A QUARTERLY JOURNAL DEVOTED TO CLINICAL AND BASIC STUDIES OF THE DIGESTIVE TRACT AND LIVER
PUBLISHED BY THE SERBIAN MEDICAL ASSOCIATION – SECTION FOR GASTROENTEROLOGY
TROMESEČNI ČASOPIS ZA KLINIČKA I BAZIČNA ISTRAŽIVANJA DIGESTIVNOG SISTEMA I JETRE
IZDAJE SRPSKO LEKARSKO DRUŠTVO – GASTROENTEROLOŠKA SEKCIJA
CO-EDITORs IN-CHIEF
GLAVNI I ODGOVORNI UREDNICI
Ivan R. Jovanović
Klinika za Gastroenterologiju i hepatologiju, KCS
Koste Todorovića 2
11000 Beograd
Daniela Bojić, Kliničko odeljenje za
gastroenterologiju i hepatologiju, KBC Zvezdara
Dimitrija Tucovića 161
11 000 Beograd
FOUNDING EDITOR
UREDNIK-OSNIVAČ
Obren Popović
SENIOR ASSOCIATE EDITORS
Goran Janković
Miodrag Krstić
CHAIRPERSON OF
EDITORIAL BOARD
PREDSEDNIK
UREĐIVAČKOG ODBORA
ASSOCIATE EDITORS FOR
HEPATOLOGY
Tamara Alempijević
Petar Svorcan
ASSOCIATE EDITORS FOR
CLINICAL CASES
Milenko Uglješić
Nikola Milinić
ASSOCIATE EDITORS FOR
ENDOSCOPY
Aleksandar Nagorni
Dragomir Damjanov
Srđan Đuranović
Nenad Perišić
Milutin Bulajić
ASSOCIATE EDITORS FOR
ONCOLOGY
Dušan Jovanović
Dino Tarabar
Nenad Mijalković
Nenad Manojlović
EDITORIAL BOARD
UREĐIVAČKI ODBOR
Mirko Bulajić
Ivan Boričić
Goran Stevanović
Radoje Doder
Predrag Dugalić
Rada Ješić
Zoran Krivokapić
Goran Barišić
Dragutin Kecmanović
Milan Ćeranić
Aleksandar Simić
Marjan Micev
Mirjana Perišić
Nada Kovačević
Nedeljko Radlović
Vojislav Perišić
Ljiljana Hadnađev
Aleksandar Simić
Miloš Bjelović
Goran Nikolić
Aleksandar Sretenović
Biljana Miličić
Zoran Radojičić
INTERNATIONAL ADVISORY
BOARD
MEĐUNARODNI SAVETODAVNI
ODBOR
Aleksandra Sokić-Milutinović
ASSOCIATE EDITORS
UREDNICI
ASSOCIATE EDITORS FOR
GASTROENTEROLOGY
Tomica Milosavljević
Njegica Jojić
During the spring 1982 by joint effort of a group of
enthusiasts, gastroenterohepatologists the Archives
of Gastroenterohepatology was created. In memory
of these pioneers, Editorial Board of the Archives
of Gastroenterohepatology is noticing their names
(alphabetically): Milan Andrejević, Mirko Bulajić,
Mihailo Elaković, Nada Kovačević, Milenko Lalić,
Ljubiša Glišić, Vera Perišić, Milentije Petrović,
Obren Popović, Jovan Teodorović
Monica Acalovschi, Cluj-Napoca, Romania
Klaus Moenkemueller, Bottrop, Germany
Ian Gralnek, Haifa, Israel
Guenter J. Krejs, Graz, Austria
Nenad Vanis, Sarajevo, Bosnia and
Hercegovina
Boric Vucelić, Zagreb, Croatia
Silvija Čučković-Čavka, Zagreb, Croatia
Simon PL Travis, Oxford, Great Britain
INSTRUCTION TO AUTHORS AND CHECKLIST
ARCHIVES OF GASTROENTEROHEPATOLOGY
publishes original papers, multi-center trials, editorials,
review articles, letters to the Editor, other articles and
informations concerned with practice and research in
the field of gastroenterology and hepatology, written in
English, or Serbian. The Editorial Board and the publisher
will provide adequate translation for the accepted articles.
Address manuscripts to:
Ivan R. Jovanović
Clinic for Gastroenterology and Hepatology
Clinical Centar of Serbia
Koste Todorovića 2
11000 Belgrade, Serbia
Daniela Bojić
Center for Gastroenterology and Hepatology,
Zvezdara University Clinical Center, Belgrade, Serbia
Dimitrija Tucovića 161
11000 Belgrade, Serbia
ARCHIVES OF GASTROENTEROHEPATOLOGY
Clinic for Gastroenterology and Hepatology,
Clinical Centre of Serbia
Koste Todorovića 2, 11000 Belgrade, Serbia
tel/fax: /+381 11/ 268-64-47
tel: /+381 11/ 366-33-46
e-mail: [email protected]
Manuscripts are prepared in accordance with Uniform
requirements for manuscripits submitted to biomedical
journals developed by the international committee of
medical journal editors (N Engl J Med 1991; 324; 424428). Consult these instructions and a recent issue of
Archives of Gastroenterohepatology in preparing your
manuscript. Original manuscripts will be accepted with
the understanding that they are solely contributed to
Archives of Gastroenterohepatology. Manuscripts, accepted
for publication, become the property of the Journal, and
may not be published elsewere without written permission
from both the editor and publisher. The Journal does
not publish papers containing material that has been
published elsewhere except as an abstract of 400 words
or less; previous publication in abstract form must be
disclosed in a footnote.
Cover letter
A cover letter (in form of a separate Word for Windows
file) contains pertinent explanations and clarifications, if
any, concerning the manuscript. Authors are encouraged to
provide on a separate page the names and addresses of one
to three experts who, in their opinion, are best qualified to
peer review the paper.
Manuscript
The manuscripts have to be processed in the Word for
Windows processing package. They can be either submitted:
a) compact disk (CD) or
b) sent via e-mail.
The manuscripts must be formatted double-spaced
throughout (including references, tables, figure legends,
and footnotes) on A4 (21 cm x 29.7 cm) page size with
wide margins. The manuscript is arranged as follows:
abstract, introduction, patients and methods/material and
methods, results, discussion, references, tables, and figures.
Each manuscript component (title page, etc.) begins
on a separate page. All pages are numbered consecutively
beginning with the title page. The first author’s last name
is typed at the top right corner of each page.
All measurements, except blood pressure, should be
expressed in Systeme Internationale (SI) units (see BMJ
1991; 302:338-41) and, if necessary, in conventional units
(in parenthesis). Generic names are used for drugs.
Authors are advised to retain backup copies of the
manuscript. Archives of Gastroenterohepatology is not
responsible for the loss or damage of the electronic media
with manuscripts in the mail.
Title page
Title page contains the title, short title, full names of all
the authors, names and full location of their departments/
institution, acknowledgements, abbreviations used, and
name and full address of the corresponding author. The
name of each author must be followed by a superscript
tag number corresponding to the one preceeding his
department/institution.
The title of the article is concise but informative, and
includes animal species if appropriate. A subtitle can be
added if necessary.
A short running title of less than 50 characters with
spaces, for use as a running head, is included. A brief
acknowledgement of grants and other assistance, if any,
is included.
A list of abbreviations used in the paper, if any, is
included. List abbreviations alphabetically followed by
an explanation of what they stand for. In general, use of
abbreviations is discouraged unless they are essential for
improving the readability of the text.
The name, telephone number, fax number, exact postal
address, and e-mail (obligatory) of the corresponding author
should be typed in the lower right corner of the title page.
Abstract page
An abstract of less than 180 words concisely states
the objective, findings and conclusion of the studies
described in the manuscript. The abstract does not
contain abbreviations, footnotes or references.
Below the abstract, 3 to 8 short keywords are provided
for indexing purposes. When possible use terms from the
MeSH list of Index Medicus.
Introduction page
The introduction is concise, and states the reason and
specific purpose of the study.
Patients and methods/Material and methods
Selection of patients or experimental animals,
including controls is described. Patient’s names and
hospital numbers are not used.
Methods are described in sufficient detail to permit
evaluation and duplication of the work by other
investigators.
When reporting experiments on human subjects,
it is necessary to indicate whether the procedures
followed were in accordance with ethical standards
of the Committee on human experimentation of the
institution in which they were done and in accordance
with the Declaration of Helsinki (see BMJ 1964; II:177).
Hazardous procedures or chemicals, if used, are described
in detail, including the safety precautions observed. When
appropriate, a statement is included verifying that the
care of laboratory animals followed accepted standards.
Statistical methods used are outlined.
Results
Results are clear and concise, and include a minimum
number of tables and figures necessary for proper
presentation.
Discussion
An exhaustive review of literature is not necessary. The
major findings should be discussed in relation to other
published work. Attempts should be made to explain
differences between the results of the present study and
those of others.
Hypothesis and speculative statements should be
clearly identified. The Discussion section should not be
a restatement of results, and new results should not be
introduced in the discussion.
References
References are identified in the text by Arabic numerals
in parenthesis. They are numbered consecutively in
the order in which they appear in the text. Personal
communications and unpublished observations are not
cited in the reference list, but may be mentioned in the text
in parenthesis. A work “in press” may be included provided
the name of the journal appears. Abbreviations of journals
conform to those used in Index Medicus. The style and
punctuation conform to Archives of Gastroenterohepatology
style requirements. The following are examples:
Article
(all authors are listed if there are six or fewer; otherwise
only the first three are listed followed by “et. a1.”)
12. Talley NJ, Zinsmeister Ar, Schleck CD, Melton LJ
III. Dyspepsia and dyspeptic subgroups: A populationbased study. Gastroenterology 1992; 102: 1259-68.
Book
17. Sherlock S. Diseases of the liver and biliary system,
8th ed. Oxford: Blackwell Sci Publ, 1989.
Chapter or article in a book
24. Trier JJ, Celiac sprue. In: Sleisenger MH, Fordtran
JS, eds. Gastrointestinal disease, 4th ed. Philadelphia: WB
Saunders Co, 1989:1134-52.
The authors are responsible for the accuracy of their
reference data.
Tables
Tables should be submitted in the same format as
your article and embedded in the article. Please note
that the Journal cannot accept Excel files. If your table(s)
are in Excel, copy and paste them into the manuscript
file. Tables should be selfexplanatory, and the data they
contain must not be duplicated in the text or figures.
Tables have numbers (Arabic) and title above the table
and explanatory notes, if any, below the table.
Figures and Figure legends
All illustrations (photographs, graphs, diagrams) are
to be considered figures, and are numbered consecutively
in the text and figure legend, in Arabic numerals. The
number of figures included is the least rCase report and
rewiev of literature.
INTRODUCTION
Starting with the mid-late nineties, the large-scale
introduction of highly active antiretroviral therapy
(HAART), significantly acted on the natural history
and course of HIV infection in industrialized countries,
leading to a rapid drop of the incidence of all opportunistic
disorders, but principally those linked to a very deep
immunodeficiency (as measurable by a CD4+ Tlymphocyte
count below 50-100 cells/μL) [1-5]. Among these last
infectious complications, we retrieve Cytomegalovirosis,
atypical micobacteriosis, cryptosporidiosis, but also the
most frequent fungal infections, also including visceral or
disseminated disease, caused by the yeasts Candida spp.
and Cryptococcus spp. A recent European multicentre
study observed also an evident decline of diagnosis of
AIDS-associated esophageal candidiasis, during the years
following HAART availability [6].
Still today, nearly 25 years after the discovery of HIV
as the causal agent of AIDS, a non-negligible number of
patients (certainly much more elevated in developing
countries) [7], is still unaware or neglected eventual previous
exposures to HIV infection. In other cases, although HIV
infection has been detected and communicated months
or often years before, the relevant patients neglected or
refused further examinations and eventual therapeutic
and chemoprophylactic recommendations, or showed
very low levels of adherence to HAART, all conditions
which strongly prompt an increased risk to develop severe
opportunistic disease already included in the diagnosis of
AIDS, after a progressive impairment of immune defence,
as demonstrated by very low CD4+ T-cell counts [8, 9].
Due to these complex epidemiological and socialhealth care motivations, the case of a novel diagnosis of
HIV infection performed when already complicated by
an AIDS-related condition (or even posed only at the
time of patient’s death, when HIV infection is detected
on retrospective basis), are still present occurrences, even
after a decade since the availability of the potent HAART
regimens [4, 10-12]. In a recent survey conducted in a
very extensive Italian cohort based on 3,483 patient
with HIV infection or AIDS, the proportion of “AIDS
presenters” increased from a 13.8% rate observed in the
pre-HAART era (until year 1996), up to 32.5% of the
period 1997-2000 [4]. A sub-study published as a part
of the Italian multicentre cohort named “ICoNA” [10]
extensively assessed all possible behavioural correlates
linked to a late access to HIV testing among 968 patients
with a newly diagnosed HIV infection, and also analyzed
the consequences on the staging of the underlying,
unrecognized and untreated HIV disease [10]. Other
Italian data coming from the National AIDS Centre in
Rome strongly witness a significant increase of AIDS
occurrences burdened by a late HIV serology testing:
in the years ranging from 1996 and 2002, an increased
risk regarded patients with sexual exposure, residence
in Italian regions with a proportionally low HIV figures,
or immigrating from developing countries [12]. Among
these patients, pneumocystosis, neurotoxoplasmosis, and
Kaposi’s sarcoma were the most common complications,
but the occurrence of multiple, concomitant
AIDSassociated disorders became apparent [12]. In
a Scottish study conducted between years 1999 and
2003, the condition of “AIDS presenter” was related to
heterosexual males and females (compared with homobisexual male) exposure to HIV [11].
Checklist for authors
Cover letter (Word for Windows document file)
Manuscript (Word for Windows document file)
Figures (TIFF, GIF, or high quality JPEG graphic files - 300dpi)
Title page
- Title
- Short running head of no more than 50 spaces
- Author(s) and affiliation(s)
- Acknowledgement (if any)
- Abbreviations (if any)
- Address, telephone and fax numbers, and e-mail of corresponding author
Article proper (double spaced)
- Abstract
- Key words
- Introduction
- Patients and methods / Material and methods (Tables, Figure legends)
- Results (Tables, Figure legends)
- Discussion
- References
- Figures
- Permission to reproduce any previously published material and patient releases to publish photographs (if any).
Submission of a manuscript implies that the work has not been published before and that is not under consideration
elsewhere.
UPUTSTVO AUTORIMA I PODSETNIK
GASTROENTEROHEPATOLOŠKI ARHIV (ARCHIVES
OF GASTROENTEROHEPATOLOGY) objavljuje originalne
radove, multicentrične studije, uvodnike, pregledne članke,
pisma Uredništvu, i druge članke i informacije vezane za
istraživanja ili praktična pitanja iz oblasti gastroenterologije
i hepatologije, na srpskom ili engleskom. Uredništvo i
izdavač će obezbediti odgovarajući prevod za članke koji su
prihvaćeni za štampu.
Radovi se šalju na sledeću adresu:
Ivan R. Jovanović
Klinika za Gastroenterologiju i hepatologiju, KCS
Koste Todorovića 2
11000 Beograd, Srbija
Daniela Bojić
Kliničko odeljenje za gastroenterologiju i hepatologiju,
KBC Zvezdara
Dimitrija Tucovića 161
11000 Beograd, Srbija
ARCHIVES OF GASTROENTEROHEPATOLOGY
Klinika za gastroenterologiju i hepatologiju,
Klinički centar Srbije
Koste Todorovića 2, 11000 Beograd, Srbija
tel/fax: /+381 11/ 268-64-47
tel: /+381 11/ 366-33-46
e-mail: [email protected]
Radovi se pripremaju u skladu sa Jednoobraznim
Pravilima za radove koji se dostavljaju biomedicinskim
časopisima, delo međunarodnog komiteta urednika
medicinskih časopisa (N Engl J Med 1991; 324; 424428). Potrebno je konsultovati ova uputstva i neki od
skorašnjih brojeva Archives of Gastroenterohepatology
pre pripreme rada. Originalni radovi biće prihvaćeni za
štampu samo uz uslov da su predati jedino za Archives
of Gastroenterohepatology. Radovi prihvaćeni za štampu,
postaju vlasništvo Časopisa, i ne smeju se drugde šampati
osim u vidu rezimea od najviše 400 reči; prethodno
objavljivanje rada u vidu rezimea mora se navesti u
napomeni.
Propratno pismo
Propratno pismo (u obliku Word for Windows
dokumenta) sadrži značajna objašnjenja koja se odnose
na rad. Autorima se preporučuje da obezbede na posebnoj
strani imena i adrese od jednog do tri stručnjaka koji
bi, po njihovom mišljenju, bili najkvalifikovaniji da
recenziraju rad.
Rukopis (Rad)
Radove uobličiti u formatu Word for Windows
dokumenta. Oni se mogu dostaviti na jedan od dva načina:
a) na kompakt disku (CD); ili
b) putem elektronske pošte (e-mail-a).
Radovi u celini moraju biti sa dvostrukim proredom
(uključujući i literaturu, tabele, legende slika i napomene)
sa stranicama formata A4 (21 cm x 29.7 cm) uz široke
margine. Struktura rada je sledeća: rezime, uvod, pacijenti
i metodi/materijal i metodi, rezultati, diskusija, literatura,
tabele, i slike.
Svaka od komponenti rada (naslovna strana, itd.)
počinje na posebnoj strani. Sve stranice se numerišu
redom, počevši od naslovne strane. Prezime prvog autora
stavlja se u gornji desni ugao svake stranice.
Sve mere, osim krvnog pritiska, treba da budu u
Systeme Internationale (SI) jedinicama (vidi BMJ 1991;
302:338-41) i, ukoliko je neophodno, mogu biti i u
konvencionalnim jedinicama (u zagradi). Za nazive
lekova se koriste isključivo generička imena.
Autorima se preporučuje da zadrže rezervne (backup)
kopije svoga rada. Archives of Gastroenterohepatology nije
odgvoran za gubitak ili oštećenje elektronskih medija koji
sadrže rad, tokom slanja poštom.
Naslovna strana
Naslovna strana sadrži naslov, kratki naslov, imena i
prezimena svih autora, naziv i tačno odredište institucija
ili odeljenja/klinike kojima pripadaju, zahvalnice,
skraćenice koje se koriste u tekstu, kao i ime i punu adresu
autora odgovornog za korespodenciju. Iza imena svakog
od autora mora stajati indeks-broj koji odgovara broju
ispred naziva i adrese njegove institucije ili odeljenja/
klinike kojoj pripada.
Naslov rada mora biti koncizan ali informativan, i
da sadrži nazive životinjskih vrsta, ako je to celishodno.
Ukoliko je neophodno, može se dodati i podnaslov.
Za potrebe zaglavlja, dodaje se i kratak radni naslov
koji treba da sadrži najviše 50 slovnih mesta, uključujući
i razmake.
Može se dodati i kratka zahvalnica vezana za dotacije,
projekte i bilo koju drugu pomoć u izradi rada.
Potrebno je navesti i listu skraćenica, ukoliko se
koriste u tekstu. Skraćenice treba navesti po abecednom
redosledu, uz objašnjenje šta znače, uopšte uzev, treba
izbegavati korišćenje skraćenica osim ukoliko nisu
neophodne za razumevanje rada.
U desnom donjem uglu naslovne strane treba navesti
ime, broj telefona, broj faksa, tačnu poštansku adresu
i e-mail adresu (obavezno!) autora odgovornog za
korespodenciju.
Rezime
Rezime od najviše 180 reči koncizno izlaže cilj, nalaze
i zaključak studije opisane u radu. Rezime ne sadrži
skraćenice, napomene ili literaturu.
Ispod rezimea navodi se 3 do 8 ključnih reči, za
potrebe indeksiranja. Kad god je to moguće, treba koristiti
termine iz MeSH liste Index Medicus-a.
Uvod
Uvod je koncizan, obrazlaže opravdanost studije i
njen specifičan cilj.
Pacijenti i metodi / Materijal i metodi
U ovom odeljku se opisuje izbor pacijenata ili
eksperimentalnih životinja, kao i kontrole grupe, ukoliko
postoji. Ne smeju se navoditi imena pacijenata ili brojevi
bolničkih protokola.
Metodi se moraju precizno opisati kako bi se
omogućilo njihovo vrednovanje i ponavljanje od strane
drugih istraživača.
Kada se opisuju istraživanja na ljudima, potrebno je
navesti da li su postupci izvedeni u skladu sa standardima
etičkog Komiteta institucije u kojoj je istraživanje
izvedeno i u skladu sa Deklaracijom iz Helsinkija (vidi
BMJ 1964; II:177). Ukoliko se koriste opasne procedure
ili hemikalije, potrebno ih je detaljno opisati, uz opis
sigurnosnih mera. Ukoliko je celishodno, treba potvrditi
da je postupak sa laboratorijskim životinjama bio u
skladu sa opšte prihvaćenim standardima.
U radu se navodi samo kratak pregled korišćenih
statističkih metoda.
Rezultati
Rezultate treba predstaviti koncizno i jasno, uz
minimum tabela i slika neophodnih za pravilnu
prezentaciju.
Diskusija
Za diskusiju nije neophodan iscrpan pregled literature.
Najvažnije rezultate treba diskutovati u vezi sa drugim
objavljenim radovima. Treba pokušati da se objasne
razlike u rezultatima postojeće i drugih studija.
Hipoteze i pretpostavke se moraju jasno identifikovati.
Odeljak Diskusije nije prosto ponavljanje rezultata, i u
njemu se ne smeju izlagati novi rezultati.
Literatura
Literatura se numeriše arapskim brojevima u zagradi,
redom kojim se pojavljuje u tekstu. Pisane komunikacije
i neobjavljeni nalazi se ne citiraju u literaturi, ali se mogu
pomenuti u tekstu u zagradama. Rad koji je „u štampi”
može biti uključen u literaturu ukoliko se navede naziv
časopisa. Skraćenice naziva časopisa treba uskladiti
sa onima koje se koriste u Index Medicus-u. Stil i
intepunkcija moraju biti usklađeni sa zahtevima Archives
of Gastroenterohepatolog-ja. Slede primeri navođenja:
Članak
(ukoliko je šest ili manje autora, svi se citiraju, ukoliko
ih je više od 6, citiraju se prva 3 i dodaje „et. a1.”)
12. Talley NJ, Zinsmeister Ar, Schleck CD, Melton LJ
III. Dyspepsia and dyspeptic subgroups: A populationbased study. Gastroenterology 1992; 102: 1259-68.
Knjiga
17. Sherlock S. Diseases of the liver and biliary system,
8th ed. Oxford: Blackwell Sci Publ, 1989.
Poglavlje ili članak u knjizi
24. Trier JJ, Celiac sprue. In: Sleisenger MH, Fordtran
JS, eds. Gastrointestinal disease, 4th ed. Philadelphia: WB
Saunders Co, 1989:1134-52.
Autori su odgovorni za tačnost svojih literaturnih
podataka.
Tabele
Tabele treba obraditi u istom formatu u kojem je i rad,
i uključiti u tekst rada. Časopis ne može da prihvati Excel
dokumenta. Ukoliko je tabela rađena u Excel-u, treba je
iskopirati i uključiti u osnovni dokument rada. Tabele
same sebe objašnjavaju, a podaci koje sadrže ne treba
ponavljati u tekstu ili na slikama. Tabele su numerisane
arapskim brojevima, imaju naslov iznad i eventualna
objašnjenja (npr. skraćenice) ispod njih.
Slike i legende slika
Sve ilustracije (fotografije, grafikoni, dijagrami) se
smatraju slikama, i numerišu se arapskim brojevima,
redosledom pojavljivanja u tekstu i na legendi slika. Broj
slika treba da bude racionalno redukovan u pogledu
iznošenja poruke rada; slika ne treba da ponavlja podatke
iznete u tabelama ili tekstu. Slike nemaju naslove. Slova,
brojevi ili simboli na slikama moraju biti jasno prikazani,
u odgovarajućoj proporciji, dovoljno veliki da budu
čitljivi kod smanjenja u štampi.
Ukoliko postoji značajno uveličavanje slike
(fotomikrografije) treba ga označiti kalibracionom
trakom na slici, a ne faktorom uvećanja u legendi slike.
Dužina kalibracione trake sa slike treba da bude navedena
u legendi slike.
Crno-bele slike (fotografije, crteži, grafikoni itd.) treba
da budu sačuvani i dostavljeni u jednom od sledećih
formata: TIFF, GIF, ili visokokvalitetni JPEG dokument
uz rezoluciju od najmanje 300 dpi.
Slike u boji treba sačuvati i priložiti: treba da budu
sačuvani i dostavljeni u jednom od sledećih formata:
TIFF, GIF, ili visokokvalitetni JPEG dokument. Grafički
dokument (fajl) slike u boji ne treba da bude veći od 1.5
MB uz rezoluciju od najmanje 300 dpi.
Ukoliko izaberete višu rezoluciju, treba adekvatno
smanjiti dimenzije slike kako bi dokument bio manji
od 1.5 MB. Sve slike treba sačuvati kao posebne grafičke
dokumente i nikako ih ne interponirati u osnovni tekst
rukopisa (Word for Windows dokument).
Ukoliko su slike bile prethodno objavljene, treba
pomenuti originalni izvor i dostaviti pisani pristanak za
reprodukciju od nosioca autorskog prava.
Štampanje slika u boji je moguće samo po zahtevu
autora, koji snosi troškove ovakve štampe.
vraćen autoru, pre završnog odobravanja. U cilju brže
realizacije, autorima neće biti poslat probni otisak, već će
taj otisak biti pregledan od strane Glavnog i odgovornog
urednika, i Urednika deska.
Poverljivost podataka
Pisma Uredniku / Kratka saopštenja
Pisma koja se pozivaju na članke objavljene u
Archives of Gastroenterohepatology, ali i ona koja se na
njih ne odnose (kratka saopštenja), biće razmatrana za
objavljivanje. Takva pisma/saopštenja mogu da sadrže
jednu tabelu ili sliku i do 5 referenci.
Za objavljivanje podataka koji, bilo sami ili u
kombinaciji, mogu da odaju identitet pacijenta (živog ili
preminulog, odraslog ili deteta) potrebno je obezbediti
pisani pristanak od strane samog pacijenta (ili, u slučaju
smrti, od rodbine). Fotografije pacijenata koji se po
njima mogu prepoznati, smeju se objaviti samo uz pisani
pristanak pacijenta.
Probni otisak
Sve radove će pažljivo pregledati urednik deska
izdavača. Samo u slučaju brojnih ispravki rad će biti
Podsetnik za autore
Propratno pismo (Word for Windows dokument)
Rukopis – Rad (Word for Windows dokument)
Slike (grafički dokumenti formata TIFF, GIF, ili visokokvalitetni JPEG – minimum 300 dpi)
Naslovna strana
- Naslov
- Kratak radni naslov do 50 slovnih mesta
- Autori i njihove institucije
- Zahvalnice (ukoliko ih ima)
- Skraćenice (ukoliko ih ima)
- Ime, tačna poštanska adresa, broj telefona, broj faksa, i e-mail adresa autora odgovornog za korespodenciju
Rad (dvostruki prored)
- Rezime
- Ključne reči
- Uvod
- Pacijenti i metodi / Materijal i metodi (tabele, legende slika)
- Results (Tables, Figure legends)
- Diskusija
- Literatura
- Slike
- Dozvola za reprodukciju bilo kog prethodno publikovanog materijala i pisane povrde pacijenata za objavljivanje
fotografija (ukoliko ih ima)
Podnošenje rukopisa – rada podrazumeva da taj rad nije prethodno objavljen niti da je već uzet u razmatranje za
publikcju na nekom drugom mestu.
In memoriam
Prof. dr Ljubiša Glišić
(1924-2011)
Ljubiša Glišić rođen je 05.12.1924. godine u Arilju.
Prvi je u svetu uveo prostigmin-pankreoziminski
Medicinski fakultet u Beogradu upisao je 1945. test, koji se pokazao posebno značajnim u razlikogodine i diplomirao 1951. godine. Specijalistički ispit vanju zapaljenske od tumorske lezije pankreasa.
iz predmeta Interna medicina položio je 1958. godine.
Bavio se problemima gastrointestinalnih
U toku studija, radio je kao demonstrator tri godi- hormona i tumorskih markera, koja istraživanja
ne u Drugoj internoj klinici. U zvanje asistenta za su bila od posebnog značaja u ranom otkrivanju
predmet Interna medicina izabran je 1954. godine, malignih tumora digestivnog trakta.
a u zvanje docenta izabran je 1971. godine. Redovni
Bio je predsednik Gastroenterološke sekcije i
profesor postao je 1982. godine.
Udruženja gastroenterologa Jugoslavije kao i organiProfesor Glišić je školske 1963/64. godine pro- zator i predsednik Organizacionog odbora Kongreveo devet meseci u SAD, kao stipendista Svetske sa gastroenterologa Jugoslavije. Tokom rada u
zdravstvene organizacije, na usavršavanju iz gastro- Internoj klinici A, najpre je bio šef Endoskopskog
enterologije u više najpoznatijih medicinskih cen- kabineta, zatim šef Gastroenterološkog odeljenja,
tara SAD. Od tog vremena, posebno se bavi gastro- a 1985. godine postao je direktor Klinike za
enterologijom u stručnom i naučnom radu.
gastroenterologiju i hepatologiju Univerzitetskog
kliničkog centra u Beogradu.
Bio je šef Petog odseka Interne klinike A (gastroenterološkog centra), a pre toga je rukovodio radom
Penzionisan je 1991. godine, ali je narednih pet
kabineta za gastroenterološku endoskopiju.
godina nastavio sa svakodnevnim radom u Kliničkom Centru Srbije. Bio je član Emeritus Udruženja
Objavio je veliki broj stručno-naučnih radova, gastroenterologa Srbije.
pretežno iz gastroenterologije, a učestvovao je u
pisanju jedanaest udžbenika iz Interne medicine i
Samo na sebi svojstven način, plenio je ljude
gastroenterologije. Pored ovih jedanaest udžbenika, koji su sa njim sarađivali. Po prirodi i naravi bio je
objavio je i četiri knjige za građanstvo i pacijente.
uvek vedrog duha i voleo humor. Tu svoju pozitivnu
energiju prenosio je i na svoje saradnike.
Od dolaska na Internu A, profesor Glišić se
posebno bavio problematikom oboljenja pankreasa
Profesor Glišić preminuo je 2011. godine. Svima
iz koje oblasti je i njegova doktorska disertacija pod nama ostaće u jednom lepom, dragom sećanju i
naslovom Funkcionalna dijagnostika pankreatitisa. uspomeni.
Obrađivao je kompletnu problematiku iz oblasti
gastroenterologije i bio je organizator raznih naučnih
Uredništvo
skupova iz ove oblasti. Sa svojim radovima učestvoGastroenterohepatološkog Arhiva
vao je na mnogim sastancima i kongresima kako
u zemlji tako i u imostranstvu. Bio je član Svetskog
udruženja gastroenterologa.
8
Alimentary tract
ARCH GASTROENTEROHEPATOL 2012; 29 (No 1) 9-14
Lucia C. Fry1,
Helmut Neumann1,
Ivan Jovanovic2,
Peter Malfertheiner1,
Klaus Mönkemüller1
1
Department of Gastroenterology, Hepatology
and Infectious Diseases, Otto-von-Guericke
University, Magdeburg, Germany
2
Clinic for Gastroenterology and Hepatology,
Clinical Center of Serbia, Belgrade
2
Faculty of Medicine, University of Belgrade,
Serbia
Keywords:
enteroscopy, double balloon enteroscopy,
push and pull enteroscopy,
balloon enteroscopy, balloon assisted enteroscopy,
small bowel, gastrointestinal bleeding,
capsule endoscopy.
Capsule endoscopy
increases the diagnostic yield of
double balloon enteroscopy in
patients being investigated for
obscure gastrointestinal bleeding
ABSTRACT:
Background: Both capsule endoscopy (CE) and double balloon
enteroscopy (DBE) are valuable methods for the evaluation of
obscure gastrointestinal bleeding (OGIB). Many experts recommend
the use of CE to guide DBE. However, the true impact of CE on the
yield of DBE in the daily clinical practice has not been evaluated. We
had the unique opportunity to observe the impact of CE on DBE in
patients with OGIB, as the introduction of CE in our clinical setting
occurred reversed, i.e. after DBE.
Aim: To evaluate the impact of CE on the yield of DBE in patients
with OGIB.
Patients and Methods: Consecutive patients evaluated for OGIB
were studied during a two-year period. The patients were categorized
into two periods: before CE (January to December 2006) and after
CE (January to December 2007).
Results: During the first period (before CE) a total of 27 patients (69
yrs, range 12-88) underwent 34 DBEs for OGIB (overt OGIB, n=20,
occult, n=7). During the second period (after CE) a total of 24 patients
(71 yrs, range 25-85) underwent 27 DBEs for OGIB (over OGIB,
n=17, occult, n=7). The diagnostic yield of DBE was 39.9% during
the first period (DBE alone), compared to 62.9% during the second
Address correspondence to:
Klaus Mönkemüller, M.D., Ph.D., FASGE
Department of Gastroenterology, Hepatology and
Infectious Diseases,
Marienhospital Bottrop
46236 Bottrop
Germany
phone: +49 2041 106 1001
fax: +49 2041 106 1019
e-mail: [email protected]
Capsule endoscopy increases the diagnostic yield of double balloon enteroscopy in patients being investigated for obscure gastrointestinal bleeding
9
period (DBE after CE) (p < 0,002). The following of endoscopic biopsies and cultures (if any),
diagnoses were made: Dieulafoy lesions, n=4, AVMs, findings on DBE, total duration of the procedure
n=10, tumors, n=4, ulcers and erosions, n=6.
and endoscopic therapy or changes in therapeutic
Conclusions: In patients with OGIB performance of management based on findings.
CE prior to DBE increases the diagnostic yield of DBE.
INTRODUCTION:
Both capsule endoscopy (CE) and double balloon
enteroscopy (DBE) are valuable methods for the
evaluation of obscure gastrointestinal bleeding
(OGIB) (1-5). Indeed, the most common indication
for performing capsule endoscopy (CE) and/or
double balloon enteroscopy (DBE) is OGIB or
suspected small bowel bleeding (1-5). Although
many experts recommend the use of CE to guide
DBE the best investigation algorithm for patients
with acute OGIB remains to be defined (6,7). In
addition, the true impact of CE on the yield of DBE
in the daily clinical practice has not been evaluated.
We had the unique opportunity to observe the
impact of CE on DBE in patients with OGIB, as the
introduction of CE in our clinical setting occurred
reversed, i.e. after DBE. Therefore, in this study we
aimed to evaluate the impact of CE on the yield of
DBE in patients with OGIB.
PATIENTS AND METHODS:
This is a retrospective single center cohort-study
of consecutive patients who were evaluated for
OGIB at University of Magdeburg Medical Center
(Universitätsklinikum Magdeburg, Otto von
Guericke Universität, Magdeburg, Germany). OGIB
was defined according to consensus guidelines (6).
Thus, all patients had undergone at least one EGD
and colonoscopy prior to being referred for DBE.
Patients referred for DBE because of abnormal CE
findings from outside institutions were excluded.
All patients provided written informed consent to
undergo CE and DBE, including endoscopic therapy
after the endoscopist and attending physician had
explained the procedure in detail to them. The study
was approved by the ethics committee and conducted
out in accordance to the Helsinki Declaration.
Data abstracted for analysis from the prospectively
collected database included patient’s demographics,
past medical history, laboratory values, indication
for endoscopy, history of co-morbid illnesses, social
history, medications, details of prior endoscopies,
fecal occult blood tests, duration of anemia, results
10
Arch Gastroenterohepatol 2012; 29 (No 1) 9-14
The study cohort was divided into two study periods
based on the local availability of CE. The first period
spanned from 1/2006 to 12/2006 (group I) and the
second period spanned from 1/2007 to 12/2007
(group II).
For the purpose of this analysis only small bowel
lesions explaining the OGIB were considered,
i.e. patients with lesions outside the small bowel
explaining the bleeding (e.g. gastric antral vascular
ectasias, ulcers, etc) or non-specific mucosal lesions
were not considered as small bowel pathologies
causing bleeding and thus were excluded.
Technical aspects:
All patients undergoing CE and DBE underwent
small bowel cleansing on the day before the
procedure using a standard colon lavage solution
(Kleanprep, Germany).
CE was performed based on the recommendations
of ICCE and was performed by an endoscopist with
expert training in CE (LCF). DBE was performed
using two types of Fujinon enteroscopes (Fujinon
intestinoscope FN 450P 5/20, Fuji, Fujinon Corp.,
Japan) by two expert endoscopists (KM, LCF).
The characteristics of these endoscopes have been
presented in detail elsewhere (4). All the DBE
were performed in our endoscopy suite dedicated
for fluoroscopic procedures. Fluoroscopy was
performed using a Philips C-arm (Philips, Holland).
All procedures were performed using conscious
sedation with propofol (Lipuro, Braun, Melsungen).
Conscious sedation was administered by one
physician.
Determination of the primary route of insertion
(oral or antegrade versus anal or retrograde)
During the first period the choice of either the anal
or oral route depended on the suspected location
of the lesions within the small bowel based on the
clinical manifestations, results of laboratory and
radiological examinations (4). In cases of obscure
overt GIB the route of insertion was dictated by
the color of the stool; in cases of melena the oral
approach was preferred, whereas in the presence
of hematochezia the anal approach was used first.
If one DBE route did not yield any diagnosis the
Figure 1. The graph depicts the yield of double-balloon enteroscopy for obscure gastrointestinal bleeding before
and after the introduction of capsule endoscopy. There is a clear rise in diagnostic yield during the second period.
Descriptive statistics were employed to describe the
patient’s demographics and clinical characteristics,
presenting means and ranges. The diagnostic yield
was calculated using percentages and the chi-square
and/or Fisher’s exact test.
RESULTS:
The study cohort comprised a total of 51 patients
that underwent 60 double balloon enteroscopies for
OGIB. During the first period (before CE) a total
of 27 patients (69 yrs, range 12-88) underwent 34
DBEs (overt OGIB, n=20, occult, n=7) (1,2 DBE
per patient) (Group I). During the second period
(after CE) a total of 24 patients (71 yrs, range 2585) underwent 27 DBEs for OGIB (overt OGIB,
n=17, occult, n=7) (1,1 DBE per patient) (Group
II). In group I seven patients underwent both anal
and oral DBE whereas in group II only two patients
Figure 2. Classical angiovascular malformation detected underwent both oral and anal DBE (p < 0.05). One
with capsule endoscopy in a patient with obscure occult patient in group II underwent two DBEs.
gastrointestinal bleeding.
The diagnostic yield of DBE for group I was 39.9%,
opposite route was used for the second investigation. compared to 62.9% for group II (p < 0,002) (figure
To confirm total enteroscopy India ink marking of 1). Overall, the following diagnoses were made:
the small bowel was performed. Total enteroscopy Dieulafoy lesions, n=4, AVMs, n=10, tumors, n=4,
was also confirmed if the cecum or colon could be ulcers and erosions, n=6 (Table) (Figures 2, 3 and 4).
visualized when using the oral approach.
During the second study period a two patients were
During the second period CE was performed first
in all patients with occult OGIB and 14 patients
with overt OGIB (6 patients with overt OGIB went
directly to DBE). The results of CE were used to
indicate the preferential endoscope insertion route.
found to have lesions not detected neither by CE
nor DBE. During the second study period, of the six
patients undergoing DBE (but no prior) for overt
OGIB a diagnosis was made in four patients (66%).
The following lesions were more common in patients
Arch Gastroenterohepatol 2012; 29 (No 1) 9-14
11
Figure 3. Ulcerated lipoma found in a patient with recurrent hemodynamically-relevant overt obscure
gastrointestinal bleeding.
Figure 4. Bleeding neuroendocrine tumor detected during double balloon enteroscopy.
undergoing both CE and DBE: tumors (3 versus 1) obscure overt GI bleed. Although this approach
might sound logical, until now there was no clinical
and Dieulafoy lesions (3 versus 1) (p = 0.06).
Three patients with negative CE and mild or no study evaluating this question. We had the unique
opportunity to observe the influence of CE on the
anemia did no undergo further DBE.
diagnostic yield of DBE because we only had the
possibility to investigate patients with suspected small
DISCUSSION:
bowel disorders with invasive enteroscopic methods.
In this study we found that in patients with OGIB This is in line with the approach of other units in the
performing CE increases the diagnostic yield of world. Prior to 2006, the year CE was introduced in
DBE. This was true for both obscure occult and our unit, CE was not widely available in Japan and
12
Arch Gastroenterohepatol 2012; 29 (No 1) 9-14
Europe and the main methods of investigation of the
small bowel were push enteroscopy, intraoperative
enteroscopy and, since 2004, DBE.
Previous expert opinion and consensus conferences
had recommended performing a CE first in patients
with OGIB (7, 8). In a series of 162 OGIB patients,
the clinical relevance of findings at prior CE and the
oral access route were found to be associated with
a significantly higher yield of DBE (7). However,
in that study all patients had undergone CE and
there was no possibility to have a “control” group in
which no CE was made, such as in our study. Thus,
our study is important for several reasons. First, it
represents a “real life” clinical scenario. Nonetheless,
the ideal study would consist of a randomization of
patients with OGIB to either CE or DBE. However,
at present time such a study would not be practical.
Second, we showed that the use of CE increases the
diagnostic yield of DBE. And third, the number
of DBEs performed decreased over time. This was
mainly due to less attempts of performing both
oral and anal DBE in one patient. DBE is a time
consuming endeavour and more importantly, the
patient is spared an invasive procedure with potential
complications (9).
There are several studies evaluating the yield of
CE and/or DBE for OGIB (2-4, 7, 10, 11). Used
independently, both tests have good yields for the
diagnosis of OGIB, ranging from 45 to 76% (2-4, 7,
10-13). However, both methods are reported to have
false negatives and positives (10-13). Because DBE
offers several advantages over CE, such as tissue
retrieval, capability to inspect in a to and fro manner,
and to provide endoscopic therapy, some experts
prefer to directly proceed with a DBE in the setting
of OGIB. However, DBE is an invasive procedure,
which can result in complications (9). Complications
can be directly related to the procedure-related (i.e.
perforation and pancreatitis) or due to sedation (i.e.
arrhythmias, hypotension, respiratory failure) (9). In
addition, DBE is a demanding and time-consuming
procedure. Thus, performing an unnecessary
investigation adds a strain on endoscopic human
and material resources. Thus, we believe that DBE
should be used judiciously (Fry APT). Other experts
prefer to start the evaluation of OGIB with a CE (7).
Some data show that patients occult OGIB and mild
anemia with a negative CE have a good prognosis on
follow-up (14, 15). However, attention should be paid
to the patient with persistent or significant anemia,
as both DBE and CE can miss malignant small bowel
tumors (8, 16). In these cases further testing using
CT, angiography or intraoperative enteroscopy is
warranted (17).
In summary, we found that CE increased the
diagnostic yield of DBE in patients being evaluated
for obscure and overt OGIB. The main implication
of our findings is that CE should be performed in all
patients with occult OGIB and considered in patients
with overt OGIB. It remains a matter of debate
whether CE needs to be performed first in patients
with frank bleeding. We believe that DBE will have
the highest yield are those having frank bleeding with
either some hemodynamic compromise or those with
significant fall of the hemoglobin (17). Patients with
recurrent frank bleeding but without hemodynamic
compromise or significant fall in hemoglobin may
benefit from CE first approach. It also makes sense
to always perform CE first in patients with minor
signs of bleeding or occult OGIB.
Table. Small bowel diagnosis in the study cohort
Arch Gastroenterohepatol 2012; 29 (No 1) 9-14
13
References:
1. Leighton JA, Triester SL, Sharma
VK. Capsule endoscopy: a metaanalysis for use with obscure
gastrointestinal bleeding and
Crohn‘s
disease.
Gastrointest
Endosc Clin N Am 2006;16:229-50.
2. Triester SL, Leighton JA,
Leontiadis GI et al. A metaanalysis of the yield of capsule
endoscopy compared to other
diagnostic modalities in patients
with
non-stricturing
small
bowel Crohn‘s disease. Am J
Gastroenterol 2006;101:954-64.
3. Heine GD, Hadithi M, Groenen MJ,
et al: Double-balloon enteroscopy:
indications, diagnostic yield,
and complications in a series
of 275 patients with suspected
small-bowel disease. Endoscopy
2006;38:42-8.
4. Mönkemüller K, Weigt J,
Treiber G, et al: Diagnostic and
therapeutic impact of doubleballoon enteroscopy. Endoscopy
2006;38:67-72.
5. Zhong J, Ma T, Zhang C et al.
A retrospective study of the
application on double-balloon
enteroscopy in 378 patients with
suspected small-bowel diseases.
Endoscopy 2007;39:208-15.
6. Pennazio M, Eisen G, Goldfarb
N. ICCE consensus for obscure
gastrointestinal bleeding. Endoscopy 37:1046-1050, 2005.
14
7. Gay G, Delvaux M, Fassler I.
Outcome of capsule endoscopy in
determining indication and route
for push-and-pull enteroscopy.
Endoscopy 38:49-58, 2006.
8. Mehdizadeh S, Ross A, Gerson L,
et al: What is the learning curve
associated with double-balloon
enteroscopy? Technical details
and early experience in 6 U.S.
tertiary care centers. Gastrointest
Endosc 64:740-50, 2006.
9. Mensink PB, Haringsma J,
Kucharzik T, et al: Complications
of double balloon enteroscopy: a
multicenter survey. Endoscopy
2007;39:613-15.
10. Pennazio M, Santucci R, Rondonotti
E, et al: Outcome of patients
with
obscure
gastrointestinal
bleeding after capsule endoscopy:
report of 100 consecutive cases.
Gastroenterology 126:643-53, 2004.
11. Hsu CM, Chiu CT, Su MY et al.
The outcome assessment of doubleballoon enteroscopy for diagnosing
and managing patients with obscure
gastrointestinal bleeding. Dig Dis
Sci 2007;52:162-6.
12. Hadithi M, Heine GD, Jacobs
MA et al. A prospective study
comparing
video
capsule
endoscopy with double-balloon
enteroscopy in patients with
obscure gastrointestinal bleeding.
Am J Gastroenterol 2006;101:52-7.
Arch Gastroenterohepatol 2012; 29 (No 1) 9-14
13. Nakamura M, Niwa Y, Ohmiya N
et al. Preliminary comparison of
capsule endoscopy and doubleballoon enteroscopy in patients with
suspected small-bowel bleeding.
Endoscopy 2006;38:59-66.
14. Toy E, Rojany M, Sheikh R,
Mann S, Prindiville T. Capsule
endoscopy’s impact on clinical
management and outcomes: a
single-center experience with
145 patients. Am J Gastroenterol.
2008;103:3022-8.
15. Kaffes AJ, Siah C, Koo JH. Clinical
outcomes after double-balloon
enteroscopy in patients with
obscure GI bleeding and a positive
capsule endoscopy. Gastrointest
Endosc 2007;66:304-9.
16. Mönkemüller K, Neumann H,
Meyer F, Kuhn R, Malfertheiner
P, Fry LC. A retrospective
analysis of emergency double
balloon enteroscopy for small
bowel
bleeding.
Endoscopy
2009;41.715-17.
17. Jovanovic
I,
Krivokapic
Z, Menkovic N, Krstic M,
Mönkemüller K. Ineffectiveness
of capsule endoscopy and total
double-balloon enteroscopy to
elicit the cause of obscure overt
gastrointestinal bleeding: think
GIST! Endoscopy. 2011;43 Suppl
2 UCTN:E91-2.
Alimentary tract
ARCH GASTROENTEROHEPATOL 2012; 29 (No 1) 15-21
Konstantinos H. Katsanos,
Vasileios E. Tsianos,
Dimitrios Christodoulou,
Epameinondas V. Tsianos
1st Division of Internal Medicine &
Hepato-Gastroenterology Unit,
Department of Medicine, Medical School,
University of Ioannina, Greece
Experimental colitis and
inflammatory bowel
disease research
Conflict of interest:
None
ABSTRACT
Key words:
inflammatory bowel disease, ulcerative colitis,
Crohn’s disease, experimental colitis,
animal model
The experimentally induced inflammatory bowel disease (IBD)
in animal models must ideally incorporate identical triggering
factors and a parallel to human IBD pathophysiology and clinical
manifestations.
Various animal models of IBD have so far been described and
during the last years genetically manipulated animals are assisting
experimental IBD research. Inducing a relevant to IBD experimental
colitis is the most difficult and critical part of the experimental
study and several methods of bowel injury have been proposed.
Mechanisms of impaired regeneration of the colonic epithelium
and mucosal healing can be studied with these animal models and
significantly contribute to IBD research.
Microscopic studies in animal models aim to assess acute or chronic
inflammation intensity, extend and depth of bowel injury, granuloma
formation and mucosal healing. In addition, several blood and tissue
parameters have been evaluated and improved our understanding of
the altered immune response during colitis attacks.
A great variety of treating protocols have been tested in IBD animal
models. A vast majority of them did not reach clinical practice but
several experimental studies really pioneered our philosophy of
better IBD understanding and treating.
Address correspondence to:
Professor Epameinondas V. Tsianos, MD, Ph.D, FEBG, AGAF
Professor of Internal Medicine
1ST Division of Internal Medicine &
Hepato-Gastroenterology Unit
Department of Medicine
Medical School, University of Ioannina
451 10 Ioannina, Greece
phone: 0030-26510-07501
fax: 00-30-26510-07016
e-mail: [email protected]
Experimental colitis and inflammatory bowel disease research
15
METHODS OF INDUCING
EXPERIMENTAL IBD
alothane and all rules of good clinical practice in
studying animal models should be followed (5).
Animal models for studying intestinal inflammation
can be divided into spontaneous and induced models
(Table 1) (1).
Several methods have been described for inducing
and studying experimental colitis in rats. Overall,
three are the basic methods of administering an
experimental drug in rats: by food, by intracolonic
administration and by intravenous administration.
Intraperitoneal administration can be also used (6).
Table 1. Animal models of intestinal inflammation
(modified from Dieleman LA et al. Scand J Gastroenterol
1997;32:99-104).
Acute colonic injury in animal models can be
induced by intracolonic administration of acetic
acid, by TNBS (Trinitrobenzensulfonic acid)/
ethanol or by feeding with DSS (Dextran sodium
sulphate) in drinking water (Table 2) (7-8). Colonic
epithelial injury is then followed by the rapid influx of
granulocytes, monocytes and macrophages defined
as acute intestinal inflammation. During the acute
phase of these models, pro-inflammatory cytokines,
such as IL-1, TNFa, IL-6, GM-CSF and the murine
chemotactic cytokine MIP are expressed, all of them
mainly produced by monocytes and macrophages.
These cytokines are just as rapidly turned off as the
mucosa heals (9-11).
Table 2. Methods of inducing colitis in rats with
exogenous agents
Crohn himself reviewed porcine ileitis and concluded
that there were similarities with human ileitis
including ulceration, dysplasia, edema, lymphnodes
and granulomata (2). For financial and many other
practical reasons rat models are the mostly preferred
and widely used. The types of animals used for
experimental colitis are usually male SpragueDawley or Wistar or Lewis rats with the first two
being the most preferred. Their usual weight ranges
from 200-350 gr during the experimental period. Rat
organs usually tested during experimental colitis are
bowel, liver, spleen, pancreas, mesenteric vessels and
of course peripheral blood. Other frequently used
rat types for experimental colitis are Charles River
strain male/female or any other possibly available (i.e
Hebrew university strain male) (3-4). Rats used as
enterocolitis models are usually fasted. More rarely
non-fasted or fed at libitum rats are used. Anesthesia
is performed usually in a purpose-built box with
16
Arch Gastroenterohepatol 2012; 29 (No 1) 15-21
The mechanism(s) by which acetic acid produces
inflammation in the rat colon appear to involve
the entry of the lipid soluble form of the acid into
the epithelium, where it dissociates to liberate
protons within the intracellular space. It is this
massive intracellular acidification that most likely
accounts for the epithelial injury observed, because
intraluminal introduction of HCl (pH 2.3) does not
produce injury or inflammation (12).
The mechanism by which TNBS mediates epithelial
cell injury remains undefined; however it was shown
that rat colonocytes are capable of metabolizing
TNBS to produce large quantities of reactive oxygen
metabolites such as superoxide, hydrogen peroxide
and hydroxyl radical in vitro (13). Administration of
5% DSS for 5-7 days in drinking water of rodents
induces acute colonic injury and is followed by a
slow colonic regeneration and concomitant chronic
colitis after stopping DSS (14-15).
of quantifying mucosal damage is the measurement
as mm2 of injured bowel/rat. The score is increased by
one mark for each additional cm of involvement (24).
Microscopic evaluation is assessing cellular and
matrix parameters of acute and chronic inflammation,
colonic injury and granuloma formation. The
timing of histological assessment varies but usually
includes the 2h, 6h, 48h, 1st and 2nd week follow up.
More specially, histological evaluation of rat bowel
biopsies consists basically by two criteria assessed
by two observers; mucosal ulceration and depth of
injury. Histological evaluation represents one of the
most difficult and critical parts of the experimental
study and consequently several methods of grading
bowel injury have so far been proposed (22).
There is no ideal animal model for studying IBD. In
practice, useful models should be reproducible, easy
to induce, belong to a widely available animal species,
have a predictable time course of inflammation,
which resembles the clinical course of IBD and
present the inflammatory mediator profile and
therapeutic response as IBD (28-37).
The depth of injury has been proposed to be calculated
as follows: 0=None, 1=only mucosal involvement,
2=mucosal
and
submucosal
involvement,
3=transmural involvement. For these calculation
subcategories a grading system (grade 0-6) also exist
for the most possible detailed description (1)
Colonocyte collection in animal models must always
follow some steps in order to guarantee the maximum
MICROSCOPIC EVALUATION OF
autentity and stability of the specimen. Colonic tissue
ANIMAL COLONIC SPECIMENS
shall be cleared from the luminal contents with water
The variables tested in experimental IBD rat models at 22% after a routine colectomy method in which
are usually mucosal permeability, epithelial cell warm ischemia is less than 3 minutes. Aliquots of
cytotoxicity, inflammation represented by regions 1ml of cells are used for experiments or storage for
of bowel wall thickening and hyperemia and further evaluation (25-27).
carcinogenesis (16-21). Several types of other specific
tissue analyses can also be included in this spectrum. THE IDEAL ANIMAL MODEL OF IBD
The ideal animal model should be identical to
human IBD. This is per se extremely difficult, as the
experimentally induced IBD in the animal model
must have the same causal factors and the same
pathology, pathophysiology and clinical spectrum
Mucosal ulceration has been suggested (23) to be regarding natural course and mucosal damage. Until
graded as following: 0=None,1=focal, 2=multifocal, today none of the existing animal models resembles
3=diffuse. For mucosal damage the Wallace human IBD. One of the highest degrees of relevancy
scoring system is also used as following: 0=no with ulcerative colitis happens in the spontaneous
damage,1=hyperemia, no ulcer, 2=linear ulceration colitis animal model of cotton top tamarin (Saguinus
only, 3=two ulcerations and inflammation in one site, oedipus).
4=two or more sites of ulceration or inflammation,
5=five sites of ulceration / inflammation or 1 major Infections, which cause ileocolic disease in animals,
site of damage >1cm long, 6-10=when area of are probably a model for Crohn’s disease although
ulceration and inflammation extends more than several differences occur (Table 3). In golden
Syrian hamsters ileal obstruction due to chronic
2cm along the length of the colon.
inflammation by a rod-shaped bacillus has 90%
The Morris grading scale for gross mucosal injury mortality. The same phenomenon happens to Swiss
is described below: 0=normal,1=only localized Webster mice with colon thickening due to a kind
hyperemia, 2=linear ulcer or ulcer scar with no of transmissible murine colonic hyperplasia (38-41).
significant inflammation, 3= number 2 with
inflammation in one site, 4=number 2 with 2 or The TNBS-induced model of colitis may be the more
more sites of ulceration/inflammation, 5=number 4 relevant model of IBD because this model involves
extending >1cm along the colon length. Another way the use of an immunologic hapten and because the
Arch Gastroenterohepatol 2012; 29 (No 1) 15-21
17
Table 3: Intestinal infections of the ileum and colon in animals (modified
from Mayberry JF et al. Gastroenterology 1980;78:1080-1084).
acute mucosal injury produced by the
barrier breaker, ethanol, resolves quickly
and is followed by a more chronic phase
of inflammation (Table 4) (7).
Regeneration during chronic DSSinduced colitis is one of the best models
for studying colonic healing, since this
process takes several weeks. Mechanisms
of impaired regeneration of the colonic
epithelium can be studied in this model
and would be relevant to IBD research in
mucosal healing.
DSS-induced colitis can also open new
fields of intervention studies with growth
factors such as EGF (Epidermal Growth
Factor), TGF-β (Transforming Growth
Factor) and IGF-I (Insulin-like Growth
Factor) and other mucosal healing
promotors (33).
Although the ideal animal model of
IBD has not yet been found, each model
can independently study pathogenetic
factors such as acute intestinal injury and
healing, acute and chronic inflammation
and regulation by key cytokines.
Figure 1. Diversion colitis
18
Arch Gastroenterohepatol 2012; 29 (No 1) 15-21
Table 4. Comparison of microscopic findings in rats given acetic
acid, ethanol, TNBS (pH 1.0) or TNBS (pH 7.4). (Modified from T.
Yamada et al Gastroenterology 1992;102:1524-1534).
TREATING AND
RESEARCH PROTOCOLS IN
EXPERIMENTALLY INDUCED
COLITIS.
A great variety of treating protocols have
been tested in inflammatory bowel diseased
rats. Many of them have been also evaluated
in clinical practice and some experimentally
tested molecules proved to be of major
therapeutic importance in IBD treating
philosophy (Table 5).
Targeting measurements of several blood
and tissue parameters have been evaluated
for years and are of major importance in
IBD. By those measurements investigators
aim to better understand the altered immune
response during colitis attacks. However, it
seems that although some of them showed
impressive results and clear implications
to human clinical practice they still keep a
restricted value until they can be translated
into terms of prognosis and therapy.
Although experimental animal models
of IBD are clearly not identical to human
IBD we may hope that proper and ethical
experimental animal use might also provoke
our destiny of fighting against chronic
diseases.
Table 5.Treating protocols in experimentally induced colitis in rats. Those marked also with (*) have been also used in
human IBD clinical practice.
Arch Gastroenterohepatol 2012; 29 (No 1) 15-21
19
aim to assess inflammation intensity, extend and
depth of bowel injury, granuloma formation and
Experimentally induced IBD in animal models must mucosal healing. Measurements of blood and
ideally parallel human IBD. Inducing experimental tissue parameters in animal models improved our
colitis, relevant to human IBD, is very difficult and understanding of the altered immune response in
still an ideal IBD animal model does not exist. Various IBD. Animal studies clearly contributed to better
animal models of IBD have so far been described understanding and treating of human IBD.
and genetically manipulated animals are important
in IBD research. Microscopic experimental studies
CONCLUSION
References:
1. Dieleman LA, Pena AS, Menwissen
SGM, van Rees EP. Role of animal
models for the pathogenesis and
treatment of inflammatory bowel
disease. Scand J Gastroenterol
1997;32:99-104.
2. Rachmilewitz D, Okon E, Karmeli
F. Sulphydryl blocker induced small
intestinal inflammation in rats; a
new model mimicking Crohn’ s
disease. Gut 1997;41:358-65.
3. Dykens JA, Baginski TJ. Urinary
8-hydroxydeoxyguanosine
excretion as a non-invasive marker
of neutrophil activation in animal
models of inflammatory bowel
disease. Scand J Gastroenterol
1998;33:628-36.
4. Shintani N, Nakajima T, Nakakubo H,
et al. Intravenous immunoglobulin
(IVIG) treatment of experimental
colitis induced by dextran sulfate
sodium in rats. Clin Exp Immunol
1997;108:340-45.
5. Millar AD, Rampton DS, Chander CL, et al. Evaluating the antioxidant potential of new treatments for inflammatory bowel
disease using a rat model of
colitis. Gut 1996;39:407-15.
6. Nairn RC, Savvas R, Hocking
G, Kovala M, Rolland JM.
Animal model of human disease:
ulcerative colitis. Am J Pathol
1979;96:647-50.
7. Yamada T, Marshall S, Specian
RD, Grisham MB. A comparative
analysis of two models of
colitis in rats. Gastroenterology
1992;102:1524-34.
20
8. Ferretti M, Gionchetti P, Rizzello F,
et al. Intracolonic release of nitric
oxide during trinitrobenzene
sulfonic acid rat colitis. Dig Dis
Sci 1997;42:2606-11.
9. Jacobson K, McHugh K, Collins
SM. Experimental colitis alters
myenteric nerve function at
inflamed and non-inflamed sites
in the rat. Gastroenterology
1995;109:718-22.
10. Carter L, Wallace JL. Alterations
in rat peripheral blood neutrophil
function as a consequence of
colitis. Dig Dis Sci 1995;40:192-7.
11. Buell MG, Berin C. Neutrophilindependence of the initiation
of colonic inury. Comparison
of results from three models of
experimental colitis in the rat. Dig
Dis Sci 1994;39:2575-88.
12. Fedorak RN, Empey LR, MacArthur C, Jewell LD. Misoprostol
provides a colonic mucosal protective effect during acetic acidinduced colitis in rats. Gastroenterology 1990;98:615-25.
13. Cooper HS, Murthy SNS, Shah RS,
Sedegran DJ. Clinicopathologic
study of dextran sulfate sodium
experimental murine colitis. Lab
Invest 1993;69:238-49.
14. Yoshikawa T, Yamaguchi T,
Yoshida N, et al. Effect of Z-103
on TNB-induced colitis in rats.
Digestion 1997;58:464-68.
15. Allgayer H, Deschryver K, Stenson WF. Treatment with 16,
16‘-dimethylprostaglandin E2 before and after induction of colitis
Arch Gastroenterohepatol 2012; 29 (No 1) 15-21
with trinitrobenzenesulfonic acid
in rats decreases inflammation.
Gastroenterology 1989;96:1290-300.
16. Lora L, Mazzon E, Martines D,
et al. Hepatocyte tight-junctional
permeability is increased in rat
experimental colitis. Gastroenterology 1997;113:1347-54.
17. Tamaru T, Kobayashi H, Kishimoto
S, Kajiyama G, Shimamoto F,
Brown WR. Histochemical study
of colonic cancer in experimental
colitis of rats. Dig Dis Sci
1993;38:529-37.
18. Chin KW, Barrett KE. Mast cells
are not essential to inflammation
in murine model of colitis. Dig
Dis Sci 1994;39:513-25.
19. Minocha A, Thomas C, Omar R.
Lack of crucial role of mast cells
in pathogenesis of experimental
colitis in rats. Dig Dis Sci
1995;40:1757-62.
20. Kajiura K, Ohkusa T, Okayasu
I. Relationship between fecal
bile acids and the occurrence
of colorectal neoplasia in
experimental murine ulcerative
colitis. Digestion 1998;59:69-72.
21. Collins SM, McHugh K, Jacobson
K, et al. Previous inflammation
alters the response of the rat
colon to stress. Gastroenterology
1996;111:1509-15.
22. Rachmilewitz D, Simon P,
Schwartz LW, Griswold DE,
Fondacaro
JD,
Wasserman
MA. Inflammatory mediators
of experimental colitis in rats.
Gastroenterology 1989;97:326-37.
23. Okayashu I, Hatakeyama S,
Yamada M, Ohkusa T, Inagaki Y,
Nakaya R. A novel method in the
induction of reliable experimental
acute and chronic ulcerative
colitis in mice. Gastroenterology
1990;98:694-702.
24. Marcus R, Watt J. Seaweeds and
ulcerative colitis in laboratory
animals. Lancet 1969; 43:489-90.
25. Eliakim R, Karmeli F, Okan E,
Rachmilewitz D. Octreotide
effectively decrases mucosal damage in experimental colitis. Gut
1993;34:264-9.
26. Yue G, Sun FF, Dunn C, Yin K,
Wong PYK. The 21-aminosteroid
tirilazad mesylate can ameliorate
inflammatory bowel disease
in rats. J Pharmacol Exp Ther
1996;276:265-70.
27. Pons L, Droy-Lefaix M-T, Bueno
L. Leukotriene D4 participates in
colonic transit disturbances induced by intracolonic administration
of
trinitrobenzene
sulfonic
acid in rats. Gastroenterology
1992;102:149-56.
28. Fedorak RN, Empey LA, Walker
K. Verapamil alters eicosanoid synthesis and accelerates healing during
experimental colitis in rats. Gastroenterology 1992;102:1229-35.
29. Aube AC, Blottiere HM,
Scarpignato C, Cherbut C, Roze
C, Galmiche JP. Inhibition of
acetylcholine induced intestinal
motility by interleukin 1b in the
rat. Gut 1996; 39:470-74.
30. Peen E, Enestrom S, Skogh T.
Distribution of lactoferrin and
60/65 KDa heat shock protein in normal and inflamed
human intestine and liver. Gut
1996;38:135-40.
31. Roediger WEW, Babidge W, Millard
S. Methionine derivatives diminish
sulphide damage to colonocytesimplication for ulcerative colitis.
Gut 1996;39:77-81.
32. Rachmilewitz D, Stamler JS,
Karmeli F, et al. Peroxynitriteinduced rat colitis-a new model
of colonic inflammation. Gastroenterology 1993;105:1681-8.
33. Howarrth GS, Fraser R, Frisby
CL, Schirmer MB, Yeoh EK.
Effects of insulin like growth
factor I administration on
radiation enteritis in rats. Scand
J Gastroenterol 1997;32:1118-24.
34. Roediger WEW, Millard S.
Selective inhibition of fatty acid
oxidation in colonocytes by
ibuprofen:a cause of colitis? Gut
1995;36:55-9.
35. Dinda PK, Holitzner CA, Morris
GP, Beck IT. Ethanol-induced
jejunal and morphological injury
in relation to histamine release
in rabbits. Gastroenterology
1993;104:361-68.
36. Rachmilewitz D, Karmeli F,
Okon E. Sulphydryl blockerinduced rat colonic inflamation is
ameliorated by inhibition of nitric
oxide synthase. Gastroenterology
1995;109:98-106.
37. Wallace JL, MacNaughton WK,
Morris GP, Beck PL. Inhibition
of leukotriene synthesis markedly
accelerates healing in a rat model
of inflammatory bowel disease.
Gastroenterology 1989;96:29-36.
38. Mayberry JF, Rhodes J, Heathley
RV. Infections which cause ileocolic disease in animals: are they
relevant to Crohn‘s disease? Gastroenterology 1980;78:1080-4.
39. O’Moráin C, Smethurst P, Doré
CJ, Levi AJ. Reversible male
infertility due to sulphasalazine:
studies in man and rat. Gut 1984;
25:1078-84.
40. Jacobson K, McHugh K, Collins
SM. The mechanism of altered
neural function in a rat model
of acute colitis. Gastroenterology
1997;112:156-62.
41. Palmen MJHJ, Dijkstra CD, Van
der Ende MB, Pena AS, Van
Rees EP. Anti-CD11B/CD18
antibodies reduce inflammation
in acute colitis in rats. Clin Exp
Immunol 1995;101:351-6.
Arch Gastroenterohepatol 2012; 29 (No 1) 15-21
21
Alimentary tract
ARCH GASTROENTEROHEPATOL 2012; 29 (No 1) 22-29
Histohemijsko ispitivanje
proliferativne aktivnosti
ćelijskih jedara maligno
alterisanih kolorektanih
adenoma metodom AgNOR
Bratislav Petrović1,
Aleksandar Nagorni1,
Aleksandar Petrović2,
Goran Bjelaković1,
Bojan Mladenović1,
Vesna Brzački1,
Mirjana Radisavljević1
1
Klinika za Gastroenterologiju i hepatologiju
Klinički Centar Niš
2
Katedra za Histologiju i embriologiju
Medicinski Fakultet Niš
Skraćenice
AgNOR – Srebrom obeleženi nukleolarni
organizacioni regioni
SAŽETAK
Ključne reči:
Kolorektalni adenomi; Proliferativna aktivnost;
AgNOR
Key words:
Colorectal adenomas; Proliferative activity;
AgNORs
UVOD: Adenomi se smatraju „greškom u koracima“ normalne
ćelijske proliferacije i apoptoze. Proliferativna aktivnost ćelija,
izražena markerima Ki-67 i AgNOR-ima, progresivno raste od
normalne sluzokože do adenoma. Cilj rada je procena proliferativne
aktivnosti ćelija, na osnovu AgNOR, kod displastičnih i maligno
alterisanih, kao i žlezdama kolorektalnih karcinoma.
METODE: Na tkivnim uzorcima 80 pacijenata sa maligno alterisanim
kolorektalnim adenomima i kontrolne grupe 10 pacijenata sa
adenokarcinomom kolona primenjena su HE metoda i histohemijsko
bojenje AgNOR-om.
REZULTATI: Prosečan broj AgNOR po jedru pokazao je statistički
značajno veće vrednosti kod maligno alterisanih žlezda u odnosu
na vrednosti kod displastičnih žlezda istovrstnih adenoma. Najveće
vrednosti prosečnih površina AgNOR nađene su u displastičnim
žlezdama teškog stepena tubuloviloznih i viloznih adenoma i oni su
za razliku od tubularnih adenoma pokazali statistički značajnu razliku
u ovim vrednostima prema obližnjim maligno alterisanim žlezdama.
Address correspondence to:
Dr Bratislav Petrović
Klinika za Gastroenterologiju i hepatologiju
Klinički Centar Niš
Bulevar Zorana Đinđića 48, 18000 Niš
telefon: 018 4537343
e-mail: [email protected]
22
ZAKLJUČAK: Displastične žlezde adenoma kolorektuma,
upotrebom tehnika AgNOR i kvantifikacijom, mogu se na osnovu
broja nukleolarnih organizacionih regiona razlikovati od maligno
alterisanih fokusa u adenomima. Proliferativna aktivnost ćelija
u adenomima kolorektuma je zavisna od stepena displazije, a
maksimum dostiže u poljima maligne alteracije i karcinomima.
Histohemijsko ispitivanje proliferativne aktivnosti ćelijskih jedara maligno alterisanih kolorektanih adenoma metodom AgNOR
homeostaza se održava na osnovu proliferacije i
spontane ćelijske smrti ili apoptoze. Pored toga, za
INTRODUCTION: Adenomas are considered as normalan ćelijski rast su neophodni odnosi ćelijske
an inaccuracy between normal cell proliferation diferencijacije i eksfolijacije (2-4).
and apoptosis. Cell proliferation expressed by Ki67 and AgNOR markers has progressive growth Kolorektalni karcinomi su najčešće žlezdani tumori
from normal mucosa to mild and severe dysplasia sa više varijanata. Oni počinju invaziju probijanjem
in adenomas. We evaluated cell proliferation, using lamine muskularis mukoze i prodorom u submukozu
AgNOR method, in malignant alteration and in dok lezije sa karakteristikama adenokarcinoma, koje
surrounding colorectal adenoma as well as in su ograničene na epitel ili zahvataju samo laminu
propriju, nemaju rizik od metastaza. U stvari, više
colorectal carcinoma.
se izraza koristi za pokazivanje takvog stanja kao
METHODS: In this study 80 patients with malignant što su „visokostepena intraepitelna neoplazija“,
alteration of colorectal adenomas and control group „adenocarcinoma in situ“ i „intramukozna
of 10 patients with adenocarcinomas were included. neoplazija“ (5-8).
Slides were stained with hematoxylin-eosin and
Digestivna cev, spada u delove tela, koja je najviše
histochemically with AgNOR.
izložena delovanju supstanci koje mogu imati
RESULTS: Average AgNOR number by nuclei kancerogena svojstva i, obzirom na njenu dužinu
shows statistically considerable higher values in predstavlja mesto češćeg kancerskog alterisanja.
glands with malignant alteration in relation to same Većina autora uzima kao inicijalni momenat za
histological type of dysplastic adenoma glands. In razvoj adenoma adenomatoznu klonalnu displaziju
contrast with tubular adenomas, highest values of kripti (9-11). Smatra se da su kripte klonalne jedinice
average AgNOR surface were found in tubulovillous kolona (9) pa su, otuda, lezije monoklonalnog
and villous adenoma glands with severe dysplasia porekla (9,10,12,13).
and statistically they are considerable towards glands
Učestalost pojavljivanja adenoma kolorektuma zavisi
with malignant alteration (P<0,05).
od postojećeg rizika za karcinom kolona u opštoj
CONCLUSION: Dysplastic adenoma glands, by populaciji, godina života, pola i porodične istorije
using AgNOR technique and quantification, can prisustva kolorektalnog karcinoma. Frekvencija
be differentiated from adenoma foci of malignant javljanja kolorektalnih adenoma varira široko među
alteration. Cells proliferative activity in adenomas populacijama, ali pokazuje tendenciju da bude
depends of degree of dysplasia, with its maximum in viša u populacijama sa većim rizikom za karcinom
kolona. Dodatno, u zemljama u kojima je prevalenca
fields of malignant alteration and carcinomas.
karcinoma kolorektuma visoka, adenomi kolorektuma
imaju tendenciju da budu veći nego u zemljama sa
UVOD
niskom prevalencom za kolorektalni karcinom (14).
ABSTRACT
Pod uticajem lokalnih, direktnih ili indirektnih
mehanizama, koji obuhvataju intraluminalni
sadržaj, različite hormone gastrointestinalnog trakta
i neurogenih faktora, kolorektum menja brzinu svoje
ćelijske obnove i adaptira se promenjenim uslovima
(hirurški, nutricioni i toksični stimulusi). Veoma
je značajno da je ćelijska proliferacija u crevima
kontrolisana kaloričnim bilansom i uzrastom
čoveka, jer starenjem epitel gastrointestinalnog
trakta ne atrofiše već, naprotiv, proliferiše, što može
stajati u osnovi mnogih polipozno-adenomatoznih
pojava. Interesantno je da perikriptalni fibroblasti
zadržavaju program linije ćelijske diferencijacije (1).
Danas sve više dobija potvrdu, u nizu istraživanja,
teorija adenoma-karcinoma redosled, po kojoj bez
predhodne adenomatozne promene monokriptalnih
ili multikriptalnih delova sluzokože kolona nema
neoplastične alteracije (15-23). Malo je pristalica
teorije da kolorektalni karcinom nastaje primarnom
kancerskom alteracijom sluzokože kolona bez predhodne adenomatozne transformacije (24,25).
Adenomi se smatraju „greškom u koracima“
normalne ćelijske proliferacije i ćelijske smrti
(apoptoze) zbog inicijalne aberacije koja se
dešava u pojedinačnim kriptama. U tom slučaju,
proliferativni proces umesto da se zadrži pri bazi i
Benigne ili maligne neoplazije su najčešće bolesti uđe u diferencijaciju, on nastavlja da se širi celom
gastrointestinalnog trakta. Normalna ćelijska visinom kripte formirajući unikriptalni adenom, čije
Arch Gastroenterohepatol 2012; 29 (No 1) 22-29
23
se ćelije na njenom vrhu nagomilavaju, preklapaju
i umeću između postojećih kripata, stvarajući
nove kripte koje se cepaju po dužini, nepravilno
pupe i granaju, gradeći splet žlezdanih ili viloznih
struktura (2,3,4,6,9,10,15,26). Praktično, počeci
maligne alteracije kripti idu po principu klonalne
proliferacije i ekspanzije (3,4,6,9,10,15). Nema
sumnje, da na ovu proliferaciju imaju značajan uticaj
subepitelni miofibroblasti, za koje neki smatraju da
potiču iz kostne srži (4). Proliferativnim promenama
sluzokože, stvaraju se mikroskopske lezije koje
mogu predhoditi stvaranju vidljivog adenoma i kod
pacijenata sa polipozom i kod onih bez toga (13).
su isključeni pacijenti sa porodičnim polipoznim
sindromima. U kontrolnu grupu, uključeno je
još 10 kliničkih slučajeva hirurški odstranjenih
adenokarcinoma kolorektuma. Kolonoskopije su
učinjene u Endoskopskom kabinetu Klinike za
Gastroneterologiju i hepatologiju Kliničkog Centra
Niš, kolonoskopima Olympus CF 20HI i 30HI (Japan).
Antitelo Ki-67 se smatra veoma značajnim markerom
proliferativne aktivnosti ćelija (27). Proliferativna
aktivnost kao izraz displazije adenoma može se
procenjivati i morfometrijskim tehnikama (28).
Mejer i Book (28) smatraju opšte da proliferativna
aktivnost tumora ogleda njihov maligni potencijal, a
da je nuklearna atipija kod adenoma u korelaciji sa
povećanom mitotskom aktivnošću. Oni smatraju da
za gradiranje displazije nije mitotski indeks vodeći i
da su potrebni drugi markeri za to. Još su Risiom i
Rossini (29) zapazili da proliferativna aktivnost ćelija
izražena markerima Ki-67 i AgNOR-ima progresivno
raste redosledom od normalne sluzokože preko
slabostepene do težestepene displazije adenoma (29).
Mikroskopski, preparati su analizirani na svetlosnom
mikroskopu sa digitalnom kamerom Leica DMR
(Leica Micro-Systems, Reuil-Malmaisom, France).
Mikroskopske slike su digitalizovane kamerom
(Leica DC 300) pod ukupnim mikroskopskim
uvećanjem od 1000x, uz upotrebu imerznog ulja, za
analizu preparata bojenih po ICAQ. Digitalne slike
su balansirane za belu boju i sačuvane kao 8-bitni,
nekomprimovani TIFF fajlovi (RGB, 2088x1552
piksela). Sa digitalnih slika, na preparatima
bojenim po ICAQ, izvršena je interaktivna
separacija nukleolarnih organizacionih regiona,
procena njihove brojnosti po jedru, površina
preseka AgNOR, kao i separacija odgovarajućih
jedara u celini, kod kojih je analizirana površina
preseka, kao i stepen njihove elongacije (aspekt).
Za potrebe morfometrijske analize, upotrebljen je
program Olympus MicroImage Software, v. 4.0 for
Windows (Media Cybernetics, Silver Spring, MD,
U.S.A). U ovom delu rada, ispitivani materijal je
podeljen na grupe prema različitim histološkim
regionima unutar maligno alterisanih adenoma
i karcinoma operativnog tipa. Naime, svaki od
adenoma tubularnog, tubuloviloznog i viloznog tipa
razmatran je zasebno prema regionima displastično
i maligno alterisanih žlezda i tome je pridodata
grupa žlezda adenokarcinoma sa operativnog
materijala. Iz spomenutih regiona, je uzeto u rad
po pet mikroskopskih polja, sa ukupnim brojem od
500 analiziranih jedara (i unutar njih odgovarajućih
subnuklearnih struktura, tj. AgNOR).
Polipektomisani i biopsirani uzorci su fiksirani u
10% rastvoru formaldehida i dovedeni rutinskim
postupkom obrade do parafinskih kalupa sa kojih
su mikrotomski isečeni tkivni uzorci debljine do
5μm. Posle deparafinisanja preparati su podvrgnuti
sledećim histohemijskim metodama: 1) klasičnom
Veoma zanimljivi su podeljeni stavovi među istra- hematoksilin-eozin (HE) metodom radi osnovne
živačima, od kojih većina smatra da aberantna orijentacije o tkivu, građi i osnovnim histološkim
proliferacija potiče sa dna kripte i ide naviše (2,3,9,11,15) promenama tkivnih uzoraka i 2) histohemijskim
i drugih, koji smatraju da se ovaj proces primarno bojenjem AgNOR prema uputstvima Međunarodnog
dešava pri vrhu kripte, a zatim spušta naniže (10).
Komiteta za kvantifikaciju AgNOR (ICAQ) (30–33).
U skladu sa gore navedenim, mi smo za cilj ovog rada
postavili procenu proliferativne aktivnosti ćelija,
na osnovu kvantitativnih karakteristika AgNOR,
kod displastičnih i maligno alterisanih žlezda
kolorektalnih adenoma različitih patohistoloških
tipova, kao i žlezdama operativno uklonjenih
kolorektalnih karcinoma.
PACIJENTI I METODE
Na Klinici za Gastroenterologiju i hepatologiju
Kliničkog Centra Niš je u ovo istraživanje uvršćeno
kliničkih slučajeva od 80 pacijenata, kod kojih
je tokom kolonoskopije načinjena polipektomija
ili biopsija, a na Institutu za Patologiju Kliničkog
Centra Niš postavljena patohistološka dijagnoza
maligno alterisanih kolorektalnih adenoma. Iz studije
24
Arch Gastroenterohepatol 2012; 29 (No 1) 22-29
pokazale veće vrednosti kod maligno alterisanih
žlezda sve tri histološke podvarijante adenoma.
Kvantitativna analiza AgNOR-a, pokazala je da Međutim, kod tubuloviloznih adenoma nije uočena
je prosečan broj AgNOR po jedru kod maligno statistički značajna razlika između nađenih vrednosti
alterisanih žlezda ispitivanih adenoma, najmanjih (P>0,05) dok se kod tubularnih i viloznih adenoma
vrednosti kod tubularnih adenoma, sa povećanjem po istom pitanju zapažaju statistički značajne razlike
preko tubuloviloznih do viloznih adenoma. Najveće (P<0,05). (Tabela 1)
vrednosti kod displastičnih žlezda zabeležene
kod tubuloviloznih adenoma. Broj AgNOR po Prosečan broj AgNOR po jedru je bio najizrazitiji kod
jedru pokazuje statistički visoko značajne razlike maligno alterisanih žlezda tubuloviloznog i viloznog
(P<0,001) između displastičnih i maligno alterisanih adenoma, međutim, statistički visoko značajne razlike
žlezda istovrsnih histoloških tipova adenoma. (P<0,001) zapažaju se isključivo između malignih
Najveće vrednosti prosečnih površina AgNOR žlezda viloznih adenoma i karcinoma operativnog
nađene su u displastičnim žlezdama teškog stepena materijala. Prosečne vrednosti površine AgNOR su
tubuloviloznih i viloznih adenoma i oni su za razliku se pokazale najvećim kod maligno alterisanih žlezda
od tubularnih adenoma pokazali statistički značajnu tubuloviloznih adenoma i nešto nižim kod tubularnih
razliku u ovim vrednostima prema obližnjim adenoma što je u poređenju sa vrednostima kod
maligno alterisanim žlezdama (P<0,05). (Tabela 1) malignih žlezda karcinoma operativnog materijala
dalo statistički značajnu razliku prema maligno
alterisanim žlezdama tubularnih adenoma (P<0,05)
U međusobnom poređenju displastičnih žlezda i visoko statistički značajnu razliku prema maligno
tubularnih i tubuloviloznih kao i tubularnih i alterisanim žlezdama tubuloviloznih adenoma
viloznih adenoma, u ispitivanju prosečnih vrednosti (P<0,001) (Tabela 1) (Slike 1, 2 i 3).
površine jedara, zapaža se statistički visoko značajna
razlika (P<0,001). Razlika između tubuloviloznih Prosečna površina jedara pokazala je najmanje
i viloznih adenoma je niže statističke značajnosti vrednosti u ćelijama žlezda invazivnih karcinoma
(P<0,05). U upoređivanju prosečnih vrednosti sa operativnog materijala, veće i približne vrednosti
površine jedara, tubularni adenomi među svim kod maligno alterisanih žlezda tubularnih i
ispitivanim adenomima pokazuju najmanje tubuloviloznih adenoma, a najveće kod maligno
vrednosti. Prosečne vrednosti površine jedara su alterisanih žlezda viloznog adenoma. Kancerske
REZULTATI
Tabela 1. Prikaz prosečnih vrednosti površine jedara (PJ), broja AgNOR po jedru (nAgNOR) i površina AgNOR
(PAgNOR), kao i njihovih standardnih devijacija (SD) u područjima maligno alterisanih žlezda tubularnih adenoma
(MaTa), tubulo-viloznih (MaTVa), viloznih adenoma (MaVa), kao i displastičnim žlezdama tubularnih adenoma
(Ta), tubulo-viloznih adenoma (TVa) i viloznih adenoma (Va), kao i žlezdama operativnog materijala (COM).
Arch Gastroenterohepatol 2012; 29 (No 1) 22-29
25
žlezde operativnog materijala su pokazale statistički
značajne razlike u vrednostima prosečne površine
jedara prema maligno alterisanim žlezdama
tubularnih i tubuloviloznih adenoma, a statistički
visoko značajne razlike prema maligno alterisanim
žlezdama viloznih adenoma (P<0,001). Po pitanju
ostalih upoređenja, a na osnovu prosečne vrednosti
površine jedara, nije bilo statistički značajnih razlika
(P>0,05).
DISKUSIJA
Kao što je u više navrata spomenuto, neoplastična
priroda adenoma se ogleda u nesposobnosti kontrole
Slika 1. Teškostepena displazija kod viloznog adenoma. rasta i gubitka diferencijacije kao kardinalna
U jedrima se zapaža veći broj krupnijih AgNOR. karakteristika. Zbog gubitka kontrolnih mehanizama
AgNOR, 1000x, imerzija.
koji kontrolišu sintezu DNK, kod adenoma se ćelijska
deoba može videti na svim nivoima kripte zbog
čega postoji nedovoljna ragularnost diferencijacije
peharastih i apsorptivnih ćelijama na njihovoj
površini (6). Iz tih razloga ćelije posetepeno prelaze
u kancerske što se karakteriše gubitkom njihovog
cilindričnog oblika, zaokrugljivanje i pleomorfizam
jedara, nagomilavanje neoplastičnih ćelija, a često i
kribriformnim izgledom unutar jedne ili više kripata
ili vilusa čime se dobija slika intraepitelijalnog ili
neinvazivnog karcinoma. Sledeća faza u ovom
adenoma-karcinoma redosledu je invazija lamine
proprije kancerskim ćelijama i žlezdama (5,6,34,35).
Yang i sar (36) su na parafinskim presecima ispitivali
Slika 2. Maligno alterisani vilozni adenom. U jedrima AgNOR tehnikom 12 tubularnih adenoma, 17
se zapaža veliki broj AgNOR manje prosečne površine. viloznih adenoma sa umerenom i teškom atipijom,
kao i 21 kolorektalni karcinom. Oni su našli da je
AgNOR, 1000x, imerzija.
prosečni broj NOR po jedru 2,67 (opseg 1,54-3,28),
kod viloznih adenoma sa umerenom atipijom 3,71
(opseg 3,07-4,36), adenoma sa teškom atipijom
4,22 (opseg 3,60-5,02), a kod adenokarcinoma 7,35
(opseg 5,53-9,33).
Sugai i sar. (37) su našli kod adenoma sa teškostepenom
displazijom da je broj AgNOR-a 4,13, dok su kod
intramukoznih kolorektalnih karcinoma našli da
ta vrednost varira od 3,12 do 7,4. Oni su takođe
dokazali statistički značajnu razliku u vrednostima
broja AgNOR između kolorektalnih karcinoma i
adenoma sa teškom displazijom (P<0,05).
Jin i sar. (38) su dokazali da broj AgNOR-ova raste
počevši od normalne mukoze preko adenoma
Slika 3. Tubulovilozni adenom. „Front“ superficijalnog
displastičnog epitela težeg stepena koji „gura“ i i adenokarcinomske sekvence. Oni su našli da
„podvalči se“ (levo) pod superficilani epitel tranzicione tip AgNOR-a ne može da se smatra važnim
parametrom. Parametri kao što su prosečni broj,
mukoze (desno). AgNOR, 630x.
26
Arch Gastroenterohepatol 2012; 29 (No 1) 22-29
pozitivni odnos, gustina i površinski faktor čestica kapriciozne histohemijske procedure bojenja
pokazali su se upotrebljivim u diferencijaciji nukleolarnih organizacionih regiona. Kao što navode
benignih od malignih tumora.
Trere (33) i Derenzini i sar. (31) moguća neadekvatna
Wood i sar. (39) su obavili istraživanje srebrom priprema u kiseloj sredini (citratni pufer pH 6,0) kao
obojenih nukleolarnih organizacionih regiona kod i odstupanja od propisanih uslova ekspozicije jonima
tubularnih, tubuloviloznih i viloznih adenoma kao srebra ili predhodni postupci vezani za fiksaciju tkiva,
i kod umereno diferentovanih adenokarcinoma. mogu biti od ključnog značaja za aglomerizaciju
Prema njihovim rezultatima normalna mukoza jona srebra u okviru nukleolarnih organizacionih
pokazuje u proseku 2,37±0,28 AgNOR-ova po jedru, regiona. Svi predhodno navedeni faktori, ukoliko
tubularni adenomi 3,67±0,64, vilozni adenomi nisu metodološki ispunjeni, mogu dovesti do slabije
4,12±0,43, tubulovilozni adenomi 3,62±0,41 i rezolucione (diferencijacione) moći tehnike bojenja,
adenokarcinomi 4,34±0,86. Oni su našli, po pitanju i samim tim slabije morfološke razlike između onih
prosečnog broja AgNOR po jedru, statistički značajnu NOR-ova koji se nalaze na bliskom rastojanju, a u
razliku između normalne mukoze i adenoma kao okviru istog jedarca, koje se sada zbog preteranog
i normalne mukoze i adenokarcinoma. Odsustvo deponovanja jona srebra prikazuju kao jedinstveni
statistički značajnosti u razlikama je zapaženo kod NOR veće površine. U našem slučaju, pojedinačni
normalne prema metaplastičnoj mukozi, kao i kod NOR-ovi bili su uvek zapaženi kao okrugle ili ovalne
srebrom obojene formacije (tamno braon do crno),
benignih prema malignim lezijama.
sa jasnom morfološkom razlikom prema ostatku
Risiom i Rossini (29) su našli progresivni porast
strukturnih komponenti nukleolusa koji se između
prosečnog broja AgNOR po jedru počevši od
njih uočava kao amorfna, svetlo braonkasta materija.
normalne mukoze preko niskostepene i visokostepene
displazije u adenomima do uznapredovalog
ZAKLJUČAK
karcinoma, međutim, bez značajnih razlika, između
ranog karcinoma i žlezda niskostepenih displazija.
Displastične žlezde kod tubularnih, tubuloviloznih
Dippe i sar. (26) su ispitujući 50 tubularnih i 50 i viloznih adenoma, uz pravilnu upotrebu tehnika
tubuloviloznih adenoma AgNOR metodologijom za vizualizaciju AgNOR i kvantifikaciju, mogu
našli da ne postoji statistički značajna razlika u se, na osnovu broja nukleolarnih organizacionih
broju AgNOR između različitih stepena displazije regiona, razlikovati od maligno alterisanih fokusa u
kod adenoma odbacijući AgNOR metodologiju kao adenomima.
neadekvatnu za diferencijaciju spomenutih procesa. Proliferativna aktivnost ćelija u adenomima je zavisna
Muskara i sar. (40) su u svom istraživanju na od stepena displazije, a svoj maksimum dostiže u
adenokarcinomima debelog creva, tubularnim poljima njegove maligne alteracije i karcinomima.
adenomima niskostepene displazije i adenomima sa
visokostepenom displazijom podelili AgNOR-e u dve
klase, male i velike, u cilju međusobnog upoređenja
spomenutih lezija. Oni su našli visoko značajnu
statistički razliku po pitanju prosečnog broja
malih AgNOR kod upoređenja adenokarcinoma sa
adenomatoznim lezijama. Pored spomenutog, oni su
našli da se niskostepena i visokostepena displazija,
prisutna kod tubularnih i viloznih adenoma, mogu
jasno razlikovati ovom procedurom.
U našim rezultaima zapaža se upadljivo veći prosečni
broj AgNOR po jedru, naročito u slučajevima žlezda
koje su pokazale malignu alteraciju bilo da se radi
o adenomima ili operativnom materijalu u odnosu
na srodnosti koje su pokazali autori u predhodnim
istraživanjima. Naime, ove razlike se mogu objasniti
rigoroznijim načinom sprovođenja relativno
Arch Gastroenterohepatol 2012; 29 (No 1) 22-29
27
Literatura
1. Fenoglio-Preiser CM. Normal
Anatomy of the Large Intestine.
In: Fenoglio-Preiser CM, eds.
Gastrointestinal Pasthology Plus.
An Atlas and Text. PhiladelphiaNew-York: Lippincott Williams
and Wilkins Publ, 1999:100-50.
2. Preston SL, Alison MR, Forbes SJ,
et al. The new stem cell biology:
something for everyone. J Clin
Pathol Mol Pathol 2003;56:86-96.
3. Akedo I, Ishikawa H, Ioka T, et
al. Evaluation of Epithelial Cell
Proliferation Rate in Normalappearing Colonic Mucosa as a
High-Risk Marker for Colorectal
Cancer.
Cancer
Epidemiol
Biomark Prev 2001;10:925-30.
4. Britton M, Wright NA. Gastrointestinal stem cells. J. Pathol.
2002; 197(4):492-509.
5. Rosai J. Gastrointestinal Tract.
In: Ackerman LV, Rosai J, eds.
Ackerman`s Surgical Pathology.
St.
Louis-Toronto
Mosby,
1989:589-814.
6. Perzin KH, Fenoglio CM, Pascal
RR. Neoplastic Diseases of the
Small and Large Intestini. In:
Silverberg SG, eds. Principles and
Practice of Surgical Pathology.
New York-Melburn: Churchill
Livingstone, 1988:899-937.
7. Katic V. Benigni, epitelni tumori
kolona i rektuma. U: Teodorovic J.
i sar, eds. Gastroenterologija II deo.
Beograd: Excelsior, 1998:489-501.
8. Katic V. Maligni tumori kolona i
rektuma. U: Todorovic J. i sar, eds.
Gastroenterologija II deo. Beograd:
Excelsior, 1998:502-20.
9. Preston SL, Wong WM, Chan
A, et al. Bottom-up Histogenesis
of Colorectal Adenoma: Origin
in the Monocryptal Adenoma
and initial Expansion by Crypt
Fission. Cancer Rechearch 2001;
63:3819-25.
10.Shit L-M, Wаng T, Traverso G, et
al. Top-down morphogenesis of
colorectal tumors. PNAS 2001;
98(5):2640-5.
28
11.Koido S, Shimoda T. Immunohistochemical study of proliferative cells in colorectal adenoma
and carcinoma. Nippon Shokagibyo Gakkai Zasshi 1992;
89(11):2664-72.
12.Hamilton SR, Vogelstein B, Kudo
S, et al. Carcinoma of the colon
and rectum. In: Hamilton SR,
Aoltonen LA, eds. Pathology
and Genetics of Tumours of the
Digestive System. Lyon: LARC
Press, 2000:103-19.
13.Fearon ER. Molecular abnormalities in colon and rectal cancer. In: Mendelsohn J, Howley
PM, Israel MA, Liotta L, eds.
The molecular Basis of cancer.
Philadelphia-Tokyo: WB Saunders
Co, 1995:324-58.
14.Correa P: Epidemilogy of polyps
and cancer. In: Morson BC,
eds. Pathogenesis of Colorectal
Cancer. Philadelphia: WB Saunders Co, 1976:126.
15.Itzkowitz SH. Colonic polyps and
polyposis syndromes. In: Feldman
M, Friedman SL, Sleisenger MH,
eds. Sleisenger and Fordtran`s
Gastrointestinal and Liver Disease. 7th ed. CD-Rom. Elsevier
Science (USA), 2002.
16.Fenoglio-Preiser CM. Carcinomas and other Epithelial and
Neuroendocrine Tumors of the
Large Intestine. In: FenoglioPreiser CM, eds. Gastrointestinal
Pathology Plus. An Atlas and
Text. Philadelphia-New York:
Lippincott Williams and Wilkins
Publ, 1999:200-73.
17.Cummings OW. Pathology of the
adenoma-carcinoma
sequence:
from aberrant crypt focus to invasive carcinoma. Semin Gastrointest
Dis. 2000; 11(4):229-37.
18.Morson BC, Dawson IMP.
Large Bowel. In: Morson BC,
eds. Gastrointestinal pathology.
Oxford-Melbourne:
Blackwell
Scientific Publl, 1972:423-602.
Arch Gastroenterohepatol 2012; 29 (No 1) 22-29
19.Morson BC, Bussey HJR:
Magnitude of risk for cancer in
patients with colorectal adenomas.
Br J surg. 1985; 72(Suppl):23-9.
20.Itzkowitz SH, Kim YS. Colonic
poyps and polyposis syndromes.
In: Feldman M, Scharschmidt BF,
Sleisenger MH, eds. Sleisenger and
Fordtran`s Gastrointestinal and
Liver Disease: Pathophysiology
(Diagnosis) Mangment. 6th ed.
Philadelphia: WB Saunders Co,
1997:467-71.
21.Muto T, Bussey HRJ, Morson BC.
The evolution of cancer of the
colon and rectum. Cancer 2002;
36:225-30.
22.Morson BC. The polyp cancer
sequence in the large bowel. Proc
Roy Soc Med. 1974; 64:451-9.
23.Nagorni A. Genetika naslednih
kolorektalnih karcinoma. Acta fac
med naiss. 2000; 17: 177-9.
24.Nakamura K. De novo cancer
and adenoma-carcinoma sequence of the colorectum-clinicopathological defferences between
de novo carcinoma and carcinoma
with the sequence. Nippon Gakkai
Zasshi. 1999; 100(12):766-75.
25.Shimoda T, Ikegami M, Fujisaki J,
et al. Early colorectal carcinoma
with special reference to its
development de novo. Cancer
1989; 64:1138-46.
26.Dippe B, Petrowsky H, Kruger
S, et al. The malignancy potential of colorectal polyps-histomorphometric, histochemical and
immunohistochemical study of
the dysplasia-carcinoma seqence.
Zentarbl Chir. 1995; 120(7):556-63.
27.Domoto H, Terahata S, Senoh
A, et al. Clear cell change in
colorectal adenomas: its incidence
and histological caracetristics.
Histopathology. 1999; 34:250-6.
28.Meijep GA, Book JPA. Qantification of proliferative activity in
colorectal adenomas by mitotic
counts: relationship to degree of
dysplasia and functional type. J
Clin Pathol. 1995; 48:620-5
29.Risiom M, Rossini FP. Cell
proliferation in colorectal adenomas containing invasive carcinoma. Anticancer Res. 1993;
13(1):43-7.
30.Baumforth K, Crocker J. Molecular
and immunological aspects of
cell proliferation. In: Crocker
J, Murray PG, eds. Molecular
biology in cellular pathology. 2nd
ed. Chichester: John Wiley & Sons
Ltd, 2003:105-35.
31.Derenzini M, Trere D, O’Donohue
M-F, Ploton D. Interphase
nucleolar organizer regions in
tumor pathology. In: Crocker
J, Murray PG, eds. Molecular
biology in cellular pathology.
2nd ed. Chichester: John Wiley &
Sons Ltd, 2003:137-52..
32.Sirri V, Roussel P, HernandezVerdun D. The AgNOR proteins:
qualitative and quantitative changes during the cell cycle. Micron
2000;31:121-6.
33.Trere D. AgNOR staining
and
quantification.
Micron
2000;31:127-31.
34.Grawford JM. The Gastrointestinal Tract. In: Cotran RS,
Kumar V, Robbins SL, eds.
Robbin Pathologic Basis of
Disease. Philadelphia-Tokyo: WB
Saunders Co, 1994:755-831.
35.Rubin E, Farber JL. The
Gastrointestinal Tract. In: Rubin
E, Farber JL, eds. Pathology.
Philadelphia: JB Lippincott Co,
1988:618-704.
36.Yang P, Huang GS, Yhu XS. Role
of nucleolar organizer regions in
differentiating malignant from
benign tumours of the colon. J
Clin Pathol 1990;43:235-8.
37. Sugai T, Nakamura S, Habano W,
et al. Usefulness of proliferative
activity, DNA ploidy pattern
and p53 products as diagnostic
adjuncts in colorectal adenomas
and intramucosal carcinomas.
Pathology International 1999; 49:
617-25.
38.Jin W, Gao M-Q, Lin Z-W, Yang
D-X. Qvantitative study of
multiple biomarkers of colorectal tumor with diagnostic
discrimination model. World J
Gastroenterol 2004; 10(3):439-42.
39.Wood AJ, Connock MJ, Allen CA,
Grace RH. AgNOR technique in
relation to colorectal neoplasia. J
Clin Pathol 1992; 45(8):743.
40.Muskara M, Gluffre G, Tuccari
G, Barresi G. Nucleolar organiser regions in dysplastic
and neoplastic lesions of the
large bowel. Eur J Basic Appl
Histochem. 1991; 35(4):401-8.
Arch Gastroenterohepatol 2012; 29 (No 1) 22-29
29
Liver and Biliary System
ARCH GASTROENTEROHEPATOL 2012; 29 (No 1) 30-34
J. Djordjevic1, D. Bojic1,2,
P. Svorcan1,2, D. Vrinic1,
Nj. Jojic1,3
1
Department of Gastroenterology and Hepatology,
Zvezdara University Clinical Center, Belgrade
2
Faculty of Medicine,
University of Belgrade, Serbia
3
Faculty of Dentistry,
University of Belgrade, Serbia
Ključne reči:
primarni sklerozirajući holangitis,
inflamatorne bolesti creva
Key words:
primary sclerosing cholangitis,
inflammatory bowel disease
Primary Sclerosing Cholangitis
and Inflammatory Bowel
Diseases: Our Experience
SAŽETAK
Primarni sklerozirajući holangitis (PSC) je hronična, holestatska
bolest jetre koju karkterišu fibroza i inflamatorna destrukcija
intrahepatičnih i/ili ekstrahepatičnih žučnih puteva. Neki pacijenti
mogu biti asimptomatski godinama. Kod drugih se u kratkom
vremenu razvija insuficijencija jetre ili holangiokarcinom. Bolest je
nepoznate etiologije. Pretpostavlja se imunološka priroda bolesti.
2/3 pacijenata sa PSC ima pridruženu neku od inflamatornih bolesti
creva (IBD), dok se PSC javlja kod 7.5% pacijenata sa ulceroznim
kolitisom (UC) i kod 4% pacijenta sa Kronovom bolešću (CD).
Cilj: Proceniti karakteristike UC/CD kod pacijenata sa PSC.
Metodi: U radu su retrospektivno analizirani biohemijski, klinički i
endoskopski nalazi pacijenata sa PSC i IBD.
Rezultati: Analizirano je 411 pacijenta sa IBDom. 262/411 (75%) je
imalo UC. CD bila prisutna kod 149/411 (25%) pacijenata. PSC je
dijagnostikovan kod 16/411 pacijenata (3.9%). U 5 pacijenata PSC se
razvio nakon kolektomije. „Backwash“ ileitis je bio prisutan kod 10/12
pacijenata sa UC dok je rektum bio pošteđen kod 11/12 pacijenta.
Od 4 pacijenta sa CD rektum je bio zahvaćen kod 2 pacijenta.
Address correspondence to:
Jelena Djordjevic
Department of Gastroenterology and Hepatology
Zvezdara University Clinical Center
Dimitrija Tucovica 161, Belgrade
e-mail: [email protected] net
30
Zaključak: UC udružen sa PSC se češće javlja kod muškaraca.
Uglavnom ima blag do umeren uz čestu poštedu rektuma i
zahvaćenost terminalnog ileuma. Nema „zajedničke“ terapije za
PSC i IBD. Posebno se leči PSC, a posebno IBD. Međutim, efekat
imunosupresivne terapije na PSC je nezadovoljavajući. Još uvek ne
postoji efikasna medikamentozna terapija koja značajno poboljšava
preživljavanje ovih pacijenata. Transplantacija jetre predstavlja jedinu
terapijsku opciju za pacijente sa uznapredovalom bolešču jetre.
Primary Sclerosing Cholangitis and Inflammatory Bowel Diseases: Our Experience
ABSTRACT
INTRODUCTION
Primary sclerosing cholangitis (PSC) is a chronic,
cholestatic liver disease. It is characterized by an
inflammation and fibrosis that can affect both the
intrahepatic and extrahepatic bile ducts. The disease
leads to irregular bile duct obliteration, including
formation of multifocal bile duct strictures. PSC
is a progressive disorder that eventually develops
into liver cirrhosis, liver failure, and hepatobiliary
malignancy. The etiology is unknown although
there is evidence that the pathogenesis is immune
mediated. Up to 80% of Northen European PSC
patients have concomitant inflammatory bowel
disease (IBD). In the majority of cases it is diagnosed
as ulcerative colitis (UC), although it is also associated
with Crohn’s disease (CD).
Primary sclerosing cholangitis (PSC) is a chronic,
cholestatic liver disease. It is characterized by an
inflammation and fibrosis that can affect both the
intrahepatic and extrahepatic bile ducts (1). The
disease leads to irregular bile duct obliteration,
including formation of multifocal bile duct strictures.
PSC is a progressive disorder that eventually develops
into liver cirrhosis, liver failure, and hepatobiliary
malignancy with the median survival of approximately
17 years of diagnosis (2). The etiology is unknown
although there is evidence that the pathogenesis is
immune mediated (3). It is more common in men,
with the male to female ratio approximately 2:1. PSC
can be diagnosed in children as well as in the elderly,
but mean age at diagnosis is around 40 years. Up to 80%
of Northen European PSC patients have concomitant
inflammatory bowel disease (IBD). In the majority
of cases it is diagnosed as ulcerative colitis (UC),
although it is also associated with Crohn’s colitis.
However, PSC occurs in 5-10% of total UC and 3-4%
of Crohn’s disease (CD). Diagnosis of PSC is made in
patients with elevated serum markers of cholestasis
when magnetic resonance cholangiopancreatography
(MRCP) or endoscopic cholangiopancreatography
(ERCP) show characteristic bile duct changes.
Patients who present with clinical, biochemical, and
histological features compatibile with PSC, but have
normal cholangiogram are classified to have small
duct PSC (4). A previous study looking at PSC/
UC patients suggested a particular UC phenotype
associated with PSC characterized by male
predominance, more quiescent colitis, rectal sparing,
backwash ileitis, increased rates of pouchitis after
colectomy, and higher rates of dysplasia/carcinoma
(5). No such review of Cohn’s/PSC patients has been
undertaken. There is no correlation between the
severity of IBD and PSC. Treatment of colits does
not improve the outcome of PSC which may progress
after colectomy. To date, trials of medical therapy
have proven to be disappointing, with no currently
available agents shown to improve survival. Several
potential treatment options such as corticosteroids,
cyclosporin, methotrexate, colchicine, and tacrolimus
have been evaluated. None of them have been found
to be efficacious (6-11). The hydrophilic bile acid,
ursodeoxycholic acid (UDCA) has been evaluated
for use in PSC. It has been shown that UDCA therapy
improves laboratory values of cholestasis including
Aim: The aim of this retrospective study was to evaluate clinical features of inflammatory bowel diseases
associated with primary sclerosing cholangitis.
Methods: 411 patients diagnosed with IBD were
enroled in the study. Clinical, biochemical, and
endoscopical findings were analysed.
Results: 411 patients with inflammatory bowel
diseases were enroled in the study, 230 (56%) males
and 181 (44%) females. 262 patients out of 411 (64%)
were diagnosed as UC and 149 out of 411 (36%) were
diagnosed as CD. PSC was present in 16/411 patients
(3.9%). In 12/16 was associated with UC (75%)
and in 4/16 was associated with CD (25%). Rectal
sparing was present in 11 out of 12 patients with UC,
and in 2 out of 4 patients with CD. Backwash ileitis
was found in 10 patients with UC.
Conclusion: UC associated with PSC is more
common in men. It is usually milde to moderate
with rectal sparing and ileal involvment. Treatment
of PSC associated with IBD is quite complicated.
Management of cholestasis, liver cirrhosis,
biliary complications, and inflammatory bowel
disease should be considered as well as specific
medical therapy and appropriate referral for
liver transplantation. Although previous studies
have showed improvement in biochemistries no
significant improvement in survival has shown. The
only treatment option for these patients that has
shown to be beneficial is liver transplantation.
Arch Gastroenterohepatol 2012; 29 (No 1) 30-34
31
alkaline phosphatase (ALP), but an improvement
in survival has not been observed (12-14). The only
treatment option that improves long-term prognosis
is liver transplantation, with 10-year survival rate
of 70% after transplantation (15). The aim of this
retrospective study was to evaluate clinical features of
inflammatory bowel diseases associated with primary
sclerosing cholangitis.
METHODS
This retrospective study included 411 patients
diagnosed as IBD who were seen at the Department
of Gastroenterology and Hepatology Zvezdara
University Clinic. The diagnosis of UC and CD
were established on previously accepted criteria. The
diagnosis of PSC was based on typical cholangiographic findings in all patients in combination with
clinical, laboratory, and histological data. In all
patients in whome PSC was suspected ERC or
MRCP were performed. The confluence of the bile
duct at the hilum was used to distinguish between
the extra- or intrahepatic biliary system. In cases of
small duct PSC with normal cholangiography, liver
biopsy was done. When available liver histological
staging was assesed according to criteria prevously
established by Ishak. Patients with small duct PSC
were excluded from this study. Symptoms and sings
including jaundince, itching, right upper abdominal
pain, fatique, cholangitis, fever, weight loss, hepatic
encephalopathy, ascites, and variceal bleeding were
recorded. The presence of ascites was determined by
physical examination and abdominal ultrasound, and
the presence of gastroesophageal varices as well as
bleeding from varices was confirmed by upper endoscopy. Biochemical and serological analyses including
total bilirubin, alkaline phospatase (ALP), aspartate aminotrasferase (AST) and albumin were performed
using standardized techiques. Other liver diseases,
such as alcoholic liver disease, primary biliary cirrhosis,
autoimune hepatitis, metabolic diseases, as well as
viral and drug induced liver diseases were excluded
by clinical evaluation and appropriate serological
tests. The first pathological cholangiography defined
the time of diagnosis of patients with large duct PSC.
In cases of small duct PSC, the first pathological liver
biopsy was chosen for diagnosis.
32
Arch Gastroenterohepatol 2012; 29 (No 1) 30-34
MRCP image of PSC, courtesy by Ivan Jovanović
RESULTS
411 patients with inflammatory bowel diseases were
enroled in the study, 230 (56%) males and 181 (44%)
females. The median age at the time of diagnosis
of PSC was 37.9 (15-51) years, and the median
age at the time of diagnosis of IBD was 30.5 (2156) years. The median age from the first diagnosis
of IBD to the first diagnosis of PSC was 6.6 years.
In 5/16 patients diagnosis were made at the same
time. 262 patients out of 411 (64%) were diagnosed
as UC and 149 out of 411 (36%) were diagnosed as
CD. PSC was present in 16/411 patients (3.9%). In
12/16 was associated with UC (75%) and in 4/16 was
associated with CD (25%). Among 16 patients (6/16)
37.5% had intrahepatic disease, 43.7% (7/16) were
diagnosed with extrahepatic, 18.8% (3/16) with both
extrahepatic and intrahepatic. 83% of patients who
were diagnosed with ulcerative colitis associated with
PSC had extensive colitis, and 17% had distal colitis.
In patients diagnosed with Crohn’s disease ileocolitis
was present. Rectal sparing was present in 11 out of
12 patients with UC, and in 2 out of 4 patients with
CD. Backwash ileitis was found in 10 patients with
UC. UC was classified as mild or moderate in 81%
and severe in 19% of patients. Liver functional tests
(LFT) were abnormal in cholestatic pattern in every
patient who was diagnosed with PSC. 5 out of 16
patients underwent hemi or total colectomy (2 with
CD and 3 with UC) due to the activity of disease or
stenosis in patients with CD and in patients with UC
colectomy was performed beucause of malignant
alteration or fulminant disease. In all of them PSC
developed after colectomy.
DISCUSSION
This retrospective study showed that inflammatory
bowel disease associated with primary sclerosing
cholangitis was characterised by a high prevalence
of pancolitis with rectal sparing and backwash
ileitis. However, the number of patients enroled
in this study was too small to evaluate the risk
for the development of colorectal neoplasia. The
study findings published by Loftus et al. (5) were
suggestive (but not definite) that PSC-IBD patients
were at higher risk for colorectal neoplasia. Most
PSC-IBD patients had extensive colitis, with or
without ileal involvement. The prevalence of isolated
ileal involvement was quite low. The high prevalence
of rectal sparing in PSC-IBD had been reported in
preliminary fashion (16). In many series, this subtype
of IBD was thought to represent indeterminate
colitis (IC) on the basis of either ileal involvement or
rectal sparing. The prevalence of CD reported in the
same series ranged from 0% to 17%, with an average
of 8% (17,18,19-21). Where specified, most of these
patients with ‘‘CD’’ had colonic involvement. Most
of these patients did not appear to have features that
were strongly suggestive of CD, such as fistulas, deep
ulcers, or granulomas. In our study PSC patients
with rectal sparing or mild ileitis were thought to
have UC rather than CD or IC.
PSC patients without bowel symptoms were found to
have not only pancolitis but also low grade dysplasia,
suggesting that the pancolitis was longstanding (23).
Other possible mechanism for the association may
include alterations in the bile salt pool. Indeed,
lower rates of colorectal neoplasia among PSC
patients treated with ursodeoxycholic acid suggests
that bile acids have certain role in the pathogenesis
of CRC (25,26).
PSC patients have 10-fold increased risk of colorectal
cancer compared to the general population, regardless
of the mechanism (27). Therefore it is important to
recognize PSC-IBD patients and such patients should
be enrolled in a colonoscopic surveillance.
Treatment of PSC associated with IBD is quite
complicated. Management of cholestasis, liver
cirrhosis, biliary complications, and inflammatory
bowel disease should be considered as well as specific
medical therapy and appropriate referral for liver
transplantation. Although previous studies showed
improvement in biochemistries no significant
improvement in survival was shown (28,29).
Furthermore, in a study of Lindor et al. (30) patients
with PSC treated with high dose of UDCA had poorer
outcome compared to placebo. Further prospective
studies need to be done to asses the effect of UDCA
on the natural course of PSC. Liver transplantation
remains the treatment of choice in these patients
with 5 year survival of 85% (15). However, PSC may
develop after LT (milder form). In addition, IBD-PSC
patients are at higher risk of colonic carcinoma after
liver transplantation (5.3% compared to 0.6%), and
LT may deteriorate natural course of inflammatory
bowel disease or may provoke development of it. All
Our study findings did not resolve the issue of these issues should be concidered before reffering
whether PSC could be an independent risk factor patient for liver transplantation.
for colorectal neoplasia in IBD. However, previous Given the high frequency of asymptomatic colitis,
meta-analysis showed increased risk for CRC rectal sparing, and colorectal neoplasia among
in patients with PSC. The adjust odds ratio for PSC-IBD patients, all patients with PSC, even
colorectal carcinoma with PSC was 4.79 (95% CI those who are asymptomatic, should undergo full
3.58-6.41) (22). The mechanism by which PSC could colonoscopy with biopsies to detect subclinical IBD
be associated with an increased risk of colorectal and/or neoplasia. Considering the high cumulative
neoplasia in IBD remains unclear. Longstanding incidence of colorectal neoplasia, and short mean
colitis and extent of colitis are well recognized risk interval between PSC diagnosis and development
factors for dysplasia and cancer, and there is a high of neoplasia, PSC-IBD patients should consider
prevalence of pancolitis in PSC-IBD. Disease activity immediate entry into a surveillance colonoscopy
of IBD in PSC patients is often mild and occasionally programme (5).
completely asymptomatic (16,23,24).
Arch Gastroenterohepatol 2012; 29 (No 1) 30-34
33
References:
1. Maggs JR, Chapman RW. An update
on primary sclerosing cholangitis.
Curr Opin Gastroenterol 2008; 24:
377-83.
2. Bambha K, Kim WR, Talwarkar J,
et al. Incidence, clinical spectrum,
and outcomes of primary sclerosing
cholangitis in the United States
community. Gastroenterology 2003;
125: (5): 1164-9
3. Karlsen TH, Scrumpf E, Boberg KM.
Genetic epidemiology of primary
sclerosing cholangitis. World J
Gastroenterol 2007; 12: 5421-31.
4. Abdalian R, Heathcote EJ. Sclerosing cholangitis: a focus on secon
dary causes. Hepatology 2006; 44:
1063-74.
5. Loftus EV Jr, Harewood GC, Loftus
CG, Tremaine WJ, Harmsen WS,
Zinsmeister AR, Jewell DA, Sandborn
WJ: PSC-IBD: a unique form of
inflammatory bowel disease associated
with primary sclerosing cholangitis.
Gut 2005; 54: 91–6.
6. Knox TA, Kaplan MM. A double
- blind controlled trial of oralpulse methotrexate therapy in the
treatment of primary sclerosing
cholangitis. Gastroenterology 1994;
106: 494-9.
7. Angulo P, Batts KP, Jorgensen RA,
LaRusso, Lindor KD. Oral budesonide
in the treatment of primary sclerosing
cholangitis. Am J Gastroenterol 2000;
95: 2333-7.
8. Sandborn WJ, Wiesner RH, Tremaine WJ, Larusso NF. Ulcerative colitis
disease activity following treatment
of associated primary sclerosing
cholangitis with cyclosporine. Gut
1993; 34: 242-6.
9. Van Thiel DH, Wright H, Carroll
P, Abu-Elmagd K, Rodriguez-Rilo
H, McMichael J, et al. Tacrolimus:
a potential new treatment for autoimmune chronic active hepatitis:
results of an open-label preliminary
trial. Am J Gastroenterol 1995; 90:
771-6.
10.Talwarkar JA, Gossard AA, Keach
JC, Jorgensen RA, Petz JL, Lindor
KD. Tacrolimus for the treatment of
primary sclerosing cholangtis. Livet
Int 2007; 27: 451-3.
34
11.Olsson R, Broome U, Danielsson
A, Hagerstrand I, Jarneror G, Loof
L, et al. Colchicine treatment of
primary sclerosing cholangitis.
Gastroenterology 1995; 108: 11991203.
12.Lindor KD. Ursodiol for primary
sclerosing
cholangitis.
Mayo
Primary Sclerosing CholangitisUrsodeoxycholic Acid Study Group.
N Engl J Med 1997; 336:691-5.
13.Olsson R, Boberg KM, de Muckadell
OS, et al. High – dose ursodeoxycholic
acid in primary sclerosing cholangitis:
a 5-year multicenter, randomized,
controlled study. Gastroenterology
2005; 29: 1464-72.
14.Lindor KD, Kowdley KV, Luketic VA,
et al. High-dose ursodeoxycholic
acid for the treatment of primary
sclerosing cholangitis. Hepatology
2009; 50(3): 808-14.
15.Graziadei IW, Wesner RF, Marotta PJ,
et al. Long-term results of patients
undergoing liver transplantation
for primary sclerosing chlangitis.
Hepatology 1999; 30: 1121-7.
16.Perdigoto R, Wiesner RH, LaRusso
NF, et al. Inflammatory bowel disease
associated with Primary Sclerosing
Cholangitis: incidence, severity
and relationship to liver disease.
Gastroenterology 1991; 100:A238.
17.Wiesner RH, LaRusso NF. Clinicopathologic features of the syndrome
of primary Sclerosing Cholangitis.
Gastroenterology 1980; 79:200–6.
18.Chapman RW, Arborgh BA, Rhodes
JM, et al. Primary Sclerosing
Cholangitis: a review of its clinical
features,
cholangiography,
and
hepatic histology. Gut 1980; 21:870–7.
19.Aadland E, Schrumpf E, Fausa O, et
al. Primary Sclerosing Cholangitis: a
long-term follow-up study. Scand J
Gastroenterol 1987; 22:655–64.
20.Stockbrugger RW, Olsson R, Jaup B,
et al. Forty-six patients with Primary
Sclerosing Cholangitis: radiological
bile duct changes in relationship
to clinical course and concomitant
inflammatory
bowel
disease.
Hepatogastroenterology 1988; 3
5:289–94.
Arch Gastroenterohepatol 2012; 29 (No 1) 30-34
21.Fausa O, Schrumpf E, Elgjo K.
Relationship of inflammatory bowel
disease and primary sclerosing
cholangitis. Semin Liver Dis 1991;
11:31–9.
22.Soetikno RM, Lin OS, Heidenreich
PA, Young HS, Blackstone MO.
Increased risk of colorectal neoplasia
in patients with primary sclerosing
cholangitis and ulcerative colitis:
a
meta-analysis.
Gastrointest
Endosc. 2002; 56(1):48-54.
23.Fausa O, Schrumpf E, Elgjo K.
Relationship of inflammatory bowel
disease and primary sclerosing
cholangitis. Semin Liver Dis 1991;
11:31–9.
24.Broome U, Lofberg R, Lundqvist
K, et al. Subclinical time span of
inflammatory bowel disease in
patients with primary sclerosing
cholangitis. Dis Colon Rectum
1995;38 : 1301-5.
25.Tung BY, Emond MJ, Haggitt RC, et
al. Ursodiol use is associated with
lower prevalence of colonic neoplasia
in patients with ulcerative colitis and
primary sclerosing cholangitis. Ann
Intern Med 2001; 34: 89–95.
26.LaRusso NF, Wiesner RH, Ludwig
J, et al. Current concepts. Primary
Sclerosing cholangitis. N Engl J Med
1984; 310:899–903.
27.Bergquist A, Ekbom A, Olsson R,
et al. Hepatic and extrahepatic
malignancies in primary sclerosing
cholangitis. J Hepatol 2002; 36:321–7.
28.Lindor KD. Ursodiol for primary
sclerosing
cholangitis.
Mayo
Primary Sclerosing Cholangitis Ursodeoxycholic Acid Study Group.
N Engl J Med 1997; 336:691-5.
29.Olsson R, Boberg KM, de Muckadell
OS, et al High – dose ursodeoxycholic
acid in primary sclerosing cholangitis:
a 5-year multicenter, randomized,
controlled study. Gastroenterology
2005; 29: 1464-72.
30.Lindor KD, Kowdley KV, Luketic VA,
et al. High-dose ursodeoxycholic
acid for the treatment of primary
sclerosing cholangitis. Hepatology
2009; 50(3): 808-14.
GAST-1029713-0001
SAMO ZA STRUÈNU JAVNOST
Broj dozvole za stavljanje leka u promet: 310/2008/12 od 05.02.2008.
Za dodatne informacije molimo Vas da pogledate
3AÞETAKÒKARAKTERISTIKAÒLEKAÒ2EMICADE
Datum poslednje revizije teksta: Februar 2010.
2EÞIMÒIZDAVANJAÒLEKAÒ,EKÒSEÒMOÞEÒUPOTREBLJAVATIÒSAMOÒU
stacionarnoj zdravstvenoj ustanovi.
Schering-Plough CE AG, Predstavništvo u Srbiji
Omladinskih brigada 90a, 11070 Beograd
Telefon 011 22 57 200, faks 011 22 88 642
Pronalazi naËin!
Plantago
Ovata
✓ Blag biljni zapreminski
laksativ
✓ Reguliπe probavu prirodnim
putem
✓ OmekπivaË stolice
✓ PreporuËuje se u svim
stanjima kada je potrebna
olakπana stolica
✓ Ne dovodi do navikavanja
grËeva ili Ëupanja u
stomaku
1Ÿ2
✓ Bezbedan i za trudnice
kesice dnevno
rastvoriti u Ëaπi vode
i odmah popiti
Predstavništvo Balkan • Koste GlaviniÊa 2/4, Beograd
Tel.: +381 11 3692 932, 3692 933 • Fax: +381 11 2652 776
E-mail: [email protected] • www.innotechbalkan.com
Alimentary tract
ARCH GASTROENTEROHEPATOL 2012; 29 (No 1) 35-41
Popović Đ. Dušan1,
Špuran Milan1,
Jovanović Ivan1,2,
1
Klinički centar Srbije, Klinika za
gastroenterologiju i hepatologiju
2
Medicinski fakultet, Univerzitet u Beogradu
Ključne reči:
hronična opstipacija, dijetalna vlakna,
Plantago ovata
Key words:
chronic constipation, dietary fibers,
Plantago ovata,
Plantago ovata u terapiji
hronične opstipacije-rezultati
multicentrične studije
SAŽETAK
Uvod: Plantago ovata (P.ovata) je biljka koja se koristi kao izvor
mucilaginoznih vlakana, te se zbog svojih osobina koristi u lečenju
hronične opstipacije. Cilj ove studije je procena efikasnosti preparata
P.ovata u terapiji hronične opstipacije.
Metodologija: Sprovedena je otvorena, prospektivna, nerandomizovana, multicentrična studija. U studiju je bilo uključeno
1864 pacijenta, od čega 1141 muškarac (61.2%) i 723 žene (38.8%).
Prosečna starost ispitanika je bila 62.4 ± 15.2 godina. Indikacija
za primenu preparata P.ovata je kod 63 pacijenata (3.4%) bila
opstipacija nakon proktoloških operacija, a kod 1801 pacijenta
(96.6%) idiopatska hronična opstipacija.
Rezultati: Primenom preparata P. ovata, nakon mesec dana i nakon
dva meseca značajno je poboljšano neredovno (p<0.001), otežano
(p<0.001) i bolno crevno pražnjenje (p<0.001), konzistencija stolice
(p<0.001) i značajno se smanjuje osećaj nepotpunog pražnjenja
(p<0.001).
Zaključak: Primena preparata P.ovata, kod pacijenata sa idiopatskom
hroničnom opstipacijom ili opstipacijom nakon proktoloških
intervencija, dovodi do poboljšanja crevnog pražnjenja, poboljšanja
konzistencije stolice i smanjenja bola kao i osećaja nepotpune
ispražnjenosti.
Address correspondence to:
Dušan Đ. Popović
Klinički centar Srbije
Klinika za gastroenterologiju i hepatologiju
Dr Koste Todorovića br. 2
11000 Beograd
telefon: +381 11 361 37 34
faks: +381 11 361 55 87
e-mail: [email protected]
Plantago ovata u terapiji hronične opstipacije-rezultati multicentrične studije
37
ABSTRACT
Introduction: Plantago ovata (P.ovata) is a plant
that is used as a source of mucilaginous fibers in the
treatment of chronic constipation. The aim of this
study was to evaluate its efficiency in the treatment
of chronic constipation.
sledećih simptoma: tvrda stolica, naprezanje pri
defekaciji, osećaj nepotpune ispražnjenosti, osećaj
analne opstrukcije, primena manuelnih manevara
za olakšanje defekacije, retko crevno pražnjnje (<3
puta nedeljno), gubitak stolice bez upotrebe laksativa
i neispunjavanje kriterijuma za IBS (sindrom iritabilnog creva) (7, 9). Navedene tegobe se moraju javljati
u ≥ 25% defekacija i biti prisutne tokom poslednja
3 meseca sa početkom najmanje 6 meseci pre
postavljanja dijagnoze (9). Simplifikovano, hronična
opstipacija se definiše kao retko (< 3 nedeljno)
crevno pražnjenje i/ili pojava tvrde stolice koja se
teško evakuiše (7, 10, 11).
Methodology: An open, prospective non-randomized, multi-centre study was conducted. The study
included 1864 patients, of whom 1141 (61.2%) were
men and 723 (38.8%) were women. The average
age was 62.4 ± 15.2 years. The indication for use
the P.ovata was the constipation after proctologic
intervention in 63 (3.4%) patients and the chronic Cilj ove studije je procena efikasnosti preparata
idiopathic constipation in 1801 (96.6%) patients.
P.ovata u terapiji hronične opstipacije i opstipacije
Results: The use of P. ovata product, after a month nakon proktoloških operacija.
and after two months significantly improves
irregular (p <0.001), difficult (p <0.001) and painful METOD
bowel movements (p <0.001), softens the stools (p
Istraživanje je sprovedeno kao otvorena, prospek<0.001) and reduces the feeling of incomplete bowel
tivna, ne-randomizovana, multicentrična studija,
evacuation (p <0.001).
u 41 zdravstvenoj ustanovi u Srbiji, u periodu od
Conclusion: The use of P.ovata product, in patients januara 2007. do marta 2008. godine. Kriterijumi
with idiopathic chronic constipation or constipation za uključivanje u studiju bili su: idiopatska hronična
after proctologic intervention, improves bowel opstipacija ili opstipacija nakon proktoloških
movements, softens the stool reduces pain during operacija (hemoroidi, perianalna fistula, analna
defecation and diminishes the feeling of incomplete fisura). U studiju nisu uključivane osobe sa poznabowel evacuation.
tom preosetljivošću na sastojke preparata, istovremena upotreba drugih preparata u terapiji
UVOD
opstipacije i osobe sa kompromitovanom pasažom
digestivnog sistema usled poznatih razloga (pretPlantago ovata (P.ovata) je biljka iz porodice hodne abdominalne i ginekološke operacije,
Plantaginaceae, čije se seme koristi kao izvor resekcije creva, dijabetičari, neurološki bolesnici
mucilaginoznih vlakana. U literaturi, kao sinonimi za i sl.). Pacijenti sa alarmnim simptomima (krv u
ovu biljku, sreću se nazivi: Indijska bokvica, Plantago stolici, anemija, gubitak telesne mase, porodična
brunnea, Plantago fastigiata, Psyllium i Ispaghula. anamneza opterećena kolorektalnim karcinomom)
Seme ove biljke se sastoji iz 35% solubilnih i 65% nisu uključivani u studiju, već su upućivani na dalje
nesolubilnih polisaharida (celuloza, hemiceluloza i gastroenterološko ispitivanje. Podaci su prikupljani
lignin) (1, 2). Od šećera sadrži visok procenat ksiloze posebno dizajniranim upitnikom (Slika 1) koji je
(74.6%) i arabinoze (22.6%), dok se ostali šećeri sadržavao procenu sledećih tegoba: redovnost crevnalaze u tragovima. Zahvaljujući visokom procentu nog pražnjenja, otežano pražnjenje, bolno pražnjenje,
nesolubilnih polisaharida, P.ovata ima sposobnost pojavu tvrde stolice i osećaj nepotpunog pražnjenja.
vezivanja vode. Naime, ukoliko se njeno seme potopi Nakon prvog pregleda svim pacijentima je objašnjena
u vodu, ono će nabubriti i povećati svoju zapreminu svrha i način sprovođenja istraživanja, te je dobijen
8-14 puta (3). U brojnim studijama je ispitivan njen njihov pismeni pristanak za uključivanje u studiju.
efekat u lečenju hronične opstipacije (4-6).
Svim pacijentima je propisano uzimanje preparata
Opstipacija je čest poremećaj, koji se javlja kod P. ovata (Laxomucil®, pulvis 3,26g, Ivančić i sinovi,
2-28% opšte populacije (7). Prevalencija joj se pove- Beograd, Srbija), u dozi od 3 kesice (merice) dnevno,
ćava sa starošću, naročito posle 70-te godine (8). rastvorene u 200 ml vode, u vremenskom periodu od
Na osnovu Roma III kriterijuma, funkcionalna dva meseca. Prilikom prvog i kontrolnih pregleda (0,
opstipacija se definiše kao prisustvo dva ili više od 1 i 2 meseca), lekar je ispunjavao upitnike.
38
Arch Gastroenterohepatol 2012; 29 (No 1) 35-41
Slika 1. Korišćeni upitnik
Statistička analiza je sprovedena programskim
paketom SPSS 16.0 za Windows (SPSS Inc., IL,
USA, 2007.). Analiza je obuhvatala primenu metoda
deskriptivne i analitičke statistike. Za procenu
značajnosti razlike korišćeni su neparametarski
testovi za vezane uzorke i to: Wilcoxon-ov test
i McNemmar-ov test. Statističa značajnost je
proglašavana za vrednosti p<0.05, odnosno p<0.001.
starost ispitanika bila je 62.4 ± 15.2 godina. Indikacija
za primenu preparata P.ovata kod 63 pacijenata
(3.4%) bila je opstipacija nakon proktoloških
operacija, a kod 1801 pacijenta (96.6%) idiopatska
hronična opstipacija.
Nakon mesec dana upotrebe ovog preparata, kod
pacijenata je značajno poboljšano neredovno
(876/1771) (Z=-21.0, p<0.001), otežano (1069/1732)
(Z=-28.7, p<0.001) i bolno crevno pražnjenje
REZULTATI
(1079/1757) (Z=-28.5, p<0.001). Postignuto je
U studiju je uključeno 1864 pacijenta, od čega 1141 razmekšanje stolice (1203/1750) (Z=-30.5, p<0.001)
muškarac (61.2%) i 723 žene (38.8%). Prosečna i smanjen je osećaj nepotpune ispražnjenosti
Arch Gastroenterohepatol 2012; 29 (No 1) 35-41
39
Tabela 1. Efekat terapije preparatom P.ovata, nakon mesec dana
Tabela 2. Efekat terapije preparatom P.ovata, nakon dva meseca
(685/1754) (χ²= 574.6, p<0.001). Rezultati su
prikazani u Tabeli 1.
nepotpune ispražnjenosti (1040/1704) (χ²= 993.9,
p<0.001). Rezultati su prikazani u tabeli 2. Uporedni
prikaz procenta pacijenata sa poboljšanjem tegoba,
nakon mesec i dva meseca primene P.ovata je
prikazan u Grafikonu 1.
Nakon dva meseca upotrebe preparata P.ovata,
takođe je zabeleženo signifikantno poboljšanje
neredovnog (1038/1716) (Z=-23.0, p<0.001),
otežanog (1288/1682) (Z=-31.5, p<0.001) i bolnog
DISKUSIJA
crevnog pražnjenja (1293/1702) (Z=-31.3, p<0.001).
Postignuto je i signifikantno razmekšanje stolice Nakon unošenja hrane i njenog mešanja sa
(1457/1702) (Z=-33.7, p<0.001) i smanjenje osećaja želudačnim sokom nastaje himus, koji ulazi u tanko
40
Arch Gastroenterohepatol 2012; 29 (No 1) 35-41
Grafikon 1. Uporedni prikaz procenta pacijenata sa poboljšanjem tegoba, nakon mesec i dva meseca primene
preparata P.ovata
crevo, gde se odvija varenje. Ostaci hrane, u tečnom
stanju, dospevaju u kolon. Apsorpcijom vode,
stolica do rektuma postaje formirana. U slučaju
da je iz nekog razloga pasaža sadržaja kroz kolon
usporena (funkcionalni poremećaj, nepravilna
ishrana, usporen tranzit i sl.), doći će do povećanja
apsorpcije vode, čime će se smanjiti volume stolice,
koja postaje konzistentnija, smanjuje se peristaltički
nadržaj, što dovodi do nastanka opstipacije. Lečenje
hronične opstipacije obuhvata primenu higijenskodijetetskih mera i primenu različitih medikamenata,
sa ciljem poboljšanja crevnog pražnjena, a u smislu
prouzrokovanja jedna ili više mekih stolica dnevno
(12, 13). Primena preparata P.ovata je efikasan,
bezbedan i pristupačan način lečenja hronične
opstipacije. (6, 9, 14, 15). Zbog relativne otpornosti
na fermentaciju, P.ovata u nepromenjenom i visoko
polimerizovanom obliku dospeva do cekuma, za 4
sata nakon ingestije (16). Svojim mucilaginoznim
svojstvima vezuje i zadržava vodu iz lumena creva,
čime se poveća volume i zapremina stolice, koja
postaje mekša, čime se olakšava defekacija. Pored
toga, ovi preparati imaju pozitivan uticaj na motilitet
kolona i mehanički čiste crevo (3). Zbog samog
mehanizma delovanja ovi preparati ne dovode do
stvaranja zavisnosti i nemaju nadražajno dejstvo na
mukozu debelog creva. Terapijski efekat preparata
P.ovata se ispoljava za 12-24 h, nakon započinjanja
terapije (2, 13). Zbog mehanizma delovanja, važno
je da pacijenti unose dovoljnu količinu tečnosti (12).
sa ranije objavljenim rezultatima istraživanja (4,
7, 17). Pored toga, mesec, ili dva meseca redovne
primene ovog preparata značajno olakšava crevno
pražnjenje, smanjuje osećaj nepotpunog pražnjenja
i smanjuju bolno pražnjenje.
Ashraf i sar. objavili su rezultate studije u kojoj
je zaključeno da P.ovata povećava učestalost,
zapreminu i obezbeđuje mekšu konzistenciju stolice,
kod pacijenata sa idiopatskom opstipacijom, dok
nema uticaja na motilitet kolona i rektuma (4). U
dvostruko slepoj, randomizovanoj studiji Ewerth
i sar. su pokazali da P.ovata značajno utiče na
razmekšanje stolice, povećavajući njemu zapreminu
i sveukupno smanjujući simptome opstipacije (17).
Međutim, u studiji Cheskin i sar., P.ovata iako
značajno smanjuje tranzitno vreme u odnosu na
placebo, nema uticaja na težinu i konzistenciju
stolice, uz trend porasta učestalosti stolica (5).
Voderholzer i sar. su 1997. u istraživanju na 149
pacijenata, došli do rezultata da 85% pacijenata sa
opstipacijom (bez patološkog supstrata) postaje
asimptomatsko, zahvaljujući primeni P.ovata (6).
Kod 80% pacijenata sa usporenim tranzitom i
63% pacijenata sa poremećajima defekacije, nema
terapijskog odgovora na dijetetska vlakna (6).
U poređenju sa laktulozom i drugim laksativima,
P.ovata je efikasnija u smislu prouzrokovanja većeg
procenta normalnih, dobro formiranih stolica, ali
i manjeg broja neželjenih efekata (dijareja, bolovi
u trbuhu) (15). Wang i sar. su koristeći Bristolsku
U našoj studiji su dobijeni podaci koji govore u klasifikaciju izgleda stolice (18) ustanovili da je
prilog značajnog poboljšanja redovnosti crevnog kombinacija polietilen glikola 3350 i elektrolita
pražnjenja, kao i konzistencije stolice, što je u skladu efikasnija u terapiji funkcionalne opstipacije od
Arch Gastroenterohepatol 2012; 29 (No 1) 35-41
41
Psylliuma i to u smislu ukupne efikasnosti (92% vs.
73%), broja stolica i normalizacije stolica (87.3% vs.
66.7%) (19). Po pitanju neželjenih efekata, autori nisu
uočili razliku između ova dva leka, niti je bilo ozbiljnijih
komplikacija u primeni ova dva laksansa (18).
Tokom sprovođenja naše studije nisu zabeleženi
neželjeni efekti primene ovog preparata. U literaturi,
kao neželjeni efekti primene P.ovata navode se:
nadimanje, pojačana flatulencija i alergijske reakcije
(12, 20). Nadimanje i pojačana flatulencija se javljaju
zbog fermentacije vlakana u kolonu (12, 13, 21).
Od alergijskih reakcija opisani su: astma, rinitis i
anafilaktička reakcija. Međutim, one se češće javljaju
kod osoba koje su profesionalno izložene Psylliumu
(12, 22, 23). U dva sistematska prikaza se nalaze
podaci koji ukazuju da ne postoji značajna razlika
u neželjenim efektima između pacijenata lečenih
Psyliumom i placebo grupe (14, 24).
Pored primarne primene u terapiji hronične
opstipacije i sindroma iritabilnog kolona, preparati
P.ovata imaju značaja i u terapiji: hemoroida,
hiperlipoproteinemije, dijabetes mellitusa, inflamatorne bolesti creva i dijareje (1-3,25). Ustanovljeno
je da ovi preparati imaju i prebiotski potencijal (26).
Kod zdravih osoba Psylium smanjuje osećaj gladi
i usporava pražnjenje želuca (21,27). Ukoliko se
ovi preparati upotrebe nakon hemoroidektomije,
dovode do bržeg uspostavljanja digestivne funkcije,
smanjenja bola nakon defekacije i skraćenja vremena
postoperativne hospitalizacije (28).
Grad; G. Jelisijević, DZ Voždovac; B. Filipović, D.
Živadinović, S. Vugdelić, KBC Bežanijska Kosa; D.
Matijašević, J. Kalaba, KBC „Dragiša Mišović”; G.
Golubović, R. Tomašević, KBC Zemun; B. Bojić, B.
Dapčević, D. Bojić, D. Kalem, D. Vrinić, J. Đorđević,
M. Šćepanović, P. Svorcan, S. Kažić, V. Gligorijević,
KBC Zvezdara; A. Pavlović, R. Kovač Šarenac, R.
Ješić Vukićević, S. Lukić, T. Cvejić, Klinički centar
Srbije; G. Vasić, DZ Rakovica, J. Jović, Z. Milenković,
VMA; Lj. Marjanović, Boljevac; S. Andrejević,
Bor; M. Miletić, P. Marković, S. Vukčević Ćuprija;
D. Višnjevac, Inđija; D. Stojanović, M. Milaš, R.
Nikolić, S. Petrović, Jagodina; R. Tomašev, Kikinda;
N. Ivašković, Kladovo, L. Mihajlović Jovanović,
Knjaževac; A. Mosurović, D. Čeliković, N.
Zdravković, Ž. Živić, KBC Kragujevac; S. Novićević,
S. Bezarević DZ Kragujevac; S. Nikolić, P. Milenković,
V. Ranković, Kraljevo; J. Janković, S. Zajić Kruševac;
D. Todorović, Leskovac; V. Vučetić, Loznica; P. Ćosić,
L. Simić, D. Miljković, M. Golubović, S. Aranđelović,
S. Milenković, S. Đokić, T. Jovanović, V. Premović, V.
Bogdanović, Niš; A. Knežević, M. Ilić, DZ Novi Sad; Z.
Petrović, KC Vojvodine; M. Kovijanić, N. Stanojević,
Pančevo; D.Stanković, Paraćin, I. Jovanović, Pirot;
N. Davidović, Požarevac; B. Naumov, Senta; D.
Radivojević, Smederevo; D. Jovanović, Smederevska
Palanka; M. Lovrić Jovanović, Sombor; R. Zec, V.
Novaković, Sremska Mitrovica; M. Bogar, S. Trkulja,
Subotica; Ž. Ristić, Trstenik; B. Ilić, Varvarin; O.
Janković, Vrnjačka Banja; D. Marček, Vršac; D. Ilić
Videnović, M. Petrović, Zaječar;
U narednim istraživanja, zanimljivo bi bilo videti
da li ima razlike u efektima same P.ovata i njene DEKLARACIJA KONFLIKTA INTERESA
kombinacije sa drugim laksativima.
Istraživanje je organizaciono i finansijski podržano
od strane kompanije: Ivančić i sinovi d.o.o.,
ZAKLJUČAK
Palmotićeva 13, Beograd.
Primena preparata P.ovata, kod pacijenata sa
idiopatskom hroničnom opstipacijom ili opstipacijom nakon proktoloških intervencija, dovodi
do poboljšanja crevnog pražnjenja, poboljšanja
konzistencije stolice i smanjnja bola kao i osećaja
nepotpune ispražnjenosti.
NAPOMENA
U sprovođenju ovog istraživanja (procena pacijenata
za uključivanje i prikupljanje podataka) učestvovali
su: J. Kovačević, Aranđelovac; V. Đajić, Banja
Luka; D. Akulov, S. Čantrak, DZ Novi Beograd;
D. Đuričić, DZ Savski Venac; S. Čaprić, DZ Stari
42
Arch Gastroenterohepatol 2012; 29 (No 1) 35-41
Literatura
1. Plantago ovata. (Psyllium). Altern
Med Rev 2002;7:155-9.
2. Ćeranić M, Kecmanović D, Pavlov
M et al. Plantago ovata. Acta Chir
Iugosl 2006;53:9-11.
3. Singh B. Psyllium as therapeutic
and drug delivery agent. Int J
Pharm 2007;334:1-14.
4. Ashraf W, Park F, Lof J et al. Effects
of psyllium therapy on stools
characteristics, colon transit and
anorectal function in chronic
idiopathic constipation. Aliment
Pharmacol Ther 1995;9:639–47.
5. Cheskin LJ, Kamal N, Crowell MD
et al. Mechanisms of constipation
in older persons and affects of
fiber compared with placebo. J
Am Geriatr Soc 1995;43:666–9.
6. VoderholzerWA, SchatkeW, Muhldorfer BE et al. Clinical response to
dietary fiber treatment in chronic
constipation. Am J Gastroenterol
1997;92:95–8.
7. Cook IJ, Talley NJ, Benninga MA et
al. Chronic constipation overview
and challenges. Neurogastroenterol Motil 2009;21(Suppl 2):1-8.
8. McCrea GL, Miaskowski C,
Stotts NA, et al. A review of the
literature on gender and age
differences in the prevalence and
characteristics of constipation in
North America. J Pain Symptom
Manage 2008;37:737–45.
9. Longstreth GF, Thompson WG,
Chey WD, et al. Functional bowel
disorders.
Gastroenterology
2006;130:1480–91.
10.Pare P, Ferrazzi S, Thompson
WG et al. An epidemiological
survey of constipation in Canada:
definitions, rates, demographics,
and predictors of health care
seeking. Am J Gastroenterol
2001;96:3130–7.
11.American College of Gastroenterology Chronic Constipation
Task Force. An evidence-based
approach to the management of
chronic constipation in north
America. Am J Gastroenterol
2005;100(suppl 1):1–4.
12.Schiller LR. Review article: the
therapy of constipation. Aliment
Pharmacol Ther 2001;15:749-63.
13.Warwick S, Crispin C. Managing
constipation in adults. Aust Prescr
2010;33:116–9.
14.Ramkumar D, Rao SS. Efficacy
and safety of traditional medical
therapies for chronic constipation:
Systematic
review.
Am
J
Gastroenterol 2005;100:936–71.
15.Dettmar PW, Sykes J. A multicentre, general practice comparison of ispaghula husk with lactulose
and other laxatives in the treatment
of simple constipation. Curr Med
Res Opin 1998;14:227-33.
16.Marteau P, Flourie B, Cherbut C, et
al. Digestibility and bulking effect
of ispaghula husks in healthy
humans. Gut 1994;35:1747-52.
17.Ewerth S, Ahlberg J, Holmström
B et al. Influence on symptoms
and transit-time of Vi-SiblinR in
diverticular disease. Acta Chir
Scand Suppl 1980;500:49-50.
18.Lewis SJ, Heaton KW. Stool form
scale as a useful guide to intestinal
transit time. Scand J Gastroenterol
1997;32:920-4.
19.Wang HJ, Liang XM, Yu ZL et
al. A Randomised, Controlled
Comparison of Low-Dose Polyethylene Glycol 3350 plus Electrolytes with Ispaghula Husk in the
Treatment of Adults with Chronic
Functional Constipation. Clin
Drug Investig 2004;24:569-76.
20.Pittler MH, Schmidt K, Ernst E.
Adverse events of herbal food
supplements for body weight
reduction: systematic review.
Obes Rev 2005;6:93-111.
21.Xing JH, Soffer EE. Adverse effects
of laxatives. Dis Colon Rectum
2001;44:1201-9.
22.Scott D. Psyllium-induced asthma: occupational exposure in a
nurse. Asthma 1987; 82: 160-1.
23.Vaswani SK, Hamilton RG,
Valentine MD, et al. Psyllium
laxative-induced
anaphylaxis,
asthma, and rhinitis. Allergy
1996;51:266-8.
24.Fleming V, Wade WE. A review
of laxative therapies for treatment
of chronic constipation in
older adults. Am J Geriatr
Pharmacother 2010;8:514-50.
25.Solà R, Godàs G, Ribalta J et al.
Effects of soluble fiber (Plantago
ovata husk) on plasma lipids,
lipoproteins, and apolipoproteins
in men with ischemic heart
disease. Am J Clin Nutr
2007;85:1157-63.
26.Elli M, Cattivelli D, Soldi S et al.
Evaluation of Prebiotic Potential
of Refined Psyllium (Plantago
ovata) fiber in Healthy Women. J
Clin Gastroenterol 2008;42:174–6.
27.Rigaud D, Paycha F, Meulemans A,
et al. Effect of psyllium on gastric
emptying, hunger feeling and
food intake in normal volunteers:
a double blind study. Eur J Clin
Nutr 1998;52:239-45.
28. Kecmanović D, Pavlov M, Ćeranić
M et al. Plantago ovata (Laxomucil)
after hemorrhoidectomy. Acta
Chir Iugosl 2004;51:121-3.
Arch Gastroenterohepatol 2012; 29 (No 1) 35-41
43
Esophagus
ARCH GASTROENTEROHEPATOL 2012; 29 (No 1) 42-44
Khamaysi Iyad
Blue Esophagus
Dept. Gastroenterology and Hepatology,
Invasive Endoscopy unit,
Rambam Medical Center, Haifa, Izrael
CASE REPORT
A 51-year old female with unremarkable history except for diabetes
mellitus type 2, presented with a 3 week history of odynophagia.
Histamine-receptor blockers induced only partial response.
On gastroscopy, bluish stripes of peeling esophageal mucosa
(pseudomembranes) were seen in the upper and middle esophagus.
The membranous tissue were easily separated from inflamed
esophageal mucosa (A).
When asked, she admitted taking Advil-liquid-gel caplets once daily
(Ibuprofen for headaches) which contain blue gel (B).
The histopathological findings were consistent with esophagitis
dissecans superficialis (“sloughing esophagitis”). No fungi or
excessive eosinophils were found (C, D)(1-3).
The patient was advised to take high dose proton-pump inhibitors.
Two weeks later, the symptoms were resolved.
Esophagitis Dissecans Superficialis is a term applied to a rare
endoscopic finding characterized by sloughing of large fragments of
the esophageal squamous mucosa that may be coughed up or vomited.
Although it has been reported in association with certain medications
and esophageal strictures, most cases remain unexplained and the
histopathologic features are inadequately described (1-4).
The blue pigment from the ingested caplets most likely was absorbed
by the sloughing esophageal mucosa making the blue esophagus
appearance.
Address correspondence to:
Dr. Iyad Khamaysi
Dept. Gastroenterology and Hepatology
Invasive Endoscopy unit
Rambam Medical Center
POB 9602, Haifa 31096,Israel
phone: +972 4 8542850
fax: +972 4 8543058
e-mail: [email protected]
44
Blue Esophagus
Figure A The membranous tissue separated from inflamed esophageal mucosa.
Figure B
Advil-liquid-gel caplets
Arch Gastroenterohepatol 2012; 29 (No 1) 42-44
45
Figure C and D.
The histopathological
findings of esophagitis
dissecans superficialis
(“sloughing esophagitis”).
No fungi or excessive
eosinophils are seen.
References:
1. Carmack SW, Vemulapalli R,
Spechler SJ, Genta RM. Esophagitis
dissecans superficialis (“sloughing
esophagitis”): a clinicopathologic
study of 12 cases. Am J Surg
Pathol 2009;33:1789-94.
2. Ponsot P, Molas G, Scoazec JY, et al.
Chronic esophagitis dissecans: an
46
unrecognized clinicopathologic
entity? Gastrointest Endosc
1997;45:38-45.
3. Patel NK, Salathé C, Vu C, Anderson SH. Esophagitis dissecans:
a rare cause of odynophagia.
Endoscopy 2007;39(Suppl 1):E127.
Arch Gastroenterohepatol 2012; 29 (No 1) 42-44
4. Hokama A, Yamamoto YI, Taira
K, et al. Esophagitis dissecans
superficialis and autoimmune
bullous dermatoses: A review.
World Journal Gastrointestinal
Endosc 2010;2(7):252-6.
Alimentary tract
ARCH GASTROENTEROHEPATOL 2012; 29 (No 1) 45-46
Konstantinos H. Katsanos1,
Emmanouil Louvros2,
Dimitrios K. Christodoulou1,
Epameinondas V. Tsianos1.
Granulomatous ileum and
oxyuriasis
1 st
1 Department of Internal Medicine &
Hepato-Gastroenterology Unit
2
Gastroenterologist
Key words:
oxyuriasis, ileum, granulomatous ileitis
CASE REPORT
The threadworm, enterobius (oxyuris) vermicularis, is a nematode
which may inhabit the human terminal ileum, colon and appendix.
Its presence in ectopic sites is uncommon. Oxuyriasis may be present
with atypical symptoms and in rare instances may mimic other
conditions including chronic relapsing diarrhea or constipation,
bowel lymphoma, abdominal mass or inflammation.
Rare cases of oxyuriasis masquerading as other conditions have been
described including a case of generalized intraperitoneal oxyuris
granulomas detected as an incidental finding at laparotomy for
tuboovarian abscess (1).
Another case of a 4-year-old boy with silent oxyuriasis initially
treated for ileo-cecal intusussception and in whom the false diagnosis
of lymphoma with resection of distant segment of small intestine
is described (2). In this child, no clinical and laboratory features
of oxyuriasis could be stated before the onset of disease, during
hospitalization and in the follow-up period. At microscopy the
hypertrophied and activated lymphatic tissue with a non-specific
inflammatory reaction to the pinworms were seen in the wall of ileum,
appendix and mesenteric lymph nodes. No neoplastic cells were found.
We present herein a 56-year-old female with relapsing episodes
of diarrhea and abdominal pain. The patient had granulomatous
terminal ileum appearance at endoscopy (Figure 1) and small bowel
biopsies were compatible with unspecific chronic inflammation of the
terminal ileum. Meticulous patient follow up and a new endoscopy
revealed oxyuriasis and the patient was treated accordingly.
Address correspondence to:
Prof. Epameinondas V. Tsianos, MD, Ph.D, FEBG, AGAF
Professor of Internal Medicine
Department of Internal Medicine
Medical School, University of Ioannina
Leoforos Panepistimiou
45 110 Ioannina
phone: ++30-26510-07501
fax: ++30-26510-07016
e-mail: [email protected]
Granulomatous ileum and oxyuriasis
47
Figure 1: Granulomatous terminal ileum in a patient with oxyuriasis.
References
1. Dalrymple JC, Hunter JC, Ferrier A, Payne W.
Disseminated intraperitoneal oxyuris granulomas.
Aust NZJ Obstet Gynaecol 1986;26:90-1.
48
Arch Gastroenterohepatol 2012; 29 (No 1) 45-46
2. Debek W, Dzienis-Koronkiewicz E, Hermanowicz
A, Nowowiejska B. Oxyuriasis-induced intestinal
obstruction in a child: a case report. Rocz Akad Med
Bialymst 2003;48:115-7.
Editorial
ARCH GASTROENTEROHEPATOL 2012; 29 (No 1) 47-48
Daniela Bojić
Medicinski fakultet Univerziteta u Beogradu i
KBC „Zvezdara“, Beograd
Faculty of Medicine, University of Belgrade,
Serbia and Zvezdara University
Clinical Center, Serbia
Da li je „ileitis terminalis”
uvek Crohn-ova bolest?
Crohn-ova bolest može da zahvati bilo koji deo digestivne cevi, ali
najčešće je lokalizovana u terminalnom ileumu. Ova lokalizacija
je toliko tipična da u svesti svakog gastroenterologa praktično
predstavlja i prvu i jedinu dijagnozu na koju pomisli kada se susretne
sa pacijentom koji ima promene na terminalnom ileumu. Međutim,
erozije i ulceracije na terminalnom ileumu mogu da nastanu i kao
rezultat nekritične upotrebe nesteroidnih anti-inflamatornih lekova
(NSAIL), limfoidne hiperplazije, limfoma, radijacionog enteritisa,
infekcija (parazitarnih – npr. Oxiuris vermicularis i bakterisjkih
– npr. Yersinia enterocolitica, Campilobacter sp, Mycobacterium
tuberculosis), ulceroznog kolitisa, karcinoida, amiloidoze,
eozinofilnog gastroenteritisa, i mnogih drugih (1). Intubacija
i biopsija terminalnog ileuma tokom kolonoskopije je danas
standardna procedura u dijagnostici i praćenju efekta terapije kod
pacijenata sa sumnjivom ili potvrđenom Crohn-ovom bolešću.
U nedavno objavljenoj studiji (2) u kojoj je rađena rutinska
kolonoskopija sa ileoskopijom kod 3921 pacijenta, 125 pacijenata je
imalo makroskopske promene na terminalnom ileumu uključujući
afte, ulceracije, nodularnu ili hiperemičnu mukozu i polipoidne lezije.
U 91% ovih pacijenata su viđene nespecifične histološke promene,
tipa nespecifične inflamacije, limfoidne hiperplazije i oštećenja
mukoze niskog stepena, koje nisu smatrane klinički značajnim.
Ovi pacijenti su potom praćeni mesec dana i nijedan od njih nije
imao rekurentne simptome. U preostalih 9% pacijenata bilo je 7 sa
Crohn-ovom bolešću, 3 sa tuberkulozom terminalnog ieluma i 1 sa
Behcetovom bolešću. (2)
Editorial
49
S druge strane, treba imati na umu da mukoza
terminalnog ileuma koja potpuno normalno
makroskopski izgleda može da pokaže značajne
promene u histološkom nalazu. Ovde je upravo mesto
da se naglas postavi pitanje: zašto bi neko uopšte i
radio biopsiju makroskopski neizmenjene sluznice
terminalnog ileuma? Na ovo pitanje su nam odgovorili
Cherian i saradnici (3) koji su hteli da provere da li
je rutinska ileoskopija korisna? Oni su uradili 2537
kolonoskopija sa ileoskopijom i biopsijama, i utvrdili
da su time povećali dijagnostičku tačnost za 19 % kod
pacijenata sa inflamatornim bolestima creva i za 8 %
kod ostalih pacijenata. U tih 8% pacijenata histološki
nalaz naizgled normalnog terminalnog ileuma je
potvrdio oštećenja usled NSAIL, primarnu ilealnu
atrofiju, ilealnu tuberkulozu i amiloidozu. Srednje
vreme koje je bilo potrebno iskusnom endoskopisti
da se iz cekuma uđe u terminalnu ileum je bilo oko 3
minuta (3).
u odsustvu jasnih dokaza, može biti štetna po
pacijenta, obzirom da takav pacijent neće dobro
odreagovati na datu terapiju, a može biti pogrešno
upućen i na hiruršku proceduru zbog nereagovanja
na „adekvatnu“ terapiju.
Ne mogu se oteti utisku da jednolik pojavni oblik
terminalnog ileitisa sa raznolikim uzrocima njegovog
nastanka veoma podsećaju na osnovni zaštitni
mehanizam u celokupnoj živoj prirodi: mimikriju.
Gotovo je neverovatno kako imunološki odgovor
na nivou crevne sluznice, iako izrazito složen i sa
„centralnim procesorom“ baš u Payerovim pločama
terminalnog ileuma, reaguje na gotovo isti način na
toliko različitih uzročnika. Zašto? Možda baš zato
što na taj način štiti svoj „centralni procesor“ od
brojnih patogena?
Veliki Albert Einstein je, u pokušaju da dokuči
bar deo tajni prirode, rekao da „priroda skriva
svoje tajne svojom veličinom i grandioznošću, a ne
Dakle, ulaganjem malo dodatnog vremena i truda svojom lukavošću“. Mislim da nemamo razloga da
mnogo dobijamo u diferencijalnoj dijagnostici pro- mu ne verujemo.
mena na terminalnom ileumu. Jasno je da pogrešno
pripisana dijagnoza Crohn-ove bolesti, naročito
References
1. D. Bojic, S. Markovic. Terminal
ileitis is not always Crohn’s disease.
Annals of Gastroenterology 2011;
24: 271-75.
50
2. Jeong SH, Lee KJ, Kim YB, et
al. Diagnostic value of terminal
ileum
intubation
during
colonoscopy. J Gastroenterol
Hepatol 2008;23:51-5.
Arch Gastroenterohepatol 2012; 29 (No 1) 47-48
3. Cherian S, Singh P. Is routine
ileoscopy useful? An observational study of procedure times,
diagnostic yield, and learning
curve. Am J Gastroenterol
2004;99:2324-9.
Esophagus
ARCH GASTROENTEROHEPATOL 2012; 29 (No 1) 49-56
Gunjić Dragan2,
Špica Bratislav2,
Babič Tamara1,
Bjelović Miloš1,2
Achalasia cardiae,
dijagnostika i lečenje
1
Medicinski fakultet, Univerzitet u Beogradu,
Srbija
2
Klinika za digestivnu hirurgiju – Prva hirurška
klinika, Klinički centar Srbije, Beograd
Ključne reči:
Jednjak, primarni motorni poremećaj,
achalasia, dijagnostika, lečenje
SAŽETAK
Ahalazija je primarni motorni poremećaj jednjaka koji uzrokuje
otežano gutanje, a karakteriše ga odsustvo relaksacije donjeg
sfinktera uz poremećaj peristaltičke aktivnosti tela jednjaka. U radu
razmatramo etiologiju i patogenezu oboljenja, standard dijagnostike
i raspoložive terapijske opcije.
Laparoskopska Heller-Dor operacija predstavlja standar lečenja
kod pacijenata kad god je to moguće. Od aprila 2006. godine
laparoskopska Heller-Dor operacija radi se kao standardna metoda
u Centru za hirurgiju jednjaka Prve hirurške klinike. Do kraja 2011.
godine na Odeljenju za minimalno invazivnu hirurgiju gornjeg dela
digestivnog trakta (X odeljenje I hirurške klinike – Centar za hirurgiju
jednjaka) urađeno je 36 laparoskopskih operacija zbog ahalazije.
Kod starijih osoba sa udruženim komorbiditetom, kao i pacijenata sa
dugotrajnim simptomima alternativu hirurškom lečenju predstavlja
endoskopska dilatacija.
DEFINICIJA
Ahalazija je primarni motorni poremećaj jednjaka koji uzrokuje
otežano gutanje, a karakteriše ga odsustvo relaksacije donjeg sfinktera
uz poremećaj peristaltičke aktivnosti tela jednjaka (1).
Address correspondence to:
Bjelović Miloš
Centar za hirurgiju jednjaka
Klinika za digestivnu hirurgiju – Prva hirurška
klinika, Klinički Centar Srbije u Beogradu
Dr Koste Todorovića broj 6, Beograd
telefon: 011/3663-703
e-mail: [email protected]
Achalasia cardiae, dijagnostika i lečenje
51
Dor operacija radi se kao standardna metoda u
Centru za hirurgiju jednjaka Prve hirurške klinike.
Sir Thomas Willis, engleski anatom, 1679. god. Do kraja 2011. godine na Odeljenju za minimalno
opisao je prvi slučaj ahalazije (1). Prvobitna terapija invazivnu hirurgiju gornjeg dela digestivnog trakta
sastojala se u dilataciji primitivnim ali efikasnim (X odeljenje I hirurške klinike – Centar za hirurgiju
dilatatorima napravljenim od kitove kosti, obložene jednjaka) urađeno je 36 laparoskopskih operacija
sunđerom. Russel je prvi opisao uspešan pokušaj zbog ahalazije (Grafikon 1).
pneumatske dilatacije 1898. godine, a Hurst i Rake
1929. godine uvode termin – ahalazija, izveden EPIDEMIOLOGIJA
od grčke reči achalasion koja označava izostanak
relaksacije (1). Najveći broj hirurških tehnika Ovaj poremećaj je podjednako zastupljen kod žena
koje se primenjuju u lečenju ahalazije razvijane i muškaraca u životnoj dobi između 30 i 60 godina.
su tokom dvadesetog veka u Nemačkoj. Prvu Prevalenca je 10 na 100 000, a incidenca 0.5 obolelih
miotomiju sa prednje i zadnje strane tela distalnog na 100 000 stanovnika. U poslednjih 50 godina ovi
jednjaka izveo je Ernest Heller, 1913. godine kao podaci su bez značajnijeg odstupanja (1).
asistent na katedri hirurgije Univerzitetske klinike u
Lajpcigu (Nemačka) (2). Njegov prvi pacijent je bio PATOFIZIOLOGIJA
49-ogodišnji muškarac sa disfagijom koja je trajala Peristaltički talas tela jednjaka nastaje i sprovodi
unazad trideset godina. Regija distalnog jednjaka se po principu receptivne relakascije. Ekscitatorni
i kardije su ga asocirali na stenozu pilorusa koju holinergički neuroni oslobađaju acetilholin koji
je do tada nebrojeno puta rešavao jednostavnom omogućava mišićnu kontrakciju uz održanje
miotomijom. Dužina miotomijske incizije od 8 cm tonusa (tonična kontrakcija) donjeg ezofagealnog
završavala se neposredno ispod ezofagogastričnog sfinktera (DES). Inhibitorni neuroni sprovode
prelaza, a nastali defekt je pokriven režnjem inhibitornu akivnost duž tela jednjaka menjajući
omentuma. Holandski hirurg Zaaijer je 1923. gradijent pritisaka koji je neophodan za adekvatnu
godine modifikovao originalnu Heller-ovu tehniku peristaltičku aktivnost, odnosno relaksaciju DES-a.
u prednju miotomiju koja se i danas koristi dok je
transtorakalnu miotomiju uveo Ellis 1958. godine. Ključni poremećaj kod ahalazije predstavljen je
Minimalno invazivni pristup za mnoge hirurške oštećenjem postganglijskih inhibitornih neurona
procedure uveden je devedesetih godina prošlog koji su odgovorni za relaksaciju cirkularnih
veka. Laparoskopsku ezofagokardiomiotomiju prvi mišićnih vlakana DES-a (Grafikon 2)(2). Impulsi
je objavio Cuschieri sa saradnicima 1991. godine izazvani dejstvom azot oksida (NO), transmitera
(1). Od aprila 2006. godine laparoskopska Heller- mijenteričnog pleksusa, predstavljaju nosioce
inhibitornog signala duž tela jednjaka i DES-a
u toku akta gutanja. Sinergično dejstvo sa
ekscitacijom, odnosno kontrakcijom omogućava
kretanje peristaltičkog talasa kroz telo jednjaka
i relaksaciju DES-a. Kod klasične ahalazije
oštećenje autonomnog inhibitornog sistema
predstavlja primarno patofiziološko dešavanje
koje je uzrokovano inflamatornim procesom koji
dovodi do gubitka ganglijskih ćelija mijenteričnog
(Auerbahovog) plekusa. Prvi opis patofiziološkog
mehanzma razvoja ahalazije datira iz 1937. god. od
strane Lendrum-a i saradnika. Inicijalni inflamatorni
infiltrat čine limfociti i eozinofili, uz prisustvo nešto
Grafikon 1. Operativno lečenje ahalazije kardije u manje populacije mastocita i plazmocita. Vremenom
Odeljenju za minimalno invazivnu hirurgiju gornjeg inflamatorni infiltrat biva zamenjen ćelijama
digestivnog trakta (X odeljenje I hirurške klinike – kolagena (fibroza), uz progresivno smanjenje broja
Centar za hirurgiju jednjaka) u periodu od aprila 2006 ganglijskih ćelija mijenteričnog plekusa (2).
ISTORIJAT
do kraja decembra 2011. godine
52
Arch Gastroenterohepatol 2012; 29 (No 1) 49-56
Grafikon 2. Etiologija i patogeneza ahalazije kardije23
Imunohistohemijskim ispitivanjem dokazano je
značajno smanjenje broja ganglijskih ćelija i aksona
koji sadrže azot oksid (NO – primarni inhibitorni
neurotransmiter) i vazoaktivni intestinalni peptid
(VIP – alternativni inhibitorni neurotransmiter)(2).
U toku primarnog dešavanja klinička slika je najčešće
nespecifična I definiše se kao nedeterminisani
motorni poremećaj jednjaka. Sa protokom vremena
I pojavom sekundarnih dešavanja, deklanšira se
tipična klinička I manometrijska slika ahalazije.
oko 1-2% populacije obolelih, a način nasleđivanja je
najverovatnije autozomno recesivni (4).
Infektivni agensi, kao što su bakterije (difterija,
pertusis, klostridija, tuberkuloza, sifilis), virusi
(herpes, varicela zoster, polio, morbili) i neki drugi
egzogeni toksini mogu još u toku embrionalnog
razvoja dovesti do oštećenja jednjaka. Nekoliko
činjenica povezuje ahalaziju sa infektvnom
etiologijom: specifična lokalizacija bolesti, činjenica
da su glatki mišići jednjaka pokriveni pločastim
Kod jednog broja pacijenata u sklopu sekundarnih epitelom, a herpes virusi imaju afinitet ka pločastom
dešavanja uznapredovale faze bolesti mogu se videti epitelu, kao i serološka ispitivanja koja bolest povezuju
degenerativne promene i gubitak nervnih ćelija u sa nekim virusima (varičela zoster, rubela)(5).
DMN (nucleus posterior nervi vagi). Ovaj nalaz nije U prilog autoimune etiologije bolesti ide prisustvo
neophodan da bi se postavila dijagnoza ahalazije (2). inflamatorne reakcije mijenteričnog pleksusa koU sklopu seundarnih dešavanja javlja se i hipertrofija jim dominiraju T limfociti, odnosno klasa II histomišićnog sloj jednjaka (prisutna kod 79% kompatibilnog kompleksa (6).
pacijenata) uz prisustvo degenerativnih promena Teorija o degenerativnim promenama dobija na
u uznapredovaloj fazi bolesti. Hipertrofija mišića značaju kod starijih pacijenata koji boluju od
predstavlja reakciju na gubitak inervacije (3).
pratećeg neurološkog ili psihijatrijskog oboljenja
Sekudnardno dešavanje predstavljaju i promene na (Parkinsonova bolest, depresija)(7).
mukozi jednjaka I one su posledica dugotrajne staze
hrane u lumenu koja dovodi do hronične infilamacije DIJAGNOSTIKA
što povećava rizik za nastanak skvamocelularnog Detaljna i pravilno uzeta anamneza predstavlja
karcinoma.
prvi I veoma bitan korak u dijagnostici ovog
oboljenja. Disfagija je dominantan simptom koji
ETIOLOGIJA
ima dugu evoluciju uz postepenu progresiju tokom
Postoji više teorija o mogućim etiološkim faktorima vremena (koje se računa u godinama). Za razliku
od sekundarnih motornih poremećaja pacijent
za nastanak ahalazije.
otežano guta i čvrstu i tečnu hranu, te se vremenom
Po jednoj od teroija sklonost ka nastanku ahalazije prilagođava nastalim tegobama koristeći različite
je genetski determiniasna. Familijarna ahalazija čini manevre kako bi ih ublažio (zabacivanje ramena
Arch Gastroenterohepatol 2012; 29 (No 1) 49-56
53
karakteristična radiografska slika završnog dela
jednjaka u obliku “mišijeg repa”. Prisustvo aksijalne
hernije hijatusa jednjaka (do 2 cm) je ređe nego
u opštoj populaciji (12). Kontrastni radiografski
Regurgitacija je vraćanje prethodno unete, nesva- pregled ima mali značaj u otkrivanju pseudoahalazije
rene hrane iz jednjaka i prisutna je kod oko 80% i on je konkluzivan kod trećine bolesnika sa
bolesnika[9]. U regurgitiranom sadržaju nema kise- pseudoahalazijom (12).
line i žuči, a posebno je opasna kada se desi tokom Gornja fleksibilna endoskopija je neizostavna
sna zbog moguće aspiracije. Kod mladih žena kod dijagnostička procedura kojom se pored dilatacije
kojih se javi regurgitacija hrane, tegobe mogu biti jednjaka različitog stepena konstatuje hipertonus
pogrešno vezane za kliničku sliku bulimije.
(spazam) DES-a čiji se elastični otpor savladava
Bol u grudima i/ili u predelu epigastrijuma prisutan lakim pritiskom endoskopa. U retroverziji se vidi
je kod oko 33% obolelih (9), obično se javlja kod karakteristična slika kardije koja čvrsto „drži“ telo
mlađih ljudi u inicijalnoj fazi bolesti i nije uzrokovan endoskopa. Endoskopski pregled je često otežan
(provociran) peristaltičkim talasom. Etiologija bola zbog prisustva manje ili veće količine retiniranog
nije poznata, ali s obzirom na karakteristike (širenje sadržaja koji dovodi do maceracije sluzokože i pojave
u vilicu i ramena) može da liči na anginozni bol. konkomitantne gljivične infekcije.
unazad, uzimanje veće količine vode uz obrok...).
Ovi manevri imaju pozitivan efekat u pražnjenju
jednjaka povećavajući intraluminalni pritisak za 10
– 20 mmHg (8).
Interesantno je da se bol ne gubi uvek posle uspešne
endoskopske dilatacije, a značajno poboljšanje
se može očekivati kod manje od 20% dilatacijom
lečenih pacijenata (10).
Manometrija predstavlja zlatni standard u postavljanju dijagnoze ahalazije i u većini centara se koristi
kao uobičajena dijagnostička procedura. Objektivnim
merenjem intraluminalnog pritiska na različitim
Gorušica je prisutna kod oko 28% obolelih, obično nivoima unutar tela jednjaka dobija se jasna informacija
se ne javlja posle obroka i ne reaguje na primenu o tipu I kvalitetu peristaltičke aktivnosti tela jednjaka
inhibitora protonske pumpe (9). Merenjem kiselosti i funkciji DES-a. Manometrijsko ispitivanje je od
u jednjaku se konstatuje blagi ili umerni porast posebnog značaja kada subjektivni simptomi I
kiselosti, bez pojave tipičnih pikova. Prisustvo lake učinjena kontrastna radiografija I gornja fleksibilna
kiselosti i osećaj gorušice nisu posledica refluksa endoskopija nisu konkluzivni (funkcionalni motorni
želudačnog sadržaja, već nastaju zbog retencije I poremećaj nejasne etiologije)(2).
subsekventnog raspadanja hrane u jednjaku koja Intraluminalni pritisci izmereni u jednjaku sa
osobođa slabe kislenine (2).
normalnom peristaltičkom aktivnošću kreću se od
Gubitak u telesnoj masi javlja se kod polovine 37 do 40 mmHg. Kod klasične ahalazije amplitude
obolelih i on je obično lakog stepena, dok se značajan kontrakcija su tipično niske i kreću se u rasponu
gubitak u telesnoj masi praćen progresivnom između 10 i 40 mmHg. Nasuprot tome, kod vigorozne
disfagijom obično vezuje za oboljenje druge etiologije ahalazije koju ima trećina bolesnika sa ahalazijom,
(pseudoahalazija). Značajan broj pacijenata je u izmereni pritisci su znatno viši (100-200 mmHg) (2).
trenutku postavljanja dijagnoze gojazan (2).
Manometrijska abnormalnost DES-a postoji kod
Nativnim radiografskim pregledom se kod 50% svih pacijenata obolelih od ahalazije bilo da se radi
pacijenata konstatuje gubitak vazdušnog mehura u o njegovom hipertonusu i/ili poremećaju relaksacije.
forniksu želuca i prisustvo hidro-aeričnog nivoa u Više od 40% obolelih ima normalan bazalni tonus
donjem medijastinumu koji je proširen zbog dilatacije DES-a, dok je kod 70 – 80% relaksacija DES-a
tela jednjaka. U parenhimu pluća može se videti nepotpuna ili je nema. Dakle povišen bazalni tonus
pneumonična konsolidacija tkiva, odnosno prisustvo DES-a nije neophodan kriterijum da bi se postavila
apscesne kolekcije nastale kao posledica dugotrajne dijagnoza ahalazije, dok prisustvo njegove kompletne
relaksacije (20 – 30% obolelih) ne isključuje postojanje
aspiracije retiniranog sadržaja jednjaka (11).
oboljenja. Postojanje rezidualnog pritiska u DES-u je
Kontrastni radiografski pregled (skopija/grafija) je
najbolji pokazatelj nekompletne relaksacije i njegova
pored gornje fleksiobilne endoskopije najznačajnija
vrednost mora biti iznad 8 – 10 mmHg (2).
dijagnostička procedura kojom se konstatuje
poremećaj peristaltike, dilatacija jednjaka različitog Ukoliko se navedenim dijagnostičkim procedurama
stepena i hipertonus DES-a, čime se formira postavi sumnja na postojanje pseudoahalazije,
54
Arch Gastroenterohepatol 2012; 29 (No 1) 49-56
se intezitet simptoma kod velikog broja pacijenata.
Pneumatskom dilatacijom smanjuje se bazalni
pritisak DES-a za 39 – 68%. Ranije upotrebljavani
dilatatori (Hurst i Malloney) su danas ustupili mesto
novim, modernijim, dilatatorima, od kojih se najčešće
koriste Rigiflex dilatatori. Pneumatska dilatacija se
započinje balonom dijametra 3.0 cm. Ukoliko kod
pacijenta perzistiraju disfagične tegobe, nakon 4
TERAPIJA
nedelje se ponavlja procedura balonom dijametra
Terapijski modaliteti lečenja ahalazije obuhvataju 3.5cm. Pozitivan terapijski efekat se kod najvećeg
konzervativnu terapiju lekovima, interventne broja pacijenata postiže balonima dijametra 3.0cm
endoskopske procedure i hirurgiju. Konzervativna i 3.5cm. Rezultati nedavnih studija su potvrdili da je
terapija ahalazije zasniva se na primeni različitih kod najvećeg broja pacijenata naknadna dilatacija
grupa lekova u cilju relaksacije glatke muskulature balonom dijametra 4cm nepotrebna. Većina autora
jednjaka. U poslednje vreme se sa umerenim sugerise trajanje dilatacije do 3min. Međutim brojuspehom primenjuju dve grupe lekova: nitrati nim studijama je potvrđeno da pravilno izvedena
(izosorbid dinitrat) i blokatori kalcijumskih kanala pneumatska dilatacija ima isti terapijski efekat bez
(nifedipin). Nakon sublingvalne primene nitrati i obzira da li sama dužina trajanja dilatacije iznosi 6 ili 60
blokatori kalcijumskih kanala izazivaju relaksaciju sekundi. U zavisnosti od studije, uspešnost procedure
glatkih mišića DES-a, uzrokujući smanjenje pritiska. se kreće u rasponu od 74 – 93% (prosečno oko 82%).
Ovi efekti dovode do smanjenja intenziteta disfagije.
Ne treba zaboraviti da je pozitivan terapijski efekat Csends i saradnici sproveli su randomizovanu studiju
kratkotrajan, uz brojne neželjene efekte ovih lekova. poredeći efekte pneumatske dilatacije i hirurgije.
Uspešnost dilatacije iznosila je 65%, pri čemu je
Zapaženo je da I Sildenafil-a (Vijagre) ima pozitivan trećina pacijenata zahtevala naknadno hiruško
efekat na relaksaciju donjeg sfingtera jednjaka lečenje. Rezultati mnogih studija slažu se oko stava
(smanjuje ukupni i rezidualni pritisak DES-a za da je efekat dilatacije bolji kod starijih pacijenata,
50%), ali pozitivan efekat traje samo sat vremena kao i kod pacijenata sa dužim trajanjem simptoma.
nakon peroralne administracije (13).
Komplikacije ove procedure nisu tako retke i
Interventne endoskopske procedure podrazumevaju mogu se svrstati u blage i teške. Blaže komplikacije
aplikaciju botulinum toksina u DES i pneumatsku obuhvataju bol u grudima, aspiracionu pneumoniju,
(balon) dilataciju.
hematemezu bez pada u krvnoj slici, prolaznu
Botulinum toksin (Botox), sintetisan iz bakterije temperaturu, kidanje mukoze bez transmuralne
Clostridium botulinum, predstavlja potentni laceracije, itd. Manje od 20% pacijenata ima
inhibitor lučenja acetilholina u presinaptičkim zabrinjavajuće refluksne simptome nakon dilatacije,
nervnim završecima. Endoskopskom aplikacijom ali 25-33% ima patoloski refluks pri pH - metrijskom
ove supstance u DES, postiže se pozitivan efekat kod testiranju. Najozbiljniju komplikaciju svakako
76% pacijenata. Regeneracija receptora tretiranih predstavlja perforacija jednjaka koja se javlja u 0 Botox-om dovodi do recidiviranja simptoma 16% (prosečno 2.3%) slučajeva (14).
neophodno je uraditi CT pregled grudnog koša i
trbuha sa dvojnim kontrastom, odnosno endoskopsku
ultrasonografiju u cilju isključenja druge (organske)
prirode disfagičnih tegoba (maligna bolest,
amiloidoza, lejomiomatoza, eozinofilni ezofagitis,
sarkoidoza, Chagas-ova bolest, diabetes melitus itd.).
kod polovine pacijenata, unutar šest meseci od
intervencije. Pozitivni terapijski efekat se smanjuje
svakom ponovnom aplikacijom Botox-a. Ova pojava
se objašnjava produkcijom antitela na strani protein.
Komplikacije same procedure su retke ali postoje
podaci o povećanoj učestalosti perforacije mukoze
tokom Heller-Dor-ove operacije kod pacijenata
prethodno tretiranih injekcijom Botox-a.
Hirurško lečenje se sastoji u prednjoj ezofagokardiomiotomiji po Heller-u (slika 1). Ova procedura
smanjuje pritisak DES-a u većem procentu nego
pneumatska dilatacija. U zavisnosti od dužine kardiomiotomije, pritisak DES-a je smanjen za 50-75%, a
rezidualni pritisak DES-a ostaje niži od 10 mmHg.
U savremenom hiruškom lečenju se uz prednju
ezofagokardiomiotomiju sprovodi i antirefluksna
Pneumatska (balon) dilatacija je najefikasnija I procedura (najčešće prednja parcijalna funduplikacija
najefikasnija nehirurška terapijska procedura. po Dor-u ili ređe zadnja parcijalna funduplikacija po
Kontrolisanim kidanjem vlakana DES-a smanjuje Toupet-u).
Arch Gastroenterohepatol 2012; 29 (No 1) 49-56
55
Sprovedenom meta analizom, Campos i saradnici
su zaključili da nema značajne razlike u uspešnosti
smanjenja intenziteta simptoma ahalazije kod
pacijenata podvrgnutih prostoj miotomiji (89.9%)
i miotomiji sa udruženom antirefluksnom
procedurom (90.3%). Incidenca postoperativne
pojave gastroezofagealnog refluksa značajno je veća
kad se operacija radi bez antirefluksne procedure
(31.5%) nego kada se pored miotomije radi i
fundoplikacija (8.8%)(14).
incidenca pojave gastroezofagealnog refluksa znatno
niža i iznosi 14.9% (14).
Sumiranjem iskustava i analizom terapijskog efekta
nehirurških i hirurških metoda lečenja, Američko
udruženje gastroenterologa predložilo je terapijski
algoritam za lečenje ahalazije (Grafikon 3)(21).
Novu terapijsku mogućnost predstavlja endoskopska
submukozna miotomija. Prvi pokušaj endoskopske
miotomije objavio je Ortega sa saradnicima 1980
godine i to kao direktnu inciziju mukoze i cirkuPrednja ezofagokardiomiotomia se kao minimalno larnog mišića, dok su prvi slučaj submukozne
invazivna hirurška procedura može izvoditi torako- miotomije objavili Inoue i saradnici 2009 godine (22).
skopski i laparoskopski. Na osnovu rezultata meta- Submukozna miotomija se započinje instilacijom
analize koju su sproveli Campos i saradnici, uspešnost 0,9% fiziološkog rastvora 5cm proksimalno od
hirurškog lečenja iznosi 77.6% kod torakoskopske, a anatomskog ezofagogastričnog prelaza, sa ciljem
89.3% kod laparoskopske procedure, što predstavlja širenja submukoznog prostora. Potom se načini
značajnurazliku.Uovojstudijitorakoskopskaprocedura mala incizija monopolarnim kauterom i kroz nju
je najčešće rađena bez antrefluksne intervencije u submukozni prostor uvede balon za dilataciju. U
dok je laparoskopska procedura bila udružena sa dilatirani submukozni prostor se uvede endoskop i
prednjom parcijalnom funduplikacijom po Dor-u. monopolarnim elektrokauterom načini miotomija
Torakoskopskim pristupom kod 28.3% pacijenata unutrašenjeg (cirkularnog) mišićnog sloja pod direkdolazi do postoperativne pojave gastroezofagealnog tnom endoskopskom vizijom. Nakon toga se iz tunela
refluksa za razliku od laparoskopske procedure sa retrograndno izvede endoskop, a lezija sluznice zatvori
udruženom parcijalnom fundoplikacijom gde je
Slika 1. Prednja ekstramukozna ezofagokardiomiotomija
56
Arch Gastroenterohepatol 2012; 29 (No 1) 49-56
Grafikon 3. Terapijski algoritam u lečenju ahalazije21
endoskopskim klipsevima. Danas se endoskopska Kod nekih pacijenata sa megaezogafusom –
submukozna miotomija radi u malom broju centara u (sigmoidno izmenjen jednjak dijametra preko 6 cm ili
strogo kontrolisanim kliničkim uslovima.
„end stage achalasia“ ) neophodna je ezofagektomija
sa rekonstrukcijom jednjaka u istom aktu. grafikoni
Arch Gastroenterohepatol 2012; 29 (No 1) 49-56
57
Literatura:
1. Pohl D, Tutuian R. Achalasia:
an overview of diagnosis and
treatment. J Gastrointestin Liver
Dis 2007;16:297-303.
2. Richter JE. Achalasia - an update.
J
Neurogastroenterol
Motil
2010;16:232-42.
3. Blennerhassett MG, Lourenssen
S. Neural regulation of intestinal
smooth muscle growth in vitro.
Am J Physiol Gastrointest Liver
Physiol 2000;279:G511-9.
4. Weber A, Wienker TF, Jung
M, et al. Linkage of the gene
for the triple A syndrome to
chromosome 12q13 near the type
II keratin gene cluster. Hum Mol
Genet 1996;5:2061-6.
5. Robertson CS, Martin BA,
Atkinson M. Varicella-zoster
virus DNA in the oesophageal
myenteric plexus in achalasia.
Gut 1993;34:299-302.
6. Verne GN, Sallustio JE, Eaker
EY. Anti-myenteric neuronal
antibodies in patients with
achalasia. A prospective study.
Dig Dis Sci 1997;42:307-13.
7. Sonnenberg A, Massey BT,
McCarty DJ, Jacobsen SJ.
Epidemiology of hospitalization
for achalasia in the United States.
Dig Dis Sci 1993;38:233-44.
8. Eckardt VF. Clinical presentations
and complications of achalasia.
Gastrointest Endosc Clin N Am
2001;11:281-92, vi.
9. Decker G, Borie F, Bouamrirene
D, et al. Gastrointestinal quality of
life before and after laparoscopic
heller myotomy with partial
posterior fundoplication. Ann
Surg 2002;236:750-8; discussion 8.
58
10. Eckardt VF, Stauf B, Bernhard G.
Chest pain in achalasia: patient
characteristics and clinical course.
Gastroenterology 1999;116:1300-4.
11. Kahrilas PJ. Esophageal motility
disorders: current concepts of
pathogenesis and treatment. Can
J Gastroenterol 2000;14:221-31.
12. Levine MS, Rubesin SE. Diseases
of the esophagus: diagnosis with
esophagography.
Radiology
2005;237:414-27.
13. Bortolotti M, Mari C, Lopilato C,
Porrazzo G, Miglioli M. Effects of
sildenafil on esophageal motility
of patients with idiopathic
achalasia.
Gastroenterology
2000;118:253-7.
14. Campos GM, Vittinghoff E,
Rabl C, et al. Endoscopic and
surgical treatments for achalasia:
a systematic review and metaanalysis. Ann Surg 2009;249:45-57.
15. Gui D, Rossi S, Runfola M,
Magalini SC. Review article:
botulinum toxin in the therapy
of
gastrointestinal
motility
disorders. Aliment Pharmacol
Ther 2003;18:1-16.
16. Lamb PJ, Griffin SM. Achalasia of
the cardia: dilatation or division?
The case for balloon dilatation.
Ann R Coll Surg Engl 2006;88:9-11.
17. Ghoshal UC, Rangan M. A
review of factors predicting
outcome of pneumatic dilation
in patients with achalasia cardia.
J
Neurogastroenterol
Motil
2011;17:9-13.
18. Roll GR, Rabl C, Ciovica R, Peeva
S, Campos GM. A controversy
that has been tough to swallow:
is the treatment of achalasia now
Arch Gastroenterohepatol 2012; 29 (No 1) 49-56
digested? J Gastrointest Surg
2010;14 Suppl 1:S33-45.
19. Bonavina
L.
Minimally
invasive surgery for esophageal
achalasia. World J Gastroenterol
2006;12:5921-5.
20. Gockel I, Sgourakis G, Drescher
DG, Lang H. Impact of minimally
invasive surgery in the spectrum of
current achalasia treatment options.
Scand J Surg 2011;100:72-7.
21. DeVault KR, Castell DO.
Updated guidelines for the
diagnosis and treatment of
gastroesophageal reflux disease.
The Practice Parameters Committee of the American College
of Gastroenterology. Am J
Gastroenterol 1999;94:1434-42.
22. Stavropoulos SN, Harris MD,
Hida S, Brathwaite C, Demetriou
C, Grendell J. Endoscopic
submucosal myotomy for the
treatment of achalasia (with
video). Gastrointest Endosc
2010;72:1309-11.
23. Paterson WG. Etiology and
pathogenesis
of
achalasia.
Gastrointest Endosc Clin N Am
2001;11:249-66, vi.
SAMO ZA STRU^NU JAVNOST
Re`im izdavanja leka: Lek se mo`e izdavati samo uz lekarski recept. Nosilac dozvole za stavljanje leka u promet: Nycomed Gmbh;
Predstavni{tvo za Srbiju; 11000 Beograd, Krunska 24/14. Broj obnove dozvole: Za pakovanje 14 x 20mg: 781/2010/12 iz 02.02.2010.;
Za pakovanje 14 x 40mg: 1438/2008/12 od 13.04.2008. Datum revizije teksta: 14x20mg - Januar 2010.; 14x40mg - Februar 2008.
Download

Archives March 2012.pdf - Udruženje Gastroenterologa Srbije