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

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

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


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.

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.


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.

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.


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

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


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

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


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

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


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.

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.


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.

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.

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


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.

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


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

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).


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

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


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

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.


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.

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.


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

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


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

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

anca romcea - teza de doctorat (rezumat ro-en 2 capete)

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