Anca Romcea - Teza de Doctorat (Rezumat RO-EN 2 CAPETE)
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Transcript of Anca Romcea - Teza de Doctorat (Rezumat RO-EN 2 CAPETE)
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Studiu prospectiv asupra
evoluiei i complicaiilor hemoragiilor variceale la
pacienii cu ciroz hepatic
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2 Studiu prospectiv asupra evoluiei i complicaiilor hemoragiilor variceale la cirotici
Cuprins
INTRODUCERE 13
STADIUL ACTUAL AL CUNOATERII
1. Date de fiziopatologie a cirozei hepatice 17
1.1.Hipertensiunea portal din ciroza hepatic 17
1.2.Particulariti fiziopatologice n hemoragiile digestive
superioare variceale la cirotici 19
2. Principii de tratament n hemoragiile variceale la cirotici 23
2.1. Noiuni de profilaxie primar a hemoragiei variceale la cirotici.
Rolul tratamentului endoscopic n profilaxia primar 23
2.1.1. Strategia profilaxiei primare a hemoragiei variceale
prin mijloace farmacologice 24
2.1.2. Rolul tratamentului endoscopic n profilaxia primar a
hemoragiei variceale 25
2.2. Tratamentul specific (hemostaza) al hemoragiei variceale active 26
2.2.1. Tratamentul cu ageni farmacologici vasoactivi ai
hemoragiei variceale active 26
2.2.2. Tratamentul endoscopic al hemoragiei variceale active 26
2.3. Noiuni de profilaxie secundar a hemoragiei variceale 28
3. Complicaiile hemoragiilor variceale la cirotici 31
3.1. Complicaii asociate cu hemoragia variceal 31
3.1.1. Encefalopatia hepatic 31
3.1.2. Infeciile bacteriene 32
3.1.3. Sindromul hepato-renal 33
3.1.4. Recidivele hemoragice 34
3.1.5. ocul hipovolemic 34
3.1.6. Consecinele hemoragiilor variceale asupra bolilor cardiovasculare 35
3.1.7. Complicaii datorate farmacoterapiei i procedurilor
terapeutice n hemoragia variceal 36
CONTRIBUIA PERSONAL
1. Ipoteza de lucru/obiective 41
2. Studiul 1. Etiopatogenia hemoragiilor digestive superioare
la cirotici i factorii de risc ai hemoragiei variceale 43
2.1. Introducere 43
2.2. Obiective 43
2.3. Material i metod 43
2.3.1.Grupul studiat 43
2.3.2.Variabile 45
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Anca Romcea 3
2.3.3. Analiza statistic 46
2.4. Rezultate 47
2.4.1. Aspecte privind etiopatogenia hemoragiilor digestive
superioare la cirotici 49
2.4.2. Aspecte privind factorii de risc ai hemoragiei variceale la cirotici 58
2.5. Discuii 67
2.6. Concluzii 69
3. Studiul 2. Evoluia i complicaiile hemoragiilor variceale la cirotici 71
3.1. Introducere 71
3.2. Obiective 72
3.3. Material i metod 72
3.3.1.Grupul studiat 72
3.3.2.Variabile 75
3.3.3.Analiza statistic 75
3.4.Rezultate 76
3.4.1.Aspecte privind prima recidiv hemoragic 78
3.4.2.Implicaiile tratamentului medicamentos i endoscopic
asupra recidivelor hemoragice variceale la pacienii cirotici. 85
3.4.3.Complicaiile recidivelor hemoragice variceale la cirotici 88
3.4.4. Analiza mortalitii prin hemoragie variceal 92
3.4.5. Factori de predicie ai supravieuirii dup hemoragiile variceale 97
3.5.Discuii 103
3.6.Concluzii 105
4. Concluzii generale 107
5. Originalitatea i contribuiile inovative ale tezei 111
REFERINE 113
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4 Studiu prospectiv asupra evoluiei i complicaiilor hemoragiilor variceale la cirotici
Cuvinte cheie:
hemoragie variceal, varice esofagiene, hemoragiile digestive superioare la
cirotici, factori de risc ai hemoragiei variceale, tratament endoscopic n
hemoragiile variceale, mortalitatea prin hemoragie variceal.
Introducere
Hemoragiile digestive superioare la pacienii cirotici reprezint una din
marile probleme ale patologiei gastroenterologice, de asemenea o problem de
sntate public prin incidena crescut, severitatea complicaiilor i costurile pe
care le presupune ngrijirea acestor pacieni.
n pofida aplicrii msurilor de profilaxie, a mbuntirii metodelor de
diagnostic i a eficienei sporite a metodelor de tratament, ciroza hepatic
mpreun cu complicaia ei cea mai de temut-hemoragia digestiv superioar,
rmne o problem major de sntate public.
Hemoragiile digestive superioare la cirotici se produc in principal din
varicele esofagiene si gastrice dar, exist i un numr semnificativ de cazuri de
hemoragii non-variceale. Din acest motiv, n cadrul primului studiu efectuat ne-
am propus analiza etiopatogeniei hemoragiilor digestive superioare la pacientul
cu ciroz hepatic i aprecierea factorilor de risc implicai n apariia hemoragiilor
variceale, studiul incluznd peste 900 de pacieni cu ciroz hepatic, ceea ce ne-a
permis s obinem o imagine de ansamblu asupra hemoragiilor digestive
superioare la pacientul cirotic.
Dup primul episod de hemoragie variceal, riscul recidivelor hemoragice
este mare, complicaiile (hepatice i extrahepatice) i mortalitatea pot fi determinate
de multipli factori: gravitatea hemoragiei (respectiv a dezechilibrului hemodinamic),
agravarea insuficienei hepatice (apreciat prin criteriile Child-Pugh), asocierea altor
patologii (infecii, diabet zaharat, boli cardiace, hepatocarcinom etc). De asemenea,
metodele de tratament urmate de pacieni la prima hemoragie variceal au implicaii
asupra frecvenei recidivelor, a momentului apariiei lor n raport cu episodul
hemoragic iniial i a supravieuirii pe termen lung.
n al doilea studiu, ne-am propus urmrirea recurenelor hemoragice
aprute la pacieni dup primul episod de hemoragie variceal, a factorilor de risc
ai primei recidive hemoragice, influena tratamentului medicamentos i
endoscopic aplicat, complicaiile aprute, aspecte privind mortalitatea i analiza
factorilor de predicie ai supravieuirii la un an de la episodul hemoragic iniial.
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Anca Romcea 5
Ghidurile internaionale cuprind o serie de recomandri printre care, o
importan major o are indicaia de efectuare a endoscopiei digestive superioare
n primele 24 ore la toi pacienii cu hemoragie digestiv superioar. n ara
noastr, conform datelor Societii Romne de Endoscopie, n puine centre
medicale exist serviciu permanent de gard de endoscopie, iar n multe din
unitile n care se efectueaz endoscopia digestiv superioar de urgen n
timpul orelor de program nu exist baza material necesar aplicrii tehnicilor de
hemostaz endoscopic. n acest sens, pentru realizarea tezei am beneficiat de
posibilitatea efecturii endoscopiei digestive superioare n cazul tuturor
pacienilor care s-au prezentat cu un episod de hemoragie n Institutul Regional
de Gastroenterologie i Hepatologie Prof.Dr. O. Fodor, datorit serviciului de
gard existent i, mai mult, toi pacienii au beneficiat de tratament endoscopic,
efectuat de endoscopiti experimentai.
Ipoteza de lucru/obiective
Cauzele hemoragiei digestive superioare pot fi variceale sau non-variceale,
de aici importana efecturii endoscopiei digestive superioare n primele 24 de
ore de la prezentarea pacientului cu HDS, putndu-se astfel preciza sursa
hemoragiei i iniia tratamentul endoscopic adecvat.
Prognosticul de via al unui pacient cu hemoragie digestiv superioar
variceal depinde de gravitatea hemoragiei, de rezerva funcional hepatic
(stadiul cirozei), gradul varicelor i localizarea acestora (esofagian sau gastric),
de vrst, de existena unor boli asociate, de tratamentul aplicat.
Din acest motiv, ne-am propus urmrirea etiopatogeniei hemoragiilor
digestive superioare la cirotici, factorilor de risc ai producerii hemoragiei
variceale, aprecierea gravitii acesteia, a eficienei tehnicilor endoscopice de
hemostaz, aprecierea recidivelor hemoragice, a mortalitii i supravieuirii
acestor pacieni.
Numeroase studii publicate au artat corelaii ntre anumii parametrii
clinici, biochimici si ecografici i riscul de apariie al hemoragiei variceale, cu
rezultate variabile i, din acest motiv, ne-am propus n primul studiu urmrirea
unora dintre ei i cauzalitatea cu hemoragiile variceale la aceti pacieni.
Rezultatele studiilor de specialitate nu pot fi extrapolate nemijlocit pe
cazuistica din teritoriu, factorii de risc ai hemoragiilor variceale putnd varia
semnificativ n funcie de caracteristicile genetice ale populaiei, de condiiile de
mediu i de condiiile socio-economice i din acest motiv am considerat util
lucrarea de fa.
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6 Studiu prospectiv asupra evoluiei i complicaiilor hemoragiilor variceale la cirotici
Studiul 1. Etiopatogenia hemoragiilor digestive superioare la cirotici
i factorii de risc ai hemoragiei variceale
Obiective
Obiectivele studiului au fost analiza etiologiei hemoragiilor non-variceale
la pacienii cirotici i urmrirea factorilor de risc ai producerii hemoragiei
variceale.
Material i metod
Grupul studiat
Studiul a fost unul de tip analitic, experimental, longitudinal, prospectiv,
desfurat n perioada 1.11.2004-31.05.2006, n Institutul Regional de
Gastroenterologie i Hepatologie Prof.Dr. O.Fodor, Cluj-Napoca.
Culegerea datelor s-a desfurat prin eantionare, grupul de pacieni fiind
alctuit sub form de eantion reprezentativ.
Lotul general a fost format din 938 pacieni, diagnosticai cu ciroz
hepatic dup criterii clinice, biochimice, ecografice i endoscopice,
documentarea fcndu-se din foile de observaie. Din cei 938 pacieni, lotul
de interes a fost reprezentat de 217 pacieni cu HDS, care au fost supui
endoscopiei digestive superioare n scop diagnostic i terapeutic, n condiii
de urgen, la Cabinetul de Endoscopie Digestiv al Institutului Regional de
Gastroenterologie i Hepatologie Prof.Dr. O.Fodor Cluj-Napoca. Lotul de
pacieni cu hemoragie l-am mprit n dou subloturi: lotul de pacieni cu
hemoragie variceal (N=168) i lotul de pacieni cu hemoragie non-
variceal (N=49). Lotul martor a fost format din pacienii fr hemoragie
(N=721).
Au fost exclui din studiu pacienii care au prezentat hemoragie digestiv
superioar din varicele gastrice.
Dup identificarea sursei variceale sau non-variceale de hemoragie
digestiv superioar, s-a aplicat terapie endoscopic, unde a fost necesar.
n cazul hemoragiilor variceale s-a efectuat scleroterapie endoscopic
folosind soluie hiperton de glucoz sau montare de ligaturi elastice n funcie de
posibilitile de moment, n condiii de urgen; n cazul hemoragiilor non-
variceale s-a injectat adrenalin 1/10000, alcool absolut sau montare de clipuri
metalice, n funcie de etiologia hemoragiei.
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Anca Romcea 7
La intrarea n studiu, fiecrui pacient i s-a ntocmit o fi de urmarire care
a cuprins:
datele personale (nume, vrst, sex)
antecedente personale patologice sugestive pentru boala de baz i
comorbiditi (infecii cu virusuri hepatice, consum de alcool,
afeciuni autoimune, diabet zaharat,HCC,etc)
diagnosticul complet (boala de baz, afeciuni asociate),integrarea n
clasa Child-Pugh
simptome i semne:
- tipul sngerrii (hematemez,melen,hematochezie)
- severitatea hemoragiei
- prezena ascitei
- prezena icterului
- gradul encefalopatiei hepatice (I,II,III,IV)
date de laborator:hemoleucograma,INR, bilirubina, transaminaze,etc
endoscopia digestiv superioar- semnalnd prezena varicelor
esofagiene i/sau gastrice, prezena/absena hemoragiei active n
momentul examinrii, cu sau fr semne de hemoragie recent
(cheaguri), gradul varicelor (I,II,III), prezena/absena semnelor roii
la nivelul varicelor esofagiene dup Ghidul Societii Japoneze de
Endoscopie, prezena hemoragiei din alte leziuni (ulcer, gastrit,
angiodisplazii, gastropatie portal hipertensiv, polipi, sdr.Mallory-
Weiss, esofagit etc)
ecografia abdominal-dimensiunile VP, splinei, prezena/absena
ascitei, a hepatocarcinomului
prezena infeciilor infecii respiratorii, infecii urinare, peritonita
bacterian spontan
tratamentul endoscopic- scleroterapie, ligaturi elastice, injectare de
adrenalin, alcool absolut, montare de clipuri metalice, coagulare cu
Plasma Argon
tratamentul medicamentos urmat propranolol, nitrai.
Fia de urmrire a pacientului conine datele clinice i paraclinice
nregistrate la momentul internrii, pe durata spitalizrii i la externare.
Studiul a fost aprobat de comitetul local de etic al Institutului Regional de
Gastroenterologie i Hepatologie Prof.Dr. O. Fodor Cluj-Napoca.
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8 Studiu prospectiv asupra evoluiei i complicaiilor hemoragiilor variceale la cirotici
Rezultate
Din cei 938 pacieni inclui n studiu, 217 au prezentat hemoragii digestive
superioare, 168 cazuri fiind hemoragii variceale i 49 cazuri non-variceale.
Hemoragia variceal a fost etiologia dominant, fiind cauza a 77,42% din
hemoragiile digestive superioare la pacienii cirotici cuprini n studiu.
Hemoragiile non-variceale s-au produs n proporie de 22,58% din totalul
hemoragiilor digestive superioare. Ulcerul peptic a determinat 12,44% din
episoadele iniiale de HDS, sindromul Mallory-Weiss 3,68%, gastrita acut eroziv
1,84%, gastropatia portal hipertensiv 1,38% i restul de 3,22% au fost hemoragii
din ulcer esofagian, angiodisplazii gastrice, ectazii vasculare antrale, polipi
duodenali i tumori gastrice.
Comparnd cele dou loturi de pacieni, cei cu hemoragie variceal
(N=168) i cei cu hemoragie non-variceal (N=49) i frecvena apariiei
hemoragiei n funcie de gravitatea cirozei hepatice, se constat o asociere
semnificativ statistic ntre clasa Child-Pugh i tipul de hemoragie. Astfel se
constat preponderena apariiei hemoragiei variceale la pacieni aflai n clasa
Child-Pugh B (74 pacieni) i C (57 pacieni), comparativ cu hemoragiile non-
variceale care au survenit mai frecvent la pacienii din clasele Child-Pugh A i B,
adic riscul de hemoragie non-variceal a fost de 2,5 ori mai mare pentru pacienii
aflai n clasa Child-Pugh A i B fa de cei din clasa Child-Pugh C (p=0,008, testul
Chi Square, OR=2,5, 95%CI 1,2-5,2).
Sindromul Mallory-Weiss, prezint o asociere semnificativ statistic
(p=0,041) cu etiologia etanolic, sexul masculin (p=0,02, RR=1,35, 95%CI 1,1-1,6), cu
prezena simultan la endoscopia digestiv superioar a varicelor gastrice (p
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Anca Romcea 9
Pentru a urmri factorii de risc ai producerii hemoragiei variceale la
cirotici, am analizat cei 168 pacieni cu hemoragie variceal, iar lotul de control a
fost reprezentat de 721 pacieni fr hemoragie (variceal sau non-variceal).
Hemoragia variceal a fost etiologia dominant, fiind cauza a 77,42% din
hemoragiile digestive superioare la pacienii cirotici cuprini n studiu.
n lotul studiat se remarc etiologia etanolic a cirozei hepatice ca factor
de risc (p
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10 Studiu prospectiv asupra evoluiei i complicaiilor hemoragiilor variceale la cirotici
Prezena hepatocarcinomului a fost evideniat la 10,12% dintre pacienii
cu hemoragie variceal, evideniat ca factor de risc al hemoragiei variceale
(RR=1,1; 95%CI:0,72-1,65) fr a se asocia semnificativ statistic cu aceasta
(p=0,68).
Pentru a determina valoarea diagnostic a unor parametrii numerici
(vrsta, diametrul longitudinal al splinei, numrul trombocitelor, diametrul venei
porte), s-au construit i comparat curbele ROC (Receiver Operating
Characteristic). Curba ROC ilustreaz relaia grafic dintre sensibilitate i
specificitate pentru anumite valori prag (cut-off) posibile. Sunt considerate puncte
de cut-off valorile optime din punct de vedere al fiabilitii parametrilor analizai.
Valoarea de cut-off (punctul unde sensibilitatea i specificitatea au valori
maxime) determinat cu o semnificaie statistic nalt (p
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Anca Romcea 11
studiu a pacienilor i, urmrirea lor, n cadrul controalelor periodice, pe
parcursul unui an, pn n 31 .08.2007, n Institutul Regional de
Gastroenterologie i Hepatologie Prof.Dr. O. Fodor Cluj-Napoca. Culegerea
datelor s-a desfurat prin eantionare, grupul de pacieni fiind alctuit sub
form de eantion reprezentativ.
Au fost inclui n studiu 198 pacieni cu hemoragie digestiv superioar
din varicele esofagiene, care au fost supui endoscopiei digestive superioare,
n scop diagnostic i terapeutic, n condiii de urgen, la Cabinetul de
Endoscopie al Institutului Regional de Gastroenterologie i Hepatologie
Prof.Dr. O.Fodor Cluj-Napoca. Au fost inclui doar pacienii care aveau ca
surs a hemoragiei efracia din varicele esofagiene, apreciat prin examen
endoscopic de urgen, efectuat la cel mult 6 ore de la internarea pacientului.
Ulterior, am urmrit 74 pacieni care au prezentat recidive hemoragice
variceale, lotul de control fiind reprezentat de pacienii fr recidive
hemoragice (N=124).
Am exclus din studiu pacienii care aveau diagnostic de ciroz hepatic
de etiologie neprecizat n momentul externrii.
Dup identificarea sursei variceale a hemoragiei digestive superioare s-
a efectuat terapie endoscopic (ligaturi elastice sau scleroterapie cu soluie de
glucoz hiperton, n funcie de posibilitile de moment).
n vederea cercetrii factorilor predictivi ai morbiditii i mortalitii
dup episoadele hemoragice, precum i ai supravieuirii, am monitorizat
recurenele hemoragice prin efracia varicelor esofagiene, apariia sau agravarea
complicaiilor specifice cirozei- encefalopatie hepatic, peritonit bacterian
spontan, ascit, apariia sau agravarea complicaiilor datorate bolilor asociate
(infecii, afeciuni cardiovasculare etc), numrul i cauza deceselor.
Controalele periodice au fost la 6 saptmni, 3 luni, 6 luni i 1 an fa de
hemoragia iniial.
Studiul a fost ntrerupt pentru fiecare pacient la finalul perioadei de
urmrire sau n caz de deces.
Studiul a fost aprobat de comitetul local de etic al Institutului Regional
de Gastroenterologie i Hepatologie Prof.Dr. O. Fodor Cluj-Napoca.
Rezultate
Din 198 pacieni cu hemoragii variceale, recurene hemoragice au aprut la
74 pacieni: 48 brbai i 26 femei.
n lotul pacienilor cu recidive hemoragice n perioada imediat urmtoare
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12 Studiu prospectiv asupra evoluiei i complicaiilor hemoragiilor variceale la cirotici
aplicrii hemostazei endoscopice, au fost n total 118 recurene hemoragice (ntre
2 i 5 episoade hemoragice per pacient).
Din cele 198 de cazuri la care s-a obinut controlul hemoragiei variceale
iniiale, prima recidiva hemoragic a fost nregistrat la 37,37% din pacieni.
Sexul, vrsta i etiologia cirozei pacienilor care au prezentat
hemoragie variceal nu s-au corelat cu riscul de apariie al primei recidive
hemoragice.
Se constat o asociere semnificativ statistic a apariiei primei recidive
hemoragice cu clasa Child-Pugh a cirozei (p=0,04); au prezentat recidiv
hemoragic cu precdere pacienii cu ciroz hepatic clasa Child-Pugh B
(37,6%) i C (44%), comparativ cu pacienii aflai n clasa Child-Pugh A la
prima hemoragie variceal (23%).
Severitatea episodului hemoragic acut iniial influeneaz asocierea
recidivei, (p
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Anca Romcea 13
- prezena hepatocarcinomului a crescut de 4 ori riscul de deces la 48 de ore
al acestor pacieni, 33,33% dintre pacienii decedai la 48 ore au avut i
hepatocarcinom (p=0,004, RR=4, 95%CI:1.5 10.63).
- prezena ascitei n cantitate mare se coreleaza cu decesul la 48 de ore (p=0,017).
Sexul i vrsta pacienilor, etiologia cirozei i tratamentul endoscopic
aplicat nu s-au corelat semnificativ statistic cu decesele nregistrate pn la 48 de
ore de la momentul hemoragiei iniiale, dar am constatat c, 33,3% din pacienii
decedai n acest interval de timp au fost diagnosticai cu ciroz hepatic de
etiologie etanolic (p=0,05).
n urmtorul interval de timp, din ziua a 3 a i pn la ase sptmni de la
episodul hemoragic iniial s-au nregistrat 40,43% din totalul deceselor n grupul
studiat i s-au produs n principal datorit ocului hemoragic (fig. 17).
Analiza mortalitii pn la 6 sptmni a evideniat asocierea semnificativ
statistic cu urmtorii factori:
- clasa Child-Pugh C a cirozei- la pacienii decedai comparativ cu severitatea
cirozei pacienilor care au supravieuit (p=0,015, RR=2,5, 95%CI:1,4-12,7)
- tratamentul medicamentos- lipsa tratamentului cu propranolol s-a corelat cu
decesul (p
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14 Studiu prospectiv asupra evoluiei i complicaiilor hemoragiilor variceale la cirotici
Factori de predicie ai supravieuirii dup
hemoragiile variceale
La sfritul unui an de la primul episod hemoragic, 47 pacieni au decedat
i 151 au supravieuit. Dup episodul iniial de hemoragie variceal, pacienii au
urmat tratament medicamentos (propranolol, nitrai sau propranolol plus nitrai)
i au fost chemai la control pentru edine de consolidare a varicelor esofagiene
prin scleroterapie sau ligaturi elastice.
Concluzii generale
Hemoragiile digestive superioare au aprut la 23,14% din pacienii cirotici
inclui in studiu, hemoragiile variceale reprezentnd etiologia dominant, fiind
cauza a 77,42% din primul episod hemoragic la aceti pacieni.
Hemoragia non-variceal s-a produs la 22,58% din totalul pacienilor cu
hemoragie digestiv superioar, fiind reprezentat n ordine descresctoare de: ulcer
peptic, sindrom Mallory-Weiss, gastrit acut eroziv, gastropatie portal hipertensiv
i alte etiologii mai rare n studiul nostru (ulcer esofagian, angiodisplazii gastrice,
ectazii vasculare antrale, polipi duodenali i tumori gastrice).
Incidena hemoragiilor digestive superioare este crescut la vrste peste 55
ani, raportul pe sexe brbai:femei fiind 2:1 n ambele loturi de pacieni (cu
hemoragie variceal i n cel cu hemoragie non-variceal).
Etiologia etanolic a fost predominant n lotul hemoragiilor variceale.
Hemoragiile digestive superioare non-variceale de tip ulcer peptic, gastrit
acut eroziv i ulcer esofagian au fost nregistrate in numr mai mare la pacieni
cu ciroz hepatic clasa Child-Pugh A i B comparativ cu cei cu ciroz hepatic
clasa Child-Pugh C.
Sindromul Mallory-Weiss, prezint o asociere semnificativ statistic cu
etiologia etanolic, sexul masculin i clasa Child-Pugh A.
n ceea ce privete hemoragia din gastropatia portal hipertensiv se observ
o asociere cu trombocitopenia (plt2 i clasa Child-Pugh C a cirozei.
Comparnd ntre ele cele dou loturi de pacieni (cu hemoragie variceal i
non-variceal), riscul de hemoragie non-variceal a fost de 2,5 ori mai mare
pentru pacienii aflai n clasa Child-Pugh A i B fa de cei din clasa Child-Pugh C .
Episodul hemoragic a fost mai sever n lotul cu hemoragii variceale fa de
non-variceale.
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Anca Romcea 15
Efracia variceal este principala surs a sngerrii n hemoragiile severe,
ulcerul peptic i sindromul Mallory-Weiss fiind diagnosticat preponderent n
hemoragiile moderate i uoare.
Efracia varicelor esofagiene este n funcie de gradul varicelor, de prezena
semnelor roii variceale i crete cu severitatea afectrii hepatice.
Prezena encefalopatiei hepatice, numrul trombocitelor 140 mm s-au corelat semnificativ statistic cu
riscul de apariie al hemoragiei variceale.
Infeciile bacteriene-peritonita bacterian spontan, infeciile respiratorii, infeciile
urinare au aprut n lotul pacienilor cu hemoragie variceal n proporie de 49,4%.
Prezena hepatocarcinomului a fost evideniat la 10,12% dintre pacienii cu
hemoragie variceal, dar nu s-a corelat cu riscul de apariie al hemoragiilor variceale.
Construind i comparnd curbele ROC pentru lotul de pacieni cu hemoragie
variceal, s-a stabilit o valoare prag pentru numrul trombocitelor de
138500/mm3, pentru diametrul longitudinal al splinei de 232,5 mm pentru a
pune diagnosticul de hemoragie variceal i n cazul dimensiunilor venei porte
sub 9,6 mm de a infirma hemoragia variceal dar, nici unul dintre aceti
parametrii nu au AUC suficient de mare nct s pun un diagnostic ferm.
Prin regresia logistic multivariat s-a stabilit c, cel mai puternic factor
predictiv al hemoragiei variceale este prezena semnelor roii pe suprafaa
varicelor esofagiene, urmat de etiologia etanolic a cirozei, clasa Child-Pugh C,
trombocitopenia sub 138500/mm3 i gradul varicelor esofagiene, cel din urm
evideniind o relaie de direct proporionalitate ntre creterea gradului
varicelor esofagiene i influena asupra apariiei hemoragiei variceale.
Riscul apariiei primei recidive hemoragice la pacienii cirotici crete cu
severitatea afectrii hepatice (clasa Child-Pugh), cu prezena ocului hemoragic i
a hepatitei acute etanolice n cursul primului episod de hemoragie variceal.
Tratamentul medicamentos cu propranolol ca profilaxie secundar, este
factor de protecie in apariia primei recidive hemoragice; tratamentul endoscopic
prin scleroterapie a determinat o frecven mai mare de apariie a primei recidive
hemoragice comparativ cu ligaturile elastice.
n cadrul tuturor recurenelor hemoragice aprute la pacienii cirotici din
studiul nostru, lipsa tratamentului cu propranolol s-a corelat semnificativ statistic
cu apariia recidivelor hemoragice, iar tratamentul endoscopic de ligaturare al
varicelor esofagiene cu scderea episoadelor de recidiv.
Complicaiile aprute n cadrul recidivelor hemoragice, s-au corelat
semnificativ statistic cu severitatea cirozei, cu prezena ocului hemoragic i a
encefalopatiei hepatice.
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16 Studiu prospectiv asupra evoluiei i complicaiilor hemoragiilor variceale la cirotici
Infeciile bacteriene (peritonita bacterian spontan, infeciile respiratorii i
infeciile urinare) au fost frecvente n cadrul primei recidive hemoragice fiind
prezente la 41,2% din aceti pacieni.
Mortalitatea global prin hemoragie variceal a fost de 23,73%.
Cauzele de deces au fost: ocul hemoragic (47%), coma hepatic(38%),
infarctul miocardic(13%) i accidentul vascular cerebral (2%).
Mortalitatea imediat, la 48 de ore de la episodul hemoragic iniial, a fost
semnificativ statistic corelat cu gradul de severitate al cirozei, cu prezena
ocului hemoragic, a ascitei n cantitate mare, a bilirubinei serice>3 mg/dl, a
hepatitei acute ischemice, cu asocierea hepatocarcinomului, a infactului miocardic
i a peritonitei bacteriene spontane la aceti pacieni.
Mortalitatea de la 3 zile pn la 45 de zile (ase sptmni) de la episodul
hemoragic iniial s-a corelat semnificativ cu clasa Child-Pugh C a cirozei, cu lipsa
tratamentului cu propranolol, cu tratamentul endoscopic prin scleroterapie
comparativ cu ligaturile sau terapia combinat, cu prezena hepatocarcinomului, a
peritonitei bacteriene spontane, a encefalopatiei hepatice, a ocului hemoragic i a
hepatitei acute ischemice la pacienii decedai comparativ cu supravieuitorii.
De la 46 de zile pn la un an de la episodul hemoragic iniial mortalitatea
nregistrat a fost de 6,56% i s-a corelat semnificativ statistic cu prezena
hepatocarcinomului i a ocului hemoragic.
Analiza statistic a evenimentelor nregistrate dup un an de la primul episod de
hemoragie variceal a ciroticilor luai n studiu, a relevat c, pacienii care au
supravieuit mai mult timp sunt pacieni cu ciroz hepatic clasa Child-Pugh A, fr
PBS, care au urmat tratament medicamentos cu propranolol, pacieni tratai prin
scleroterapie plus ligaturi elastice a varicelor esofagiene, cu absena ocului
hemoragic n cursul episodului acut i cu vrsta sub 55 ani. Cei mai importani factori
n prognosticul supravieuirii-analizai prin regresia multivariat Cox au fost: ocul
hemoragic, PBS, tratamentul cu propranolol i tratamentul endoscopic aplicat.
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16 Prospective study on the development and complications of variceal bleeding in patients with liver cirrhosis
occurrence of bleeding relapse, while the endoscopic ligation treatment of the
esophageal varices correlated with a decrease in relapse episodes.
Bleeding complications that occurred during relapses were found to have a
statistically significant correlation with the severity of cirrhosis, the presence of
hemorrhagic shock and the hepatic encephalopathy.
Bacterial infections (spontaneous bacterial peritonitis, respiratory and
urinary tract infections) were common in the first bleeding relapse and were
present in 41.2% of these patients.
Overall mortality by variceal bleeding was 23.73%.
The causes of death were: hemorrhagic shock (47%), hepatic coma (38%),
myocardial infarction (13%) and stroke (2%).
Immediate mortality, within the first 48 hours after the initial bleeding
episode, was statistically significantly correlated with the severity of the liver
cirrhosis, with the presence of hemorrhagic shock, with a large amount of ascites,
with serum bilirubin> 3 mg / dl, with acute ischemic hepatitis, with HCC, with
myocardial infarction and spontaneous bacterial peritonitis in these patients.
Mortality within 3 days to 45 days (six weeks) of the initial bleeding episode
significantly correlated with Child-Pugh class C cirrhosis, with no treatment with
propranolol, with the endoscopic sclerotherapy treatment versus ligation or
combined therapy, with HCC, with the spontaneous bacterial peritonitis, with the
hepatic encephalopathy, with the hemorrhagic shock and acute ischemic hepatitis
in patients who died, in comparison with the survivors from our study.
From 46 days up until one year after the initial bleeding episode, mortality
was recorded in 6.56% of the patients and our study found it statistically
significantly correlated with the presence of HCC and the hemorrhagic shock.
The statistical analysis of the events recorded after one year from the first
episode of variceal bleeding in the cirrhotic patients from our study revealed that
the patients who survived longer were patients with Child-Pugh class A liver
cirrhosis, without PBS, who were given drug treatment with propranolol and
whose esophageal varices were treated by sclerotherapy plus elastic ligatures;
these patients had no hemorrhagic shock during the acute episode and were aged
under 55 years. The most important survival prognostic factors analyzed by
multivariate Cox regression were: the hemorrhagic shock, PBS, the treatment with
propranolol and the applied endoscopic treatment.
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Anca Romcea 15
The bleeding episode was more severe in the group with variceal bleeding
than in the non-variceal bleeding group.
The variceal intrusion was the main bleeding source in severe bleeding;
peptic ulcer and Mallory-Weiss syndrome were mainly diagnosed in moderate
and mild bleeding.
The esophageal varices intrusion depended on the varices grade, on the presence
of variceal red wheals and it increased with the severity of the liver damage.
The presence of hepatic encephalopathy, platelet count 140 mm were found to have a statistically
significant correlation with the risk of variceal bleeding.
Bacterial infections - spontaneous bacterial peritonitis, respiratory infections,
and urinary tract infections occurred in 49.4% of the patients in the group with
variceal bleeding.
The presence of HCC was found in 10.12% of the patients with variceal
bleeding, but did not correlate with the risk of variceal bleeding.
Building and comparing ROC curves for the group of patients with variceal
bleeding, a threshold of 138,500 / mm3 for the platelet count was set and of 232.5
mm for the longitudinal spleen diameter to make the diagnosis of variceal
bleeding. The size of the portal vein was set below 9.6 mm in order to refute
variceal bleeding. However, none of these parameters had a big enough AUC to
make a firm diagnosis.
By multivariate logistic regression it was found that the strongest predictor
of variceal bleeding was the presence of red weals on the surface of esophageal
varices, followed by the ethanol etiology of cirrhosis, Child-Pugh class C,
thrombocytopenia below 138,500 / mm3 and the grade of the esophageal
varices, the latter highlighting a directly proportional relationship between a
higher grade of the esophageal varices and the influence on the occurrence of
variceal haemorrhage.
The risk for the first bleeding relapse in cirrhotic patients increased with
the severity of the liver disease (Child-Pugh class), with the presence of
hemorrhagic shock and of acute alcoholic hepatitis during the first episode of
variceal bleeding.
The drug treatment with propranolol as secondary prophylaxis is a
protection factor for the first bleeding relapse; the endoscopic sclerotherapy
treatment resulted in a higher incidence of the first bleeding relapse than that
performed with elastic ligatures.
In all the bleeding relapses that occurred in the cirrhotic patients from our
study, no treatment with propranolol statistically significantly correlated with the
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14 Prospective study on the development and complications of variceal bleeding in patients with liver cirrhosis
Prediction factors of survival after variceal bleeding
At the end of one year since the first bleeding episode, 47 patients died and
151 survived. After the initial episode of variceal bleeding, patients were given
medication (propranolol, nitrates or propranolol plus nitrates) and were called
for check-ups to undergo consolidation therapy for the esophageal varices by
sclerotherapy or elastic ligatures.
General conclusions
UGI bleeding occurred in 23.14% of the cirrhotic patients included in the
study, the variceal bleeding representing the dominant etiology and accounting
for 77.42% of the first episode of bleeding in these patients.
Non-variceal bleeding occurred in 22.58% of all the patients with upper
gastrointestinal bleeding and was represented, in descending order, by: peptic
ulcer, Mallory-Weiss syndrome, acute erosive gastritis, portal hypertensive
gastropathy and other etiologies which were seldom found in our study
(esophageal ulcer, gastric angiodysplasia, antral vascular ectasia, duodenal polyps
and gastric tumors).
The incidence of UGI bleeding was high in patients aged over 55 years, the
gender ratio male:female being 2:1 in both groups of patients (both in the variceal
bleeding goup and in the non-variceal bleeding group).
Alcoholic etiology was predominant in the variceal bleeding group.
Non-variceal upper gastrointestinal bleeding such as those of peptic ulcer
type, acute erosive gastritis and esophageal ulcer were recorded in greater
numbers in patients with Child-Pugh class A and B liver cirrhosis, in comparison
to those with Child-Pugh class C liver cirrhosis.
Mallory-Weiss syndrome shows a statistically significant correlation with
ethanolic etiology, male gender and Child-Pugh class A.
portal hypertensive gastropathy bleeding was found in correlation with
thrombocytopenia (plt 2 and Child-Pugh class C cirrhosis.
Comparing the two groups of patients (the variceal bleeding group vs.
the non-variceal bleeding group), the risk for non-variceal bleeding was 2.5
times higher in patients with Child-Pugh class A and B than in patients with
Child-Pugh class C.
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Anca Romcea 13
- large amount of ascites - correlates with death at 48 hours (p = 0.017).
Gender and the age of patients, the etiology of cirrhosis and the endoscopic
treatment were not found to have significantly correlated with the deaths
recorded within 48 hours after the initial bleeding, but we found that 33.3% of the
patients who died in this period were diagnosed with liver cirrhosis of alcohol
consumption etiology (p = 0.05).
In the following period, from day 3 and up to six weeks after the initial
bleeding episode, 40.43% of all deaths in the study group were recorded and they
mainly occurred because of hemorrhagic shock (Fig. 17) .
The analysis of mortality up to 6 weeks showed statistically significant
correlation with the following factors:
- Child-Pugh C liver cirrhosis - in the deceased patients compared with the
cirrhosis severity in the patients who survived (p = 0.015, RR = 2.5, 95% CI:
1.4 to 12.7)
- treatment with medication - no treatment with propranolol was correlated
with death (p
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12 Prospective study on the development and complications of variceal bleeding in patients with liver cirrhosis
Out of the 198 cases in which control over the initial variceal bleeding was
obtained, the first hemorrhagic relapse was recorded in 37.37% of the patients.
Gender, age and etiology of cirrhosis of patients who experienced variceal bleeding
did not correlate with the risk for a first bleeding relapse. There is a statistically
significant correlation of the first bleeding relapse with the Child-Pugh liver cirrhosis
(p = 0.04); mainly patients with liver cirrhosis of Child-Pugh class B (37.6%) and C
(44%) presented a bleeding relapse, in comparison with patients in Child-Pugh class
A who had their first variceal bleeding (23%). The severity of the acute bleeding
episode originally influences the occurrence of the relapse (p
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Anca Romcea 11
inclusion and study of patients within regular check-ups took place at "Prof.
Fodor O. " Regional Institute of Gastroenterology and Hepatology, Cluj-Napoca,
for over a year, until 31.08.2007. Data collection was conducted by sampling
and the study group consisted of a representative patient sample. The study
included 198 patients, with upper gastrointestinal bleeding from esophageal
varices, who underwent diagnostic and therapeutic upper gastrointestinal
endoscopy, under emergency conditions, at the Office of "Prof. O.Fodor"
Regional Institute Endoscopy Gastroenterology and Hepatology Cluj-Napoca.
The study included only patients whose source of bleeding was the esophageal
varices intrusion. This was assessed by emergency endoscopic examination
performed within 6 hours of the patients admission at the latest.
Subsequently, we studied 74 patients who had variceal bleeding relapses while
the control group was formed of patients without bleeding relapses (N = 124).
Patients, who had a diagnosis of cirrhosis of unknown etiology at the time of
discharge, were excluded from the study. After the source of variceal bleeding
in the UGI bleeding had been identified, endoscopic therapy was performed
(elastic ligatures or sclerotherapy with hypertonic glucose solution, depending
on the specific possibilities). In order to investigate the factors predictive of
morbidity and mortality after bleeding episodes, as well as those predictive of
survival, we monitored bleeding relapses because of esophageal varices
intrusion, the occurrence or worsening of specific complications of cirrhosis -
hepatic encephalopathy, spontaneous bacterial peritonitis, ascites, the
occurrence or worsening of complications due to associated diseases
(infections, cardiovascular diseases, etc.), the number and causes of deaths.
Regular check-ups were carried out after 6 weeks, 3 months, 6 months and 1
year of the initial bleeding.
The study was stopped for each patient at the end of the follow-up
period or in case of death. The study was approved by the local ethics
committee of "Prof. O. Fodor" Regional Institute of Gastroenterology and
Hepatology, Cluj-Napoca.
Results
Out of the 198 patients with variceal bleeding, bleeding relapses occurred
in 74 patients: 48 men and 26 women. In the group of patients with bleeding
relapses, there were a total of 118 bleeding relapses in the period immediately
after the application of endoscopic hemostasis, (between 2 and 5 bleeding
episodes per patient).
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10 Prospective study on the development and complications of variceal bleeding in patients with liver cirrhosis
The presence of HCC was found in 10.12% of the patients with variceal
bleeding and it was highlighted as a risk factor for variceal bleeding (RR = 1.1; 95%
CI: 0.72 to 1.65). However, it was not found to be statistically significantly
associated with the variceal bleeding (p = 0.68). To determine the diagnostic value
of certain numeric parameters (patients age, the longitudinal diameter of the
spleen, platelet count, the portal vein diameter) the ROC curves (Receiver Operating
Characteristic) were constructed and compared. The ROC curve graphically
illustrates the relationship between sensitivity and specificity for certain possible
cut-off values. The optimal values in terms of reliability of the analyzed parameters
are considered cut-off points. The cut-off value (the point where sensitivity and
specificity are at a maximum) determined with highly statistical significance (p
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Anca Romcea 9
bleeding. The variceal intrusion is the main source of bleeding in severe bleeding
(87.42%), whereas peptic ulcer and the Mallory-Weiss syndrome are mainly
diagnosed in moderate and mild bleeding (71.4%). To analyze the risk factors for
variceal bleeding in cirrhotic patients, we studied 168 patients with variceal
bleeding, in comparison with the control group, which included 721 patients
without bleeding (variceal or non-variceal). The variceal bleeding was the
dominant etiology, accounting for 77.42% of the upper gastrointestinal bleeding
in the cirrhotic patients included in the study. In the study group, the ethanolic
etiology of liver cirrhosis as a risk factor (p
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8 Prospective study on the development and complications of variceal bleeding in patients with liver cirrhosis
The patients record chart contains clinical and laboratory data recorded
on admission, during hospitalization and at hospital discharge.
The study was approved by the local ethics committee of "Prof. O. Fodor"
Regional Institute of Gastroenterology and Hepatology, Cluj-Napoca.
Results
Out of the 938 patients included in the study, 217 patients had upper
gastrointestinal bleeding (168 variceal bleeding cases and 49 non-variceal cases).
The variceal bleeding was the dominant etiology, accounting for 77.42% of the
upper gastrointestinal bleeding in the cirrhotic patients included in the study.
Non-variceal bleeding occurred at a rate of 22.58% of the upper gastrointestinal
bleeding. Peptic ulcer caused 12.44% of the initial episodes of UGI bleeding,
Mallory-Weiss syndrome caused 3.68%, acute erosive gastritis 1.84%, portal
hypertensive gastropathy 1.38% and the remaining 3.22% were bleeding from
the esophageal ulcer, gastric angiodysplasia, antral vascular ectasia, duodenal
polyps and gastric tumors.
Comparing the two groups of patients, those with variceal bleeding (N =
168) and the non-variceal bleeding ones (N = 49), in terms of the incidence of
bleeding depending on the cirrhosis severity, a statistically significant association
was found between the Child-Pugh class and the type of bleeding. Thus, there is a
higher occurrence of variceal bleeding in the patients from Child-Pugh class B (74
patients) and C (57 patients), compared with non-variceal bleeding that occurred
more frequently in patients from Child-Pugh A and B, ie the non-variceal bleeding
risk was 2.5 times higher in patients from Child-Pugh class A and B than in those
from the Child-Pugh class C (p = 0.008, Chi Square test, oR = 2.5, 95% CI 1.2 to 5.2).
The Mallory-Weiss syndrome shows a statistically significant association (p =
0.041) with ethanolic etiology, male gender (p = 0.02, RR = 1.35, 95% CI 1.1-1.6), with
the simultaneous presence of gastric varices on the upper gastrointestinal endoscopy
(p
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Anca Romcea 7
After the variceal or non-variceal source of the UGI bleeding was identified,
endoscopic therapy was applied where necessary.
In the cases of variceal bleeding, endoscopic sclerotherapy was
performed by using hypertonic glucose solution or by inserting elastic ligatures
according to possibilities, under emergency conditions; in the cases of non-
variceal bleeding, adrenaline 1/10000 and absolute alcohol were injected or
metal clips were inserted, depending on the etiology of the bleeding.
A record chart, which included the following data, was completed for each
patient, upon inclusion in the study:
personal data (name, age, gender)
personal pathological history suggestive of the underlying disease and of
comorbidities (liver virus infections, alcohol consumption, autoimmune
diseases, diabetes mellitus, HCC, etc.)
complete diagnosis (the underlying disease, associated diseases),
classification according to the Child-Pugh criteria
symptoms and signs:
- type of bleeding (hematemesis, melena, hematochezia)
- severity of the bleeding
- ascites
- jaundice
- the degree of hepatic encephalopathy (I, II, III, IV)
laboratory findings: complete blood count, INR, bilirubin, transaminases,
etc.
upper GI endoscopy - signaling the presence of esophageal and / or
gastric varices, the presence / absence of active bleeding on examination,
with or without signs of recent bleeding (clots), varices grade (I, II, III),
the presence / absence of red signs on the esophageal varices according
to the Guide of the Japanese Society of Endoscopy, the presence of other
bleeding lesions (ulcers, gastritis, angiodysplasia, portal hypertensive
gastropathy, polyps, Mallory-Weiss syndrome - MWS, esophagitis, etc.)
abdominal ultrasound- spleen, VP size, presence / absence of ascites, of
HCC
infections - respiratory infections, urinary infections, spontaneous
bacterial peritonitis
endoscopic treatment- sclerotherapy, elastic ligatures, injection of
adrenaline, absolute alcohol, metal clips insertion, argon plasma
coagulation (APC)
patients drug therapy -propranolol, nitrates.
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6 Prospective study on the development and complications of variceal bleeding in patients with liver cirrhosis
The results of speciality studies cannot be extrapolated directly onto the
cases in the territory as the variceal bleeding risk factors can significantly vary
depending on the populations genetics, on environmental conditions and on
socio-economic conditions. This is the reason why, we considered the present
doctoral thesis useful.
Study 1. The etiopathogenesis of upper gastrointestinal bleeding in
cirrhotic patients and the variceal bleeding risk factors
Objectives
The objectives of the study were to analyze the etiology of non-variceal
bleeding in cirrhotic patients and the risk factors for variceal bleeding.
Materials and methods
The study group
The study was an analytical, experimental, longitudinal and prospective
type of study conducted in the period 1.11.2004-31.05.2006, in the "Prof. O.Fodor
" Regional Institute of Gastroenterology and Hepatology, Cluj-Napoca.
Data collection was conducted by sampling, the patients study group
consisting of a representative sample.
The general group included 938 patients diagnosed with liver cirrhosis
according to clinical, biochemical, ultrasonographic and endoscopic criteria,
whereas the documentation was completed from the patients observation
charts. Out of the 938 patients, the group of study interest included 217 patients
with UGI bleeding, who underwent upper gastrointestinal endoscopy for
diagnosis and treatment, under emergency conditions, in the Digestive
Endoscopy Office of the"Prof. Dr. O.Fodor" Regional Institute of
Gastroenterology and Hepatology, Cluj-Napoca.
The study group of patients with bleeding was divided into two
subgroups: the group of patients with variceal bleeding (N = 168) and the group
of patients with non-variceal bleeding (N = 49). The control group consisted of
patients with no bleeding (N = 721). The patients who had upper
gastrointestinal bleeding from gastric varices were excluded from the study.
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Anca Romcea 5
treatment, the complications and the mortality issues. We also analyzed the
prediction factors of survival at one year of the initial bleeding episode. International
guidelines contain a number of recommendations including an essential one, namely:
the indication to perform the upper gastrointestinal endoscopy within the first 24
hours in all patients with upper gastrointestinal bleeding.
In our country, according to the data from the Romanian Society of
Endoscopy, there are few medical centers in which on duty permanent endoscopy
service exists, and in many of the units in which emergency upper gastrointestinal
endoscopy is performed during office hours there are no resources required for
performing endoscopic hemostasis. In this respect, in order to complete the
present thesis, due to the existing on duty service, we benefited from the
possibility of performing upper gastrointestinal endoscopy in all the patients who
presented with an episode of bleeding, in the "Prof. O. Fodor" Regional Institute of
Gastroenterology and Hepatology. Moreover, all the patients received endoscopic
treatment conducted by experienced endoscopy specialists.
Hypothesis/ Objectives
The causes of upper gastrointestinal bleeding (UGI bleeding) may be
variceal or non-variceal, hence the importance of performing the upper
gastrointestinal endoscopy within the first 24 hours of admission of the UGI
bleeding patient. Thus, the source of bleeding can be specified and the
appropriate endoscopic treatment initiated.
The life prognosis of a patient with variceal upper gastrointestinal
bleeding depends on the severity of the haemorrhage, on the hepatic functional
reserve (cirrhosis stage), on the degree and location of the varices (esophageal or
gastric), on the patients age, on the existence of associated diseases, on the
specific treatment, etc.
For this reason, we decided to monitor the etiopathogenesis of upper
gastrointestinal bleeding in cirrhotic patients, the risk factors for variceal
bleeding, its severity, the efficiency of the endoscopic hemostasis techniques, the
assessment of bleeding relapses, the mortality and survival of these patients.
Numerous published studies have shown correlations between certain
clinical, biochemical and ultrasound parameters and the risk for variceal bleeding,
with variable results. Therefore, our first study, in this thesis, looked into some of
these aspects and into what causes variceal bleeding in these patients.
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4 Prospective study on the development and complications of variceal bleeding in patients with liver cirrhosis
Keywords:
variceal bleeding, esophageal varices, upper gastrointestinal bleeding in cirrhotic
patients, variceal bleeding risk factors, endoscopic treatment for variceal
bleeding, mortality in variceal bleeding.
Introduction
The upper gastrointestinal bleeding in cirrhotic patients is one of the
major pathology problems of Gastroenterology and it is also a public health
issue with high incidence, severe complications and high costs involved in giving
the required health care to these patients.
In spite of the application of preventive measures, as well as despite the
improvement of diagnostic methods and the greater efficiency of treatment
methods, liver cirrhosis with its most feared complication - the upper
gastrointestinal bleeding - remains a major public health problem.
The upper gastrointestinal bleeding in cirrhotic patients mainly occurs
because of esophageal and gastric varices. However, there are a significant
number of non-variceal bleeding cases too. Therefore, the first study aimed to
analyze the etiopathogenesis of the upper gastrointestinal bleeding in patients
with liver cirrhosis and to assess the risk factors involved in the occurrence of
variceal bleeding. The study included 900 patients with cirrhosis, which allowed
us to have an overview of the upper gastrointestinal bleeding in cirrhotic patients.
After the first episode of variceal bleeding, the risk for a bleeding relapse is
high, whereas complications (hepatic and extrahepatic ones) and mortality may
be due to multiple factors: the severity of bleeding (ie hemodynamic imbalance),
worsening of the liver failure (assessed by the Child-Pugh criteria), the
association of other diseases (infections, diabetes mellitus, heart disease,
hepatocellular carcinoma, etc.). Moreover, the methods of treatment applied to
the patients, when they experience the first variceal bleeding, involve a change in
the frequency of relapses, in the timing of their occurrence in relation to the initial
bleeding episode and in the long-term survival.
The second study looked into the bleeding relapses that occurred in patients
after the first variceal bleeding episode. Moreover, we studied the risk factors for the
first bleeding relapse, the influence of medication and that of the endoscopic
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Anca Romcea 3
2.3.3. Statistical analysis 46
2.4. Results 47
2.4.1. Aspects of pathogenesis of the upper gastrointestinal bleeding in
cirrhotic patients 49
2.4.2. Aspects of risk factors of variceal bleeding in cirrhotic patients 58
2.5. Discussions 67
2.6. Conclusions 69
3. Study 2. Evolution and complications of the variceal bleeding in cirrhotic
patients 71
3.1. Introduction 71
3.2. Objectives 72
3.3. Materials and methods 72
3.3.1. Study group 72
3.3.2. Variables 75
3.3.3 Statistical analysis 75
3.4. Results 76
3.4.1. Aspects of the first bleeding relapse 78
3.4.2. Implications of the drug and endoscopic treatment in relapses
of variceal bleeding in cirrhotic patients. 85
3.4.3. Complications in relapses of variceal bleeding in cirrhotic patients 88
3.4.4. Analysis of mortality in variceal bleeding 92
3.4.5. Prediction factors of survival after variceal bleeding 97
3.5. Discussions 103
3.6. Conclusions 105
4. General conclusions 107
5. Originality and innovative contributions of the thesis 111
REFERENCES 113
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2 Prospective study on the development and complications of variceal bleeding in patients with liver cirrhosis
Contents
INTRODUCTION 13
PRESENT KNOWLEDGE IN LITERATURE
1. Pathophysiology data of liver cirrhosis 17
1.1. Portal hypertension in liver cirrhosis 17
1.2. Pathophysiological features of upper variceal gastrointestinal
bleeding in cirrhotic patients 19
2. Treatment principles of variceal bleeding in cirrhotic patients 23
2.1. Concepts of primary prophylaxis of variceal bleeding in cirrhotic patients.
The role of endoscopic therapy in primary prevention 23
2.1.1. Primary prevention strategy of variceal bleeding by
pharmacological means 24
2.1.2. The role of endoscopic therapy in the primary prevention
of variceal bleeding 25
2.2. Specific treatment (hemostasis) of active variceal bleeding 26
2.2.1. Treatment with vasoactive pharmacological agents of active
variceal bleeding 26
2.2.2. Endoscopic treatment of active variceal bleeding 26
2.3. Concepts of secondary prophylaxis of variceal bleeding 28
3. Complications of variceal bleeding in cirrhotic patients 31
3.1. Complications associated with variceal bleeding 31
3.1.1. Hepatic encephalopathy 31
3.1.2. Bacterial infections 32
3.1.3. Hepato-renal syndrome 33
3.1.4. Bleeding relapses 34
3.1.5. Hypovolemic shock 34
3.1.6. Variceal bleeding consequences on cardiovascular diseases 35
3.1.7. Complications due to pharmacotherapy and to therapeutic
procedures in variceal bleeding 36
ORIGINAL PART
1. Hypothesis / objectives 41
2. Study 1. The etiopathogenesis of the upper gastrointestinal bleeding
in cirrhotic patients and the variceal bleeding risk factors 43
2.1. Introduction 43
2.2. Objectives 43
2.3. Materials and methods 43
2.3.1. Study group 43
2.3.2. Variables 45
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Cover
Prospective study on the
development and complications
of variceal bleeding in patients
with liver cirrhosis
CopertaCuprinsCuvinte cheie:IntroducereIpoteza de lucru/obiectiveStudiul 1. Etiopatogenia hemoragiilor digestive superioare la cirotici i factorii de risc ai hemoragiei varicealeObiectiveMaterial i metodGrupul studiatRezultate
Studiul 2. Evoluia i complicaiile hemoragiilor variceale la ciroticiObiectiveMaterial i metodGrupul studiatRezultate
Analiza mortalitii prin hemoragie variceal Factori de predicie ai supravieuirii dup hemoragiile variceale Concluzii generaleRezumat EN Anca Romcea Teza de doctorat (v.2014.10.14).pdfCoverContentsKeywords:IntroductionHypothesis/ ObjectivesStudy 1. The etiopathogenesis of upper gastrointestinal bleeding in cirrhotic patients and the variceal bleeding risk factorsObjectivesMaterials and methodsThe study groupResults
Study 2. Evolution and complications of variceal bleeding in cirrhosisObjectivesMaterials and methodsThe study groupResults
Analysis of variceal bleeding mortality Prediction factors of survival after variceal bleeding General conclusions