULTS: Of the 66 patients, 34 were in the patient group, and 32 were in the control group. Males accounted for 66.7% (n=44) of the study population. In predicting pneumothorax, the areas under receiver operating characteristic (ROC) curves of PSSmax and PSSdifference were 0.989 and 0.990, respectively. While the sensitivity of the SLS was 88% and the sensitivity of the SSS was 56%, the specificities of the SLS and SSS were 100%. Based on our findings, accuracy ranking was as follows: PSSmax = PSSdifference > SLS > SSS. CONCLUSION: New applications of thorax USG are rapidly growing. Our findings have to be confirmed in a large patient series. PSS is not a novel method, but it enhanced the importance of USG in the diagnosis of pneumothorax. We can stipulate that it can replace thorax computed tomography imaging particularly for the diagnosis of occult pneumothoraxes. Keywords: Emergency medicine, chest; pleural sound sign; pneumothorax; ultrasonography.

Cite this article as: Goknil Calik S, Calik M, Girisgin S, Karaoglan O, Dundar ZD, Ergin M. How successful is “pleural sound sign” in the identification of pneumothorax? North Clin Istanb 2019;6(3):273–278.

rauma is the most common cause of death and disability among people younger than 45 years. Mortality prevention begins with rapid diagnosis of lifethreatening trauma or traumas and their simultaneous treatment [1]. Pneumothorax, defined as the collection of air in the pleural cavity, is the second most common complication after rib fractures that are observed particularly due to chest trauma. It is a significant cause of

mortality and morbidity [2]. It is often diagnosed using lung X-rays, which provide limited information, and thorax computed tomography (CT) scan is used for more detailed assessment. Among patients with a history of trauma, whose anteroposterior lung X-rays did not show pneumothorax, 2%–15% actually had pneumothorax as demonstrated by CT scans [3]. This is particularly true in the presence of small and anterior-basal pneumotho-

Received: October 11, 2017 Accepted: December 20, 2018 Online: July 30, 2019 Correspondence: Dr. Mustafa CALIK. Saglik Bilimleri Universitesi, Konya Egitim ve Arastırma Hastanesi, Gogus Cerrahisi Klinigi, Konya, Turkey. Tel: +90 505 858 48 98 e-mail: drmcalik@hotmail.com © Copyright 2019 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

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raxes, which are called occult pneumothorax. Both imaging modalities have limitations, such as the time required for the transfer of patient and completion of the scan, radiation exposure, and increased healthcare costs. Nevertheless, they are invaluable for the assessment of lung pathologies [4]. CT is even considered to be the gold standard for the diagnosis of pneumothorax in patients who can undergo a CT scan [5, 6]. It is not easy to assess trauma patients in the emergency departments. Ultrasonography (USG) is an ideal method for the initial assessment of trauma patients since it can show bleedings, particularly in the pericardial, pleural, and peritoneal regions. Since 1971, it has been used to evaluate the free peritoneal fluids. However, its use for the assessment of thorax began at a later time, in 1986, and interestingly, it was first used on horses. A year later, it was used by Wernecke et al. in humans for the diagnosis of pneumothorax [1, 7]. As gas and/or air prevent the transmission of ultrasound waves, the lung parenchyma cannot be seen beyond the pleura. However, in case of acute lung injury, parenchyma and ventilation of the lungs can be almost fully and correctly evaluated by USG. Actually, the space between the two pleura is a real gap. It is between 0.2 and 0.4 mm and is hard to visualize with ordinary USG devices. When the probe position is vertical to both intercostal spaces, only the parietal pleura appears as a net echogenic line due to acoustic reflections. A hyperechoic and sliding line moving forward and backward during breathing and exhalation is visible 5 mm below the rib line and is called the “pleural line” (Fig. 1, white arrow). The real-time motion image of this line is called the “sliding lung sign” (SLS). In the M-mode (time–motion mode), the immobile pleural line and the homogeneous granular appearance beneath it is called the “seashore sign” (SSS). The absence of this movement is observed in pneumothorax. In the M-mode, this absence of motion can be detected and called as the “barcode or stratosphere sign” [8]. These findings can be demonstrated by M-mode, B-mode, or both modes in USG. The findings used to diagnose pneumothorax include SLS, lung point sign, SSS, and “barcode sign/stratosphere sign” [8–11]. In the present study, in thorax USG Doppler images obtained from cases with occult pneumothorax, we investigated the status of pulsatile pleural sounds over the pleural line (Fig. 1) and called these as the pleural sound sign (PSS). PSS’s operating logic is very simple. Although similar pulsatile sounds can also be recorded from the lung tissue below the pleural line, the intensity

North Clin Istanb

Figure 1. Doppler can collect pulsatile pleural sounds in the pleural lines during inspirations and expirations. White arrow indicates the PSS in the pleural line.

Figure 2. In addition, similar pulsatile sounds can be identified in the lungs below the pleural line that was marked with a white arrow.

of the sound decreases as the distance from the pleural line increases (Fig. 2). This sound is weak and continuous in subcutaneous tissues, contrary to the PSS (Fig. 3). We believe that the PSS can be an objective version of the findings obtained in the SLS since we performed an objective measurement [8]. The purpose of the present study was to identify the efficacy of the proposed PSS in diagnosing pneumothorax and to compare it with the other USG findings including the SLS and SSS. MATERIALS AND METHODS The present study was conducted in the emergency unit of the emergency medicine department of a tertiary university hospital between October 1, 2009 and January

Goknil Calik et al., How successful is “pleural sound sign” in the identification of pneumothorax?

Figure 3. On the other hand, the voice’s strength decreases as it moves away from the pleural line (white arrow). This voice in the subcutaneous tissues is slight and permanent, as opposed to pulsatile pleural sounds.

31, 2010. The study was approved by the local ethics committee of a university (2010/047) and conducted in accordance with the principles of good clinical practice. Informed consent was obtained from all the participants in the study prior to the commencement of the research. Study Population The study included two groups: patient group and control group. Patients aged ≥18 years who were referred to the emergency unit with a blunt trauma constituted the patient group. Patients who had a serious and lifethreatening pathology (serious hypoxia, serious tachypnea, tension pneumothorax, and open pneumothorax) and those who did not sign the informed consent form were excluded from the study. The control group included healthy subjects aged ≥18 years who provided consent for participation in the study. Study Protocol Subjects included in the patient and control groups underwent pleural USG examination performed by independent emergency care specialists. To detect pneumothorax, these examinations involved pleural USG of four different regions of the thorax (from the left and right midclavicular lines of the third or the fourth intercostal space and from between the mid-axillary and posterior axillary lines of the fourth or the fifth intercostal space). USG was performed by emergency care physicians who had received emergency USG training and had been per-

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forming emergency USG for at least 2 years. Particular attention was given not to interrupt the clinical followup of the patients during the USG procedure. PSS, SLS, and SSS based on USG were recorded for both groups. USG was performed using 3–12 MHz linear probe of a sonography device (Philips EnVisor C HD M2540A; Bothell, WA, USA). The amplitude of the sound waves observed in duplex Doppler mode was measured in millimeters (mm) and used for the objective estimation of the PSS. The distance between the starting point of the measured sound wave and the basal line was defined as PSSmin, and the distance between the peak value of the sound wave and the basal line was defined as PSSmax. PSS difference was accepted as the numeric difference between PSSmax and PSSmin (PSS difference = PSS max − PSS min). Subjects in the patient group whose thorax CT confirmed pneumothorax were included into the examinations for comparison to the control group. Since pneumothorax pathology is isolated to a single region of the hemithorax and decreased PSS can only be detected at the region with pneumothorax, the lowest PSS values measured in the patient group were taken into account. Since there are no normal values defined for the PSS in the literature, the control group was selected among healthy volunteers to estimate the normal interval. It is an expected outcome that all measurements obtained from different regions of the thorax will be similar in a healthy individual without a pleural pathology. The mean value of PSS measurements obtained from four regions of the thorax was taken into account in the control group to minimize the errors associated with the device and measurement methods. The success of the SLS, SSS, and PSS in diagnosing pneumothorax was compared between the patient and control groups. Statistical Analysis Receiver operating characteristic (ROC) curves were constructed to detect the power of PSSmax and PSSdifference parameters in estimating pneumothorax (Fig. 4). Cutoff values were defined for all parameters using the Youden index (sensitivity + specificity − 1). Based on defined cutoff values, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy rates were calculated for all parameters, along with 95% confidence intervals (CIs).

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Sensitivity

0.8 0.6 0.4 PSSmax PSS difference Reference line

0.2 0.0 0.0

0.2

0.4 0.6 1 - Specificity

0.8

1.0

Figure 4. Receiver operating characteristic curves comparing pleural sound sign maximum and difference with respect to predicting pneumothorax. Cross-tables were drawn for the patient and control groups to determine the diagnostic value of the SLS and SSS. The sensitivity, specificity, PPV, NPV, and accuracy rates were calculated separately for both parameters, along with 95% CIs. RESULTS A total of 66 consecutive cases were included in the study. Of the 66 patients, 34 were in the patient group, and 32 were in the control group. Males accounted for 66.7% (n=44) of the study population. The median ages were 48 (26–80) years in the patient group and 40 years in the control group. Age distribution was not significantly different between the study groups. Male/female ratios were 52.9% (n=18)/47.1% (n=16) in the patient group and 68.7% (n=22)/31.1% (n=10) in the control group. Gender distribution was not significantly different between the study groups (p=0.189). The area under

ROC curve for PSSmax in predicting pneumothorax was 0.989 (95% CI 0.971–1.006, p<0.001). The optimum cutoff value was found to be 9.25. For this cutoff value, sensitivity was 97%, specificity was 94%, PPV was 94%, and NPV was 97% (Table 1 and Fig. 4). The area under ROC curve for PSSdifference in predicting pneumothorax was 0.990 (95% CI 0.974–1.005, p < 0.001). The optimum cutoff value was calculated as 6.5. For this cutoff value, sensitivity was 97%, specificity was 94%, PPV was 94%, and NPV was 97% (Table 1 and Fig. 4). When the patient and control groups were compared for the SLS, its sensitivity was 88%, specificity was 100%, PPV was 100%, and NPV was 89% (Table 1). When the patient and control groups were compared for the SSS, its sensitivity was 56%, specificity was 100%, PPV was 100%, and NPV was 68% (Table 1). Based on our findings, accuracy ranking was as follows: PSSmax = PSSdifference > SLS > SSS (Table 1). DISCUSSION Lichtenstein et al. demonstrated the ability of USG in detecting pneumothorax in their studies performed at different time points using the SLS, comet tail, lung point, or various combinations of these parameters. While one of these studies reported that the SLS had 95.3% sensitivity, 91.1% specificity, 100% NPV, and 87% PPV in predicting pneumothorax, these figures were updated as 100% sensitivity, 78% specificity, 100% NPV, and 40% PPV in a later study [5, 6, 12, 13]. Other studies in the literature also highlighted the NPV of the SLS, at rates ranging between 96.3% and 100%. In other words, the presence of the SLS in a patient at supine position effectively eliminates the diagnosis of pneumothorax, independent of its traumatic or non-traumatic origin [14, 15]. On the other hand, the absence of the SLS does not always mean that a patient has a pneumothorax.

Table 1. Performances of parameters in terms of predicting pneumothorax PSS, max PSS, difference SLS SSS

Sens

Spes

PPV

97 (87–100) 94 (84–97) 94 (85–97) 97 (87–100) 94 (84–97) 94 (85–97) 88 (79–88) 100 (89–100) 100 (89–100) 56 (46–56) 100 (89–100) 100 (82–100)

NPV 97 97 89 68

(86–99) (86–99) (80–89) (61–68)

Accuracy 96 96 94 77

(86–98) (86–98) (84–94) (67–77)

LR+ 15.53 (5.29–30.30) 15.53 (5.29–30.30) inf (7.85–inf) inf (4.26–inf)

PPV: Positive predictive value; NPV: Negative predictive value; PSS: Pleural sliding sound; SLS: Sliding lung sign; SSS: Seashore sign.

LR0.03 0.03 0.12 0.44

(0.00–0.15) (0.00–0.15) (0.12–0.24) (0.44–0.61)

Goknil Calik et al., How successful is “pleural sound sign” in the identification of pneumothorax?

Severe chronic obstructive pulmonary disease and bullous diseases may impair the SLS in some regions of the lungs and mimic pneumothorax in USG. Additionally, a history of pneumonectomy, pulmonary fibrosis, high-frequency ventilation, pulmonary fibrosis, and adult respiratory distress syndrome complicate diagnosing pneumothorax by USG [16, 17]. Based on the patient population, its specificity varies between 60% and 99%. While this rate is higher in the overall population, it was found to be lower among intensive care patients and patients with acute respiratory distress syndrome [5, 6, 14, 18]. While studies in the literature underline that the absence of the SLS is not specific to pneumothorax diagnosis, its combination with other USG findings was suggested to increase the possibility of making a correct diagnosis [8–10, 13]. In the present study, the specificity and PPV of the SLS were found to be 100%. Contrary to the previous studies in the literature, the control group consisting of healthy subjects was used in the present study to define a normal range for the PSS. Therefore, the specificity and PPV values in the present study were higher than those in previous studies. SLS is the dynamic normal sign on the pleural line. M-mode can be used to detect more objective signs of pleural movements. In M-mode, the presence of pleural movement is demonstrated by the SSS. If the SLS is lost, a characteristic image in the form of a “stratosphere sign” can be seen in the M-mode setting [19]. In our literature search, we did not encounter any study reporting the specificity and sensitivity values for the SSS. In the present study, both specificity and PPV were found to be 100%. However, compared with all other signs, SSS had the lowest accuracy. For the diagnosis of pneumothorax, SLS and SSS can only be assessed as present or absent. Both signs depend on the operator. Cunningham et al. recommended the use of power color Doppler ultrasound for diagnosing pneumothorax to facilitate documentation and interpretation and to reduce operator dependency. They reported that this approach provides a real-time assessment based on a simple sonographic image, instead of recording the dynamic dislocation process of pleural leaflets for a long period of the respiratory cycle [20]. However, in this technique, even the gain adjustment of colored Doppler can result in misinterpretation of an assessment. In the present study, we detected pulsatile pleural sounds over the pleural line by using Doppler property of the ultra-

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sound device, and we used numeric and objective values to measure the amplitude of the sound wave over the basal line [11]. Moreover, we decreased the problems originating from the operator or device settings by making the pleural findings of pneumothorax measurable by numeric values. In the present study, we demonstrated that PSSmax and PSSdifference outcomes are more sensitive than SLS and SSS and have similar specificity to SLS and SSS in diagnosing pneumothorax. Moreover, its accuracy in predicting pneumothorax diagnosis was found to be higher than SLS and SSS. Although we determined a cutoff value for PSS measurements in the present study, this study alone is not sufficient to make any comments on the inter-individual variability of PSS measurements. However, our findings indicated that the PSS based on the measurements obtained from four regions of the thorax was lower on the side with pneumothorax than on the other sides. Even the assessment of intra-individual variability in patients with suspected pneumothorax can provide valuable clinical information. We believe that the findings of the present study should be confirmed in further studies performed by independent authors. We are also conducting new studies to investigate the efficacy of the PSS in diagnosing pneumothorax in non-traumatic and intensive care patients. As in any work, there are some limitations to this work in particular, because of the prospective nature of the research. Owing to ethical concerns, the control group consisted of patients for whom CT scans were indicated. This might have led to selection bias. Several studies in the literature reported the benefits of USG, particularly in the presence of traumatic pneumothoraxes. A recent meta-analysis showed that bedside USG performed by clinicians has high sensitivity and similar specificity compared with lung imaging for the diagnosis of pneumothorax. Another aspect that was highlighted was the experience of clinicians in performing USG. Conclusion By its nature, pneumothorax should be diagnosed quickly and treated adequately. New applications of thorax USG are rapidly growing [4]. PSS is one of those new applications, and although it has similar specificity for the diagnosis of pneumothorax compared with the other methods, it has higher accuracy and sensitivity. USG is important as it can be performed bedside by the clinician in the absence of an additional specialist, and as it allows

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simultaneous diagnosis and treatment without interruption of resuscitation and without transferring patients to other services, such as the radiology unit. Another important aspect of the PSS is that it is based on objective values, and thus it overcomes the subjectivity associated with the clinician’s inexperience. Our findings have to be confirmed in a large patient series. PSS is not a novel method, but it enhanced the importance of USG in the diagnosis of pneumothorax. We can stipulate that it can replace thorax CT imaging particularly for the diagnosis of occult pneumothoraxes in critically ill patients who cannot be transferred for diagnosis, such as emergency services and intensive care units, or whose general condition does not permit transfer. Ethics Committee Approval: This study was approved by the Ethics Committee of the Necmettin Erbakan University (2010/047). 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. Authorship Contributions: Concept – SGC, MC, SG, OK, ZDD, ME; Design – SGC, MC, SG, OK, ZDD, ME; Supervision – SGC, MC, SG, OK, ZDD, ME; Materials – SGC, MC, SG, OK, ZDD, ME; Data collection and/or processing – SGC, MC, SG, OK, ZDD, ME; Analysis and/ or interpretation – SGC, MC, SG; Writing – SGC, MC, SG; Critical review – SGC, MC, SG.

REFERENCES 1. Wongwaisayawan S, Suwannanon R, Prachanukool T, Sricharoen P, Saksobhavivat N, Kaewlai R. Trauma Ultrasound. Ultrasound Med Biol 2015;41:2543–61. 2. Yadav K, Jalili M, Zehtabchi S. Management of traumatic occult pneumothorax. Resuscitation 2010;81:1063–8. 3. Llaquet Bayo H, Montmany Vioque S, Rebasa P, Navarro Soto S. Results of conservative treatment in patients with occult pneumothorax. [Article in Spanish]. Cir Esp 2016;94:232–6. 4. Moghekar A, Mehta A. Thoracic ultrasound: Picture worth a thousand sounds. Ann Thorac Med 2014;9:185–6.

North Clin Istanb 5. Lichtenstein DA, Mezière G, Lascols N, Biderman P, Courret JP, Gepner A, et al. Ultrasound diagnosis of occult pneumothorax. Crit Care Med 2005;33:1231–8. 6. Lichtenstein DA, Menu Y. A bedside ultrasound sign ruling out pneumothorax in the critically ill. Lung sliding. Chest 1995;108:1345–8. 7. Chan SS. Emergency bedside ultrasound to detect pneumothorax. Acad Emerg Med 2003;10:91–4. 8. Ergin M, Girişgin AS, Karaoğlan O, Çalık G, Koçak S, Cander B. A new development in emergency department ultrasonography: Pleural Sliding Sound (PSS). Pak J Med Sci 2012;28:948–51. 9. Kline JP, Dionisio D, Sullivan K, Early T, Wolf J, Kline D. Detection of pneumothorax with ultrasound. AANA J 2013;81:265–71. 10. Husain LF, Hagopian L, Wayman D, Baker WE, Carmody KA. Sonographic diagnosis of pneumothorax. J Emerg Trauma Shock 2012;5:76–81. 11. Lichtenstein DA, Mezière GA, Lagoueyte JF, Biderman P, Goldstein I, Gepner A. A-lines and B-lines: lung ultrasound as a bedside tool for predicting pulmonary artery occlusion pressure in the critically ill. Chest 2009;136:1014–20. 12. Schiller O, Schonfeld T, Yaniv I, Stein J, Kadmon G, Nahum E. Bi-level positive airway pressure ventilation in pediatric oncology patients with acute respiratory failure. J Intensive Care Med 2009;24:383–8. 13. Lichtenstein D, Mezière G, Biderman P, Gepner A. The “lung point”: an ultrasound sign specific to pneumothorax. Intensive Care Med 2000;26:1434–40. 14. Blaivas M, Lyon M, Duggal S. A prospective comparison of supine chest radiography and bedside ultrasound for the diagnosis of traumatic pneumothorax. Acad Emerg Med 2005;12:844–9. 15. Zhang M, Liu ZH, Yang JX, Gan JX, Xu SW, You XD, et al. Rapid detection of pneumothorax by ultrasonography in patients with multiple trauma. Crit Care 2006;10:R112. 16. Gardelli G, Feletti F, Nanni A, Mughetti M, Piraccini A, Zompatori M. Chest ultrasonography in the ICU. Respir Care 2012;57:773–81. 17. Murphy M, Nagdev A, Sisson C. Lack of lung sliding on ultrasound does not always indicate a pneumothorax. Resuscitation 2008;77:270. 18. De Luca C, Valentino M, Rimondi MR, Branchini M, Baleni MC, Barozzi L. Use of chest sonography in acute-care radiology(). J Ultrasound 2008;11:125–34. 19. Lichtenstein DA. Ultrasound in the management of thoracic disease. Crit Care Med 2007;35:S250–61. 20. Cunningham J, Kirkpatrick AW, Nicolaou S, Liu D, Hamilton DR, Lawless B, et al. Enhanced recognition of “lung sliding” with power color Doppler imaging in the diagnosis of pneumothorax. J Trauma 2002;52:769–71.

Orıgınal Article

CARDIAC SURGERY

North Clin Istanb

2019;6(3):279–283 doi: 10.14744/nci.2018.76992

Comparison of intraoperative ultrasonography guidance with an open surgical method for venous port catheter placement in chemotherapy Ozan Onur Balkanay,1,2

Suleyman Demiryas3

Department of Cardiovascular Surgery, Manisa Government Hospital, Manisa, Turkey

Department of Cardiovascular Surgery, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, Istanbul, Turkey

Department of General Surgery, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, Istanbul, Turkey

ABSTRACT OBJECTIVE: One of the leading venous access methods in chemotherapy is the use of a venous port catheter (VPC). An open surgical or ultrasound-guided technique can be performed. In our study, the VPC placement via both of these techniques was compared. METHODS: A total of 180 consecutive patients who underwent the VPC placement procedure either via the open or ultrasound-guided methods in two centers between January 2014 and January 2016 were included in the study. Patients’ data were reviewed retrospectively. Groups were compared in terms of intervention-related complication rates, a total procedure time, and the requirement of control imaging with ionizing radiation. RESULTS: The mean total procedure time was significantly shorter (19.5±4.6 min, 46.7±19.6 min, p<0.001) in the ultrasound-guided group than the open method. The rate of catheter malposition was significantly less in the ultrasound-guided group than in the open group (p<0.001). The need for per-operative imaging with ionizing radiation and the need of reversion in the preferred technique were not observed in the ultrasound-guided group, whereas in the open group, they were observed in 90 (100%) and 6 (6.7%) patients, respectively (p<0.001, p=0.01). CONCLUSION: Intraoperative ultrasound guidance for the VPC placement shortens the processing time and eliminates the need for routine imaging methods that require the use of ionizing radiation. In accordance with the current guidelines recommendations, intraoperative ultrasonography should be preferred as much as possible during the VPC placement. However, the need for the surgical teams in centers to maintain the necessary educational processes for both techniques should not be overlooked. Keywords: Central; interventional, ultrasound; operative procedures; venous catheterization.

Cite this article as: Balkanay OO, Demiryas S. Comparison of intraoperative ultrasonography guidance with an open surgical method for venous port catheter placement in chemotherapy. North Clin Istanb 2019;6(3):279–283.

n patients with malignancy, there is an increasing need for a better venous access for blood sampling in the routine control, parenteral fluid and blood products administration, and chemotherapy applications [1]. One of the leading methods in the venous access for chemotherapy is the placement of a venous port catheter (VPC) [2]. VPC systems,

which are used for these purposes, allow multiple punctures [1]. Open surgical or ultrasound-guided techniques can be both performed in this procedure [1–3]. In our study, patients who were planned to undergo chemotherapy and underwent the VPC placement either via the open surgical or the ultrasound-guided technique were compared.

Received: March 05, 2018 Accepted: November 12, 2018 Online: November 28, 2018 Correspondence: Dr. Ozan Onur BALKANAY. Istanbul Universitesi-Cerrahpasa, Cerrahpasa Tip Fakultesi, Kalp ve Damar Cerrahisi Anabilim Dalı, Cerrahpasa, 34098 Fatih, Istanbul, Turkey. Tel: +90 212 414 30 00 - 23129 e-mail: balkanay@doctor.com © Copyright 2019 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

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MATERIALS AND METHODS A total of 180 consecutive patients who underwent the VPC placement for chemotherapy either via an open surgical method or with an ultrasound-guided technique in two centers between January 2014 and January 2016 were included in the study after the informed consent was obtained. Study was approved by the local ethics committee (approval number: 83045809-604.01.02A-25). Both techniques were used in both centers. Patients’ data were reviewed, and the study was conducted retrospectively in accordance with the principles of the Helsinki Declaration. Statistical comparisons were made between the two groups in terms of demographic variables, intervention-related complication rates, a total procedure time, and the requirement of control imaging with ionizing radiation. A routine pre-interventional ultrasound evaluation was performed for the puncture/ surgical intervention sites. All patients were monitored via ECG tracing, pulse oximetry, and blood pressure measurements during the procedure. During the ultrasound-guided technique, an ultrasound probe was covered with a sterile sheath and positioned in the surgical field. Both the ipsilateral and contralateral sites of the subclavian and internal jugular vein regions were prepared and draped for the ultrasound evaluation for malposition. In addition, if the advancement of the guide wire failed, other sites were ready in the surgical field. During the procedure, 1% lidocaine hydrochloride was used for local anesthesia. All ultrasound-guided punctures were made in the right internal jugular vein site. The guide wire image in the venous lumen was evaluated at the puncture site as well as other contralateral and ipsilateral venous regions. In the ultrasound-guided technique, the length of the catheter line was measured externally and individually in a patientbased manner. Then, the catheter line was propagated to the puncture sheath via the right internal jugular vein. The skin incision in the delto-pectoral sulcus region was made, and a pocket for the main body of VPC was prepared in both techniques. In the ultrasound-guided technique, the proximal part of the catheter line was passed through a curved C-shaped tunnel to reach the delto-pectoral pocket region. The open surgical technique included the exploration of the cephalic vein and the placement of the catheter line via cephalic vein. Routine X-ray imaging control was used in the open surgical technique for the validation of the catheter posi-

North Clin Istanb

tion. In addition, the length of the catheter line was determined using this control imaging in the open surgical technique as well. The connection between the line and the main body was then made, and the main body of the VPC was placed into the delto-pectoral pocket in both techniques. Stay sutures were used to fix the VPC main body. The VPC was controlled via blood aspiration, and then main body and catheter line were washed out with 10 mL of saline solution, which included 50 IU/mL standardized heparin. Statistical Analysis Categorical variables were expressed as the number (percentage) and continuous variables as the mean±standard deviation. Categorical variables were compared using the chi-squared test and Fisher’s exact test, and continuous variables using Student’s t-test. The p-value of <0.05 was considered statistically significant. The IBM SPSS software package version 21.0 (SPSS, Chicago, IL, USA) was used for statistical analysis. RESULTS There were 90 patients in both groups. The mean age of all patients was 58.7±11.9 years. Sixty-nine patients (38.3%) were female. There were no significant differences between the two groups in terms of demographic data such as age and gender (Table 1). The mean duration of the intervention for all patients was 33.1±19.7 minutes. The mean total procedure time was significantly shorter (19.5±4.6 min, 46.7±19.6 min) (p﹤0.001) in the procedures performed with the ultrasound-guided technique than the open surgical technique (Table 2). The rate of catheter malposition was significantly less in the ultrasound-guided technique group than in the open surgical technique group (0 [0%], 34 [37.8%], respectively) (p﹤0.001). All catheter malpositions were corrected under the guidance of fluoroscopy in the open

Table 1. Demographic variables Variable Age (years) mean±SD Gender (female) n (%)

OST (n=90)

UGT (n=90)

57.6±12.4 35 (38.9)

59.8±11.3 34 (37.8)

0.22 0.88

OST: Open surgical technique; UGT: Ultrasound guided technique; SD: Standard deviation.

Balkanay et al., Comparison of ultrasonography guidance with open method for venous port

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Table 2. Intervention-related variables Variable

OST (n=90)

Total number of vein punctures (mean±SD) Duration of the intervention/surgery (minutes) (mean±SD) Need of reversion in the preferred technique* Control imaging including ionizing radiation Complications (total) Arterial puncture External bleeding Local hematoma Pneumothorax Catheter malpositioning Early catheter dysfunction

– 46.7±19.6 6 6.7 90 100 39 43.3 0 0 2 2.2 2 2.2 1 1.1 34 37.8 0 0

UGT (n=90) n

1.1±0.3 19.5±4.6 0 0 0 0 1 1.1 0 0 0 0 1 1.1 0 0 0 0 0 0

– <0.001 0.01 <0.001 <0.001 1 0.16 0.56 0.32 <0.001 1

*: Reversion to open surgical technique in the failure of the ultrasound guided technique or reversion to the ultrasound guided technique in the failure of the open surgical technique. OST: Open surgical technique; UGT: Ultrasound guided technique; SD: Standard deviation.

surgical technique. The total rate of complications except the catheter malposition for all patients was 6 of 180 (3.3%). The rates of arterial puncture, bleeding, local hematomas, pneumothorax, and early catheter dysfunction were similar for both groups (p > 0.05). Pneumothorax developed in one patient (1.1%) in the open surgical technique group. This patient had the need of reversion in the preferred technique and had multiple punctures by using an anatomical landmark technique in the right subclavian vein region. The need for per-operative imaging with ionizing radiation and the need of reversion in the preferred technique were not observed in the ultrasound-guided technique group, whereas in the open surgical technique group, they were observed in 90 patients (100%), and six patients (6.7%), respectively (p﹤0.001; p = 0.01). Among these six patients in whom the preferred techniques were reversed, four of them were catheterized in the right subclavian vein region and two of them in the right internal jugular vein region. DISCUSSION The total number of venous puncture requirements is increased for various reasons in patients with malignancy [1]. Therefore, the VPC placement can be a life-saving procedure for these patients. VPCs have a special membrane at their puncture site allowing multiple punctures [1]. There are two major techniques for the VPC place-

ment that have been previously described: an open surgical exploration technique and ultrasound-guided technique. It is a conventional method of placement of the VPC, which is considered to be the insertion of the port catheter line by exploration of the cephalic vein with the open surgical technique. The placement of the VPC by surgical exploration of the vein is considered to have a lower risk of damage to the adjacent arterial and neural structures than those using blind anatomical landmark puncture techniques. However, due to higher procedural success rates, the VPC placement with the subclavian or internal jugular vein puncture has begun [4, 5]. The risk of pneumothorax, hemothorax, arterial puncture, hematoma development, or catheter malposition is present during both VPC implantation techniques [6– 8]. To place the catheter in the proper position, imaging methods are frequently used for verification purposes. The most commonly used imaging methods are direct radiographic or fluoroscopic imaging with ionizing radiation. There are also additional methods including the ultrasound-guided technique used in the detection of complications such as the malposition of the catheter and pneumothorax [9]. It is currently not recommended to routinely use X-ray imaging methods for position confirmation during and after the VPC placement [10–13]. However, the use of X-ray imaging is recommended if a clinical suspicion suggests pneumothorax presence [1]. At this point, performing an open surgical procedure re-

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quires an imaging confirmation, even though it provides an advantage for catheter positioning. In addition, in the open surgical procedure, the position of the catheter line was determined during the confirmation with the use of the ionizing radiation imaging method, while the catheter length was determined individually by the patient-based external line measurement in ultrasound-guided procedures. In our study, all of 90 patients in the open surgical technique group needed per-operative imaging with ionizing radiation, while none of the patients needed it in the ultrasound-guided technique group (p﹤0.001). The main explanation of this major difference was about the procedure requirement. The approach in the surgical group included the advancement of the guide wire through the subclavian vein. This region had a high risk of malposition to the contralateral subclavian, as well as the ipsilateral internal jugular vein. Therefore, in the open surgical technique group, the position of the guide wire and the catheter usually had to be validated using intraoperative imaging with ionizing radiation. Furthermore, open surgical procedures can prolong the processing time. We found that the mean total procedure time was significantly shorter in the ultrasound-guided technique group (19.5±4.6 min) than in the open surgical technique group (46.7±19.6 min) (p﹤0.001). For this reason, the ultrasound-guided technique can be used more frequently nowadays with the distinct advantages for the placement of VPC for chemotherapy [14–19]. In addition, it was found to be safe and effective to place the line of the VPC systems in the right internal jugular vein with the ultrasound-guided technique [1]. Due to the continuity of the right internal jugular vein with the superior vena cava and right atrium, the possibility of catheter malposition is significantly reduced. Although there have been some studies describing the single-incision techniques for the VPC placement, complications including the arterial puncture, vein thrombosis, and a malpositioned guide wire were also described [20]. Contrary to these findings, we found no such complications in the ultrasound-guided technique via the right internal jugular vein. As in the case of the VPC placement, the use of ultrasonography in the central venous catheterization provides significant advantages both before and during the procedure [21]. The use of the ultrasound-guided technique may allow a faster confirmation of the catheter position [21, 22]. Catheter malposition has been reported in the cen-

North Clin Istanb

tral venous catheterizations in 2%–37% of cases [6, 23, 24]. Herein, the anatomic position, extension of the vein, and the presence of collateral veins in which the puncture is to be performed is important. In addition, distal vein site punctures carry a greater malposition risk than those performed from a more proximal vein. In terms of the anatomic position advantage, the use of the right internal jugular vein region instead of the subclavian vein comes out to the forefront [6, 25]. For these reasons, the right internal jugular vein region was preferred in all our ultrasound-guided procedures. In our study, we found that the rate of the catheter malposition was significantly less in the ultrasound-guided technique group than in the open surgical technique group (0 [0%], 34 [37.8%], respectively) (p﹤0.001). The development of pneumothorax is reported in 0.5%–3% of central venous catheterization procedures [10, 26]. The risk of developing pneumothorax has also been reported in punctures performed in the right internal jugular vein [14, 19]. More ratios than these series have been reported in the series where the subclavian vein puncture was preferred [25]. In our study, pneumothorax was developed in one patient (1.1%) in the open surgical technique group. This patient needed reversion in the preferred technique and had multiple punctures in the right subclavian vein region. At this point, the use of the blunt anatomical landmark technique, subclavian vein as puncture zone, and the need for multiple punctures are leading factors that increase the risk of pneumothorax development [1, 25, 26]. To reduce this risk, it was suggested that the ultrasoundguided technique should be preferred before and during the procedure and that the right internal jugular vein site should be preferred as the puncture region [1]. In parallel to these literature suggestions, in our study, it was shown that preferring the right internal jugular vein as the puncture region and performing the procedure with the ultrasound-guided technique could help to minimize possible risks. If the center has the facility, it is recommended to prefer ultrasound-guided procedures. It should be however kept in mind that explicit instructions must also be applied to complete the learning curve, which is necessary for open surgical intervention in emergencies, at all centers. On the other hand, the retrospective conduction and a small number of patients could be accepted as limitations to our study. However, the results of comparison of two different techniques could inspire further studies.

Balkanay et al., Comparison of ultrasonography guidance with open method for venous port

Conclusion The intraoperative ultrasound-guided technique for venous port catheter placement shortens the procedure time and eliminates the need for routine imaging methods that require the use of ionizing radiation. In accordance with the recommendations of the current guidelines, intraoperative ultrasonography should be preferred as much as possible during the VPC placement [27]. However, the need for the surgical teams in centers to maintain the necessary educational processes for both techniques should not be overlooked. Ethics Committee Approval: Istanbul University-Cerrahpasa, Cerrahpasa faculty of Medicine, the local ethics committee date/approval number: 2018/ 83045809-604.01.02-A-25. Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors have no proprietary or financial interest in any products used in this study. Authorship Contributions: Concept – OOB, SD; Design – OOB, SD; Supervision – OOB, SD; Materials – OOB, SD; Data collection and/or processing – OOB, SD; Analysis and/or interpretation – OOB, SD; Writing – OOB, SD; Critical review – OOB, SD.

REFERENCES 1. Miccini M, Cassini D, Gregori M, Gazzanelli S, Cassibba S, Biacchi D. Ultrasound-Guided Placement of Central Venous Port Systems via the Right InternalJugular Vein: Are Chest X-Ray and/or Fluoroscopy Needed to Confirm the CorrectPlacement of the Device? World J Surg 2016;40:2353–8. 2. Niederhuber JE, Ensminger W, Gyves JW, Liepman M, Doan K, Cozzi E. Totally implanted venous and arterial access system to replace external catheters in cancer treatment. Surgery 1982;92:706–12. 3. de Gregorio MA, Miguelena JM, Fernández JA, de Gregorio C, Tres A, Alfonso ER. Subcutaneous ports in the radiology suite: an effective and safe procedure for care in cancer patients. Eur Radiol 1996;6:748–52. 4. Seiler CM, Frohlich BE, Dorsam UJ, Kienle P, Buchler MW, Knaebel HP. Surgical technique for totally implantable access ports (TIAP) needs improvement: a multivariate analysis of 400 patients. J Surg Oncol 2006;93:24–9. 5. McGee WT, Ackerman BL, Rouben LR, Prasad VM, Bandi V, Mallory DL. Accurate placement of central venous catheters: a prospective, randomized, multicenter trial. Crit Care Med 1993;21:1118–23. 6. Yilmazlar A, Bilgin H, Korfali G, Eren A, Ozkan U. Complications of 1303 central venous cannulations. J R Soc Med 1997;90:319–21. 7. Patel RY, Friedman A, Shams JN, Silberzweig JE. Central venous catheter tip malposition. J Med Imaging Radiat Oncol 2010;54:35–42. 8. Plumhans C, Mahnken AH, Ocklenburg C, Keil S, Behrendt FF, Günther RW, et al. Jugular versus subclavian totally implantable access ports: catheter position, complications and intrainterventional pain perception. Eur J Radiol 2011;79:338–42. 9. Lichtenstein D, Mezière G, Biderman P, Gepner A. The comet-tail artifact: an ultrasound sign ruling out pneumothorax. Intensive Care Med 1999;25:383–8. 10. Brown JR, Slomski C, Saxe AW. Is routine postoperative chest x-ray

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necessary after fluoroscopic-guided subclavian central venous port placement? J Am Coll Surg 2009;208:517–9. 11. Losert H, Prokesch R, Grabenwöger M, Waltl B, Apsner R, SunderPlassmann G, et al. Inadvertent transpericardial insertion of a central venous line with cardiac tamponade failure of preventive practices. Intensive Care Med 2000;26:1147–50. 12. Vezzani A, Brusasco C, Palermo S, Launo C, Mergoni M, Corradi F. Ultrasound localization of central vein catheter and detection of postprocedural pneumothorax: an alternative to chest radiography. Crit Care Med 2010;38:533–8. 13. van Beek EJ. Routine chest radiographs following central line insertion: not always necessary! Chest 2005;127:10–2. 14. Ahn SJ, Kim HC, Chung JW, An SB, Yin YH, Jae HJ, et al. Ultrasound and fluoroscopy-guided placement of central venous ports via internal jugular vein: retrospective analysis of 1254 port implantations at a single center. Korean J Radiol 2012;13:314–23. 15. Sanabria A, Henao C, Bonilla R, Castrillón C, Cruz H, Ramírez W, et al. Routine chest roentgenogram after central venous catheter insertion is not always necessary. Am J Surg 2003;186:35–9. 16. Gebauer B, El-Sheik M, Vogt M, Wagner HJ. Combined ultrasound and fluoroscopy guided port catheter implantation--high success and low complication rate. Eur J Radiol 2009;69:517–22. 17. Maury E, Guglielminotti J, Alzieu M, Guidet B, Offenstadt G. Ultrasonic examination: an alternative to chest radiography after central venous catheter insertion? Am J Respir Crit Care Med 2001;164:403–5. 18. Dede D, Akmangit I, Yildirim ZN, Sanverdi E, Sayin B. Ultrasonography and fluoroscopy-guided insertion of chest ports. Eur J Surg Oncol 2008;34:1340–3. 19. Cavanna L, Civardi G, Vallisa D, Di Nunzio C, Cappucciati L, Bertè R, et al. Ultrasound-guided central venous catheterization in cancer patients improves the success rate of cannulation and reduces mechanical complications: a prospective observational study of 1,978 consecutive catheterizations. World J Surg Oncol 2010;8:91. 20. Seo TS, Song MG, Kang EY, Lee CH, Yong HS, Doo K. A single-incision technique for placement of implantable venous access ports via the axillary vein. J Vasc Interv Radiol 2014;25:1439–46. 21. Balkanay OO. The use of Doppler ultrasound and double-control method during catheterization for hemodialysis. Damar Cer Derg 2017;26:104–10. 22. Gekle R, Dubensky L, Haddad S, Bramante R, Cirilli A, Catlin T, et al. Saline Flush Test: Can Bedside Sonography Replace Conventional Radiography for Confirmation of Above-the-Diaphragm Central Venous Catheter Placement? J Ultrasound Med 2015;34:1295–9. 23. Trerotola SO, Thompson S, Chittams J, Vierregger KS. Analysis of tip malposition and correction in peripherally inserted central catheters placed at bedside by a dedicated nursing team. J Vasc Interv Radiol 2007;18:513–8. 24. Venkatesan T, Sen N, Korula PJ, Surendrababu NR, Raj JP, John P, et al. Blind placements of peripherally inserted antecubital central catheters: initial cathetertip position in relation to carina. Br J Anaesth 2007;98:83–8. 25. Miao J, Ji L, Lu J, Chen J. Randomized clinical trial comparing ultrasound-guided procedure with the Seldinger’s technique for placement of implantable venous ports. Cell Biochem Biophys 2014;70:559–63. 26. Mudan S, Giakoustidis A, Morrison D, Iosifidou S, Raobaikady R, Neofytou K, et al. 1000 Port-A-Cath ® placements by subclavian vein approach: single surgeon experience. World J Surg 2015;39:328–34. 27. Frykholm P, Pikwer A, Hammarskjöld F, Larsson AT, Lindgren S, Lindwall R, et al. Clinical guidelines on central venous catheterisation. Swedish Society of Anaesthesiology and Intensive Care Medicine. Acta Anaesthesiol Scand 2014;58:508–24.

Orıgınal Article

PUBLIC HEALTH

North Clin Istanb

2019;6(3):284–292 doi: 10.14744/nci.2018.50024

Otorhinolaryngological symptoms among smokeless tobacco (Maras powder) users Saime Sagiroglu,1

Aysegul Erdogan,2

Adem Doganer,3

Ramazan Azim Okyay2

Department of Otorhinolaringology, Kahramanmaras Sutcu Imam University Faculty of Medicine, Kahramanmaras, Turkey

Department of Public Health, Kahramanmaras Sutcu Imam University Faculty of Medicine, Kahramanmaras, Turkey

Department of Biostatistics and Medical Informatics, Kahramanmaras Sutcu Imam University Faculty of Medicine, Kahramanmaras, Turkey

ABSTRACT OBJECTIVE: This study aims to investigate the relationship between smokeless tobacco (maras powder) consumption and otorhinolaryngological symptoms. METHODS: This descriptive study was carried out on 599 participants. The participants were divided into two groups. Of these, 299 (49.9%) patients aged over 18 years were the first group; they used smokeless tobacco for at least 5 years. The remaining patients comprised the second group, which included 300 (50.1%) healthy volunteers who did not use tobacco or its products and demonstrated some similarities with the first group. For the purpose of data collection, a questionnaire consisting of 45 questions was administered to the participants. RESULTS: Cough, sputum, shortness of breath, dysphagia, snoring, and apnea-hypopnea were found to be significantly increased in smokeless tobacco users. The highest odds ratio (OR) found was for sputum at 2.615. Similarly, other oral cavity symptoms such as mouth tickling, dryness of throat, mouth sores, halitosis, taste disorders, and toothache were found to be significantly increased in smokeless tobacco users. It is noteworthy that halitosis was 9.4 times more prevalent among smokeless tobacco users than in the non-tobacco users. Sinonasal symptoms such as sneezing, headache, facial fullness, and anorexia were found to be significantly increased in smokeless tobacco users. However, there were no differences between the groups in terms of ear symptoms. CONCLUSION: This study demonstrated that the negative effects of smokeless tobacco consumption were particularly higher in the oral cavity, which in turn gave rise to a number of serious upper respiratory tract complaints. Keywords: Maras powder; otorhinolaryngology; smokeless tobacco; symptoms.

Cite this article as: Sagiroglu S, Erdogan A, Doganer A, Okyay RA. Otorhinolaryngological symptoms among smokeless tobacco (Maras powder) users. North Clin Istanb 2019;6(3):284–292.

ecently, tobacco consumption has soared, particularly in developing countries. According to the World Health Organization (WHO), the tobacco epidemic is one of the biggest public health threats the world has ever faced, killing over 7 million people a year. Over 6 million of those deaths are the result of direct tobacco use, while around 890.000 result from passive exposure to tobacco smoke [1].

Although tobacco consumption occurs mainly in the form of cigarette smoking, other smokeless forms of tobacco usage are also prevalent. Smokeless tobacco is used by many cultures all over the world, including the United States, Sweden, India, and the Middle East [2–5]. Some commonly used smokeless tobacco products include chewing tobacco, snuff, snus, and topical tobacco paste [4]. In Turkey, the most common smokeless

Received: January 25, 2018 Accepted: May 04, 2018 Online: August 08, 2018 Correspondence: Dr. Saime SAGIROGLU. Kahramanmaras Sutcu Imam Universitesi Tip Fakultesi, Kulak Burun Bogaz Bas ve Boyun Cerrahisi Anabilim Dali, Kahramanmaras, Turkey. Tel: +90 505 240 05 44 e-mail: ssguzelsoy@hotmail.com © Copyright 2019 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

Sagiroglu et al., Otorhinolaryngological symptoms among smokeless tobacco (Maras powder) users

tobacco product is maras powder, a snus-like product that is used by compressing a powder-filled mini bag in the buccal mucosa between the teeth and lips [6]. Maras powder is obtained from a plant called Nicotina rustica linn. The nicotine content of this plant is 6â&#x20AC;&#x201C;10 times higher than that of Nicotina tobacum, which cigarettes are produced from [7]. The prevalence of smoking in Turkey is well-known. According to WHO data, the age-standardized estimated prevalence of people aged 15 years or more ever having smoked tobacco is 41.6% for men and 13.2% for women. The health effects of cigarette smoking [8], its role in carcinogenesis [9], and its respiratory symptomatology [10] have been examined in detail in the literature. However, to the best of our knowledge, to date there is no study on the symptomatology of smokeless tobacco use in Turkey [11]. In light of this knowledge gap, we aimed to investigate the relationship between the use of smokeless tobacco and the related otorhinolaryngological symptoms in Kahramanmaras, the city that gives the smokeless tobacco product maras powder its name, and where its usage is extremely common. MATERIALS AND METHODS Study Design This descriptive study was carried out in Kahramanmaras, Turkey in 2016. A questionnaire consisting of 45 questions was administered to the participants. The first 9 questions were regarding the socio-demographic characteristics and the rest of the questions were related to otorhinolaryngological symptoms and smokeless tobacco consumption. Data Collection At total of 299 (49.9%) patients aged over 18 years who applied to the Department of Otorhinolaryngology polyclinic between April 2016 and September 2016 and who consumed smokeless tobacco 3 times or more per day for at least 5 years were included in the study as the smokeless tobacco user group. A total of 300 (50.1%) healthy volunteers, who did not use tobacco or its products and demonstrated similarities to the smokeless tobacco user group in terms of age, gender, and certain socio-demographic characteristics formed the non-tobacco user group. The participants with upper respiratory tract infec-

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tions and chronic respiratory system diseases such as chronic obstructive pulmonary disease and asthma were excluded from the study. The smokeless tobacco user group enrolled only those who did not have an obvious pathological explanation for their symptoms. The nontobacco user group included healthy individuals who had no health problems. Each member of both groups filled and signed the detailed questionnaire form that queried socio-demographic characteristics and otorhinolaryngological symptoms. Statistical Analysis Data were analyzed using the SPSS statistical software version 22. Symptoms and socio-demographic variables were presented as frequencies and percentages in tables. The Pearson chi-square test and Studentâ&#x20AC;&#x2122;s t-test were applied to assess the results. The level of statistical significance was accepted as p<0.05 and the estimated odds ratios (OR) were presented with a 95% confidence interval. Ethical Considerations The study was approved by the Local Scientific Research Ethics Committee. Written informed consent was obtained from all participants, and their participation in the study was purely voluntary. RESULTS A total of 599 participants were included in the research. Of these, 299 had used smokeless tobacco for at least 5 years prior to the study and the remaining 300 people were not tobacco users. The distribution of some sociodemographic factors such as age, gender, marital status, education, economic status, and place of settlement of the groups are shown in Table 1. There were no differences between the groups in terms of age, gender, marital status, education, economic status, and place of settlement (p>0.05). Comparison of smokeless tobacco users and non-tobacco users according to upper respiratory tract symptoms is shown in Table 2. Cough, sputum, shortness of breath, dysphagia, snoring, and apnea-hypopnea were found to be significantly increased in smokeless tobacco users (p<0.05). There were no significant differences between the groups in terms of hoarseness, reflux, neck pain, swelling in the neck, and pruritus (p=0.031, p=0.938, p=0.785, p=0.879, p=0.287 respectively). The highest odds ratio found was for sputum at 2.615.

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Table 1. Comparison of smokeless tobacco users and non-tobacco users according to social demographic characteristics Socio-demographic characteristics

Smokeless tobacco users

Non-tobacco users

n %* n %*

Age 36.80Âą15.42 38.92Âą14.44 0.123 Gender Female 24 38.7 38 61.3 0.062 Male 275 51.2 262 48.8 Marital status Married 198 47.3 221 52.7 Single 91 58.3 65 41.7 0.055 Divorced 8 44.4 10 55.6 Education Illiterate 6 35.3 11 64.7 Literate 22 61.1 14 38.9 Elementary school 82 54.7 68 45.3 0.091 Middle school 38 44.7 47 55.3 High school 101 53.4 88 46.6 University 49 41.9 68 58.1 Economic status Low 49 41.5 69 58.5 Moderate 220 52.9 196 47.1 0.080 High 26 46.4 30 53.6 Settlement place Village 36 61.0 23 39.0 District 50 43.9 64 56.1 0.100 City 210 50.4 207 49.6 *Row percentage.

Comparison of groups regarding oral cavity symptoms is shown in Table 3. Mouth tickling, dryness of throat, mouth sores, halitosis, taste disorders, and toothache were found to be significantly increased in smokeless tobacco users (p<0.05). It is noteworthy that halitosis was 9.4 times more among smokeless tobacco users than among the non-tobacco users. However, there were no differences between the groups in terms of sore throat, throat stinging, and gingival bleeding (p=0.187, p=0.790, p=0.424 respectively). Comparison of smokeless tobacco users and non-tobacco users according to sinonasal symptoms is shown in Table 4. Sneezing, headache, facial fullness, and anorexia were found to be significantly increased in smokeless tobacco users (p<0.05). There were no significant differences between the groups in terms of runny nose,

nasal bleeding, postnasal drainage, and nausea (p=0.134, p=0.345, p=0.475, p=0.084 respectively). Comparison of groups regarding ear symptoms is shown in Table 5. There were no differences between the groups in terms of hearing loss, dizziness, ear disorders, ear fullness, and tinnitus (p=0.310, p=0.185, p=0.248, p=0.330, p=0.586 respectively). DISCUSSION Maras powder is obtained from a plant that has a higher nicotine content than the plants that are used in regular cigarette production. It is mostly consumed in Kahramanmaras and Gaziantep, cities located in the Southeastern Region of Turkey. There is a misguided public opinion that the use of maras powder does not carry

Sagiroglu et al., Otorhinolaryngological symptoms among smokeless tobacco (Maras powder) users

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Table 2. Comparison of smokeless tobacco users and non-tobacco users according to upper respiratory tract symptoms Upper respiratory tract symptoms

Smokeless tobacco users

n % n %

Cough Yes No Sputum Yes No Hoarseness Yes No Shortness of breath Yes No Reflux Yes No Dysphagia Yes No Snore Yes No Apnea hypopnea Yes No Neck pain Yes No Swelling in the neck Yes No Pruritus Yes No

Non-tobacco users

x²

111 60.7 72 39.3 187 45.2 227 54.8

12.17

<0.001

1.871 (1.313–2.667)

127 65.8 66 34.2 170 42.4 231 57.6

28.55

<0.001 2.615 (1.829–3.738)

62 53.4 54 46.6 0.62 237 49.4 243 50.6 99 59.3 68 40.7 7.99 199 46.4 230 53.6

0.031

–

<0.005 1.683 (1.171–2.418)

85 50.0 85 50.0 0.00 213 50.4 210 49.6

0.938

65 60.7 42 39.3 6.43 226 47.2 253 52.8

0.011 1.733 (1.130–2.657)

155 55.6 124 44.4 6.87 142 42.8 175 52.2

0.009 1.540 (1.115–2.129)

68 63.0 40 37.0 8.75 230 47.2 257 52.8

0.003 1.900 (1.237–2.918)

82 49.1 85 50.9 0.07 217 50.3 214 49.7

0.785

–

24 51.1 23 48.1 0.02 275 49.9 276 50.1

0.879

–

46 55.4 37 44.6 1.13 253 49.1 262 50.9

0.287

–

Pearson Chi-Square Test; α: 0.05.

the same detrimental health effects as cigarette smoking. On the contrary, studies show that maras powder can cause many systemic diseases in humans [12–14]. Consumption of maras powder causes genotoxic, mutagenic, and carcinogenic effects, particularly due to the N-nitrosamines in its content.

There is much evidence that nicotine is a major immunosuppressant. Nicotine induces ACTH secretion, which releases catecholamines that have suppressive effects on the immune system [15]. This leads to the emergence of clinical symptoms, which are indicators of several diseases. Smoking also causes changes in the

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Table 3. Comparison of smokeless tobacco users and non-tobacco users according to oral cavity symptoms Oral cavity symtoms

Smokeless tobacco users

n % n %

Mouth tickling Yes No Dryness of throat Yes No Sore throat Yes No Throat stinging Yes No Mouth sores Yes No Halitosis Yes No Taste disorders Yes No Toothache Yes No Gingival bleeding Yes No

Non-tobacco users

x²

114 69.1 51 30.9 33.94 <0.001 3.038 (2.074–4.451) 181 42.4 246 57.2 168 66.4 85 33.6 48.84 <0.001 3.304 (2.351–4.645) 128 37.4 214 62.6 87 54.4 73 45.6 1.73 211 48.3 226 51.7

0.187

–

61 50.8 59 49.2 0.07 236 49.5 241 50.5

0.790

–

56 62.2 34 37.8 6.50 242 47.6 266 52.4

0.011 1.810 (1.143–2.869)

226 72

75.1 24.2

75 225

24.9 75.8

154.56

<0.001 9.417 (6.489–13.665)

75 63.3 43 36.4 11.08 223 46.5 257 53.5

<0.001 2.010 (1.327–3.046)

111 56.6 85 43.4 5.26 187 46.6 214 53.4

0.022 1.494 (1.060–2.108)

111 52.1 102 47.9 0.63 187 48.7 197 51.3

0.424

–

Pearson Chi-Square Test; α: 0.05.

mucus production mechanism. Chronic exposure to smoke increases the number and size of goblet cells, resulting in metaplastic changes in the respiratory mucosa and a consequent increase in upper respiratory secretion [16, 17]. Although there are many studies in the literature about the effect of cigarette smoking on the upper respiratory tract, there is limited research on the effects of smokeless tobacco. In a study which the effect of local herbal tobacco use on pulmonary function was assessed, pulmonary dysfunction was determined in chronic consumption and symptoms such as coughing were reported to be high [18]. Another study [19] re-

ported a higher risk of chronic bronchitis in smokeless tobacco users. Even though the systemic effects of maras powder taken orally are different from the direct effects of cigarette smoke, we found that cough, sputum, and shortness of breath were significantly higher among the smokeless tobacco users than the non-tobacco users. We agreed that these symptoms paved the way for pulmonary disorders in the future. In chronic voice disorders, the negative effect of cigarette smoke on vocal cords is a known fact. However, as expected, we found that smokeless tobacco did not have any effect on voice morbidity. Smoking negatively affects

Sagiroglu et al., Otorhinolaryngological symptoms among smokeless tobacco (Maras powder) users

289

Table 4. Comparison of smokeless tobacco users and non-tobacco users according to sinonasal symptoms Sinonasal symtoms

Smokeless tobacco users

n % n %

Runny nose Yes No Nasal bleeding Yes No Sneeze Yes No Postnasal drainage Yes No Smell disorders Yes No Headache Yes No Facial fullness Yes No Nausea Yes No Anorexia Yes No

Non-tobacco users

x²

89 54.9 73 45.3 2.24 210 48.1 227 50.9

0.134

–

36 45.0 44 55.0 0.89 263 50.7 256 49.3

0.345

–

157 54.9 129 45.1 5.25 142 45.5 170 54.5

0.022 1.457 (1.056–2.011)

69 52.7 62 47.3 0.51 229 49.1 237 50.9

0.475

–

56 57.1 42 42.9 2.33 243 48.7 256 51.3

0.126

–

150 54.5 125 45.5 4.35 149 46.0 175 54.0

0.037 1.409 (1.021–1.946)

58 59.2 40 40.8 4.02 241 48.1 260 51.9

0.045 1.564 (1.008–2.427)

71 56.8 54 43.2 2.99 228 48.1 246 51.9

0.084

97 61.8 60 38.2 12.00 201 45.7 239 54.3

0.001 1.922 (1.324–2.790)

–

Pearson Chi-Square Test; α: 0.05.

the gastroesophageal reflex and pharyngeal swallowing reflex [20, 21] and may cause dysphagia and respiratory complications due to gastroesophageal reflux. Aro et al. [22] found that smokeless tobacco significantly changes the histology of the distal esophagus but does not lead to gastrointestinal symptoms or peptic ulcers. In our study, the rate of reflux symptoms was similar in both groups. However, dysphagia was found to be higher among smokeless tobacco users. Due to its high nicotine content, sleepiness tends to increase during the day in people using smokeless tobacco. Studies have shown that there is a synergistic effect

between smoking and snoring, and smoking increases the risk of cardiovascular disease with both oxidative stress and endothelial dysfunction through abnormal inflammatory response [12, 13, 23]. In our study, snoring and apnea-hypopnea rates were higher in smokeless tobacco users. Over 700 species of bacteria have been identified in the human oral cavity [24, 25]. These bacteria play a role in both oral and systemic health. One of the causes of halitosis is the deterioration of the bacterial flora. These bacteria cause oral malodor by producing various substances such as sulfur compounds, diamines, and short

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Table 5. Comparison of smokeless tobacco users and non-tobacco users according to ear symptoms Ear symtoms

Smokeless tobacco users

x²

53 54.6 44 45.4 246 49.0 256 51.0

1.03

0.310

–

91 54.2 77 45.8 207 48.1 223 51.9

1.75

0.185

–

46 44.7 57 55.3 252 50.9 243 49.1

1.33

0.248

–

33 266

0.94

0.330

–

88 51.8 82 48.2 0.29 211 49.3 217 50.7

0.586

–

Hearing loss Yes No Dizziness Yes No Ear disorders Yes No Ear fullness Yes No Tinnitus Yes No

Non-tobacco users

n % n %

55.9 49.3

26 274

44.1 50.7

Pearson Chi-Square Test; α: 0.05.

chain fatty acids [26, 27]. Keene and Johnson [28] found that Streptococcus mutans (S. mutans) increases in the oral mucosa due to increased nicotine. Increased levels of nicotine in saliva have been thought to stimulate the colonization of S. mutans and increase the risk of oral carriage. In our study, the most notable of the oral symptoms in smokeless tobacco users was halitosis. In an in vitro study, it was found that the number of fibroblasts and the amount of gingiva type 1 collagen increased with nicotine use [29], which indicates that nicotine causes fibrosis in the oral mucosa. As a matter of fact, we found that mouth tickling, dryness of throat, throat stinging, taste disorders, and toothache were higher among smokeless tobacco users. These findings suggest that smokeless tobacco consumption may lead to a deterioration of the oral flora and a rise in the risk of infection. Smokeless tobacco may cause hyperkeratotic lesions, periodontal diseases and intra-oral premalignant lesions in the oral mucosa. It also chronically stimulates the lymphoid tissue in the oral mucosa and consequently raises the risk of gingivitis, erythroplakia, leukoplakia, submucous fibrosis, and lichen planus. Epidemiological and experimental studies have shown a strong association between oral and pharyngeal cancers and smokeless tobacco

[30, 31]. Dodani et al. [32] found pathological findings in mucosa as a result of direct exposure of gingiva to various toxic chemicals. In previous studies, epithelial anomalies and precancerous lesions were determined from biopsies of gingival tissues of maras powder users [6, 33]. With increased nicotine-induced vasoconstriction, the gingival keratinization increases, as a result of which smokers are prone to less gingival bleeding. Although we found a higher number of mouth sores in smokeless tobacco users, gingival bleeding and sore throat were not different from the non-tobacco users. Epidemiological studies suggest a correlation between exposure to tobacco smoke and rhinosinusitis. Goldstein-Daruech et al. [34] found that exposure to tobacco led the formation of a synonasal biofilm and contributed to the conversion of a transient and medically treatable infection to a tenacious and therapeutic persistent state. Mahakit et al. [35] showed that cigarette smoking negatively affects the mucociliary function. Sanli et al. [36] found that while nasal obstruction, malodor, and snoring were significantly higher in smokers, symptoms such as nasal discharge, sneezing, nasal discharge, and headache were similar to the control group. In our study, while sneezing, headache, facial fullness, and anorexia were

Sagiroglu et al., Otorhinolaryngological symptoms among smokeless tobacco (Maras powder) users

higher in smokeless tobacco users, the rates of runny nose, nasal bleeding, post nasal drainage, and smell disorders were similar in both groups. These results suggest that the negative effects of cigarette smoke on nasal function are higher than smokeless tobacco. Gaur et al. [37] found that smokers had more otological diseases. Sanli et al. [36] found that ear discharge, hearing loss, dizziness, and tinnitus were more common in smokers. While there are many studies in the literature proving that cigarette disrupts cochlear function, not many studies on the effect of smokeless tobacco on the ear have been researched [37–39]. In our study, we found equal rates of ear symptoms in both groups. However, we believe that there is a need for more extensive research in this regard. Strengths and Limitations A strength of the present study was that it was conducted in a city where smokeless tobacco consumption is prevalent. Another strength was that the study population was relatively large. However, there were several limitations. First, the study was carried out on the applicants of a hospital, which hinders extrapolation of the results to the general population. Second, the duration of smokeless tobacco presence in the oral cavity was not questioned, therefore, the dose-response relationship between the usage habit and symptoms could not be assessed. Lastly, as this was a survey study, the inconsistencies in patients’ memory may have affected the responses to the questionnaire. Conclusion Our study revealed that the effect of smokeless tobacco on the oral cavity was excessive and that there was no difference between the groups in terms of any ear symptoms. We found that smokeless tobacco users had significant potential clinical symptoms compared to non-tobacco users, which are premonitors of several diseases. By the elimination of the etiology that causes the symptoms and by performing screening for the emerged symptoms, the disease may be prevented. Thus, preventive medicine should be brought to the forefront. Ethics Committee Approval: The study was approved by the clinical research local ethics committee of Kahramanmaras Sutcu Imam University (2016/138). Informed Consent: Written informed consent was obtained from the patient who participated in this study.

291

Conflict of Interest: The authors have no conflict of interests. Financial Disclosure: The authors declared that this study has received no financial support. Authorship Contributions: Concept – SS; Supervision – AE; Materials – SS, AE, RAO; Data collection and/or processing – SS, AE, AD; Analysis and/or interpretation – AE, AD, RAO; Writing – SS, AD; Critical review – SS, RAO, AE.

REFERENCES 1. WHO. Tobacco fact sheet. World Health Organization: Geneva; 2016. 2. Cullen D, Keithly L, Kane K, Land T, Paskowsky M, Chen L, et al. Smokeless tobacco products sold in Massachusetts from 2003 to 2012: trends and variations in brand availability, nicotine contents and design features. Tob Control 2015;24:256–62. 3. Leon ME, Lugo A, Boffetta P, Gilmore A, Ross H, Schüz J, et al. Smokeless tobacco use in Sweden and other 17 European countries. Eur J Public Health 2016;26:817–21. 4. Shaik SS, Doshi D, Bandari SR, Madupu PR, Kulkarni S. Tobacco Use Cessation and Prevention - A Review. J Clin Diagn Res 2016;10:ZE13– 7. 5. Alsanosy RM. Smokeless tobacco (shammah) in Saudi Arabia: a review of its pattern of use, prevalence, and potential role in oral cancer. Asian Pac J Cancer Prev 2014;15:6477–83. 6. Erenmemisoglu A, Ustun H, Kartal M. Carcinoma of buccal mucosa in smokeless tobacco users: a preliminary study of the use of cytology for early detection. Cytopathology 1995;6:403–8. 7. Saitoh F, Noma M, Kawashima N. The alkaloid contents of sixty Nicotiana species. Phytochemistry 1985;24:477–80. 8. World Health Organization. WHO report on the global tobacco epidemic, 2015: Raising taxes on tobacco—Appendix VII: Country profiles. Available at: https://www.who.int/tobacco/global_report/2015/ en/. Accessed May 28, 2017. 9. Duaso M, Duncan D. Health impact of smoking and smoking cessation strategies: current evidence. Br J Community Nurs 2012;17:356–63. 10. Collaborative Group on Epidemiological Studies of Ovarian Cancer, Beral V, Gaitskell K, Hermon C, Moser K, Reeves G, Peto R. Ovarian cancer and smoking: individual participant meta-analysis including 28,114 women with ovarian cancer from 51 epidemiological studies. Lancet Oncol 2012;13:946–56. 11. Lawless MH, Harrison KA, Grandits GA, Eberly LE, Allen SS. Perceived stress and smoking-related behaviors and symptomatology in male and female smokers. Addict Behav 2015;51:80–3. 12. Bolinder G, Alfredsson L, Englund A, de Faire U. Smokeless tobacco use and increased cardiovascular mortality among Swedish construction workers. Am J Public Health 1994;84:399–404. 13. Guven A, Tolun F. Effects of smokeless tobacco “Maras powder” use on nitric oxide and cardiovascular risk parameters. Int J Med Sci 2012;9:786–92. 14. Cok I, Ozturk R. Urinary cotinine levels of smokeless tobacco (Maraş powder) users. Hum Exp Toxicol 2000;19:650–5. 15. Sopori ML, Kozak W. Immunomodulatory effects of cigarette smoke. J Neuroimmunol 1998;83:148–56. 16. Tamashiro E, Cohen NA, Palmer JN, Lima WT. Effects of cigarette smoking on the respiratory epithelium and its role in the pathogenesis of chronic rhinosinusitis. Braz J Otorhinolaryngol 2009;75:903–7. 17. Mullen JB, Wright JL, Wiggs BR, Paré PD, Hogg JC. Structure of central airways in current smokers and ex-smokers with and without mucus

292 hypersecretion: relationship to lung function. Thorax 1987;42:843–8. 18. Maduka SO, Osim EE, Nneli RO, Anyabolu AE. Effect of occupational exposure to local powdered tobacco (snuff ) on pulmonaryfunction in south eastern Nigerians. Niger J Physiol Sci 2009;24:195–202. 19. Ayo-Yusuf OA, Reddy PS, van den Borne BW. Association of snuff use with chronic bronchitis among South African women: implications for tobacco harm reduction. Tob Control 2008;17:99–104. 20. Dua K, Bardan E, Ren J, Sui Z, Shaker R. Effect of chronic and acute cigarette smoking on the pharyngoglottal closure reflex. Gut 2002;51:771–5. 21. Dua K, Bardan E, Ren J, Sui Z, Shaker R. Effect of chronic and acute cigarette smoking on the pharyngo-upper oesophagealsphincter contractile reflex and reflexive pharyngeal swallow. Gut 1998;43:537–41. 22. Aro P, Ronkainen J, Storskrubb T, Vieth M, Engstrand L, Johansson SE, et al. Use of tobacco products and gastrointestinal morbidity: an endoscopic population-based study (the Kalixanda study). Eur J Epidemiol 2010;25:741–50. 23. Kilinc M, Okur E, Kurutas EB, Guler FI, Yildirim I. The effects of Maras powder (smokeless tobacco) on oxidative stress in users. Cell Biochem Funct 2004;22:233–6. 24. Paster BJ, Olsen I, Aas JA, Dewhirst FE. The breadth of bacterial diversity in the human periodontal pocket and other oralsites. Periodontol 2000 2006;42:80–7. 25. Kirst ME, Li EC, Alfant B, Chi YY, Walker C, Magnusson I, et al. Dysbiosis and alterations in predicted functions of the subgingival microbiome in chronic periodontitis. Appl Environ Microbiol 2015;81:783–93. 26. Motta LJ, Bachiega JC, Guedes CC, Laranja LT, Bussadori SK. Association between halitosis and mouth breathing in children. Clinics (Sao Paulo) 2011;66:939–42. 27. Madhushankari GS, Yamunadevi A, Selvamani M, Mohan Kumar KP, Basandi PS. Halitosis – An overview: Part-I – Classification, etiology, and pathophysiology of halitosis. J Pharm Bioallied Sci 2015;7:S339– 43. 28. Keene K, Johnson RB. The effect of nicotine on growth of Streptococcus

North Clin Istanb mutans. Miss Dent Assoc J 1999;55:38–9. 29. Takeuchi H, Kubota S, Murakashi E, Zhou Y, Endo K, Ng PS, et al. Nicotine-induced CCN2: from smoking to periodontal fibrosis. J Dent Res 2010;89:34–9. 30. Goud SN, Zhang L, Kaplan AM. Immunostimulatory potential of smokeless tobacco extract in in vitro cultures of murine lymphoid tissues. Immunopharmacology 1993;25:95–105. 31. Erenmemisoglu A, Tekol Y, Kartal M, Kurucu S. The use of a smokeless tobacco in our country “Maras powder”. In: Proceedings of the 2nd International Symposium of Pharmaceutical Sciences. Ankara, Turkey; June 1991. 32. Dodani K, Anumala N, Avula H, Reddy K, Varre S, Kalakonda BB, et al. Periodontal findings in patients with oral submucous fibrosis and comet assay of affected gingival epithelial cells. J Periodontol 2012;83:1038–47. 33. Okur E, Yildirim I, Kiliç MA, Saşmaz S. Clinical changes in the oral cavity resulting from smokeless tobacco (Maraş powder). Kulak Burun Bogaz Ihtis Derg 2004;13:72–6. 34. Goldstein-Daruech N, Cope EK, Zhao KQ, Vukovic K, Kofonow JM, Doghramji L, et al. Tobacco smoke mediated induction of sinonasal microbial biofilms. PLoS One 2011;6:e15700. 35. Mahakit P, Pumhirun P. A preliminary study of nasal mucociliary clearance in smokers, sinusitis and allergicrhinitis patients. Asian Pac J Allergy Immunol 1995;13:119–21. 36. Şanlı A, Bekmez E, Yıldız G, Erdoğan BA, Yılmaz HB, Altın G. Relationship between smoking and otorhinolaryngological symptoms. Kulak Burun Bogaz Ihtis Derg 2016;26:28–33. 37. Gaur K, Kasliwal N, Gupta R. Association of smoking or tobacco use with ear diseases among men: a retrospective study. Tob Induc Dis 2012;10:4. 38. Chung DY, Gannon RP, Mason K. Factors affecting the prevalence of tinnitus. Audiology 1984;23:441–52. 39. Paschoal CP, Azevedo MF. Cigarette smoking as a risk factor for auditory problems. Braz J Otorhinolaryngol 2009;75:893–902.

Orıgınal Article

GENERAL SURGERY

North Clin Istanb

2019;6(3):293–301 doi: 10.14744/nci.2019.93457

Evaluation of the predictive power of laboratory markers in the diagnosis of acute appendicitis in the elderly Savas Bayrak,1 Kemal Tekesin,3

Cihad Tatar,1

Ekrem Cakar,1

Bunyamin Gurbulak,1

Sukru Colak,1

Erdem Kinaci,1

Mehmet Emin Gunes,2

Mert Mahsuni Sevinc1

Department of General Surgery, Istanbul Training and Research Hospital, Istanbul, Turkey

Department of General Surgery, Bakirkoy Sadi Konuk Training and Research Hospital, Istanbul, Turkey

Department of General Surgery, Umraniye Training and Research Hospital, Istanbul, Turkey

ABSTRACT OBJECTIVE: The aim of this study was to analyze the predictive value of preoperative laboratory findings in acute appendicitis in geriatric patients aged >65 years. METHODS: We enrolled a total of 4121 patients. A retrospective evaluation of the demographic features was made using preoperative laboratory values such as the white blood cell (WBC), neutrophil, and lymphocyte counts; platelet counts; the mean platelet volume and bilirubin values; and postoperative pathological data of the patients from the electronic file system. The neutrophil-to-WBC and neutrophil-to-lymphocyte ratios were calculated. Patients were divided into two groups, as geriatric (≥65 years old, n=140) and non-geriatric (<65 years old, n=3981). RESULTS: The white blood cell and lymphocyte counts, and the neutrophil-to-WBC ratio, were significantly higher in the non-geriatric group (p<0.001, p=0.013, and p=0.021, respectively). The neutrophil and platelet counts were higher in the non-geriatric group, but this difference was not statistically significant (p=0.073 and p=0.072, respectively). A higher neutrophil-to-lymphocyte ratio was determined in the geriatric group, but the difference was not significant (p=0.176). According to the optimumal cutoff value of 12.11×103/µL for WBC, specificity and sensitivity values of 65.4% and 57.9% were calculated, respectively; the AUC value was 0.632±0.024 (p<0.001). A receiver operating characteristic (ROC) analysis was used to calculate the optimum cutoff values of neutrophil-to-WBC ratio, lymphocyte, and the mean platelet volume, but the diagnostic accuracy of these tests was inadequate with an AUC of <0.6. CONCLUSION: WBC values >12.11×103/µL were predictive of acute appendicitis in geriatric patients. The other parameters were not predictive, and further studies are required. Keywords: Acute appendicitis; geriatric patients; laboratory parameters.

Cite this article as: Bayrak S, Tatar C, Cakar E, Colak S, Gunes ME, Tekesin K, et al. Evaluation of the predictive power of laboratory markers in the diagnosis of acute appendicitis in the elderly. North Clin Istanb 2019;6(3):293–301.

cute appendicitis resulting from inflammation of the appendix is one of the most common clinical situations necessitating an abdominal surgical intervention [1–3]. The incidence of appendicitis is 233:100,000, and its lifetime incidence is approximately 7%–10% [4]. Ap-

pendicitis is often seen in young adults in the second and third decades of life, and its incidence is highest in those aged 10–19 years. The main management goal is early diagnosis with appropriate and timely surgical procedures. In cases where patients have not sought medical care, the

Received: April 16, 2019 Accepted: May 14, 2019 Online: July 08, 2019 Correspondence: Dr. Savas BAYRAK. Istanbul Egitim ve Arastirma Hastanesi, Genel Cerrahi Klinigi, Istanbul, Turkey. Tel: +90 533 248 0409 e-mail: savasbayrak74@gmail.com © Copyright 2019 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

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diagnosis may be delayed and difficult [5]. Negative appendectomies have previously been acceptable at a rate of approximately 15%. However, as imaging methods have become increasingly common, this rate has decreased to <10% [6]. Clinical approaches to the management of acute appendicitis may be complicated in some patient groups, particularly children, women of reproductive age, and geriatric patients [7]. Acute appendicitis is not rare in geriatric patients; 0.05% of the geriatric population develops acute appendicitis each year. In developed countries, appendicitis in the geriatric population is even rarer, although it is now becoming more common [8]. Appendicitis has become a significant cause of abdominal pain in older patients. Due to a blunted inflammatory response (such as leukocytosis and cytokine pool), elderly patients generally have a less remarkable history and physical findings [9]. This clinical situation may lead to a delayed diagnosis and increased complication rates, such as perforation on presentation [10, 11]. Perforation particularly significantly increases morbidity and mortality [12]. Geriatric patients also have a higher tendency for comorbidities, which increases morbidity and mortality rates. They often have other conditions such as diverticulitis or neoplasms that can mimic acute appendicitis. Thus, a broad list should be considered during the differential diagnosis of a geriatric population [13]. Computed tomography can increase the rate of accurate diagnosis [14], and laparoscopic appendectomies offer a shorter hospitalization time and fewer complications in geriatric patients [15–17]. Several studies have evaluated the value of parameters such as preoperative complete blood count (CBC), white blood cell (WBC), neutrophil-to-lymphocyte ratio (NLR), neutrophil percentage (neutrophil/WBC ratio, NWR), the mean platelet volume (MPV), and bilirubin levels in acute appendicitis [18–23]. However, studies investigating the predictive value of laboratory parameters in acute appendicitis in the geriatric population are limited. The aim of this study was to analyze the predictive value of preoperative laboratory findings in acute appendicitis in geriatric patients aged >65 years. MATERIALS AND METHODS This study, which was approved by the ethical board of the Istanbul Training and Research Hospital (09/22/20171090), included 4144 patients who applied with open or laparoscopic appendectomy in our clinic between March 2005 and December 2016. Informed consent was obtained

North Clin Istanb

from all individual participants included in the study. The data of 23 patients could not be retrieved. Thus, the demographic features and preoperative laboratory values such as WBC, neutrophil, lymphocyte and platelet counts, MPV and bilirubin values, and postoperative histopathological results of 4121 patients were collected from the electronic file system. CBC and bilirubin were measured with an automated hematology analyzer and chemiluminescence, respectively. The NWR and NLR ratios were calculated. The study included patients aged 15–95 years who were then grouped as <65 years or ≥65 years. Patients aged <15 years, pregnant patients, and those with chronic liver disease or malignancy were excluded. Statistical Analysis Data analysis used the SPSS 22.0 (IBM Corporation, Armonk, New York, USA) and Medcalc 14 (Acacialaan 22, B-8400 Ostend, Belgium) programs. The conformity of the univariate data to normal distribution was evaluated using the Shapiro– Wilk test. When comparing two independent groups according to quantitative data, the Mann–Whitney U test was used with the Monte Carlo results. When comparing categorical variables, the Pearson chi-squared exact test was applied. The association between the classification separated by cutoff values calculated according to variables, and real classification was analyzed with a receiver operating characteristic (ROC) curve. Quantitative and categorical variables were shown in the tables as the median range (maximum–minimum) and number (n) and percentage (%), respectively. Variables were examined at the 95% confidence interval, and a p-value <0.05 was accepted as statistically significant. RESULTS The patients included 1574 (37.98%) females and 2547 (62.02%) males, with a mean age of 34.55±12.14 years (median age, 32 years; age range, 15–95 years). The patients were classified as geriatric (≥65 years old) and non-geriatric (<65 years old) groups according to their age. The geriatric group comprised 140 (3.4%) of the total patient group with statistically significantly more females in the geriatric group than the non-geriatric groups (p=0.001) (Fig. 1). Perforation was detected in 24 (17.14%) and 598 (15.02%) patients in the geriatric and non-geriatric group, respectively. There is no statistically significant difference between groups in terms of perforation rates. The WBC mean of 24 patients with perforated ap-

100 90 80 70 60 50 40 30 20 10 0

Male Female 2502

15.00 68

1502 Non-geriatric

295

Geriatric

Lymphocyte

% of patiens

Bayrak et al., Laboratory markers in elderly acute appendicitis

10.00

5.00

Figure 1. Gender differences between the geriatric and nongeriatric groups. 0.00

50.00

Age

≥65

Figure 3.

The comparison of lymphocyte counts between the age groups.

40.00 WBC

<65

30.00 1.20 20.00 10.00 0.00

<65

≥65 Age

Figure 2. The comparison of WBC counts between the age groups.

Neutrophil/WBC

1.00 0.80 0.60 0.40 0.20 0.00

pendicitis in the geriatric group was 13.39×103/μL, and the WBC mean of the 598 patients with perforated appendicitis was 16.4×103/μL. This analysis shows that there is no statistically significant difference between the geriatric and non-geriatric patients (p=0.094). The WBC, lymphocyte counts, and NWR were significantly higher in the non-geriatric group (p<0.001, p=0.013, and p=0.021, respectively). These distributions are shown in Figures 2, 3, and 4. Neutrophil and platelet counts were higher in the non-geriatric group, but this difference was not statistically significant (p=0.073 and p=0.072, respectively). A higher NLR was determined in the geriatric group, but the difference was not significant (p=0.176). The MPV values were increased in geriatric patients (p=0.036). Bilirubin levels of the patients were similar between the age groups (p=0.797). Acute perforated gangrenous appendicitis was determined in 87.47% of the non-geriatric cases and in 77.14% of the

<65

≥65 Age

Figure 4. The distribution of NWR between the age groups. geriatric patients, according to pathological results, with a significant difference between the age groups (p=0.001) (Fig. 5). The demographic and clinical features of the patients are shown in Table 1. The predictive values of the preoperative laboratory results of the patients were examined using a ROC analysis. At a cutoff value of 12.11×103/µL for WBC, the specificity and sensitivity were 65.4% and 57.9%, respectively, and the AUC was 0.632±0.024 (p<0.001). A ROC analysis with optimum cutoff values of NWR, lymphocyte, and MPV gave inadequate diagnostic accuracy; the AUC values were <0.6. The ROC analysis results for these laboratory parameters are shown in Table 2 and Figures 6–9.

% of patiens

296

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100 90 80 70 60 50 40 30 20 10 0

499

3482

108

Age <65 Age ≥65 Acute perforated-gangrenous appendicitis Subacute appendicitis

Figure 5. Pathological analysis according to the age groups. DISCUSSION Approximately half of the geriatric patients who present to the Emergency Depatment have abdominal pain complaints [24]. Intestinal obstruction and biliary diseases are the most common causes of acute abdomen in geriatric patients, followed by acute appendicitis [25]. The prognosis may be unfavorable, and geriatric patients may experience more complications compared to younger patients because their clinical signs of appendicitis may be atypical [26]. For example, this age group has increased perforation rates compared to younger patients, which may be associated with a diagnostic delay due to both late

admission and a lack of classic signs and symptoms [27]. In our study, the geriatric group had a perforation ratio that was higher than in the non-geriatric group, but this difference was not statistically significant. An analysis of the subgroups of perforated patients showed no statistically significant difference in the WBC values between geriatric and non-geriatric patients. Higher rates of misdiagnosis (up to 50%) are observed in the geriatric patient group, and some of those patients require more than a day to be diagnosed [27]. To improve the diagnostic accuracy in appendicitis, several scoring systems have been developed such as the Alvarado score that was first described in 1986 [28–34]. The Alvarado scoring system consists of several par–ameters including leukocytosis (WBC>10×103/µL) and neutrophil-toWBC ratio. Some other clinical features of the patients were also considered. Although there are several studies in the literature evaluating the accuracy of this scoring system in patients with appendicitis, there have been only a few studies that have only investigated the predictive role of preoperative laboratory parameters. Furthermore, studies of the predictive value of scoring systems and laboratory parameters are rare in older patients. Inflammatory markers that emerge in acute appendicitis may change according to several factors, such as the bone marrow capacity, liver synthesis function, co-

Table 1. Demographic features and laboratory values of the patients

Age <65 Median (Max.-Min.)

Age ≥65 Median (Max.-Min.)

Total Median (Max.-Min.)

WBC Neutrophil NWR Lymphocyte NLR Platelet MPV Bilirubin Gender, n (%) Female Male Pathological analysis, n (%) Sub-lymphoid hyperplasia Acute-perforated-gangrenous appendicitis

13.70 (41.80–2) 9.71 (27.56–0.03) 0.740 (1-0) 1.95 (14.70–0.03) 5.07 (324–0.01) 247 (789–20.90) 8.30 (18–0.10) 0.60 (6.60–0.10)

11.70 (26–4.86) 8.70 (18.30–1) 0.751 (1–0) 1.73 (11.70–0.10) 5.48 (72–0.54) 232.50 (533–38) 8.40 (11.50–5.90) 0.60 (2.50–0.10)

13.60 (41.80–2) 9.70 (27.56–0.03) 0.740 (1-0) 1.94 (14.70–0.03) 5.08 (324–0.01) 247 (789–20.90) 8.30 (18–0.10) 0.60 (6.60–0.10)

<0.001 0.073 0.021 0.013 0.176 0.072 0.036 0.797

1502 (37.51) 2502 (62.49)

72 (51.43) 68 (48.57)

1574 (37.98) 2570 (62.02)

0.001

499 (12.53) 3482 (87.47)

32 (22.86) 108 (77.14)

531 (12.89) 3590 (87.11)

0.001

Max.: Maximum; Min.: Minimum. Mann Whitney U Test (Monte Carlo) - Pearson Chi-Square Test (Exact).

Bayrak et al., Laboratory markers in elderly acute appendicitis

297

Table 2. Analysis for optimal cutoff values of predictive laboratory parameters WBC >12.11 ≤12.11 NWR ≤0.5449 >0.5449 Lymphocyte >1.3 ≤1.3 MPV ≤9.25 >9.25

Age <65

Age ≥65

AUC±SE.

2616 1387

65.4** 34.6

59 81

42.1 57.9*

0.632±0.024

<0.001

708 3293

17.7** 82.3

8 132

5.7 94.3*

0.552±0.023

0.028

3097 903

77.4** 22.6

85 55

60.7 39.3*

0.562±0.028

0.026

3269 602

84.4** 15.6

102 36

73.9 26.1*

0.552±0.026

0.043

AUC: Area under the ROC; WBC: White blood cell; MPV: Mean platelet volume. (Roc (Receiver Operating Curve) Analysis (Honley&McNell - Youdenindex J).

Neutrophil / WBC 100

Sensitivity

WBC 100

Sensitivity: 57.9 Specificity: 65.4 Criterion: ≤12.11

60 40 20

20 0

Sensitivity: 94.3 Specificity: 17.7 Criterion: >0.5449

40 60 100-Specificity

100

40 60 100-Specificity

100

ing the predictive value for the white blood cell count (WBC).

Figure 7. Receiver operating characteristics (ROC) curve showing the predictive value for NWR.

morbidities, and drugs. The age of the patient is one of the most important factors affecting the degree of elevation in inflammatory markers. The WBC count is one of these inflammatory markers. Although there are many studies that have evaluated the benefits of using WBC, consensus has yet been reached [35]. Paajanen et al. investigated the preoperative WBC and C-reactive protein (CRP) levels of 6,000 patients consisting of all age groups including infants, children,

adolescents, adults, and geriatric patients [36]. A ROC analysis showed that WBC counts were better than CRP in suggesting the correct diagnosis in all age groups, except for those aged 0–5 years. However, systemic infections may generally result in less leukocytosis in geriatric patients, and some studies investigating infective endocarditis have shown a blunted leukocytosis response in older patients [37]. Acute appendicitis might also produce a very high degree of inflammation. Moreover, in

Figure 6. Receiver operating characteristics (ROC) curve show-

298

North Clin Istanb MPV 100

60 40

Sensitivity

Lymphocyte 100

Sensitivity: 39.3 Specificity: 77.4 Criterion: ≤1.3

20 0

60 40 Sensitivity: 20.1 Specificity: 84.4 Criterion: >9.25

40 60 100-Specificity

100

40 60 100-Specificity

100

Figure 8. Receiver operating characteristics (ROC) curve showing the predictive value for lymphocytes.

Figure 9. Receiver operating characteristics (ROC) curve show-

geriatric patients, decreased production of WBC and CRP due to diminished capacity can hinder the prompt diagnosis of appendicitis [36]. Thus, geriatric patients have generally less remarkable inflammatory factors [38]. In this study, geriatric patients with appendicitis had lower WBC counts than the non-geriatric group. Increased WBC counts were also determined to be predictive in the geriatric group. Sevinc et al. analyzed 3392 patients undergoing appendectomy and classified the patients according to pathological examination: those with a normal appendix (n=531) or with appendicitis (n=2861) [38]. The optimum cutoff value for WBC was 11.9x103/ µL, and a ROC analysis showed an AUC value >0.6. Therefore, elevated WBC levels (>11.9x103/µL) were predictive of appendicitis with a positive predictive value of 0.92. This study included all patients over the age of 15 years who underwent appendectomy. Styrud et al. investigated 47 patients aged >80 years who underwent appendectomy with a pre-diagnosis of appendicitis. They found higher complication rates in the older age group [39]. In contrast, they showed that the inflammatory parameters did not differ in the older group compared to the younger group. Therefore, elevated inflammatory markers were not associated with complications in the geriatric population. Grönroos et al. [40] evaluated 83 patients who underwent abdominal surgery with a clinical diagnosis of acute appendicitis. Histopathological analysis of the surgical specimens revealed that 10 patients had a non-inflamed appendix, and the others had acute appendicitis. These two groups were compared in terms of preoperative WBC and CRP values, and analysis showed that

all patients with acute appendicitis had histopathologically confirmed elevated preoperative WBC and/or CRP levels. In that study, normal leukocyte counts and CRP excluded acute appendicitis with a predictive value of 100%. Similar to our study, they showed that elevated leukocyte counts were an important finding for the prediction of acute appendicitis, but there was no examination of ROC curves or analysis of any cutoff values for the leukocyte counts. The NWR is another important parameter to diagnose or predict complications in acute appendicitis. However, studies evaluating these patients generally consider the absolute neutrophil count rather than the NWR. Here higher NWR values were seen in geriatric patients compared to the non-geriatric group, but the diagnostic accuracy of NWR was inadequate (AUC<0.6). Jung et al. evaluated 103 geriatric patients with acute appendicitis [41], 56.3% of whom developed perforation; a ROC analysis was performed to identify the optimal cutoff values. The cutoff value for WBC was 10.6×103/ µL. The odds ratio was 5.29, and the AUC was 0.664. The neutrophil count was predictive for perforation with a cutoff value of 8.1×103/µL (odds ratio of 4.776; AUC of 0.699). The NWR is considered when calculating the “appendicitis inflammatory response” score, but the NWR was not analyzed with ROC analysis. Ayrık et al. compared 254 patients with appendicitis, 66 of whom had a normal appendix according to the postoperative pathological examination [42]. That study was not restricted to geriatric patients. The positive (PPV) and negative

ing the predictive value for the mean platelet volume (MPV).

Bayrak et al., Laboratory markers in elderly acute appendicitis

predictive values (NPV) of WBC were 88% and 33.3%, respectively, in predicting the diagnosis of acute appendicitis (AUC=0.660). The cutoff value for NWR was >73, and the PPV and NPV were 88.2% and 42.9% (AUC=0.701) for diagnosis of acute appendicitis. When differentiating complicated and uncomplicated appendicitis, a cutoff value of 78.51 for NWR was not statistically significant. A multiple logistic regression analysis showed that an increased NWR could increase the risk of uncomplicated and complicated appendicitis (OR 1.082 and 1.066, respectively). These results suggest that surgical treatment of acute appendicitis can be selected by considering NWR [42]. Yang et al. [43] showed that the NWR was higher in patients with acute appendicitis than in patients with a normal appendix in the geriatric population. In another study, NWR was shown to be higher in complicated appendicitis than in uncomplicated cases [44]. However, another study showed no significant differences for WBC or NWR between patients with perforated and non-perforated acute appendicitis [45]. Elangoven et al. [46] showed a very high predictive value and an increased percentage of band forms (>6%) in predicting acute appendicitis in patients aged ≥60 years. Leukocytosis also increased the specificity in that study. In recent years, some hematological parameters such as NLR have gained importance in addition to classical blood counts. The NLR is a pro-inflammatory marker in some studies [47–49]. NLR is a simple, cheap, and effective biomarker. It has been widely investigated for predicting morbidity and mortality in inflammatory disorders, neoplastic diseases, and solid tumors [50–54]. Recent studies have suggested that the NLR can predict cardiovascular diseases and cancer [47–49]. The predictive value of NLR in acute appendicitis was first studied by Goodman et al. [55]. The NLR is more sensitive than the WBC count in predicting acute appendicitis. Here, the NLR was higher in the non-geriatric group, but the difference was not significant. Cigsar et al. [56] investigated 755 patients who underwent surgery with a pre-diagnosis of appendicitis and grouped the patients as geriatric and non-geriatric. The patients were also grouped as positive or negative appendectomy according to postoperative pathological analysis. The NLR was higher in both the geriatric and non-geriatric patients with a positive appendectomy. The cutoff value of NLR was determined to be 4.90 with a sensitivity of 73.3% and specificity of 73.3%. When the age, gender, and

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NLR were analyzed together in the negative and positive appendectomy groups, the NLR could independently predict positive appendectomy (p<0.001). Sevinc et al. also found NLR to be predictive for appendicitis with a positive predictive value of 0.89 in patients aged >15 years [38]. Jung et al. studied patients with acute appendicitis and found that the highest AUC value among inflammatory markers for predicting perforation was with NLR [41]. The NLR marker points to subclinical inflammation. It has been investigated in several studies including in patients with acute appendicitis [57]. Aydin et al. [58] investigated 195 patients with acute complicated or noncomplicated appendicitis. The cutoff values for WBC and NLR were >13.8×103/µL (AUC=0.614) and >4.87 (AUC=0.641), respectively. The OR of WBC and NLR were calculated for complicated appendicitis (3.103 and 3.025, respectively). Other studies have compared the NLR in patients with acute appendicitis to those in patients with other acute abdominal pain. For example, increased WBC and NWR were found to be predictive for appendicitis in a study of renal colic and acute appendicitis [59]. MPV is another marker of inflammation. It has been broadly investigated in clinical studies. MPV reflects the platelet size and is part of a CBC analysis; however, practitioners often overlook its importance [60]. It can indicate inflammation and disease activity in several conditions including acute coronary syndromes, inflammatory bowel diseases, and pancreatitis [61]. It has been postulated that MPV is an inflammatory marker in severe inflammatory conditions—primarily acute appendicitis. Here, the MPV value was higher in geriatric patients with acute appendicitis than the non-geriatric group. However, this parameter had an inadequate value in predicting acute appendicitis—at an optimum cutoff value of 9.25, the AUC level was <0.6. Previously, MPV levels in patients with acute appendicitis (n=226) were found to be lower than normal [62]. However, contrasting results were also detected in other studies. Narci et al. [63] compared patients with acute appendicitis (n=503) to a control group (n=121). The MPV levels were statistically significantly higher in patients with acute appendicitis (median MPV=7.92 fL) than the control group (median MPV=7.43 fL) (p<0.001). The optimum cutoff value was 7.87 fL according to the ROC analysis (AUC=0.62). Studies on the predictive value of MPV in geriatric patients with acute appendicitis are limited.

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Bilirubin levels have been proposed to an appendicitis prediction tool. Although the value of hyperbilirubinemia for predicting severe appendicitis is well known [64], this parameter has not been used in routine clinical management. Some authors have suggested that bilirubin levels predict complicated appendicitis. However, in our study, there was no significant difference between the geriatric and non-geriatric groups according to bilirubin levels. In a study evaluating 103 geriatric patients with acute appendicitis, bilirubin was found to be predictive for perforation [41]. In that study, the cutoff value, odds ratio, and AUC values for total bilirubin were 0.7 mg/dL, 4.41, and 0.646, respectively. Further studies are needed in geriatric patients to evaluate the predictive value of bilirubin in appendicitis. There is no single symptom or clinical sign, laboratory test, or radiological finding to make a precise diagnosis of acute appendicitis. It is absolutely necessary to consider all clinical and laboratory findings, as well as the radiological methods for diagnosing acute appendicitis. Further studies are required to clearly define the predictive values of inflammatory markers in geriatric patients with acute appendicitis. In conclusion, the results showed that WBC and lymphocyte counts as well as the NLR were higher in the nongeriatric group. The NWR and MPV were higher in the geriatric group. The WBC counts >12.11×103/µL were predictive for acute appendicitis in the geriatric group. Ethics Committee Approval: This study, which was approved by the ethical board of the Istanbul Training and Research Hospital (09/22/2017-1090). 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. Authorship Contributions: Concept – CT, SB; Design – SB, EC; Supervision – EK, MMS; Materials – EC, MMS; Data collection and/or processing – SC, MMS, EC; Analysis and/or interpretation – BG, CT; Writing – CT, SB; Critical review – KT, MEG.

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Original Images

RADIOLOGICAL

North Clin Istanb

2019;6(3):302–303 doi: 10.14744/nci.2018.25991

Ascariasis-associated perforated appendicitis: Computed tomography findings Serdar Aslan,

Mehmet Selim Nural

Department of Radiology, Ondokuz Mayis University Faculty of Medicine, Samsun, Turkey

Cite this article as: Aslan S, Nural MS. Ascariasis-associated perforated appendicitis: Computed tomography findings. North Clin Istanb 2019;6(3):302–303.

57-year-old woman was admitted to our emergency department with complaints of newly developed widespread abdominal pain and high fever. The patient’s medical history was unremarkable except hypertension. Physical examination conducted revealed widespread sensitivity in the abdomen and rebound in the lower right quadrant. Blood test showed increased WBC (26500/ µL). Eosinophil level was normal. Abdominal X-ray revealed the presence of a few air–fluid levels in the right lower quadrant. Computed tomography (CT) (Discovery CT750 HD, GE Healthcare) was performed with a preliminary diagnosis of perforated acute appendicitis in the patient. The CT examination revealed that the appendiceal diameter of 20 mm in the widest area and an incidence of appendicitis appearance in the proximal section. In the proximal segment, there was absence in the appendiceal wall and a 50×30 mm collection of air was observed in

the adjacent fatty tissue. In the distal segment, the appendiceal wall integrity was disturbed in some places and small perforated areas were observed (Fig. 1). Moreover, wall thickening in the cecal and ileal segments and thin band-like structures in the cecal and jejunal segments were present (Fig. 2). Considering these findings, a diagnosis of perforated appendicitis due to parasitic infection was considered. The patient underwent emergent surgery. It was observed that the appendix was perforated from the proximal segment and the cecum was completely filled with parasites. The diagnosis of perforated appendicitis due to ascariasis with surgical findings was confirmed. Ascariasis is the most common parasitic infection worldwide. Ascariasis carriers are typically asymptomatic. Acute appendicitis may occur due to the occlusion of the appendiceal lumen by adult Ascaris worms or may result from the secondary infection of Ascaris eggs. Ultrasonography is the imaging

Figure 1. Axial CT image showing the proximal perforation area of the appendix (green arrow) and the small abscess formation (red arrow).

Figure 2. Coronal CT image showing the worms appearing in numerous thin band patterns in the cecal and jejunal segments (green arrows).

Received: March 24, 2018 Accepted: August 23, 2019 Online: August 27, 2019 Correspondence: Dr. Serdar ASLAN. Ondokuz Mayis Universitesi Tip Fakultesi, Radyoloji Anabilim Dali, 55139 Kurupelit, Samsun, Turkey. Tel: +90 362 312 19 19 e-mail: serdaraslan28@hotmail.com © Copyright 2019 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

Aslan et al., Ascariasis-associated perforated appendicitis: Computed tomography findings

method used for patients with acute appendicitis. Using this method, worms appear as moving echogenic tubular structures. Perforated appendicitis due to ascariasis is rare. However, ultrasonography may be inadequate in cases of perforated appendicitis. In such cases, CT as an imaging method is quite effective. The appearance of thin

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band-like folded structures in bowel segments in CT could lead to a suspected diagnosis of ascariasis. Parasitic infections should be considered, particularly in endemic areas that encompass various causes of acute appendicitis. CT facilitates the identification of the cause of acute appendicitis and reveals whether it is perforated.

Case Report

CARDIOLOGY

North Clin Istanb

2019;6(3):304–307 doi: 10.14744/nci.2018.65148

Unusual combined cause of Takotsubo cardiomyopathy: Hyponatremia and seizure Ersin Cagri Simsek,1

Sadik Volkan Emren,2

Oner Ozdogan1

Department of Cardiology, Tepecik Training and Research Hospital, Izmir, Turkey

Department of Cardiology, Katip Celebi University Ataturk Training and Research Hospital, Izmir, Turkey

ABSTRACT Takotsubo cardiomyopathy (TTC) is characterized by transient systolic dysfunction of the left ventricle and changes of electrocardiographic or cardiac markers, resembling an acute coronary syndrome. Although the etiology of TTC is still unknown, a wide variability in the psychological and physical triggers for TTC is present. In this article, we describe the case of 69-year-old female with a history of epilepsy and who presented in the emergency room with a new-onset generalized tonic–clonic seizure activity. After finding out that her biochemistry results indicated severe hyponatremia, a diagnosis of TTC was established through echocardiography and angiography. Keywords: Apical ballooning syndrome; Takotsubo cardiomyopathy; hyponatremia; seizure.

Cite this article as: Simsek EC, Emren SV, Ozdogan O. Unusual combined cause of Takotsubo cardiomyopathy: Hyponatremia and seizure. North Clin Istanb 2019;6(3):304–307.

akotsubo cardiomyopathy (TTC) is characterized by transient systolic dysfunction of the left ventricle and changes of electrocardiographic or cardiac markers, resembling an acute coronary syndrome. Mostly, TTC develops following emotional or physical stress in the absence of obstructive coronary disease or without angiographic evidence of acute plaque rupture [1–4]. The pathophysiology of TTC is unclear. An excessive release of catecholamines following emotional or physical stress seems to have a pivotal role in the development of TTC [5]. On the other hand, TTC can be triggered by some noncardiac clinical conditions such as hyponatremia and seizure [6–10]. In this article, we describe a case of TTC that developed following seizure and severe hyponatremia. CASE REPORT A 69-year-old female having a history of epilepsy was presented to the emergency room with a new-onset generalized tonic–clonic seizure activity. Upon admis-

sion, there was no chest pain or any cardiac symptom. Her medical history indicates she had hypertension and epilepsy, and these were treated with indapamide, carbamazepine, and levetiracetam. Her physical examination was unremarkable. Moreover, routine laboratory values revealed her serum sodium level was 112 mmol/L, initial troponin was 7.13 ng/mL (normal range 0.0–0.06 ng/ mL), and serum carbamazepine concentration was 7.1 ng/mL (therapeutic range 4–12 ng/mL). The first electrocardiogram (ECG) showed sinus rhythm with diffuse upsloping 1 mm ST-segment elevation (Fig. 1). After transthoracic echocardiography (TTE), there was apical hypokinesia with an estimated ejection fraction (EF) of 36% (Fig. 2). Although TTC was suggested after initial clinical findings, the patient underwent coronary angiography to rule out coronary artery disease. After the procedure, it was found that coronary angiography revealed no stenosis in any coronary artery (Fig. 3) and that left ventriculography showed anteroapical, inferoapical, and apical akinesis (Fig. 4).

Received: November 12, 2017 Accepted: July 02, 2018 Online: August 08, 2018 Correspondence: Dr. Ersin Cagri SIMSEK. Tepecik Egitim ve Arastirma Hastanesi, Kardiyoloji Klnigi, 35110 Yenisehir, Izmi̇ r, Turkey. Phone: +90 232 244 35 60 e-mail: ercagsim@hotmail.com © Copyright 2019 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

Simsek et al., Unusual combined cause of Takotsubo cardiomyopathy: Hyponatremia and seizure

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Figure 1. Electrocardiogram showing sinus rhythm with diffuse 1 mm upsloping ST-segment elevation.

Figure 3.

Coronary angiography showing normal coronary

arteries.

Figure 2. Transthoracic echocardiography demonstrating apical hypokinesia with an ejection fraction estimated at 36% in apical 4-chamber view. (A) Left ventricle systole. (B) Left ventricle diastole, red arrow; apical hypokinesia. (LA: left atrium; RA: Right atrium; RV: Right ventricle). Figure 4. Hypothyroidism and adrenal insufficiency, both are causes of hyponatremia, were ruled out by determining thyroid-stimulating hormone levels [1.5 μIU/mL (normal range 0.5–6.2 μIU/mL)] and serum cortisol levels [20 μg/dL (normal range 10–20 μg/dL)]. After suffering from withdrawal to both indapamide and carbamazepine, the patient was subsequently treated with an intravenous infusion of 3% saline, and her sodium then increased to 135 mmol/L at the end of the first week. In this context, it was thought that TTC develops by hyponatremia due to indapamide and carbamazepine. There was then a discharge on aspirin (100 mg/d), metoprolol (50 mg twice daily), ramipril (5 mg/d), subcutaneous enoxaparin (0.8 mL twice daily), valproic acid (500 mg twice daily), and levetiracetam (500 mg twice daily) and a discontinuation of carbamazepine and indapamide treatment. Full recovery of EF (60%) was demonstrated through TTE at two weeks of discharge (Fig. 5). After two months, the patient

Left ventriculography demonstrating apical ballooning in the right anterior oblique view. (A) Left ventricle in systole. (B) Left ventricle in diastole.

Figure 5.

Control TTE showing full recovery in apical 4-chamber view after two weeks. (A) Left ventricle systole. (B) Left ventricle diastole.

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was referred to the hospital after suffering from recurrent hyponatremia with a serum sodium level of 115 mmol/L. However, she presented with no cardiac symptoms and seizure. ECG and TTE also did not show any ST-segment changes or wall motion abnormality. Because of this, treatment with carbamazepine, after being stopped on the first hospital admission, had to be started and continued with a lower limit of therapeutic range [4.55 ng/mL (therapeutic range 4–12 ng/mL)] to prevent epileptic seizures. DISCUSSION Although its pathophysiology is unclear, TTC is defined as a reversible left ventricular hypokinesis. It was proposed that coronary artery vasospasm, transient obstruction of the left ventricular outflow tract, and microcirculatory dysfunction are the possible causes of this disease [11]. Hyponatremia is the most common electrolyte disorder in hospitalized patients, and its severity is determined according to serum sodium levels that are categorized into three: mild (serum sodium, 130–134 mmol/L), significant (125–129 mmol/L), and severe (<125 mmol/L) [12]. While asymptomatic patients do not require immediate correction, symptomatic hyponatremia is a medical emergency that needs prompt and prudent treatment. Moreover, acute severe hyponatremia is associated with neurologic symptoms, such as seizures and coma, and should be treated meticulously to prevent cerebral edema and encephalopathy. In present case, several clinical factors revealed that seizure is not associated with acute severe hyponatremia. First, the patient has been suffering from recurrent seizures due to epilepsy for a long time. Second, hyponatremia in this patient is chronic and recurrent. This patient is suffering from severe hyponatremia due to several contributing factors including drugs such as carbamazepine and indapamide. The association between hyponatremia and carbamazepine has been well described. However, the mechanisms on how carbamazepine causes hyponatremia are not fully understood. Carbamazepine may increase the secretion of antidiuretic hormone (ADH) from the posterior pituitary and sensitize the osmoreceptors to ADH in the distal convoluted tubules [13]. It can be noted that several case reports have established a causal relationship between indapamide and severe hyponatremia [14]. In this case, these two drugs (carbamazepine and indapamide) with different activity are thought to cause hyponatremia. According to the a few previous case reports, TTC is associated with severe hyponatremia in several cases,

North Clin Istanb

even with the absence of adrenal insufficiency and hypothyroidism [6, 9, 10]. In our case, we ruled out hypothyroidism and adrenal insufficiency. On the second admission, the patient had been taking carbamazepine without receiving indapamide for two months, and this eventually decreased serum sodium level similarly. On the first admission, the serum sodium level was 112 mEq/L when TTC occurred, whereas it did not occur on the second admission when the serum sodium level was 115 mEq/L. In this context, we can assume that the recurrence of hyponatremia may not induce TTC. Singh et al. reported that there was a negative correlation between the use of renin angiotensin aldosterone system blockers and the recurrence of TTC [15]. However, we speculate that if the medication was started after the first TTC, it might have prevented the recurrence of TTC in spite of recurrent hyponatremia. There is also an association between seizure and Takotsubo cardiomyopathy [16]. The mechanism of seizure-associated TTC can be explained by excessive catecholamine release during epileptic seizures. On the first admission, despite the reason of TTC occurrence was seizure instead of hyponatremia, the patient had a history of seizures. Because of this, we are unable to determine whether TTC occurred together with the previous seizures. In fact, both hyponatremia and seizure might separately cause TTC; however, we conclude that both hyponatremia and seizure were predisposing factors together in the present case. Informed Consent: Written informed consent was obtained from the patient for the publication of the case report and the accompanying images. 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. Authorship Contributions: Concept – ECS; Design – ECS; Supervision – SVE; Materials – ECS; Data collection &/or processing – ECS, OO; Analysis and/or interpretation – SVE; Writing – ECS; Critical review – OO.

REFERENCES 1. Prasad A, Lerman A, Rihal CS. Apical ballooning syndrome (Tako-Tsubo or stress cardiomyopathy): a mimic of acute myocardial infarction. Am Heart J 2008;155:408–17. 2. Tsuchihashi K, Ueshima K, Uchida T, Oh-mura N, Kimura K, Owa M, et al. Transient left ventricular apical ballooning without coronary artery stenosis: a novelheart syndrome mimicking acute myocardial in-

Simsek et al., Unusual combined cause of Takotsubo cardiomyopathy: Hyponatremia and seizure

5. 6.

farction. Angina Pectoris-Myocardial Infarction Investigations in Japan. J Am Coll Cardiol 2001;38:11–8. Parodi G, Bellandi B, Del Pace S, Barchielli A, Zampini L, Velluzzi S, et al. Natural history of tako-tsubo cardiomyopathy. Chest 2011;139:887–92. Kurowski V, Kaiser A, von Hof K, Killermann DP, Mayer B, Hartmann F, et al. Apical and midventricular transient left ventricular dysfunction syndrome (tako-tsubo cardiomyopathy): frequency, mechanisms, and prognosis. Chest 2007;132:809–16. Nef HM, Möllmann H, Akashi YJ, Hamm CW. Mechanisms of stress (Takotsubo) cardiomyopathy. Nat Rev Cardiol 2010;7:187–93. Worthley MI, Anderson TJ. Transient left ventricular apical ballooning syndrome following a hyponatraemicseizure. Int J Cardiol 2007;115:e102–4. Lemke DM, Hussain SI, Wolfe TJ, Torbey MA, Lynch JR, Carlin A, et al. Takotsubo cardiomyopathy associated with seizures. Neurocrit Care 2008;9:112–7. Kawano H, Matsumoto Y, Arakawa S, Hayano M, Fijisawa H. Takotsubo cardiomyopathy in a patient with severe hyponatremia associated with syndrome of inappropriate antidiuretic hormone. Intern Med 2011;50:727–32. AbouEzzeddine O, Prasad A. Apical ballooning syndrome precipitated

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by hyponatremia. Int J Cardiol 2010;145:e26–9. 10. Sagiv O, Vukelic S, Czak S, Messineo F, Coplan NL. Apical ballooning syndrome associated with isolated severe hyponatremia: case report and suggested pathophysiology. Rev Cardiovasc Med 2012;13:e198–202. 11. Komamura K, Fukui M, Iwasaku T, Hirotani S, Masuyama T. Takotsubo cardiomyopathy: Pathophysiology, diagnosis and treatment. World J Cardiol 2014;6:602–9. 12. Spasovski G, Vanholder R, Allolio B, Annane D, Ball S, Bichet D, et al. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Eur J Endocrinol 2014;170:G1–47. 13. Kuz GM, Manssourian A. Carbamazepine-induced hyponatremia: assessment of risk factors. Ann Pharmacother 2005;39:1943–6. 14. Santos M, Dias V, Meireles A, Gomes C, Luz A, Mendes D, et al. Hyponatremia-an unusual trigger of Takotsubo cardiomyopathy. Rev Port Cardiol 2011;30:845–8. 15. Singh K, Carson K, Usmani Z, Sawhney G, Shah R, Horowitz J. Systematic review and meta-analysis of incidence and correlates of recurrence of takotsubo cardiomyopathy. Int J Cardiol 2014;174:696–701. 16. Sakuragi S, Tokunaga N, Okawa K, Kakishita M, Ohe T. A case of takotsubo cardiomyopathy associated with epileptic seizure: reversible leftventricular wall motion abnormality and ST-segment elevation. Heart Vessels 2007;22:59–63.

Case Report

ENDOCRINOLOGY

North Clin Istanb

2019;6(3):308–311 doi: 10.14744/nci.2018.57625

46 XX male syndrome with hypogonadotropic hypogonadism: A case report Mehmet M Yalcin,1 Alev Altinova,1

Cigdem Ozkan,1

Ayhan Karakoc,1

Mujde Akturk,1

Goksun Ayvaz,1

Ferda Emriye Percin,2 Nuri Cakir1

Department of Endocrinology and Metabolism, Gazi University Faculty of Medicine, Ankara, Turkey

Department of Medical Genetics, Gazi University Faculty of Medicine, Ankara, Turkey

ABSTRACT We report a 46 XX male syndrome diagnosed after failure of gonadotropin therapy taken for hypogonadotropic hypogonadism due to a pituitary macroadenoma. A 39-year-old man with a non-functioning pituitary macroadenoma was admitted to our clinic due to vision loss and infertility. After pituitary surgery, vision loss improved while infertility still existed. Low testosterone levels without elevated gonadotropins were established suggesting hypogonadotropic hypogonadism due to pituitary adenoma. Gonadotropin treatment was initiated. There was no response to treatment after 12 months. A karyotype analysis was ordered to investigate other causes of infertility. Karyotype analysis showed a 46 XX male syndrome that can explain the failure of gonadotropin therapy. Testosterone therapy was started instead of gonadotropin therapy. 46 XX male syndrome usually presents with hypergonadotropic hypogonadism. However, in our case, it presented with hypogonadotropic hypogonadism due to pituitary mass not responding to gonadotropin therapy. It is important to keep in mind to obtain a genetic analysis of patients whose gonadotropin therapy failed, even if their gonadotropin levels are not elevated. Keywords: Hypogonadism; infertility; 46 XX male.

Cite this article as: Yalcin MM, Ozkan C, Akturk M, Percin FE, Altinova A, Karakoc A, et al. 46 XX male syndrome with hypogonadotropic hypogonadism: A case report. North Clin Istanb 2019;6(3):308–311.

nfertility is defined as the inability of achieving pregnancy without contraception in a couple regularly having intercourse for 1 year [1]. It may occur due to male factors (30%), female factors (45%), or both (25%). Male factors can be categorized as sexual disorders, primary testicular defect in sperm production, endocrinopathies that affect spermatogenesis, and defects in sperm transportation. According to Jungwirth et al., 10.1% of infertile males have hypogonadism that can be defined as the inability of the testicles to produce testosterone [2]. Hypogonadism is divided into two categories according to gonadotropin levels: hypergonadotropic hypogonadism (primary hypogonadism) and hypogonadotropic hypogonadism (secondary hypogonadism). Differential diagnosis of hypogonadism is crucial for the treatment of fertility. Gonadotropin therapy could achieve pregnancy in

patients with hypogonadotropic hypogonadism, which is different from hypergonadotropic hypogonadism. It can be hard to diagnose or treat a patient with different causes of hypogonadism. Here, we report a case with 46 XX male syndrome presenting with hypogonadotropic hypogonadism due to coexisting non-functioning pituitary adenoma. CASE REPORT A 39-year-old man was referred to our clinic with a pituitary mass. He had right-sided vision loss that occurred suddenly. A 45×28×40 mm pituitary adenoma was detected while evaluating vision loss. Hormonal analyses showed hypogonadotropic hypogonadism without any excess or deficient hormone levels as shown in Table 1.

Received: November 26, 2017 Accepted: April 12, 2018 Online: September 05, 2018 Correspondence: Dr. Mehmet M. YALCIN. Dr. Ersin Arslan Egitim ve Arastirma Hastanesi, Sahinbey, Gaziantep Turkey. Phone: +90 505 525 25 48 e-mail: yalcin.muhittin@gmail.com © Copyright 2019 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

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Table 1. Testosterone, FSH, LH, prolactin, and estradiol levels; testicular volume; and semen analysis before and after treatment

Before the first operation

Before the second operation

Before gonadotropin treatment

After 1 years of gonadotropin treatment

32.0 4.1 1.71 7.7 14 R: 1.6 mL R:1.4 mL No sperm

76.0 5.5 1.64 18.7 <10 L: 1.4 mL L: 1.5 mL No sperm

Total testosterone (ng/dL) (262–1593) 23.8 36.0 FSH (mIU/mL) (0.70–11.0) 6.5 4.6 LH (mIU/mL) (0.80–7.60) 1.97 1.50 Prolactin (mg/mL) (2.50–17.0) 14.0 12.4 Estradiol (pg/mL) (11–44) NA 24 Testicular volume (-) (-) Semen analysis No sperm No sperm

Normal ranges for analyses were given in the paranthesis. FSH: Follicle stimulating hormone; LH: Luteinizing hormone; NA: Not available.

A transcranial pituitary adenomectomy was performed. The pathology of the surgical specimen was considered as an adenoma that had no immunostaining for thyroidstimulating hormone (TSH), adrenocorticotropic hormone (ACTH), growth hormone (GH), and prolactin. After the operation, his vision loss improved. When he was readmitted to our clinic, he was suffering from loss of libido, infertility, headaches, and relapsing of vision loss on the right side of the eye that started 4 years after his pituitary operation. He had no child. His height and weight were 161 cm and 71 kg, respectively, with a body mass index of 27.4 kg/m2. His physical examination was normal, except for bilateral gynecomastia and small testicles. Hormonal analyses showed hypogonadotropic hypogonadism as shown in Table 1. Magnetic resonance imaging of the pituitary gland revealed a 37×32×28 mm residual pituitary mass. Second pituitary adenomectomy was performed, but there was still a residual pituitary mass of 24×25×20 mm after the second operation (Fig. 1). Histopathology of the specimen revealed pituitary adenoma without immunostaining for TSH, ACTH, GH, and prolactin. Although the patient had no headaches and vision problems after the operation, he was still suffering from loss of libido and infertility. According to his laboratory results, hypogonadotropic hypogonadism still existed, and there was no any disturbance of other pituitary hormones (Table 1). Ultrasonography of the testicles revealed that both testicles were small as shown in Table 1. His semen analysis showed no sperm since the patient and his wife desired to have a child. Initially, human chorionic gonadotropin (hCG) (1500 units, 3 days/week) treatment was started.

Figure 1. Pituitary magnetic resonance imaging after the second operation.

After 3 months, as testicular volume was still too small and there was no improvement on testosterone levels, hCG dose was increased to 3000 units for 3 days/week, and human menopausal gonadotropin (hMG) 75 μg for 3 days/week was added to hCG treatment. Then, hMG treatment was increased up to 150 μg for 3 days/week while he was on hCG (3000 units, 3 days/week). After 12 months, because of no improvement on both testosterone levels, sperm production, and testicular size, a

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chromosomal analysis was performed to investigate other causes of infertility. As a result of the analysis, GTG banding procedure was performed on metaphase chromosomes obtained from peripheral blood lymphocytes of the patient. The karyotype 46 XX was observed on 100 metaphases to exclude mosaicism and chimerism. Diagnostic testing of deletions of the sex-determining region Y (SRY), ZFY genes, and AZF region located on the long arm of the Y chromosome was performed by realtime polymerase chain reaction (PCR) amplification. The set of PCR primers that was used in multiplex PCRs for the diagnosis of microdeletion of these regions included: sY14 (SRY), ZFX/ZFY, sY84, sY86, sY127, sY134, sY254, and sY255. Molecular analysis revealed that ZFY and SRY genes were intact, but AZF region was deleted. Therefore, SRY+ 46 XX male sex reversal was diagnosed. Since no treatment could induce spermatogenesis in 46 XX males, testosterone therapy was started instead of gonadotropin therapy. A genetic consultation and alternative ways of having a child (e.g., adoption) were recommended to the couple. In addition, the couple was advised to have psychological support if they needed it. DISCUSSION We presented an infertile patient with hypogonadotropic hypogonadism due to a pituitary adenoma in whom fertility treatment with hCG and hMG failed. Underlying 46 XX male syndrome was diagnosed after chromosomal analysis. Hypergonadotropic hypogonadism can be defined as elevated gonadotropin levels in a male with hypogonadism. Testicular diseases should be investigated for the etiology of hypergonadotropic hypogonadism. Gonadotropin treatment is considered for sperm induction in males with hypogonadotropic hypogonadism. Although hypogonadotropic hypogonadism is the cause of only 2%–3% of male infertility, fertility and sperm production can be achieved with gonadotropin treatment only in this group [3]. Congenital factors, such as Kallmann syndrome and idiopathic hypogonadotropic hypogonadism, or acquired forms, such as hypothalamopituitary tumors, granulomatous diseases, empty sella syndrome, obesity, and the use of anabolic steroids, can cause hypogonadotropic hypogonadism. Non-functioning pituitary adenomas may lead to hypogonadotropic hypogonadism, because of the mass effect of the adenoma or complication of pituitary surgery. After removing the adenoma–the underlying cause of hypogonadism–, fer-

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tility can be achieved spontaneously in some cases. Fertility can be achieved by gonadotropin treatment (hCG and hMG) in patients with persistent hypogonadism despite surgical treatment. hCG treatment can induce sperm production by increasing intratesticular testosterone levels [3, 4]. hMG can be added to hCG therapy, if adequate sperm production could not be achieved after 3–6 months of therapy with hCG [5–9]. Pregnancy has been shown to be achieved in 40%–53% of patients with gonadotropin replacement therapy in 24–36 months [4, 5]. If there is no improvement in fertility despite using gonadotropin treatment, the clinician should investigate for other diseases that lead to male infertility etiologies. According to the algorithm for infertile men published by Anawalt et al., a chromosomal analysis is recommended if gonadotropin treatment fails in a man with hypogonadotropic hypogonadism [5]. Actually, genetic analysis is recommended for patients with hypergonadotropic hypogonadism, whereas it is not a routine investigation for patients with hypogonadotropic hypogonadism [5, 10]. The prevalence of chromosomal abnormalities in infertile men has been reported as 3%–19% in different studies [11]. Although Klinefelter syndrome is the most frequent genetic disorder causing infertility, 46 XX male syndrome can be found in 0.3% of infertile men who ordered for chromosomal analysis [12]. Sex reversal syndromes consist of 46 XY females and 46 XX males [13]. 46 XX male syndrome is a rare disorder, and it was first described by De la Chapelle et al. in 1964 [14]. It can be seen in 1 of 20,000–25,000 births [15]. It is characterized by a male phenotype with a 46 XX karyotype. 46 XX male syndrome is divided into the sex-determining region Y (SRY)+ (80%) and SRY− (20%) according to the presence of the SRY region on the X chromosome. SRY− 46 XX males often have genital anomalies and loss of masculinization as they are almost always diagnosed at early childhood [16]. SRY+ 46 XX males often have normal puberty, whereas some of them have cryptorchidism [16]. They are often diagnosed while evaluating for infertility or gynecomastia in early adulthood. They have normal secondary sexual characters, but they do not produce sperm. Elevated gonadotropin levels are often determined while testosterone levels can be low, normal, or even high [16]. None of the infertility treatments induce sperm production. In our case, FSH level was inappropriately in normal range, whereas LH level was low. Gonadotropin levels cannot be elevated despite low testosterone levels in hypogonadotropic hypogonadism. However, FSH levels,

Yalcin et al., 46 XX male syndrome with hypogonadotropic hypogonadism

which were in normal range in our case, could be related with 46 XX male syndrome, because highly elevated FSH levels were reported in case reports with 46 XX male syndrome [17–22]. In addition, FSH levels were almost always higher than other causes affecting the Y chromosome according to the literature [20]. We suggest that if gonadotropin therapy fails to provide a sufficient amount of testosterone level and/or an amount of sperm, which are needed in fertility, in a man with hypogonadotropic hypogonadism, other diseases that cause infertility, such as 46 XX male syndrome, should be investigated by genetic analysis. Early diagnosis for 46 XX male syndrome may be useful to provide early genetic consultation, to prevent using unnecessary painful and expensive gonadotrophin therapy, and to contribute to the early initiation of the adoption process. We report a case of 46 XX male syndrome with inappropriately normal FSH and low LH levels, in spite of there was too low testosterone levels. He was diagnosed after failure of gonadotropin therapy for hypogonadism with low levels of gonadotropins, because of pituitary adenoma. The presence of pituitary adenoma was a confounding factor and delayed the diagnosis in our case. It is important to keep in mind to obtain a genetic analysis in patients whose gonadotropin therapy failed, even if their gonadotropin levels are not elevated. To the best of our knowledge, this is the first case of 46 XX male syndrome presenting with hypogonadotropic hypogonadism due to pituitary adenoma in adults. Informed Consent: Written informed consent was obtained from the patient for the publication of the case report and the accompanying images. Conflict of Interest: The authors declare that they have no conflict of interest. Financial Disclosure: The authors declared that this study has received no financial support. Authorship contributions: All the authors participated in the clinical follow-up of the patient, F. E. P.; performed the genetic analysis including karyotype analysis and PCR analysis, M. M. Y., M. A. and A. A. wrote the manuscript, M. M. Y. and M. A. edited the manuscript.

REFERENCES 1. Gnoth C, Godehardt E, Frank-Herrmann P, Friol K, Tigges J, Freundl G. Definition and prevalence of subfertility and infertility. Hum Reprod 2005;20:1144–7. 2. Jungwirth A, Giwercman A, Tournaye H, Diemer T, Kopa Z, Dohle G, et al; European Association of Urology Working Group on Male Infertility. European Association of Urology guidelines on Male Infertility: the 2012 update. Eur Urol 2012;62:324–32.

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3. Roth MY, Page ST, Lin K, Anawalt BD, Matsumoto AM, Snyder CN, et al. Dose-dependent increase in intratesticular testosterone by very lowdose human chorionic gonadotropin in normal men with experimental gonadotropin deficiency. J Clin Endocrinol Metab 2010;95:3806–13. 4. Coviello AD, Matsumoto AM, Bremner WJ, Herbst KL, Amory JK, Anawalt BD, et al. Low-dose human chorionic gonadotropin maintains intratesticular testosterone in normal men with testosterone-induced gonadotropin suppression. J Clin Endocrinol Metab 2005;90:2595– 602. 5. Anawalt BD. Approach to male infertility and induction of spermatogenesis. J Clin Endocrinol Metab 2013;98:3532–42. 6. Fraietta R, Zylberstejn DS, Esteves SC. Hypogonadotropic hypogonadism revisited. Clinics (Sao Paulo) 2013;68 Suppl 1:81–8. 7. Zacharin M, Sabin MA, Nair VV, Dabadghao P. Addition of recombinant follicle-stimulating hormone to human chorionic gonadotropin treatment in adolescents and young adults with hypogonadotropic hypogonadism promotes normal testicular growth and may promote early spermatogenesis. Fertil Steril 2012;98:836–42. 8. Barrio R, de Luis D, Alonso M, Lamas A, Moreno JC. Induction of puberty with human chorionic gonadotropin and follicle-stimulating hormone in adolescent males with hypogonadotropic hypogonadism. Fertil Steril 1999;71:244–8. 9. Oldereid NB, Abyholm T, Tanbo TG. Spermatogenesis and fertility outcome in male hypogonadotrophic hypogonadism. Hum Fertil (Camb) 2010;13:83–9. 10. Layman LC. Hypogonadotropic hypogonadism. Endocrinol Metab Clin North Am 2007;36:283–96. 11. Martin RH. Cytogenetic determinants of male fertility. Hum Reprod Update 2008;14:379–90. 12. Hofherr SE, Wiktor AE, Kipp BR, Dawson DB, Van Dyke DL. Clinical diagnostic testing for the cytogenetic and molecular causes of male infertility: the Mayo Clinic experience. J Assist Reprod Genet 2011;28:1091–8. 13. Wang T, Liu JH, Yang J, Chen J, Ye ZQ. 46, XX male sex reversal syndrome: a case report and review of the genetic basis. Andrologia 2009;41:59–62. 14. de la Chapelle A. The etiology of maleness in XX men. Hum Genet 1981;58:105–16. 15. Rajender S, Rajani V, Gupta NJ, Chakravarty B, Singh L, Thangaraj K. SRY-negative 46,XX male with normal genitals, complete masculinization and infertility. Mol Hum Reprod 2006;12:341–6. 16. Frühmesser A, Kotzot D. Chromosomal variants in klinefelter syndrome. Sex Dev 2011;5:109–23. 17. Gunes S, Asci R, Okten G, Atac F, Onat OE, Ogur G, et al. Two males with SRY-positive 46,XX testicular disorder of sex development. Syst Biol Reprod Med 2013;59:42–7. 18. Agrawala RK, Choudhury AK, Mohanty BK, Baliarsinha AK. All males do not have 46 xy karyotype: A rare case report. Indian J Endocrinol Metab 2013;17:S271–3. 19. Anık A, Çatlı G, Abacı A, Böber E. 46,XX male disorder of sexual development:a case report. J Clin Res Pediatr Endocrinol 2013;5:258–60. 20. Chiang HS, Wu YN, Wu CC, Hwang JL. Cytogenic and molecular analyses of 46,XX male syndrome with clinical comparison to other groups with testicular azoospermia of genetic origin. J Formos Med Assoc 2013;112:72–8. 21. Gao X, Chen G, Huang J, Bai Q, Zhao N, Shao M, et al. Clinical, cytogenetic, and molecular analysis with 46,XX male sex reversal syndrome: case reports. J Assist Reprod Genet 2013;30:431–5. 22. Jain M, V V, Chaudhary I, Halder A. The Sertoli Cell Only Syndrome and Glaucoma in a Sex - Determining Region Y (SRY) Positive XX Infertile Male. J Clin Diagn Res 2013;7:1457–9.

Case Report

RADIOLOGY

North Clin Istanb

2019;6(3):312–314 doi: 10.14744/nci.2018.26566

Subperiosteal hemorrhage due to a distal femoral physeal fracture in a neonate Mesut Ozturk,1

Alparslan Yurtbay,2

Davut Keskin,2

Ahmet Veysel Polat,1

Mustafa Bekir Selcuk1

Department of Radiology, Ondokuz Mayis University Faculty of Medicine, Samsun, Turkey

Department of Orthopedics and Traumatology, Ondokuz Mayis University Faculty of Medicine, Samsun, Turkey

ABSTRACT Femoral physeal fractures have been rarely reported as a birth-related injury. As the plain radiograph findings are variable, the diagnosis may be challenging. In this case report, we describe a male neonate presenting with periosteal elevation at the left distal femur. A radiological evaluation demonstrated posteromedial displacement of the distal femoral epiphysis. The final diagnosis was subperiosteal hemorrhage due to a distal femoral physeal fracture. Keywords: Birth injuries; distal femur; neonate; subperiosteal hemorrhage; physeal fracture.

Cite this article as: Ozturk M, Yurtbay A, Keskin D, Polat AV, Selcuk MB. Subperiosteal hemorrhage due to a distal femoral physeal fracture in a neonate. North Clin Istanb 2019;6(3):312–314.

irth-related limb injuries have been rarely reported. This spectrum includes simple bruises, swelling, forceps scars, loss of the nerve and motor function, or rarely a fracture [1]. Injuries related to the femur are usually found at the shaft and proximal physis, but distal femoral physeal fractures are rarely reported [1–3]. Herein, we reported a male newborn with the periosteal elevation at the left distal femur. Magnetic resonance imaging (MRI) demonstrated a distal femoral physeal fracture. CASE REPORT An informed consent was obtained for this case presentation. A 13-day-old male neonate was referred to our health center with the complaint of swelling and immobility in his left thigh. He was born at the 40th gestational week by a vaginal delivery with an APGAR score of 10. He was appropriate for the gestational age, and his birth weight was 3400 g. An initial physical examination was unremarkable. The obstetrician reported no complications related to delivery. The mother attended her follow-

ups regularly during the pregnancy, and the pregnancy was uneventful. At the 2nd day following birth, the mother noticed soft tissue swelling around the patient’s left knee and distal femur. On physical examination, there was slight swelling around the left knee and distal femur. Femoral and dorsal pedal pulses were palpable. The range of motion at the knee joint was normal without any evidence of joint instability or dislocation. His white blood cell count was 11,090 /µL, the hemoglobin level 14.2 g/dl, platelet count 629,000 /µL, and serum C-reactive protein level <1 mg/L. Coagulation parameters including the prothrombin time and activated partial thromboplastin time were also within the normal range. Plain radiograph of the region was normal. The patient started to receive antibiotic treatment for 10 days with a preliminary diagnosis of soft tissue infection. After the antibiotherapy, his swelling around the left distal femur was still present. A repeated radiograph of the left thigh demonstrated a periosteal reaction around the left distal femur (Fig. 1). No fracture line could be identified, but a slight poste-

Received: December 31, 2017 Accepted: April 13, 2018 Online: August 08, 2018 Correspondence: Dr. Mesut OZTURK. Ondokuz Mayis Universitesi Tip Fakultesi, Radyoloji Anabilim Dali, 55132 Samsun, Turkey. Phone: +90 362 312 19 19 - 2541 e-mail: dr.mesutozturk@gmail.com © Copyright 2019 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

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Figure 1. A radiograph of the left femur and knee demonstrates periosteal reaction (arrowheads) and soft tissue swelling at the left distal femur. Slight posterior displacement of the femoral epiphyseal ossification center is visible (arrow). No fracture line is identified.

Figure 3. Sagittal T2-weighted magnetic resonance imaging of the left thigh shows posterior displacement of the distal physeal (asterix) and periosteal elevation (arrowheads) around the distal femur (F). Figure 2. Sagittal ultrasound image of the left distal femur shows a calcified periosteal elevation (arrowheads) at the distal femur (F).

rior displacement of the distal femoral epiphysis was suspected. Further investigation with ultrasound (US) demonstrated a calcified periosteal elevation (Fig. 2). The patient underwent an MRI, which demonstrated posterior displacement of the distal femoral epiphysis (Fig. 3). A femoral physeal fracture and subperiosteal hemorrhage was the final diagnosis. Serum vitamin C levels in both the patient and his mother were tested to rule out neonatal scurvy, and they were within the normal range. A skeletal survey was performed to rule out a non-accidental trauma, and no other fractures were identified. Metabolic tests for osteogenesis imperfecta were negative. The family was advised that

the fracture was already in the healing process, and no active therapeutic intervention was needed. The infant was discharged and closely followed up. The follow-up plain radiograph performed 3 weeks later demonstrated a periosteal new bone formation at the distal femur (Fig. 4). DISCUSSION A distal femoral physeal fracture is a rare birth-related injury causing subperiosteal hemorrhage in newborns. It may occur after a difficult vaginal or cesarean delivery [2, 3]. Traumatic femoral physeal fractures are usually associated with a sudden, forced traction of the limb, with acute angulation or twisting. The force causes rupture at the epiphyseal attachment of the periosteum, where is the weakest portion [2]. A tear in the periosteum results in subperiosteal hemorrhage, which gradually calcifies and

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Figure 4. Follow-up plain radiograph of the left femur shows periosteal new bone formation (arrowheads).

results in callus and new subperiosteal bone formation. Infants present with swelling, erythema, and tenderness at the affected area. It is often mistaken for septic arthritis or osteomyelitis, and many patients receive antibiotics [3]. Coexistence of the subperiosteal hemorrhage with an epiphyseal fracture is important to exclude other causes of subperiosteal hemorrhage such as infection, tumor, or scurvy [4]. Initial radiographs of a physeal fracture in a neonate may demonstrate soft tissue swelling, but if the physis is not ossified, they may reveal no bone abnormality. Plain radiograph findings include epiphyseal displacement, widening of the physis, and haziness of the smooth margins of the metaphysis and epiphysis [5]. MRI and US proved to be useful in making the correct diagnosis [3, 6, 7]. They may show the periosteal elevation around the distal femur and displacement of the epiphysis. If the periosteal reaction calcifies, an acoustic shadow due to calcification may obscure the fracture. Follow-up radiographs can confirm the diagnosis by showing a periosteal reaction and new bone formation at the injured site [5]. Treatment strategies differ widely, from an uneventful spontaneous healing process to a closed reduction [8]. An initial evaluation of our patient was in another local hospital, and the initial radiograph was evaluated as normal by a pediatrician. There was no history of any birth-related complication, so a physeal fracture was not considered in the differential list, and the patient received antibiotics for a preliminary diagnosis of a soft tissue in-

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fection. After the patient did not respond to the medical therapy and the immobility of the joint was noticed, he was re-evaluated in our center. A combined interpretation of the plain radiograph and MRI of the region demonstrated a distal femoral physeal fracture. As the physeal fractures are rare, and their radiological findings are variable, they present a diagnostic challenge in newborns. Physeal fractures should be considered in the differential list in any neonate presenting with a limb swelling. Thus, invasive procedures such as joint aspiration for diagnostic purposes or unnecessary use of antibiotics can be avoided. An MRI is very helpful in making the correct diagnosis. Pediatricians, orthopedists, and radiologists dealing with newborns should be familiar with this rare condition. Informed Consent: Written informed consent was obtained from the patient for the publication of the case report and the accompanying images. Conflict of Interest: The authors declare that they have no conflict of interest. Financial Disclosure: The authors declared that this study has received no financial support. Authorship Contributions: Concept – MO, AY; Design – MO, AY; Supervision – MO, AY, DK, AVP, MBS; Materials – MO, AY, DK, AVP, MBS; Data collection &/or processing – MO, AY; Analysis and/or interpretation – MO, AY; Writing – MO, AY, DK, AVP, MBS.

REFERENCES 1. Kancherla R, Sankineani SR, Naranje S, Rijal L, Kumar R, Ansari T, et al. Birth-related femoral fracture in newborns: risk factors and management. J Child Orthop 2012;6:177–80. 2. Rutherford Y, Fomufod AK, Gopalakrishnan LJ, Beeks EC. Traumatic distal femoral periostitis of the newborn: a breech delivery birth injury. J Natl Med Assoc 1983;75:933–5. 3. Jain R, Bielski RJ. Fracture of lower femoral epiphysis in an infant at birth: a rare obstetrical injury. J Perinatol 2001;21:550–2. 4. Polat AV, Bekci T, Say F, Bolukbas E, Selcuk MB. Osteoskeletal manifestations of scurvy: MRI and ultrasound findings. Skeletal Radiol 2015;44:1161–4. 5. Rogers LF, Poznanski AK. Imaging of epiphyseal injuries. Radiology 1994;191:297–308. 6. White PG, Mah JY, Friedman L. Magnetic resonance imaging in acute physeal injuries. Skeletal Radiol 1994;23:627–31. 7. Carey J, Spence L, Blickman H, Eustace S. MRI of pediatric growth plate injury: correlation with plain film radiographs and clinical outcome. Skeletal Radiol 1998;27:250–5. 8. Kamaci S, Danisman M, Marangoz S. Neonatal physeal separation of distal humerus during cesarean section. Am J Orthop (Belle Mead NJ) 2014;43:E279–81.

Case Report

GASTROENTEROLOGY

North Clin Istanb

2019;6(3):315–316 doi: 10.14744/nci.2018.36539

Lansoprazole as an uncommon cause of anaphylaxis: What to give next? Ali Attila Aydin,1

Sedat Bilge,2

Tolga Duzenli,3

Harun Aslan,4

Guclu Aydin2

Department of Emergency Medicine, Acibadem Hospital, Istanbul, Turkey

Department of Emergency Medicine, Gulhane Training and Research Hospital, Ankara, Turkey

Department of Gastroenterology, Sultan Abdulhamid Han Training and Research Hospital, Istanbul, Turkey

Department of Internal Medicine, Koc University Hospital, Istanbul, Turkey

ABSTRACT Proton pump inhibitors (PPIs) are one of the most prescribed drugs worldwide. Anaphylactic reactions of PPIs are rare; however, several cases have been reported. Here, we report a rare case of anaphylaxis that occurred immediately following lansoprazole intake. Following the successful management in the emergency department, skin prick and oral controlled challenge tests were performed to evaluate cross-reactivity. Thereafter, lansoprazole was switched to pantoprazole, which was well tolerated. Skin prick and oral controlled challenge tests can be performed for determining the cross-reactivity of PPIs to prevent adverse reactions. Keywords: Anaphylaxis; cross-reactivity; lansoprazole; proton pump inhibitors.

Cite this article as: Aydin AA, Bilge S, Duzenli T, Aslan H, Aydin G. Lansoprazole as an uncommon cause of anaphylaxis: What to give next? North Clin Istanb 2019;6(3):315–316.

roton pump inhibitors (PPIs) are frequently prescribed drugs that are mainly used for acid peptic disorders. PPI use has shown a gradual increase; however, the incidence of adverse effects has remained constant. Although hypersensitivity reactions, such as skin rash or itching, are common, anaphylaxis caused by lansoprazole is rare and only a few cases have been reported. Here, we aimed to present a case of lansoprazole anaphylaxis that was successfully managed and to emphasize the life-threatening adverse effects of this relatively safe drug via a literature review. CASE REPORT A 42-year-old woman was admitted to our emergency department with the complaint of stomach ache lasting for 1 week. The patient was not allergic, did not have any chronic disease, or was not prescribed medications in her history. She had swallowed 30 mg of lansoprazole capsule 20 min before admission. During the physical examination, she developed difficulty in breathing and itching all over the

skin. She was quickly shifted to reanimation room from triage. During this time, her physical examination results were as follows: arterial blood pressure, 70/40 mmHg; SpO2, 92%; pulse, 117/min; and body temperature, 36°C. Further, edema in the uvula, mucous membranes, and lips and itchy erythematous plaques on her face and upper body were observed. Her breath sounds were decreased without rales and rhonchi. With the preliminary diagnosis of anaphylaxis, 0.5 mg of epinephrine was injected to the upper leg in the vastus lateralis muscle. She was monitorized and 6 L/min O2 by mask was initiated. In addition, 1200 mL of bolus 0.9% NaCl, 120 mg of methylprednisolone, 50 mg of diphenhydramine, and 50 mg of ranitidine was rapidly administered via the intravenous route. Subsequently, the hypoperfusion findings decreased within 10 min after the initial treatment; her vitals were as follows: arterial blood pressure, 110/80 mmHg; SpO2, 96%; pulse, 98/min; and body temperature, 36°C. No complications were noted throughout her follow-up period in the emergency department and she was discharged

Received: December 06, 2017 Accepted: May 28, 2018 Online: August 08, 2018 Correspondence: Dr. Tolga DUZENLI. Sultan Abdulhamid Han Egitim ve Arastirma Hastanesi, Gastroenteroloji Klinigi, Tıbbiye Caddesi, Uskudar, Istanbul Turkey. Phone: +90 216 542 35 02 e-mail: tolgaduzenli@yahoo.com © Copyright 2019 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

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after 24 h. Thereafter, skin prick tests and oral controlled challenge tests using lansoprazole, omeprazole, pantoprazole, esomeprazole, and rabeprazole were performed. An immediate positive reaction to lansoprazole was observed; however, the reaction to the remaining drugs was negative. We switched to pantoprazole, which was well tolerated. Moreover, we reported this adverse drug reaction to the Turkish Pharmacovigilance Center (TUFAM). DISCUSSION Anaphylaxis is a life-threatening systemic allergic reaction that affects respiratory and cardiovascular systems. Degranulation of the mast cells and basophiles leads to anaphylaxis. Foods, drugs, and insect bites are the most common causes of anaphylaxis. Delayed diagnosis and treatment may lead to hypoxic ischemic encephalopathy and death. In the literature, a few cases of PPI-associated anaphylaxis have been reported [1–3]. In case of our patient, she experienced anaphylaxis in the emergency department where the treatment could immediately be provided. This factor has probably contributed to the rapid improvement of the clinical condition. All reports of PPI-associated anaphylaxis in the literature emphasize the potential of anaphylaxis cause by such reliable and safe drugs. The cross-reactivity between PPIs is a challenging issue that remains debatable. In a recent case of anaphylaxis due to pantoprazole reported by Turedi et al. [4], cross-reactivity to all other PPIs was reported. However, Karabacak et al. [5] reported a case of anaphylaxis induced by lansoprazole that showed good tolerance to other PPIs including rabeprazole. Another case report by Choi SW et al. described a patient who had consumed esomeprazole 20 mg/day for 1 month without any side effects before experiencing anaphylaxis to lansoprazole [6]. Moreover, in a report by Aksu et al., anaphylaxis to lansoprazole was observed with tolerance to omeprazole [7]. On the other hand, Lobera et al. reported 9 cases of omeprazole allergy that showed no cross-reactivity with lansoprazole [8]. They stated that lansoprozole is a good alternative treatment. Our patient showed no cross-reactivity to other PPIs, which was consistent with most of the literature. Prospective large studies are required to further elucidate this incidence. A recent national multicenter retrospective study by Kepil Ozdemir S et al. evaluated the characteristics of patients with suspected PPI hypersensitivity in Turkey. Their study comprised 60 patients with PPI hypersensitivity reactions as observed using standardized skin prick, intradermal, and oral controlled challenge tests. They reported that 40 patients had anaphy-

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laxis and 17 patients had urticaria; 10 patients showed cross-reactivity to at least, 4 patients showed extensive cross-reactivity (>2 PPIs) [9]. Furthermore, in a large review reported in 2013 by Bose et al., 118 cases of immune-mediated hypersensitivity reactions to PPIs were investigated and omeprazole was the prominent drug that caused hypersensitivity reactions [10]. In conclusion, lansoprazole is a typically well-tolerated drug that can readily be prescribed. On the other hand, patients with risk factors should be identified before administering lansoprazole treatment and should be evaluated using skin prick and oral controlled challenge tests to prevent the occurrence of undesired adverse effects. Informed Consent: Written informed consent was obtained from the patient for the publication of the case report. Conflict of Interest: We do not have conflict of interest. Financial Disclosure: The authors declared that this study has received no financial support. Authorship Contributions: Concept – AAT, SB, TD; Design – AAT, SB, TD; Supervision – AAT, SB, TD, HA, GA; Materials – AAT, SB, GA; Data collection and/or processing – AAT, SB, GA; Analysis and/or interpretation – AAT, SB, TD, HA, GA; Writing – AAT, TD, HA; Critical review – AAT, SB, TD, HA, GA.

REFERENCES 1. Candar M, Gunes H, Boz BV, Kandis H, Kutlucan L, Saritas A. Asystole after the first dose of lansoprazole. Am J Emerg Med 2014;32:1302.e3–4. 2. Demirkan K, Bozkurt B, Karakaya G, Kalyoncu AF. Anaphylactic reaction to drugs commonly used for gastrointestinal system diseases: 3 case reports and review of the literature. J Investig Allergol Clin Immunol 2006;16:203–9. 3. Kara M, Tanoglu A, Kutlu A, Sirkeci O, Kekilli M. Esomeprazole: a safe alternative to lansoprazole allergy? Iran J Allergy Asthma Immunol 2014;13:296–7. 4. Turedi O, Sozener ZC, Kendirlinan R, Bavbek S. A Case of Pantoprazole Anaphylaxis with Cross Reactivity to All Proton Pump Inhibitors: Finding a Safe Alternative. Curr Drug Saf 2017;12:198–200. 5. Karabacak E, Kutlu A, Aydin E, Ozturk S. Hypersensitivity to lansoprazole with tolerance to other proton pump inhibitors: does cross-reactivity between proton pump inhibitors really exist? Allergol Immunopathol (Madr) 2013;41:136–7. 6. Choi SW, Han JM, Bae YJ, Lee YS, Cho YS, Moon HB, et al. Lessons from two cases of anaphylaxis to proton pump inhibitors. J Clin Pharm Ther 2012;37:614–6. 7. Aksu K, Kurt E. Anaphylaxis to lansoprazole with tolerance to omeprazole. Allergol Immunopathol (Madr) 2012;40:393–4. 8. Lobera T, Navarro B, Del Pozo MD, González I, Blasco A, Escudero R, et al. Nine cases of omeprazole allergy: cross-reactivity between proton pump inhibitors. J Investig Allergol Clin Immunol 2009;19:57–60. 9. Kepil Özdemir S, Öner Erkekol F, Ünal D, Büyüköztürk S, Gelincik A, Dursun AB, et al. Management of Hypersensitivity Reactions to Proton Pump Inhibitors: A Retrospective Experience. Int Arch Allergy Immunol 2016;171:54–60. 10. Bose S, Guyer A, Long A, Banerji A. Evaluation and management of hypersensitivity to proton pump inhibitors. Ann Allergy Asthma Immunol 2013;111:452–7.

Review

UROLOGY

North Clin Istanb

2019;6(3):317–319 doi: 10.14744/nci.2018.52296

History of establishment and evaluation of Ottoman-Turkish urology inside the surgical science Ayhan Verit,1 Ahmet Urkmez,2 Sedat Tellaloglu3 Department of Urology, University of Health Sciences Faculty of Medicine, Fatih Sultan Mehmet Training and Research Hospital, Istanbul, Turkey

Department of Urology, University of Health Sciences Faculty of Medicine, Haydarpasa Training and Research Hospital, Istanbul, Turkey

Department of Urology (Retaired), Istanbul University Faculty of Medicine, Istanbul, Turkey

ABSTRACT The first urological international organization occurred in Paris in 1908, and three Ottoman urologists were present among a total of 29. In that year, the Ottoman Urological society had only nine urologists, and almost all were from the Ottoman minorities with the exception of two under the main branch of General Surgery. Among them, Cemil Pasha who was the first dean and department chief of Surgery and Urology of the Medical School in a modern manner (1909) was the most dominant pioneer of the Turkish Surgery-Urology. Four beds out of 20 were separated for the urology clinic. Keywords: History of urology; Ottoman; Turkish.

Cite this article as: Verit A, Urkmez A, Tellaloğlu S. History of establishment and evaluation of Ottoman-Turkish urology inside the surgical science. North Clin Istanb 2019;6(3):317–319.

he Ottoman Empire (1299–1922) was an important historical region located at the center of the ancient three continents with Istanbul as the capital and settled near Bosporus, which is the border between Europe and Asia. Although the nineteenth century was regarded the declining period of the Empire, modern activities also had begun in this period. A western type Medical education were attempted to develop in this period. During the dissolution period in the early twentieth century, the Ottoman and German collaboration had increased in every aspect [1]. The military held the leading position in this regard. Ottoman’s first medical academy, Gülhane Military Medical Academy, was established with the contributions of the German physicians Prof., MD R. Rieder and G. Deycke in Istanbul in 1898 [2, 3]. Dr. Reider was the pioneer in the usage of ether instead of chloroform for the anesthesia as a medical revolution during the sur-

gical procedures in Ottoman medicine [4]. Meanwhile, in the Europe, since the improvement of surgical techniques along with the development of the surgical devices, national urological associations were established during the late nineteenth century. The French urological association established is 1896 was an initiative in urology with an idea to collaborate with the national associations under the international umbrella. This idea was realized in 1908 in Paris under the presidency of Prof. Guyon [5]. In the same period, Ottoman Urology saw the day light with a few urologists under the influence of French school who attempted to revolutionize all the fields of Ottoman Medicine. Among the 29 delegates of the first international committee, Dr. Tomasos Sgurdeos, from RUM [Greek of Turkish citizenship] Hospital Kazlıçeşme-Istanbul was an Ottoman urological delegate. Dr. Andrea Antippas and Dr. Leon Lacombe, both from

This manuscript was presented in European Association of Urology (EAU) Annual Congress, History section; P-374, Munich, March 11–15, 2016.

Received: November 08, 2017 Accepted: February 21, 2018 Online: August 14, 2018 Correspondence: Dr. Ayhan VERIT. Saglik Bilimleri Universitesi Tip Fakultesi, Fatih Sultan Mehmet Hastanesi, Uroloji Klinigi, Atasehir, Istanbul, Turkey. Tel: +90 216 578 30 00 e-mail: veritayhan@yahoo.com © Copyright 2019 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

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Figure 1. The first medical faculty in a modern manner was formed with the combination of military and civil medical schools at Haydarpasha Hospital in the year 1909.

Istanbul, also participated in the congress under the Turkish title. In the year 1908, the Ottoman Urological national association had a total nine urologists under the main branch as General Surgery who were from Istanbul with one exception of Izmir, a city located at the shore of Aegean (Dr. Psaltoff from Izmir RUM Hospital). All, except two, of these members originated from Ottoman minorities. In the following years, the interest in Urology had begun to increase among the Turkish medical population [5, 6]. Meanwhile, the first medical faculty in the modern world was formed with the combination of military and civil medical schools at Haydarpasha Hospital in the year 1909 (Fig. 1) [3–6]. Moreover, Ottoman urology was given the same reorganization with a 4-bed unit under the discipline of General Surgery [7]. Cemil Topuzlu Pasha was an important figure of the surgical sciences and connected with the nine Urologists (Fig. 2). He was one of the pioneers of Ottoman-Turkish Urologists, trained in Paris (1887) in Prof. Guyon’s clinic, and a founded member of the French Urologic Society and some other European surgical associations. He was the first dean of the faculty and department Chief of General Surgery and conducted many invasive procedures in almost all surgical fields [3, 8–10]. Cemil Pasha approved Dr. Alexandre Pappas (also a brilliant painter) who also had Urologic training in Paris for a director with the title of associated professor of this pioneer four-bed Urology unit of Medical Faculty. Dr. Pappas separated from the Medical Faculty in 1908, settled in Greece, positioned as the Health minister for a period, and continued his

Figure 2. Cemil Topuzlu Pasha (1866–1958), the founder of Modern surgery, and Urology in particular, in Ottoman-Turkey. life in Athens (Fig. 3). The first Urology resident (Prof. Sabit Erduran) was on duty at 1915 and now the Urology clinic has 20 beds and can be an independent department [7, 11]. However, the long period of wars, such as First World War and subsequent Turkish independence war, interrupted the development of this academic scenario. Cemil Pasha was also involved in Ottoman Official Bureaucracy. He conducted the position of “Mayor of Istanbul province” for the period of 1912–1920 [3]. Then, he was elected as Ottoman Minister of “public works” in the last years of the Empire. In fact, Cemil Pasha was also a private doctor of Sultan V. Mehmet Reşad (1909– 1918) who suffered from bladder stones for 6 years [12]. Thus, the rapid and early improvement of Turkish Urology can be attributed to the Sultan Reşad’s Urological health problem that negatively contributed to the quality of life for many years until his surgery in 1915 [12]. It is not considered an exaggeration to mention that Sultan’s stones were the milestones of Ottoman-Turkish Urology because the training facilities in Europe were under the

Verit et al., History of establishment and evaluation of Ottoman-Turkish urology inside the surgical science

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Ottoman Empire had recently been collapsed, as already had realized by the Urologists, and a new Turkish republic was born after an independent war. Despite of the ongoing political, sociocultural discussions, whether the state of Ottoman-Turkey within or outside Europe, Turkish Urology has been already involved in the history of European Urological community since the beginning. This process gave rise to the quick development of Turkish urology as a separate branch many years earlier rather than the other modern surgical departments of Turkey. 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.

Figure 3. Dr. Alaexandre Pappas (1877–1942; self-portrait), teaching staff of the first urology department. permission of Sultan. During this period, the Ottoman State trained nearly 60 educational staff in Europe to comprise the staff of Istanbul University under the confirmation of Sultan [6]. Since the Ottoman officials did not prefer to use the name of “Turkey” in official communications, the official notes of the first international Urological association (The former form of Societe International d`Urologie –SIU-, 1908) interestingly pointed to delegates of “Turquie,” which is the name of subsequent Turkish state that established later in 1923 [5]. In our opinion, the Ottoman urologist as also the high educated political figures of the country had already realized that their empire was in ending period ; thus, the idea of a new state with its special name was formed with a modern era under the influence of French type nationalism. SIU separated during World War I (WWI) and was reestablished in Paris in 1919. However, in that period, such international scientific societies were under the influence of politics, and the defeated nations of WWI, such as Germany, Ottoman Empire and Austria, were not reaccepted to the association. This point of view did not change in the next SIU meeting in 1924, although

Authorship Contributions: Concept – AV, AU, ST; Design – AV, AU, ST; Supervision – AV, AU, ST; Materials – AV, AU, ST; Data collection and/or processing – AV, AU, ST; Analysis and/or interpretation – AV, AU, ST; Writing – AV, AU, ST; Critical review – AV, AU, ST.

REFERENCES 1. https://en.wikipedia.org/wiki/Ottoman_Empire. Accessed Jul 25, 2019. 2. https://tip.sbu.edu.tr/GenelBilgiler/Tarihce 3. Ataç A. 19. Yüzyılda Türkiye’de Cerrahinin Gelişimi ve Op. Dr. Cemil Topuzlu Paşa. Ankara Üniversitesi Osmanlı Tarihi Araştırma Merkezi Dergisi, 2004:16:65–71. 4. Akpir K. History of Anesthesiology in Turkey. Lokman Hekim Journal 2013;3:53–67. 5. Solok V. Uluslararası üroloji birliğinin kuruluşu, I ve II uluslararası kurultayları ve Osmanlı hekimleri. Cerrahpaşa Tıp Fakültesi Dergisi 1975;6:127–36. 6. Solok V. Three names in the urology of Ottoman period. Turk J Urol 2010;36:219–25. 7. Solok V. Foundation of urology in Turkey and Professor Behçet Sabit Erduran (in the memory of 25th anniversary of his death). Turk J Urol 2006;32:153-161. 8. Batirel HF, Yüksel M. Cemil Topuzlu Pacha and his arterial suture technique. Ann Thorac Surg 1997;64:1201–3. 9. Mut M, Dinç G, Naderi S. On the report of the first successful surgical treatment of brain abscess in the Ottoman Empire by Dr. Cemil Topuzlu in 1891. Neurosurgery 2007;61:869–72. 10. Karatepe M, Tomatir E, Bozkurt P. The resuscitation greats. Cemil Topuzlu Pasha: one of the forgotten pioneers in the history of open chest cardiac massage. Resuscitation 2006;68:179–83. 11. Solok V. Prof. Dr. Behçet Sabri Erduran, 1886-1980. Turk J Urol 1980;6:153–8. 12. Altıntaş A, Sınar N. Sultan Reşat’ın Ameliyatı. Tarih ve Medeniyet 1997;34:50–3.