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UNIVERSITATEA DE MEDICIN I
FARMACIE IULIU HAIEGANU CLUJ-
NAPOCA
DAN GHEBAN
HEPATOPATII CRONICE LA
COPIL
- REZUMAT -
TEZA DE DOCTORAT
PENTRU OBINEREA TITLULUI TIIIFIC DE
DOCTOR N TIINE MEDICALE DOMENIUL
MEDICIN
CONDUCTOR TIINIFIC
PROFESOR DR. PETRE FLORESCU
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2!
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CUPRINS
P"#$%" I-" & B"'% $%(#%$)*%
1. Dezvoltarea embriologic a ficatului
2. Structura microscopic a ficatului
3. Variante structurale ale ficatului
4. Examenul imunohistochimic al ficatului normal i patologic
!. Examinarea stan"ar" a biopsiei hepatice
#. $egenerarea ficatului
P"#$%" II-" & C(+$#),-)) .%#/(+"0%
1. S$-2)-0 *#%$%#)) +(#3"0% " 4)*"$-0-)
1.1. %ntro"ucere
1.2. &naliza proliferrii hepatocitare normale la copil
prin meto"a citometriei 'n flux
1.3. &naliza proliferrii hepatocitare normale la copil
cu a(utorul regiunilor organizatoare nucleolare
1.4. &naliza proliferrii hepatocitare normale la copil
)u a(utorul mar*erului imunohistochimic +i,#-
1.!. &naliza apoptozei "in ficatul normal "e copil cu
a(utorul tehnicii "e hibri"izare in situ ./01E23
1.#. )orelaii 'ntre stu"iile efectuate pe ficat normal "e copil
2. H%."$)$" 5)#"06 *#(+)*6 0" *(.)0 7+ 3"$%#)"0-0 ,)(.$)* "0 S.)$"0-0-) C0)+)* 2% U#8%+96
.%+$#- C(.)) C0-:; .% .%#)("2" 1!!<-2=
2.1. 4remize teoretice
2.2. 5aterial i 5eto"
2.3. $ezultate i Discuii
2.4. )oncluzii
>. P"#$)*-0"#)$6)0% *)#('%) ?%."$)*% 0" *(.)0
3.1. 4remize teoretice
3.2. 5aterial i 5eto"
3.3. $ezultate i Discuii
3.4. )oncluzii
<. A.0)*"#%" $%?+)*)0(# 3(2%#+% 2% 3(#4(3%$#)% *(3.-$%#)'"$6 7+ /$-2)-0 *)#('%) 0" *(.)0
4.1. 5orfometria no"ulilor i septelor con(unctive
4.1.1. 4remize teoretice
4.1.2. 5eto"a
4.1.3. 5aterial
4.1.4. $ezultate i Discu6ii
4.2. 4oten6ialul reversibil al cirozei copilului 7 stu"iu morfometric
4.2.1. 4remize teoretice
4.2.2. Scopul
4.2.3. 5aterial i 5eto"
4.2.4. $ezultate i Discu6ii
4.3. )oncluzii
@. CONCLUZII GENERALE
C-5)+$% *?%)%A creterea ficatului, hepatite cronice, ciroze, pronostic, involuia cirozei,
copil
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1. STUDIUL CRETERII NORMALE A FICATULUI
Scopul acestei lucrri este "e a cerceta mecanismul prin care crete ficatul copilului pe
perioa"a copilriei i a"olescen6ei. 8n aceast perioa" ficatul crete "e la aproximativ 129:!
gr. la natere p;n la aproximativ 1!<< gr. la v;rsta "e 2< ani: "up care: greutatea hepatic
rm;ne aproximativ constant p;n la captul vie6ii. Din c;te cunoatem noi: un asemenea
stu"iu nu s,a fcut 'nc pentru nici un organ. 4entru atingerea acestui scop: am urmrit
proliferarea hepatocitar utiliz;n" mai multe tehnici: citometria 'n flux: tehnica &g1=$:
imunohistochimia pentru anticorpul +i,#- >5%?,1@ precum i stu"iul moar6ii hepatocitare
prin apoptoz utiliz;n" marcarea celulelor apoptotice "up principiul tehnicii /01E2.
Detaliez 'n continuare strict stu"iul ce a comparat proliferarea hepatocitar utiliz;n" in"exul
"e proliferare +i,#- i apoptoza hepatocitar utiliz;n" in"exul apoptotic &pop/ag.
M"$%#)"0 B) M%$(26
4entru atingerea scopului men6ionat: am luat 'n stu"iu un numr "e 31 "e fragmente
hepatice normale: fixate i incluse 'n parafin: provenite "e la copii cu v;rsta cuprins 'ntre <
i 21 "e ani >"in materialul Serviciului "e &natomie 4atologic a ).A.0 $ouen , Bran6a@.
/oate aceste fragmente au fost examinate 'n colora6ie A.E. pentru precizarea "iagnosticului
"e normalitate histologic. 0lterior toate aceste fragmente au fost marcate cu anticorpul +i,
#-: clona 5%?,1 >pentru sec6iuni la parafin@: conform in"ica6iilor men6ionate 'n prospectul
pro"usului livrat "e firma D&+=. 0n numr "e 12 fragmente hepatice "in cele 31 luate 'n
stu"iu au fost marcate i cu *itul &pop/agC livrat "e firma =ncor %nc.
D
: conform meto"ei
"escrise 'n prospectul pro"usului. $ezultatele au fost ob6inute apreciin" numrul "e celule
marcate E 1<<< "e celule pentru fiecare "in cele 3 zone ale lobului hepatic: 'n final
calcul;n"u,se me"ia procentual a celulelor marcate E lobul la fiecare caz 'n parte.
R%'-0$"$%A
$ezultatele ob6inute 'n urma aplicrii meto"ologiei prezentate au fost grupate 'n #
grupe: 'n func6ie "e v;rst i "e caracteristicile ritmului "e cretere ale perioa"ei "e v;rst
men6ionate. >tabelul nr. 1@
Tabelul nr. 1:
V"0("#%" )+2%C-0-) 2% .#(0)4%#"#% B) " )+2%C-0-) ".(.$($)* 7+ 4-+*9)% 2% 5D#/$6A
G#-." 2% 5D#/$6 E#)$3 2% *#%B$%#%
" 8#%-$69)) *(#.(#"0%F
I+2%C 2% .#(0)4%#"#% EG)-HIF I+2%C ".(.$($)* EA.(.T"8JF
<,1 an >!<< gr.Elun@ <:2F <:<4
1,3 ani >12! gr.Elun@ <:23 ,
3,1< ani >2<< gr.Elun@ <:1 <:<1
1<,1# ani >3!< gr.Elun@
>perioa"a pubertar@
1
<:!3 <:<F
1#,2< ani >2!< gr.Elun@ <:21 <:13
> 20 ani E"2-0$F <:2#
2
<:2
$ezultatele prezentate 'n tabelul nr. 1 sunt reprezentate grafic 'n figura nr. 1
1
a fost ales acest interval pentru a compensa "iferen6ele legate "e sex: inerente acestei perioa"e
2
literatura men6ioneaz un in"ex "e proliferare me"iu pentru a"ul6i "e <:22 G 1 >4@
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0 . 6
0 . 5
0 . 4
0 . 3
%n"ex "e proliferare
%n"ex apoptotic
%n"ex "e proliferare me"iu H <:2#
0 . 2
0 . 1
0
0 5 1 0 1 5 2 0 2 5
ani
F)8.1A Varia6ia in"exului "e proliferare i a in"exului apoptotic 'n func6ie "e v;rst
D)/*-9))A
Valoarea me"ie a in"exului "e proliferare hepatocitar ob6inut pentru perioa"a <,2< ani
><:2#@ este foarte apropiat "e cea raportat 'n literatur pentru v;rsta "e a"ult > <:22 G 1@>4@:
astfel 'nc;t se poate aprecia c valoarea in"exului "e proliferare a hepatocitelor este
aproximativ constant "e,a lungul vie6ii. Varia6iile fa6 "e me"ie ale in"exului "e proliferare
hepatocitar sunt legate "e perioa"a prepuberatar i pubertar: fiin" "irect corelabile cu ritmul
general "e cretere a organismului 'n aceste perioa"e precum i cu profilul secretor al
hormonului "e cretere >IA@ i a %IB,1: 'n func6ie "e v;rst.
&naliza reparti6iei intralobulare a marca(ului cu +i,#-: arat o pre"ominen6 a
activit6ii proliferative 'n zona %,a >periportal@ i zona a %%,a >interme"iar@: "istribu6ie care
"e altfel a mai fost sesizat 'n literatur.
Deoarece valoarea me"ie a in"icelui "e proliferare hepatocitar are aproximativ
aceeai valoare pe perioa"a copilriei ca i ulterior 'n perioa"a a"ult: suntem nevoi6i "e a
consi"era c creterea hepatic "in perioa"a copilriei: nu se "atoreaz unui in"ex "e
proliferare superior ci unui in"ex apoptotic "e aproximativ 1< ori mai sczut pe perioa"a
copilriei spre "eosebire "e perioa"a a"ult. >figura 1@. 1ivelul aproximativ constant al
in"exului "e proliferare hepatocitar "in perioa"a copilriei i perioa"a a"ult: ob6inut cu
a(utorul anticorpului +i,#- >5%?,1@: a fost confirmat i "e un stu"iu efectuat cu a(utorul
citometriei 'n flux >"ate personale nepublicate@ precum i "e un stu"iu efectuat cu a(utorul
meto"ei &g1=$.
&ctualul stu"iu a mai putut observa faptul c activitatea proliferativ hepatic nu este
un fenomen "ifuz 'n masa hepatic ci este un fenomen focal ce intereseaz "oar anumi6i
lobuli 'n timp ce restul lobulilor >ma(oritatea@ nu prezint o activitate proliferativ
semnificativ. &cest fenomen "e focalitate al activit6ii proliferative este concor"ant cu
no6iunile nou intro"use "e lobul simplu i lobul complex: precum i cu no6iunile "e
heterogenitate local: zonal i regional a ficatului.
&ctivitatea apoptotic care este foarte slab 'n perioa"a copilriei are i ea ten"in6a "e
a "e "istribu6ie focal "ar mai pu6in evi"ent. De asemenea aceasta are ten"in6a "e a se
aglomera 'n zona a %%%,a >centrolobular@: fapt "e altfel sesizat "e(a 'n literatur.
2. HEPATITA VIRAL CRONIC LA COPIL & N MATERIALUL BIOPTIC AL
SPITALULUI CLINIC DE URGEN PENTRU COPII CLUJ
PE PERIOADA 1!!< & 2=
M"$%#)"0 B) M%$(26
&m extras "in baza "e "ate ce con6ine toate rezultatele bioptice elaborate "e 2aborator
"in <1.<1.1994 p;n 'n prezent o nou baz "e "ate: selectiv: con6in;n" "oar cazurile "e
hepatit cronic a copilului >viral i neviral@. &ceast nou baz "e "ate a fost construit "e
asemenea manier 'nc;t s permit stabilirea "e corela6ii clinico,etiologico,patologice care
vor fi prezentate 'n continuare ca rezultate ale acestei lucrri. &ceast baz "e "ate este *%"
3") 3"#% 2% "*%/$ 8%+ "2-+"$6 .D+6 0" (#" "*$-"06 7+ R(3D+)" i permite o semnificativ
privire general a hepatitelor virale la copii "in zon.
R%'-0$"$% B) D)/*-9))
8n perioa"a <1.<1.1994 7 <1.<1.2<<9: 'n 2aboratorul "e &natomie 4atologic a Spitalului
)linic "e )opii "in )lu(,1apoca: "up exclu"erea biopsiilor albe au fost trimise un numr "e
H>2 "e biopsiiEpunc6ii biopsii hepatice.
F)8.2A 4revalen6a "iverselor entit6i patologice 'nt;lnite 'n cele #32 "e 4?AE?A
examinate 'n perioa"a 1994,2<<F.
C
S Medicamentoasa
2%
4%
VHC
3%
H.Criptogen
a
3%
VHB+VHC
13%
VHB
!%
F)8.>. Etiologia celor 43< "e hepatite cronice 'nregistrate
&m analizat separat cazurile care vaccinate fiin" "up 199#: au fost totui "epistate ca
av;n" hepatit cronic cu VA?.
1I *"'-#)
Ira" me"iu H 1:F ><,4@
11.-J gra" 4 >fa6 "e 2J 'n general@
Sta"iu me"iu H 2:29 >1,3@
< ciroze >maxim 12 ani "e evolu6ie@
0 0 0 0
0
ll,ll
6,66
4,54
5,4
l7,l4
7,69
0
40
20
%
l0
l994 l995 l996 l997 l998 l999 2000 200l 2002 2003 2004 2005 2006 2007 2008
F)8. <A Aepatita cronic cu VA? la vaccina6i
Existen6a acestor cazuri arat c vaccinarea nu a avut o eficien6 "e 1<<J. Dei 'n
genere aceste cazuri au prezentat 'n principiu o gravitate similar cu a cazurilor nevaccinate:
se poate totui remarca c gra"ul necroinflamator maxim a fost mult mai "es 'nt;lnit la aceste
cazuri: sensibilizarea sistemului imun 'n urma vaccinrii av;n" acest efect: "ar totui nici un
caz "in acest lot: 'nc restr;ns: nu a fost "epistat 'n sta"iul "e ciroz.
>. PARTICULARITILE CIROZELOR HEPATICE LA COPIL
S$-2)- .% 3"$%#)"0-0 "-$(./)* B) ,)(.$)* "0 S.)$"0-0-) C0)+)* 2% U#8%+96 .%+$#- C(.))
C0-:
M"$%#)"0 B) 3%$(26
&cest stu"iu a fost bazat pe analiza a 2 loturi "e cazuriK
L($-0 1A 2- "e cazuri "e copii "ece"a6i cu cizoz i autopsia6i
L($-0 2A 13# "e cazuri "e copii cu ciroz: biopsia6i
R%'-0$"$% B) D)/*-9))
Statistic general
L($-0 1
)ele 2- "e cazuri autopsiate i "iagnosticate cu ciroz 'n 2aboratorul "e &natomie
patologic al Spitalului )linic "e 0rgen6 pentru )opii )lu(: pe perioa"a 19-4 7 2<<F: fac
parte "in cele 3F!< "e autopsii efectuate 'n aceast perioa". )u alte cuvinte: "ecesul prin
ciroz la copil: este un eveniment rar E;I1K; a"ic: 'n me"ie ;= *)#('% 2%*%2"$%L"+F.
L($-0 2
)ele 13F "e biopsii hepatice "iagnosticate cu ciroz: provin "e la copii cu v;rsta
cuprins 'ntre 1 lun i 1- ani >medie 8,55 ani, mediana de 10,48 ani: "eriva6ie stan"ar" "e
1<:<-@.
Etiologia cirozelor
L($-0 1
Etiologia cirozelor 'nt;lnite 'n cazuistica noastr la copii "ece"a6i a fostK
1. )iroz postnecroticEpostinfec6ioasEtoxic 7 11 cazuri >4<J@
2. )iroza biliar 7 11 cazuri >4<J@
3. )iroza metabolic 7 ! cazuri >2<J@
4. )iroza vascular 7 < cazuri
!. )iroza criptogenic 7 < cazuri
L($-0 2A
Etiologia cirozelor 'nt;lnite 'n cazuistica noastr pe 4?A a fostK
1. )iroz postnecroticEpostinfec6ioasEtoxic 7 1<< cazuri >-!J@
2. )iroza biliar 7 1# cazuri >12J@
3. )iroza metabolic 7 - cazuri >!J@
4. )iroza vascular 7 < cazuri
!. )iroza criptogenic 7 11 cazuri >FJ@
<. APLICAREA TEHNICILOR MODERNE DE MORFOMETRIE
COMPUTERIZAT N STUDIUL CIROZEI LA COPIL
<.1. MORFOMETRIA NODULILOR I SEPTELOR CONJUNCTIVE
<.1.>. M"$%#)"0
2ot "e 1< "e biopsii hepatice >nu 4?A pentru a avea suprafa6 mare "e examinare@ sau
fragmente hepatice autopsice: "e cazuri cu ciroz hepatic. ! biopsii hepatice cu ciroz:
provenite "in Spitalul )linic "e )opii )lu(: provin "e la cazuri aflate 'n stare clinic
compensat. &lte ! fragmente hepatice au fost ob6inute "e la autopsii 'n care cauza "ecesului
a fost ciroza i complica6iile ei: provenite "in Spitalul )linic Lu"e6ean sau 5unicipal "e
&"ul6i >ciroze avansate "ecompensate letal@.
<.1.<. R%'-0$"$% B) D)/*-9))
)onform ateptrilor: cazurile provenite "e la copii: s,au "ove"it 'n urma
msurtorilor micrometrice a fi 'nca"rabile 'n categoria cirozelor cu septe sub6iri i no"uli
mari.
)azurile a"ulte: "ece"ate cu ciroz s,au "ove"it a fi 'nca"rabile la cirozele cu septe
groase i no"uli mici: "ei i 'n acest caz: "imensiunile no"ulilor s,au "ove"it a fi extrem "e
variabile.
10 0,0 0%
9 0,0 0%
8 0,0 0%
7 0,0 0%
6 0,0 0%
5 0,0 0%
4 0,0 0%
3 0,0 0%
2 0,0 0%
1 0,0 0%
0,0 0%
Copii Adul ti
1
4, 88% 16 ,9 6%
2
6, 63% 20 ,5 7%
3 10 ,82 % 20 ,6 1%
4
13 ,27 % 29 ,5 7%
5
15 ,29 % 62 ,1 3%
F)8.@A Spectru procentului "e fibroz la cele 2 loturi stu"iate
<.2. POTENIALUL REVERSIBIL AL CIROZEI COPILULUI & STUDIU
MORFOMETRIC
S*(.-0
1. &naliza "iferen6iat a colagenului matur i imatur este aplicat pentru stabilirea
v;rstei unui 6esut con(unctiv fibrilar: cu c;t acesta este mai bogat 'n colagen matur el
este mai 'n v;rst i mai rezistent: "ar i mai greu "e resorbit 'n timp ce un 6esut
con(unctiv t;nr: bogat 'n colagen imatur este mai elastic: mai pu6in rigi" i rezistent
"ar i mai susceptibil "e a fi resorbit "e organism.
2. Demonstrarea printr,o tehnic cantitativ: "e analiz "e imagine: a faptului c o ciroz
poate fi caracterizat nu "oar cantitativ >procent 6esut con(unctiv@ ci i ca
vechimeEpoten6ial "e reversibilite: prin banale tehnici histochimice.
M"$%#)"0 B) M%$(26
4entru atingerea scopului propus am efectuat preparate histologice "in ?A cu ciroz
la a"ult >presupus bogat 'n 6esut con(unctiv matur@ i ?A cu ciroz "e la copii >presupus bogat
'n colagen imatur@. 4relucrarea acestor piese a fost una stan"ar" >fixare: inclu"ere 'n parafin:
sec6ionare: colorare: montare@ tehnicile "e colora6ie histochimic fiin" prezentate 'n stu"iul
prece"ent.
L($-0 2% /$-2)-
& fost acelai "in stu"iul anterior "eoarece pentru fiecare caz 'n parte era "e(a
cunoscut: "in stu"iul anterior: 'nca"rarea 'n clasificarea Male a severit6ii histologice a cirozei.
R%'-0$"$% B) D)/*-9))
prim o!servaie: este faptul c 0" "2-0$ at;t septele groase >prepon"erente@ c;t i
cele sub6iri sunt bogate 'n colagen matur 'n timp ce 0" *(.)0 cele "ou tipuri "e colagen
coexist 'n propor6ii apropiate.
a doua o!servaie este faptul c 'n interiorul no"ulilor hepatocitari cirotici:
colagenul "epus 'n ca"rul aa numitei .capilarizri3 a sinusoi"elor este rezorbabil pentru
cazurile infantile aflate 'n faz clinic compensat >incipient@ i nerezorbabil pentru cazurile
a"ulte aflate 'n sta"iu avansat clinic.
CONCLUZII GENERALE
1. Bicatul "e copil este un organ 'n cretere. El crete "atorit unei apoptoze fiziologice
re"use i nu "atorit unei proliferri celulare mai accentuate: acest aspect fc;n"u,l
"iferit "e ficatul "e a"ult 'n reac6ia sa fa6 "e agresiuni etiologice "iverse.
2. %maturitatea imun specific copilului favorizeaz cronicizarea infec6iilor cu virus
hepatitic ? i ): "ar maturizarea imun postpubertar poate "uce la oprirea spontan
"in evolu6ie >'n orice sta"iu fibrotic@ a hepatitelor cronice: inclusiv 'n faz "e ciroz.
3. Vaccinarea anti,hepatitic ? obligatorie a nou,nscu6ilor: intro"us "up 199# a "us la
re"ucerea treptat a prevalen6ei hepatitei cronice cu VA? la copil.
4. Dei prevalen6a infec6iei cronice cu VA) la copil nu a crescut cantitativ semnificativ:
prin "ispari6ia treptat a cazurilor infectate cronic cu VA? s,a a(uns la situa6ia
aparentei prepon"eren6e a infec6iei cu VA) 'n popula6ia infantil local: cel pu6in pe
materialul bioptic stu"iat "e noi.
!. Evolu6ia p;n la sta"iul "e ciroz a hepatitelor cronice este posibil i la copil >'n
special la bie6i@ "ar ciroza "evine arareori "ecompensat clinic i cauz "e moarte la
aceast categorie "e pacien6i.
#. Din cauza creterii hepatice >mai ales 'n puseul "e cretere pubertar@: fibroza
acumulat prin evolu6ia inflama6iei cronice are ten"in6a "e a se ."ilua3 treptat fapt ce
permite "ispari6ia cirozei eventual "e(a instalate 'n mica copilrie: o"at cu creterea
i oprirea spontan "in evolu6ie a cirozei prin maturizarea sistemului imun
postpubertar >cel pu6in la o parte "in pacien6i@.
-. 8n plus: 6esutul con(unctiv "in structura cirozei infantile este imatur fapt ce
favorizeaz resorb6ia acestuia 'n timp >'n mo" special a colagenului "ispus 'n spa6iul
Disse@ i implicit 'mbuntirea capacit6ii func6ionale a ficatului cirotic o"at cu
creterea copilului.
C"##$C"%"M
V$&'(
)*me+ GHEBAN
,ren*me+ Dan
-ata . i /oc*/ na.terii+ 25.l0.l962, Romania
St*dii+
, Liceul de tiin|e ale Naturii, Cluj-Napoca l98l
, lMF Cluj-Napoca, Facultatea de MG, Sec|ia Pediatrie l988
& it/*ri academice+
2008- ef de Lucrri, Catedra de Anatomie Patologic, UMF Cluj-Napoca
l994-2008 Asistent, Catedra de Anatomie Patologic, UMF Cluj-Napoca
l99l-l994 Preparator Catedra de Anatomie Patologic, UMF Cluj-Napoca
(0perien1 a pro2esiona/3+
, l999 Medic primar anatomopatolog
, 1997-1998 AFSA, CHU Rouen, Franta
, l994 Specialist anatomopatolog
, l988 Medic
C3s3torit4 1 53iat de 16 ani
'rtico/e origina/e p*5/icate in 7*rna/e $S$ 8 30+
l. )orma/ 9epatic gro:t9+ St*d; o2 t9e ,ro/i2erati<e Capacit; and
'poptosis o2 t9e )orma/ %i<er d*ring C9i/d9ood; D .G h e b a n ; Pediatric
and Developmental Pathology vol.3 pag. 70-72, ianuarie-februarie 2000
'rtico/e origina/e p*5/icate in 7*rna/e n a1i on a/ e non=$S$
, !! artico/e p*5/icate >n 1ar34 din care 1 ca prim a*tor. 13 dintre acestea
pe s*5iect /egat de pato/ogia 9epatic3
l. Gheban Dan: St*di*/ capacit31ii pro/i2erati<e a 2icat*/*i /a copi/4 >n
condi1ii norma/e .i pato/ogice c* a7*tor*/ metodei 'g)?#, Jurnalul
Romn de Patologie, vol.l nr.l, pag.6l-63, l997
2. Gheban Dan: )orma/ Hepatic @ro:t9+ St*d; o2 t9e ,ro/i2erati<e
Capacit; and 'poptosis in t9e )orma/ %i<er d*ring C9i/d9ood,
Pediatric and Developmental Pa- thology, vol.3, pag. 70-72, 2000
3. Gheban Dan: Adobe Photoshop ca program de analiz de imagine n
anatomie patologic, Jurnalul Roman de Patologie, vol.8 nr.l/2, 2005
4. Gheban Dan: Capi/ar*/ sin*soid 9epatic .i ce/*/e/e asociate /*i, Jurnalul
Romn de
Patologie, nr.l (vol.l) l997 pag.32-40
5. Gheban Dan: Moartea ce/*/e/or 9epatice, Jurnalul Romn de Patologie, nr.2
(vol.l) l997, pag. 25-29
6. Gheban Dan: Ai5rogeneBa 9epatic3, Jurnalul Romn de Patologie, nr. 3 (vol.l)
l997,
pag.34-43
7. Gheban Dan: Hepatite/e cronice. 'specte te9nice >n e0aminarea ,BH .i
BH, Jurnalul
Romn de Patologie, nr. 3 (vol.l) l997, pag.90-93
8. Gheban Dan: 'p/icarea te9nici/or de 9i5ridiBare >n pato/ogie, Jurnalul
Romn de
Patologie, nr. 2 (vol.2) august l998, pag.l4l-l50
9. Gheban Dan: Matricea e0trace/*/ar3 9epatic3, Jurnalul Romn de Patologie, nr.
3/4
(vol.2) noiembrie l998, pag.264-27l
l0. Gheban Dan: Micro<asc*/ariBa1ia 2icat*/*i, Jurnalul Romn de Patologie, nr. 3/4
(vol.4)
decembrie 2000, pag.264-27l
ll. Gheban Dan: CiroBa. #e<ersi5i/3C, Jurnalul Romn de Patologie, nr. 3/4 (vol.4)
decembrie
2000
l2. Gheban Dan, Florescu Petre: #egenerarea 9epatic3 /a r3spDntie de concep1ii ,
Jurnalul
Romn de Patologie, nr. 3/4 (vol.6) 2002, pag. 3l7-324
l3. Gheban Dan: Hepatite/e <ira/e cronice a/e copi/*/*i , Pediatru.ro, anul lll,
nr.7/2007, pag.6-
l4
11 /*cr3ri preBentate >n Congrese $nterna1iona/e .i 34 de /*cr3ri preBentate >n
Congrese sa*
Mese #ot*nde )a1iona/e
%ista deta/iata a /*cr3ri/or de dip/om3 2ina/iBate >ndr*mate
l. Marcu Gabriel: "Studiul capacit|ii proliferative a ficatului de copil n condi|ii
normale i patologice, cu ajutorul metodei AgNOR" l996
2. Cmpian Simina: "Hepatitele cronice ale copilului" l998
3. loana erban: "Tumorile benigne ale glandelor salivare" l999
4. Sandu lleana: "Biopsia renala n materialul Laboratorului de Anatomie Patologic
a
Spitalului Clinic de Copii, Cluj" l999
5. Mihaela Leordean: "Diverticolulul Meckel" l999
6. Carceie Simona Alina: "Patologie osoas netumoral a copilului" 2000
7. Fechete Anamaria: "Patologia osoas tumoral a copilului" 2000
8. Bunda Radu-Cristian: "Biopsia gastric i duodenal la copil" 2002
9. lulia Balbach Tuleu: "Nefropatia asociat VHB" 2004
l0. Teodora Paul: "Analiza morfometric a fibrozei hepatice" 2005
ll. Cmpean Teodora Anca: "Ciroza hepatic a copilului n materialul autopsic" 2005
l2. Tudor Bucur: "Ciroza hepatic a copilului n materialul bioptic" 2005
l3. Neam| Ana-Maria: "Pattern-ul imunohistocolora|iei antigenelor VHB n hepatita
cronic a adultului" 2007
l4. Naumenco Adina: "Caracterizarea fibrozei hepatice din ciroz" 2007
l5. C| lrina: Cuantificarea cantitativ a colagenului tnr i vechi cu ajutorul
programului
Adobe Photoshop, 2006
l6. lulia Duminic: Corela|ii morfo-func|ionale ale activit|ii Kupfferiene hepatice, 2008
l7. Filip Ramona: Tumora cu celulele gigante a osului, 2008
l8. V iorica Sireteanu, Studii experimentale de inginerie tisular: Histopatologia
osteogenezei
induse, 2009
%im5i str3ine c*nosc*te+ engleza, franceza
UNIVERSITM OF MEDICINE AND PHARMACM
IULIU HAIEGANU CLUJ-NAPOCA
DAN GHEBAN
CHRONIC HEPATOPATHIES IN
CHILDREN
- RESUME -
DOCTORATE THESIS
FOR ATTAINING THE SCIENTIFIC TITLE
OF DOCTOR IN MEDICAL SCIENCE
MEDICAL SPECIALTM
S*)%+$)4)* *((#2)+"$(#A
PROFESSOR DR. PETRE FLORESCU
2!
CONTENTS
P"#$ 1 & T?%(#%$)*"0 /$#-*$-#%
-. Embrionic groNth of the liver
F. /he microscopic structure of the liver
9. Structural variants of the liver
1<. %munohistochemical exam of the normal an" pathological liver
11. Stan"ar" examination of the hepatic biopsO
12. 2iver regeneration
P"#$ 2 & P%#/(+"0 *(+$#),-$)(+/
1. S$-2N (4 +(#3"0 0)5%# 8#(O$?
1.1. %ntro"uction
1.2. &nalOsis of normal chil" hepatocite proliferation
through flux citometrO metho"
1.3. &nalOsis of normal chil" hepatocite proliferation
Nith the help of nuclear organiser regions
1.4. &nalOsis of normal chil" hepatocite proliferation
Nith the help of the immunohistochemistrO +i,#- mar*er
1.!. &nalOsis of normal chil"ren liver apoptosis Nith
in situ ./011E2PP hibri"isation techniQue.
1.#. )onnections betNeen stu"ies ma"e on normal chil" livers.
2. C?#(+)* 5)#"0 *?)02 ?%."$)$)/ )+ $?% ,)(.$)* 3"$%#)"0 "$ $?% C?)02#%+P/ E3%#8%+*N
H(/.)$"0 C0-:; 2-#)+8 1!!<-2=
2.1. /heoretical premises
2.2. 5etho" an" materials
2.3. $esults an" "iscussions
2.4. )onclusions
>. P"#$)*-0"#)$)%/ (4 *?)02 ?%."$)* *)##?(/)/
3.1. /heoretical premises
3.2. 5etho" an" materials
3.3. $esults an" "iscussions
3.4. )onclusions
<. A..0)"+*% (4 3(2%#+ *(3.-$%#)'%2 3(#.?(3%$#N $%*?+)Q-% )+ $?%
*(3.-$%#)'%2 /$-2N (4 *?)02 *)##?(/)/
4.1. 5orphometrO of con(unctive no"ules an" septas
4.1.1. /heoretical premises
4.1.2. 5etho"
4.1.3. 5aterial
4.1.4. $esults an" "iscussions
4.2. 4otential of reversing chil" cirrhosis 7 morphometric stu"O
4.2.1. /heoretical premises
4.2.2. =b(ective
4.2.3. 5etho" an" materials
4.2.4. $esults an" "iscussions
4.3. )onclusions
@. GENERAL CONCLUSIONS
2. STUDM OF NORMAL LIVER GRORTH
The aim of this study consist of researching the mechanism that leads to the child's
liver growing through the adolescence. ln this period the liver grows from
approximately
l29.5 gr. at birth to approximately l.500 gr. at 20 years of age; after that the hepatic
weight rests approximately at a constant value till the end of life. We kept track of the
hepatocyte proliferation by using Ki-67 antibody (MlB-l) as well as hepatocyte death
caused by apoptosis, by marking the apoptotic cells, according to the principle of
TUNEL techniques.
Materia/ and Met9od+ We studied 3l normal liver fragments from children aged 0 to
2l years (from the material of the Pathology Department of C.H.U. Rouen - France),
formalin fixed and paraffin processed conventionally. All these fragments were
examined with hematoxilin and eosin staining to confirm the diagnosis of
histologic normality. Sections were then marked with Ki-67 antibody, MlB-l clona
(for paraffined sections), in conformity with the directions written in the booklet of the
product by DAKO. 2l liver fragments out of
3l included in the study were also marked with ApopTag' Kit, by Oncor

lnc.,
according to
the method written in the product booklet. The results were obtained assessing the
number of the marked cells / l,000 cells for each of the 3 zones of the
hepatic lobule, finally calculating the percentage average in the marked cells /
lobule for each separate case.
#es*/ts+ The results obtained after performing the presented methodology
were divided into 6 groups as a function of age and features of growth rate for the
period of mentioned age. (Table l)
&a5/e 1+ Value of the proliferation and apoptoic index as a function of age.
'ge
@ro*ps
E5od; :eig9t gro:t9
,ro/i2eration inde0
)o. EFi=G anti5od;H
'poptotic inde0
)o. E'poptag' FitH
,ro/i2erationI
apoptosis rate
0 - l
year
(500 gr. /
month)
l - 3
year
(l25 gr. /
month)
3 l0
years
(200 gr. /
month)
0.28 l9
0.23 3
0.l l
0.53 5
0.2l 2
0.26
4
l
0.04
6
-
-
0.0l
l
0.08
2
7
-
l0
6.6
l.6
l.3
The proliferation/apoptosis ratio as function of age is graphically represented in Fig.
l. Supplementary we have the occasion to observe a predominance of the Ki-67
marking in the l
st
and 2
nd
zone and the predominance of apoptosis in the 3
rd
zone of
the hepatic lobule. An important observation is the fact that the proliferative and
apoptotic index are distributed mostly focal in the hepatic mass, these two
phenomena being localized, especially at the level of simple lobules predominantly
in a subcapsular position.
-isc*ssions+ The average value of the proliferation index in the liver obtained for 0-
20 years (0.26) is very close to that reported in literature for the adult age (0.22
l). (4) So
3
This interval has been chosen to compensate the differences related to sex
4
ln the literature(4) the average proliferation index for adults is 0.22 l
one can asses that the index value of hepatocytes proliferation is approximately
constant during life. The variation of the proliferative index towards the average
value are related to the pre- and puberty periods, connected directly with the general
growth rate of the body during these physiological periods as well as with the
secretion profile of the growing hormones (GH) and lGF-l, as a function of age.
The analysis of intralobular repartition of Ki-67 marking has shown a
predominance of the proliferation activity in the l
st
(periportal) and 2
nd
(intermediary)
zones, a distribution that has already been noticed in the literature.
Because the average value of the proliferation index in the liver has shown
approximately the same value through out childhood as well as in the adult period,
we conclude that hepatic growth during childhood is not due to a high proliferation
index but an approximately l0 times lower apoptoic index. Compared with the adult
apoptoic index (see figure l). The approximate constant level of the hepatocyte
proliferation index during childhood and adult period obtained with Ki-67 antibody
(MlB-l), was also confirmed by a study carried out by flow citometry (published
personal data) as well as by a study utilizing the AgNOR method.
12
10
8
6
4
2
0
0 5 10 15 20 25
years
Fig.l: Proliferation / apoptotic ratio as function of age
The present study also found that hepatic proliferation activity is not a diffuse
phenomena, but a focal phenomena, which is found only in certain lobules, while the
rest of lobules (most of them) do not show significant activity of proliferation. This
phenomenon of focal proliferation supports the recently introduced concept of
simple and complex lobule, as well as the concept of local, zonal and regional
heterogeneity of the liver anatomy.
The apoptotic activity which is very low during childhood, also has the trend
to show a focal distribution, but less evidently. Also this activity tends to
agglomerate in the 3
rd
(centrolobular) zone, a fact that has already been documented
in literature.
ln conclusion, this study reveals the fact that the liver growing in children
is not linked to a high proliferation index but to a very low apoptotic index, compared
with that in adults. The proliferation and apoptotic activity are mostly focal
phenomena in the hepatic mass. Within the hepatic lobule the proliferation activity
has the trend to place it self to the peripheral zone (l
st
zone) and the apoptotic
activity to the central zone (3
rd
zone) of lobule.
2. CHRONIC VIRAL HEPATITIS AT CHILDREN & IN THE BIOPTIC MATERIAL
OF THE CHILDRENPS EMERGENCM HOSPITAL CLUJ BETREEN 1!!<-2=
M%$?(2 "+2 M"$%#)"0
%Pve extracte" from the "atabase that contains all the bioptic results ma"e from the
2aboratorO from <1.<1.1994 until present: a neN "atabase: selective: containing onlO the
cases of chronic hepatitis in chil"ren >viral an" non,viral@. /his neN "atabase Nas built in
such manner that it alloNs the establishment of clinical,ethological,pathological connections
to be ma"e an" presente" afterNar"s as results of these operations. /his "atabase is $?%
0"#8%/$ (4 $?% S)+2 -+$)0 +(O $( ,% 8"$?%#%2 )+ R(3"+)" an" it alloNs a significant general
aspect of the viral chil"ren hepatitis in the area.
R%/-0$/ "+2 D)/*-//)(+/
During the perio" of <1.<1.1994 7 <1.<1.2<<9: in the 2aboratorO of 4athologic &natomO
of the )hil"renPs Aospital in )lu( 1apoca: after exclu"ing the Nhite biopsies: there Nas a
number of H>2 hepatic biopsies sent.
F)8.2A 4revalence of "iverse pathologic entities in the #32 cases of 4?AE?A examine"
"uring 1994,2<<F.
C
S Medicamentoasa
2%
4%
VHC
3%
H.Criptogen
a
3%
VHB+VHC
13%
VHB
!%
F)8.>. EtiologO of the 43< cases of chronic hepatitis registere"
%Pve separatelO analOze" the cases vaccinate" after 199#: theO Nere trace" to have ha"
VA? chronic hepatitis.
1I *"/%/
&verage Ira"e H 1:F ><,4@
11.-J gra"e 4 >unli*e 2J in general@
&verage Stage H 2:29 >1,3@
< cases of cirrhosis >maximum 12 Oears of evolution@
0 0 0 0
0
ll,ll
6,66
4,54
5,4
l7,l4
7,69
0
40
20
%
l0
l994 l995 l996 l997 l998 l999 2000 200l 2002 2003 2004 2005 2006 2007 2008
F)8. <A VA? )hronic hepatitis in vaccinate" patients
/he existence of these cases shoNs that the vaccination Nas not 1<<J efficient. &l,
though in general these cases presente" a similar gravitO Nith the non,vaccinate" cases: it can
be sai" hoNever that maximum necro,inflamatorO percentage Nas allot more often "etecte"
in these cases: sensibilising the immune sOstem after vaccination having this effect: but in no
case from this stu"O set: still restraine": NasnPt trace" in cirrhotic state.
>. CHILDREN HEPATIC CIROSIS PARTICULARITIES
S$-2N (+ $?% "-$(./)* "+2 ,)(.$)* 3"$%#)"0 (4 $?% E3%#8%+*N C?)02#%+ H(/.)$"0 C0-:.
M"$%#)"0 "+2 M%$?(2
/his stu"O Nas base" on the analOsis of 2 case setsK
S%$ 1A 2- cases of "ecease" chil"ren Nith cirrhosis an" autopsie"
S%$ 2A 13# cases of cirrhotic chil"ren: biopsie"
R%/-0$/ "+2 D)/*-//)(+/
"eneral Statistic
S%$ 1
/he 2- autopsie" an" "iagnose" cases of cirrhosis in the 2aboratorO of 4athologic
&natomO of the EmergencO )hil"ren Aospital )lu(: "uring 19-4,2<<F: are part of the 3F!<
autopsies ma"e in this perio". %n other Nor"s: cirrhotic "eath of a chil": is a rare happening
><.-1J: means: in average <.F cirrhosis cases "ecease" per Oear@.
S%$ 2
/he 13F cases of "iagnose" cirrhotic hepatic biopsies: come from chil"ren betNeen
the age of 1 month an" 1- Oears >in average F.!! Oears: me"ian of 1<.4F Oears: stan"ar"
"erivation of 1<.<-@.
#irrhotic etiolog$
S%$ 1
/he cirrhotic etiologO met in our cases of "ecease" chil"ren NasK
#. 4ost,necroticE4ost,infectiousE/oxic )irrhosis 7 11 cases >4<J@
-. ?iliarO )irrhosis 7 11 cases >4<J@
F. 5etabolic )irrhosis 7 ! cases >2<J@
9. Vascular )irrhosis 7 < cases
1<. )rOptogenic )irrhosis 7 < cases
S%$ 2A
/he cirrhotic etiologO met in our cases of 4?A NasK
#. 4ost,necroticE4ost,infectiousE/oxic )irrhosis 71<< cases >-!J@
-. ?iliarO )irrhosis 7 1# cases >12J@
F. 5etabolic )irrhosis 7 - cases >!J@
9. Vascular )irrhosis 7 < cases
1<. )rOptogenic )irrhosis 7 11 cases >FJ@
<. APPLIANCE OF MODERN TECHNITUES OF COMPUTERISED MORPHOME-
TRM IN THE STUDM OF CHILD CIROSIS
<.1. NODULE AND CONJUNCTIVE SEPT MORPHOMETRM
<.1.>. M"$%#)"0
& set of 1< hepatic biopsies >non 4?A to have a Ni"er examination surface@ or hepatic
autopsO fragments: of cases Nith hepatic cirrhosis. ! hepatic biopsO cases: coming from the
EmergencO )hil"ren Aospital )lu(: come from cases in compensate" clinical state. =ther !
hepatic fragments have been obtaine" from autopsies in Nhich the "eath cause Nas cirosis
an" itPs complications: coming from the )ountrO )linical Aospital or 5unicipal &"ult
Aospital >a"vance" cirrhosis lethallO "ecompensate"@.
<.1.<. R%/-0$/ "+2 D)/*-//)(+/
&ccor"ing to expectations: cases coming from chil"ren: prove" after the micrometric
counting to be peaceable in the thin septa an" big no"ule cirrhotic categorO.
&"ult cases: cirrhotic "ecease" prove" to be particular to the large septa an" small
no"ule cirrhosis tOpe: although in this case also: the sizes of the no"ules seeme" to be
extremelO variable.
10 0,0 0%
9 0,0 0%
8 0,0 0%
7 0,0 0%
6 0,0 0%
5 0,0 0%
4 0,0 0%
3 0,0 0%
2 0,0 0%
1 0,0 0%
0,0 0%
Copii Adul ti
1
4, 88% 16 ,9 6%
2
6, 63% 20 ,5 7%
3 10 ,82 % 20 ,6 1%
4
13 ,27 % 29 ,5 7%
5
15 ,29 % 62 ,1 3%
F)8.@A Bibrosis percentage spectrum in the 2 stu"ie" sets
<.2. CHILDREN CIROSIS REVERSIBLE POTENTIAL & MORPHOMETRIC
STUDM
O,:%*$)5%
3. Differential analOsis of the mature an" immature collagen is applie" to establishing
the age of a fibrillarO con(unctive tissue: the richer in collagen it is the ol"er an" more
resistant it is: but also har"er to be reabsorbe" Nhile a Ooung con(unctive tissue: rich
in immature collagen is more elastic: less rigi" an" resistant an" also more susceptible
to be reabsorbe" bO the organism.
4. Demonstration through Quantitative techniQue: of image analOsis: of the fact that a
cirosis can be "escribe" not onlO QuantitativelO >con(unctive tissue percentage@ but
also as age an" reversible potential: through simple histochemical techniQues.
M%$?(2 "+2 M"$%#)"0
Bor reaching the propose" ob(ective NePve ma"e histological preparations from ?A
Nith cirrhosis in a"ult >suppose" rich in mature con(unctive tissue@ an" ?A Nith chil"ren
cirosis >suppose" rich in immature collagen@. 5anufacturing these pieces Nas a stan"ar"
proce"ure >fixation: paraffin inclusion: sectioning: coloring: mounting@ the histochemical
coloration techniQues being presente" in the prece"ent stu"O.
S$-2N 0($
%t Nas the same as the stu"O before because in each case partlO it Nas *noNn the
inclusion of the Male classification of histological severitO of cirrhosis.
R%/-0$/ "+2 D)/*-//)(+/
ne first o!servation, is the fact that "$ "2-0$/: both the large septa >prepon"erant@
an" the thin ones are rich in mature collagen Nhile "$ *?)02 the tNo tOpes of collagen coexist
in close proportions.
%he second o!servation is the fact that insi"e the cirotic hepatocitarO no"ules: the
colagen "eposite" in the so calle" .capillarizations3 of the sinusoi"s is reabsorbable for the
infantile cases situate" in compensate" >starting@ clinical phase an" unabsorbable for the a"ult
cases situate" in the a"vance" clinical stage.
GENERAL CONCLUSIONS
F. & chil"Ps liver is a groNing organ. %t groNs because of a re"uce" phOsiological
apoptosis an" not because of a more intense cellular proliferation this aspect ma*ing it
"ifferent than the a"ult liver in itPs reaction toNar"s the "iverse etiological
aggressions.
9. %mmunitO immaturitO specific to the chil" favoritesP the chronic infections Nith
hepatitis virus ? an" ): but the postpubertarO immune maturation maO lea" to
spontaneous evolutionarO stop >in anO fibrotic stage@ of the chronic hepatitis:
inclu"ing the cirrhotic phase.
1<. &nti,hepatic ? vaccination: a must on neN born chil"ren: intro"uce" after 199# le" to
the stea"O "iscount of VA? chronic hepatitis prevalence in chil"ren.
11. &lthough the VA) chronic infection prevalence at chil"ren "i"nPt groN significantlO
in QuantitO: through the stea"O "isappearance of chronic infection cases of VA? it
reache" the point of apparent prepon"erant situation of VA) infection in the local
infantile population: at least on the bioptic material stu"ie" bO us.
12. Evolution until the state of cirrhosis of the chronic hepatitis is possible at chil" also
>especiallO at boOs@ but cirrhosis rarelO gets clinicallO "ecompensate" an" cases "eath
at this patient categorO.
13. ?ecause of hepatic groNth >especiallO in pubertarO groNth@: the accumulate" fibrosis
through chronic inflammatorO evolution has a ten"encO of ."iluting3 stea"ilO Nhich
in fact permits the "isappearance of cirrhosis: eventuallO alrea"O installe" in Ooung
chil"hoo": once Nith groNth an" spontaneous stop of evolution of cirrhosis through
the maturation of the postpubertarO immune sOstem >at least in part of the patients@.
14. %n a""ition: con(unctive tissue in the infantile cirrhotic structure is immature: fact that
favoritesP itPs resorption in time >especiallO of the collagen "eposite" in the Disse
space@ an" implicitlO the better functionalitO of the functional cirrhotic liver capacitO
once Nith chil" groNth.
C"##$C"%"M
V$&'(
Airst )ame+ Dan
)ame+ GHEBAN
-ate and 5irt9 p/ace+ 25.l0.l962, Romania
(d*cation 5acJgro*nd+
, Natural Sciences High School, Cluj-Napoca l98l
, lnstitute of Medicine and Pharmacology Cluj-Napoca l988
'cademic & it/es+
2008- Professor assistant, Pathology Department, UMF Cluj-Napoca
l994-2008 Assistant, Pathology Department, UMF Cluj-Napoca
l99l-l994 Research assistant, Pathology Department, UMF Cluj-Napoca
,ro2essiona/
e0perience+
, l999 Senior Pathologist
, 1997-1998 AFSA, CHU Rouen, France
, l994 - Junior Pathologist
, l988 - doctor
Married4 1 5o; 16 ;rs
o/d
$S$ 8 30 ,*5/is9ed artic/es+
2. )orma/ 9epatic gro:t9+ St*d; o2 t9e ,ro/i2erati<e Capacit; and
'poptosis o2 t9e )orma/ %i<er d*ring C9i/d9ood; D .G h e b a n ; Pediatric
and Developmental Pathology vol.3 pag. 70-72, ianuarie-februarie 2000
non=$S$ ,*5/is9ed artic/es+
, !! p*5/is9ed artic/es in #omanian Ko*rna/s4 2rom :9ic9 1 as 2irst
a*t9or4 13 5eing re/ated :it9 /i<er pat9o/og;
l4. Gheban Dan: St*di*/ capacit31ii pro/i2erati<e a 2icat*/*i /a copi/4 >n
condi1ii norma/e .i pato/ogice c* a7*tor*/ metodei 'g)?#, Jurnalul
Romn de Patologie, vol.l nr.l, pag.6l-63, l997
l5. Gheban Dan: )orma/ Hepatic @ro:t9+ St*d; o2 t9e ,ro/i2erati<e
Capacit; and 'poptosis in t9e )orma/ %i<er d*ring C9i/d9ood,
Pediatric and Developmental Pa- thology, vol.3, pag. 70-72, 2000
l6. Gheban Dan: Adobe Photoshop ca program de analiz de imagine n
anatomie patologic, Jurnalul Roman de Patologie, vol.8 nr.l/2, 2005
l7. Gheban Dan: Capi/ar*/ sin*soid 9epatic .i ce/*/e/e asociate /*i, Jurnalul
Romn de
Patologie, nr.l (vol.l) l997 pag.32-40
l8. Gheban Dan: Moartea ce/*/e/or 9epatice, Jurnalul Romn de Patologie, nr.2 (vol.l)
l997,
pag. 25-29
l9. Gheban Dan: Ai5rogeneBa 9epatic3, Jurnalul Romn de Patologie, nr. 3 (vol.l)
l997,
pag.34-43
20. Gheban Dan: Hepatite/e cronice. 'specte te9nice >n e0aminarea ,BH .i
BH, Jurnalul
Romn de Patologie, nr. 3 (vol.l) l997, pag.90-93
2l. Gheban Dan: 'p/icarea te9nici/or de 9i5ridiBare >n pato/ogie, Jurnalul
Romn de
Patologie, nr. 2 (vol.2) august l998, pag.l4l-l50
22. Gheban Dan: Matricea e0trace/*/ar3 9epatic3, Jurnalul Romn de Patologie, nr.
3/4
(vol.2) noiembrie l998, pag.264-27l
23. Gheban Dan: Micro<asc*/ariBa1ia 2icat*/*i, Jurnalul Romn de Patologie, nr. 3/4
(vol.4) de- cembrie 2000, pag.264-27l
24. Gheban Dan: CiroBa. #e<ersi5i/3C, Jurnalul Romn de Patologie, nr. 3/4 (vol.4)
decembrie
2000
25. Gheban Dan, Florescu Petre: #egenerarea 9epatic3 /a r3spDntie de concep1ii ,
Jurnalul
Romn de Patologie, nr. 3/4 (vol.6) 2002, pag. 3l7-324
26. Gheban Dan: Hepatite/e <ira/e cronice a/e copi/*/*i , Pediatru.ro, anul lll,
nr.7/2007, pag.6-
l4
11 papers presented in $nternationa/ Congresses and 34 papers in )ationa/
Congresses
&9e /ist :it9 coordinated /icense t9esis+
l9. Marcu Gabriel: "Studiul capacit|ii proliferative a ficatului de copil n condi|ii
normale i patologice, cu ajutorul metodei AgNOR" l996
20. Cmpian Simina: "Hepatitele cronice ale copilului" l998
2l. loana erban: "Tumorile benigne ale glandelor salivare" l999
22. Sandu lleana: "Biopsia renala n materialul Laboratorului de Anatomie Patologic
a Spita-
lului Clinic de Copii, Cluj" l999
23. Mihaela Leordean: "Diverticolulul Meckel" l999
24. Carceie Simona Alina: "Patologie osoas netumoral a copilului" 2000
25. Fechete Anamaria: "Patologia osoas tumoral a copilului" 2000
26. Bunda Radu-Cristian: "Biopsia gastric i duodenal la copil" 2002
27. lulia Balbach Tuleu: "Nefropatia asociat VHB" 2004
28. Teodora Paul: "Analiza morfometric a fibrozei hepatice" 2005
29. Cmpean Teodora Anca: "Ciroza hepatic a copilului n materialul autopsic" 2005
30. Tudor Bucur: "Ciroza hepatic a copilului n materialul bioptic" 2005
3l. Neam| Ana-Maria: "Pattern-ul imunohistocolora|iei antigenelor VHB n hepatita
cronic a adultului" 2007
32. Naumenco Adina: "Caracterizarea fibrozei hepatice din ciroz" 2007
33. C| lrina: Cuantificarea cantitativ a colagenului tnr i vechi cu ajutorul
programului
Adobe Photoshop, 2006
34. lulia Duminic: Corela|ii morfo-func|ionale ale activit|ii Kupfferiene hepatice, 2008
35. Filip Ramona: Tumora cu celulele gigante a osului, 2008
36. V iorica Sireteanu, Studii experimentale de inginerie tisular: Histopatologia
osteogenezei
induse, 2009
Aoreign /ang*ages+ English, French