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MEDICINSKI GLASNIK
Official publication of the Medical Association of Zenica-Doboj Canton, Bosnia and Herzegovina
Volume 7 Number 2, August 2010.
ISSN 1840-0132
Published and copyright by: Medical Assotiation of Zenica-Doboj Canton; Address: Zenica, 72000, Bulevar kralja Tvrtka I 4, Bosnia and Herzegovina;
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For ordering information please contact: Tatjana Žilo, [email protected]; Access to this journal is available free online trough: www.ljkzedo.com.ba
The Journal is indexed by MEDLINE, Science Citation Index Expanded (SciSearch®), and Journal Citation Reports/Science Edition, EMBASE (Exerpta
Medica), Scopus, EBSCO; ISSN 1840-0132
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Medicinski Glasnik
Official Publication of the Medical Association of
Zenica-Doboj Canton
Bosnia and Herzegovina
Editorial Board
Editor-in-chief
Selma Uzunović-Kamberović
Zenica, Bosnia and Herzegovina
MANAGING
Harun Drljević
Zenica, Bosnia and Herzegovina
Editors
Adem Balić, Tuzla, Bosnia and Herzegovina
Dubravka Bartolek, Zagreb, Croatia
Branka Bedenić, Zagreb, Croatia
Asja Čelebić, Zagreb, Croatia
Josip Čulig, Zagreb, Croatia
Filip Čulo, Mostar, Bosnia and Herzegovina
Jordan Dimanovski, Zagreb, Croatia
Branko Dmitrović, Osijek, Croatia
Davorin Đanić, Slavonski Brod, Croatia
Lejla Ibrahimagić-Šeper, Zenica, Bosnia and Herzegovina
Tatjana Ille, Belgrade, Serbia
Vjekoslav Jerolimov, Zagreb, Croatia
Mirko Šamija, Zagreb, Croatia
Ines Drenjančević-Perić, Osijek, Croatia
Sven Kurbel, Osijek, Croatia
Snježana Pejičić, Banja Luka, Bosnia and Herzegovina
Belma Pojskić, Zenica, Bosnia and Herzegovina
Asja Prohić, Sarajevo, Bosnia and Herzegovina
Velimir Profozić, Zagreb, Croatia
Zlatko Puvačić, Sarajevo, Bosnia and Herzegovina
Radivoje Radić, Osijek, Croatia
Amira Redžić, Sarajevo, Bosnia and Herzegovina
Suad Sivić, Zenica, Bosnia and Herzegovina
Sonja Smole-Možina, Ljubljana, Slovenia
Vladimir Šimunović, Mostar, Bosnia and Herzegovina
Adrijana Vince, Zagreb, Croatia
Jasmina Vraneš, Zagreb, Croatia
Živojin Žagar, Zagreb, Croatia
Secretary: Tatjana Žilo;
Proofreaders: Aras Borić (Bosnian, Croatian, Serbian),
Glorija Alić (English),
Cover: Miroslav Šetka - The Flower
MEDICINSKI GLASNIK
Official Publication of the Medical Association of Zenica-Doboj Canton, Bosnia and Herzegovina
Volume 7, Number 2, August 2010
Free full-text online at: www.ljkzedo.com.ba, and www.doaj.org (DOAJ, Directory of Open Access
Journals)
EDITORIAL
Review
Original
article
89
Posebnosti genitalnih infekcija humanim papiloma virusom u muškaraca
Mihael Skerlev, Suzana Ljubojević
96
Surveillance of wildlife zoonotic diseases in the Balkans Region
Mirsada Hukić, Fatima Numanović, Maida Šiširak, Almedina Moro, Edina
Dervović, Sanja Jakovac, Irma Salimović Bešić
106
Beginnings and successes in preventing anophelism by means of gambusia
fish on the island of Krk in Croatia from 1922 to 1927
Ante Škrobonja, Neven Materljan, Ivana Škrobonja
111
Emanuel Edward Klein, a diligent and industrious plodder or the father of
British microbiology
Bruno Atalić, Ines Drenjančević-Perić, Stella Fatovic-Ferenčić
116
Efficiency of hypertonic and isotonic seawater
solutions in chronic rhinosinusitis
Josip Čulig, Marcel Leppée, Andrijana Včeva, Davorin Djanic
124
Promjene u strukturi i kliničkom značenju pozitivnih rezultata
pretransfuzijskog testiranja kod prijelaza s klasične metode aglutinacije u
epruveti na metodu u gel mikrostupcu
Changes in the structure and clinical significance of the positive results of
pretransfusion testing during the switching from tube test agglutination to
gel microcolumn technique
Alma Petrušić-Kafedžić, Zdravko Ivanković, Sabahudin Ekinović, Lejla
Ibrahimagić-Šeper
132
Etiologija limfadenopatija dječije dobi
Etiology of lymphadenopathy in childhood
Edo Hasanbegović, Senada Mehadžić
137
Lunarni ciklus i cerebralni napadi u djece
The lunar cycle and seizures in children
Devleta Hadžić, Nada Mladina, Belkisa Čolić-Hadžić, Amela Numanović
143
Increased P wave dispersion in patients with liver steatosis
Mustafa Aparci, Zafer Isilak, Omer Uz, Ejder Kardesoglu, Omer Yiginer, Onur
Sildiroglu, Murat Yalcin, Namık Ozmen, Bekir Yilmaz Cingozbay, Bekir Sitki
Cebeci
148
Impact of reversionary and other etiological factors on prognosis and
course of schizophrenia
Ifeta Ličanin, Amira Redžić
153
Standardi fetalnog rasta za Tuzlansku regiju
Intrauterine growth standards for Tuzla region
Adem Balić, Devleta Balić
160
Notes
Case
reports
Erratum
166
Stereološka analiza sinciciotrofoblasta resorpcijske resice posteljice
trudnica mlađe i starije životne dobi
Stereological analysis of syncytiotrophoblast in resorption villi of placentas
of young and older pregnant women
Sergije Marković, Zlata Žigić, Suada Ramić, Jasminka Hadžihalilović
Operativni tretman endometrioze u u Kliničkom centru Kragujevac u
periodu 2004 -2008.godine
Operative treatment of endometriosis in the Clinical Centre of Kragujevac
during the period 2004-2008
Momčilo Đorđević, Božidar Jovanović, Gordana Đorđević
169
Emerging risk for viral hepatitis A in Croatian adults
Vladimir Mićović, Albert Cattunar, Danijela Štimac, Krunoslav Capak, Dražen
Stojanović, Davor Jurišić
172
Intaktna blizanačka tubarna trudnoća
Intact twin tubal pregnancy
Jasmin Hodžić, Abdulah Granić, Nina Hodžić, Aida Idrizbegović
174
Obstruction of left ventricular outflow tract by a calcified mass at mitral
valve
Miro Bakula, Željka Gavranović , Maja Bakula , Roman Urek , Nikola
Jankovic , Goran Milicevic
177
Laparoscopic treatment of achalasia
Ferid Latić, Vlatka Pitlović, Josip Samardžić, Azra Latić, Hrvoje Pitlović, Đuro
Miškić
180
Medicinski Glasnik is indexed by MEDLINE, Science Citation Index Expanded (SciSearch®), and
Journal Citation Reports/Science Edition, EMBASE (Exerpta Medica), Scopus, EBSCO.
EDITORIAL
Medicinski Glasnik is reaching MEDLINE after five years of
publishing
I am very pleased to be in a position to introduce
a new era of the Medicinski Glasnik (MG), reaching MEDLINE after five years of publishing. It
was a great personal honour to be asked to take
up the challenge of leading our publication to the
indexing in MEDLINE, for mutual benefit of our
authors and scientific community, so I did it!
As you already know, our publication has been
selected for coverage by Elsevier Bibliographic
Databases from 2006 (Vol 3 No 1) onwards.
These include EMBASE (Excerpta Medica),
EMNursing, Compendex, GEOBASE, several
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Databases, please visit www.elsevier.com (click
on Bibliographic databases) and www.info.
scopus.com.
Since 2007 (Vol 4 No 1) the MG has been selected for coverage by Thomson Reuters, which
includes Science Citation Index Expanded (SciSearch®) and Journal Citation Reports (JCR)/
Science Edition (http://scientific.thomson.com )
and covers more than 8,000 of the world’s most
highly cited, peer-reviewed journals from 3,300
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with quantifiable, statistical information based on
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levels, and shows the relationship between citing
and cited journals. Science Citation Index Expanded (SciSearch®), accssed via Web of Science®
provides researches, administrators, faculty, and
students with quick, powerful access to the bibliographic and citation information they need to
find research data, analyze trends, journals and
researches, and share their findings.
In order to increase dissemination of authors’
papers published in the MG we have decided to
include the MG and all its contents free of charge
in the Directory of Open Access Journals (DOAJ,
www.doaj.org) from 2005 onwards. This service
covers free, full text, quality controlled scientific and scholarly journals. There are now 5021
journals in the directory, and 2063 journals are
searchable at the article level.
In the 2008 we also accepted an offer by EBSCO
Publishing, Academic Search Complete (www.
ebscohost.com) for inclusion of the MG in this
database. It is the world’s most valuable comprehensive scholary, mulstidisciplinary full-text database, with more than 5500 full-text periodicals,
including more than 4600 peer-reviewed journals.
Finally, I am very pleased to inform all of you
that as of 2010, Vol 7 No 1 the Medicinski Glasnik has been selected for coverage by MEDLINE, US National Library of Medicine® (NLM®)
(the National Institutes of Health, NIH), which
is a premier bibliographic database, covering biomedicine and life sciences topics vital to biomedical practitioners, educators, and researches,
such as bioengineering, public health, clinical
care, and plant and animal science, nursing, dentistry, veterinary medicine, marine biology, and
preclinical sciences. MEDLINE provides global
coverage, indexing content from over 4,900 journals in 30 languages (http://www.ncbi.nlm.nih.
gov/pubmed/)
VII
Official abbreviation of our journal is: Med Glas
Ljek komore Zenicko-doboj kantona
Harun Drljević, remains the Managing Editor
mainly in charge of dealing with our publisher.
As you know, inclusion in the abstract and indexing databases increases dissemination of
authors’ papers because sophisticated linking technologies drive additional traffic to individual
articles. This in turn promotes journal brand awareness and subscription sales.
The immediate ambition of the Editorial Team
was to make the MG the foremost regional journal for all medical and related professionals.
However, to achieve this goal, we need continuous support of our readers, including authors and
reviewers of submissions that we receive. I hope
that we can rely on your support and that you will
consider the MG to be a suitable journal for publishing some of your best articles in the future.
We look forward to receiving your submissions
and feedback and thank you in anticipation of
your collaboration.
Our readers have already noticed a number of
stylistic changes to the journal. Considerable
changes in format and style of its content have
also been made. Further details can be found in
our updated ‘Guidelines for Authors’ posted on
our reconstructed new-old web site:
www.ljkzedo.com.ba
The editorial process has also undergone significant modifications. I am very grateful to have
the support of an enthusiastic team of Editors and
numerous reviewers who assist with the evaluation of manuscripts. The final stages of the scientific editorial process are my responsibility, while
It will be of great importance for the development
and improvement of the MG in the future, because it is our main goal. All submissions are very
welcome. We especially encourage you to write
your papers in English, and I can promise, on behalf of the Editorial Board and myself, that we
will extend any help and support you may need.
Editor-in-Chief
Selma Uzunovic-Kamberovic
REVIEW
Posebnosti genitalnih infekcija humanim papiloma virusom u
muškaraca
Klinika za kožne i spolne bolesti Kliničkog bolničkog centra Zagreb i Medicinskog fakulteta Sveučilišta u Zagrebu, Zagreb, Hrvatska
SAŽETAK
Fax.: +385 1 4920 017
Genitalne infekcije uzrokovane humanim papiloma virusom (HPV)
sve su više predmetom istraživanja, s obzirom na njihovu najvišu
učestalost unutar skupine virusnih spolno prenosivih infekcija,
sklonost recidivima, dugotrajno liječenje i povezanost s pojavom
zloćudnih bolesti. Zahvaljujući razvoju suvremenih metoda molekulske medicine, prije svega rekombinantne tehnologije DNA,
do danas je utvrđeno oko 150 tipova HPV-a. Genitalne infekcije
uzrokovane HPV-om, klinički se najčešće manifestiraju kao širok
spektar dermatoveneroloških bolesti, od kojih se posebno ističu
condylomata acuminata (šiljasti kondilomi), condylomata plana
(ravni kondilomi), gigantski kondilom Buschke-Löwenstein, papulosis Bowenoides, kao i razne druge kliničke manifestacije intraepitelnih neoplazija (IN) vanjskog genitalnog sustava (dakle, ne
samo cervikalne intraepitelne neoplazije, CIN), poput npr. penilne
(PIN), analne (AIN), vulvarne (VIN), skrotalne (SIN) ili vaginalne (VAIN) intraepitelne neoplazije. Izbor liječenja ovisi o općem
stanju i dobi bolesnika, o obliku, veličini i lokalizaciji promjena,
kao i o iskustvu terapeuta. No, svakako treba istaći da još uvijek ne
postoji specifično protuvirusno liječenje HPV genitalnih infekcija;
recidivi su česti (30-70%), a raznovrsni terapijski pristupi ponekad
vrlo neugodni za bolesnika i zahtjevni za liječnika. S obzirom na
sve navedeno, kao i na dostupnost cjepiva protiv HPV infekcija,
danas je HPV cijepljenje oba spola ozbiljan pomak koji značajno
unapređuje pristup ovom problemu.
E-mail: [email protected]
Ključne riječi: HPV, muškarci, HPV vakcina
Corresponding author: Mihael Skerlev,
Klinika za kožne i spolne bolesti
Kliničkog bolničkog centra Zagreb i
Medicinskog fakulteta Sveučilišta u
Zagrebu,
Šalata 4, 10000 Zagreb, Hrvatska
Phone: +385 1 2368 981;
Originalna prijava:
20. januar 2010.;
Prihvaćeno:
14. februar 2010.
Med Glas Ljek komore Zenicko-doboj kantona 2010; 7(2):89-95
89
Medicinski Glasnik, Volumen 7, Number 2, August 2010
UVOD
Genitalne infekcije uzrokovane humanim papiloma virusom (HPV) sve su više predmetom
istraživanja, s obzirom na njihovu relativno visoku učestalost unutar skupine spolno prenosivih
infekcija (engl. sexually transmitted infections
STIs), sklonost recidivima, dugotrajno liječenje i
mogućnost povezanosti s pojavom zloćudnih bolesti. Osim toga, važno je napomenuti da se HPV
genitalne infekcije najčešće pojavljuju u mladoj,
generativno sposobnoj populaciji, te je stoga njihovo uspješno praćenje i liječenje obveza svakog
društva koje teži napretku.
ETIOLOGIJA
Danas je poznato oko 150 tipova HPV-a. Na temelju
povezanosti prisustva pojedinog genotipa HPV-a na
vratu maternice i pojave raka vrata maternice, standardno se određuje onkogeni rizik tipova HPV-a.
Tako postoje HPV DNA tipovi niskog rizika (6, 11,
30, 42, 43, 44 itd. ) i HPV DNA tipovi visokog rizika (16, 18, 31, 33, 35, 45, 52, 56 itd.), a neki autori
navode i HPV DNA tipove srednjeg rizika (31, 33,
35, 39, 51, 52, 58, 61 itd.). Treba svakako pripomenuti da navedena podjela nije, naravno, konačna, s
obzirom da se sustavno otkrivaju i klasificiraju novi
tipovi HPV-a, međutim, potrebno je, ipak, određeno vrijeme da se potvrdi onkogeno značenje svakog
pojedinog tipa HPV-a (1, 2).
EPIDEMIOLOGIJA
U epidemiološkom smislu HPV genitalne infekcije su ubikvitarne i njihov je broj, čini se, u stalnom
porastu (3). Prema rezultatima nekih opsežnih
studija u Sjedinjenim Američkim Državama, broj
se posjeta liječničkim ordinacijama zbog HPV
genitalnih infekcija ušesterostručio u posljednja
tri desetljeća (4, 5). Stoga je incidencija HPV genitalnih infekcija (13/100.000 u 1960. godini u
odnosu na 106/100.000 u 1990. i 200/100.000 u
2000. godini) danas tri puta veća u usporedbi s genitalnim herpesom (6, 7), koji, uz HPV genitalne
infekcije, predstavlja jedan od najvećih problema
u venerološkoj praksi. U Hrvatskoj, također, HPV
genitalne infekcije pripadaju među najčešće STD
bolesti (8-10). Prema rezultatima nekih epidemioloških studija, kod 60% seksualno aktivnih žena
pronađen je HPV u obrisku vrata maternice (9).
Znaci HPV bolesti pronađeni su kod 40-60% muških partnera žena s virusološki dokazanom HPV
genitalnom infekcijom (6-7). Incidencija HPV
90
genitalnih infekcija najviša je u dobi od 20 do 24
godine (11) i bitno opada nakon 40. godine života,
međutim, sve se više pojavljuju (ili prepoznavaju!?) slučajevi HPV genitalne infekcije u dječjoj
dobi, kao i u menopuazi, odnosno andropauzi (12).
Epidemiološki podaci o HPV genitalnim infekcijama najviše su ispitivani u vezi s pojavom raka
vrata maternice. Smatra se da se u svijetu godišnje
dijagnosticira 500.000 novih slučajeva raka vrata
maternice, te da je taj karcinom drugi po redu učestalosti zloćudnih tumora u ženskoj populaciji (6,
7, 13). Uzevši u obzir činjenicu da je inkubacija
HPV genitalnih infekcija relativno duga i da traje
od 2 do 9 mjeseci (i dulje) (11, 12), zaražene osobe
mogu predstavljati neprepoznati supklinički izvor
zaraze i vjerojatno su razlogom relativno teškog
načina otkrivanja izvora i praćenja putova širenja
HPV genitalne infekcije (12-13).
Što se tiče onkogenog aspekta HPV-a, zur Hausen
(13) je prvi dokazao uzročno-posljedičnu vezu
između HPV infekcije, tipom 16 i 18, i karcinoma vrata maternice, zbog čega mu je i dodijeljena
Nobelova nagrada za fiziologiju i medicinu 2008.
godine.
Rizični čimbenici i način prenošenja
Čimbenici rizika za prijenos HPV infekcije prvenstveno ovise o imunološkom stanju organizma pojedinca. Prvi spolni odnos u ranoj životnoj dobi,
udaja i rađanje u ranoj životnoj dobi, višebrojni
spolni partneri, porodi većeg broja djece, spolni
odnosi s rizičnim muškim/ženskim partnerom, niski socioekonomski status jesu najčešći čimbenici
(14, 15). Drugi potencijalni čimbenici su korištenje oralnih kontraceptiva, pušenje, konzumacija
alkohola, nedostatak vitamina, spolno prenosive
bolesti izazvane herpes simplex virusom (HSV),
te druge spolno prenosive bolesti (Chlamydia trachomatis, Neisseria gonorrrhoeae, Gardnerella
vaginalis, Mycoplasma hominis, Trichomonas vaginalis, citomegalo virus infekcije) (14-26). Spolno prenosivi put jeste najčešći put prenošenja. S
obzirom da se HPV opisuje i kod djevica, novorođenčadi, djece (kao juvenilna laringealna papilomatoza), zaključilo se da se HPV može prenositi i
drugim putevima (27-32). Stoga su opisani i drugi
načini prenošenja, kao autoinokulacija, perinatalni
prijenos, te prenošenje putem kirurških instrumenata (27-32). Načini prenošenja uključuju vertikalni, ‘’nevini’’ (autoinokulacija i heteroinokulacija s bradavica na ruci) i spolni odnos (28).
Skerlev et al Genitalne HPV infekcije u muškaraca
PATOGENEZA
Jedan od ključnih patogenetskih koraka u razvitku
tumorske bolesti jeste nekontrolirana proliferacija
stanica (3). Temeljni molekularni mehanizmi, koji
pokreću i održavaju nekontroliranu diobu tumorske
stanice, jesu aktivacija onkogena i inaktivacija tumor supresorskih gena (33-35). Onkogeni su geni
oni čija je aktivnost povezana sa zloćudnom preobrazbom stanice, dok su tumor supresorski geni oni
čija aktivnost koči zloćudnu preobrazbu (33-35).
Integracija virusa u genom domaćina smatra se bitnim mehanizmom u karcinogenezi (36, 37).
Međutim, u posljednje se vrijeme sve veća pozornost
pridaje, uz već relativno dobro istraženu povezanost
HPV-a i cervikalne intraepitelijske neoplazije, intraepitelijskim neoplazijama vanjskog genitala u oba
spola povezanim s HPV-om (38). Stoga se sve više
govori o, primjerice, penilnoj (PIN), analnoj (AIN),
vaginalnoj (VAIN) (38), vulvarnoj (VIN) (38-41) i
skrotalnoj (SIN) intraepitelijskoj neoplaziji. Studije
koje istražuju povezanost HPV-a i karcinoma muškog genitalnog sustava (najčešće glans, prepucij ili
skrotum), ukazuju na povezanost HPV-a 16 i 18 sa
spinocelularnim karcinomom penisa u 44% slučajeva (40). U nekim je slučajevima bio izoliran HPV 16
u sjemenoj tekućini i obrisku uretre kod bolesnika sa
spinocelularnim karcinomom glansa (41). Značenje
HPV-a kod karcinoma prostate nije do kraja razjašnjeno, iako postoje studije koje ukazuju na prisustvo
HPV-a 16 i 18 u hipertrofiji i karcinomu prostate
(40, 41).
KLINIČKA SLIKA
Genitalne infekcije HPV-a mogu se podijeliti u tri
skupine: klinička, supklinička i latentna infekcija.
Kliničke infekcije jesu one koje se vide pri pregledu, dok su supkliničke one koje su vidljive nakon
premazivanja 3-5% octene kiseline, uz primjenu
kolposkopske tehnike. Latentna infekcija karakterizirana je prisutnošću HPV DNA u tkivu, dok je
virus odsutan u kolposkopskim i histološkim nalazima, a otkriva se HPV DNA genotipizacijskim
metodama (42, 43). Što se kliničkog aspekta HPV
genitalnih infekcija tiče, najčešće govorimo o slijedećim entitetima: condylomata acuminata (šiljasti
kondilomi), condylomata plana (ravni kondilomi),
gigantski kondilom Buschke-Löwenstein i papulosis Bowenoides i Mb. Bowen u genitalnoj regiji
(Tablica 1). Ni u kom slučaju ne treba zanemariti
ni planocelularni karcinom penisa, karakterističan
za stariju životnu dob, no, u posljednje se vrijeme
Tablica 1. Kliničke manifestacije i odgovarajući HPV tipovi
(Skerlev M., Ljubojević S.)
ANOGENITALNE BOLESTI
HPV TIP
Šiljasti kondilomi (condylomata
acuminata)
Bowenoidna papuloza
6, 11, 30, 42, 43, 44, 45, 51,
52, 54; rjeđe 16,18, 33
16, 18, 34, 39, 42, 45
Bowenova bolest
16, 18, 31, 34
Gigantski kondilom (BuschkeLöwenstein)
6, 11; rijetko 16, 18
Nespecificirana intraepitelna
neoplazija
30, 34, 39, 40, 53, 57, 59,
61, 62, 64, 66, 67, 68, 69
Intraepitelna neoplazija niskog
stupnja
6, 11, 43
Intraepitelna neoplazija srednjeg
stupnja
31, 33, 35, 42, 44, 45, 51, 52
Intraepitelna neoplazija visokog
stupnja
16, 18, 56, 58
Karcinom vulve
6, 11, 16, 18
Karcinom vagine
16
Karcinom cerviksa
16, 18, 31
Karcinom anusa
16, 31, 32, 33
Karcinom in situ penisa (erythroplasia Queyrat)
16
Karcinom penisa
16, 18
opisuju sve češći slučajevi pojave ove bolesti i kod
mlađih muškaraca (38). Od svih navedenih entiteta
najčešći su šiljasti kondilomi - condylomata acuminata. To su papulozne ili nodozne tvorbe, papilomatoznog, odnosno verukoidnog izgleda, najčešće
lokalizirane na vanjskom genitalu (Slika 1), često
na distalnom dijelu korpusa penisa ili na prepuciju
kod muškaraca (39), odnosno na vulvi kod žena ili
pak na analnoj regiji kod oba spola. U posljednje
se vrijeme sve više navodi značenje intrauretralnih
(meatalnih) kondiloma zbog mogućnosti prijenosa
HPV-a u unutrašnje dijelove mokraćnog sustava
zbog moguće povezanosti intrauretralnih kondiloma s pojavom karcinoma mokraćnog mjehura i
prostate (40, 41, 44), kao i zbog rezistentnosti na
uobičajenu terapiju. No, značenje šiljastih kondiloma ne treba ‘’banalizirati“ s obzirom da se u 1020% slučajeva šiljastih kondiloma mogu detektirati
Slika 1. HPV-genitalna infekcija (šiljasti kondilomi);
lokalizacija na distalnom dijelu korpusa genitala (solitarne
promjene) i na pubičnoj regiji (konfluentne promjene) (Skerlev M, Ljubojević S, iz zbirke slika 2009.)
91
HPV visokog rizika (10, 41). U novijoj literaturi
(41) posebno se opisuju ravni kondilomi - condylomata plana, koji su prije bili opisivani kao varijanta kliničke slike šiljastih kondiloma. Condylomata plana su papilomatozne tvorbe ravnog oblika,
najčešće uzrokovane HPV tipovima 16, 18, 31 ili
33. Većina autora ravne kondilome izdvojila je u
poseban entitet, ne samo zbog njihovog drugačijeg
oblika od šiljastih kondiloma, već i zbog njihove
teže kliničke uočljivosti i zbog njihovog znatno
većeg onkogenog potencijala u usporedbi s ‘’klasičnim’’ šiljastim kondilomima. Najveći broj HPV
genitalnih infekcija vrata maternice, kao i određeni broj asimptomatskih promjena kod muškaraca,
pripadaju baš ovom kliničkom obrascu (11, 13).
Gigantski kondilom Buschke-Löwenstein (BL) je
masivna tumorska lezija anogenitalne regije. No,
osim kliničke impresivnosti, treba, ipak, navesti i
rezultate najnovijih studija koji ukazuju na kliničke
i histološke znakove malignosti (u smislu verukoznog karcinoma) i detekciju HPV tipova visokog
rizika kod ovog entiteta (44-47). Kod bovenoidne
se papuloze, tvorbe sastavljene od multiplih papula
najčešće lokaliziranih na vanjskom spolovilu, histološki nalaze znaci stanične atipije koji podsjećaju na Morbus Bowen ili spinocelularni karcinom
in situ (48). Iz bovenoidne papuloze izoliran je najčešće HPV 16 (48). Na temelju svega navedenog
vidljivo je da danas govorimo o širokom spektru
kliničkih promjena izazvanih HPV-om. Međutim,
u posljednje se vrijeme sve veća pozornost pridaje,
uz već relativno dobro istraženu povezanost HPV-a
i cervikalne intraepitelijske neoplazije, intraepitelijskim neoplazijama vanjskog genitala u oba spola
povezanim s HPV-om (49). Stoga se sve više govori o, primjerice, penilnoj (PIN), analnoj (AIN), vaginalnoj (VAIN) (49), vulvarnoj (VIN) (41, 49-51)
i skrotalnoj (SIN) intraepitelijskoj neoplaziji. Studije koje istražuju povezanost HPV-a i karcinoma
muškog genitalnog sustava (najčešće glans, prepucij ili skrotum) ukazuju na povezanost HPV-a 16 i
18 sa spinocelularnim karcinomom penisa u 44%
slučajeva (51). U nekim je slučajevima bio izoliran
HPV 16 u sjemenoj tekućini i obrisku uretre kod
bolesnika s planocelularnim karcinomom glansa (38). Značenje HPV-a kod karcinoma prostate
nije do kraja razjašnjeno, iako postoje studije koje
ukazuju na prisustvo HPV-a 16 i 18 u hipertrofiji i
karcinomu prostate (38, 51). Na temelju svega navedenog vidljivo je da danas govorimo o širokom
spektru kliničkih promjena izazvanih HPV-om.
92
DIJAGNOZA
Klinički pregled je osnova za postavljanje dijagnoze vidljivih HPV lezija vanjskog spolovila. Pregledati treba cijelu anogenitalnu regiju, uz pomoć
jakog svjetla i povećala. Supklinički oblik bolesti
može se vidjeti tek nakon premazivanja tkiva 3-5%tnom octenom kiselinom i primjenom kolposkopa.
Supkliničke lezije, vidljive peniskopom, mogu se
klasificirati kao ravne, papularne, PIN promjene
(u acidobijelom epitelu punktacije), klasični kondilom i nespecifične lezije (52). Nespecifični i/ili
lažno pozitivni peniskopski nalaz najčešće nalazimo kod mikrotrauma, upalnih procesa, najčešćih
gljivičnih infekcija (kandidijaza ili trihomonijaza),
zatim folikulitisa, kontaktnog alergijskog ili iritativnog dermatitisa, te nekih bolesti poput vulgarne
psorijaze i lichnen planusa (53). Karakteristične
histološke promjene HPV genitalnih infekcija su
koilociti. Koilociti su morfološki promijenjene
stanice, koje su inficirane HPV-om (54). Te stanice karakterizira perinuklearna citoplazmatska
vakuolizacija, veći broj nepravilnih jezgra, grube
nakupine kromatina i polikromazija. Javljaju se u
slučaju produktivne infekcije (’’vegetativne’’) viralne replikacije. Osim svjetlosnim mikroskopom,
prisutnost HPV-a može se dokazati elektronskim
mikroskopom i imunohistokemijskim metodama
(55, 56). Međutim, sve ove metode imaju relativno nisku osjetljivost i specifičnost, a osim toga, ne
omogućavaju genotipizaciju HPV-a. Danas se za
preciznu dijagnostiku zaraze HPV-om isključivo
upotrebljavaju metode molekularne dijagnostike.
Molekularne metode za detekciju DNA temelje se
na lančanoj reakciji polimeraze (engl. polymerase
chain reaction, PCR) ili na hibridizaciji nukleinskih kiselina (57-59).
LIJEČENJE
Još uvijek ne postoji idealno sredstvo za etiološko liječenje HPV infekcija urogenitalnog trakta.
Liječenje se, u načelu, svodi na mehaničko odstranjenje manifestacija HPV genitalne infekcije.
Iako jedan dio neliječenih genitalnih infekcija
(osobito onih koje nisu jasno klinički manifestne,
dakle, latentne i/ili supkliničke infekcije) može
spontano regredirati, moguća je i perzistencija
HPV-a, koja može dovesti do progresije bolesti.
U svakom slučaju, iznimno je važna što ranija dijagnoza HPV genitalnih infekcija u oba partnera,
kako bi se spriječio nastanak prekanceroza, kao i
karcinoma urogenitalnog trakta.
Infekcije izazvane HPV-om mogu se liječiti
podofilinom, podofilatoksinom, krioterapijom,
lokalnom primjenom 5-fluorouracila, triklor octenom kiselinom, imiquimodom, intralezijski ili
peroralno primijenjenim interferonom, intralezijski primijenjenim bleomicinom, ekskohleacijom,
elektrokoagulacijom, klasičnom i laserskom
kirurškom terapijom (60-64) (Tablica 2). Treba
svakako napomenuti da izbor terapijskog sredstva ovisi i o izraženosti i lokalizaciji kliničkih
promjena, iskustvu terapeuta, stavu bolesnika,
kao i o ekonomskim okolnostima. Terapijske su
opcije ponekad vrlo neugodne za bolesnika, frustrirajuće za liječnika i, unatoč svemu, recidivi
mogu biti česti i terapijski uspjeh skroman.
PREVENCIJA PRIMJENOM HPV VAKCINE
Svakako treba napomenuti da su u svijetu, pa
tako i u Hrvatskoj, registrirane dvije vakcine protiv HPV-a: četverovalentno cjepivo protiv četiri
najčešća HPV DNA tipa (HPV DNA 6, 11, 16 i
18) i dvovalentno protiv dva najčešća tipa visokog rizika (HPV DNA 16 i 18). HPV vakcina definitivno predstavlja značajan pomak u pristupu
HPV genitalnim infekcijama, pri čemu, jasno, ne
smiju biti zanemareni ni ostali aspekti prevencije
poput edukacije, odgovornog spolnog ponašanja
i primjene kondoma. Navedene su vakcine, kao i
Tablica 2. Liječenje anogenitalnih bradavica (Skerlev M.,
Ljubojević S.)
PRIMJENJUJE LIJEČNIK
Krioterapija tekućim dušikom
Elektrokoagulacija
MOŽE PRIMIJENITI I
SÂM BOLESNIK
Podofilotoksin 0.5% tekućina
ili 0.15% krema
Imiquimod 5% krema
Ekskohleacija
Ekscizija
Laser
Trikloroctena kiselina 70-90%
Podofilin 20% tekućina (Pazi!!!
Obvezatno ispiranje tretiranih
promjena nakon 5h!)
većina drugih vakcina, prije svega, profilaktičke,
te se očekuje uvođenje HPV vakcine u rutinski
program cijepljenja. Četverovalentno cjepivo
usmjereno je na prevenciju cervikalne intraepitelne neoplazije (CIN), intraepitelne neoplazije
drugih dijelova vanjskog genitalnog sustava
žena i muškaraca, kao npr. vulve (VIN), vagine
(VAIN), penisa (PIN) ili anusa (AIN), te na prevenciju anogenitalnih bradavica oba spola. Prevencijom pojave navedenih invazivnih lezija,
spriječila bi se progresija bolesti prema karcinomu vrata maternice (65). Dvovalentno cjepivo
usmjereno je na prevenciju cervikalne intraepitelne neoplazije (CIN) i prevenciju karcinoma vrata
maternice. Stoga je cilj cijepljenja zaštititi djecu
i adolescente, oba spola, prije prvog mogućeg
kontakta s HPV-om (66). U tu svrhu važno je
procijepiti mladu populaciju u dobi već od devet, odnosno 12 godina. Najnoviji rezultati multicentričnih studija učinkovitosti četverovalentne
HPV vakcine na velikom broju muških ispitanika, nedvosmisleno ukazuju na visoku učinkovitost protiv sva četiri ispitivana HPV DNA tipa,
obuhvaćena ovim cjepivom (65).
Svakako treba uzeti u obzir i činjenicu da, u užem
smislu riječi, etiološka terapija HPV-a još uvijek
ne postoji i da je liječenje najčešće višekratno,
ponekad neugodno za bolesnika i zahtjevno za
liječnika, a recidivi se mogu, unatoč liječenju,
pojaviti u 30-70% slučajeva. Na temelju svega
navedenog jasno je da su HPV genitalne infekcije vrlo veliki zdravstveni problem i muškarcima,
kako zbog epidemioloških, tako i zbog onkoloških i psiholoških reperkusija, te tu činjenicu treba
uzeti u obzir pri razvoju suvremene strategije za
prevenciju spolno prenosivih bolesti.
ZAHVALE/IZJAVA
Komercijalni ili potencijalni dvostruki interes
ne postoji.
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The specifities of the HPV-genital infections in males
University Department of Dermatology and Venereology, Zagreb University Hospital Centre and Zagreb University School of Medicine,
Zagreb, Croatia.
ABSTRACT
Anogenital infections caused by Human papillomavirus (HPV) are the most frequently diagnosed sexually
transmitted infections of viral origin and up to 150 HPV DNA types have been recognized so far. Anogenital warts (condylomata acuminata) are the most common lesions presented in men, however, during the
last decade the other HPV-associated exaggerated lesions such as condylomata plana, penile, scrotal, and
anal intraepithelial neoplasias, as well as the penile, urine bladder and prostate cancer have been studied
somewhat more extensively. The clinical variations might range from clinically invisible, asymptomatic
lesions to the bizarre forms of giant condyloma of Buschke-Löwenstein type, including Bowenoid papulosis, Mb. Bowen, different kinds of eryhtroplasia both in men and women and a large spectrum of
HPV-induced dermatovenereological entities in genital region including high-grade intraepithelial genital
neoplasias, such as penile, anal, scrotal, vulvar, vaginal etc. (thus not only cervical), and, last but not least
- the anogenital warts. A prophylactic vaccine that targets these types should thus substantially reduce the
burden of HPV-associated clinical diseases. Ultimately, within the spectrum of therapeutic options for condylomata, no method is really superior to others; recurrences occurred in 30-70% of cases. We definitely
need the HPV vaccination programme to eliminate one of the oldest and up to now unsolved problems of
the mankind. Since HPV is transmitted by sexual intercourse, treatment of both partners is necessary in
order to eliminate the virus from the population. Approaches to this include prophylactic vaccines such as
quadrivalent HPV vaccine for both men and women.
Key words: HPV, men, HPV vaccine
Original submission: 20 January 2010; Accepted: 14 February 2010.
95
REVIEW
Surveillance of wildlife zoonotic diseases in the Balkans Region
Mirsada Hukić1, Fatima Numanović2, Maida Šiširak1, Almedina Moro1, Edina Dervović1, Sanja Jakovac3,
Irma Salimović Bešić1
Institute of Clinical Microbiology, Clinical Center of the University of Sarajevo, 2Institute of Microbiology, Clinical Center of the University of Tuzla, 3Institute of Microbiology, Clinical Center of the University of Mostar; Bosnia and Herzegovina
1
ABSTRACT
Corresponding author:
Mirsada Hukić
Institute of Clinical Microbiology,
Clinical Center University of Sarajevo,
Bonička 25, 71000 Sarajevo, Bosnia and
Herzegovina
Phone/fax: +387 33 440 447;
Original submission:
14 December 2009;
Revised submission:
30 December 2009;
The countries of the Balkan Peninsula have become the region
with frequent outbreaks of the emerging and re-emerging diseases during the last decade of the 20th and the first decade of the
21st century. The majority of outbreaks were wildlife zoonotic,
and vector-borne diseases, such as brucellosis, leptospirosis, listeriosis, tularemia, Q-fever, Lyme disease, anthrax, rabies, viral
hemorrhagic fevers, sandfly fever, tick-borne encephalitis and leishmainiasis. Epidemiological factors determined by ecology of
causative agents are often the most useful diagnostic clues. The
recognition of evolving problems of emerging and re-emerging
diseases emphasizes the need for the development of better laboratory diagnostic methods for the surveillance and tracking of
the diseases, and for continued research of factors contributing to
the transmission of the organisms. The continuous occurrence of
previously unidentified infections requires prospective national
strategies for timely recognition of the syndromes, causative agent
identification, establishment of criteria and methods for the diagnosis, optimization of the treatment regime, and determination
of successful approaches to prevention and control. Wildlife diseases surveillance in the most of the Balkan countries has been
coordinated by the WHO since 1992. Although new technology
and communication have extremely improved in the last decade,
there is a need for optimal communication lines among the Balkan
countries, better exploitation of communication technologies like
the Internet and other media in the field of emerging diseases.
Key words: surveillance, wildlife zoonotic diseases, Balkan Penninsula
Accepted:
05 January 2010
96
Hukić et al Wildlife zoonoses in the Balkans Region
INTRODUCTION
A zoonosis is an animal disease that may be transmitted to humans in natural conditions. Almost
a half out of 1700 known pathogens affecting
humans are estimated to be zoonotic (1). It has
been reported that there are up to 335 pathogens
which were associated with emerging infectious
diseases (EID) in the global human population
between 1940 and 2004, and majority of them
were caused by the wildlife zoonotic diseases,
while vector-borne diseases were responsible for
up to 22.8% (1).
Many wildlife zoonotic disease (WZD) outbreaks
were reported in the area of the Balkan Peninsula
during the last twenty years (2). The wartime period (1992-1995) was associated with socio-economic, human demographics, behavioral, ecological and environmental (climate, ecosystems,
microbial adaptation) changes that had significant impact on public health and global economy,
as well as to wildlife zoonotic diseases (3). The
additional variables which mostly influence zoonoses and vector borne diseases are human population density, human population growth, and
wildlife and non-wildlife host species richness
(1, 3-5). Breaking of communications channels
between the former Yugoslav countries during
the wartime and some years in post-war periods,
and lack of political will to control the diseases
have also greatly contributed to the appearance
of WZD outbreaks in the Balkans area.
There is a need for different actions to be undertaken in order to recognize and control EIDs and
WZDs. First of all, it is important to improve
the reporting system of infectious diseases at the
state, regional and World Health Organization level. It is also important to improve several tools
for controlling EIDs and WZDs such as epidemiologic field investigation, control, elimination and eradication, training, diagnostic development, and basic and applied research activities
including technology transfer. Surveillance of
infectious diseases and continuous systematic
collection, collation, analysis and interpretation
of data and the dissemination of information to
the authorities have to be established in order to
take any actions (4-7). The purpose of the disease
surveillance is to identify the changes of infection and/or health status of animal and human populations, and it is essential to provide rigorous
evidence of the disease absence or to determine
pathogen prevalence.
To be successful in the understanding WZDs a basic lack of integration between disciplines needs
to be eliminated, the most noticeably between
human and veterinary medicine and also among
different branches within these fields. Although
new technology and communications have extremely advanced in the last decade, there is still a
need for better exploitation of communication technologies such as the Internet and other media
in the field of EIDs (5-7).
WILDLIFE ZOONOSIS IN THE BALKANS REGION
The epidemiological situation related to zoonoses in the Balkan countries is not well characterized due to the difficult circumstances prevailing
during the previous decade. There is a lack of
reporting and publishing system of the infection
and/or health status of animal and human populations. Although there were no readily accessible
data concerning epidemiology and epizootology of WZDs, limited official and published data
were analyzed.
Anthrax
Anthrax is endemic in some regions of the Balkan Peninsula, but it is not a significant public
health problem (2). However, in the past century
cutaneous anthrax cases with several clinical signs of septicemia were recorded in Bulgaria, Bosnia and Herzegovina (B&H) and Croatia, with a
low mortality rate (1.64%) (7-9).
Brucellosis
Brucellosis is a significant health problem among
animals and humans in the Balkan Peninsula. Brucellosis is spread in Greece, the former Yugoslav
Republic of Macedonia, Kosovo, Serbia and Croatia (10, 11). It is an endemic disease among animals
and humans in the southern part of the Balkan Peninsula, Greece, the Former Yugoslav Republic of
Macedonia and Kosovo at the end of 20th century,
which was a consequence of the changes in political situation in this area followed by the wartime.
Appearance of brucellosis represents a classical
example of spreading zoonosis as a result of the
population and animal migration (9, 12, 13).
Brucellosis is an EID in B&H and it is still an
increasing public health problem. Only one case
97
of human brucellosis was reported in 1999, while
in 2008 there were 988 cases reported (14). The
current animal health situation in B&H shows
an increase in the number of reported outbreaks
in ruminants. The number of seropositive cases
as compared with the number of processed serums in last four years has ranged from 0.047%
to 1.09% (11).
In Greece, cattle are also affected either by B.
melitensis or B. abortus. Wild boars (Sus scrofa) were found to be carriers and reservoirs of
Brucella suis biovar 2 in Croatia (15), whereas
Brucella suis biovar 3 was isolated from horses
in Croatia (16).
Due to the dimension of the disease-related problems, there is a need to establish cooperation
in the elimination and prevention of brucellosis
among all countries in the region, supported by
World Health Organization.
Leptospirosis
Leptospirosis is an endemic zoonosis existing
Croatia and B&H (17-20). This is a widely spread disease with frequent epidemic occurrence,
especially among miners in B&H and foresters in
Croatia (18, 21, 22). Serological testing conducted in 1983 revealed antibodies to Leptospira serovares pomona, grippotyphosa, sejroe, australis
and bataviae (21) in 10.08% of the B&H miners
population. Leptospiroisis outbreak among miners in B&H occurred 25 years later (2005) but
caused by new serovars: L. ballum, L. ictrohaemorrhagiae, L. sejroe and L. tarassovi (22).
Serological tests in patients from Croatia have
shown 18 different serovars of Leptospira, with
the highest prevalence of L. sejroe, L.pomona, L.
australis and L. icterohaemorrhagiae (23).
Leptospira seroprevalence among small rodents
captured in shafts of the lignite mines in B&H of
37.5% was noted in 1983 (21).
An analysis of Leptospira sp. among small rodents in Croatia revealed three different species: L. borgpetersenii, L. kirschneri and L. interrogans. Mus musculus exhibited the highest
infection level which was confirmed as a major
reservoir of the serogroup Sejroë (23). Leptospira infection was also found among European
brown bears (Ursus arctos) in Croatia (24), and
based on the antibody titers, several serovars found were implicated: australis, sejroe, canicola
98
and icterohaemorrhagiae. A strong correlation
between serovars in bears and serovars previously isolated from small mammals in Croatia was
noted (25).
Listeriosis
Listeriosis is present in the area of the Balkan Peninsula, but it is not a considerable public health
problem. However, occasional cases of different
clinical forms of leptospirosis have been recorded recently (26, 27). The analysis of the contamination level of different kinds of raw meat (raw
beef, pork and chicken) in B&H showed overall
presence of Listeria spp. in 49.4% samples; L.
monocytogenes detected in 23.3%, L. innocua in
22.2% and L. welshimeri in 3.9% analyzed row
meat samples (28). Both beef and pork were
mostly contaminated by L. monocytogenes, in
34.3% and 25.7%, respectively. Chicken had
the lowest level of contamination amounting to
10.0% (28). In a study conducted in Serbia, 45%
of all pigs examined harboured L. monocytogenes
in their tonsils, and 3% were intestinal carriers.
L. monocytogenes was detected in 29% of swabs
from retropharyngeal nodes and in 19% of fecal
samples of cattle. L. monocytogenes was found in
69% of minced meat (mixed pork and beef) samples, in 19% of raw dry sausages, and in 21% of
vacuum-packaged hot smoked sausages. However, L. monocytogenes was not detected in the hot
smoked sausages heated to internal temperature
of 70-75 °C after the fumigation process (29).
Tularemia
Francisella tularensis has been recognized as a
human pathogen for almost 100 years and it is the
etiological agent of the zoonotic disease, tularemia. The organism has been isolated from over
250 different species, including fish, birds, amphibians, rabbits, squirrels, hares, voles, ticks and
flies. An important aspect of F. tularensis pathogenesis is the transmission via arthropod vectors
into mammalian host. Chrysops spp. and Tabanus spp. also designated as deer fly and horsefly,
respectively, are common arthropod vectors of
Francisella transmission to humans, resulting in
initial clinical presentation with ulceroglandular
form of the disease (30, 31)
Due to its easy dissemination, multiple routes
and low dose infection, morbidity and mortali-
ty rates, F. tularensis subsp. tularensis has been
classified as a category A bioterrorism agent by
the CDC (32).
Tularemia is an emergent infectious disease in
several countries at the Balkan Peninsula. The
first outbreak of tularemia occurred in B&H in
1995, during the wartime (33). A large tularemia outbreak occurred in Kosovo in the early
postwar period, 1999-2000 (34). Only sporadic
cases of tularemia have been recognized and reported since the first epidemic in Kosovo (32,
34). There are no data about tularemia seroprevalence in general population or in the high risk
groups, e.g. foresters, hunters, veterinarians, or
soldiers.
Epidemiological and environmental investigations were conducted to identify sources of infection, modes of transmission, and household risk
factors in Kosovo. The results suggested that the
infection was transmitted through contaminated
food or water and that the source of the infection
were rodents (34). Environmental circumstances
in the war-torn Kosovo led to epizootic rodent
tularemia and its spread to displaced rural populations living under circumstances of substandard
housing, hygiene, and sanitation (34).
Tularemia outbreak areas in 1962 and 1997-2006
periods in Bulgaria were different. The first case
of tularemia was reported in 1997. Starting from
1998 to 2008, 296 cases were registered. Amplified fragment length polymorphism (AFLP) and
multiple-locus variable number of tandem-repeats analysis (MLVA) typing, confirmed epidemic
spread and evolution, and comparison of strains
isolated from different regions in Bulgaria and
Turkey resulted in the finding of the common
“Balkan” genovar of Francisella. In addition,
several novel genotypes of endosymbionts of
Francisella-like organisms have been found in
Hyalomma and Dermacentor ticks (9).
Lyme disease
Lyme boreliosis is an emergent disease in many
Balkan countries: Bosnia and Herzegovina, Croatia, Slovenia, Serbia and Bulgaria (35-39). It is
a zoonosis transmitted from animals to humans
by ticks of Ixodes ricinus complex. Lyme borreliosis is caused by Borelia burgdorferi sensu lato,
which has four different species (36). In order to
evaluate prevalence rate of tick-borne bacterial
pathogens, unfed adult Ixodes ricinus ticks were
collected from vegetation at 18 localities throughout Serbia in 2001, 2003, and 2004, a total of
287 ticks were examined by PCR technique for
the presence of Borrelia burgdorferi sensu lato;
prevalence rate for B. burgdorferi sensu lato was
42.5% (36, 39). The presence of five B. burgdorferi sensu lato genospecies, namely B. burgdorferi sensu stricto, B. afzelii, B. garinii, B. lusitaniae, and B. valaisiana was identified by restriction
fragment length polymorphism (RFLP) analysis
(39). The most frequent B. burgdorferi sensu lato
genospecies was B. lusitaniae, followed by B.
burgdorferi sensu stricto. These findings indicate
a public health threat in Serbia related to tickborne diseases caused by B. burgdorferi sensu
lato (39).
Q-fever
Q-fever has been present in the region of the
Balkan Peninsula since it was first recorded as
‘’the Balkans flu’’ (1941–1942), and it occurs in
the form of small-scale epidemics and epizooties (8, 40). Across the ex-Yugoslavia territories
Q fever was discovered rather early – in Zagreb (1948), Banat (1950), Bosnia (1951, 1953),
Sandzak (1953), Serbia (1953, 1956 – the Pirot
strain), Dalmatia (1957), Vojvodina (1957), Gacko (1959), Croatia (1962), B&H (1964), Pula
(1972), Vojvodina (1983), Croatia (1984), Vojvodina (1984), Bosnia (1985), Kosovo and Metohija, Cacak (1985), Vojvodina (1991, 1992, 1993,
1994, 1995), Macva (in sheep from Kosovo
1998), Montenegro (1999), Serbia (2003), B&H
(1998., 2000., 2002., 2004) (41,42).
Analyzing the available epizootiological and epidemiological data on the incidence of Q fever
in the region, it could be concluded that beside
classical locally focused character of the disease,
incidence of new epidemics was also influenced
by uncontrolled dislocation of animals, mostly
sheep and goats (41- 44). Although some experts
deny the significance of Q fever from the viewpoint of veterinary medicine, the latent forms of
this disease in domestic animals and abortions
in sheep and goats result in huge economic losses, thus confirming the importance of Q fever
as a problem of the veterinary practice (39. 41).
Moreover, having also in mind the fact that veterinarians together with other professionals are
99
very exposed to this infection, it is obvious that
Q fever must not remain marginalized in the veterinary science. The frequent incidence of this
disease in humans should be followed by systematic investigations of the infections in animals
and natural reservoirs (42, 43).
Hantavirus infections
The Balkan Peninsula has been known as a highly endemic region for hantavirus infections. So
far our research has shown that at least two different Hantaviruses (HTV) (the murine Dobrava
(DOBV) and the avricoline Puumala (PUUV) viruses), each carried by a different rodent species,
have been circulating in the area (44,45).
So far two viruses, Puumala and Dobrava have
been identified as causative agents of hemorrhagic fever with renal syndrome in Albania, B&H,
Greece, Croatia, Kosovo, Montenegro, Slovenia and Serbia (45-50). Additionally, Tula virus,
which is considered a non-pathogenic hantavirus
was detected in small mammals (51). However,
Clethrionomys glareolus, Apodemus agrarius and
Apodemus flavicollis are the main reservoirs of
hantaviruses in the region (46). The incidence of
haemorrhagic fever with renal syndrome (HFRS)
varies in a cyclic fashion, with peaks occurring
every three to four years, coinciding with peaks in
rodents population (45). Several HFRS outbreaks
were registered in the area of the Balkan Peninsula in: 1967, 1986, 1987, 1989, 1995 (45, 51),
and 2002 with more than 1000 HFRS cases. Dual
infections with hantaviruses and leptospira were
also detected in humans as well as in rodents (52).
In the Balkan states where PUU and DOB viruses
co-circulate, seroprevalence in general population
is between 1.6% (Slovenia) up to 5.18% in B&H,
which has been recognized as a highly endemic
region for hantavirus infections for over 56 years
(45,51,53). As early as in 1952 the first ‘’probable’’ HFRS case was described in the region - the
victim was a soldier and infection occurred near
Fojnica city, B&H. The first documented HFRS
outbreak was reported in 1967, followed by five
outbreaks in the region and the majority of the affected population was located in B&H. The total
number of HFRS reported cases was 1242, but
the real number of HFRS cases is probably higher
because the surveillance of infectious disease had
not been regular until 1992 (53).
100
Rabies
Rabies remains endemic within a number of countries in Southeast Europe including Romania,
Bulgaria, B&H and Turkey (7, 44, 55, 56). With
the exception of Turkey, the red fox (Vulpes vulpes) is the principal disease reservoir in Southeast
Europe. However, cases of rabies in dog (Canis
familiaris) are regularly reported. In contrast to
Northern Europe, the raccoon dog (Nyctereutes
procyonoides) does not appear to be a vector in
the south. In Bulgaria, dogs are the main vectors
bringing rabies into contact with humans and livestock. Foxes are the principal reservoir species
for rabies in Romania although cases in dogs are
regularly reported. Despite a gradual decline in
dog rabies, urban pockets of the disease remain
in many regions of Turkey. Furthermore, there is
some evidence that the foxes have been a significant vector for rabies and might be responsible
for increased rabies in cattle. Rabies in Croatia
has been registered in wild animals (mostly foxes)
and sporadically in domestic animals (dogs, cats).
The last human case was described in 1964. The
fox and dogs are the principal reservoir species
for rabies in B&H. Throughout the region there is
evidence of cross-border movement of rabies by
both wildlife and canine vectors (55,56).
The lyssaviruses currently consist of 7 established genotypes or lineaages of rabies(-like) viruses (56) of which classical rabies virus is found
throughout the world and associated with terrestrial mammalian hosts and American bats forms
genotype 1. Phylogenetic relationships among
sequences of five viruses isolated in B&H have
shown the presence of two phylogenetic lines,
one which is present in the Northwestern part and
the other, which is present in the Northeastern
part of the country. Viruses are closely related to
Western European isolates of rabies virus (56).
Tick-borne encephalitis
Tick-borne encephalitis virus is the causative
agent of the most prevalent arboviral human
infections in Europe. Three subtypes have been
identified: European (TBEV-Eu), Far Eastern
(TBV-FE) and Siberian (TBEV-Sib). The vector
of TBEV-Eu transmission is the tick Ixodes ricinus, whereas I. persulcatus is the vector of other
two subtypes. The virus is maintained in nature
through cycles involving tick and wild vertebra-
te hosts and also by transovarial and transstadial
transmission in its vector. Many different vertebrates have been implicated in the maintenances
and circulation of the TBE virus. The major causative role in Central Europe seems to belong
to Apodemus flavicollis and Myodes glareolus,
not only because they are abundant in the regions
where TBE incidence is high and they are excellent hosts for both nymphal and larval stages of
the tick, but also because they promote transmission by co-feeding (44,57,58).
The distribution of TBEV is well coordinated
with its vector distribution. There is a lack of data
related to TBEV seroprevalence among the wild
animals in the Balkan region. Data from Slovenia
have shown that the infection prevalence in rodents sampled in Slovenia in the period between
1990 and 2008 entirely varied based on the rodent species, from 14% in Myodes glareolus to
2-4% in Apodemus species (57-59).
Tick-borne encephalitis (TBE) in Slovenia represents a serious public health problem with hundred official reported cases (58). In Croatia TBE
was first discovered in 1953. The only really documented natural focus of tick-borne encephalitis
was the northern part of the country, between the
Sava and Drava rivers. Alleged cases from other
parts of Croatia still have to be confirmed and
analyzed, and additional research and collaboration between different professionals is required
(44, 57, 59). Official data show no occurrence of
TBE in Albania, Bosnia and Herzegovina, Bulgaria, the Former Yugoslav Republic of Macedonia
and Turkey (57).
Sandfly fever
Sandfly fever viruses (SFV) are moderately endemic along the Adriatic coast of Albania, Croatia,
B&H, Slovenia and landlocked Serbia, and focally distributed throughout Greece and the former Yugoslav Republic Macedonia (44, 60-65).
Historical data of the sandfly fever (Pappataci
fever) indicate its origin in B&H at the end of the
19th century (62, 63). Before the World War II,
the pappataci fever in the former Yugoslavia was
mainly detected in Herzegovina, Dalmatia, Montenegro and especially in Macedonia, where its
prevalence coincided with that of Phlebotomus
papatasi (64, 66). Most of the clinical and epidemiologic studies had been conducted in B&H
between 1886 and 1962 (66-68), but there was no
published data about the SFV infection between
1971 and 2006. The recent infection was found in
9.38% to 12.50% of patients during the period of
three years (2006-2008) (68).
The first extensive serological investigations of
the prevalence of the arbovirus infection were
reported in 1975-1982 (64, 68-70). The results
indicated a high prevalence of the antibodies to
Naples and Sicilian sandfly fever viruses in Dalmatian population, North Croatia and Kosovo.
On the island of Brač, 57.6% of the population
had antibodies for the Naples virus and 15.6% for
the Sicilian virus, in Kosovo- 27.9% and 9.6%,
respectively. The prevalence of the Naples virus
infection reached 62.1% in the inhabitants of
B&H in 1962 (69). These results indicated the
continuous circulation of Naples virus in nature.
Finding the TOSV positive results in clinical
samples after more than forty years (66), means
that the virus has been circulating in this region,
but has not been the point of interest of local researchers. It is very important to direct the attention
of clinicians to sandfly fever (papatasi fever) because the disease was unrecognized in the region
until recently.
Leishmainiasis
Leishmainiasis is widespread on the Balkan Peninsula. It is a protozoan parasitic infection caused by Leishmania infantum that is transmitted
to human beings through the bite of an infected
female sadfly (71). The disease occurs in urban
centers and rural highland villages in Albania,
B&H, Croatia, Greece, Montenegro, Serbia, Romania and Slovenia (71-76). Zoonotic visceral
leishmaniasis (VL) is a re-emerging disease in
the Balkan area (1, 3-5, 73, 74). The re-emerging
is probably due to a combination of factors including increased monitoring, intensified research,
demographic change, land-use/land cover changes that create new habitants and/or changes in
microclimate, and changes in seasonal climate
(2). Some human cases are usually detected in
the area every year (74-76). Visceral leishmaniasis in 50 children was reported from Albania in
2009 (72).
Leishmaniasis is mostly a problem in veterinary
medicine. The investigation of 272 dogs sera
originating from different regions in Albania
101
and Kosovo have shown specific antibodies for
Leishmania in 3.3% of animals. All leishmaniapositive animals were stray dogs (74, 75). Those
animals contribute to the maintenance of Leishmania transmission in endemic areas, and a control of the canine stray population should be considered (74-78). A historical review on human and
canine leishmaniasis in Croatia documents the
presence of stable disease foci in coastal and insular territories of central and southern Dalmatia
since the beginning of the 20th century (71,74).
Among the species which may act as Leishmania
infantum vectors in Croatia, Phlebotomus tobbi
and P. neglectus were the most abundant (74).
Echinococcosis
Echinococcosis remains a very serious public
health problem in Southeast Europe, although a
decrease in incidence has been observed in some
endemic areas during the last decades (77-80).
However, in some non-endemic areas an increase
in infected cases and new foci of animal echinococcosis were registered during the same time
(77). The disease is very common in the Balkan
Peninsula, with the former republics of Yugoslavia having one of the highest prevalence rates
(77-80). Echinococcosis is zoonosis transmitted
by dogs in livestock-raising areas and accidentally affects men. The most frequent site of hydatid cysts is in the liver (78%), followed by lungs
(17%), and less frequently, spleen, kidneys, heart, bones, central nervous system, and elsewhere
(80).
Trichinelosis
In the majority of Southeast European countries
cases of trichinellosis among the human and animal populations were described in the late 19th
or early 20th century (80-81). Trichinella infections among wildlife were also described in the
aforementioned countries (5, 80). Today, the prevalence of trichinellosis between the Balkans and
bordering countries is different (81-83). A high
prevalence of trichinellosis in domestic animals
and humans has been reported in Bulgaria, Serbia
and Montenegro, Romania and Croatia (80-84),
and a moderate prevalence was found in B&H.
Trichinellosis has not been found among domestic animals and humans in Greece and Macedonia in recent years, while in Turkey and Slovenia
102
human trichinellosis is sporadic (83). A re-emergence of trichinellosis is connected with the changes in the social and political systems in Bulgaria
and Romania (81, 84). In B&H, Kosovo, Serbia
as well in Croatia, however, the re-emergence of
trichinellosis did not only happen due to political
and social changes, but also due to the war that
took place in these countries during the last years
of the 20th century (84).
There are some other zoonoses and vector-borne diseases with more or less documented evidence on epidemiological, clinical or etiological
features (1, 8, 44, 85, 86). The special attention
deserves tuberculosis and rickettiosis, because
the outbreaks affected the history of the Balkan
Peninsula.
THE SURVEILLANCE OF WILDLIFE ZOONOSIS
DISEASES
The last outbreaks of avian A (H5N1) and swine
influenza A (H1N1) showed the importance of
greater collaboration between physicians and veterinarians as well as for the disease surveillance
in humans, domestic animals and wild animals
(5). The surveillance of diseases in wild animals
is a relatively new activity compared to the surveillance of diseases in humans or domestic animals (5, 7). At the moment, there is no Balkanwide network of health surveillance. Since 1992,
the disease surveillance in most Balkan countries is irregular and coordinated by the WHO. A
number of new zoonotic infections emerged or
re-emerged during the past 17 years, caused by
social, political, climate and environmental changes in the area. The communication channels
among Balkan countries were broken, so preventive action has not been done. There is an urgent
need for building of a European health surveillance network. It should include the following
elements: national surveillance programs that
cover the whole country; human diseases, domestic animal diseases, all wildlife species, and all
diseases; comparable methodology among surveillance programs, so that it is valid to compare
results; strong interaction among surveillance
programs, so that new information and knowledge is rapidly and efficiently shared.
Recent initiative called One Health, which supports the unique approach to zoonoses, is a concept of the worldwide strategy for expanding
interdisciplinary collaborations and communications in all aspects of health care for humans and
animals (86).
ACKNOWLEDGEMENTS/DISCLOSURES
Competing interests: none declared.
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105
REVIEW
Beginnings and success in preventing anophelism by means of
gambusia fish on the island of Krk in Croatia from 1922 to 1927
Ante Škrobonja1, Neven Materljan2, Ivana Škrobonja3
Departement for the History of Medicine, Rijeka University School of Medicine, 2Associate Department for the History of Medicine,
Rijeka University School of Medicine, 3Clinic Hospital Centre Rijeka, Department for Clinical Microbiology; Rijeka, Croatia
1
ABSTRACT
Ante Škrobonja,
Rijeka University School of Medicine,
Braće Branchetta 20, 51000 Rijeka,
Croatia
Phone: ++385 51 651 165;
Fax: +385 51 651 180;
The introductory part has summarized the role of malaria in the
course of history and various attempts of its eradication in Croatia
before the World War I. Furthemore, there is a list of activities and
results accomplished between 1922 and 1927 on the island of Krk
by Dr. Otmar Trausmiller. After a systematic sanitation of all anopheles habitats, primarily natural and artificial bodies of still water,
and introduction of imported gambusia to those bodies of water,
anopheles was virtually eradicated on the island. What followed
was an evident decrease of new malaria incidents, and in the campaign against malaria there was still major concern in the form of
chronic patients and intensive quinine therapy. Today, about eighty
years after it was introduced to Krk, gambusia still abides in ponds
across the island and it represents one of the main factors in the
protection against potential revival of indigenous malaria.
Key words: history of medicine, malaria, gambusia fish, eradication, Otmar Trausmiller, the island of Krk, Croatia
31 July 2009;
Revised submission:
16 September 2009;
Accepted:
30 October 2009
106
Škrobonja et al Preventing anophelism on the island of Krk
MALARIA IN CROATIA BEFORE WORLD WAR I
Although malaria has been present in Croatia for
as long as anyone can remember, particularly in
the vicinity of larger rivers and especially in the
Croatian Littoral, Istria and Dalmatia, the first
written documents on malaria in Croatia date
from the 16th century and concern Istria . Before
the end of the 16th century, malaria was spread
across almost the entire territory of Croatia. The
first studies of the disease, as described in “De
morbo Naroniano tractatus” (On the “Neretva disease”), written by the Paduan professor Giusepe
Antonio Pujati, were performed as early as the
18th century (1).
In the western part of Croatia, especially in the
Kvarner region, as the public health problem of
malaria was present mainly on the islands of Krk,
Rab and Pag (2), where an outbreak of epidemic
known as Škrljevo disease (at the turn of the 8th
and early 19th century), and after its settling (3)
remain the leading health problem. However,
the mainland, with a few exceptions, was not
affected by malaria. On these islands the main
malaria mosquito habitats were mostly artificial
ponds for cattle watering and lakes in the vicinity
of Omišalj on the island of Krk and Velo Blato on
Pag. The prevailing type of mosquito was again
Anopheles maculipennis, which, apart from the
zoophylous type, was also represented by the antropophylous type Labranchiae. Earlier authors
claim that this type of malaria was usually a benign tertiary infection (4).
Malaria, which was present endemically near
rivers, swamps (particularly near swamps along
karst rivers) and ponds, was sometimes a decisive factor in some of the historical events in Istria
from the ancient times until the 20th century. The
best example is the city of Dvigrad (Ital., Due
Castelli) that had coped with several epidemics
of the plague or similar diseases from the antiquity, but life ceased there in the 18th century, after the adjacent river had changed its course and
gave way to fatal swamps (5). On the other hand,
many swampy areas were brought to life by the
effective land-reclamation and eradication of mosquitoes, as was achieved on the Brijuni Islands
thanks to Robert Koch (6).
Although the problem of malaria was more systematically dealt with by the authorities in Dalmatia as early as during providur Dandol’s rule (who
was a pharmacist by profession) and Napoleon’s
Illyrian provinces (1808 – 1813) (7), and the first
results were achieved, more detailed data on the
spread and the character of malaria in Dalmatia
date only from 1905, when it was estimated that
approximately 80,000 persons infected with malaria lived in the area, and that the prevalence of
malaria in certain districts varied between 29%
in Knin and 63% in Zadar. After the invitation
of the Royal Regency, the Italian malariologist
Giovanni Battista Grassi and the German epidemiologist Fritz Richard Schaudin soon came to
Dalmatia and prepared and applied “quinisation”. In 1902., Rudolf Battara eradicated malaria
in Nin, Croatian Royal Town. In 1908, under dr.
Jakov Gljivanović, 25 doctors and 423 pill distributors were included in the quinisation. They
went around villages on a regular basis, distributed pills and monitored their use. Comprehensive
assanations of the terrain were also conducted.
This soon yielded positive results (8).
Following World War I malaria spread again.
Tropical malaria was more widely spread and
the number of malaria patients was estimated to
reach 150,000. The specific index was also significantly higher and in some areas reached 70 to
90% (9).
DR. OTMAR TRAUSMILER AND GAMBUSIA FISH
IN FIGHTING MALARIA ON THE ISLAND OF KRK
A new organised anti-malaria campaign in the
Croatian littoral area began after World War I
and was lead from two centres: the Institute for
the Research and Fighting of Malaria in Trogir
and the Public Health Institute in Sušak (10,11).
Extensive malariometric surveys and anophelism
surveys were conducted. Moreover, many new
malaria centres were set up. Systematic assanation in Dalmatia was focused on the melioration of
swampy areas and on making wells out of ponds.
Anophelism was also successfully combated by
applying paraffin and Paris Green. In the Croatian Littoral, particularly on the island of Krk,
apart from what was just said about 1924, ponds
were stocked with gambusia fish (Gambusia holbrochi Grd.) (12).
Gambusia fish live in warm still waters of the
central part of the New World. There are two
types of these larvivorous small fish, Gambusia
affinis i Gambusia holbrochi.
107
Gambusia are viviparous, which is a great evolutionaty advantage. A large number of gambusia
survive their youth and reach sexual maturity.
The females in the aquarium reach sexual maturity at four months of age, and have a brood of
200 young at a time. They multiply during the
warm season in temperate climate and have one
brood of young every three to six months. In tropical climate, gambusia fish multiply throughout the year. They are not too choosy about their
food; however, after it had been noticed that they
had a strong affinity for Anopheles larvae that
feed on the water surface, there was an attempt
of transmitting them to other parts of the world
as a means of eradicating Anopheles. This biological method of fighting Anopheles was very
successful and appropriate since the living and
breeding conditions for this fish were very favourable and the ecological risks minimal (13).
On the largest Croatian island of Krk (406 km2),
known for its endemic malaria from the times of
antiquity, the main sources of the disease were
many artificial ponds for cattle watering that were
virtually infested with Anopheles larvae (4).
In 1923 an extensive and the Sušak Public Health Institute co-ordinated anti-malaria action on
the Island of Krk was to be carried by Dr. Otmar
Trausmiler. As for the basic hydrotechnical works, Dr. Trausmiler could rely solely on the local
labourers, hand tools, and scanty resources. Under such circumstance, Dr. Trausmiler decided to
apply a new method of ‘’bio-weaponry’’ by introducing a new, alochtonic species to the island
– the tropical Gambusia fish. He would widely
report on this idea, its realization as well as the
results in his 1927 monography entitled ‘’Malaria on the Island of Krk’’ (Figure 1-3). This work
was accompanied by exquisite photographs and
drawings, while the results were displayed in tables and graphs and supported by the recent references from the international publications (12).
After he had made a detailed and soundly grounded presentation of the historical and actual
circumstance related to malaria on the island, the
author elaborated on the project of assanation of
all the Anopheles habitats, mainly the natural and
artificial still waters and their stocking with the
imported Gambusia fish.
Dr. Trausmiler’s presentation of the results opens
with the statement that despite the minimum fi-
108
nancial support and scanty technical equipment
the initial hydrotechnical works had been finished
and the conditions set for experimental stocking
so that by the end of August 1924 400 Gambusia holbrochi Grd. fish from Italy were imported. The fish were dropped into several ponds as
soon as they had been brought. Due to the stress
they had undergone in transport almost half of
the Gambusia fish instantly died. Luckily enough, the remaining Gambusia accommodated fast
and well and a large number of them survived the
winter 1924/1925 in a new habitat. In May 1925
the first young Gambusia fish were noticed in the
fish-stocked ponds and then they were systematically transmitted into other ponds. By the fall
1925 there were 25 newly stocked ponds on the
Island of Krk, and fish-stocking was continued
with the same intensity. There were at least 1000
to 2000 Gambusia in every fish-stocked pond.
The winter 1925/1926 was exceedingly cold so
that every pond on the island was covered with
Figure 1. Črna Lokva (Black pond) the first breeding pond for
Gambusia fish on the island of Krk (Photo by Dr. O. Trausmiler,
1927) (accepted from: Trausmiler O. Malarija na otoku Krku epidemiologija i pobijanje 1923.-1926. Sušak: Dom narodnog
zdravlja, 1927., p. 76)
Figure 2. Pond with a wall constructed of stone (Photo by Dr.
O. Trausmiler, 1927). (accepted from: Trausmiler O. Malarija na
otoku Krku epidemiologija i pobijanje 1923.-1926. Sušak: Dom
narodnog zdravlja, 1927., p. 77)
Škrobonja et al Preventing anophelism on the island of Krk
ice. The Gambusia fish survived and in the spring
1926 they again started to multiply fast so that Dr.
Trausmiler’s field-workers proceeded with even
more intense fish-stocking of the remaining ponds on the island. Dr Trausmiler pinpoints the first
positive effects: the Anopheles larvae vanished
from the ponds whose edges were walled, cleaned
of water plants, and stocked with Gambusia fish.
The fish that were dropped into ponds in springtime would multiply until summer and eat all the
Anopheles and Culex larvae. A considerable decrease in the incidence of the new cases of malaria
was soon registered. The chronic malaria patients
anf the intensive quinine therapy thus became a
priority of the anti-malaria campaign.
DISCUSSION
Thanks to the introduction of Gambusia fish to
the Island of Krk, the two traditional methods of
the Anopheles larvae eradication have been abandoned – relatively expensive paraffin, and Paris
Green, effective in certain conditions alone. Spilt
onto the pool surface, paraffin would mechani-
Figure 3. Coverpage of Trausmiler’s book “Malaria on the
Island of Krk: Epidemiology and melioration, 1923.-1926.”
from 1927. (accepted from: Trausmiler O. Malarija na otoku
Krku -epidemiologija i pobijanje 1923.-1926. Sušak: Dom
narodnog zdravlja, 1927.)
cally smother the Anopheles larvae, and would
evaporate in a couple of days, which would make
ponds usable for cattle watering again. The less
expensive Paris Green was a powder insecticide
blend of arsenic and copper. Prior to application,
Paris Green was to be mixed with gravel dust.
Since the latter was scarce on the Island of Krk,
it was replaced by sifted ash. In order to apply
Paris Green, there should have been no wind to
ripple the water surface; as it was often windy
on the island of Krk, Paris Green could be rarely
applied.
In contrast to these methods, Gambusia fish served as an effective non-toxic and inexpensive biological means against Anopheles larvae. It was
enough to catch Gambusia fish with an improvised fishing net, transport them in a bucket or
any other vessel and drop them into an Anopheles
larvae infected pond; moreover, Gambusia fish
made a permanent larvicidial means that did not
endanger natural balance. The ponds were mainly artificial cattle watering places without traditional aquatic life; therefore, the use of Gambusia
fish as a larvicidal means in this case meant no
threat to the local aquatic life.This is even more
important because the imprudent introduction of
Gambusia fish and its residence in larger water
bodies have brought about dramatic changes of
eco-systems, especially those of running waters
in various parts of the world. It has brought on
the decrease in number and a permanent threat
to the survival of local invertebrates, fishes, and
amphibians. It has been established lately that
the dropping of Gambusia fish into some natural
ponds and small lakes in California has brought
on a considerable decrease in number of the endemic fairy shrimp (Linderiella occidentalis) (13),
while in New Zealand Gambusia fish represents a
threat to the endemic fish of dwarf inganga (Galaxias gracilis) (14).
Although Gambusia fish were not used in the
continental but solely Mediterrannean part of
Croatia, they vastly contributed to the eradication
of malaria in Croatia. The most successful of the
methods used after World War II was the action
started in 1950 using the concept of prof. Branko
Richter from the School of Public Health “Andrija Štampar” in Zagreb, based on the application of the new chemical DDT, followed by other
new insecticides in all endemic areas. This, along
109
with the systematic assanation of the terrain and
the improved social and economic conditions of
the people, finally resulted in uprooting malaria
in Croatia. The last indigenous cases of malaria
infections were registered in 1958 and WHO in
1964 officially declared that malaria in Croatia
was eradicated. Despite the setbacks, up until
1969, when the global eradication policy was finally abandoned, the following European countries had managed to completely eradicate endemic
malaria by interrupting transmission: Hungary,
Bulgaria, Romania, Spain, Poland, Italy, Netherlands, Portugal and former Yugoslavia (15,16).
In conclusion, today, eighty years after the introduction of Gambusia fish to the Island of Krk,
they still live in the ponds across the island. They
probably make their 200th generation. Gambusia
fish still tirelessly devour mosquito larvae and
thus reduce the number of Anopheles and Culex
on the island. Entirely acclimatized and domesticated, these tropical fish represent a contingent
and precious larvicidal means in the hands of
experts.
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3.
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110
Gregurić Gračner G, Vučevac Bajt V. History of
Eradication of malaria in Croatia. Orvostort Kozl
2002;47:145-55.
Azman J, Muzur A, Frković V, Pavletic H, Prunk A,
Skrobonja A. Public health problems in the medieval
statutes of Vinodol, Vrbnik and Senj (West Croatia).
J Public Health (Oxf) 2006; 28:166-7.
Muzur A, Škrobonja A. Škrljevo disease: Between
myth an reality. Croat Med J 2004; 45:428-31.
Cubich GB. Notizie naturali e storiche sull’isola di
Veglia. Trieste: Stabilimento tipografico Appolonio
& Caprin, 1874-75.
Čehić M, Karabajić M. Dvigrad – simbol medicinske nemoći. U: Rašajski R. urednik. Zbornik 2. naučnog kongresa. Vršac: Naučno društvo za historiju
zdravstvene kulture Jugoslavije, 1970., pp. 181-5.
Fatović-Ferenčić S. Brijuni Archipelago: story of
Kupelwieser, Koch and the Cultivation of 14 islands.
Croat Med J 2006; 47:369-71.
Fisković C. Zdravstvene prilike u Splitu krajem
XVIII. i prvih godina XIX. stoljeća. U: Grmek
M.D., Dujmušić S, urednici. Iz hrvatske medicinske
prošlosti. Zagreb: Zbor liječnika Hrvatske, 1954, pp.
238-54.
Nežić E. Historija endemske malarije u Dalmaciji
do 1923. godine. U: Zbornik. Prvi simpozij o historiji mikrobiologije i imunologije u Hrvatskoj do
1926. godine. Zagreb: JAZU, 1973., pp. 71-80.
Simić C. Malarija. Beograd-Zagreb: Medicinska
knjiga, 1948., pp. 237-42.
10. Emili H. Razvoj preventivne zdravstvene službe na
sjevernojadranskoj obali od otvaranja Doma narodnog zdravlja u Sušaku do početka II svjetskog rata
– 1926. do 1941. Liječ Vjesn 1988; 110:118-24.
11. Bakašun V, Alebić-Juretić A. Sto godina preventivne
medicine na Riječkom području. Liječ Vjesn 2002;
124:380-9.
12. Trausmiler O. Malarija na otoku Krku epidemiologija i pobijanje 1923.-1926. Sušak: Dom narodnog
zdravlja, 1927.
13. Duryea R, Donnelly J, Guthrie D, Claudia O’malley
C, Romanowski M, Schmidt R. Gambusia Affinis
effectiveness in New Jersey Mosquito Control. Proceedings of the Eighty-Third Annual Meeting of
the New Jersey Mosquito Control Association, Inc.
1996, pp 95-102. [Online] http://www.rci.rutgers.
edu/~insects/gamb2.htm (23 September 2009).
14. Rowe D. Manegement trials to restore dwarf inganga show mosquitofish a threat to native fish. Water
and Atmosphere 1998; 6:10-12
15. Richter B. Osvrt na dosadašnji rad antimalarične službe i njezine zadatke u 1950. godini. Higijena 1950;
4:299-311.
16. Richter B. Doprinos Jugoslavije u konceptu eradikacije malarije U: Angelovski A, urednik. Eradikacija
na malarijata vo Jugoslavija. Skopje: Makedonsko
lekarsko društvo, 1973., pp. 43-9.
ORIGINAL ARTICLE
Emanuel Edward Klein, a diligent and industrious plodder or the
father of British microbiology
Bruno Atalić1,2, Ines Drenjančević-Perić1, Stella Fatovic-Ferenčić2
Department for the Physiology and Immunology, 2Department for the Family Medicine, History of Medicine and Medical Ethics; School
of Medicine, Josip Juraj Strossmayer University, Osijek, Croatia
1
ABSTRACT
Bruno Atalić
Department for the Physiology and
Immunology and Department for the
Family Medicine, History of Medicine and
Medical Ethics
School of Medicine,
Josip Juraj Strossmayer University
Josip Huttler 4, 31000 Osijek, Croatia
Emanuel Edward Klein (Osijek, 1844 - Hove, 1925) was a British
microbiologist of Croatian origin. He completed his medical studies in Vienna in 1869. In 1869 he was sent to England to determine
terms for the translation of Samuel Stricker’s manual Handbuch
von den Geweben des Menchen und der Tiere. During his visit he
made a good impression on John Burdon Sanderson and John Simon, which was the main reason why he was invited to London in
1871 to conduct investigations under their guidance. In 1873 Klein
began his collaboration with the Saint Bartholomew‘s Hospital,
where he was appointed as a Joint Professor of General Anatomy
and Physiology. His researches were in the fields of anatomy, histology, pathology, embryology, physiology, and especially microbiology. He did a great deal to its development in Britain. He has
written about 260 scientific papers on a broad range of different
topics. Despite all the aforementioned facts, his work was never
properly studied, and he is almost unknown outside academic circles. For that reason, attitudes towards him still range between the
extremes of calling him the father of British microbiology on one
side, and attributing him as a diligent and industrious plodder on
the other. In this paper we will try to prove the first attitude. We
will put his researches in a general context. Finally we will highlight his original achievements in the isolation of new microbes.
Key words: Klein, Emanuel Edward; United Kingdom; Microbiology; 19th Century; 20th Century
Phone: ++385 31 512 500;
Fax: ++385 31 512 566;
29 May 2009.;
Revised submission:
03 August 2009.;
Accepted:
11 August 2009.
111
INTRODUCTION
The germ theory gave public health functions
a plausible new rationale mainly in setting up
bacteriological laboratories for infective diseases starting from the half of the 19th century on.
Important research centres for investigations into
typhoid fever, typhus, scarlet fever, small pox,
cholera, and tuberculosis, laboratories sprang up
and their researches were not just fuelled by the
professional curiosity, but also by the political
competition. This was particularly true for France
and Germany, which, according to Latour, after
the defeat of the French Empire and the proclamation of the German Empire in 1871, switched
from military campaigns to scientific pursuits (1).
The major proponents of medical microbiology
in Britain were the Scottish surgeon Joseph Lister (1827-1912), who introduced antisepsis with
the carbolic acid spray in Glasgow in 1871, and
Emanuel Edward Klein, who was the first general
bacteriologist (2). Lister has made a major contribution to medical practice with his invention of
antisepsis, because of which he is widely known,
but Klein has made only minor contributions to
medical science, which is the reason why he is
generally unknown. His work was never studied
in depth, although he was occasionally mentioned as an example of medical contacts between
the two nations (3).
In this paper we shall concentrate only on Klein’s
microbiological researches as the main field of
his professional career focusing primarily on
his isolation of ‘’Streptococcus pneumoniae’’,
‘’Streptococcus scarlatinae’’, ‘’Bacillus enteritidis sporogenes’’, ‘’Bacillus cadaveris’’, and ‘’Bacillus carnis’’ today known as Streptococcus pneumoniae, Streptococcus pyogenes, Salmonella
enteritidis, Clostridium cadaveris, and Clostridium carnis, as his original contributions in the
isolation of new microbes. Our research is based
on primary and secondary sources mostly kept in
the Oxford Bodleian Library - Radcliffe Science
Library, the Cambridge University Library - Rare
Books Department, and Saint Bartholomew’s
Hospital Archive in London, United Kingdom.
LIFE AND LEGACY
Emanuel Edward Klein was born on 31 October
1844 in Osijek, in the Virovitica County, in the
Kingdom of Slavonia, which was then part of the
112
Austrian-Hungarian Empire, to a German speaking, non-observant Jewish family. He finished
the grammar school in his hometown and graduated in 1863. With the help of a scholarship he studied medicine in Vienna, and obtained the M.D.
in 1869, but actually never practiced medicine.
At first he worked with physiologist Ernst von
Brücke, and later with pathologist Salomon Stricker (1834-1898). Klein soon achieved the title of
Privat Dozent (4).
In 1869 Klein was sent to England to determine
terms for the translation of Samuel Stricker’s manual Handbuch von den Geweben des Menchen
und der Tiere (Leipzig 1869-1872, London 18701873) (5). During his visit he was introduced to
John Burdon Sanderson, superintendent at the
Brown Sanitary Institution, John Simon, medical
officer to the Local Government Board, and Thomas Henry Huxley, founder of the Natural History
Museum in London, on whom he made an excellent impression. This was the main reason why in
1871 he was invited by Sanderson to work at his
private laboratory in Howland Street. In 1873 he
was appointed as an Assistant Professor of Comparative Pathology at the Brown Sanitary Institution in order to conduct pathological, clinical and
epidemiological researches, under the supervision
of Simon. Klein was in charge of the bacteriological research laboratory (5). His research was at
first conducted in a histological manner, by looking for the infecting agent with a microscope,
and then after a couple of years he adopted the
cultivation approach. He zealously implemented
the Continental improvements into his work. In
this respect he did a great deal to develop English
bacteriology. In recognition of his investigations
he was elected a Fellow of the Royal Society of
London on 3 June 1875 after his nomination from
the general knowledge by John Tyndall, and from
the personal one by Charles Darwin (6) (Figure
1). Later on he was recommended by the President
and Council of the Royal Society of London for
election into the Council for the year 1889 (7).
In 1873 Klein began his collaboration with the
Saint Bartholomew‘s Hospital, the oldest hospital in London, founded in 1123 by the monk
Rahere, which was to last until his retirement in
1911. During his 38 working years at the Saint
Bartholomew‘s Hospital, Klein was Joint Lecturer in General Anatomy and Physiology (1873-
Atalić et al Edward Emanuel Klein
RESEARCH IN MICROBIOLOGY
Emanuel Edward Klein was employed as an
Assistant Professor of Comparative Pathology
at the Brown Sanitary Institution between 1873
and 1897. He conducted scientific researches on
the commission from the Local Government Board, and they can be analyzed primarily from his
numerous annual papers sent for publication in
the Reports of the Local Government Board. In
1884 Klein identified a new micrococcus from
the lymph of ill sheep, and claimed it to be the cause of foot-and-mouth disease. Due to its shape,
Klein first named it Diplococcus, then Micrococcus, and finally Streptococcus (12), but in 1901
it was renamed Streptococcus pneumoniae by the
American pathologist William Chester, who proved that it was not the cause of foot-and-mouth
disease, but of pneumonia (13).
Figure 1. “Certificate of a Candidate for Election into the
Royal Society of London” (Public Domain of the Wellcome
Institute Library in London; http://images.wellcome.ac.uk)
1902), Lecturer in Histology (1873-82), Lecturer
in Microscopic Anatomy (1874-92), Lecturer in
General Anatomy and Physiology (1882-1903),
Lecturer in Bacteriology (1903-12), Lecturer in
Advanced Bacteriology (1910-11), and he retired
with the title of Emeritus Professor (8). His teaching was always in the forefront of the newest
scientific discoveries. In 1889 he was elected as
a Professor of Bacteriology in the College of State Medicine (Jenner Institution), founded by the
retired surgeons-general of the Navy, Army and
Indian Services, where he held lectures and tutorials until 1891 (9). In 1890 he opened a private
school in Great Russell Street and gave practical
and technical bacteriological classes to pupils
like Sir Ronald Ross (1857-1932) (10). In 1891
he was invited by the Medical School authorities
of the Saint Bartholomew‘s Hospital to conduct
full-time researches for them and was allotted a
laboratory composed of three rooms at the top of
the school building. His laboratory was always
open to students, who were encouraged in bacteriological researches (11).
At the end of 1885 and the beginning of 1886 an
extensive outbreak of an unknown disease occurred among the cows at a farm in Hendon (14). It
was described as scarlet fever and called the Hendon Disease by Klein and as cowpox by Crookshank. Although in the end Crookshank was victorious and became an unofficial leader of the so
called British bacteriological school, Klein also
made a significant discovery (15). He managed to
isolate four different species of micrococci: ‘Micrococcus citreus’, ‘Micrococcus aurantiacus’,
‘Staphylococcus pyogenes’, and ‘Micrococcus
scarlatinae’, from the tissues obtained from the
Hendon cows and from scarlet fever patients. Together with the local MOH, William Power, Klein
proved that ‘Micrococcus scarlatinae’ came into
milk not indirectly from the milkers’ hands, but
directly from the cows’ udders, which in the end
developed into one of the most important preventive measures against scarlet fever epidemics (16,
17). Although it was later renamed Streptococcus
pyogenes, due to the suggestion of the German
physician Anton Rosenbach, who described its
properties already in 1884, the explanation of the
streptococcal origin of scarlet fever was Klein’s
contribution (13).
Emanuel Edward Klein had been engaged as a
lecturer at the Medical School of the SBH since
1873. In 1891 he completely transferred his laboratory work to the newly built laboratory allotted
to him, and stayed there until his retirement in
1911. In this period he was free to pursue micro-
113
biological investigations according to his own
interests. Their results were published overwhelmingly in The Lancet, but also in Public Health
and Saint Bartholomew’s Hospital Reports. On
2 March 1889 Klein announced the isolation of
a microorganism responsible for the summer diarrhoea epidemic at the SBH, which he named
‘Bacillus enteritidis sporogenes’, and which was
later renamed Salmonella enteritidis. It was isolated from the stool specimens, and described as
an aerobic bacillus, which formed large oval spores. When inoculated into guinea pigs, it caused
haemorrhagic oedema, necrosis, and death (18).
In 1889 Klein isolated a microorganism from the
peritoneum of a rabbit, and named it ‘Bacillus cadaveris’. He proved that it was not pathogenic for
guinea-pigs and rabbits. Due to its occurrence in
human cadavers, today it is know as Clostridium
cadaveris. Again in 1904 Klein isolated another
one from soil, and named it ‘Bacillus carnis’.
When inoculated into a rabbit it produced oedema, necrosis, and death. Nowadays it is know
as Clostridium carnis. The mentioned bacilli are
still named after Klein, who was the first one to
isolate them (13).
DISCUSSION
Due to the fact that attitudes of various historiographers towards Klein’s investigations were
exceedingly diverse, his legacy needs a profound
revaluation. According to Bulloch, for example,
Klein was ‘a tremendously diligent plodder with
an untiring industry’ who failed to make any discovery of permanent value, due to his individual,
dogmatic and polemical character (9). Waddington is also on this track, by stating that Klein
was more interested in his own research, than in
the shaping of medical education, and characterizing him as undiplomatic, blunt, and unpopular
(10). His obituaries compromised by admitting
that he himself did not make any significant discovery, because he was self-taught, influenced by
the Jennerian tradition of connecting diseases of
humans and animals, and conducted experiments
not in accordance with his intuition, but on the
requests of the Local Government Board, and by
giving him credit for the comprehensive education of future microbiologists (6, 9, 19).
On the other side, Lambert in his influential book
on the development of public health in England
114
called Klein ‘the father of English bacteriology‘,
gave him the credit for the significant discoveries, and portrayed him as the most prominent
member of the Brown Sanitary Institution (20).
Foster was also on this track by placing the emphasis on his discovery of the streptococcal origin
of scarlet fever (17). Moreover, Waller described
him as the first person in microbiological history
to undertake an auto-experiment, by drinking
water infected with the Vibrio cholerae in July
1884 (21). Morrant put Klein in the same context
as Edgar Crookshank, Henry Gradle, and George Sternberg, by emphasizing the importance
of his handbook Micro-organisms and Diseases
(22) published in 1884 as the first British microbiological handbook, which made Pasteur’s and
Koch’s bacteriological discoveries published in
French and German journals available to English and American scientists (23). Rupke tried
to put his vivisections into the European context,
by showing that the physiologists conducted the
same experiments in Britain and on the Continent,
despite different public attitudes (24). Finally,
Worboys balanced the afore mentioned extremes
by showing the influence of Klein’s experimental
work on popularization of bacteriology in the public health, surgery and medicine (25).
Our analysis has proved that Klein’s microbiological achievements can be recognized on the
three levels: microbiology in general, British microbiology, and that of his original contributions
to the identification of new microorganisms. Regarding the microbiology in general, Klein certainly can be compared neither with Pasteur, who
formulated the germ theory, nor with Koch, who
developed microbiological techniques, or Lister,
who invented antisepsis with carbolic acid. We
should bear in mind that Klein’s importance was
not in the original contributions, but in the work
of critical evaluation by his experiments and the
scientific propagation through his writings of the
original contributions of other microbiologists,
which is represented by his 264 scientific papers, published in the most prestigious journals.
Moreover, with his insistence on the necessary
connection between microscopical identification,
cultural isolation, and animal inoculation as the
three phases in the connection between specific germ and specific disease, he established the
standards of microbiological research. While his
Atalić et al Edward Emanuel Klein
contemporaries were followers of either Pasteur
or Koch, Klein was self-confident or stubborn
enough to pursue his own way, thus making
British microbiology at least autonomous, if not
original, in its development. Furthermore, due to
the breadth of his researches, rigorous implementation of the Continental improvements, and the
continuous education of future microbiologists,
he laid the foundations of the mentioned discipline in this country. It is true that Klein claimed
the discoveries of new microbes, or opposed
the other microbiologists in claiming the same,
which were both later refuted, but the work of
every serious scientist in a developing discipline
is composed of a series of attempts and mistakes,
which in the end leads to the right conclusion. In
this respect, the identifications of ‘Streptococcus
pneumoniae’, ‘Streptococcus scarlatinae’, ‘Bacillus enteritidis sporogenes’, ‘Bacillus cadaveris’,
and ‘Bacillus carnis’, although later mainly renamed according to the contemporary approaches,
are still regarded as his original contributions to
the development of microbiology (13). If we take
into account that he conducted his researches at
the request of the Local Government Board in order to improve public health policies, and not to
seek his own fame, that he was equally ready to
acknowledge his own mistakes as to criticize the
mistakes of others, and finally, that despite the
fact that he himself was self-taught, he unselfishly passed his knowledge to his pupils, it would
be more objective to remember him as the father
of British microbiology, than as a diligent and
industrious plodder, as well as the first general
British microbiologist.
This paper is a result of the research financed
by the National Foundation for Science, Higher
Education and Technological Development of
the Republic of Croatia, and Ministry of Science,
Education and Sports projects No. 219-21601332034 and No. 101-1012555-2553.
REFERENCES
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Latour B. The Pasteurization of France. Cambridge
and London: Harvard University Press, 1988.
Belicza B. Klein Emanuel. In: Padovan I. (Ed.).
Medicinski leksikon. Zagreb: Leksikografski Zavod
Miroslav Krleža, 1992.
Loewenthal Z. Anglo-Yugoslav medical relations in
peace and war. BMJ 1961; 2-5267:1634-7.
Loewenthal Z. Klein Emanuel. In: Grmek MD.
(Ed.). Medicinska enciklopedija. Zagreb: Hrvatska
medicinska bibliografija, 1970.
Bulloch W. The history of bacteriology. Oxford:
Oxford University Press, 1938.
Andrewes FW. In Memoriam – Edward Emanuel
Klein, MD, FRS. Saint Bartholomew‘s Hospital Reports 1925; 58:1-6.
Anonymous. The Council of the Royal Society. BMJ
1888; 2:1454.
Saint Bartholomew’s Hospital: Handbooks to bacteriology; MS 20; London: Medical College Handbooks.
Bulloch W. In Memoriam: Emanuel Klein: 18441925. The Journal of Pathology and Bacteriology
1925; 28:684-97.
Waddington K. Medical education at Saint
Bartholomew’s Hospital, 1123-1995. Woodbridge:
The Boydell Press, 2003.
Medvei VC, Thornton JL. The Royal Hospital of Saint Bartholomew, 1123-1973. London: The Royal
Hospital of Saint Bartholomew, 1974.
Klein, EE. The etiology of foot-and-mouth disease.
The Lancet 1886; 127-3253: 15.
Euzeby JP. List of bacterial names with standing
in nomenclature. http://www.bacterio.net (18 April
2009).
14. Klein EE. Some of the infectious diseases common
to men and lower animals. The Lancet 1887; 1303355:124-6.
15. Klein EE. Report of the medical officer for 1885.
15th Annual Report of the Local Government Board
1886; 15:90-110.
16. Russell JB, Chalmers AK, Klein EE. Report on
an outbreak of scarlet fever in Glasgow. Glasgow,
1893.
17. Foster WD. A history of medical bacteriology and
immunology. London: Cox and Wyman Ltd., 1970.
18. Klein EE. On the causation of the summer diarrhoea. Saint Bartholomew’s Hospital Journal 1889;
6-9:133.
19. DA P. Obituary. Saint Bartholomew’s Hospital Journal 1925; 32: 89-90.
20. Lambert R. Sir John Simone 1816-1904: and English Social Administration. London: MacGibbon
and Kee, 1963.
21. Waller, J. The Discovery of the Germ. Duxford: Icon
Books, 2002.
22. Klein EE. Micro-organisms and disease: an introduction into the study of specific micro-organisms.
London: Macmillan, 1884.
23. Mortimer PP. The Bacteria Craze of 1880s. The Lancet 1999; 353 (1999): 581-84.
24. Rupke NA. Vivisection in Historical Perspective.
London: Routledge, 1987.
25. Worboys M. Spreading germs: disease theories and
medical practice in Britain, 1865-1900. Cambridge:
Cambridge University Press, 2000.
115
ORIGINAL ARTICLE
Efficiency of hypertonic and isotonic seawater solutions in
chronic rhinosinusitis
Josip Čulig1,2, Marcel Leppée1, Andrijana Včeva3, Davorin Djanic4
Department of Pharmacoepidemiology, Andrija Štampar Institute of Public Health, Zagreb, Croatia, 2Department of Pharmacology, School of Medicine, Josip Juraj Strossmayer University Osijek, Osijek, Croatia, 3Department of Otorhinolaryngology, School of
Medicine, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia, 4Department of Otorhinolaryngology and Cervicofacial Surgery,
General Hospital Dr. Josip Benčević, Slavonski Brod, Croatia
1,2
ABSTRACT
Aim To compare the efficiency of isotonic and hypertonic seawater solutions used for nasal lavage and quality of life of the patients
with chronic rhinosinusitis.
Methods A random and controlled clinical study was performed.
The study included 60 patients with history of chronic rhinosinusitis. At the beginning of the study, each subject was given a Patient
Logbook, which needed to be filled out daily during the 15-day
study period. There were three visits per each patient during the
study.
Josip Čulig
Andrija Štampar Institute of Public Health
Mirogojska 16, 10000 Zagreb, Croatia
Phone.: +385 1 469 6150;
fax: +385 1 4678012
Results Patient Logbook notes showed significant statistical differences in all symptoms in the group of patients using hypertonic
seawater solution. However, while the notes showed significant
statistical differences in congestion and rhinorrhea, in the group of
patients using isotonic seawater solution, other symptoms showed
no major changes during the study period.
Conclusion Hypertonic seawater solution has been proven to be
better than isotonic seawater solution in eliminating the symptoms
of nasal congestion, rhinorrhea, cough, headache and waking up
during the night.
Key words: seawater solution, chronic rhinosinusitis, hypertonic,
isotonic, QoL
18 April 2010;
Revised submission:
04 May 2010;
Accepted:
23 May 2010.
116
Čulig et al Seawater solutions in chronic rhinosinusitis
introduction
Some discrepancies among definitions of chronic
rhinosinusitis occur mainly because of the usage of different criteria, such as symptom type,
duration, intensity, as well as the need for other
exploration methods, such as radiologic imaging
or bacterial culture test. In the definition proposed by the International Conference on Sinus
Disease, the criteria for chronic rhinosinusitis
in adults are symptoms and signs persisting for
eight weeks, or four episodes of recurrent acute
rhinosinusitis per year, each lasting for at least
10 days, in association with persistent changes on
computerized tomography scans, at four weeks
of medical treatment, without intervening acute
infection (1). The new and more specific Task
Force definition is as follows: “Chronic rhinosinusitis is a group of multifactorial diseases characterized by inflammation of the mucosa of the
nose and paranasal sinuses, with a history of at
least 12 weeks of persistent symptoms and signs,
despite maximum medical therapy” (2). Chronic rhinosinusitis has been reported to affect a
varying percentage of the population. According
to the National Health Interview Survey in the
United States, the rate of chronic rhinosinusitis
ranges from 14% to 16%. However, current prevalence may often be exaggerated (3).
The clinical picture of chronic rhinosinusitis is
predominated by nasal obstruction and increased nasal discharge. Irrespective of the etiology of chronic inflammation, topical therapy by
lavage and administration of vasoconstrictive
agents is the main mode of treatment aimed at
the restitution of the nasal physiologic functions
(4). Stimulators of alpha-adrenergic receptors
are most frequently used for nasal decongestion
(2). The decongestion of nasal mucosa is crucial
in the management of nasal obstruction of any
etiology. When sympathomimetics are used, the
possible undesired effects should be taken in
consideration. Therefore, the use sympathomimetics should be limited to a few days only (5).
Discontinuation of prolonged sympathomimetic
therapy may also result in side effects characterized by vasodilation, congestion and rhinorrhea.
These events are attributed to the so-called rebound phenomenon (5).
The nasal mucosa lavage with isotonic saline is
definitely useful. Nasal mucosa produces about
half a liter of mucus per 24 hours, which contains
2% mucin and 1%-2% salt, pH 6.5-7.2 (4). The
use of hypertonic solution may reduce the need
of nasal decongestives, thus avoiding the risk of
side effects due to the overstimulation of adrenergic receptors in the nasal mucosa (6).
Patients with rhinosinusitis experience symptoms
of nasal disease, along with associated symptoms,
such as headaches (7). Each of the symptoms
may influence the individual’s physical, occupational or social functioning to a certain extent (7).
The great impact of these diseases on the quality
of life (QoL) may occasionally be inadequately
recognized by the patient’s environment (7).
In rhinosinusitis patients, the aim of treatment
is to alleviate the disease signs and symptoms.
Therefore, this clinical study also included an
assessment of the impact that health conditions have on the QoL as the primary disease
outcome. QoL assessment frequently implies
different terms for different people, thus making its definition more difficult (7). The QoL
is influenced by health, material conditions and
the general state of mind of each individual (7).
The health-dependent QoL is part of the overall
QoL that is primarily determined by the overall
state of health, and it can be influenced by clinical intervention (7). It should be assessed as
a functional impact of the disease. The patient
is preoccupied by discomforts associated with
the disease. It is especially emphasized in clinical conditions, where the primary therapeutic
goal is the patient’s wellbeing, and the majority
of patients suffering from rhinosinusitis expect
some improvement as the ultimate result (8).
In chronic rhinosinusitis, clinicians evaluate the
clinical status of the nasal region on the basis of
nasal symptoms, objective examination, rhinomanometry, and radiologic examination. These
usual parameters of nasal mucosa inflammation
indicate the condition of the nose itself, but do
not refer to the issue of the reduced QoL in patients with rhinosinusitis (8). Rhinosinusitis can
cause sleep disorders and consequently chronic
fatigue (9). Patients suffer from frequent headaches, which, in some cases, may lead to transient
inability to work. In addition, patients encounter various other problems of varying intensity,
depending on their ability to cope with the problems (9).
117
The primary aim of the study was to compare the
efficiency of isotonic and hypertonic seawater
solutions used for nasal lavage and maintaining
patency in chronic rhinosinusitis. The secondary
aim was to evaluate the improvement in the QoL
of patients suffering from chronic rhinosinusitis
with the use of seawater solutions.
MATERIALS AND METHODS
Data were collected at ENT Outpatient Clinic,
University Hospital in Osijek and ENT Outpatient Clinic, Josip Benčević General Hospital in
Slavonski Brod, Croatia. The treatment lasted for
two weeks. The study started on November 15,
2008, with the anticipated inclusion period of
three months, i.e. till February 14, 2009, and was
completed on February 28, 2009.
Subjects
The study included 60 patients with the history
of chronic rhinosinusitis who wanted to participate in the study were required to sign an informed consent form. Patients needed to be at least
18 years of age, of whichever sex, and needed
to have clinically established signs of the disease. These signs were determined by a physical
examination and included nasal discharge, nasal
obstruction, headaches, pain in the facial region,
and high body temperature. Sinus endoscopy or
x-ray finding was not necessary for including criteria; they were already performed and recorded
in patient’s file (5). If all of these criteria were
met, patients were thoroughly informed on the
aims, preparations and methodology which were
to be used in the study, after which they were administered the informed consent form to sign.
Exclusion criteria were the subject’s decision
not to take part in the study, his/her physician’s
request, intolerance to seawater solution, and any
circumstance incompatible with the study protocol. Excluded patients could have been replaced
unless the inclusion period had not yet expired.
The study included 60 patients with chronic
rhinosinusitis, 30 per study location, who met
the inclusion criteria and signed the informed
consent form. Along with therapy prescribed by
their physicians, study patients applied either nasal spray at least three times daily or six times if
necessary, keeping notes on the exact daily dose
in the Patient Logbook.
118
Study preparations
The efficiency of the two seawater solutions: isotonic solution (Sterimar) and hypertonic solution
(Sterimar Hypertonic) was investigated. Sterimar
is an isotonic seawater solution available in the
form of a microspray with an anatomic applicator. The active substance is natural seawater,
mean salinity 2.80%-2.85%. The solution contains 31.82 mL of seawater in 100 mL solution,
with physiologic NaCl concentration of 0.9%.
Apart from NaCl, the solution contains natural
minerals and oligoelements in traces, i.e. in lower
than physiologic concentrations. The solution is
intended for daily nose hygiene and nasal mucosa lavage in infants, children and adults. The
solution is applied 3-6 times daily by pressing the
applicator for at least 3 seconds, spraying the solution into both nares.
Sterimar Hypertonic is a solution in a microspray
with anatomic applicator. The active substance is
natural seawater, mean salinity 2.80%-2.85%. The
preparation contains 75.00 mL seawater in 100
mL solution, with NaCl concentration of 2.12%.
Besides NaCl, the solution contains natural minerals and oligoelements in traces, i.e. in lower
concentrations than physiologic ones. The solution is additionally enriched with monohydrated
manganese (Mn) salts and pentahydrated copper
(Cu) salts to the concentrations identical to those
found in body cells. The preparation is intended
for nasal lavage and maintaining nasal mucosa
patency, which is achieved by osmotic effect induced by the higher solution NaCl concentration
and natural decongestive action. The use is identical to that described for isotonic solution.
The study was designed as an open and random
controlled trial. Study subjects continued taking
their previous medication (e.g., antibiotics, steroids, vasoconstrictors, etc.), as advised by the
physician, which was recorded in the Test List.
The use of vasoconstrictive drops (each administration) was additionally noted in the Logbook.
Randomization
Randomization was performed using a table of
random numbers for cohorts of 30 subjects each.
Group 1 included numbers 1 to 30, and group 2
included numbers 31 to 60. Each group had randomly distributed 15 even numbers and 15 odd
numbers. Study subjects were allocated numbers
according to randomization, whereby those allocated even numbers received the isotonic solution, and those allocated odd numbers received
the hypertonic solution. For example, group 1-30
included the number sequence 12, 15, 22, 11, 28,
10, 13, 9, etc., and the respective subjects were
administered study solutions as follows: 12 Sterimar, 15 Sterimar Hypertonic, 22 Sterimar, 11
Sterimar Hypertonic, 28 Sterimar, 10 Sterimar,
etc. (source: Random Sequence Generator, Sequence 1 and 2).
Test List
History data and data obtained by clinical physical examination were entered into the Test List.
The history included demographic data (age and
sex), socioeconomic status (employed, unemployed or retired), educational level (elementary
school, high school or university), current disease (onset and frequency) and other diseases,
medication used and side effects (if present). On
physical examination, the presence of rhinorrhea,
congestion, cough, headache and sinus region
sensitivity on palpation were assessed in grades 0
(symptom-free) to 3 (severe); breath sounds were
assessed by auscultation. Current medication was
recorded in the Test List.
Patient Logbook
At study entry, each subject was administered
a Patient Logbook to be filled out daily during
the 15-day study period; day 0 in the Logbook
corresponded to the day of the first follow up visit
noted in the Test List. Study subjects entered data
on total dosage, i.e. number of Sterimar applications, and on total doses of other drugs taken along
with Sterimar, e.g., nasal decongestives, antihistamines, corticosteroid drops and possibly other
topical therapies. In addition, data on particular
symptoms such as nasal obstruction, rhinorrhea,
cough, headache, and related waking episodes
were entered in grades ranging from symptomfree condition to fully pronounced symptoms.
Accordingly, the patient followed up nearly the
same symptoms as the physician, with the exception of facial sensitivity on palpation evaluated
by the physician after physical examination,
whereas the patient recorded possible episodes of
symptom-induced waking during the night. The
physician assessed the symptoms during the follow up examination, whereas patients did it by
self-assessment.
QoL questionnaire
Study subjects filled out the QoL questionnaire
(self-assessment) on day 0, at the first follow up
visit and at the end of the study, i.e. at the end of
week 2. They entered data on the following six
groups of symptoms: nasal disease symptoms,
other symptoms, sleep, activities, daily problems,
and emotions, grading them on the visual analog
scale 0-10, marking the grade corresponding best
to the difficulties caused by rhinosinusitis and
experienced during the study period.
Statistical analysis
Apart from the descriptive analysis of the data
collected, statistical significance of between-group differences was determined. Student’s t-test,
Whitney Rank Sum test and Chi-square test with
a significance level of p<0.05 were used when
appropriate for the evaluation of the results. The
analysis had enough statistical power to detect
the significant difference that would have been
evident if the statistical power had been greater.
Odds ratios were calculated by cross-tabulation
with a 95% confidence interval. All analyses
were performed with SigmaStat 3.0 for Windows (SPSS Science software products, Chicago, IL, US).
Follow up of adverse events
The randomized controlled clinical study protocol
included the recording of any possible untoward
event (e.g., side effect, associated disease, etc.)
in the Test List. According to the protocol, data
on the type, date, duration, therapy and outcome
of the adverse event were recorded. Any serious
adverse event should have been readily reported
to the Agency for Drugs and Medicinal Products
of the Republic of Croatia, while the investigator
was obliged to fill out the severe adverse event
reporting form.
RESULTS
The study included more female than male subjects (n=47; 78.3% vs. n=13; 21.7%), therefore
women predominated in the use of both study
preparations (Table 1).
119
According to age, the 20-29 age group prevailed
(n=14; 23.3%). Generally, two thirds of the study
subjects (n=37; 61.7%) were aged 20-49. The
hypertonic solution was mostly administered in
the 20-29 age group (n=11; 36.7%) and isotonic
solution in the 30-39 and 40-49 age groups (n=7;
23.3%).
In the majority of study patients, the disease duration was 7 or more years, or 85 or more months
(n=26; 43.3%).
The mean number of daily doses declined in
both patients taking hypertonic solution and those using isotonic solution, i.e. from 4.17 to 3.40
(18.5%) and from 3.60 to 2.97 (17.5%), respectively.
From previous therapy for chronic rhinosinusitis, most patients were taking medications in the
following order: antibiotics (n=43/60; 71.7%),
nasal decongestives (40; 66.7%), intranasal corticosteroids (27; 45.0) and antihistamines (23;
38.3%). There were no significant statistical differences between the two study groups. During
2nd visit the number of patients who were still
taking other medications beside the saline solutions were significantly reduced. Antibiotics were
Table 1. Demographic and clinical characteristics of study
sample and patients
No. of patients
n (% on
total)
Hypertonic
n (%)
Isotonic
n (%)
60 (100.0)
30 (50.0)
30 (50.0)
Age groups
10-19
5 (8.3)
3 (10.0)
2 (6.7)
20-29
14 (23.3)
11 (36.7)
3 (10.0)
30-39
11 (18.3)
4 (13.3)
7 (23.3)
40-49
12 (20.0)
5 (16.7)
7 (23.3)
50-59
9 (15.0)
5 (16.7)
4 (13.3)
60-69
8 (13.3)
2 (6.7)
6 (20.0)
70-79
1 (1.7)
0 (0.0)
1 (3.3)
= >80
0 (0.0)
0 (0.0)
0 (0.0)
prescribed to three patients in hypertonic solution
group and one in isotonic solution group. Corticosteroids were used by five patients in hypertonic group and four in isotonic group, but nasal
decongestants were taken only by two patients in
isotonic group. There was no statistical significant difference between the two patient groups,
but there was a significant difference between
the number of prescribed medications before the
beginning of the study and 2nd and 3rd visit during
the trial with everyday administration of saline
solutions (p<0,05).
During the two-week study period, five symptoms closely associated with chronic rhinosinusitis, i.e. rhinorrhea, congestion, cough, headache
and facial sensitivity on palpation, were followed
up and recorded in the Test List. On the initial
examination (1st follow up visit), there was no
difference in the symptoms between the subjects
using hypertonic solution and those using isotonic solution. At the 2nd follow up visit, a statistically significant between-group difference was
found for congestion, and on the 3rd follow up
visit, at two weeks of seawater solution application, such a difference was recorded for congestion
and cough (Table 2).
On day 0 in the Logbook notes, there was no difference in the symptoms between the groups of
subjects using hypertonic and isotonic seawater
solutions. The earliest statistically significant
difference was recorded for congestion (day 4),
followed by waking (day 6, just for a while, then
Table 2. Symptom variations between hypertonic and isotonic
solution groups at 1st, 2nd and 3rd follow up visit
Symptom
Rhinorrhea
Gender
Males
13 (21.7)
5 (16.7)
8 (26.7)
Females
47 (78.3)
25 (83.3)
22 (73.3)
Congestion
Duration of illness (months)
≤12
6 (10.0)
2 (6.7)
4 (13.3)
13-24
4 (6.7)
3 (10.0)
1 (3.3)
25-36
7 (11.7)
6 (20.0)
1 (3.3)
37-48
6 (10.0)
4 (13.3)
2 (6.7)
49-60
5 (8.3)
4 (13.3)
1 (3.3)
61-72
4 (6.7)
3 (10.0)
1 (3.3)
73-84
1 (1.7)
1 (3.3)
0 (0.0)
26 (43.3)
7 (23.3)
19 (63.3)
1 (6.7)
0 (0.0)
1 (3.3)
85+
Missing
120
Cough
Headache
Facial sensitivity on
palpation
Follow
up visit
P value*
Statistical significance of difference
1st visit
0.295
No
2nd visit
0.711
No
3rd visit
0.145
No
1st visit
0.994
No
2nd visit
0.038
Yes
3rd visit
0.009
Yes
1st visit
0.728
No
2nd visit
0.318
No
3rd visit
0.040
Yes
1st visit
0.506
No
2nd visit
0.549
No
3rd visit
0.300
No
1st visit
0.061
No
2nd visit
0.813
No
3rd visit
0.652
No
Source: Test List; *Mann-Whitney Rank Sum Test
again on day 9), headache (day 11), cough (day
14), and no such difference for rhinorrhea (Table 3).
Testing for significance of difference in particular symptoms between day 0 and day 15 of the
Patient Logbook notes yielded statistically significant differences in all symptoms in the group
of patients using hypertonic seawater solution.
Testing for significance of difference in particular symptoms between day 0 and day 15 of the
Patient Logbook notes yielded statistically significant differences in congestion and rhinorrhea,
whereas other symptoms showed no major changes during the study period in the group of patients using isotonic seawater solution.
A comparison was made between the symptoms
recorded by the physician on the 1st, 2nd and 3rd
physical examination (taken at 7-day intervals
and noted in the Test List) and the same symptoms recorded by the study patients in the Logbook on day 1, day 8 and day 15, separately for the
groups of patients receiving isotonic and hypertonic seawater solutions.
Symptom patterns in patient groups administered hypertonic and isotonic seawater solutions
as recorded in the QoL questionnaire filled in
by study patients at study entry, then at week 1
and week 2, are shown below. Mean values were
presented; patients graded their symptoms on a
0-10 scale, where 10 indicated severe and very
frequent symptoms, and 0 indicated a symptomfree condition.
Table 3. Symptom differences between subjects using hypertonic and isotonic seawater solution
Day
Rhinorrhea
Congestion
Cough
Headache
Waking
1
0.684
0.106
0.169
0.367
0.965
2
0.363
0.141
0.231
0.420
0.290
3
0.344
0.056
0.332
0.610
0.085
4
0.965
0.027*
0.237
0.918
0.063
5
0.862
0.030*
0.180
0.762
0.183
6
0.574
0.027*
0.251
0.424
0.034*
7
0.679
0.014*
0.631
0.277
0.158
8
0.476
0.017*
0.665
0.143
0.082
9
0.848
0.019*
0.807
0.157
0.030*
10
0.178
0.027*
0.524
0.110
0.034*
0.001*
11
0.099
0.070*
0.303
0.006*
12
0.252
0.018*
0.141
0.025*
0.011*
13
0.147
0.005*
0.102
0.023*
0.031*
14
0.112
0.013*
0.028*
0.007*
0.022*
15
0.154
0.001*
0.023*
0.001*
0.015*
Source: Patient Logbook
The severity of almost all of the symptoms present in the patient group using Hypertonic seawater solution, as evaluated at three time points
(initial, at week 1 and week 2), was reduced by
over 50%. The greatest reduction was recorded in
the following symptoms: morning weariness and
sleep deprivation (75.6%), anxiety (70.8%), unease for nasal disease symptoms (70.4%), sleeping
difficulties (68.8%), headaches (67.9%), frustration (67.5%).
The grade of reduction in the symptom patterns
in the patient group using isotonic seawater solution, evaluated at three time points (initial, at
week 1 and week 2), greatly varied. The greatest
reduction was recorded in the following symptoms: sleeping difficulties (46.4%), waking during the night (38.7%), cough (38.1% ).
No side effects were recorded during the clinical
trial period (15 days).
DISCUSSION
The role of mucus in the inflammatory process
has been widely discussed. Some studies demonstrated the potential disease association with mucociliary functional changes, with special reference to the role of mucus within the nasal cavity
(10). The mucus transport ratio decreases significantly in patients with chronic rhinosinusitis,
as compared with healthy subjects, and modified
mucus properties rather than ciliary abnormalities are considered to underlie pathologic changes
(11). In another study, seawater solution applied in the form of spray considerably improved
the rate of nasal mucociliary clearance in cystic
fibrosis patients, free from sinus disease symptoms (11). A study in healthy subjects free from
nasal or sinus disease symptoms revealed that the
clearance rate only improves upon lavage with
a hypertonic saline, but not with a physiological
(isotonic) saline (8).
The destruction of the ciliary epithelium, due
to long-lasting nasal mucosa colonization with
pathogenic microorganisms, is another cause of
reduced nasal mucociliary clearance in chronic
rhinosinusitis patients (12). It is manifested as a
decreased frequency of ciliary movements, which
increases with long-term antibiotic therapy (13).
A continuous reduction of disease symptoms is
one of the indicators of the seawater solution
efficiency recorded in the present study, 18,5%
121
and 17,5% with hypertonic and isotonic seawater solution, respectively. Results of this clinical
trial showed that the use of seawater solution is
beneficial in patients with chronic rhinosinusitis.
In addition, hypertonic seawater solution proved to be better than isotonic seawater solution
in removing the symptoms of nasal congestion,
rhinorrhea, cough, headache and waking due to
discomforts caused by the disease.
The evaluation of the effectiveness and safety
of topical saline in the management of chronic
rhinosinusitis were done by searching the Cochrane Central Register of Controlled Trials (4).
There is evidence that saline is beneficial in the
treatment of the symptoms of chronic rhinosinusitis when used as the sole therapy. Two studies
compared different hypertonic solutions against
isotonic saline. Some evidence suggests that
hypertonic solutions improve objective measures but the impact on symptoms is less clear. In
our study hypertonic solution showed superiority on the symptoms of congestion (2nd visit , p=
0,038 ; 3rd visit .p= 0,009 ) and cough ( 3rd visit,
p=0,04).
The size of the study sample was based on the
prevalence of chronic rhinosinusitis in Croatia of
1.5‰ according to the health statistics data, or
1.5 per 1000 inhabitants older than 18. As Osijek
has 88767 citizens older than 18, the calculated
prevalence is 133, and for Slavonski Brod with
47613 citizens older than 18 it is 71, or 204 in
total. According to the total sample size (N=204),
the study sample should have consisted of 134
patients. However, the present study included 60
patients. This sample size was considered adequate because of the low phenomenon variability
(strictly defined symptoms of chronic rhinosinusitis) and for financial restrictions (1,10).
A number of randomized controlled trials have
tested nasal and antral irrigation with isotonic or
hypertonic saline in the treatment of acute/intermittent and chronic/persistent rhinosinusitis (4).
Although saline is considered a control treatment
itself, patients in these randomized trials were
assigned different modalities of saline application, hypertonic saline, or hypertonic compared
to isotonic saline. Group results were compared.
Most of them offer evidence that nasal washouts,
or irrigations with isotonic or hypertonic saline,
are beneficial in terms of symptom alleviation,
122
endoscopic findings and Health-Related QoL
improvement in patients with chronic persistent
rhinosinusitis (14). Hypertonic saline is preferred
to isotonic treatment for rhinosinusitis by some
authors in the USA, mostly based on a paper indicating it significantly improves nasal mucociliary
clearance, measured by saccharine test, in healthy volunteers (5, 6).
The present study showed that the QoL in patients with chronic rhinosinusitis improves sooner
with the use of hypertonic seawater solution. During the two-week study period, a follow up of
the five symptoms closely associated with chronic rhinosinusitis yielded a statistically significant difference in improvement of the symptoms
of nasal congestion and cough. Apart from these
medical findings, study patients made notes on
favorable changes themselves, with the earliest
statistically significant difference recorded for
nasal congestion (day 4), waking up for a while
(day 6, then again on day 9), headache (day 11)
and cough (day 14), but not for rhinorrhea. The
spray was well tolerated and was not associated
with any significant adverse event. The superiority of hypertonic seawater solution was manifested by the statistically significant reduction
in all of the symptoms observed, unlike with the
isotonic seawater solution, where some symptom
reduction was only recorded in nasal congestion
and rhinorrhea.
Most questionnaires concentrate on the duration
of the symptoms and not on the severity of the
symptoms. A QoL questionnaire, developed by
Damm et al, includes the severity of the symptom scale (15). The domains in the questionnaire
are the overall QoL, nasal breathing obstruction,
post-nasal drip or discharge, dry mucosa, smell,
headache and asthmatic complaints.
In a generic SF-36 survey, the scores of chronic
rhinosinusitis patients were compared to those of
a healthy population. The results showed statistically significant differences in seven of eight
domains (7). Gliklich and Metson (9) have reported that patients with chronic rhinosinusitis have
more bodily pain and worse social functioning
than for example, patients with chronic obstructive pulmonary disease, congestive heart failure,
or back pain.
The questionnaire used in the present study was
validated in the previous research (16).
It has a similar structure to the one used in the
study with allergic rhinitis patients. The day to
day analysis showed the high sensitivity, noticing
even short, intermittent changes, which is characteristic of chronic diseases.
The results of this clinical trial have shown that
the use of seawater solution is beneficial to patients with chronic rhinosinusitis. Hypertonic
seawater solution has been found to be better
than isotonic seawater solution in eliminating the
symptoms of nasal congestion, rhinorrhea, cough, headache and waking up during the night.
The study demonstrated that the QoL in patients
with chronic rhinosinusitis improves sooner with
the use of hypertonic seawater solution. Additional topical therapy with nasal decongestants was
required in only four study patients (two in the
group receiving hypertonic and isotonic seawater
solution each, during the study period only in the
patients using isotonic solutions), which was statistically non-significant.
The authors are grateful to the companies Pharmatheka Consult and Sofibel-Laboratoires Fumouze for providing the products and financial
support.
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123
ORIGINAL ARTICLE
Promjene u strukturi i kliničkom značenju pozitivnih rezultata
pretransfuzijskog testiranja kod prijelaza s klasične metode
aglutinacije u epruveti na metodu u gel mikrostupcu
Alma Petrušić-Kafedžić1, Zdravko Ivanković2, Sabahudin Ekinović³, Lejla Ibrahimagić-Šeper4
Služba za transfuziju krvi, Kantonalna bolnica Zenica, Zenica, Bosna i Hercegovina, 2DiaHem, Buelach, Švicarska, ³Rektorat Univerziteta
u Zenici, Univerzitet u Zenici, Zenica, Bosna i Hercegovina, 4JU Dom zdravlja, Zenica, Bosna i Hercegovina.
1
SAŽETAK
Cilj Istražiti promjene pretransfuzijskog testiranja iregularnih antitijela kod prijelaza s aglutinacijskog testa u epruveti na test u
gelu.
Metode Klinički značaj pozitivnih rezultata analiziran je u 7667
pretransfuzijskih testiranja (s 16610 interakcija) učinjenih testom
u epruveti u 2005.-2006. godini, te u 7372 pretransfuzijskih ispitivanja (s 17294 interakcija) učinjenih u 2007.-2008. godini testom
u gelu.
Alma Petrušić-Kafedžić,
Služba za transfuziju krvi,
Kantonalna bolnica Zenica,
Crkvice 67, 72000 Zenica,
Bosna i Hercegovina
Phone: ++387 32 406 279;
Fax: ++387 32 202 502;
Originalna prijava:
09. april 2009.;
Korigirana verzija:
28. oktobar 2009.;
Prihvaćeno:
Rezultati Detekcija iregularnih antitijela, u oba ispitivana perioda,
bila je pozitivna u 1,3%, a interakcija u 0,3% slučajeva. Barem
jedan od tih testova nađen je pozitivan u 1,4% pretransfuzijskih
testiranja testom u epruveti, odnosno u 1,3% testom u gelu, uz
>75% pozitivnih rezultata u žena. Gledajući slučajeve s pozitivnom interakcijom, a negativnom detekcijom iregularnih antitijela, osam od deset slučajeva, nađenih testom u epruveti, bilo je
uzrokovano ‘’hladnim’’, a sva tri slučaja testom u gelu ‘’toplim
nespecifičnim’’ antitijelima. Testom u gelu nađen je veći udio
imunih antitijela nego testom u epruveti (69,8%, odnosno 41,3%,
p<0,001), uz dvostruki porast udjela anti-K i Rh-antitijela. Testom
u epruveti nađena su 24, a testom u gelu nijedan slučaj klinički
beznačajnih antitijela (p<0,001). ‘’Nespecifična antitijela’’ češće
su uzrokovala pozitivnu interakciju nego detekciju iregularnih antitijela (42,6%, odnosno 29,9% testom u epruveti, 28,9%, odnosno
18,3% testom u gelu). Iako blizu u pogledu detekcije iregularnih
antitijela (p=0,062), razlika testa u epruveti i u gelu nije dosegla
značaj. ‘’Nespecifična antitijela’’ nađena su ovim testovima češće
u žena, dok se faktor odjela pokazao bez značaja.
Zaključak Gel test se pokazao kao optimalnija tehnika pretransfuzijskog ispitivanja. Detekcija iregularnih antitijela preporuča
se kao obavezni dio pretransfuzijskog testiranja.
Ključne riječi: pretransfuzijsko testiranje, gel test, specifičnost
05. februar 2010.
124
Petrušić-Kafedžić et al Pretransfuzijsko testiranje: gel stubac
UVOD
Pretransfuzijsko testiranje (PT) (1-5), koje se
danas provodi tehnikom aglutinacije eritrocita,
a posebno indirektnim antiglobulinskim testom
(IAT) (4-7), ima za cilj izbjegavanje hemolitičke
transfuzijske reakcije (HTR) kod transfundiranog bolesnika.
Uz aglutinacijski test u epruveti (TE) uvedena je
aglutinacija u mikrostupcu, posebno test u gelu
(GT), koji je omogućio značajnu standardizaciju, objektivizaciju i reproducibilnost testiranja,
uz niz drugih prednosti (8-9). Najveći doprinos
GT-a, s obzirom na sigurnost transfundiranog pacijenta, jeste povećanje specifičnosti i reproducibilnosti testa (izbjegavanje klinički beznačajnih
antitijela reaktivnih pretežno na temperaturama
ispod tjelesne i izbjegavanje varijabilnosti u izvođenju i očitanju testova) (8-13). Uz GT detektiraju se najčešće samo ‘’imuna’’ antitijela (nastala
pravom eritrocitnom imunizacijom i sposobna
izazvati kliničku HTR), čime se i značajno smanjuje broj nepotrebno odgođenih transfuzija,
zbog pozitivnih, a klinički beznačajnih rezultata
testiranja (8-24).
Prije svakog transfuzijskog liječenja produktima
koji sadrže eritrocite, provodi se obavezno PT,
koje uključuje provjeru ABO i RhD antigena bolesnika i doze krvi, detekciju iregularnih antitijela (IRA) i interakciju (IRR) između bolesnikovog
seruma i eritrocita davaoca (4-6). Detekcija IRA
i IRR, posebno se često provode putem GT-a, i
to tehnikom IAT-a, koja je osnovna tehnika PT-a
u svim internacionalnim i nacionalnim vodičima,
te praksi (6, 25-28).
Iako je prevalencija HTR-a uz GT smanjena na
oko 0,04% (5), još uvijek nisu dovoljno istražene
karakteristike ovog modela PT-a. Optimizacija
PT-a, u općem i lokalnom smislu, ostaje trajni zadatak svake transfuzijske službe, kako one koja
se bavi formiranjem nacionalnih preporuka, tako
i one čiji je zadatak na terenu i praktično brinuti
o određenoj populaciji.
Stoga je, osim ispitivanja promjena u općoj učestalosti pozitivnih pretransfuzijskih testiranja i
strukturi nađenih antitijela nakon uvođenja GT-a,
cilj ovoga istraživanja bio ispitati potrebu uvođenja eventualnih akcija u saniranju mogućih
propusta napravljenih tokom desetljeća upotrebe
TE-a. Osim toga, cilj ispitivanja bio je odrediti
učestalost i strukturu tzv. nespecifičnih rezultata,
koji najviše doprinose nepotrebnom odgađanju
transfuzija krvi, te utjecaj nekih lokalnih faktora
na uspješnost GT-a, a time i na kontrolne postupke pri njenom uvođenju. Ti bi podaci mogli, u
nacionalnim okvirima, ukazati na optimalnu konfiguraciju PT-a putem GT-a i u ostalim ustanovama naše zemlje.
ISPITANICI I METODE
U Službi za transfuziju krvi Kantonalne bolnice
Zenica provedeno je retrospektivno-prospektivno
istraživanje rezultata pretransfuzijskog testiranja
(PT) u svih bolesnika koji su liječeni transfuzijama
eritrocitnih produkata krvi, u razdoblju od 2005.
do 2008. godine u Kantonalnoj bolnici Zenica.
Obavezno PT, u ispitivanom razdoblju, provedeno je u sukladu s internacionalnim preporukama
(6, 25, 26) koje u svakom PT-u propisuju obaveznu detekciju iregularnih antitijela (IRA) u bolesnika, kao i interakciju (IRR) seruma bolesnika
s eritrocitima doze krvi predviđene za transfuziju tehnikom indirektnog antiglobulinskog testa
(IAT), a u sukladu s uputama iz literature (6, 7),
te proizvođača reagensa.
U 2005. i 2006. godini, PT je provedeno klasičnim testom u epruveti (TE) na uzorku krvi bez
antikoagulansa, tehnikom IAT-a, koristeći za detekciju IRA test eritrocite Panoscreen I-II (GAMMA Immucor, Norcross, SAD) i polispecifični
antihumani serum (BioGnost, Zagreb, Hrvatska),
koji se koristio i u IRR-u.
Tokom 2007. i 2008. godine cjelokupno PT provedeno je tehnikom IAT-a, no upotrebom testa
u gelu (GT) na uzorku krvi s EDTA antikoagulansom, koristeći za detekciju IRA test eritrocite
ID-DiaCell I-II i gel kartice s dodanim antihumanoglobulinskim serumom ID-LISS Coombs,
koje su korištene i za IRR (DiaMed, Cressier sur
Morat, Švicarska).
Svaka pozitivna detekcija IRA i/ili IRR ponovljena je u duplikatu istim reagensima korištenim
i u osnovnom testu. Svaki uzorak s barem jednim
ponovljeno pozitivnim rezultatom upućen je na
identifikaciju prisutnih antitijela.
Identifikacija antitijela također je učinjena metodom kao u osnovnom PT-u, u 2005. i 2006.
godini putem TE, koristeći test eritrocite PanoCell-10 (GAMMA Immucor, Norcross, SAD) i
125
antihumani serum (BioGnost, Zagreb, Hrvatska),
a u godinama 2007. i 2008. putem GT-a, koristeći test eritrocite ID-DiaCell I-II i gel karticu
ID-LISS Coombs (DiaMed, Cressier sur Morat,
Švicarska). U prvom razdoblju identifikacija antitijela provedena je, prema pravilima za TE, na
sobnoj temperaturi, na 37°C i nakon dodatka antihumanoglobulinskog reagensa. U drugom razdoblju, prema pravilima GT-a, identifikacija je
provedena nakon inkubacije, samo na 37 °C.
Identificirana specifična antitijela označena su kao
‘’imuna’’ (klinički značajna), ‘’potencijalno klinički značajna’’ ili ‘’klinički beznačajna’’, prema
uobičajenim kriterijima za mogućnost izazivanja
hemolitičke transfuzijske reakcije (HTR) (1-7).
Antitijela, u oba perioda, koja su u identifikaciji pokazala reaktivnost s određenim eritrocitima
panela, no nisu pokazala obrazac specifičnih antitijela, označavana su kao ‘’nespecifična’’, i to
‘’nespecifična hladna’’ (ako je reaktivnost bila na
temperaturama ispod tjelesne) ili ‘’nespecifična
topla’’ (ako je reaktivnost bila samo na 37 oC).
Učestalost nespecifičnih rezultata stavljena je u
korelaciju sa spolom, dobi i matičnim odjelom
bolesnika. U testiranju korelacija posebna pažnja
posvećena je kliničkom značaju pozitivnih i negativnih rezultata, uključujući i one koji utječu na
nepotrebno odgađanje transfuzijskog liječenja.
Statistička značajnost izračunata je χ2 testom, uz
prihvaćenu razinu značaja od p<0.05.
REZULTATI
U periodu 2005.-2006. godine, kada je pretransfuzijsko testiranje (PT) provedeno putem testa
u epruveti (TE), učinjeno je ukupno 7667 (3787
i 3880) testova, s 16610 interakcija (IRR). U periodu 2007.-2008. godine, kada je PT provedeno
koristeći gel test (GT), učinjeno je ukupno 7372
(3765 i 3607) testova, s 17294 IRR.
U TE periodu detekcija IRA je nađena pozitivna
u 97 (1,3%), a IRR u 54 (0,3%) PT, a kod ukupno
109 (1,4%) pretransfuzijskih ispitivanja barem je
jedan od ovih testova nađen pozitivan, i to najvećim dijelom kod žena (82, 75.2%). Oba su testa
bila pozitivna u 42 slučaja.
U GT periodu detekcija IRA je nađena pozitivna
u 93 (1,3%), a IRR u 45 (0,3%) PT. Oba testa također su nađena pozitivna u 42 slučaja. Ukupno
je barem jedan pozitivan test nađen u 96 (1,3%)
126
PT-a, a 76 bolesnika s barem jednim pozitivnim
testom (79.2%) bilo je ženskog spola.
Učestalosti pozitivne detekcije IRA ili IRR u TE
i GT periodima, kao i spolna distribucija bila je
podjednaka (p>0,05).
Statističku značajnost u oba perioda (p<0.05) dosegla je samo veća učestalost žena među bolesnicima s pozitivnim testovima.
Prosječna dob bolesnika s pozitivnom detekcijom IRA ili IRR u TE periodu iznosila je 50,0
(10-75), a u GT 49,6 (19-77) godina (p>0,05).
U oba razdoblja nađena je veća učestalost pozitivne detekcije IRA-e nego pozitivne IRR (1,3%
prema 0,3%, p<0,05). No, u TE periodu opažen
je veći broj slučajeva s pozitivnom IRR, a negativnom detekcijom IRA-e (N=10), u usporedbi
s GT periodom (N=3) (p<0,05). I uzroci takvih
nalaza razlikovali su se između dva perioda: u TE
periodu u osam od 10 slučajeva nađena su antitijela s optimumom reakcije na temperaturi <370C
(‘’nespecifična hladna’’ u tri, anti-Lea u dva, te
anti-M, anti-P1 i anti-Leb u po jednom slučaju), a
samo u dva slučaja radilo se o ‘’nespecifičnim toplim’’ antitijelima; nasuprot tome, sva tri slučaja
u GT periodu bila su uzrokovana ‘’nespecifičnim
toplim’’ antitijelima.
Učestalost pojedinih antitijela nađenih u uzorcima s pozitivnim PT prikazana je u Tablici 1. U
GT periodu među detektiranim antitijelima nađen je značajno veći udio imunih antitijela (67
od 96, 69,8%) u odnosu na TE period (45 od 109,
41,3%) (p<0.001), s najvećim porastom udjela
anti-K, a zatim anti-D i ostalih Rh-antitijela u
Tablica 1. Broj i udio pojedinih antitijela identificiranih u
uzorcima s pozitivnim pretransfuzijskim testiranjem (detekcija
iregularnih antitijela i interakcije, sumarno)
Antitijela
Test u epruveti (TE) Test u gelu (GT)
(2005/06.)
(2007/08.)
N (%)
N (%)
Anti-D (+/- C)
14 (12,8%)
18 (18,8%)*
Ostala Rh (uključujući
c+E)
12 (11,0%)
18 (18,8%)*
Anti-K
11(10,1%)
21 (21,9%)*
Ostala imuna
5 (4,6%)
6 (6,3%)
Više imunih
3 (2,8%)
4 (4,2%)
Potencijalno klin. značajna (M, Lea, P1, Lu)
14 (12,8%)
9 (9,4%)
Klinički beznačajna (Leb,
nesp. hladna)
24 (22,0%)
0†
“Nespecifična topla” †
26 (23,9%)
20 (20,8%)
109
96
Ukupno
*p<0,05; †nalaz identifikacije na 37 oC: reakcija na određene eritrocite panela, no bez obrasca specifičnog antitijela
Tablica 2. Raspodjela pozitivnih testova detekcije iregularnih
antitijela kod kojih nije nađeno specifično antitijelo prema spolu
Tehnika/period
Pozitivan test detekcije gdje nije
nađeno specifično antitijelo
Ukupno
Tehnika/
period
Žene
N (%)
Muškarci
N (%)
Test u epruveti (TE)
(2005/06)
21
(72,4%)
8
(27,6%)
29
Test u gelu (GT)
(2007/08)
11
(64,7%)
6
(35,3%)
17
32
14
36
Ukupno
GT. U GT periodu niti u jednom slučaju nisu detektirana klinički beznačajna antitijela, nasuprot
24 slučaja u TE periodu (p<0,001). Gledajući sumarno prevalenciju pojedinih kategorija antitijela
u ukupnom broju učinjenih detekcija IRA i IRR,
onda su u TE periodu imuna antitijela nađena s
učestalošću 45 u 24277 svih testiranja (0,19%),
dok je u GT periodu incidencija povećana na 66
u 24666 testova (0,27%) (p<0,05).
Slučajevi u kojima se specifičnost antitijela nije mogla odrediti (nespecifična hladna i
nespecifična topla antitijela), u TE periodu činili
su 29 od 97 (29,9%) pozitivnih detekcija IRA i
23 od 54 (42,6%) pozitivnih IRR, nasuprot 17 od
93 (18,3%) pozitivnih detekcija IRA i 13 od 45
(28,9%) pozitivnih IRR u GT periodu. U pogledu IRR razlika TE i GT perioda nije se pokazala
signifikantnom (p=0,2), no u pogledu detekcije
IRA, iako je nije dosegla, razlika se približila statističkoj značajnosti (p=0,062).
Statistički značajna razlika (p<0,05) zamijećena
je u učestalosti nespecifičnih nalaza između detekcije IRA i IRR: u oba perioda antitijela bez nađene specifičnosti češće su uzrokovala pozitivnu
IRR, no pozitivnu detekciju IRA (42,6% prema
29,9% u TE, odnosno 28,9% prema 18,3% u GT
periodu).
Pozitivno PT, a bez identificiranih specifičnih antitijela, nađeno je češće u žena nego u muškaraca
(p<0,05) i blaga tendencija većeg udjela žena u
nespecifično pozitivnim testovima u TE nego u
GT periodu: 72,4% prema 64,7% kod detekciTablica 3. Raspodjela pozitivne interakcije kod kojih nije
nađeno specifično antitijelo prema spolu
Tehnika/period
Pozitivna interakcija gdje nije
Tablica 4. Pozitivni testovi detekcije iregularnih antitijela
kod kojih nije nađeno specifično antitijelo: raspodjela prema
matičnim odjelima pacijenata
Ukupno
Test u
epruveti (TE)
(2005/06)
Test u
gelu (GT)
(2007/08)
Ukupno
Pozitivan test detekcije
gdje nije nađeno specifično antitijelo
kirurške
grane
N (%)
Ukupno
internističke ginekologija i
grane
porodiljstvo
N (%)
N (%)
9
(31,0%)
9
(31,0%)
11
(37,9%)
29
5
(29,4%)
6
(35,3%)
6
(35,3%)
17
14
15
17
36
je IRA, odnosno 73,9% prema 61,5% kod IRR
(p=0,11) (Tablice 2 i 3).
Distribucija matičnih odjela pacijenata s pozitivnim PT-om, a bez identificiranih specifičnih antitijela, prikazana je u Tablicama 4 i 5. Značajnih
razlika između TE i GT perioda nije zamijećeno
ni u jednoj ispitivanoj kategoriji, iako je u pacijentica Odjela za ginekologiju i porodiljstvo zamijećena tendencija veće učestalosti nespecifično
pozitivnih IRR u TE nego u GT periodu (p=0,2).
DISKUSIJA
Uvođenje testa aglutinacije u gel mikrostupcu nesumnjivo je dovelo do velikih promjena u
pretransfuzijskom ispitivanju, posebno u detekciji klinički značajnih antitijela (8-24), što su
pokazali i rezultati ovoga istraživanja, uz održanu opću razinu učestalosti pozitivnih testova.
Najveći porast broja detektiranih antitijela bio je
zamijećen kod anti-K i Rh-antitijela, za koja je
poznato da se i inače najčešće pojavljuju u imuniziranih bolesnika (1-6, 29, 30). U isto vrijeme, u
GT periodu nije zamijećen nijedan slučaj klinički
beznačajnih, ‘’hladnih’’ antitijela, što je za direktnu posljedicu imalo smanjen broj nepotrebno
odgođenih transfuzija. Naša ispitivana populacija, s gotovo 50000 pretransfuzijskih testiranja, na
način kako propisuju međunarodni standardi i uz
raspodjelu prema spolu i dobi navedenoj i u druTablica 5. Pozitivne interakcije kod kojih nije nađeno
specifično antitijelo: raspodjela prema matičnim odjelima
pacijenata
Tehnika/
period
Pozitivne interakcije kod kojih nije
Žene
N (%)
Muškarci
N (%)
Test u epruveti (TE)
(2005/06)
17
(73,9%)
6
(26,1%)
23
Test u epruveti
(TE) (2005/06)
8
(34,8%)
7
(30,4%)
8
(34,8%)
23
Test u gelu (GT)
(2007/08)
8
(61,5%)
5
(38,5%)
13
Test u gelu
(GT) (2007/08)
6
(46,2%)
5
(38,5%)
2
(15,4%)
13
25
11
36
Ukupno
14
12
10
36
Ukupno
kirurške
grane
Ukupno
internističke ginekologija i
grane
porodiljstvo
127
gim radovima (29-32), zasigurno je adekvatna za
donošenje zaključaka o poboljšanoj detekciji klinički značajnih imunih antitijela.
Ipak, cilj u našem ispitivanju bio je odrediti i druge aspekte ‘’novog’’ pretransfuzijskog testiranja.
Ako ispitivanja pokažu da su testiranjem u epruveti godinama propuštana pojedina imuna antitijela, onda je zadatak transfuzijske službe, u najmanju ruku, analizirati potrebu za retrogradnim
ispitivanjem. Detekcija iregularnih antitijela u
toku sadašnjih PT-a može biti nedovoljna, jer titar
pojedinih antitijela, tokom godina, u čak do 3040% slučajeva pada ispod razine detekcije, a ipak
nakon nove ekspozicije antigenu brzo poraste i
dovodi do odgođene HTR (6, 29). Takvi bi se bolesnici mogli potencijalno detektirati samo retrogradnom detekcijom IRA u arhiviranom uzorku, i
to gel testom, što je zahtjevan proces i mora imati
uporište u konkretnim dokazima o njenoj potrebi.
U tom pogledu, poznato je da antitijela iz Kidd
sistema, zbog brzog pada i rasta titra antitijela,
uzrokuju najteže slučajeve odgođenih reakcija, a
nakon toga po učestalosti slijede sistemi Duffy,
Kell i MNSs (1-6, 27, 29). U našem radu Kidd i
Duffy antitijela nađena su s ponešto većom učestalosti u GT periodu, no razlika, najvjerojatnije
zbog malog broja antitijela, nije dosegla razinu
značaja, dok je, pak, porast učestalosti detekcije
Kell i MNSs antitijela dosegao tu razinu. Posebno je bio značajan porast anti-K antitijela zbog
njegovog kliničkog značaja, učestalosti i činjenice da se K-antigen u BiH rutinski ne određuje u
davaoca, niti u primaoca transfuzije.
Ipak, nekoliko činjenica ne govore u prilog neophodne potrebe za opsežnom detekcijom IRA
u arhiviranim uzorcima u službama koje su desetljećima koristile klasičan test u epruveti. Prije
svega, ako i pretpostavimo da je GT u detekciji
anti-K i drugih antitijela višestruko osjetljiviji od
TE-a (odnosno da je to uzrok učestalije detekcije
u 2007.-2008. godini), ostaje nepoznanica koliko
bi se antitijela zaista detektiralo u arhiviranom
uzorku, putem GT-a, u koliko bi od tih slučajeva titar pao ispod detektibilnog kod GT-a, koliko
takvih slučajeva pripada bolesnicima koji učestalo primaju transfuzije, s većom šansom da prime
npr. K-pozitivnu transfuziju, gdje je učestalost antigena <10% (1-6)? Osim toga, takva akcija trebala bi preživjeti analizu ekonomske opravdanosti
i konačno, u našim uvjetima, upitna je i tehnička
128
izvodivost ovog ispitivanja, budući da zahtijeva
odlično održavanu arhivu uzoraka i podataka.
Zbog svega toga, dojam je da je u pitanju detekcije mogućih propuštenih, djelotvornije sistemski
riješiti pitanje unificiranog provođenja potpunog
PT-a putem GT-a i pitanje određivanja pojedinih,
posebno K-antigena u svih davalaca krvi.
U našem radu jasno je pokazana prednost detekcije IRA pred IRR. Detekcija IRA, gdje se koriste
test eritrociti definirane konfiguracije i jače ekspresije klinički značajnih antigena, pruža znatno
veću mogućnost otkrivanja iregularnih antitijela
nego pojedinačna IRR, gdje se serum pacijenta
inkubira s eritrocitima samo jedne osobe, slučajne konfiguracije i ponekad slabo izraženih antigena. Uz to, u našem radu, detekcija IRA putem
GT-a bila je ‘’otpornija’’ na nespecifične rezultate od IRR. Zbog svega toga, detekcija IRA i u
BiH mora biti nezaobilazan dio PT-a, kako je to
predviđeno u praktično svim međunarodnim i nacionalnim preporukama (5, 6, 18, 24, 25). Uz to,
u većini je europskih zemalja, no još ne i u BiH,
određivanje K-antigena u davaoca krvi prihvaćeno kao rutinski postupak nakon ABO i Rh određivanja (6, 26, 27). U našoj ustanovi uvedene su
i obavezna detekcija IRA i određivanje Kell-antigena kod svih davaoca krvi i pacijenata s iregularnim antitijelima. Mada isplativost ovih akcija
zahtijeva opsežniju analizu, zasigurno je ona više
na strani opravdanosti od retrogradne detekcije u
arhiviranim uzorcima.
Najčešći nespecifični rezultati u ovom istraživanju bili su slučajevi s pozitivnim samo jednim
pretransfuzijskim testom. U TE periodu opažen je
značajno veći broj slučajeva s pozitivnom samo
IRR, a uzrok tome, kao i u većini drugih radova
(10-19), mahom su bila ‘’hladna’’, klinički beznačajna antitijela. Ako se dodaju i rezultati našeg prethodnog ispitivanja (33), koji su pokazali
veću učestalost nespecifičnih nalaza u jutarnjoj
smjeni i među mlađim tehničarima, jasno je kako
GT itekako može utjecati na sigurnost transfundiranih pacijenata. Sva tri nespecifična rezultata
u GT periodu bila su povezana s ‘’toplim nespecifičnim’’ antitijelima, dok je iz dostupne literature poznato da su u GT metodi najznačajniji uzrok
ovih nalaza antitijela HLA specifičnosti (34-37).
Kako HLA antitijela, prema dostupnim podacima, izuzetno rijetko ili nikada ne uzrokuju klinički izražene hemolitičke reakcije, to u eri GT-a
može dovesti do praktičnog razmišljanja: kako je
velika većina nespecifičnih nalaza u GT-u uzrokovana ovim putem, onda pacijenti s negativnom detekcijom IRA, a pozitivnom IRR, mogu
u hitnoći s relativno velikom dozom sigurnosti
primiti drugu, IRR negativnu dozu, čak i prije opsežne identifikacije uzroka pozitivnog testa. Ako
se takav pristup pokaže prihvaćen, GT metoda
donijela bi dodatnu prednost pred klasičnom TE
metodom, koje je bila karakterizirana često nepotrebnim odgađanjima transfuzijskog liječenja.
Pozitivno PT općenito se češće nalazi u žena, poglavito zbog učestalih imunizacija tokom trudnoće
(1). Zbog toga ne čudi ni viša stopa nespecifično
pozitivnih rezultata u žena, u našem, kao i u drugim ispitivanjima (30, 32, 34). Iznenađujuće, u TE
periodu, opaženo je nešto veće (no, ne i statistički
značajno) učešće žena u nespecifičnim rezultatima, uz neočekivano učestala nespecifična ‘’topla’’
antitijela. Uzroci takvog nalaza najvjerojatnije su
visok titar HLA-antitijela u žena naše regije, detektibilan i putem TE-a, ili pak nemogućnost tačne identifikacije antitijela samo jednim dostupnim
panelom test eritrocita, kao što je slučaj u našoj
ustanovi. Uzevši u obzir dob bolesnica (u prosjeku oko 50 godina) i veći broj trudnoća kojima su
tradicionalno izložene u našoj regiji, te činjenicu
da se jednim panelom ne može identificirati samo
relativno mali broj pojedinačnih antitijela ili rijetkih kombinacija, visok titar HLA-antitijela čini se
potencijalno značajnim uzrokom.
U vezi utjecaja matičnih odjela, odnosno osnovnih
bolesti bolesnika, na nespecifične rezultate PT-a,
očito je potreban veći broj bolesnika s točno raščlanjenim bolestima, jer je teško zamisliti da bolesti poput hematoloških nemaju značajnog utjecaja na učestalost nespecifičnih rezultata PT-a.
U zaključku, promjene, zabilježene u prve dvije
godine upotrebe GT-a u našoj ustanovi, bez sumnje ohrabruju njegovu najširu upotrebu. S druge
strane, ispitivanje nekih manje istraženih i lokalnih faktora kliničkog značaja detektiranih antitijela pokazalo je da prijelaz na GT može imati još
značajniji utjecaj na neke kategorije bolesnika,
poput žena s većim brojem prethodnih trudnoća.
I konačno, rezultati ovog ispitivanja upućuju i
na neophodne promjene uobičajenog pretransfuzijskog ispitivanja u BiH, u sferi dovršenja i
praktičnog provođenja propisa o pretransfuzijskom testiranju. S gledišta rezultata ovoga rada,
najpotrebnijim se čine akcije uvođenja obavezne
detekcije iregularnih antitijela u svako pretransfuzijsko ispitivanje i rutinsko odredjivanje Kantigena u svih davalaca krvi.
ZAHVALE/IZJAVE
Posebnu zahvalu autori žele uputiti prim. dr. Aliji
Striki, direktoru Kantonalne bolnice Zenica, koji
je, svih ovih godina, pokazao izuzetno razumijevanje i bezrezervnu podršku uvođenju najsuvremenije dijagnostike, te općem podizanju stručnog nivoa cijele transfuzijske službe Kantonalne
bolnice Zenica, kao i zahvalu osoblju Službe za
transfuziju krvi koje je to provelo u praksu.
Komercijalni ili potencijalni dvostruki interes ne
postoji.
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Changes in the structure and clinical significance of the positive
results of pretransfusion testing during the switching from tube
test agglutination to gel microcolumn technique
Petrušić-Kafedžić Alma1, Ivanković Zdravko2, Ekinović Sabahudin³, Ibrahimagić-Šeper Lejla4
Department for Transfusiology, Cantonal Hospital Zenica, Zenica, Bosnia and Herzegovina, 2DiaHem, Buelach, Switzerland, ³ Faculty
of mechanical engineering, University of Zenica, Zenica, 4Health Care Center Zenica; Zenica, Bosnia and Herzegovina
1
ABSTRACT
Aim To investigate the changes in pretransfusion testing during the switch from the agglutination tube
test to the gel test.
Methods Clinical significance of positive results has been analyzed in 7667 pretransfusion tests (with
16610 cross-matches) performed by the tube test in 2005-2006, and in 7372 pretransfusion tests (with
17294 cross-matches) performed in 2007-2008 by the gel test.
Results In both analyzed periods antibody detection was positive in 1.3% and cross-matching in 0.3%
cases. At least one test was positive in 1.4% pretransfusions tested by the tube test and in 1.3% by
the gel test, with >75% positive results in women. Analyzing cases with positive cross-matching but
negative antibody detection, eight of ten such cases found by the tube test were caused by ‘cold antibodies’ whereas ‘warm non-specific antibodies’ caused all three cases found by the gel test. The gel test
detected higher proportion of immune antibodies than the tube test (69.8% vs 41.3%, p<0.001), with a
double increase in anti-K and Rh antibodies. The tube test detected 24 cases of clinically non-significant
antibodies, as compared with no cases found by the gel test (p<0,001). ‘Non-specific antibodies’ more
often caused positive cross-matches than antibody detection (42.6% vs. 29.9% by the tube test, 28.9%
vs. 18.3% by the gel test). Despite of being close in the detection of irregular antibodies (p=0.062), the
difference between the tube and gel test was not significant. ‘Non-specific antibodies’ were found by
both tests more often in women, while clinical departments were of no significance.
Conclusion The gel test has proved to be a more optimal technique of pretransfusion testing. The detection of irregular antibodies is recommended as an obligatory part of pretransfusion testing.
Key words: pretransfusion testing, gel test, specificity
Original submission: 09 April 2009; Revised submission: 28 October 2009; Accepted: 05 February 2010
131
ORIGINAL ARTICLE
Etiologija limfadenopatije dječije dobi
Edo Hasanbegović, Senada Mehadžić,
Pedijatrijska klinika Kliničkog centra Univerziteta u Sarajevu
SAŽETAK
Cilj rada Utvrditi etiologiju i stepen rasprostranjenosti limfadenopatije kod djece.
Metode Uzorak je obuhvatao 150 djece, uzrasta od 0-15 godina,
kojima je na Pedijatrijskoj klinici u Sarajevu, tokom 2008. godine,
dijagnosticirana limfadenopatija. Analizirani su dob, spol, etiologija i distribucija rasprostranjenosti limfadenopatije.
Edo Hasanbegović,
Pedijatrijska klinika Kliničkog centra
Univerziteta u Sarajevu,
Patriotske lige 81, 71000 Sarajevo,
Bosna i Hercegovina
Phone: ++ 387 33 566 428; 566 400;
Fax: ++ 387 71 566 525;
Rezultati Nije bilo statistički signifikantne razlike (p>0,05) u
spolnoj i dobnoj strukturi ispitanika. U etiologiji limfadenopatije
prednjačile su infekcije, kod 94 (62,7%), te malignomi, kod 20
(13,3%) pacijenata. Najčešće izolovani uzročnici infektivnih limfadenopatija bili su virusi kod 65 (69%) i bakterije kod 26 (28%)
pacijenata. U etiologiji malignih limfadenopatija najčešće su bile
zastupljene leukemije, i to akutne limfoblastne leukemije kod 11
(55%) i akutne mijeloične leukemije kod dvoje (10%) djece. Regionalna limfadenopatija bila je zastupljena kod 103 (68,7%), a
generalizirana kod 47 (31,3%) pacijenata. Kod regionalne limfadenopatije najčešće su bile zahvaćene regije vrata, kod 83 (80,5%),
aksile, kod 8 (7,8%) i prepone, 5 (4,8%) pacijenata.
Zaključak Regionalne i generalizirane limfadenopatije uslovljene
su etiologijom bolesti i značajno su utjecale na prognozu bolesti.
Ključne riječi: limfadenopatija, etiologija, djeca
Originalna prijava:
13. maj 2009.;
Korigirana verzija:
11. august 2009.;
Prihvaćeno:
16. septembar 2009.
132
Hasanbegović et al Etiologija limfadenopatije kod djece
UVOD
Limfadenopatija je termin koji se upotrebljava za
uvećane limfne čvorove i predstavlja jedan od čestih dijagnostičkih problema u pedijatrijskoj praksi.
Smatra se da limfni čvor veći od 1 cm, u jednoj
ili više regija, predstavlja limfadenopatiju, mada
se njihova veličina razlikuje od regije do regije.
Limfadenopatija može biti regionalna ili generalizirana. Regionalna limfadenopatija podrazumijeva
povećanje jednog ili više čvorova u jednoj regiji,
a generalizirana podrazumijeva povećanje limfnih
čvorova u dvije ili više regija (2). Limfadenopatija može biti uzrokovana infektivnim i neinfektivnim uzročnicima. Infektivne limfadenopatije ili
limfadenitisi mogu biti uzrokovani bakterijama,
virusima, gljivama, protozoama ili parazitima.
Neinfektivne limfadenopatije uzrokovane su imunološkom reakcijom u limfnim čvorovima ili malignom infiltracijom limfnih čvorova (1, 2).
U diferencijalnoj dijagnozi limfadenopatije najvažnije je etiološki razjasniti uzrok nastanka limfadenopatije, odnosno prepoznati na vrijeme maligne bolesti limfnog i nelimfnog tkiva, koje se
prezentiraju povećanim limfnim čvorovima (3).
Cilj ovoga rada je utvrditi etiologiju i učestalost
regionalne i generalizirane limfadenopatije kod
djece, liječene na Pedijatrijskoj klinici u Sarajevu,
u jednogodišnjem periodu. Budući da je dječija
limfadenopatija čest diferencijalno- dijagnostički
problem u pedijatrijskoj praksi, rezultati ovoga
istraživanja poslužit će ljekarima primarne, sekundarne i tercijarne zdravstvene zaštite, koji se
bave liječenjem djece za brzu i tačnu trijažu, dijagnostiku i terapiju ovog stanja. Naime, u našoj
zemlji nije bilo sličnih istraživanja, a slične studije rađene su u Turskoj i Austriji (4-6).
ISPITANICI I METODE
U ovome retrospektivno-prospektivnom istraživanju obuhvaćena su sva djeca, uzrasta od 0-15
godina, kojima je na Pedijatrijskoj klinici Kliničkog centra u Sarajevu dijagnosticirana limfadenopatija, u periodu 01. 01. do 31. 12. 2008.
godine. U studiju su uključena djeca kojima je
prvi put postavljena dijagnoza limfadenopatije.
Izvor podataka bile su istorije bolesti i anketni
upitnik koji je posebno pripremljen za ovu studiju. Anketni upitnik sadržavao je slijedeće elemente: opšte podatke o pacijentu (ime i prezime,
datum rođenja); ličnu i porodičnu anamnezu;
nalaz kliničkog pregleda; laboratorijske pretrage
(sedimentacija, kompletna krvna slika, transaminaze, bakar, beta-2-globulin); mikrobiološke
pretrage (bris guše i nosa) i serološka analiza na
Ebstein-Barrov virus (EBV) i citomegalovirus
(CMV); radiološku pretragu grudnog koša (Rtg);
ultrazvučni pregled (UZ) vrata i abdomena; te citološke i patohistološke pretrage.
Virusna etiologija bolesti dokazivana je serološkim pretragama na EBV-u i CMV-u, te na temelju
hematoloških pretraga (u perifernoj krvnoj slici leukopenija s limfocitozom, monocitozom i atipičnim limfocitima, uz isključenje druge etiologije).
Prema dobnim skupinama formirane su tri grupe
ispitanika: 0-5, 6-10 i 11-15 godina. Prema etiologiji limfadenopatije ispitanici su podijeljeni u
dvije grupe, infektivnu i neinfektivnu, a prema
stepenu rasprostranjenosti, na regionalnu i generaliziranu limfadenopatiju. Pod infektivnim limfadenopatijama podrazumijevane su one kod kojih
je, na osnovu laboratorijskih i mikrobioloških
pretraga, potvrđen infektivni uzrok bolesti. Neinfektivne limfadenopatije podrazumijevale su
maligne, autoimune i atopijske bolesti. U akutne
limfadenopatije uključili smo one koje su trajale
1-2 mjeseca, a kod kojih je, nakon tog vremena,
došlo do smanjenja promjera limfnih čvorova do
ispod 1-1,5 cm; a u kronične limfadenopatije one
koje su trajale duže od 2 mjeseca, te su limfni
čvorovi ostali povećani više od 1,5 cm poslije završene terapije.
U statističkoj obradi podataka korištene su standardne metode deskriptivne statistike (mjere centralne tendencije, mjere disperzije). Za testiranje
značajnosti razlika među uzorcima korišteni su
parametarski i neparametarski testovi signifikantnosti (medijan hi kvadrat test- X²-test, Studentov
t-test). Statističke hipoteze testirane su na nivou
značajnosti od 95% (p< 0,05).
Ovo istraživanje odobrili su etički komiteti Kliničkog centra Univerziteta u Sarajevu i Medicinskog fakulteta u Sarajevu.
REZULTATI
Ukupno je ispitano 150 djece, od kojih je 97
(64,66%) bilo dječaka, a 53 (35,34%) djevojčice
(1,8:1) (p = 0,826). Interval starosne dobi pojave
bolesti iznosio je 0,3-15 godina za dječake i 0,615 godina za djevojčice.
133
Tabela 1. Etiologija limfadenopatije s obzirom na spol djece
Infektivna
Maligna
Ostala*
Nepoznata
Dječaci
(n=97)
59
13
6
20
97
Djevojčice (n=53)
35
7
6
4
53
Ukupno
(n= 150)
94
(62.7%)
20
(13.3%)
12
(8%)
24
(16%)
150
Tabela 3. Etiologija regionalne i generalizirane limfadenopatije
Ukupno
Infektivna Maligna Ostala* Nepoznata
Regionalna
Dječaci
(n=63)
37
8
3
15
Djevojčice
(n=40)
27
6
3
4
Ukupno
(n=103)
64
(62,1%)
14
(13,6%)
6
(5,8%)
19
(18,5%)
Dječaci
(n=34)
22
5
2
5
8
1
4
0
*autoimune bolesti (n=6) , atopijske bolesti (n=4) i ciste glandule
parotis (n=1) i glandule tireoidee (n=1).
Iako je u svim dobnim skupinama (0-5, 6-10 i 1115 godina) broj dječaka s limfadenopatijom bio
veći od broja djevojčica, 45, 38 i 14, odnosno 28,
20 i 5, razlika nije bila statistički značajna (p > 0
,05).
Najčešće zabilježena bila je infektivna etiologija
limfadenopatije, kod 94 (62,7%) pacijenta, a maligna limfadenopatija kod 20 (13,3 %) pacijenata
(Tabela 1).
Virusi su bili najčešći uzročnici infektivnih limfadenopatija, kod 65 (69%) djece, i to EbsteinBarrov virus (EBV) kod 15 i citomeglovirus kod
12, te drugi virusi kod 38 pacijenata. Bakterije su
bile uzročnici kod 26 (28%) djece, i to Staphylococcus aureus kod 7, Streptococcus beta haemoliticus kod 6, Streptococcus pneumoniae i Bartonella henselae svaki kod 3, te Mycobacterium
tuberculosis kod 7 djece.
Analiza etiologije malignih limfadenopatija pokazala je da su najčešće bile zastupljene leukemije, i to najčešće akutne limfoblastne leukemije
(ALL), kod 11 (55%) djece (Tabela 2).
Od limfadenopatija druge etiologije, koje su bile
zastupljene kod 12 (8%) pacijenata, autoimune
bolesti su nađene kod šest i atopijske bolesti kod
četvoro djece (u istom broju kod dječaka i djevojčica), dok je kod jednog dječaka i jedne djevojčice ustanovljena cista glandule parotis, odnosno
cista glandule tireoidee.
Tabela 2. Distribucija maligne limfadenopatije prema
etiologiji*
ALL AML CML HL
NHL RMS PNET Ukupno
Dječaci
9
1
1
0
2
2
0
15
Djevojčice
2
1
0
1
0
0
1
5
Uku11
2
1
1
2
2
1
20
pno (55 %) (10%) (5 %) (5 %) (10%) (10%) (5 %) (100 %)
*ALL, akutna limfoblastna leukemija; AML, akutna mijeloična
leukemija; CML, kronična mijeloična leukemija; HL, Hodgkin limfom; NHL, Non-Hodgkin limfom; RMS, rabdomiosarcoma; PNET,
primitivni neuroektodermalni tumor
134
Genera- Djevojčice
lizirana
(n=13)
Ukupno
(n=47)
30
(63,8%)
6
6
(12,8%) (12,8%)
5
(10,6%)
*autoimune bolesti (n=6), atopijske bolesti (n=4), ciste glandule
parotis (n=1), ciste glandulae tireoidee (n=1).
Regionalna limfadenopatija bila je češće zastupljena, kod 103 (63 dječaka i 40 djevojčica) djece
(68,7%), a generalizirana kod 47 (34 dječaka i 13
djevojčica) (31,3%) djece, bez statistički značajne razlike (p= 0,253).
I regionalne i generalizirane limfadenopatije, u
oba spola, bile su najčešće infektivne prirode,
u 64 (62,1%), odnosno u 30 (63,8%) slučajeva
(Tabela 3).
Kod regionalnih limfadenopatija najčešće je bila
zahvaćena regija vrata, kod 83 (55 dječaka i 28
djevojčica) (80,5%) djece, zatim regije aksile
kod osam (podjednako kod dječaka i djevojčica)
(7,8%), prepone kod pet (četiri dječaka i jedne
djevojčice) (4,8%), te u regijama medijastinuma
i abdomena kod četvoro (tri dječaka i jedne djevojčice), odnosno troje (dva dječaka i jedne djevojčice) djece (3,9%, odnosno 2,9%).
Akutna limfadenopatija bila je češće zastupljena
od kronične, u 103, odnosno 47 (68,7%, odnosno
31,3%) djece (Tabela 4).
DISKUSIJA
Od ukupno 150 pacijenata s limfadenopatijom, u
našoj studiji, bilo je više dječaka od djevojčica u
odnosu (1,8:1), što odgovara opisanim podacima
iz literature (4, 5). Schaffer i saradnici, dva puta
Tabela 4. Način javljanja i stepen rasprostranjenosti limfadenopatije*
Regionalna (n=103) Generalizirana (n=47)
Akutna (n=103)
68
35
Kronična (n=47)
35
12
* p = 0.398
Hasanbegović et al Etiologija limfadenopatije kod djece
veći broj dječaka s limfadenopatijom u odnosu na
djevojčice, objasnili su činjenicom da su novorođenčad, dojenčad i djeca do tri godine muškog
spola, osjetljivija na bakterijske i virusne infekcije
zbog razlike na nivou spolnih kromosoma i zbog
više koncentracije IgM antitijela kod muške djece,
a djevojčice tek u dobi od oko tri godine starosti
dosežu nivo IgM antitijela muške djece (7).
U etiologiji limfadenopatije u ovom istraživanju prednjačila je infektivna i maligna, (62,7%,
odnosno 13,3%). Visoka prevalencija malignih
limfadenopatija u našoj studiji (13,3%) rezultat je velikog broja djece upućene iz primarne
zdravstvene zaštite, gdje je i postavljena sumnja
na malignitet. Infektivna limfadenopatija, koja je
inače puno češća, ne zahtijeva pregled i liječenje
hematologa na klinici.
Infektivna etiologija, u nekim istraživanjima, zastupljena je i do 81% slučajeva, a maligna 1624% (4, 5, 8).
U studiji Granado RMJ i saradnika, iz 1992. godine, pronađeno je 16% limfadenopatija maligne
etiologije, što je slično našim rezultatima (8).
Virusna etiologija limfadenopatije, u našoj studiji, imala je značajno učešće, kako u regionalnoj,
tako i u generaliziranoj limfadenopatiji (69%), te
zatim bakterije (28%). Najčešće izoliran bio je
EBV (21,7%), što je u skladu s rezultatima drugih studija (6). Relativno mali broj mikrobiološki
potvrđenih bakterijskih izolata može se tumačiti
činjenicom da je 50% naših pacijenata već bilo
pod antibiotskom terapijom, kada su došli na
našu kliniku. U nekim istraživanjima procenat
bakterijskih infekcija bio je i do 35% (9, 10).
Prema podacima iz literature, prevalencija tuberkulozne etiologije od 15-32% bila je znatno veća
nego u našoj studiji (4,7%) (11).
Regionalna limfadenopatija, u našem istraživanju, bila je češće zastupljena i kod akutnih i
kod kroničnih limfadenopatija, što je u skladu s
objavljenim podacima (4, 5). Prema podacima u
literaturi, najčešće zahvaćena regija kod infektivne etiologije bila je cervikalna, a zatim aksilarna
i ingvinalna, što je u potpunosti u skladu s našim
rezultatima (3). Osim toga, cervikalna limfadenopatija javlja se i u više od 70 djece oboljele
od limfoma (Hodgkin i Non Hodgkin) (12). Osim
u regijama dostupnim fizikalnom pregledu, limfadenopatija može biti hilarna, medijastinalna i
abdominalna (13, 14). Druga po učestalosti je
aksilarna limfadenopatija, što je također u skladu
s našim rezultatima. Prisustvo supraklavikularne
limfadenopatije postavlja temeljnu sumnju na
malignu etiologiju (12, 15). U dvije trećine slučajeva cervikalna limfadenopatija udružena je s
medijastinalnom masom (16). Ove različite lokalizacije maligne limfadenopatije, već pri prvom
kontaktu s pacijentom, mogu usmjeriti dijagnostiku prema malignom oboljenju. Limfadenopatija predstavlja veliki diferencijalno-dijagnostički
problem za ljekara, te treba imati na umu da je
zastupljenost regionalne i generalizirane limfadenopatije uslovljena etiologijom bolesti. Najčešći uzrok nastanka i regionalne, i generalizirane
limfadenopatije, jesu infekcije izazvane virusima
i bakterijama, ali je značajan broj limfadenopatija
maligne etiologije (leukemije), na što uvijek treba misliti ukoliko povećani limfni čvorovi dugo
traju i nema pozitivnog odgovora na antibiotsku
terapiju.
ZAHVALE/IZJAVE
postoji.
LITERATURA
1.
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3.
Camitta B. The lymphatic system. U: Kliegeman
BM, Behrman RE, Jenson HB. Stanton BF, urednici.
Nelson textbook of pediatrics. 18. izd. Philadelphia:
Saunders Elsevier, 2007:1677- 9.
Stunzner D, Mangge H, Schenkeli R, Deutsch J.
Peripheral lymphadenopathy in childhood-recommandations for diagnostic evaluation. Klin Pediatric
2000; 212: 277-82.
Bazemore AW, Smucker DR. Lymphadenopathy and
malignancy. Am Fam Physicians 2002; 66:210310.
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Oguz A, Karadeniz C, Temel E, Citak E, Okur F.
Evaluation of peripheral lymphadenopathy in children. Pediatr Hematol Oncol 2006; 23: 549-61.
Ceyda K, Aynur O, Ustun E, Gulyuz O, Ayse D. The
etiology of peripheral lymphadenopathy in children.
Pediatr Hematol Oncol 1999;16:525-31.
Benesch M, Kerbl R, Winsberger A, Stunzner D,
Mangge H, Schenkeli R, Deutsch J. Peripheral
lymphadenopathy in childhood-recommandations for diagnostic evaluation. Klin Pediatric 2000;
212:277-82.
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Schaffer A J, Avery ME. Infections. U: Schaffer
AJ,Avery ME, urednici. Disease of the newborn.
3. izd. Philadelphia: W.B. Saunders Company, 1997:
632-5.
8. Granado RMJ, A Guisasola FJ, Gomez MI, Bobillo del AH, Quirus B, Mateos Otero JJ. Diagnostic
evaluation of cervical adenopathies in childhood. An
Esp Pediatr 1992; 37:233-7.
9. Schleiss MR. Streptococcal infection. Pediatr Infect
Dis J 2002; 21:796-7.
10. Trobs RB, Grafe G, Muller P, Handrick W. Bacterial
cervical lymphadenitis- surgical aspect. Klin Pediatr
2003; 215:208-12.
11. Batra V, Ang JY, Asmar BI. Tuberculosis. South
Med J 2003; 96:206-8.
12. Howard SC, Metzger MI, Hudson MM. Pediatric
Hodgkin lymphoma. U:Antillon FA, Bernoala E,
Sierrasesumaga I, urednici. Pediatric oncology. Pearson Education, 2006.
13. Hasanbegović E. Kliničke i hematološke karakteristike dječijih leukemija. ed Arh 2006; 60 (Suppl.
2):84-86.
14. Dahl GV, Weinstein HJ. Acute myeloid leukemia in
children. U: Hoffman R, Benz EJ, Shatil SJ, Fuzie
B, Colie HJ, urednici. Hematology: Basic principles
and practice. Philadelphia: Churchil Lyvingstone,
2004:1121-33.
15. Rue D, Thomas RK, Behringer K, Diehl V. From
Hodgkin disease to Hodgkin lymphoma: biologic
insights and therapeutic potential. Blood 2005; 105:
4553-60.
16. Predojević-Samardžić J, Roganović J. Limfomi u
djece. Pedijatrija danas 2009; 5:51-61.
Etiology of lymphadenopathy in childhood
Edo Hasanbegović, Senada Mehadžić
Pediatric Clinic, Clinical Centre University of Sarajevo
ABSTRACT
Aim To establish etiology and level of prevalence of lymphadenopathy in children. Methods: One
hundred and fifteen children aged 0-15 years with diagnosed lymphadenopathy at the Pediatric Clinic
in Sarajevo during 2008 were included in the study. It analyzed age, sex, etiology and distribution and
prevalence of lymphadenopathy.
Results There was no statistically significant difference (p > 0,05) according to gender and age of children with lymphadenopathy. Leading etiological causes of lymphadenopathy were infections in 95%
(62,7 %) and malignancies in 20 (13,3 %) cases. The most frequent isolated microorganisms were viruses in 65 children (65 %) and bacteria in 26 (28%) of children. Most frequent causes of malignant lymphadenopathy were acute lymphoblastic leukemia in 11 children (55 %) and acute myeloid leukemia in
two (10%) children. Regional lymphadenopathy was more frequent than generalized lymphadenopathy,
in 103 children (68,7%) and 47 (31,3 %) children, respectively. Most frequent localizations of regional
lymphadenopathy were neck, axillae and groin, in 83, 8, and 5 (80,5 %, 7,8%, 4,8%) children.
Conclusion The regional and generalized lymphadenopathies in children depend on their etiology and
have significant prognostic value for the disease.
Key words lymphadenopathy, etiology, children
Original submission: 13 May 2009.; Revised submission: 11 August 2009.; Accepted: 16 September 2009
136
ORIGINAL ARTICLE
Lunarni ciklus i cerebralni napadi u djece
Univerzitetski klinički centar Tuzla, Klinika za dječije bolesti
SAŽETAK
Cilj Analizirati jednogodišnji trend hospitalizacije djece liječene
zbog cerebralnih napada i mogući uticaj lunarnog ciklusa.
Metode Retrospektivno su analizirani podaci koji se odnose na
sezonsku distribuciju prijema u bolnicu (mjesec, sedmica, datum
i čas prijema, dan u sedmici, doba dana, te odnos prema lunarnim
ciklusima) svih pacijenata liječenih zbog cerebralnih napada (konvulzije, epi napad, kriza svijesti i epi napad u djece s neurorazvojnim poremećajima), tokom 2008. godine, u Klinici za dječije
bolesti Univerzitetskog kliničkog centra.
Devleta Hadžić,
Univerzitetski klinički centar Tuzla,
Klinika za dječije bolesti
Trnovac bb, 75000 Tuzla
Bosna i Hercegovina
Phone.: ++387 35 303 713;
Fax.: ++387 35 250-474;
Originalna prijava:
14. april 2009.;
Rezultati Od ukupno 234 liječene djece, dojenčadi je bilo 55
(23,5%), djece do šest godina 101 (43,1%), a djece školskog
uzrasta 78 (33,3%). Najčešći oblik cerebralnih napada bile su konvulzije, 123 (52,6 %). Sredinom sedmice zabilježen je veći broj
napada nego vikendom. Najveći broj djece liječen je u januaru,
februaru, julu i augustu, odnosno, u 4., 7., 27. i 31. sedmici u godini. U 149 pacijenata (63,7%) cerebralni napad dogodio se tokom
dana, a kod 84 pacijenta (35,9%) tokom noći (p < 0,0034). Broj
liječenih pacijenata bio je značajno veći u trećoj i četvrtoj lunarnoj
fazi (p < 0,018).
Zaključak Budući da su rezultati istraživanja pokazali sezonski i
sedmični trend hospitalizacije pacijenata zbog cerebralnih napada,
te povezanost s cirkadijanim i lunarnim ciklusom, oni bi mogli
poslužiti kao osnova za daljnje i detaljnije istraživanje na većem
uzorku s ciljem provjere rezultata i eventualnih novih saznanja.
To bi moglo doprinijeti boljem razumijevanju i jedinstvenijem
tumačenju teorija o uticaju mjeseca i njegovih pojedinih faza na
zdravlje ljudi.
Ključne riječi: lunarni ciklus, cerebralni napadi, djeca;
Korigirana verzija:
31. juli 2009.;
Prihvaćeno:
19. august 2009.
137
UVOD
ISPITANICI I METODE
Po definiciji cerebralni napadi obilježeni su
naglom, ali prolaznom pojavom psihičkih, motoričkih, senzornih ili vegetativnih simptoma,
koji su posljedica prolazne disfunkcije mozga
(1). Prema patogenezi dijele se na epileptičke,
hipoksične, metaboličke, toksične, psihogene i
neepileptičke; s tim da se mogu kombinirati i
izazivati jedan drugi (2). Najčešći pojavni oblik
cerebralnih napada u djece jesu različiti oblici
konvulzija, s prevalencijom u ukupnoj populaciji djece do 5 godina starosti od 5-7% (1, 2). Na
svu sreću, konvulzije ili cerebralni napadi većinom ne predstavljaju epilepsiju, već su prolazne
epizode koje prestaju kada se ukloni uzrok (3).
Epilepsije su hronične bolesti mozga različitog
uzroka, obilježene ponavljanjem epileptičkih
napada i u pravilu praćene elektroencefalografskim abnormalnostima. Hroničnost, odnosno
recidivi napada, jedno su od bitnih obilježja
epilepsije. Kada govorimo o epilepsiji, želimo
istaknuti da postoji više različitih oblika ove bolesti koji se međusobno razlikuju po uzrocima,
dobi javljanja, kliničkoj slici, liječenju i prognozi (4). Svaka deseta osoba u svom životu doživi
epileptički napad ili je njime u stanovitoj mjeri
ugrožena (3).
Retrospektivno, koristeći protokole prijema, kao
i historije bolesti, analizirani su svi pacijenti liječeni zbog cerebralnih napada u Klinici za dječije
bolesti Univerzitetskog kliničkog centra (UKC)
Tuzla, u periodu od 01. 01. do 31. 12. 2008. godine. Istraživanje je provedeno u skladu s etičkim
normama i standardima, te odobreno od strane
Etičkog komiteta ove ustanove.
Uzroci pojave cerebralnih napada su različiti.
Osim osnovnih uzroka, postoji veliki broj poznatih i nepoznatih svakodnevnih provocirajućih i
dispozicijskih faktora koji mogu provocirati napad, kao naprimjer: spavanje, neprospavana noć,
fotostimulusi, duboko disanje, povišena temperatura, vrsta prehrane, opstipacija, napetost ili
opuštenost, emocionalne promjene, napori, poremećaji metabolizma, izlaganje suncu, vremenske promjene i dr. (3, 4). U nekim istraživanjima
ustanovljena je povezanost povećanog broja pacijenata s konvulzijama, epilepsijom i drugim bolestima s precipitirajućim okolinskim faktorima,
kao što su dnevne, sedmične, mjesečne, sezonske
oscilacije (5, 6), dok je u drugim predmet istraživanja bio lunarni ciklus i njegov mogući uticaj na
čovjeka i zdravlje (7, 8).
Cilj ovog istraživanja bio je da se analizom jednogodišnjeg kretanja broja pacijenata, primljenih
zbog cerebralnih napada u Kliniku za dječije bolesti Tuzla, istraži mogući uticaj lunarnog ciklusa
na trend hospitalizacije.
138
Cerebralni napadi, u našem istraživanju, svrstani
su u četiri grupe: konvulzije, epi napad, kriza
svijesti i epi napad u djece s neurorazvojnim
poremećajima (NRP). Analizirani su dob, spol,
mjesto stanovanja i sezonska distribucija prijema
u bolnicu (mjesec, sedmica, datum i čas prijema,
dan u sedmici, doba dana, te odnos prema lunarnim ciklusima). U istraživanju je korištena i druga baza podataka dobijena iz aktuelnog lunarnog
kalendara (9) za period koji je bio obuhvaćen
istraživanjem. Lunarni kalendar sadrži 12 lunarnih mjeseci koji traju 29,5 dana. Svaki lunarni
mjesec sadrži četiri lunarne faze od po sedam
dana. Prva i druga faza jesu faze rastućeg mjeseca, a treća i četvrta faze mjeseca u opadanju.
Između druge i treće faze su dani punog mjeseca
(9). Podaci iz ovog kalendara pridruženi su odgovarajućim podacima iz važećeg solarnog gregorijanskog kalendara za period koji je obuhvaćen
istraživanjem. Svakom pacijentu izračunata je
pripadajuća lunarna faza u vrijeme prijema u bolnicu, odnosno u vrijeme doživljenog cerebralnog
napada.
U statističkoj obradi podataka korištene su standardne metode deskriptivne statistike (mjere centralne tendencije, mjere disperzije). Za testiranje
značajnosti razlika među uzorcima korišteni su
parametarski i neparametarski testovi signifikantnosti (X²-test, Studentov t-test), kao i metoda
linearne korelacije. Statističke hipoteze testirane
su na nivou signifikantnosti od 95% (p < 0,05).
REZULTATI
U promatranom jednogodišnjem periodu u Klinici za dječije bolesti UKC Tuzla, liječeno je 3470
pacijenata. Od toga su 234 (6,74%) pacijenta, u
dobi od jednog mjeseca do 15 godina, bili hitno
primljeni zbog cerebralnih napada: konvulzije,
epilepsije, krize svijesti i epilepsije u sklopu neurorazvojnih bolesti. Prosječna starosna dob uzor-
Hadžić et al Lunarni ciklus i cerebralni napadi u djece
Grafikon 1. Dobna i spolna distribucija djece liječene zbog
cerebralnih napada
Grafikon 2. Distribucija uzorka prema spolu i vrsti napada
ka iznosila je 4,9 ± 4,6 godina. Distribucija po
spolu pokazala je da su 116 (49,6%) pacijenata
bili dječaci, a 118 (50,4%) djevojčice. Dojenčadi je bilo 55 (23,5%), pacijenata od jedne do
šest godina 101 (43,1%), a školskog uzrasta 78
(33,3%) pacijenata (Grafikon 1).
Raspodjela uzorka prema zabilježenom satu napada pokazala je najčešću pojavu napada u periodu između 12 i 15 sati, kod 44 pacijenta (18,8%),
a najmanji broj napada zabilježen je u periodu
između 3 i 6 sati ujutro, kod 10 pacijenata (4,3%)
(Grafikon 4).
Od ukupnog broja liječenih pacijenata najveći
broj bio je liječen zbog konvulzija, ukupno 123
pacijenta (52,6%) (Grafikon 2).
Od ukupno 234 pacijenta, kod 149 (63,7%) cerebralni napad dogodio se tokom dana, dok se kod
84 pacijenta (35,9%) cerebralni napad dogodio
tokom noći (Grafikon 4).
Geografska distribucija uzorka djece liječene
zbog cerebralnih napada, u toku jednogodišnjeg
perioda, gotovo je u potpunosti odgovarala geografskoj distribuciji ukupne populacije djece do
15 godina za područje Tuzlanskog kantona. Najveći broj djece liječen je u januaru, februaru, julu
i augustu (Slika 1).
Najveći broj pacijenata liječen je u 4., 7., 27. i 31.
sedmici u godini (Slika 2).
Najveći broj napada dogodio se četvrtkom, kod
49 pacijenata (20,9%), a najmanji broj napada
subotom, kod 21 (9%) pacijenta (p < 0,041) (Grafikon 3).
Slika 1. Distribucija pacijenata s cerebralnim napadom po
mjesecima
Broj liječenih pacijenata bio je značajno veći u
periodu mjeseca u opadanju (treća i četvrta faza),
124, u odnosu na period mjeseca u porastu (prva i
druga faza), 110 (p < 0,018) (Grafikon 5).
Konvulzije nisu imale značajne razlike u učestalosti tokom pojedinih lunarnih faza, dok su epi
napadi bili značajno češći u trećoj i četvrtoj lunarnoj fazi. Krize svijesti i epi napadi u djece s
neurorazvojnim poremećajima bili su najčešći u
trećoj lunarnoj fazi (Grafikon 6).
Slika 1. Distribucija pacijenata s cerebralnim napadom po
sedmicama
139
Grafikon 3. Distribucija pojava napada prema danima u
sedmici
Grafikon 5. Broj liječenih pacijenata u pojedinim mjesečevim
fazama
Konvulzije kod dječaka bile su češće u prvoj i
trećoj lunarnoj fazi, 21 (34,4%), 17 pacijenata
(27,9%), za razliku od djevojčica kod kojih su
konvulzije bile češće u drugoj i četvrtoj lunarnoj
fazi, 18 (29,0%), odnosno 16 pacijenata (25,8%).
Epi napad u dječaka bio je najčešći u trećoj, a
u djevojčica u četvrtoj lunarnoj fazi, 8 pacijenata u obje grupe (38,1%, odnosno 44,4%). Krize
svijesti, i u dječaka i u djevojčica, bile su najčešće u trećoj lunarnoj fazi, 9 (32,1%), odnosno
10 (27,8%). U djece s neurorazvojnim poremećajima učestalost epi napada u dječaka nije se
značajno mijenjala tokom lunarnih faza, dok je
u djevojčica s neurorazvojnim poremećajima epi
napad zabilježen u trećoj lunarnoj fazi kod obje
(Slika 3).
lokalizacije epi fokusa. Ravnoteža ovog cirkadijanog ritma i neuroendokrinog cirkadijanog ciklusa, ritma spavanje/budnost, te niza okolinskih
faktora, jesu pretpostavljeni ambijent koji rezultira pojavom cerebralnih napada (5, 10, 11).
Najveći broj pacijenata liječenih zbog cerebralnih napada u Klinici za dječije bolesti UKC Tuzla, tokom 2008. godine, bili su u uzrastu do šest
godina. Ova dobna raspodjela odgovara vrsti zabilježenih napada jer su konvulzije bile najčešći
oblik cerebralnih napada. Na trend hospitalizacije nisu bitnije utjecali spol i mjesto stanovanja,
ali je statistički značajno ustanovljen sezonski i
sedmični karakter, te povezanost s cirkadijanim
i lunarnim ciklusom. Do sada objavljeni podaci
sugeriraju o cirkadijanom karakteru cerebralnih
napada, koji zavisi od vrste napada i eventualne
Vjerovanje da puni mjesec ima uticaja na zdravlje ljudi perzistira uprkos 50-godišnjim studijama
koje pokazuju da ova veza ne postoji (12). Ove
studije trasirale su historijsku putanju vjerovanju
moći mjeseca da izazove mentalne poremećaje,
prije svega nesanicu i epilepsiju. Vul je 1976. godine, na bazi matematičke analize 84000 slučajeva konvulzije tokom 101 promatrane mjesečeve
faze, ustanovio porast konvulzija u pacijenata
s epilepsijom u odnosu na pacijenate s ostalim
oblicima konvulzija tokom promatranih perioda
punog i mladog mjeseca, što je objasnio utjecajem fizičkih faktora, kao što je magnetna teorija
nastanka epileptičkog procesa (13). Prioritet u
napretku novim spoznajama o uticaju mjeseca
bio je kroz spoznaju da mjesec, preko fenomena
osvjetljenja, narušava ciklus san/buđenje s tendencijom da izazove deprivaciju od sna u vrijeme faze punog mjeseca (8, 12). Ova parcijalna
deprivacija od sna dovoljna je da inducira maniju, hipomaniju ili mogući bipolarni poremećaj,
ili konvulzivni napad u pacijenata s epilepsijom.
Moderna saznanja umanjuju značaj ovom lunarnom efektu, pogotovo u modernim urbanim
područjima gdje je provedena većina studija o
Grafikon 4. Distribucija uzorka prema satu pojave napada u
toku dana
Grafikon 6. Distribucija pojedinih oblika cerebralnih napada
po lunarnim fazama
DISKUSIJA
140
Hadžić et al Lunarni ciklus i cerebralni napadi u djece
Slika 3. Distribucija pacijenata prema vrsti napada, spolu i
lunarnoj fazi
lunarnom efektu u 20. stoljeću (13).
Analiza lunarnog ciklusa i broja hospitaliziranih
pacijenata zbog cerebralnih napada, u našem je
istraživanju pokazala da je broj liječenih pacijenata bio značajno veći u trećoj i četvrtoj lunarnoj fazi (period mjeseca u opadanju), u odnosu
na prvu i drugu lunarnu fazu (mjesec u porastu),
te da se učestalost konvulzija nije mijenjala tokom pojedinih lunarnih faza, dok su epi napadi
bili značajno češći u trećoj i četvrtoj lunarnoj
fazi, i to u dječaka u trećoj, a u djevojčica u četvrtoj lunarnoj fazi. Rezultati objavljenih studija u kojima je analiziran uticaj lunarnih faza na
trend hospitalizacije zbog konvulzija i epilepsije
nisu jedinstveni. Benbadis i saradnici 2004. godine, analizirajući trend prijema u bolnicu zbog
epileptičkih i neepileptičkih konvulzija, u ukupnom uzorku nisu ustanovili statistički značajnu
povezanost s pojedinim fazama lunarnog ciklusa,
dok je pojedinačna analiza pokazala porast neepileptičkih konvulzija u danima punog mjeseca,
a epileptičkih konvulzija u četvrtoj fazi lunarnog
ciklusa (14). Za razliku od ove studije, Polychro-
nopolulos i saradnici 2006. godine registrovali su
signifikantno grupisanje broja napada u periodu
punog mjeseca (15). U prilog ovom su i rezultati
studije Terra-Bustamante i saradnika, objavljeni
2008. godine, koji sugeriraju moguću korelaciju punog mjeseca i iznenadne smrti u epilepsiji
(16). Rezultate slične našima objavili su Ruegg
i saradnici 2008. godine, te ustanovili signifikantno češću hospitalizaciju pacijenata u epilepsijskom statusu tokom dana, najčešće između 16 i
17 sati, a najmanji broj prijema u ranim jutarnjim
satima. Prijem je statistički značajno varirao tokom pojedinih faza lunarnog ciklusa, a incidenca
prijema bila je signifikantno niža tokom vikenda (7). U studiji Baxendalea i Fisfera iz 2008.
godine, nađena je značajna negativna korelacija
između prosjeka broja napada i stepena mjesečeve osvijetljenosti, što je sugeriralo važniju ulogu
mjesečeve osvijetljenosti nego same mjesečeve
faze (17).
U zaključku možemo reći da najnovije studije potvrđuju uticaj mjeseca i njegovih pojedinih faza
na trend hospitalizacije pacijenata zbog cerebralnih napada, prije svega epilepsije, ali da mehanizam uticaja i povezanosti ipak još uvijek nije do
kraja razjašnjen. U našem istraživanju trend hospitalizacije pacijenata zbog cerebralnih napada
bio je statistički značajno povezan s okolinskim
faktorima, kao što su sezonski, sedmični i cirkadijani ciklus. Uticaj lunarnog ciklusa također se
pokazao značajnim jer je broj liječenih pacijenata bio značajno veći u trećoj i četvrtoj lunarnoj
fazi u odnosu na prvu i drugu fazu. Ovi rezultati
mogli bi biti osnova za daljnju, detaljniju analizu
i istraživanje na većem uzorku, s ciljem provjere rezultata i eventualnih novih saznanja. To bi
moglo doprinijeti boljem razumijevanju i jedinstvenijem tumačenju teorija o uticaju mjeseca i
njegovih pojedinih faza na zdravlje ljudi.
ZAHVALE/IZJAVE
postoji.
LITERATURA
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7. Ruegg S, Hunziker P, Marsch S, Schindler C. Association of environmental factors with the onset of
status epilepticus. Epilepsy Behav 2008; 12:66-73.
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Chroni E. Lunar phases and seizure occurrence: just
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16. Terra-Bustamante VC, Scorza CA, de Albuquerque
M, Sakamoto AC, Machado HR, Arida RM, Cavalheiro EA, Scorza FA. Does the lunar phase have
an effect on sudden unexpected death in epilepsy?
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The lunar cycle and seizures in children
Pediatrics Clinic, University Clinical Center of Tuzla
ABSTRACT
Aim To analyze the annual trend of hospitalization and potential influence of the lunar cycle of children
treated for seizures.
Methods The data of the patients treated for seizures (convulsions, epileptic seizures, disturbance of
consciousness and epileptic seizures in children with neurodevelopmental disability) in the Pediatrics
Clinic of the University Clinical Center of Tuzla were retrospectively analyzed during 2008 in relation
to seasonal distribution, admission time (month, week, admission moment, day in a week, time of the
day) and the lunar cycle.
Results Out f the total of 234 treated children, 55 (23,5%) were infants, 101 (43,1%) were under six
years of age and 78 (33,3%) were of school age. The most common type of seizures were convulsions,
123 (42,6%). The seizures were numerous in the midst of the week, as opposed to weekends. The
highest number of children was treated in January, February, July and August, that it, in the fourth, seventh, twenty-seventh and thirty-first week of the year. Seizures occured during the day in 149 patients
(63,7%) and during the night in 84 (35,9%) patients (p < 0,0034). The number of treated patients was
significantly larger in the third and fourth lunar phases (p < 0,018).
Conclusion The results suggested seasonal and weekly trends of hospitalization of patients with seizures and their relation with circadian and lunar cycles. There is a need for further prospective studies in
order to get better understanding of the influence of the lunar cycle on health.
Key words: the lunar cycle, seizures, children.
Original submission: 14 April 2009.; Revised submission: 31 July 2009.; Accepted: 19 August 2009
142
ORIGINAL ARTICLE
Increased P wave dispersion in patients with liver steatosis
Mustafa Aparci1, Zafer Isilak2, Omer Uz2, Ejder Kardesoglu2, Omer Yiginer2, Onur Sildiroglu3, Murat
Yalcin4, Namık Ozmen2, Bekir Yilmaz Cingozbay2, Bekir Sitki Cebeci2
1
3
Air Force Academy Hospital, Cardiology Service, Istanbul, 2GATA Haydarpaşa Teaching Hospital, Department of Cardiology, Istanbul,
GATA Haydarpaşa Teaching Hospital, Department of Radiology, İstanbul, 4Izmir Military Hospital, Cardiology Service, Izmir, Turkey
ABSTRACT
Aim Hepatic steatosis is associated with metabolic and hemodynamic abnormalities induced by insulin resistance and inflammatory
state. Since abnormalities of P wave dispersion may be accompanied with latter issues we evaluated this subject in patients with
hepatic steatosis.
Methods Total of 106 patients and 56 healthy subjects were enrolled and performed hepatic ultrasonography, echocardiography,
electrocardiogram, and biochemistry tests. Clinical features, laboratory and echocardiographic parameters, P wave dispersion were
compared between groups and analyzed for any correlation among
parameters.
Mustafa Aparci
Air Force Academy Hospital,
Cardiology Service
Yesilyurt/ Istanbul/ Turkey
Phone: ++90 505 3947131;
Fax: ++90 212 233 44 56;
Email: [email protected]
06 July 2009.;
Revised submission:
25 August 2009.;
Accepted:
04 November 2009.
Results Body mass index (BMI), waist circumference, systolic
and diastolic blood pressure, levels of total and LDL cholesterol,
and fasting blood glucose (FBG), and left atrial diameter were significantly higher in patients with hepatic steatosis. Peak velocities of mitral E and A waves and their ratio were abnormally changed in patients compared to normals. In multiple linear regression
analysis, approximately all of the variables previously correlated
within Pearsons’ correlation test were found to be significantly
correlated with P wave dispersion [ waist circumference (ß=0.151,
p=0.048), LDL cholesterol (ß=0.234, p=0.000), FBG (ß=0.402,
p= 0.000), alanine aminotransferase (ALT) (ß=0.205, p= 0.006),
alkaline phosphatase (ALP) (ß=0.277, p=0.000), γ-glutamyl transferase (γ-GT) (ß=0.240, p=0.000), left atrial diameter (ß=0.204,
p=0.003), heart rate (ß=0.123, p=0.037)].
Conclusion Increased P wave dispersion may indicate a risk of
atrial arrhythmia which may be complicated with disabling symptoms and thromboembolism in patients with hepatic steatosis.
Consequently, hepatic steatosis is associated with increased risk
for cardiovascular disease due to metabolic and hemodynamic abnormalities probably induced by insulin resistance and inflammatory state.
Key words: fatty liver, arrhythmia, echocardiography, insulin, inflammation
143
INTRODUCTION
Prevalence of hepatic steatosis is growing in developed countries probably due to lifestyle and
dietary habits which potentially promote atherosclerosis. Consequently an increase in prevalence of cardiovascular diseases among either
diabetic or non-diabetic patients with hepatic
steatosis is being observed (1). Thus this clinical issue is suggested to be a novel component of
metabolic syndrome (2).
It was documented that hepatic steatosis was closely associated with insulin resistance and increased
levels of oxidative stress and endothelial dysfunction (3). Since liver steatosis is a low-grade inflammatory disease of the liver atherosclerosis in which
inflammatory mediators might have had an important role could easily be initiated and progress (4).
Also insulin resistance and subclinical inflammation have a reciprocal and an additive relationship
which may induce a predisposition to atherosclerosis. Moreover, those abnormalities may induce
sympathetic over-activity which could induce inhomogeneous electrical activity of myocardium
and also atrium (5,6). Sympathetic over-activity
and sub-inflammation may coexist and are probably the essential features of hemodynamic abnormalities clustered in metabolic syndrome (7).
P wave is the reflection of atrial electrical activity
on the surface electrocardiogram (8). It may potentially be influenced by the hemodynamic and
metabolic abnormalities which are frequent in
patients with liver steatosis (9). Thus, we aimed
to evaluate the P wave dispersion in patients with
hepatic steatosis in this study.
PATIENTS AND METHODS
The total of 106 patients with hepatic steatosis and
56 healthy subjects underwent clinical examination, echocardiography, hepatic ultrasonography,
and 12 lead electrocardiograhy. All participants
were informed about the study and signed informed consent forms. Electrocardiograms (ECG)
were recorded at 50 mm/sec rate and 10 mm/mV
and analyzed digitally. P wave dispersion was
determined as the difference between minimum
and maximum P wave durations by a cardiologist
blinded to the study project and clinical information of patients. (P wave dispersion=PMaximum-PMi). Participants with ECG abnormalities (<60
nimum
144
or >100 beats per minute, ST segment and T wave
abnormalities, short PR interval, left ventricular
hypertrophy criteria, etc.) were excluded.
Hepatic ultrasonography was performed by a
single experienced radiologist who was bound to
study project. Ultrasonography has a sensitivity
of 90% and a specificity of 95% in diagnosing and
grading of hepatic steatosis (10). Serum levels of
plasma liver tests including alanine aminotransferase (ALT), aspartate aminotransferase (AST),
alkaline phosphatase (ALP) and GGT, and total
cholesterol, LDL cholesterol, HDL cholesterol,
and triglyceride, fasting blood glucose (FBG)
were determined from venous blood samples
obtained at 12 hour fasting state. Patients with
cirrhotic liver disease, positive serology for viral
hepatitis B and C, history of hepatotoxic medication, heavy smoking and alcohol consumption,
overt diabetes and hypertension, familial hyperlipidemia were excluded from the study.
We used Independent-Samples-t test for comparison of continuous variables. Associations of P
wave with clinical, echocardiographic and laboratory parameters assessed by Pearson’s correlation test and independent relationships were
assessed by multiple linear regression analysis
and reported as standardized regression coefficients and their significance. A 2-tailed p value
<0.05 was considered as statistically significant.
Statistical analyses were performed using SPSS
11.0 for Windows.
RESULTS
In comparison of patients with liver steatosis and
healthy subjects, body mass index (BMI), waist
circumference, systolic and diastolic blood pressures were significantly higher in patients with
liver steatosis (p<0.01) (Table 1). Also laboratory parameters such as levels of total cholesterol , LDL and HDL cholesterol, triglyceride,
fasting blood glucose were abnormally increased
in patients’ group (p<0.05). Serum levels of liver enzymes such as ALT, ALP, and γ-glutamyl
transferase (γ-GT) except AST were significantly
higher in patients with liver steatosis as expected
(p<0.01). In comparison of echocardiographic
parameters ejection fraction was slightly higher
in healthy subjects and left atrial diameter was
significantly increased in patients with liver steatosis (p<0.01). Peak velocities of both mitral E
Aparci et al P wave dispersion in hepatic steatosis
and A waves were significantly increased in patients with liver steatosis as compared to healthy
subjects (p<0.05). Additionally, ratio of peak velocities of mitral E wave to A wave was significantly decreased in the patients’ group (p<0.05).
Deceleration time of mitral E wave and isovolumic relaxation time were not statistically significant between groups (p>0.05). Heart rate was
Table 1. Comparison of clinical features, laboratory parameters and parameters of aortic elasticity among patients with
liver steatosis and healthy individuals
Patients with
liver steatosis
(n=102)
Healthy
Subjects
(n=56)
34,5±7,0
33,1±6,3
0.064
66/36
38/18
0.23**
p
Clinical features*
Age (years)
Gender (M/F)
BMI (kg/m2)
27.32±3.2
24.8±2.4
0.000
Waist circumference M
F
104.2±10.7
90.4±8.2
96.7±9.2
84.6±9.2
0.001
Systolic blood pressure
(mm Hg)
120.8±7.0
115.0±10.9
0.000
Diastolic blood pressure
(mm Hg)
72.2±7.5
64,6±9.6
0.000
Laboratory parameters
Total cholesterol (mg/dl) 214.06±42.6
194.8±32.2
0.007
LDL cholesterol (mg/dl)
120.4±24.8
0.007
HDL cholesterol (mg/dl)
136.0±30.8
42.8±8.2
39.8±6.0
0.013
Triglyceride (mg/dl)
158.8±64.6
150.4±60.6
0.377
FBG (mg/dl)
97.4±10.8
94.6±6.0
0.043
BUN (mg/dl)
13.2±3.1
13.8±1.8
0.327
AST (IU/L)
26.8±10.5
24.4±8.1
0.46
ALT (IU/L)
52.8±23.6
34.6±7.4
0.000
ALP (IU/L)
74.2±18.6
54.4±20.8
0.000
γ-GT (IU/L)
48.8±11.8
40.2±8.4
0.003
Echocardiography
LVIDd (mm)
45.9±3.2
45.4±2.7
0.276
LVIDs (mm)
28.6±3.7
28.2±2.4
0.348
EF (%)
65.8±4.7
67.3±3.0
0.067
LAD (mm)
33.6±2.6
32.0±2.5
0.000
Mitral E wave velocity
(m/s)
0.72±0.14
0.63±0.16
0.000
Mitral A wave velocity
(m/s)
0.58±0.10
0.46±0.16
0.022
E/A ratio
1.37±0.22
1.47±0.39
0.016
E wave DT (msec) 167.40±45.35 160.31±34.01 0.289
IVRT (msec) 100.4±21.66
101.9±30.3
significantly higher in patients with liver steatosis (p<0.01). Also P wave dispersion was significantly increased in patients with liver steatosis as
compared to healthy subjects (41.6±6.5 msec vs
36.2±4.8 msec, p<0.01) (Table 1).
P wave dispersion was significantly correlated with waist circumference, LDL cholesterol,
fasting blood glucose, levels of ALT, ALP, and
γ-GT, left atrial diameter, and also heart rate in
bivariate correlation analysis (p<0.05) (Table 2).
In multiple linear regression analysis, approximately all of the variables previously correlated within Pearsons’ correlation test were found to be
significantly correlated with P wave dispersion [
waist circumference (ß=0.151, p=0.048), LDL
cholesterol (ß=0.234, p=0.000), FBG (ß=0.402,
p= 0.000), ALT (ß=0.205, p= 0.006), ALP
(ß=0.277, p=0.000), γ-GT (ß=0.240, p=0.000),
left atrial diameter (ß=0.204, p=0.003), heart rate
(ß=0.123, p=0.037)] (Table 2).
DISCUSSION
The main result of our study is that P wave dispersion was significantly increased and also
correlated with laboratory, metabolic and echocardiographic abnormalities in patients with liver
steatosis (Table 1, 2). Liver steatosis, a candidate
to be a novel component of metabolic syndrome,
is closely associated with insulin resistance (2,
11, 12). Insulin resistance causes metabolic derangements, increased central blood volume and
abnormal sympathetic activity (13). Increased
SBP, DBP, heart rate and FBG might have been
consequences of those abnormalities induced by
insulin resistance. P wave duration and P wave
dispersion were reported to be influenced by abTable 2. Bivariate and multivariate correlations of P wave
dispersion with clinical and echocardiographic variables in
patients with liver steatosis*
P wave dispersion (msec)
0.680
Pearson
correlation
coefficient
p
Standardized
ß regression
coefficients
p
Waist circumference
0.160
0.014
0.151
0.048
LDL cholesterol
0.213
0.001
0.234
0.000
FBG
0.140
0.032
0.402
0.000
ALT
0.148
0.023
0.205
0.006
γ-GT
0.174
0.004
0.240
0.000
ALP
0.161
0.013
0.277
0.000
LAD
0.381
0.000
0.204
0.003
Heart Rate
0.148
0.032
0.123
0.037
Electrocardiographic
features
Variables
Heart rate (bpm)
84.6±12.2
79.8±8.2
0.001
Pdisp (msec)
41.6±6.5
36.2±4.8
0.000
*M/F, Male/Female; BMI, Body mass index; LDL, low density lipoprotein; HDL, high density lipoprotein; FBG, fasting blood glucose;
BUN, blood urea nitrogen; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase; γ-GT, γ-glutamyl
transferase; LVIDd/s, diastolic and systolic internal diameters of left
ventricle; EF, left ventricular ejection fraction; LAD, left atrial diameter; DT, deceleration time; IVRT, isovolumic relaxation time; bpm,
beat per minute; Pdisp, dispersion of P wave duration; **Chi-Square
test; p<0.05, statistically significant
*abbreviations as in Table 1
145
normal autonomic tone (14). Increased heart rate
and FBG but not the blood pressure values were
significantly correlated with P wave dispersion in
our study (Table 2).
Left atrial diameter was significantly enlarged
and correlated with P wave dispersion in patients with liver steatosis. Left atrial volume and
diameters are the strong indicators of inhomogeneous propagation of the sinus impulse through
the atriums in congestive heart failure (15). This
association may be present in hepatic steatosis
as well as in congestive heart failure. Atrial enlargement is probably a consequence of atrial
remodeling as a response to the increased filling
pressures and chronic pressure overload induced
by insulin resistance in hepatic steatosis (13, 16).
Nicolaou et al reported that metabolic syndrome
favor the occurrence of paroxysmal atrial fibrillation by increasing atrial size (17). Peak velocities of mitral E and A waves but not their ratio
were significantly higher and may also reflect
the atrial pressure overload and the dependence
of left ventricular filling to atrial contractions in
patients with liver steatosis (Table 1). Mureddu et
al reported that impairment of myocardial relaxation in obese patients was predominantly induced
by insulin resistance (18).
Roes et al reported that both the insulin resistance and low grade inflammation may contribute to
the abnormal diastolic function in patients with
metabolic syndrome (19). Low grade inflammatory state is accompanied with increased levels of
soluble intercellular and vascular adhesion molecules, oxidative stress, and endothelial dysfunction (20). It is associated with increased P wave
dispersion and also risk of atrial fibrillation in
patients with chronic non-cardiac diseases (21,
22). Pleiotropic anti-inflammatory effect of statins may be one of the rationales on reducing the
risk of post-operatively new-onset atrial fibrillation (23, 24). In fact, hepatic steatosis is a chronic
inflammatory disease of liver (25). Also, P wave
dispersion was found to be significantly correlated with those liver enzymes in our study.
Watanabe et al reported that metabolic syndrome
was associated with increased risk of atrial fibrillation probably due to metabolic derangements
(9). P wave dispersion longer than ≥ 40 msec is
clinically important (26). Thus, a mean P wave
dispersion about 41.6±6.5 msec in our patients
with liver steatosis may indicate an increased risk
of atrial fibrillation as well as in other clinical
conditions; hypertension, pre-hypertension, diabetes, obesity, metabolic syndrome, etc (27-29).
It is probably a consequence of both the metabolic derangements due to insulin resistance and the
inflammatory state due to liver steatosis.
In this study we did not measure the insulin levels to determine the insulin resistance. Although
this seems to be a limitation of our study, the role
of insulin levels in diagnosis of insulin resistance
is still a disputable issue (30). Additionally, we
did not evaluate the level of inflammation and
inflammatory markers since the latter issue was
reported to be higher in liver steatosis by numerous studies (20, 25).
P wave dispersion, which is clinically important
for atrial arrhythmia, is increased in patients with
liver steatosis. Atrial arrhythmia may increase
the burden of cardiovascular diseases by either
disabling symptoms or thromboembolic events in
patients with liver steatosis. Consequently, liver
steatosis, potentially a novel component of metabolic syndrome, is associated with increased risk
for cardiovascular disease due to metabolic and
hemodynamic abnormalities probably induced
by insulin resistance and inflammatory state.
ACKNOWLWEDGEMENTS/DISCLOSURES
This study was partly presented by Zafer Isilak,
Mustafa Aparcı, Omer Yiginer, Ejder Kardesoglu,
Namik Ozmen, Omer Uz, Murat Yalcın, Bekir Yilmaz Cingozbay, Bekir Sitki Cebeci. Increased QTc
and P wave dispersion in patients with hepatosteaosis. Proceedings of the 6th International Mediterranean Meeting of Hypertension and Atherosclerosis, Antalya, Turkey, March 24-28, 2009.
Competing interests: none declared
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147
ORIGINAL ARTICLE
Impact of reversionary and other etiological factors on prognosis
and course of schizophrenia
Ifeta Ličanin¹, Amira Redžić²
¹Psychiatric Clinics, Clinical Center, University of Sarajevo, ²Department of Biology and Human Genetics, School of Medicine, University of Sarajevo; Sarajevo, Bosnia and Herzegovina
ABSTRACT
Aim To identify the presence of schizophrenia among patients and
their relatives, factors affecting duration and prognosis of the disease and other etiological factors related to schizophrenia.
Corresponding Author:
Ifeta Ličanin
Psychiatric Clinics, Clinical Center,
University of Sarajevo,
Bolnička 25, 71000, Sarajevo,
Bosnia and Herzegovina
Phone; ++387 33 297 228;
fax.: ++387 33 265 710
email: [email protected]
9 February 2009;
Revised submission:
13 June 2009;
Methods This retrospective, descriptive, analytical and epidemiological research, which was conducted at the Psychiatric hospital
of the Clinical Center of the University of Sarajevo during 2007,
covered randomly selected 100 hospitalized patients with schizophrenia according to diagnostic criteria of the Diagnostic and
Statistical Manual of Mental Disorders (DSM-IV). Diagnosis of
schizophrenia among relatives was based on anamnesis- Structural
Clinical Interview (SCID) and it was applied to confirm DSM-IV
diagnosis of schizophrenia.
Results The presence of schizophrenia among patient relatives was
the most important in etiology of schizophrenia (62%), and etiological factors were represented in 38 % of examinees (p=0,0001).
Among relatives of examinees aged 20 – 30 years, schizophrenia
was present in 37 (59.7%) cases. Schizophrenia among relatives
caused earlier appearance of the disease. Duration of hospitalization of over 60 days was in the group of examinees which have
the relatives with schizophrenia, 18 (29.0%); multiple hospitalizations were noted in the group of relatives in 40 (64.5%) cases; in
one case (8.3%) traumatic experience was noted, in three (42.8%)
acute stress, and in four 4 cases (28.6%) non-adequate living conditions.
Conclusions The results of this study show that reversionary
factors are responsible for inducing schizophrenia, which leads
towards chronic course of the disease and worsened prognosis.
Key words: schizophrenia, relatives, reversion, stress, etiology,
epidemiology.
Accepted:
02 November 2009
148
Ličanin et al Etiological factors and schizophrenia
INTRODUCTION
Schizophrenia is the most serious and most common mental disorder that is mostly characterized
with disruptions in opinion making and observation process, while emotions are non-adequate
or blunt (1). Disease has a chronic course with
deteriorations and remissions and it is a significant medical – sociological issue (2-5). Etiological factors of schizophrenia could be separated
into predisposing (genetic factors, environmental
factors), precipitating (acute stress) and perpetuating (chronic stress, emotional “atmosphere”
that patient is living at) (6- 8).
Reduction of epidemiological researches from the
social community to the family level has enabled
a more precise research of the role and importance
of reversionary factors (a person is likely to have
schizophrenia if other members of the family also
have schizophrenia and that the likelihood of the
person’s having schizophrenia is correlated with
the closeness of the relationships: e.g. first-degree
or second-degree relative) as well as environmental factors relevant for mental health, on-set and
course of psychiatric disorders (9-11). Genealogical studies represent the oldest and most relevant
form of researches about the presence of schizophrenia among relatives (5,12-15).
The risk of developing schizophrenia is higher if
one or both parents have the schizophrenia, but it
does not mean that every child with schizophrenic parents would develop the disease itself (2).
Even though it is clear that there is a heredity basis of schizophrenia, frequency of diseases with
monozygotic twins could be different, which indicates that disease with certain gene-type is not
reversionary, but reversionary is predisposition
or tendency to develop the disorder (5, 6, 9, 10).
This statement is supported by many studies on
progenies of monozygotic twins with different
diseases (one twin develops a disease, and other
does not) that indicate comparable risk for developing diseases with progenies of affected and
non-affected twin (7,8,16).
This shows that specific presence of schizophrenia among relatives that confirm and transfer a
predisposition to disease are transferred, and they
do not have to be expressed (17).
Environmental factors are among the etiological
factors involved in the appearance of schizophre-
nia. Diagnose of schizophrenia among relatives
could cause inheritance of neurotransmiter abnormalities among relatives (17,18). Relevant world
researches are mostly related to studies on multiple genes, genomes, and environmental factors.
There is a lack of studies in our region related to
comparison of reversionary and other etiological
factors of schizophrenia. That is one of the reasons why we decided to conduct our study.
The aim of this study was to determine the agespecific prevalence of schizophrenia, the presence of schizophrenia among patient relatives,
etiological factors responsible for the development of schizophrenia, other etiological factors
affecting course and prognosis of the disease (by
observing a number of cases and duration of hospitalization).
PATIENTS AND METHODS
After an approval of Ethic Committee Clinical
Centre Sarajevo University had been obtained
one hundred patients who were hospitalized
because of the diagnosed schizophrenia during
2007 were assessed retrospectively. Subjects
were evaluated by experienced clinicians using
the SCID-I interview for DSM-IV at the Psychiatric Clinic of the Clinical Center of the University
in Sarajevo. Inclusion criteria for the study were
one hundred patients randomly selected whose
diagnosis of schizophrenia was confirmed according to the Diagnostic and Statistical Manual of
Mental Disorders (DSM-IV F20X, irrespective
of subtype) (19).
Patients’ medical records were used for the examination of variables: demographic data (gender,
age, education level, employment, income and
socio-economic status, marital status, occurrence of schizophrenia within the family, number
and duration of hospitalizations), the presence
of schizophrenia among patients’ relatives, or
presence of schizophrenia in parents, siblings or
cousins), other etiological factors involved in the
appearance of schizophrenia (traumatic event,
acute stress, non adequate living conditions). Family relations were determined according to the
Structured Clinical Interview for DSM disorders
RESULTS
The prevalence of schizophrenia was significantly higher in females, 65 (65%), than in males,
149
Table 1. Etiological factors of schizophrenia in relation to patients age of disease occurrence*
Age (years) when disease was diagnosed
Presence among
relatives (%)
Traumatic events
(%)
Acute stress Chronic stress
Inadequate
(%)
(%)
living conditions (%)
Total
(%)
20-30
37 (59.7)
2 (16.7)
0
0
8 (57.1)
47 (47.0)
30-40
10 (16.1)
7 (58.3)
6 (85.7)
0 (,0)
2 (14.3)
25 (25.0)
40-50
15 (24.1)
0
0
4 (80.0)
0
19 (19.0)
50-60
0
3 (25.0)
1 (14.3)
1 (20.0)
4 (28.6)
9 (9.0)
Total
62 (62.0)
12 (12.0)
7 (7.0)
5 (5.0)
14 (14.0)
100
*X2=61,921p=0,0001
35 (35%). The prevalence of schizophrenia was
decreasing with the decrease of patients’ age: the
highest prevalence was noted in patients 20-30
years of age, 47 (47%), and lowest one in patients
50-60 years of age, nine of them (9%). In the age
groups 30-40 and 40-50 years the prevalence was
25 (25%) and 19 (19%), respectively.
examinees with acquired etiological factors, e. g.
traumatic events in twelve (12%), acute stress in
seven (7%), chronic stress in five (5%), and bad
living conditions in four (4%) cases.
Table 3 represents the number of hospitalizations
in relation to etiological factors: multiple hospitalizations were the most frequent among patients with the disease among relatives (4, 5%),
and none among patients with chronic stress as
an etiological factor.
The reversionary factors were mostly presented in etiology of schizophrenia, in 62 patients
(62%). Acquired etiological factors were presented in 38 (38%) patients: traumatic events were
responsible for the disease occurrence in 12%,
acute stress in 7%, chronic stress in 5%, and nonadequate living conditions in 14% of cases.
DISCUSSION
The results of this research have shown female/
male ratio of 35:65, and the highest prevalence of schizophrenia in patients in the age group
20-30 (47%), which is in accordance with the results of other researches (2-5). The presence of
schizophrenia among relatives was the most important factor in etiology of schizophrenia in this
research (62%), whereas among other etiological
factors (38%) traumatic events were responsible
for disease appearance in 12%, acute stress in
7%, chronic stress in 5%, and non-adequate living conditions in 14% cases.
Table 1 shows etiological factors of schizophrenia
in relation to the age when the disease occurred.
The most common presence of schizophrenia
among relatives was noted within the age group
of 20-30, in 37 (59.7%) of cases.
Table 2 shows duration of hospitalization in relation to etiological factors, with different tendencies. Multiple and extended (more than 60 days)
hospitalizations were noted among examinees
with positive history of schizophrenia among
their relatives, in 62 (62%) cases. Shorter and
less often hospitalizations were noted among
Dominant genetic etiological factors, as well as
some risk factors for disease development in he-
Table 2. Duration of hospitalization of patients with schizophrenia in relation to etiological factors*
Duration of
hospitalization (days)
Presence among
relatives (%)
Traumatic events
(%)
Acute stress
(%)
Chronic stress
(%)
Inadequate
Total
< 15
8 (12.9)
2 (16.7)
2 (28.6)
2 (40.0)
3 (21.4)
17 (17.0)
15 – 30
12 (19.4)
3 (25.0)
3 (42.9)
1 (20.0)
4 (28.6)
23 (23.0)
30 -45
14 (22.6)
3 (25.0)
1 (14.3)
2 (40.0)
3 (21.4)
23 (23.0)
45 -60
10 (16.1)
2 (16.7)
1 (14.3)
0
4 (28.6)
17 (17.0)
> 60
18 (29.0)
2 (16.7)
0
0
0
20 (20.0)
Total
62 (62.0)
12 (12.0)
7 (7.0)
5 (5.0)
14 (14.0)
100 (100.0)
*X2=14,631, p=0,0001
Table 3. Number of hospitalization in relation to etiological factors*
Number of
hospitalizations
Second hospitalization
Presence among
relatives (%)
10 (16.1)
Traumatic events
(%)
7 (58.7)
Acute stress
(%)
2 (28.6)
Chronic stress
(%)
3 (60.0)
Inadequate
4 (28.6)
Total
(%)
26 (26.0)
26 (26.0)
Third hospitalization
12 (19.4)
4 (33.3)
2 (28.6)
2 (40.0)
6 (42.8)
Multiple hospitalizations
40 (64.5)
1 (8.3)
3 (42.8)
0
4 (28.6)
48 (48.0)
Total
62 (62.0)
12 (12.0)
7 (7.0)
5 (5.0)
14 (14.0)
100 (100.0)
X2=23.648, p=0.0001
150
Ličanin et al Etiological factors and schizophrenia
althy individuals were also shown in other researches (3, 19). According to this, some authors
recommend screening of vulnerable patients in
prevention of schizophrenia on-set (3, 19-21).
The most common presence of schizophrenia
among relatives was noted within the age group
of 20-30, in 37 (59.7%) cases. These results were
similar to other results (5,14, 20). Current data
indicate the appearance of the disease in early
twenties in the examinees with positive heredity,
as well as much more malignant course of the disease, or the worse prognosis (22-24).
The group of authors from Spain has stated that
the appearance of schizophrenia in an earlier age
of life has a better prognostic sign, which is opposite to our results. The same authors indicated
irrelevance of other socio-demographic factors to
the development of schizophrenia (25).
Multiple and extended (more than 60 days) hospitalizations were noted among examinees with
positive history of schizophrenia among their relatives (62%). Shorter and less frequent hospitalizations occured among examinees with acquired
etiological factors (38%). These results match the
results of researches, where authors indicated the
appearance of the disease with a bad prognostic
sign, especially according to the number and dura-
tion of hospitalizations. The same authors also discuss living conditions, education level and age as
bad for prognostic factors for the disease (26-30).
This research has shown that most of the presented factors responsible for the appearance of
schizophrenia occured in patients with positive
family history for schizophrenia, which leads
towards a chronic course of the disease and worsened prognosis.
Prevention of schizophrenia is an important issue
related to the treatment. There are two steps in
the prevention: identification of persons at risk,
and their successful treatment.
Investigation of the factors involved in the appearance of schizophrenia from a specific geographic region (Bosnia and Herzegovina) could serve
as a basis for its comparison with other regions in
order to bring better understanding and develop
prevention of this disorder. This study could be
continued with a large sample and conducted in
multiple mental centers aimed at prevention and
better understanding of causes and consequences
of the disease.
ACKNOWLEGEMENT/DISCLOSURE
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ORIGINAL ARTICLE
Standardi fetalnog rasta za tuzlansku regiju
Adem Balić1, Devleta Balić2
1
Služba za ginekologiju i perinatologiju, Dom zdravlja u Tuzli; 2 Ginekološka ordinacija „Dr. Balić” Tuzla; Tuzla, Bosna i Hercegovina
SAŽETAK
Cilj ovoga rada je izrađivanje standarda normalnog intrauterinog
rasta za područje Tuzlanskog kantona.
Metode U periodu 2002-2005. godine provedeno je prospektivno
praćenje fetalnog rasta (biparijetalni i abdominalni dijametar, obim
glave i abdomena, te dužina femura), prema kriterijima FIGO-a
(Federation International Gynaecologist and Obstetrician) (FIGO,
1986), kod stotinu zdravih trudnica s normalnom jednoplodnom
trudnoćom koje su se spontano vaginalno porodile između 38. i
41. nedjelje trudnoće. Mjerenja su vršena najmanje jednom u četiri
nedjelje, počev od 12. pa do kraja 41. nedjelje.
Adem Balić,
Služba za ginekologiju i perinatologiju,
Dom zdravlja u Tuzli,
Kojšino 25, 75000 Tuzla
Phone: +387 35 286 724;
fax.: +387 35 286-724
Originalna prijava:
Rezultati Prosječna težina novorođenčadi u 38. nedjelji iznosila
je 3280 ± 345 g, u 39. nedjelji 3360 ± 280 g, u 40. nedjelji 3596
± 320 g i u 41. nedjelji 3732 ± 380 g. Dobijeni standardi pokazali
su nešto manje vrijednosti svih ispitivanih parametara i u svim
nedjeljama trudnoće, s tim da su razlike bilo vrlo male kod standarda za BPD i FL, dok su bile znatno veće kod standarda za obim
glave i obim abdomena, koja su bila najizraženija u zadnje četiri
nedjelje.
Zaključak Imajući u vidu uočene razlike između vrijednosti dobivenih standarda i onih koje smo najviše koristili (Hadlock, 1983
i Latin, 2000), a koje su najveće u zadnje četiri nedjelje trudnoće
kada su varijacije fetalnog rasta i najveće, izrada standarda fetalnog rasta za našu populaciju bila je opravdana, te će njegova primjena sigurno doprinijeti daljnjem sniženju perinatalnog mortaliteta u Bosni i Hercegovini.
Ključne riječi: fetalni rast, standard, BPD, FL
18. novembar 2009.;
Korigirana verzija:
15. januar 2010.;
Prihvaćeno:
19. januar 2010.
153
UVOD
Rast i razvoj ljudskog ploda od davnina je pobuđivao veliku radoznalost s obzirom na njegovu
tijesnu povezanost s perinatalnim ishodom, odnosno s neonatalnim morbiditetom i mortalitetom.
Do uvođenja ultrazvuka u akušerstvo početkom
sedamdesetih godina, intrauterini rast je procjenjivan indirektno prema veličini uterusa, obimu
trbuha i udaljenosti fundus-simfiza, u čemu su
odstupanja ponekad bila vrlo velika. Ultrazvučna dijagnostika omogućila je brzo, neinvazivno i
tačno mjerenje različitih fetalnih struktura, a time
i pouzdanu procjenu njegove težine (1). Mjereni
su različiti dijelovi tijela fetusa, a najviše su korišteni: biparijetalni dijametar (BPD), frontookcipitalni dijametar (FOD), obim glave (HC, head
circumpherence), poprečni abdominalni dijametar (ABD), obim abdomena (AC, abdominal circumpherence) i dužina femura (FL, femur lenght),
s obzirom da su se pokazali najpogodnijim za procjenu fetalnog rasta tokom cijele trudnoće (2).
Naime, otkad postoji akušerstvo, poznata je činjenica da je novorođenče veće i teže što trudnoća duže traje, ali dileme vezane za odstupanja od
ovoga rasvijetljene su tek zahvaljujući ultrazvučnim mjerenjima (3). Među prvima je Gruenwald
(4) jasno diferencirao dva pojma - nasljedni i stečeni potencijal za rast. Nasljedni ili genetski potencijal za rast koga je nazvao ‘’intrinsic factor’’,
a to je, prije svega, rasno i etničko porijeklo,
može biti razlogom rođenja većih ili manjih novorođenčadi. S druge strane, stečeni faktor rasta
vezan je za transplacentarni dotok hranjivih tvari
na što mogu uticati različiti poremećaji zdravstvenog stanja majke, ishrane, uslova življenja i
slično (5). To je i bio povod da je veći broj autora,
za svoje područje, izradio krivulje fetalnog rasta
(6-10).
U našoj sredini do 1990. godine, odnosno do početka rata, korišteni su standardi intrauterinog rasta beogradske populacije iz 1974. (9), a u toku
i nakon rata, koriste se različiti standardi instalirani u ultrazvučnim aparatima. To je nerijetko razlog pogrešne procjene devijacije fetalnog rasta
i svih dijagnostičkih procedura koje nakon toga
slijede. Iako je potreba za fetalnim standardima
prilično stara, objektivni razlozi za kašnjenje njihove izrade jesu ratna i poratna zbivanja u Bosni
i Hercegovini koja su imala uticaj na mnoge sfere
života, a samim tim i na fetalni rast, te standardi
154
rađeni u tom periodu ne bi bili pravi odraz fetalnog rasta u našoj sredini. Istraživanje Skokićeve
pokazalo je da je težina novorođenčadi u toku
rata bila značajno manja (235 g !) nego u prijeratnom i poslijeratnom periodu (11).
Cilj ove prospektivne studije bio je utvrditi normalan fetalni rast kod trudnica s jednoplodnom,
nekomplikovanom trudnoćom, koje gravitiraju
području Tuzlanskog kantona, te kreirati njihov
normogram.
MATERIJAL I METODE
U četverogodišnjem periodu, počev od 01. 01.
2003. godine, praćen je fetalni rast kod stotinu
trudnica s normalnom, jednoplodnom trudnoćom,
prema kriterijima FIGO-a (Federation International Gynacologist and Obstetrician) (FIGO) (12),
u Službi za zdravstvenu zaštitu žena i trudnica
Doma zdravlja u Tuzli i Ginekološkoj ordinaciji
‘’Dr. Balić’’ u Tuzli (Tabela 1). Mjerenja su vršena kod svih trudnica koje su se javljale na preglede u navedenim ustanovama tokom ispitivanog
perioda, a koje su ispunjavale navedene kriterije.
Istraživanje je sprovedeno u skladu s odlukom
Etičkog komiteta JZU Dom zdravlja Tuzla.
Tačnost gestacijske dobi utvrđena je na osnovu
slaganja procjene veličine trudnoće prema datumu zadnje menstruacije i ultrazvučne biometrije
u prvom trimestru.
Studijom su bile obuhvaćene samo one trudnice
koje su ispunjavale sve kriterije FIGO-a, odnosno koje su spontano dobile porođajne bolove i
koje su rodile djecu bez anomalija. Trudnice kod
kojih je u toku trudnoće došlo do komplikacija
(krvarenje, hipertenzija, zastoj u rastu), koje su
se porodile prije 39. nedjelje ili carskim rezom, te
zbog nekih drugih elemenata predviđenih kriterijima FIGO-a, nisu uključene u studiju.
Tabela 1. Kriteriji za ispitivanu grupu trudnica i njihovih
fetusa (FIGO - 1986)
Zdrava žena
Nepušač i neuživalac droga i drugih opojnih sredstava
Nije imala prekidâ trudnoće, perinatalne smrti čeda ili dijete s
usporenim rastom
Pouzdan datum zadnje menstruacije (po mogućnosti potvrđen ultrazvučnim pregledom u prvom trimestru)
Jednostruka trudnoća
Trudnoća bez komplikacija
Bez krvarenja u trudnoći
Spontani trudovi između 38. i 41. nedjelje trudnoće
Živahno dijete pri porođaju
Odsutnost kongenitalnih anomalija ploda
Balić et al Standardi fetalnog rasta
Fetalni rast je procjenjivan na osnovu slijedećih
ultrazvučnih parametara: biparijetalni dijametar
(BPD), frontookcipitalni dijametar (FOD), obim
glave (head circumpherency – HC), poprečni dijametar abdomena (ABD), obim abdomena (abdominal circumpherency - AC) i dužina bedrene
kosti (femur lenght - FL). BPD i FOD su mjereni
po modifikaciji Campbella (13), tj. najveći uzdužni i poprečni promjeri fetalne glavice na nivou središnje linije, talamusa, corpus callosuma
i cavuma septi pelucidi. Vrijednosti obima glave
računate su na osnovu veličine BPD-a i FOD-a
korištenjem formule za elipsu: y = (D1+D2) x
1,62 (Slika 1).
Dužina femura mjerena je metodom O’Briena i
saradnika (14); nakon određivanja uzdužne osovine ploda, sonda se na nju postavi pod pravim
uglom, a zatim se pomjeri ka fetalnoj karlici i rotira za 35-45° prema abdomenu da bi se dobila
cijela dužina femura (Slika 2).
Obim abdomena izračunat je na osnovu mjerenja transverzalnog i anteroposteriornog dijametra prema formuli za elipsu. Mjerenja su vršena
na presjeku ispod srčane sjene gdje se prikazuju
strukture jetre, bifurkacija portalne vene, želudac, abdominalna aorta i kičma (15) (Slika 3).
Sva mjerenja, prema navedenim kriterijima, u
intervalima od 2 do 4 nedjelje, obavljalo je pet
iskusnih ultrasoničara.
Za ultrazvučne preglede korišteni su General
Electric Logic 200 (Beč, Austrija) i Aloka 1700
SSD (Tokio, Japan), General Electric Voluson
730 Expert (Beč, Austrija) s transabdominalnim
sondama 3-5 MHz.
Osim navedenih biometrijskih parametara, analizirani su i paritet, zanimanje, visina, težina, mjesto boravka i starosna dob trudnica.
Statistička obrada rezultata izvršena je računanjem srednje vrijednosti i standardne devijacije
za svaki ispitivani biometrijski parametar i za
svaku nedjelju trudnoće, a dobivene vrijednosti
uvrštavane su kao vrijednosti za tekuće nedjelje
(npr. 40. nedjelja = 39+1 do 40+0).
REZULTATI
U četverogodišnjem periodu prospektivno je
praćen fetalni rast kod trudnica kontrolisanih u
Savjetovalištu za trudnice Službe za zdravstvenu
zaštitu žena i trudnica Doma zdravlja u Tuzli i
Tabela 2. Težina novorođenčadi na rođenju prema gestacijskoj dobi
Gestaciona dob 37/1 - 38/0 38/1 -39/0 NG 39/1-40/0 NG 40/1-41/0 NG
(nedjelje)
Tjelesna
masa na
3280 ± 345
rođenju
ug
3360 ± 280
3596 ± 320
3732 ± 380
Ginekološkoj ordinaciji ‘’Dr. Balić“. Prema kriterijima FIGO-a ultrazvučna mjerenja izvršena
su kod stotinu trudnica s normalnom, jednoplodnom trudnoćom. Mjerenja su vršena svake dvije
do četiri nedjelje, tako da je svaka trudnica imala
najmanje na pet mjerenja.
Najveći je broj trudnica bio iz Tuzle [79, (79%)],
dok su ostale bile sa šireg područja Tuzlanskog
kantona (Kladanj, Kalesija, Dokanj, Seljublje,
Živinice, Sapna, Gradačac, Teočak i Lukavac).
Prema zanimanju 51 (51%) trudnica bila je nezaposlena, a 49 (49%) zaposlene. Prema stepenu obrazovanja četiri (4%) ispitanice bile su bez
obrazovanja, 28 (28%) s osnovnim, 56 (56%)
sa srednjim i 12 (12%) s visokim obrazovanjem.
Prema paritetnoj strukturi bilo je 54 (54%) prvorotki, 30 (30%) drugorotki, 14 (14%) trećerotki i
dvije (2%) višerotke. Prosječna životna dob ispiTabela 3. Biparijetalni dijametar (BPD) i obim glave (HC) kod
fetusa u normalnoj trudnoći*
NG
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
BPD (mm)
18,9
22,7
25,8
27,7
32,6
38,7
40,6
44,5
46,3
49,2
50,3
54,5
59,1
61,0
65,5
67,8
69,1
74,3
76,5
78,7
81,3
85,6
86,3
86,6
88,6
90,6
91,7
93,5
94,5
SD
2,64
2,18
1,83
0,58
0,89
1,52
1,39
1,29
2,85
2,64
2,50
2,56
2,89
2,22
2,41
2,5
2,96
3,21
3,01
2,33
2,97
1,17
2,64
2,87
1,60
2,60
2,46
1,77
3,53
HC (mm)
72,1
77,2
105,3
109,4
125,1
134,2
146,4
155,3
166,1
179,5
181,5
192,2
207,1
222,4
229,8
238,4
247,7
259,8
272,4
280,5
287,8
294,4
300,2
308,1
315,4
318,8
323,4
328,1
333,2
SD
2,1
2,8
3,1
3,4
3,8
3,99
4,11
3,91
4,89
4,42
5,46
4,83
5,12
5,7
4,9
5,1
4,92
7,8
8,9
11,25
11,47
12,85
12,11
10,24
10,9
11,8
12,84
13,22
12,5
* NG, nedjelje gestacije; BPD, biparijetalni dijametar; HC, head
circumpherency; SD, standardna devijacija;
155
tanica bila je 26,55 ± 4,2 godine (najmlađa 18, a
najstarija 38 godina), prosječna visina 167,65 ±
4,83 cm, a prosječna težina 65,35 ± 8,58 kg. Prema spolu novorođenčadi 54 (54%) su bili muškog, a 46 (46%) ženskog spola.
Najveća prosječna težina novorođenčadi na rođenju iznosila je 380 g u 40. nedjelji (porast za oko
200 g sa standardnom devijacijom) (Tabela 2).
Prosječne vrijednosti biparijetalnog dijametra
iznosile su od 18,9 u 12. nedjelji do 94,5 u 40.
nedjelji (standardna devijacija od 0,58 do 3,53).
Porast BPD-a u zadnjim nedjeljama trudnoće
iznosio je oko 1 mm (Tabela 3).
Prosječne vrijednosti za obim glave iznosile su
od 72,1 mm u 12. nedjelji do 333,2 u 40. nedjelji.
Porast u zadnjim nedjeljama iznosio je 5-7 mm
(SD između 10,9 i 13,22) (Tabela 3).
Srednje vrijednosti i standardna devijacija (SD)
za poprečni dijametar abdomena (ABD) i obim
abdomena (AC) po nedjeljama trudnoće prikazane su u Tabeli 4. Rast po nedjeljama kretao se od
1,4 do 2,9 mm za ABD i 3-10 mm za AC, dok se
SD za ABD kretala od 1,2 mm (12. nedjelja) do
7,9 mm (40. nedjelja), a SD za AC kretala se od
Tabela 4. Poprečni dijametar (ABD) i obim abdomena (AC)
kod fetusa u normalnoj trudnoći*
NG
ABD (mm)
SD
AC (mm)
SD
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
18,7
21,8
24,2
28,2
31,4
36,8
41,3
45,2
47,8
51,2
54,1
55,6
58,1
61,4
65,1
68,9
71,2
74,8
78,2
83,1
84,8
90,4
93,2
95,1
97,4
98,1
99,5
102,9
105
1,2
1,41
2,12
1,71
2,4
2,5
2,7
29
3,12
3,4
3,9
4,4
5,2
5,5
38
2,15
4,2
3,8
3,91
4,4
4,5
4,76
4,91
5,1
5,9
6,2
6,7
7,08
7,9
61
64
80
88
97
115
128
140
148
155
162
169
178
194
205
216
223
235
245
260
273
282
292
298
304
310
315
323
329,5
2,4
2,8
3,9
4,2
3,91
5,2
4,8
6,1
7,3
8,2
8,9
9,1
9,2
9,9
10,1
11,3
11,9
13,1
13,9
14,2
14,8
14,7
13,8
12,9
14,5
15,1
13,2
15,8
16,0
* NG, nedjelje gestacije; ABD, abdominalni dijametar; AC, abdominal circumpherency; SD, standardna devijacija;
156
2,4 mm (12. nedjelja) do 16 mm (40. nedjelja).
Prosječne vrijednosti rasta femura u normalnoj
trudnoći po nedjeljama bile su ujednačene, za 2
mm u prosjeku (minimalno 1,9 mm u 13. nedjelji
i maksimalno 3 mm u 21. nedjelji) (SD je iznosila
od 0,74 do 2,96) (Tabela 5).
DISKUSIJA
Prema preporukama FIGO-a (12) prospektivno
je praćen fetalni rast na osnovu odabranih ultrazvučnih biometrijskih parametara, kod zdravih
trudnica s jednoplodnom normalnom trudnoćom,
s urednom reproduktivnom anamnezom, a koje
su se porodile spontano vaginalno, u periodu
između navršene 38. i 41. nedjelje, te da su sva
djeca bila živahna na porodu i bez anomalija.
Statistički su obrađeni podaci za stotinu trudnica
koje su ispunile navedene kriterije, mada je broj
uključenih u studiju bio znatno veći, ali su one
zbog krvarenja, hipertenzije, gestacijskog dijabetesa, prijevremenog ili porođaja carskim rezom,
isključene iz studije. To je glavni razlog zašto je
broj trudnica u ovoj studiji značajno manji nego u
drugim (6-10, 13-16) jer je, na ovaj način, izračunat vrlo važan i značajan idealan fetalni rast budući da su korišteni aparati koji imaju mogućnost
Tabela 5. Dužina femura (FL) kod fetusa u normalnoj trudnoći*
NG
FL (mm)
SD
12
8,05
0,74
13
10,9
1,06
14
12,7
1,55
15
17,1
1,51
16
19,5
1,6
17
23,8
1,83
18
26,2
2,19
19
29,6
2,26
20
31,8
2,1
21
34,5
2,3
22
37,5
2,9
23
40,2
1,48
24
41,7
2,05
25
44,1
2,59
26
48,3
2,29
27
51,1
2,65
28
53,5
2,18
29
55,7
1,87
30
57,3
2,61
31
59,1
2,96
32
61,8
2,7
33
63,3
2,72
34
65,3
2,89
35
66,8
2,8
36
68,8
2,75
37
71,1
2,11
38
72,5
2,27
39
73,6
1,7
40
74,5
2,08
* NG, nedjelje gestacije; FL, femur lenght; SD, standardna devijacija;
Tabela 6. Uporedne vrijednosti biparijetalnog dijametra, obima glave, obima abdomena i dužine femura u određenim periodima
trudnoće*
BPD
NG
13
20
30
34
37
38
39
40
HC
Balić
Hadlock
(16)
Latin
(10)
22,7
46,3
76,5
86,3
90,6
91,2
93,5
94,5
23
48
76
85
91
92
94
96
23,8
47
76,8
85,5
90,8
92,4
94
94,8
AC
Balić
Hadlock
(16)
Latin
(10)
77
166
272
300
319
323
328
333
80
175
277
309
330
337
344
350
83
175
283
317
339
346
352
358
FL
Balić
Hadlock
(16)
Latin
(10)
74
148
245
292
310
315
323
329,5
75
150
259
299
329
339
348
355
75,3
158,5
256
302
331
336
350
366
Balić
Hadlock
(16)
Latin
(10)
10,9
31,8
57,3
65,3
71,1
72,5
73,6
74,5
11
33
58
66
73
74
76
78
11,9
33,6
56
64,2
71,5
70,4
72,9
75,3
* NG, nedjelje gestacije; BPD, biparijetalni dijametar; HC, head circumpherency; AC, abdominal circumpherency; FL, femur lenght;
‘’cine loop“ (tzv. vraćanja izvjesnog broja sličica), što je omogućavalo lakše i brže pronalaženje
idealnih presjeka za mjerenje, te mogućnost mjerenja i desetog dijela milimetra.
u mjerenjima, budući da je na mjerenju radilo
samo pet iskusnih ultrasoničara, kao i kvaliteta
ultrazvučnih aparata koja je omogućila visoku
preciznost mjerenja.
Sve su trudnice ispunjavale kriterije FIGO-a, te
je uzorak bio reprezentativan za populaciju tuzlanske regije s očekivano normalnim prirastom
težine tokom trudnoće.
Standardi intrauterinog rasta važni su za određeno populaciono područje ne samo zbog validnog
uvida u fetalni rast, nego i radi blagovremene dijagnostike različitih poremećaja koji u trudnoći
mogu nastupiti. S obzirom da je još Gruenwald
(4) ukazao na urođeni potencijal za fetalni rast, u
mnogim su sredinama izrađeni odgovarajući standardi kako bi se izbjegle ili bar svele na najmanju
moguću mjeru, greške u procjeni gestacijske dobi
zbog razlika po etničkoj i rasnoj osnovi.
Poredeći prosječnu težinu djece s rezultatima
drugih, uočava se da je novorođenčad naših ispitanica teža (u 38. do 41. nedjelji iznosila je 3280
g do 3732 g), što su pokazali i rezultati iz Tuzle
za 2002. godinu, kada je prosječna težina svih živorođenih iznosila 3520 g, odnosno bila je veća
nego u drugim gradovima i regijama (11). Tako
je prosječna tjelesna težina na rođenju u 39. nedjelji, u Zagrebu 3231 g (17), u Beogradu 3378
g (9), Novom Sadu 3344 g (8) i Nikšiću 3400 g
(18). Ovdje takođe treba istaći da su drugi autori
obrađivali i podatke fetalnog rasta kod trudnica
koje se nisu spontano porodile ili koje su imale
neke poremećaje u trudnoći kao što su krvarenje,
hipertenzija i gestacijski dijabetes, čime se još
može objasniti nešto veća porođajna težina.
U poređenju sa standardima po Hadlocku (16) i
Latinu (10) (Tabela 6) uočava se da su vrijednosti svih naših ispitivanih parametara intrauterinog
rasta nešto manje, što je u suprotnosti od očekivanih prema podacima o porođajnoj težini. Kada
su u pitanju BPD i dužina femura, razlike su minimalne, dok su razlike kod obima abdomena i
obima glave očite. Ove razlike mogu se objasniti
činjenicom da su korištene različite formule za
računanje obima elipse, te izvjesnim odstupanjima kod mjerenja drugog prečnika, kao i već
pomenutim, mada minimalnim, razlikama u mjerenju samog BPD-a i ABD-a. Osim toga, jedan
od mogućih razloga jesu i minimalne varijacije
S obzirom da je do sada procjena intrauterinog
rasta u tuzlanskoj regiji, ali i šire, vršena na osnovu različitih standarda koji su nam se empirijski
činili najprihvatljivijim, dešavalo se da ona bude
pogrešna, pa tako i svi postupci koji su proistekli
iz takve procjene. Isključivši ostale moguće uzroke devijacije fetalnog rasta, ostala je i mogućnost
da standardi po Hadlocku i sar. iz 1983. godine
(16), koji su instalirani u ultrazvučnim aparatima, a po kojima većina ultrasoničara radi, nisu
odgovarajući za našu populaciju. Mogućnost
greške u procjeni fetalnog rasta najizraženija je
u grupi trudnica s nepouzdanim terminom, čija
se učestalost kreće između 10% i 20% (3, 20).
Tako, naprimjer, Dražančić predlaže da porodilišta s preko 1000 poroda odrede posebno kvalificiranog liječnika za konačnu prosudbu dobi
trudnoće (3).
Imajući u vidu sve ove činjenice, više puta je pokušano da se naprave standardi fetalnog rasta za
bosanskohercegovačku populaciju, ali bez uspjeha, jer je devedesetih godina, kada su se stekli
realni uslovi za realizaciju ovoga projekta, izbio
rat koji je doveo do prave perinatalne katastro-
157
fe: smrtnost majki iznosila je 80/100.000 (19), a
perinatalni mortalitet preko 25‰ (20). Međutim,
i poslije rata, niz faktora (obnova zemlje, nezaposlenost, siromaštvo, promjena demografske
strukture) imali su negativan uticaj na perinatalna
zbivanja, te se moralo sačekati da se perinatalni
mortalitet vrati na prijeratne vrijednosti, što se
desilo tek u zadnjih nekoliko godina (11, 21).
unatoč svemu bila opravdana, te da će njihova
primjena smanjiti broj pogrešnih procjena fetalnog rasta, posebno kod trudnica s nepouzdanim
terminom, što bi trebalo uticati na daljnje smanjenje perinatalnog mortaliteta u Bosni i Hercegovini.
Prezentirani standardi intrauterinog rasta za tuzlansku regiju pokazuju veliku sličnost sa standardima Hadlocka i saradnika, kao i aktuelnim
standardima koji se koriste u Hrvatskoj kada su u
pitanju BPD i FL, s tim što su standardi dobiveni u ovom istraživanju, ipak, u svim nedjeljama
nešto niži. Razlike u obimu glave i abdomena su
značajnije, što znači da je izrada ovih standarda
Autori zahvaljuju specijalistima ginekologije i
akušerstva Doma zdravlja u Tuzli prim. dr. Jasmini Dragović, prim. dr. Ameli Adžajlić i prim.
dr. Amri Habibović, na pomoći kod praćenja intrauterinog rasta na osnovu ultrazvučnih parametara kod ispitivane grupe trudnica.
ZAHVALE/IZJAVE
postoji.
LITERATURA
1.
Balić A. Ultrazvuk u trudnoći. U: Balić A i sar., ur.
Perinatologija. Tuzla: PrintCom 2007: 43-66.
2. Siemer J, Wolf T, Hart N, Schrauder M, Meurer B,
Goecke T, Beckmann MW, Schild RL. Increased
accuracy of fetl weight estimation with a gender
– specific weight formula. Fetal Diagn Ther 2008;
24:321-6.
3. Dražančić A. Krivulje fetalnog rasta, usporeni fetalni
rast, dismaturnost. Ginekol Perinatol 2009; 18:1-18.
4. Gruenwald P. Growth of the human fetus I. Normal
growth and its variation. AM J Obstet Gynaecol
1966; 94:1112-9.
5. Gruenwald P. Growth of the human fetus II. Abnormal growth in twins and in infants of mothers with
diabetes, hypertension or isoimunisation. AM J Obstet Gynaecol 1966; 94:1120-32.
6. Lubchenco LO, Hamsamn Ch, Dressler M, Boyd E.
Intrauterine growth as estimated from live-born birth weight at 24 to 42 weeks of gestation. Pediatrics
1963; 32:793-800.
7. Sterky G. Swedish standard curves for intrauterine
growth. Pediatrics 1970; 46: 7-9.
8. Nikolić Lj. Intrauterini rast živorođene djece. Jugoslav ginekol opstet 1973; 16:131-7.
9. Radojković Z, Ivanović Lj, Avramović K. Standardi
intrauterinog rasta živorođene djece. Jugoslav Ginekol Opstet 1974; 15:99-106.
10. Latin V, Klobučar A, Kos M. Fetalna biometrija
i procjena gestacijske dobi. U: Kurjak A i sar., ur.
Ultrazvuk u ginekologiji i porodništvu. Zegreb: Art
Studio Azinović 2000: 250-64.
11. Skokić F, Radoja G, Fatušić Z, Muratović S, Šabić
N, Babović A. Postnatal estimation of intrauterine
growth in three different socioeconomic period. Acta
Med Sal 2003; 32:93-6.
158
12. Report of the FIGo subcomitee on Perinatal Epidemiology and Health statistics following a Workshop
in Cairo 1984 on the Metodology of Measurement
and Recording of Infant Growth in the Perinatal Period. Int J Gynaecol Obstet 1986; 26: 483.
13. Campbell S. An important metohod of fetal cephalometry by ultrasound. J Obstet Gynaecol Br Cwth
1968; 12: 23-30.
14. Jeanty P, Romero R. Obstetrical ultrasound. New
York: McGrow Hill, 1984:55-56.
15. O’Brien GD, Queenan JT, Campbell S. Assement of
gestational age in the second trimester by real time
ultrasound of the femur lenght. Am J Obstet Gynaecol 1981; 138:875-80.
16. Hadlock FP, Harrist RB, Deter RL. A prospective
evaluation of fetal femoral lenght and biparietal diameter in predicting gestational age. J Ultrasound
Med 1983; 2:111-7.
17. Dražančić A. Rast fetusa u Zagrebu. Jugoslav Ginekol Perinatol; 1988; 28: 13-20.
18. Kaluđerović M. Krivulja percentilne težine i duljine donesene djece općine Nikšić. Magistarski rad.
Zagreb 1982.
19. Balić A, Balić D, Balić B. Protocol for determining
the gestational age an due date of patients with uncertain term. Prenat Neonat Med 2000; 2:72.
20. Balić B. Impact of the war on maternal mortality. In:
Voto SL. Margulies M, Cosmi EV ed. IV World Congress of Perinatal Medicine, Buenos Aires, Argentina, April 18-22, 1999. Bologna: Monduzzi Editore
1999; 907-910.
21. Balić A, Balić D. Perinatalna zbivanja u Tuzlanskoj
regiji kroz naučni rad i djelo prof. dr. sci. Branislave
Balić. Tuzla: PrintCom 2006; 1-110.
Intrauterine growth standards for Tuzla region
Adem Balić1, Devleta Balić2
Department of Obstetric and Gynaecology, Health Centre Tuzla, Gynaecological Office “Dr Balić” Tuzla
ABSTRACT
Aim To evaluate normal fetal growth and create a normogram for the population of the Tuzla Canton.
Methods In the period 2002-2005 we evaluated fetal growth by ultrasound measurements (biparietal diameter -BPD, head circumpherency -HC, abdominal diameter -ABD, abdominal circumpherency
-AC, femur length - FL) according to the criteria of FIGO (1986) in 100 healthy pregnant women with
normal singleton pregnancy. All of them had spontaneous vaginal delivery between the 38th and 41st
week. These measurements were done once per month starting from 12 to 41 weeks.
Results Mean birth weight value in 38th week was 3280 ± 345g, in 39th week 3360 ± 280g, in 40th week
3596 ± 320g and in 41st week 3732 ± 38 g. These standards have shown lower values of all examined
parameters in all the gestation weeks. Values of BPD and FL were very similar but differences between
our values of HC and AC in the last four weeks were very high.
Conclusion We found significant differences between our standards and others (Hadlock, 1983 i Latin,
2000) especially in the last four weeks of gestation. Now, when we have standards of fetal growth for
our population we expect better evaluation of gestational age and lower perinatal mortality in Bosnia
and Herzegovina.
Key words fetal growth, standards, BPD, FL
Original submission: 18 November 2009; Revised submission: 15 January 2010; Accepted: 19 January 2010.
159
ORIGINAL ARTICLE
Stereološka analiza sinciciotrofoblasta resorpcijske resice posteljice trudnica mlađe i starije životne dobi
Sergije Marković1, Zlata Žigić1, Suada Ramić1, Jasminka Hadžihalilović2
1
Zavod za histologiju i embriologiju, Medicinski fakultet, Univerzitet u Tuzli; 2Prirodno-matematički fakultet, Univerzitet u Tuzli; Tuzla,
Bosna i Hercegovina
SAŽETAK
Cilj Odrediti kvantitativne parametre volumenske gustoće i apsolutnog volumena sinciciotrofoblasta resorpcijske resice kontrolne
i eksperimentalne skupine, te dobijene rezultate uporediti i ustanoviti postoje li statistički značajne razlike analiziranih strukturnih parametara resorpcijskih resica u zavisnosti od životne dobi
trudnice.
Sergije Marković,
Univerzitet u Tuzli, Medicinski fakultet,
Univerzitetska 1, 75000 Tuzla,
Bosna i Hercegovina
Phone: +387 35 320 640;
fax: +387 35 320 601
Originalna prijava:
22. januar 2009.;
Korigirana verzija:
08. mart 2010..;
Prihvaćeno:
01. april 2010.
Metode Istraživanje je izvršeno na 60 humanih posteljica terminske trudnoće, podijeljenih u dvije skupine: 30 posteljica trudnica
od 20. - 34. godine životne dobi (kontrolna skupina) i 30 posteljica
trudnica od 35. godine životne dobi i više (eksperimentalna skupina). Stereološka analiza izvršena je mnogonamjenskim testnim
sistemom M-42, uz povećanje objektiva 40x.
Rezultati Prosječna volumenska gustoća sinciciotrofoblasta resorpcijskih resica eksperimentalne skupine iznosila je Vvss =
(0,489 ± 0,032) mm0, a kontrolne grupe Vvsm = (0,389 ± 0,078)
mm0. Statistička analiza rezultata Studentovim t-testom pokazala
je kako je volumenska gustoća sinciciotrofoblasta resorpcijskih
resica eksperimentalne skupine bila značajno veća u odnosu na
kontrolnu skupinu (p<0,001). Apsolutni volumen sinciciotrofoblasta resorpcijskih resica eksperimentalne skupine iznosio je Vss =
(205,250 ± 40,894) cm3, a kontrolne skupine Vsm = (178,386 ±
44,413) cm3. Utvrđeno je da je apsolutni volumen sinciciotrofoblasta resorpcijskih resica eksperimentalne skupine značajno veći
u odnosu na kontrolnu skupinu (p<0,005).
Zaključak Statistički značajno veće vrijednosti volumenske gustoće i apsolutnog volumena sinciciotrofoblasta resorpcijskih resica posteljica trudnica starije životne dobi, predstavljaju kompenzatorni mehanizam kao odgovor na smanjenu metaboličku izmjenu
tvari između majke i ploda.
Ključne riječi: posteljica, resorpcijska resica, sinciciotrofoblast,
trudnice mlađe i starije životne dobi, stereološka analiza.
160
Marković et al Stereološka analiza sinciciotrofoblasta
UVOD
Optimalna životna dob žene za trudnoću i rađanje
je između 20. i 29. godine života, a trudnoće žena
starijih od 35. godine smatraju se rizičnim (1, 2).
Promjene unutar placentne membrane kroz koju
se vrši razmjena materija između krvi majke i krvi
ploda, u zavisnosti od intenziteta i dužine trajanja
promjene, mogu dovesti do intrauterine patnje i
poremećenog razvoja ploda (3). Ove promjene
mogu imati za posljedicu rađanje hipotrofične i
nedonešene djece, pojavu respiratornog distresa,
akutnu ili hroničnu hipoksiju, povišen perinatalni
morbiditet i mortalitet (4, 5).
Do sada provedena kvantitativna istraživanja
trofoblasta posteljice terminske trudnoće i poroda odnosila su se na cjelokupni trofoblast
resorpcijskih resica (6-9). Analize strukturnih
komponenti (sinusoidni kapilari, stroma, sinciciotrofoblast) resorpcijskih resica posteljice,
pokazale su kako su one mjesto najvećih morfoloških promjena u posteljici za vrijeme desetog
lunarnog mjeseca (8). Kako rizik za djecu raste
kod trudnica starije životne dobi, poznavanje
veličine površina dostupnih za transport tvari
važno je za ocjenjivanje količine hranidbenih
tvari koje mogu biti prenesene fetusu za njegov
normalan rast i razvoj.
Zbog velikog značenja koje se u cijelom svijetu pridaje utjecaju starije životne dobi na tok i
ishod trudnoće, a zbog nedostatka ispitivanja
kompenzatorne uloge strukturnih dijelova trofoblasta, sprovedeno je istraživanje u cilju kvantitativnog određivanja vrijednosti fetomaternalne
izmjene tvari, volumenske gustoće i apsolutnog
volumena sinciciotrofoblasta resorpcijske resice, posteljice trudnica mlađe i trudnica starije
žđivotne dobi.
MATERIJAL I METODE
Istraživanje je izvršeno na 60 humanih posteljica
terminske trudnoće na Ginekološko-akušerskoj
klinici UKC-a Tuzla, u periodu od decembra
2005. do decembra 2006. godine. Ispitanice su
bile podijeljene u dvije skupine: trudnice od 20.
- 34. godine životne dobi (kontrolna skupina) i
trudnice od 35. godine životne dobi i više (eksperimentalna skupina). U svakoj skupini istraživalo se po 30 posteljica. Dob trudnoće određivana
je prema prvom danu zadnje menstruacije kod
trudnica s redovnim menstruacionim ciklusom,
a potvrđena je UZ pregledom u prvom trimestru
trudnoće.
Sa svake istraživane posteljice najprije su odstranjeni ovoji i pupkovina. Masa posteljice određivana je vaganjem (u gramima), a njen je volumen
određivan indirektno, mjerenjem istisnute tekućine (mm3). Za histološku obradu uzimani su uzorci
tkiva debljinom čitavog organa, od horionske do
bazalne ploče (parenhimski dio). Tkivo je fiksirano u 10% vodenoj otopini neutralnog formalina,
uklopljeno u parafin i rezano na rezove debljine 8
µm. Deparafinizirani rezovi su obojeni hemalaunom i eozinom.
Za stereološku analizu referentni prostor bila je
resorpcijska resica posteljice, a stereološka analiza izvršena je na histološkim preparatima. Veličina uzorka, odnosno potreban broj stereoloških
mjerenja za svaku istraživanu varijablu, u obje
skupine trudnica, određen je postupkom po de
Hoffu (Slika 1) (10). Dobijeni broj ''n'' predstavlja broj testnih polja koje je trebalo stereološki
analizirati pri 95% intervalu povjerenja, kako rezultat ne bi odstupao od stvarne vrijednosti prosjeka populacije za više od 10%.
Slika 1. Formula 1. Postupak po de Hoffu (10)
Stereološka analiza izvršena je mnogonamjenskim testnim sistemom M-42, uz povećanje
objektiva 40x, te je obuhvatila relativne i apsolutne varijable. Od relativnih stereoloških varijabli određena je volumenska gustoća sinciciotrofoblasta (Vvs). Volumenska gustoća je relativna
stereološka varijabla koja predstavlja udio ispitivane strukture u jedinici volumena (Slika 2):
Slika 2. Formula za izračunavanje volumenske gustoće (10)
161
Od apsolutnih varijabli određen je apsolutni volumen (V), kojim je označen ukupni volumen
istraživanih strukturnih komponenti unutar volumena čitavog organa (mm3) (Slika 3):
Vf =Vvf ·Vo
Slika 3. Formula za izračunavanje apsolutnog volumena (10)
Dobijeni rezultati obrađeni su slijedećim statističkim metodama: izračunate su aritmetička sredina
(x), standardna devijacija (s) i standardna greška
(SE). Značaj razlike rezultata između posteljica u
odnosu na starost trudnice, određena je Studentovim t-testom. Koeficijent varijabilnosti (KV)
izračunat je za relativne i apsolutne vrijednosti
istraživanih varijabli u navedenim posteljicama.
162
Grafikon 2. Prosječna vrijednost i standardna devijacija volumenske gustoće sinciciotrofoblasta (Vvs) resorpcijskih resica
istraživanih posteljica trudnica mlađe i starije životne dobi (mm0)
REZULTATI
prikazana je na Grafikonu 2. Volumenska gustoća
sinciciotrofoblasta resorpcijskih resica posteljica
trudnica starije životne dobi imala je značajno
veću vrijednost u odnosu na trudnice mlađe životne dobi (p<0,001).
Relativne stereološke varijable
Apsolutne stereološke varijable
Volumenska gustoća sinciciotrofoblasta (Vvs)
resorpcijskih resica posteljica trudnica mlađe životne dobi (Vvsm), za istraživane posteljice, kretala se u rasponu 0,25 - 0,58 mm0, a kod trudnica
starije životne dobi (Vvss) u rasponu 0,43 - 0,56
mm3. Učestalost volumenske gustoće sinciciotrofoblasta (Vvs) resorpcijskih resica istraživanih
posteljica trudnica mlađe i starije životne dobi
prikazana je na Grafikonu 1. Prosječna volumenska gustoća sinciciotrofoblasta resorpcijskih resica posteljica trudnica mlađe životne dobi iznosila
je Vvsm = (0,389 ± 0,078 mm0), dok je kod trudnica starije životne dobi iznosila Vvss = (0,489
± 0,032 mm0). Prosječna vrijednost i standardna
devijacija volumenske gustoće sinciciotrofoblasta (Vvs) resorpcijskih resica istraživanih posteljica trudnica mlađe i starije životne dobi (mm0)
Apsolutni volumen sinciciotrofoblasta (Vs) resorpcijskih resica posteljica trudnica mlađe životne
dobi (Vsm), za istraživane posteljice, kretao se u
rasponu od 112,98 - 296,20 cm3, a kod trudnica
starije životne dobi (Vss) u rasponu od 139,93
- 332,73 cm3. Frekvencija rezultata apsolutnog
volumena sinciciotrofoblasta (Vs) resorpcijskih
resica posteljica trudnica mlađe i starije životne
dobi prikazana je na Grafikonu 3.
Grafikon 1. Frekvencija rezultata volumenske gustoće sinciciotrofoblasta (Vvs) resorpcijskih resica istraživanih posteljica trudnica
mlađe i starije životne dobi
Grafikon 3. Frekvencija rezultata apsolutnog volumena sinciciotrofoblasta (Vs) resorpcijskih resica posteljica trudnica mlađe
i starije životne dobi
Prosječna vrijednost apsolutnog volumena sinciciotrofoblasta resorpcijskih resica posteljica
trudnica mlađe životne dobi iznosila je Vsm =
(178,386 ± 44,413 cm3), a kod trudnica starije životne dobi Vss = (205,250 ± 40,894 cm3).
Prosječna vrijednost i standardna devijacija apsolutnog volumena sinciciotrofoblasta (Vs) resorpcijskih resica posteljica trudnica mlađe i starije
ljica trudnica koje pripadaju grupi EPH gestoza
(edemi-proteinuria-hipertenzija). To ukazuje na
jače odbacivanje istrošenih dijelova trofoblasta
koje prevladava nad proliferacijom i diferencijacijom. Drugi su autori (15) ustanovili kako je
prosječna vrijednost površinske gustoće resorpcijskih resica iznosila 22,190 mm-1 kod mlađih,
a 22,098 mm-1 kod starijih (razlika između obje
grupe nije bila statistički značajna).
Grafikon 4. Prosječna vrijednost i standardna devijacija apsolutnog volumena sinciciotrofoblasta (Vs) resorpcijskih resica
posteljica trudnica mlađe i starije životne dobi (cm3)
životne dobi (cm3) prikazana je na Grafikonu 4.
Apsolutni volumen sinciciotrofoblasta resorpcijskih resica posteljica trudnica starije životne dobi
bio je značajno veći u odnosu na trudnice mlađe
životne dobi (p<0,005).
DISKUSIJA
Rezultati našeg istraživanja pokazali su kako je
prosječna vrijednost volumenske gustoće sinciciotrofoblasta iznosila 38,85% resorpcijske resice
kod posteljica trudnica mlađe životne dobi, a kod
trudnica starije životne dobi 48,85%. Posteljice
trudnica starije životne dobi imale su 25,74%
veći udio trofoblasta resorpcijske resice nego posteljice trudnica mlađe životne dobi, uz statistički
značajnu razliku, što upućuje na zaključak da je
došlo do aktivacije kompenzacijskih mehanizama
i rezervnih kapaciteta posteljice kako bi se održala zadovoljavajuća fetomaternalna izmjena tvari
potrebna za normalan rast i razvoj ploda (11).
Do sada provedena kvantitativna istraživanja
sinciciotrofoblasta posteljice normalne trudnoće
i poroda odnosila su se na cjelokupni trofoblast
resorpcijskih resica, te je ustanovljeno da iznosi
35% volumena posteljice (6) i 28,7% terminalne
resice (8). Pojedini autori izvještavaju o smanjenju sinciciotrofoblastne membrane kod intrauterinog zaostajanja u rastu i razvoju ploda i hipoksije ploda, a što se pripisuje kompenzatornom
mehanizmu (12, 13).
Imunocitohemijskim metodama (14) dokazano je
da je apoptoza trofoblasta u porastu kod poste-
Pored relativnih vrijednosti, manji broj istraživača
opisuje apsolutnu vrijednost volumena trofoblasta (16), ali ne i sinciciotrofoblasta resorpcijske
resice posteljica. U našem istraživanju prosječni
apsolutni volumen sinciciotrofoblasta resorpcijskih resica posteljica trudnica starije životne dobi
iznosio je 205,250 cm3, a kod onih mlađe životne dobi 178,386 cm3 (p<0,005). Naši su rezultati
potvrdili da se i u posteljicama starijih trudnica
pokreću kompenzacijski mehanizmi koji osiguravaju dostatnu fetomaternalnu izmjenu tvari,
pa i posteljice trudnica starije životne dobi funkcijski udovoljavaju potrebama normalnog rasta
i razvoja fetusa (11), kao i da nema značajnog
gubitka trofoblasta, te da se ne očekuju promjene
na nivou fetomaternalne izmjene tvari (17). Rezultati ovog istraživanja navode i na zaključak da
bit patološkog mehanizma posteljice nije u ukupnom volumenu resice, nego u strukturalnom i
funkcionalnom kvalitetu same resice, što utiče na
fetomaternalnu i metaboličku izmjenu tvari (15).
Dobijeni rezultati dodatno objašnjavaju fiziologiju posteljice trudnica starije životne dobi i njenu
sposobnost da pokrene kompenzatorne mehanizme čiji je glavni cilj dostatna fetomaternalna
izmjena tvari. Dobijene vrijednosti jedan su od
parametara za prosuđivanje funkcionalnih kapaciteta posteljice u pogledu izmjene tvari između
majke i ploda.
Određivanjem kvantitativnih parametara o građi
posteljica trudnica različite životne dobi, postavljeni su kriteriji za ocjenjivanje njenih funkcionalnih kapaciteta, kao i patoloških strukturnih
promjena (4, 18).
ZAHVALE/IZJAVE
postoji.
163
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15. Ramić S, Žigić Z, Alečković M. Stereological analysis of mature human placenta of pregnant women
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Neonatal Med 2003; 13: 45-9.
Stereological analysis of syncytiotrophoblast in resorption villi of
placentas of young and older pregnant women
Sergije Marković1, Zlata Žigić1, Suada Ramić1, Jasminka Hadžihalilović2
Department of Histology and Embryology, School of Medicine, 2 School of Natural Sciences; University of Tuzla, Tuzla, Bosnia and
Herzegovina
1
ABSTRACT
Aim To determine quantitative parameters of volume density and absolute volume of syncytiotrophoblast in resorption villi of control and experimental group, compare the results and search for correlation
between structural parameters of resorption villi and pregnancy age.
Metods The research was performed on 60 human placentas of term pregnancy: 30 placentas of pregnant women of age 20 - 34 (control group), and 30 placentas of pregnant women of age 35 and older
(experimental group). Stereological analysis was performed on multipurpose testing system M42 with
40 times objective magnification.
Results Average volume density of syncytiotrophoblast in resorption villi of experimental and control
group was Vvss = (0,489 ± 0,032) mm0 and Vvsm = (0,389 ± 0,078) mm0 , respectively. Statistical analysis of results using Student t-test indicated a significantly higher volume density of syncytiotrophoblast
of resorption villi in the experimental than in the control group (p<0,001). Absolute volume of syncytiotrophoblast in resorption villi of the experimental and control groups was Vss = (205,250±40,894) cm3
and Vsm = (178,386 ± 44,413) cm3, respectively. We have found a significantly higher absolute volume
of syncytiotrophoblast in resorption villi in the experimental than in the control group (p<0,005).
Conclusion Statistically significant higher values of volume density and absolute volume of syncytiotrophoblast in resorption villi of placentas in older pregnant women represent a compensatory mechanism as a response to decreased metabolic exchange between a mother and a fetus.
Key words: placenta, resorption villi, syncytiotrophoblast, young and older pregnant women, stereological analysis.
Original submission: 22 January 2009; Revised submission: 08 March 2010; Accepted: 01. April 2010
165
NOTES
Operativni tretman endometrioze u
Kliničkom centru Kragujevac u periodu
2004.-2008. godine
Momčilo \orđević1, Božidar Jovanović1, Gordana
\orđević2
Ginekološko-akušerska klinika, Klinički centar Kragujevac, 2
Medicinski fakultet u Kragujevcu; Kragujevac, Srbija
1
Corresponding author: Momčilo \orđević, Ginekološkoakušerska klinika, Klinički centar Kragujevac, Zmaj Jovina 25/8,
34000 Kragujevac, Srbija, Tel: ++ 381 34 345-230; E mail:
[email protected]
Originalna prijava: 17. mart 2009.; Korigirana verzija: 11. maj
2009.; Prihvaćeno: 28. august 2009.
SAŽETAK
U ovom retrospektivnom istraživanju analizirani
su parametri vezani za nastanak i lečenje pelvične endometrioze (operativni zahvat, godine starosti, operativni pristup i konzervativnost operacije, rasprostranjenost endometrioze na okolne
organe male karlice) na Ginekološko-akušerskoj
klinici Kliničkog centra Kragujevac, tokom petogodišnjeg perioda. Od ukupno 88 pacijentkinja
koje su imale cistu na jajniku i povišenu vrednost
tumorskog markera Ca 125, te patohistološku verifikaciju endometrioze, najviše ih je bilo starosne dobi od 26 do 35 godina (56,8%). Najčešće je
primenjivan radikalni hirurški zahvat, adneksektomija kod 53 (60,2%) i hosterektomija kod 24
(45,83%) pacijentkinje (p<0,01), a s gotovo podjednakom verovatnoćom primenjivane su laparotomija i laparoskopija (p>0,01). Endometrioza
jajnika često je bila udružena i s endometriozom
na drugim organima male karlice.
Ključne riječi: pelvična endometrioza, endometrioza, laparoskopija
UVOD
Endometrioza je treći uzrok hospitalizacije u
SAD-u među ginekološkim obolenjima (1, 2).
Uprkos visokom morbiditetu i troškovima koja
ova bolest iziskuje, malo se zna o njenoj etiologiji i patogenezi za koju postoji mnogo teorija (2).
Šira definicija endometrioze podrazumeva prisustvo endometrijalnog tkiva van šupljine materice,
što je udruženo sa simptomima dismenoreje, dispareunije, hroničnog pelvičnog bola i subfertil-
166
nosti (3). Prava dijagnoza postavlja se patohistološkom analizom (3). Bolest se klasifikuje strogo
koristeći tradicionalni revidirani sistem Američke asocijacije za fertilitet (The American Fertility
Association) na četiri stadijuma, od minimalne
do ozbiljne, bazirajući se na veličini implantata,
prisustvu cista i adhezija (3).
Dijagnoza endometrioze može se postaviti samo
vizuelizacijom i histološkom verifikacijom, što je
jedino moguće laparoskopijom ili laparotomijom
(3). Jedini neinvazivni test koji može sugerisati
endometriozu jeste tumorski marker CA-125 (4).
Zato prevalenca u opštoj populaciji nije poznata.
Endometrioza se javlja u najvećem procentu u
fertilnom periodu (1-3).
Glavna etiološka hipoteza za nastanak endometrioze je retrogradno menstruiranje (3). Međutim,
retrogradna se menstruacija viđa kod čak 90%
žena, što pretpostavlja i ulogu drugih faktora u
nastanku endometrioze (1, 5-7).
Cilj ovoga istraživanja bio je ispitati parametre
vezane za nastanak i lečenje pelvične endometrioze (operativni zahvat, godine starosti, operativni pristup i konzervativnost operacije, rasprostranjenost endometrioze na okolne organe male
karlice) na Ginekološko-akušerskoj klinici Kliničkog centra Kragujevac. U našem okruženju
nisu rađena slična istraživanja, te je svrha ovog
istraživanja evaluacija dosadašnjeg stava o operativnom pristupu i radikalnosti.
ISPITANICI I METODE
Tokom 2009. godine provedena je retrospektivna
studija na Ginekološko-akušerskoj klinici Kliničkog centra Kragujevac u Kragujevcu. U istraživanje su bile uključene pacijentkinje u kojih je
verificirana cista na jajniku, veća od 5 cm, koja
je perzistirala najmanje 3 meseca, povišene vrednosti tumorskog markera Ca-125 (> 35 IU/L), te
patohistološka verifikacija endometrioze. Kod
pacijentkinja koje nisu ispunjavale ove kriterije
bila je rezervisana samo medikamentozna terapija s gonadotropin-releasing hormonom (GNRH),
i to u trajanju od 4 meseca kod pacijentkinja koje
su rađale, te u trajanju od 6 meseci kod onih koje
nisu rađale.
Kod ispitanica su određivani sledeći parametri:
godine starosti, operativni pristup i konzervativnost operacije, te rasprostranjenost endometrioze
na okolne organe male karlice.
Notes
Zaključivanje o validnosti razlika između pojedinih parametara i njihovih verovatnoća utvrđena
je primenom χ2 testa. Za nivo pouzdanosti uzeto
je do 5% (p < 0,05).
REZULTATI
U periodu 2004.-2008. godine, na Ginekološkoakušerskoj klinici Kliničkog centra Kragujevac,
zabeleženo je 88 pacijentkinja kod koji je dijagnostikovana pelvična endometrioza. Najveći
broj pacijentkinja zabeležen je 2007. godine (20),
a najmanji 2004. godine (16).
Najviše su obolevale žene u dobi od 26 do 35
godina (56,8%), zatim žene od 36 do 45 godina
(30,7%), mlađih od 25 godina bilo je 7 (8,0%), a
starijih od 45 godina 4 (4,5%).
Prisustvo endometrioze je statistički značajno češće ustanovljeno samo na jajniku (kod 65 (73,9%)
žena), dok je kod 23 (26,1%) žene endometrioza
ustanovljena i na jajniku i na okolnim organima
male karlice (p < 0,01). Najčešće su bili zahvaćeni peritoneum (kod 15 (65,2%) slučajeva), zatim
na materici (kod 5 (21,7%) slučajeva), te na crijevima i bešiki kod dva, odnosno jednom slučaju.
Značajno češće primenjivana je radikalna operacija (kod 53 (60,2%) pacijentkinje), i to adneksektomija kod 29 (54,17%), te histerektomija
kod 24 (45,83%) pacijentkinje, dok je resekcija
jajnika primenjena kod 35 (39,8%) pacijentkinja
(p < 0,01).
Laparoskopija je rađena kod pacijentkinja koje
nisu rađale i kod kojih je bilo potrebno da se izvrši konzervacija jajnika, što nije uspelo u samo
jednom slučaju kada je urađena adneksektomija. Recidiv je zabeležen kod 3, a trudnoća kod
9 pacijentkinja. Niti kod jedne pacijentkinje nije
zabeležena teža komplikacija vezana za operativni zahvat ili anesteziju, osim kod jedne pacijentkinje gde je izvršena konverzija laparoskopije
u laparotomiju zbog opsežnosti endometrijalnih
promena. Značajno češće primenjivana je laparotomija, kod 52 (59,1%), dok je laparoskopija
primenjena kod 36 (40,9%) slučajeva (p > 0,01).
DISKUSIJA
U našoj studiji za razmatranje su uzete samo ozbiljnije forme endometrioze koje podrazumevaju
prisustvo endometrijalnih cista na jajniku i endometriozu na okolnim organima male karlice, s
povišenim vrednostima tumorskog markera Ca125. Treba naglasiti da vrednosti Ca 125 mogu
biti povišene i u perimenstruacijskom razdoblju,
kod upale i u neoangiogenezi (4).
Endometrioza se u najvećem procentu javlja
u fertilnom periodu. Najviše obolelih, u našem
istraživanju, bilo je u dobi 26-35 godina (56,8%),
što je u skladu s rezultatima drugih (1, 8), a prosečna starost kod naših pacijentkinja (32,3 godine) bila je nešto viša u odnosu na rezultate drugih
istraživanja (29,4 godine) (8, 9). Razlog tome je
verovatno činjenica da su u našem ispitivanju
učestvovale pacijentkinje s dijagnostikovanom
cistom na jajniku, većom od 5 cm.
Endometrioza nije retka bolest ni kod adolesceneta. Aproksimativno polovina žena ispod 20
godina, koje imaju hronični pelvični bol ili dispareuniju, imaju ovu bolest (7). Oko 5% endometrioznih slučajeva viđaju se kod žena u postmenopauzi, budući da egzogeno davanje estrogena
ima ulogu u nastanku endometrioze (9), te su i u
ovome istraživanju zabeleženi slični rezultati kod
žena starijih od 45 godina.
Najčešći operativni zahvat koji je primenjivan
u zbrinjavanju pelvične endometrioze u našem
istraživanju bio je radikalni (60,2%), što je za
posledicu imalo adneksektomiju kod 32,9% i histerektomiju kod 27,3% pacijentkinje, a značajno manje konzervacija jajnika, kod 39,8% pacijentkinja. Histerektomija kod belkinja u SAD-u
primenjuje se kod 11%, što je značajno manje u
odnosu na naše istraživanje (2, 10).
Resekcija jajnika, kao konzervativni operativni
tretman, povoljnija je za pacijentkinju jer kasnije, u kombinaciji s GNRH, manje remeti daljnju
fertilnu sposobnost i rezervisana je pretežno za
mlađe pacijentkinje (11). I u našem istraživanju
najbrojnije su bile mlađe pacijentkinje, te je posle kombinovane terapije (hirurške i medikamentozne) zabeleženo 9 trudnoća. Rezultati našeg
istraživanja pokazali su visoku prevalencu adneksektomija (samostalno ili u kombinaciji s histerektomijom), što se delimično može opravdati
činjenicom da kod velikih endometriotičnih cista
nije moguće uraditi konzervaciju ovarijuma, zatim u raširenosti endometrioze na druge organe,
završenoj reproduktivnoj funkciji žene, starosti.
Radikalnost operativnih zahvata kod pacijentkinja gde su postojali uslovi za resekciju ovarijuma
nema neko veliko uporište (8).
167
Kod naših pacijentkinja, s gotovo podjednakom
verovatnoćom, primenjivane su laparotomija
(59,1%) i laparoskopija (40,9%). Iako su poznate
prednosti laparoskopije, ipak nešto veća primena
laparotomije, premda bez statističke značajnosti,
posledica je verovatno više faktora. Pored neopravdanih razloga (primena kod pacijentkinja
koje su rađale, nedovoljno poznavanje tehnike
laparoskopije), razlog za ovako visoku prevalencu primene laparotomije kod naših pacijentkinja
jeste i nemogućnost postavljanja adekvatne preoperativne dijagnoze (sumnja na benignu bolest).
Stoga je kod naših pacijentkinja laparotomija
i primenjivana kod onih starije dobi, kao i kod
onih kod kojih je završena reproduktivna funkcija. Laparoskopija je samo novi način pristupa
operativnom polju, a nije posebna vrsta operativnog zahvata, te bi indikacije za laparoskopiju
trebale biti identične onima u klasičnoj hirurgiji,
odnosno ovisne o dijagnozi bolesti (10).
Endometrioza ne može da se razmatra separatno
od adhezija koje zahvataju razne organe. Najčešća je na ovarijumu, zatim na peritoneumu i kao
duboka infiltrišuća endometrioza, a ređe na ostalim organima, što je u saglasju s našim rezultatima (11, 12). Tretman podrazumeva operativni
zahvat i hormonalnu supresiju, ali, na žalost, kod
mnogih bez očekivanog uspeha (10, 13-15).
Postavljanje dijagnoze pelvične endometrioze,
kao i odabir terapije, kompleksan je problem. S
obzirom da se endometrioza najčešće javlja u fertilnom dobu i da ozbiljnije forme uvek zahtevaju,
pored medikamentozne, i hiruršku terapiju, tome
treba prilagoditi vrstu operativnog pristupa i radikalnost operacija.
ZAHVALE/IZJAVE
postoji.
LITERATURA
1.
2.
3.
4.
168
Missmer SA, Hankinson SE, Spiegelman D, Barbieri
RL, Malspeis S, Willett WC, Hunter DJ. Reproductive history and endometriosis among premenopausal
women. ACOG. Obstet Gynecol 2004; 104:965-74.
Kyama CM, Mwenda JM, Machoki J, Mihalul A,
Simsa P, Chai DC, D’Hooghe TM. Endometriosis in
African women. J Women’s Health 2007; 3:629-35.
Zondervan KT, Cardon LR, Kennedy SH. What
makes a good case-control study? Design issuesfor
complex traits such asendometriosis. Hum Reprod
2002; 17:1415-23.
Hornstein MD, Harlow BL, Thomas PP, Check
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
JH. Endometriosis: Use of a new CA 125 assay in
the diagnosis of endometriosis. Hum Reprod 1995;
10:932-34.
Jašović-Siveska E, Jašović V. Povezanost kontrolisane hiperstimulacije ovarijuma kod bolesnica
sablagim oblikom endometrioze. Vojnosanit Pregl
2008; 65:147-52.
Seleem MI, Hashemy AM, Obeid MA. Umbilical
endometriosis: a diagnostic dilemma - case report. J
Kuwait Med 2002; 34:303-05.
Attia GR, Zeitoun K, Edwards D, Johns A, Carr BR
and Bulun SE. Progesterone receptor isoform A but
not B is expressed in endometriosis. J Clin Endocrinol 2000; 85:2897-02.
Blanco G, Parithivel VS, Shah AK, Gumbs MA,
Schein M, Gerst PH. Abdominal wall endometriomas. Am J Surg 2003; 185:596-98.
Shawky Badawy ZA, Liberatore C, Farhat MA, Valente AL, Landas S. Cervical endometriosis stimulated by estrogen therapy following supracervical
hysterectomy. J Gynecol Surg 2003; 19:141-44.
Ozkan S, Murk W, Arici A. Endometriosis and Infertility. Epidemiology and Evidence-based Treatments.
Ann N Y Acad Sci 2008; 1127:92-100.??
C. Chapron, H. Barakat, X. Fritel, J.-B. Dubuisson,
G. Breart, Fauconnier A. Presurgical diagnosis of
posterior deep infiltrating endometriosis based on
a standardized questionnaire. Hum Reprod 2005;
20:507-13.
Erel CT, Senturk LM. Is laparoscopy necessary before assisted reproductive technology?. Curr Opin
Obstet Gynecol. 2005; 17:243-48.
Story L, Kennedy S. Animal studies in endometriosis: A Review. ILAR J 2004; 45:132-39.
Bazot M, Detchev R, Cortez A, Amouyal P, Uzan
S and Dara E. Transvaginal sonography and rectal
endoscopic sonography for the assessment of pelvic
endometriosis: a preliminary comparison. Hum Reprod 2003; 18:1686-92.
Bazot M, Darai E, Hourani R, Thomassin I, Cortez
A, Uzan S. Deep pelvic endometriosis. Radiology
2004; 232:379-89.
Operative treatment of endometriosis in
the Clinical Centre of Kragujevac during
the period 2004-2008
ABSTRACT
In this retrospective research parameters connected to the pathogenesis and treatment of pelvic endometriosis have been analyzed (surgical
operation, age, surgical approach and conservativeness of the operation, spreading of the endometrioses to the surrounding pelvic organs)
at Gynecology and Obstetric Clinic of Clinical
Centre in Kragujevac during a five year period.
The total number of observed patients was 88.
They all had ovary cysts and a high value of the
Ca 125 tumor marker and pathological verification of endometrioses. The greatest number of
Notes
patients were in the age group 26-35 (56,8%).
The most common procedure was radical surgical operation adnexectomy in 53 (60,2%) and
hysterectomy in 24 (45,83%) patients (p<0,01).
With almost equal probability both laparotomy
and laparoscopy were performed (p>0,01). Ovary
endometriosis was often joined with other pelvic
organs endometriosis.
Key words: pelvic endometriosis, endometriosis, laparoscopy
Original submission: 17 March 2009; Revised submission: 11
May 2009; Accepted: 28 August 2009;
NOTES
Emerging risk for viral hepatitis A in
Croatian adults
Vladimir Mićović 1, Albert Cattunar1, Danijela
Štimac 2, Krunoslav Capak3, Dražen Stojanović 4,
Davor Jurišić5
Department of Environmental Health, School of Medicine,
University of Rijeka, 2Zagreb Institute of Public Health, Zagreb,
3
Croatian National Institute of Public Health, Zagreb, 4Department of Social Medicine and Epidemiology, School of Medicine,
University of Rijeka, 5University Hospital Center Rijeka; Croatia
1
Corresponding author: Danijela Štimac, Zagreb Institute of Public Health, Mirogojska 16, 10000 Zagreb, Croatia, Phone +385
1 4696172; fax +385 1 4678019, Email: danijela.stimac@
stampar.hr
Original submission: 10 April 2009; Revised submission: 27
October 2009; Accepted: 04 January 2010
ABSTRACT
An objective of the study was to determine the
changes in the risk of developing hepatitis A in
the 30-years period and discuss the need for vaccination against HAV infection in Croatia and
the city of Rijeka comparing incidence of hepatitis A between 1970-1974 and 2000-2004 periods. Hepatitis A declined in both populations
and affected more prominently older population
groups. Improvement of hygiene and sanitary
conditions appears to have decreased hepatitis A
incidence among children and adults, but only a
seroepidemiological study can give more accurate data as a basis for discussion on the necessity
of vaccination as a further measure in reducing
hepatitis A incidence.
Key words: adults, children, hepatitis A, incidence
INTRODUCTION
In recent years in Croatia the incidence of diseases
associated with low hygienic and living standards,
i.e. typhoid fever, bacillary dysentery, and hepatitis A, has clearly regressed to the levels typical of
developed countries (1). An 8-year monitoring of
infectious disease cases and deaths revealed a low
and relatively stabilized trend of hepatitis A virus
(HAV) infections in Croatia, in spite of a certain
rise after the lowest incidence rate of 34/100 000
in 1998. However, these levels are far below those
of the 1960s when up to 14 000/100 000 cases
had been registered annually (2).
During the past decades more adult than child/
adolescent patients with HAV infection were
hospitalized, and clear decline in incidence was
observed through the national system of the reporting infectious diseases (3). A similar phenomenon of declining HAV morbidity and shift of
age distribution was observed in several European countries (4,5).
The objective of the study was to determine the
risk of developing HAV infection and discuss the
feasibility of vaccination against HAV infection.
METHODS
The study of HAV infection incidence was carried out in the database of the Croatian Registry of
Infectious Diseases of the Croatian National Institute of Public Health. The clinical diagnosis of
HAV infection was supported by epidemiological
data and confirmed with a serological test by the
local hospital or public health institute laboratory. Following confirmation, the case has been
reported to the local epidemiological service and
then notified at the national level. The notification system is compulsory in Croatia according
to the Act on Population Protection against Communicable Diseases. For the purpose of this study
the population of the City of Rijeka and Republic
of Croatia have been selected. Crude annual cumulative incidence (CI) for Rijeka and Croatia
was calculated per 100 000 inhabitants. Five-year CI per 100 000 inhabitants of the disease was
age-adjusted to the standard world population by
direct method for each age group.
169
The age distribution of cumulative reported cases
was compared between children (ages 0-14) and
adults (older than 15) in the two 5-year periods
30 years apart (1970-74 and 2000-04). The 5-year periods were considered suitable for the analysis in order to avoid potential bias of annual variation in disease incidence caused by outbreaks.
Frequencies of the reported cases between study
periods (1970-74 and 2000-04) were compared
by chi square test at alpha level of 0.05.
Table 1. Cummulative incidence of the hepatitis A in Rijeka
and Croatia in 1970-74 and 2000-04 periods compared
between children and adults (15 and above)
RESULTS
ference in incidence between children and adults
was statistically significant for the city of Rijeka.
More than 20-fold decline of the annual crude CI
per 100 000 inhabitants of the acute HAV infection
was observed during the study period (Figure 1).
During the first 5 study years, 42 900 cases of
hepatitis A were reported in the whole of Croatia (1731 in Rijeka, 41 187 in the rest of Croatia). After 30 years the values decreased: 1946
reported cases in Croatia, out of which 29 were
in Rijeka and 1917 in the rest of Croatia. Ageadjusted 5-year CI in Croatia was 5220/100
000 (7828/100 000 in Rijeka) during 1970-74.
Between 2000 and 2004 the incidence in Croatia
declined to 273/100 000 (57/100 000 in Rijeka).
Differences between affected children and adults
in the 1970-74 period and the 2000-04 period
were statistically significant in Rijeka (χ2=11,19;
p=0,0008), but not in the rest of Croatia (χ2=0,14;
p=0,7067) (Table 1).
DISCUSSION
Between periods 1970-74 and 2000-04 the incidence of hepatitis A declined from 42 900/100 000
to 1946/100 000 in Croatia, and from 1731/100
000 to 29/100 000 in the city of Rijeka. The dif-
Region
Period
5-years
CI*
1970 - 74
7828
1776
733
1197
2000 - 04
57
0
12
20
8†
17†
1970 - 74
5220
450
1912
1485
512
861
2000 - 04
273
58
91
55
30
39
Age groups
0 - 4 5 - 9 10 - 14 15 - 19 > 20
Rijeka
Croatia‡
1499 2623
* CI=cummulative incidence/ 100 000
†
statistically significant (χ2 = 11,19; p=0,0008)
‡
cases from Rijeka were excluded form Croatian total
Results of this study have shown that HAV infection in the second period of examination affected more frequently (with statistical significance) adults (up to one half of all patients), in
comparison to the 1970-1974 period, for both the
city of Rijeka and Croatia as a whole. The agedistribution morbidity has changed, e.g. shifted
toward adults. This is a phenomenon observed in
developed countries (6-8). However, the CI in the
city of Rijeka was higher than the national one,
which could be ascribed to higher population
density which is known to stimulate transmission
of infectious diseases (9).
During the 20th century Croatia underwent improvements in the general prophylactic measures
against infectious diseases. In 2001, the death
rate for infectious diseases was 1.03/100 000
(10). Better individual hygiene, improved food,
water supply and sewage disposal, especially in
day-care centers, kindergartens and schools, were
of particular importance in reducing transmission
of infectious diseases related to sanitary conditions and HAV infection (11).
Figure 1. Crude annual cumulative incidence of reported hepatitis A cases per 100 000 inhabitants during 1970-2004
170
Notes
Experience in administration of HAV vaccine for
immunization of children in low endemic countries has shown that significant results could be
achieved in further morbidity reduction, even in
minor coverage, due to the effects of herd immunity. The above was noted in the USA after
1999, when the recommendation on routine infant vaccination was adopted (12), and in Israel
and Spain where the same routine vaccination of
children led to significant further morbidity reduction (13,14).
However, Hepatitis A is a cyclic disease and any
valid conclusions regarding the benefits of vaccination in low endemicity conditions will require
more time. Vaccination against HAV infection is
available in Croatia, but only for international
travelers to high risk areas, and on request.
Results of this study have shown that HAV infection in Croatia continuously declines followed by
peaks in epidemic years. Due to improved sanitary conditions less children contract hepatitis A
during childhood, and more older children, adolescents and adults are susceptible, so in the near
future further changes in age distribution of HAV
infection could be expected. Decreasing the incidence of HAV infection will make the population
more susceptible to the disease, as a consequence
of a larger number of non-immune persons (15). A
constant trend of decline in morbidity will gradually decrease the number of naturally immune persons in upcoming decades. Loss of natural immunization during childhood will cause a remarkable
shift of morbidity toward adults. This process was
noticed in the countries of Western Europe and
Scandinavia during the past decades (16).
Adults are more susceptible than children to the
clinical form of disease, as well as complications
such as fulminant hepatitis (17). While considering the applicability and feasibility of introducing vaccination against hepatitis A in Croatia,
one should be extremely cautious and bear numerous factors in mind.
Morbidity reduction in infants, when inapparent
infection predominates, leads to an increase in
sensitivity in older age groups with predominant
symptomatic diseases and more common complications. This study reflects reported cases – clinically evidenced HAV infection. Underreporting
of HAV infection is a well known problem due to
unapparent cases (18). The problem has persisted
over the years and caused absolute figures to be
less accurate. It is reasonable to believe, though,
that this error is always similar, thus portraying
accurate trends. This may be of particular practical importance, because more accurate seroprevalence studies, which are very expensive, have
to be conducted for the purpose of a survey of
HAV infection. However, this study emphasizes
that HAV infection burden cannot be estimated
without a seroepidemiological study of HAV seroprevalence. Furthermore, too short a time has
elapsed between vaccine registration and now,
while applicability studies were conducted in
only few low endemicity countries, which, unlike
Croatia, are immigrant countries. The disease can
be controlled by improving hygienic and sanitary
living conditions, as well as wise application of
vaccines for high risk individuals.
Thanks to Bernard Kaić, MD, MSc, epidemiologist of the Croatian National Institute of Public
Health, Department of Epidemiology, for providing the data records at the national level.
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seroprevalence: a global rewiew and analisys. Epidemiol Infect 2004; 132:1005-22.
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Health Service Yearbook 2000. Zagreb: Croatian
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M, Bertin T, Renzulli G. Changing epidemiology of
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east Italy. Ital J Gastroenterol 1991; 23:344-6.
Frosner G, Willers H, Muller R, Schenzle D, Deinhardt F, Hopken W. Decrease in incidence of hepatitis A infections in Germany. Infection 1978; 6:25960.
Marino RT, Valente AR, Ramatho FJ, de Moura MC.
The changing epidemiological pattern of hepatitis
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Medicinski Glasnik, Volumen 7, Number 1,
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National Institute of Public Health, 2002:248
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MJ, Liang JT, Dienstag JL, ur. Viral Hepatitis and
Liver Disease. London: International Medical Press,
2002:9-14.
Wasley A, Samandari T, Bell BP. Incidence of hepatitis A in the United States in the era of vaccination.
JAMA 2005; 294:194-201.
Dagan R, Leventhal A, AnisE, Slater P,Ashur Y, Shouval D. Incidence of hepatitis A in Israel following
universal immunisation of toddlers. JAMA 2005;
294:202-10.
Lopalco PL, Salleras L, Barbuti S, Germinario C,
Bruguera M, Buti M, Dominiguez A. Hepatitis A
and B in children and adolescents-what can be learn
from Puglia (Italy) and Catalonia (Spain)? Vaccine
2001; 19:470-4.
Gdalevich M, Grotto I, Mandel Y, et al. Hepatitis
A antibody prevalence among young adults in Israel-the decline continues. Epidemiol Infect 1998;
121:477-9.
Melnick J. History and epidemiology of hepatitis A
virus. J Infect Dis 1995; 171 (Suppl 1): S2-8.
Lednar W, Lemon S, Kirkpatrik J, Redfield R, Fields
M, Kelley P. Frequency of illness associated with
epidemic hepatitis A virus infections in adults. Am J
Epidemiol 1985; 122:226-33.
Hadler S. Global impact of hepatitis A virus infection; changing patterns. U: Lemon S, Margolis H, ur.
Viral hepatitis and liver disease. Baltimore: Williams
and Wilkins, 1991:4-20.
CASE REPORT
Intaktna blizanačka tubarna trudnoća
Jasmin Hodžić, Abdulah Granić, Nina Hodžić,
Aida Idrizbegović
Služba za ženske bolesti, neonatologiju i perinatologiju, Kantonalna bolnica Zenica, Zenica, Bosna i Hercegovina
Corresponding author: Jasmin Hodžić, Služba za ženske bolesti, neonatologiju i perinatologiju, Kantonalna bolnica Zenica,
Crkvice 67, 72000 Zenica, Bosna i Hercegovina, Phone: +387
32 446 670; fax.: +387 32 448 102, E-mail: drjassmin@
hotmail.com
Originalna prijava: 06. novembar 2009.; Korigirana verzija:
03. decembar 2009.; Prihvaćeno: 22. decembar 2009.
SAŽETAK
U radu je prezentiran slučaj intaktne blizanačke
ektopične trudnoće u osmoj sedmici, koja je otkrivena transvaginalnim ultrazvučnim pregledom
u desnom jajovodu kod 35-godišnje multipare.
Nakon operativnog zahvata učinjenog putem transverzalne laparotomije, odstranjen je desni jajovod u kome su se nalazila dva intaktna gestacijska
172
mješka. Do sada je u svijetu opisano tek nešto više
od 100 slučajeva ektopične blizanačke trudnoće.
Ključne riječi: blizanačka ektopična trudnoća,
transvaginalni ultrazvučni pregled, transverzalna
laparatomija
UVOD
Blizanačka ektopična trudnoća izuzetno je rijetka
pojava. Od prvog opisa bolesnice s unilateralnom
blizanačkom trudnoćom u jajovodu, koju je objavio De Ott još 1891. godine, ove su se trudnoće
javljale pojedinačno jednom godišnje, te je od
tada do danas u literaturi opisano tek nešto više
od 100 slučajeva (1, 2). Incidenca blizanačke
ektopične trudnoće kreće se oko 1:125.000 trudnoćâ, a samo u osam objavljenih slučajeva bila je
evidentirana srčana akcija embriona (3).
U ovom radu prikazat ćemo slučaj tubarne ektopične trudnoće multipare s anamnestičkim podacima koji govore u prilog čestih upalnih promjena reproduktivnih organa.
PRIKAZ SLUČAJA
Tridesetpetogodišnja multipara (četiri vaginalna
poroda i jedan porod dovršen operativnim putem)
upućena je na ginekološki odjel Kantonalne bolnice Zenica radi oskudnog vaginalnog krvarenja
i bolova u dnu stomaka koji su trajali unazad dva
dana. Zadnju menstruaciju pacijentica je imala
osam sedmica ranije i nije koristila nijedan oblik
kontacepcije. Iz anamneze pacijentica je navela
operaciju appendixa prije deset godina, carski rez
prije četiri godine i učestale vaginalne infekcije.
Grav-index, koji je bio učinjen u 5. sedmici amenoreje od strane nadležnog ginekologa radi sumnje na trudnoću, bio je pozitivan.
Na prijemu pacijentica je bila hemodinamski
stabilna, krvni pritisak je iznosio 110/70 mmHg,
a srčana frekvenca 80 otkucaja/min. Palpatornim nalazom abdomena ustanovljena je bolna
osjetljivost u predjelu desne ilijačne regije gdje
se istovremeno palpirala cistično-tjestasta konzistencija proširenog desnog jajovoda. Nije bilo
znakova akutnog abdomena. Pregledom, uz pomoć spekuluma, uočeno je oskudno krvarenje
iz uterusa. Bimanuelnim vaginalnim pregledom
ustanovljeno je razmekšanje, te bolna osjetljivost
grlića maternice na palpaciju.
Laboratorijske analize pokazale su sljedeće vrijednosti: Le 10,5 x 109/L, Er 4,17 x 10¹²/L, Hgb
12,7 g/L, Htc 0,37 L/L, trombociti 333 109/L.
Grav-index je bio pozitivan.
Case report
Pregledom transvaginalnim kolor-doplerom
(TVCD), sondom jačine 6,5 MHz, ustanovljeno
je sljedeće: maternica normalne veličine s praznim materništem i decidualno promijenjenim
endometrijem; nepromijenjeni lijevi adneksi; u
predjelu desnih adneksa jasno su uočena dva odvojena gestacijska mješka sa zamecima. Udaljenost tjeme-trtica jednog zametka iznosila je 15,9
mm s evidentnom srčanom akcijom. U drugom,
manjem, gestacijskom mješku zametak nije ultrazvučno izmjeren, te u njemu nije bilo evidentne
srčane akcije (Slika 1).
Dan nakon prijema učinjena je transverzalna laparotomija. Pri zahvatu je ustanovljen proširen
ampularni dio desnog jajovoda, tankog i napetog
zida koji je plavičasto prosijavao (promjera 5-6
cm) s nešto malo krvi u Douglasovom prostoru,
što je upućivalo na intaktnu tubarnu trudnoću.
Ostali organi male zdjelice bili su bez vidljivih
promjena. U toku operacije učinjena je salpingektomija s desne strane, a na lični zahtjev pacijentice, urađena je sterilizacija lijeve tube po
metodi Pomeroya. Nakon operativnog zahvata
odstranjena desna tuba s intaktnim gestacijskim
mješcima je presječena i na taj način su se prikazala dva zametka koji su se razvijali u odvojenim
gestacijskim mješcima (Slika 2).
stavlja jedan od najvećih zdravstvenih rizika kod
žena (4). Prevalencija ektopične trudnoće povećala se u zadnjih nekoliko godina, te sada iznosi
1-2% svih trudnoća, odnosno 2,1-9,4% u potpomognutim trudnoćama (5). Blizanačka ektopična
trudnoća javlja se s incidencom od 1 na 200 svih
ektopičnih trudnoća i ne prati trend porasta incidence ektopičnih trudnoća (6).
Rizik pojave ektopičnih trudnoća povećan je u
uvjetima koji mijenjaju normalnu funkciju jajovoda kao što su upalne promjene u zdjelici, prijašnje
ektopične trudnoće, hirurški zahvati na jajovodima,
operacije u zdjelici, trudnoće nakon asistirane humane reprodukcije, unutarmaternični uložak, žene
starije od 35 i mlađe od 25 godina (7). U našem slučaju predisponirajući faktori za nastanak ektopične
trudnoće bili su česte upalne promjene u zdjelici i
prethodni porod dovršen operativnim putem.
Dijagnoza ektopične trudnoće postavlja se anamnestički, općim i ginekološkim pregledom,
biohemijskim biljezima (βHCG, estriol, progesteron), te ultrazvučnim pregledom (8). U normalnoj trudnoći, razina βHCG-a u plazmi udvostručuje se svakih 1,4-2,1 dan, dok kod ektopične
trudnoće razina ovog hormona u plazmi pokazuje
znatno niže vrijednosti (9).
Uprkos tehnološkom napretku rane dijagnostike
i tretmana, ektopična trudnoća još uvijek pred-
Pojavom transvaginalnog ultrazvuka dijagnosticiranje ektopične trudnoće znatno je olakšano.
Transvaginalni ultrazvuk pokazao se vrlo pouzdanim u dijagnostici jer je u 90,9% slučajeva
prije operativnog zahvata potvrdio ektopičnu
trudnoću (10). Transabdominalnim ultrazvukom
moguće je dijagnosticirati ektopičnu trudnoću
kod vrijednosti βHCG od 5000-6000 mIU/mL,
a transvaginalnim ultrazvukom kod vrijednosti
βHCG od 1000-1500 mIU/mL (11). Posljednjih
godina tehnološkim usavršavanjem transvaginal-
Slika 1. Ultrazvučni prikaz blizanačke tubarne trudnoće u
osmoj nedjelji (I, prvi gestacijski mešak; II, drugi gestacijski
mešak; III, uterus) (Hodžić J, 2009.)
Slika 2. Prikaz otvorenog desnog jajovoda i dva zametka sa
horionskim tkivom (Hodžić J, 2009.)
Postoperativni tok je protekao bez komplikacija, te
je pacijentica nakon 4. dana otpuštena s ginekološkog odjela Kantonalne bolnice Zenica. Patohistološki nalaz proširene desne tube uterine potvrdio
je prisustvo ugrušaka krvi s mladim horijalnim resicama. Stroma proširenog dijela tube bila je decidualno transformirana, a u zidu, u svim slojevima,
bilo je umnoženo vezivo infiltrirano limfocitima.
173
nog doplera u boji i 3D ultrazvuka omogućeno je
jasno prikazivanje ranih stadija blizanačkih trudnoća u jajovodima (12).
Liječenje ektopične trudnoće može biti hirurško i
konzervativno. Konzervativno liječenje metotreksatom i prostaglandinima primjenjuje se u slučajevima male nerupturirane ektopične trudnoće
(manje od 4 cm) s isključenom heterotopičnom
trudnoćom, kod koje su vrijednosti βHCG-a ≤
3000 mIU/ml, vrijednosti progesterona manje od
40 nmol/L i kod hemodinamski stabilne pacijentice (7). Međutim, još uvijek ne postoje usaglašeni
stavovi o adekvatnoj dozi metotreksata u liječenju
unilateralne ektopične blizanačke trudnoće. Hirurško liječenje provodi se radikalno salpingektomijom (kao što je to bio slučaj kod naše pacijentice)
i konzervativno kod mlađih žena koje nisu rađale
(fimbrijalna ekspresija, linearna salpingotomija,
sedimentalna resekcija i laparoskopska aspiracija).
Brojna su istraživanja pokazala da su za uspjeh liječenja manje važni metoda i vrsta hirurškog zahvata u odnosu na razloge koji su doveli do ektopične
trudnoće. Ipak, pravovremena dijagnoza i liječenje ektopične trudnoće spašavaju život pacijentice, pa pristup dijagnosticiranju mora biti krajnje
ozbiljan. Kombinacija kliničke slike, transvaginalnog ultrazvuka, serijskog βHCG-a i laparoskopije,
predstavljaju ‘’zlatnu kombinaciju’’ ranog dijagnosticiranja ektopične trudnoće. Zahvaljujući boljoj dijagnostici i razvoju endoskopije, ektopična
trudnoća, od 1993. godine, uglavnom se tretira laparoskopski (13) što predstavlja ‘’zlatni standard’’
hirurškog liječenja ektopične trudnoće.
LITERATURA
1. De Ott. A case of unilateral twin gestation. Ann Gynaecol Obstet 1891; 36:304–5.
2. Aty E, Lam SL. Clinics in diagnostics imaging (106).
Viable left tubal twin ectopic
pregnancy. Singapore Med J 2005; 46:651–5.
3. Parker J, Hewson AD, Calder-Mason T, Lai J. Transvaginal ultrasound diagnosis of a live twin tubal ectopic pregnancy. Australas Radiol 1999; 43:95-7.
4. Murray H, Baakdah H, Bardell T, Tulandi T. Diagnosis and treatment of ectopic pregnancy. CMAJ 2005;
173:905-12.
5. Pyrgiotis E, Sultan KM, Neal GS. Ectopic pregnancies after in-vitro fertilization and embryo transfer. J
Assist Reprod Gen 1994; 5:185–8.
6. Hanchate V, Garg A, Sheth R, Rao J, Jadhav PJ, Karayil D. Transvaginal sonographic diagnosis of live
monochorionic twin ectopic pregnancy. J Clin Ultrasound 2002; 30:52-56.
7. Šimunić V. Izvanmaterična trudnoća. U: Šimunić V
i sur. (ur.) Ginekologija. Zagreb: Naklada Ljevak,
2001:183-94.
174
8. Lurie S. The history of the diagnosis and treatment
of ectopic pregnancy. A medical adventure. Eur J
Obstet Gynecol Reprod Biol 1992; 43:1–7.
9. Greer IA, Cameron IT, Kitchener HC, Prentice A.
Mosby’s color atlas and text of Obstetrics and Gynecology. London: Mosby International Limited 2001;
4:88-93.
10. Ash KM, Lyons EA, Levi CS, Lindsay DJ. Endovaginal sonographic diagnosis of ectopic twin gestation. J
Ultrasound Med 1991; 10:497–500.
11. Farquhar MC. Ectopic pregnancy. Lancet 2005;
366:583-91.
12. Gabrielli s, Marconi R, Ceccarini M , Valeri B, de
Iaco P, Pilu G. Transvaginal and three ultrasound diagnosis of twin tubal pregnancy. Prenatal Diagn 2006;
26:85-93.
13. Gualandi M, Steemers N, Keyser JL. First reported
case of preoperative diagnosis and laparoscopic treatment of unilateral twin tubal pregnancy. Rev Fr
Gynecol Obstet 1994; 89:134–6.
Intact twin tubal pregnancy
Jasmin Hodžić, Abdulah Granić, Nina Hodžić,
Aida Idrizbegović
Department of Women’s Health, Neonatology and Perinatology,
Cantonal Hospital Zenica
ABSTRACT
A case of a unilateral eight-week twin ectopic pregnancy diagnosed with transvaginal sonography is
presented here. This ectopic pregnancy was found
in the right Fallopian tube of a 35-year old woman. After the surgical procedure conducted by
the method of transversal laparotomy, we removed
the right Fallopian tube with two gestational sacs.
So far only a hundred of such cases of ectopic twin
pregnancy have been described worldwide.
Key words: twin Fallopian tube pregnancy, transvaginal sonography diagnostics, surgical treatment.
Original submission: 06 November 2009.; Revised submission: 03 December 2009.; Accepted: 22 December 2009
Case report
Obstruction of left ventricular outflow
tract by a calcified mass at mitral valve
Miro Bakula1, Zeljka Gavranovic2, Maja Bakula3,
Roman Urek1, Nikola Jankovic4, Goran Milicevic1
Department of Cardiology, Clinical Hospital Sveti Duh, Medical
School Zagreb and Medical School Osijek, 2 Department of
Anesthesiology and Intensive Care, University Hospital Sestre
Milosrdnice, 3 Vuk Vrhovac University Clinic for Diabetes and
Metabolic Diseases, 4Department of Nephrology, Clinical Hospital Sveti Duh; Zagreb, Croatia
1
Case report
Corresponding author: Goran Miličević, Division of Cardiology,
University Department of Medicine, Medical School Osijek, Clinical Hospital Sveti Duh, Sveti Duh 64, 10000 Zagreb, Croatia,
Phone: +385 1 371 2248; fax. +385 1 371 2112, E-mail
address: [email protected]
Original submission: 28 October 2009; Revised submission:
08 March 2010; Accepted: 11 March 2010.
ABSTRACT
A case of an unusual left ventricular outflow tract
obstruction by mitral valve pathology in a 35-year
old female with diabetes and end-stage renal disease is presented in the study. The patient suffered
from fever of an unknown origin after lower-leg
amputation. Although the wound healed well, fever persisted for three weeks despite a triple antibiotic treatment until the infection was resolved
with vancomycin. Three months later echocardiography displayed a floating mass attached to mitral valve, producing a newly developed systolic
murmur and a mild haemodynamic obstruction
of the left ventricular outflow tract. The calcified
vegetation was probably formed during an unrecognized subacute infective endocarditis.
Key words: left ventricular outflow tract obstruction, mitral valve, infective endocarditis, echocardiography, haemodialysis
INTRODUCTION
Left ventricular outflow tract (LVOT) obstruction
caused by mitral valve pathology is very rare. It
has been described in patients with accessory
mitral cusp (1) or retained native anterior leaflet
following mitral valve replacement (2), in those
with anterior leaflet diverticula (3) or anomalous
papillary muscle insertion (4), in patients with
myxomas (5) or giant blood cysts of the anterior
mitral leaflet (6), and in massive posterior mitral
annular calcification with mitral valve protrusion
into the LVOT (7). The case of mitral valve endocarditis presented by Chandraratna et al. has indicated a possible LVOT obstruction, but haemodynamic measurements were not done (8). This
paper presents a rare case of LVOT obstruction
caused by calcified vegetation of the mitral valve
in an end-stage renal disease patient
CASE REPORT
A 35-year old female patient was admitted to the
hospital for diagnostic evaluation prior to elective
parathyroidectomy due to secondary hyperparathyroidism. She has had diabetes for 23 years,
developing all chronic complications, including
renal failure. Diabetes was treated with basal-bolus
regimen, combination of two doses of basal insulin
analogue and three prandial doses of rapid-acting
insulin analogue (lyspro). Physical examination
revealed a previously unrecorded grade 3/6 systolic murmur above the precordium with the punctum maximum just above the aortal ostium. Three
months before the current hospitalization, the
patient had been hospitalized for a left foot phlegmon. Gangrene developed and a below-knee amputation was performed. Despite the prolonged and
adequately dosed antibiotic treatment (a combination of cefuroxime, metronidazole and gentamicin)
and a well-healing leg stump, elevated body temperature (up to 38.2 ºC) persisted for three weeks.
Leukocyte count and C-reactive protein were increased (13.5 x109/L and 83 mg/L, respectively),
and haemoglobin was found to be decreased (77
g/L). Repeated haemoculture, urine culture and
peritoneal catheter smear analysed for aerobic and
anaerobic bacteria and fungi were sterile.
After a six-week empirical vancomycin treatment
the patient became afebrile, without clinical and
laboratory signs of infection. In addition, medical history revealed chronic peritoneal dialysis
during the last five years, with an occasional intermittent hemodialysis via arteriovenous fistula,
and sometimes via subclavian catheter as well.
Secondary hyperparathyroidism was diagnosed
a month prior to the current hospitalization and
peripheral vascular disease five months earlier.
Echocardiographic examination performed du-
Figure 1. Apical four chamber echocardiographic view revealed a floating calcified mass at the anterior mitral cusp and
adjoining tendinous cords, measuring 3.0x1.2 cm, protruding
towards LVOT in systole. The arrow indicates calcified vegetation. (Roman Urek, MD, PhD, 2006.) (LV, left ventricle; RV, right
ventricle; LA, left atrium; RA, right atrium).
175
ring the current hospitalization revealed a hyperechogenic, floating mass of 3.0x1.2 cm in size,
attached at anterior mitral cusp and adjoining
tendinous cords. The mass protruded towards the
LVOT in systole (Figure 1). Colour Doppler imaging showed a turbulent flow at LVOT (Figure
2). A mild haemodynamic obstruction produced
a 23 mmHg pressure gradient.
Besides anaemia of a chronic disease type (haemoglobin 100 g/L), laboratory results revealed
an increased parathyroid hormone value (71
pmol/L) with serum calcium being 2.59 mmol/L.
Diabetes was poorly regulated. Glycated haemoglobin value was 7.9%. Blood glucose levels
were 16, 9.6, 10.8 and 10.1 mmol/L at 8, 12, 18
and 21 hours, respectively. Infection parameters
were within the normal range (L 9.2 x 109/L, CRP
15.4 mg/L). Repeated haemoculture and urine
culture were sterile. The patient refused further
diagnostic evaluation and a possible surgical intervention.
DISCUSSION
The rare case of LVOT obstruction caused by a
calcified vegetation of the mitral valve is presented. The calcified vegetation was assumed to be a
consequence of an unrecognized subacute infective endocarditis with a rapidly progressing calcification in a milieu of end-stage renal disease and
hyperparathyroidism.
LVOT obstruction caused by a mitral valve pathology in the absence of systolic anterior motion
is very rare. To our knowledge, a possible LVOT
obstruction has previously been described in only
one case of mitral valve endocarditis (8). That
case, described in 1977, was based on M-mode
Figure 2. Colour Doppler showed turbulent flow at LVOT, above
and below the point of obstruction. (Roman Urek, MD, PhD,
2006.) (LV, left ventricle; RV, right ventricle; LA, left atrium; RA,
right atrium).
176
echocardiography finding. Although convincing
with illustrative M-mode echocardiography imaging and pathological specimens, it did not contain
haemodynamic measurements, either Doppler or
invasive ones. Our report, however, undoubtedly
confirmed the influence of mitral valve calcified
vegetation on LVOT haemodynamics.
Intracavitary obstruction of LVOT, most often found in idiopathic hypertrophic subaortic stenosis,
may lead to serious complications, because it rises left ventricular intracavitary pressure, first systolic and then end-diastolic, as well as left atrial
pressure, which may results in pulmonary congestion. In our patient intracavitary pressure gradient was too low to produce such haemodynamic
consequences, but the progression of the disease
could lead to other complications, such as to mitral valve chordal rupture and onset of acute mitral valve regurgitation (9), as well as to peripheral
embolisation (10). Although the embolic potential of a fibronised, partially calcified structure was
low, that point has to be emphasized considering
surgical approach, which was, as well as additional examinations, rejected by the patient.
The lack of microbiological or histo-pathological confirmation of the calcified mass etiology is
a limitation of our case report. The mass on the
mitral apparatus might have resembled a marked
calcification of endocardial structures that are
common in dialysed patients (11), but other cardiac structures were not as calcified as the mass.
The diagnosis of infective endocarditis matched
one main and two minor Duke’s criteria: a newly
developed heart murmur with positive echocardiographic finding, fever and intravenous access
via a subclavian catheter (12). Repeated negative
haemocultures could be explained by the previous antibiotic treatment of the foot phlegmon. In
a retrospective study by Aguada et al. causative
microorganism could not be identified for the
same reason in 20% of cases of infective endocarditis (13). Other clinical circumstances and
laboratory findings strongly suggested an unrecognised subacute infective endocarditis as a
cause of the development of the mass. Although
infective endocarditis probably originated from
bacteraemia that developed during the left foot
phlegmon, any dialysis procedure might also
have resulted in this problem (14).
The most frequently isolated microorganisms
Case report
causing infective endocarditis in hemodialysis
patients (Staphylococcus aureus, Staphylococcus
epidermidis and Enterococcus species) are susceptible to vankomycine therapy, which was used
to treat our patient (15) .
In conclusion, we have found this case to be interesting, as LVOT obstruction caused by mitral
valve vegetation occurs extremely rarely. Although there were no serious haemodynamic consequences, surgical intervention might be needed
in the close future to prevent further mitral valve
damage and embolic incident with a potentially
fatal outcome.
ACKNOWLEDGMENT/DISCLOSURES
REFERENCES
McGlinchey P, Fitzpatrick S, Purvis J. Accessory
mitral valve leaflet causing left ventricular outflow
tract obstruction in an adult. Heart 2009; 95:1219.
2. Okamoto K, Kiso I, Inoue Y, Matayoshi H, Takahashi R, Umezu Y. Left ventricular outflow obstruction
after mitral valve replacement preserving native anterior leaflet. Ann Thorac Surg 2006; 82:735-7.
3. Agathos EA, Moran M, Mangion J, Lovell A, Engelman RM, Rousou JA. “Diverticula” of anterior
mitral valve leaflet as a cause of subvalvular aortic
stenosis. J Heart Valve Dis 1996; 5:309-11.
4. Yang HS, Lee KS, Chaliki HP, Tazelaar HD, Lusk
JL, Chandrasekaran K, Tajik AJ. Anomalous insertion of the papillary muscle causing left ventricular
outflow obstruction: visualization by real-time threedimensional echocardiography. Eur J Echocardiogr
2008; 9:855-60.
5. Ozcan AV, Evrengul H, Bir F, Tanriverdi H, Goksin
I, Kaftan A. Multiple myxomas originating from anterior and posterior mitral leaflets in the left ventricle
leading to LV outflow tract obstruction. Circ J 2008;
72:1709-11.
6. Minneci C, Casolo G, Popoff G, Sulla A, Comin CE,
Pedemonti E. A rare case of left ventricular outflow
obstruction. Eur J Echocardiogr 2004; 5:72-5.
7. Puri P, Sarma R, Ostrzega EL, Varadarajan P, Pai
RG. Massive posterior mitral annular calcification causing dynamic left ventricular outflow tract
obstruction: mechanism and management implications. J Am Soc Echocardiogr 2005; 18:1106.
8. Chandraratna PAN, Robinson MJ, Byrd C, Pitha JV.
Significance of abnormal echoes in left ventricular
outflow tract. Br Heart J 1977; 39:381-9.
9. Kaymaz C, Nihal Özdemir N, Özkan M. Differentiating clinical and echocardiographic characteristics of
chordal rupture detected in patients with rheumatic
mitral valve disease and floppy mitral valve: impact
of the infective endocarditis on chordal rupture. Eur
J Echocardiogr 2005; 6:117-26.
10. Snygg-Martin U, Gustafsson L, Rosengren L, Alsiö
Å, Ackerholm P, Andersson R, Olaison L. Cerebrovascular Complications in Patients with Left -Sided
11.
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15.
Infective Endocarditis Are Common: A Prospective
Study Using Magnetic Resonance Imaging and Neurochemical Brain Damage Markers. Clinical Infectious Diseases 2008; 47:23-30.
Madu EC, D’Cruz IA, Wall B, Mansour N, Shearin
S. Transesophageal echocardiographic spectrum of
calcific mitral abnormalities in patients with end-stage renal disease. Echocardiography 2000; 17:29-35.
Durack, DT, Lukes, AS, Bright, DK. New criteria
for diagnosis of infective endocarditis: utilization of
specific echocardiographic findings. Duke Endocarditis Service. Am J Med 1994; 96:200.
Aguado JM, Gonzalez-Vilchez F, Martin-Duran R,
Arjona R, Vazquez de Prada J. Perivalvular abscess
associated with endocarditis: clinical features and
diagnostic accuracy of two-dimensional echocardiography. Chest 1993; 104:88-93
Abbot KC, Agodoa LY. Hospitalizations for bacterial endocarditis after initiation of chronic dialysis in
the United States. Nephron 2002; 91:203-9.
Robinson DL, Flower VG, Sexton DJ, Corey RG,
Conlon PJ. Bacterial endocarditis in hemodialysis
patients. Am Jour Kidney Dis 1997; 30:521-4.
1.
CASE REPORT
Laparoscopic treatment of achalasia first case in Croatia
Ferid Latić, Vlatka Pitlović , Josip Samardžić,
Azra Latić, Hrvoje Pitlović,\uro Miškić,
Department of Surgery, General Hospital “Dr. Josip Benčević”,
Slavonski Brod, Croatia
Corresponding author: Vlatka Pitlović, Department of Surgery
General Hospital “Dr. Josip Benčević”, Andrije Štampara 42, 35
000 Slavonski Brod, Croatia, Phone : +385 35 201 653
Original submission: 24 December 2009; Revised submission:
21 March 2010; Accepted: 21 March 2010.
ABSTRACT
Esophageal achalasia is a primary esophageal
motility disorder. Commonly used treatments are
botulinum toxin injections, endoscopic balloon
dilation and surgical myotomy with or without fundoplication. We are hereby presenting the
first case of laproscopic myotomy with fundoplication performed in Croatia. A 32-year old
female was admitted to the hospital due to the
symptoms of dysphagia, regurgitation, chest pain
and weight loss. Upper gastrointestinal tract radiography with contrast and flexible endoscopy
confirmed the clinical diagnosis of achalasia. She
was treated by the Heller laparoscopic procedure and Dor anterior fundoplication. The patient
177
had a successful recovery and was discharged on
the fifth postoperative day. This case shows that
laparoscopic treatment of achalasia is a feasibile
and safe procedure which can be performed even
in a small country hospital, but it requires great
technical care and experience of the surgeon.
Key words: esophageal achalasia, laparoscopic
myotomy, anterior fundoplication.
INTRODUCTION
Esophageal achalasia is primary esophageal motility disorder (1), characterized by the absence
of esophageal peristalsis and increased pressure
at the lower esophageal sphincter due to the inability of the sphincter to relax (2). Clinical symptoms of advanced achalasia are dysphagia, regurgitation, chest pain and weight loss. The exact
diagnosis is achieved by upper gastrointestinal
tract radiography with barium and oesophageal
gastric duodenoscopy (3).Commonly used treatments are botulinum toxin injections, endoscopic balloon dilation and surgical myotomy with
or without fundoplication (1). Laparoscopic
myotomy of distal oesophagus and gastric cardia with antireflux anterior partial fundoplication
has gained popularity in recent years and is now
considered to be a treatment of choice for oesophageal achalasia in most centres (4).
In this paper we have presented the case of the
first laparoscopic treatment of a 32-year old female with achalasia in Croatia.
CASE REPORT
A thirty-two year old female was admitted to
hospital because of dysphagia, regurgitation,
chest pain and weight loss symptoms. Chest
radiography, upper gastrointestinal radiography
with barium (Figure 1) and oesophageal gastric
duodenoscopy confirmed our clinical diagnosis
of achalasia.
After the standard preoperative assessment we
have performed the laparoscopic Heller myotomy with anterior partial fundoplication (Dor).
During this procedure, the patient is placed in
a supine position with reverse Trendelenburg
maneuver and separated legs. The first surgeon
stands between the patient’s legs with a camera
on the right side of the patient and the second surgeon on the left. Trocars are placed as follows:
1 on the left flank on the hemiclavicular line, 1
transumbilicaly for the camera, 1 left subcostally,
and 1 left and 1 right periumbilically.
A pneumoperitoneum is created by CO2 insufflation with a 12 mmHg pressure.
After retracting the stomach and liver and detecting the gastroesophageal junction, the phrenoesophageal ligaments are cut and isolation of
oesophagus is achieved. Anteriorly, a myotomy
is then carried out (Figure 2), leading to mucosal
herniation, with muscle dissection approximately
7 cm.
Air insufflation through a nasogastric tube aims
at excluding perforation of the
herniated esophageal mucosa, and the presence
Figure 1. Upper gastrointestinal radiography with barium
(Department of Radiology, General Hospital “Dr. Josip Benčević
“, Slavonski Brod, 2003)
178
Figure 2. Laparoscopic myotomy and cutting of phrenoesophageal ligaments (F. Latić, 2003)
Case report
of air bubbles at the myotomy site must be ruled
out as well. The procedure is completed with a
180° anterior funduplication to protect the herniated mucosa and prevent gastroesophageal reflux. The nasogastric tube inserted at the moment
of surgery was removed after 24 to 48 hours, and
patient resumed oral feeding on the 3rd day postoperatively and was discharged on the 5th day.
The aim of the therapy is to relieve dysphagia.
Commonly used treatments are botulinum toxin
injections, endoscopic balloon dilatation and surgical myotomy with or without fundoplication(1).
Pharmacological therapy is the only non-invasive
treatment for achalasia, but provides a short-term
clinical response and it is considered as an option for patients who are too frail for endoscopic
or surgical treatment (5). Endoscopic botulinum
toxin injections should be reserved for elderly
patients with severe comorbidity (1) and balloon
dilatation has many side effects. Surgical therapy seems to accomplish the aim of therapy with
reproducible results and low morbidity. Surgical
approach includes open thoracic and transabdominal, thoracoscopic and laparoscopic techniques. With the adaptation of laparoscopy to many
conventional surgical procedures, this minimally
invasive procedure has become a good alternative
for the treatment of achalasia. However, whether
it is performed abdominally or thoracically, the
length of myotomy at the esophagus, the length
of myotomy at the stomach, and the choice of additive antireflux procedure are the aspects of the
procedure that still need to be evaluated (6). The
main reason for controversy about the choice of
surgical method in achalasia is the possibility of
postoperative dysphagia and reflux. The length
of esophageal myotomy has been reported to be
between 5 and 12 cm (7, 8). We performed the
myotomy with the length of 7 cm. It is reported that esophageal myotomy with a length of <5
cm results in a high incidence of dysphagia (8).
We performed the laparoscopic esophagomyotomy with Dor anterior fundoplication without
any postoperative complications. The majority of
studies reported no case of esophageal mucosal
perforation and excellent or good results in 78100% of cases (relief from symptoms or occasional dysphagia not requiring medication or dietary
restriction) (9,11).
This case has shown that laparoscopic esophagomyotomy has the advantages of minimal invasive
surgery, including less mobilization of the esophagus, less dysphagia and reflux with appropriate
esophagogastric myotomy, short hospitalization,
and minimal post-operative pain. It is feasible
and safe procedure which can be performed even
in a small country hospital, but it requires great
technical care and experience of the surgeon.
ACKNOWLEDGMENT/DISCLOCURE
Competing interests: none declared
REFERENCES
1. Campos GM, Vittinghoff E, Rabl C, Takata M, Gadenstätter M, Lin F, Ciovica R. Endoscopic and surgical treatments for achalasia: a systematic review
and meta-analysis. Ann Surg 2009; 249:45-57.
2. Swanstrom LL, Pennings J. Laparoscopic esophagomyotomy for achalasia. Surg Endosc1995; 9:286-92.
3. Levine MS, Rubesin SE. Diseases of the esophagus:
diagnosis with esophagography.Radiology 2005;
237:414-27.
4. Patient Care Committee; Society for Surgery of the
Alimentary Tract: Esophageal Achalasia. SSAT
patient care guidelines. J Gastrointest Surg 2004,
8:367-8.
5. Leyden JE, Moss AC, MacMathuna P. Endoscopic
pneumatic dilatation versus botulinum toxin injection in the management of primary achalasia. Cohrane
Database Rev 2006; CD005046.
6. Ígcí A, Müslümanoglu M, Dolay K, Yamaner S,
Asoglu O, Avci C. Laparoscopic esophagomyotomy
without an antireflux. Procedure for the treatment of
achalasia. J Laparoendosc Adv Surg Tech A 1998;
6:409-16.
7. Bonavina L, Nosadini A, Bardini R. Primary treatment of esophageal achalasia. Long-term results of
myotomy and Dor fundoplication. Arch Surg 1992;
127:222-7.
8. Piciocchi A, Cardillo G, D’ugo D, Castrucci G. Surgical treatment of achalasia: a retrospective comparative study. Jpn J Surg 1993; 23:855-9.
9. Robertson GSM, Lloyd DM, Wicks ACB, DeCaestecker J, Veitch PS. Laparoscopic Heller’s cardiomyotomy without an antireflux procedure. Br J Surg 1995;
82:957-9.
10. Delgado F, Bolufer JM, Martinez-Abad M. Laparoscopic treatment of esophageal achalasia. Surg Laparosc Endosc 1996; 6:83-90.
11. Hunter JG, Trus TL, Branum GD, Waring JP. Laparoscopic Heller myotomy and fundoplication for achalasia. Ann Surg 1997; 225:655-65.
179
ERRATUM
Volume 7, No. 1, February 2010
EDITORIAL
This thematic issue of the Medicinski Glasnik
deals with the diagnosis and treatment of genitourinary tract infections. Out of 13 papers, six
were presented during the 1 Croatian Congress
on Urogenital and Sexually Transmitted Infections held in Opatija, Croatia, in June 2009.
st
The main goal of the thematic issue is to discuss
the management of genitourinary tract infections,
with the particular emphasis on bacterial resistance. The increasing bacterial resistance, especially
among older antimicrobial drugs, presents new
clinical and therapeutic dilemmas, which necessitate a deeper understanding of current and new
potential strategies. Since urinary tract infections
(UTIs) in women are a common problem in primary care settings, treatment of uncomplicated
UTIs is the main topic of the most authors (Uzunović-Kamberović at al., Tićac at al, Marijan at
al.). Community-acquired UTIs are caused by
Escherichia coli in approximately 90% of cases,
and less commonly, by other Enterobacteriaceae,
such as Klebsiella spp. and Proteus spp. The current management of acute uncomplicated cysti-
tis is usually empirical, without the use of urine
culture or susceptibilities testing to guide therapy
(Škerk and Markotić). However, as with many
other community-acquired infections, antimicrobial resistance to different groups of antibiotics is
increasing due to the spread and high-level usage of antibiotics (Culig at al). Knowledge about
such specific antimicrobial resistance patterns in
particular geographic areas is of the utmost importance when recommending the most suitable
antibiotic treatment (Bedenić at al.),
The second, though not less important goal of
this issue, is to present new opportunities in diagnostics of the most prevalent infections of genital tract, chlamydial and human papilloma virus
(HPV) infections (Ljubin Sternak and Škerk, Židovec Lepej and Vince, Žele Starčević at al).
Prof. Jasmina Vraneš, MD, PhD
Guest Editor
Ass. Prof. Selma Uzunović-Kamberović, MD,
MA, PhD
Editor-in-Chief
Medicinski Glasnik
180

medicinski glasnik 13.indd

Transcription

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