Translational studies in biliary atresia

Robert Cornelis Lind

Translational studies in biliary atresia

Robert Cornelis Lind

Onderzoeksoutput: Thesis fully internal (DIV)

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Samenvatting

Dit proefschrift onderzoekt verschillende aspecten van biliaire atresie (BA). BA wordt gekenmerkt door progressieve cholestase, snel ontwikkelende lever fibrose en levercirrose in de neonaat. Cirrose leidt tot eindstadium leverziekte en uiteindelijk is een levertransplantatie noodzakelijk voor overleving. BA is de meest frequente indicatie voor levertransplantatie bij kinderen.
Er zijn meerdere diermodellen voor BA echter geschiktheid hiervan is nog niet vastgesteld. Een van deze modellen is het Rhesus Rotavisus muismodel. De aanwezigheid van lever fibrose in dit model wordt in dit proefschrift voor het eerst aangetoond waarmee de geschiktheid van dit muismodel voor verder onderzoek naar de pathogenese/fysiologie wordt bevestigd. De aanwezigheid van een van de mogelijke pathofysiologische mechanisme, het epitheliaal naar mesenchymale transitie (EMT), wordt met behulp van het muismodel en humane lever biopsieën onderzocht. Tijdens EMT krijgen epitheelcellen (cholangiocyten) een meer mesenchymaal fenotype (fibroblasten). Er wordt geen bewijs gevonden voor EMT bij zowel de muizen als menselijke BA-patiënten.
Voor BA wordt een 10-jaars overleving van 66-89% en een 20-jaars overleving van 43-78% gerapporteerd. Lange termijnoverleving gaat echter wel gepaard met onzekerheid bij patiënten over mogelijke complicaties en frequente ziekenhuisopnamen. Deze continue “dreiging” kan een negatief effect hebben op de kwaliteit van leven op latere leeftijd. In dit proefschrift wordt kwaliteit van leven en levensloop van BA-patiënten die de volwassen leeftijd bereiken, met of zonder levertransplantatie, voor het eerst onderzocht. BA-patiënten hebben op volwassen leeftijd een kwaliteit van leven die vergelijkbaar is met gezonde leeftijdsgenoten. Wel zijn patiënten na een levertransplantatie in alle opzichten vertraagd in het behalen van hun ontwikkelingsmijlpalen

Originele taal-2	English
Kwalificatie	Doctor of Philosophy
Toekennende instantie	Rijksuniversiteit Groningen
Begeleider(s)/adviseur	Verkade, Henkjan, Supervisor Hulscher, Jan, Co-supervisor Hoekstra - Weebers, Josephine, Co-supervisor
Datum van toekenning	7-okt.-2016
Plaats van publicatie	[Groningen]
Uitgever	Rijksuniversiteit Groningen
Gedrukte ISBN's	978-94-6299-423-2
Elektronische ISBN's	978-94-6299-424-9
Status	Published - 2016

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Title and contents Final publisher's version, 601 KB
Chapter 1 Final publisher's version, 1,64 MB
Chapter 2 Final publisher's version, 1,1 MB
Chapter 3 Final publisher's version, 1,14 MB
Chapter 4 Final publisher's version, 1 MB
Chapter 5 Final publisher's version, 876 KB
Chapter 6Final publisher's version, 761 KB
Chapter 7 Final publisher's version, 847 KB
Chapter 8 Final publisher's version, 687 KB
Chapter 9 Final publisher's version, 684 KB
Complete thesisFinal publisher's version, 3,39 MB
PropositionsFinal publisher's version, 212 KB

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title = "Translational studies in biliary atresia",

abstract = "This thesis investigates different aspects of biliary atresia (BA). BA is characterized by progressive cholestasis, rapid liver fibrosis and cirrhosis in the neonatal period. Cirrhosis leads end-stage liver disease for which a liver transplantation is required for survival. BA is the most frequent indication for pediatric liver transplantation.Multiple animal models of BA have been suggested though the suitability of these models still needs to be established. One of these models is the Rhesus Rotavirus mouse model. The presence of liver fibrosis in this animal model is demonstrated for the first time in this thesis and confirms its suitability as a tool for future research into the pathogeneses/physiology of BA. Using this model and human biopsies one of the potential mechanisms involved in the development of liver fibrosis in BA, epithelial to mesenchymal transition (EMT), was investigated. No evidence for EMT in BA related liver fibrosis was found. 10- and 20-years overall survival of 66-89% and 43-78%, respectively, are now being reported for BA. Longterm survival exposes patients to continuing uncertainty of complications and frequent hospitalization. This constant “peril” may have a negative impact on their quality of life. This thesis investigates the quality of life for BA patients surviving into adulthood and the course of life after a liver transplantation during childhood. Adult BA patients (with or without liver transplantation) report a quality of life similar to healthy peers. Young adults after pediatric liver transplantation do, however, show a delay in their developmental milestones in every dimension.",

author = "Lind, {Robert Cornelis}",

year = "2016",

language = "English",

isbn = "978-94-6299-423-2",

publisher = "Rijksuniversiteit Groningen",

school = "University of Groningen",

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TY - THES

T1 - Translational studies in biliary atresia

AU - Lind, Robert Cornelis

PY - 2016

Y1 - 2016

N2 - This thesis investigates different aspects of biliary atresia (BA). BA is characterized by progressive cholestasis, rapid liver fibrosis and cirrhosis in the neonatal period. Cirrhosis leads end-stage liver disease for which a liver transplantation is required for survival. BA is the most frequent indication for pediatric liver transplantation.Multiple animal models of BA have been suggested though the suitability of these models still needs to be established. One of these models is the Rhesus Rotavirus mouse model. The presence of liver fibrosis in this animal model is demonstrated for the first time in this thesis and confirms its suitability as a tool for future research into the pathogeneses/physiology of BA. Using this model and human biopsies one of the potential mechanisms involved in the development of liver fibrosis in BA, epithelial to mesenchymal transition (EMT), was investigated. No evidence for EMT in BA related liver fibrosis was found. 10- and 20-years overall survival of 66-89% and 43-78%, respectively, are now being reported for BA. Longterm survival exposes patients to continuing uncertainty of complications and frequent hospitalization. This constant “peril” may have a negative impact on their quality of life. This thesis investigates the quality of life for BA patients surviving into adulthood and the course of life after a liver transplantation during childhood. Adult BA patients (with or without liver transplantation) report a quality of life similar to healthy peers. Young adults after pediatric liver transplantation do, however, show a delay in their developmental milestones in every dimension.

AB - This thesis investigates different aspects of biliary atresia (BA). BA is characterized by progressive cholestasis, rapid liver fibrosis and cirrhosis in the neonatal period. Cirrhosis leads end-stage liver disease for which a liver transplantation is required for survival. BA is the most frequent indication for pediatric liver transplantation.Multiple animal models of BA have been suggested though the suitability of these models still needs to be established. One of these models is the Rhesus Rotavirus mouse model. The presence of liver fibrosis in this animal model is demonstrated for the first time in this thesis and confirms its suitability as a tool for future research into the pathogeneses/physiology of BA. Using this model and human biopsies one of the potential mechanisms involved in the development of liver fibrosis in BA, epithelial to mesenchymal transition (EMT), was investigated. No evidence for EMT in BA related liver fibrosis was found. 10- and 20-years overall survival of 66-89% and 43-78%, respectively, are now being reported for BA. Longterm survival exposes patients to continuing uncertainty of complications and frequent hospitalization. This constant “peril” may have a negative impact on their quality of life. This thesis investigates the quality of life for BA patients surviving into adulthood and the course of life after a liver transplantation during childhood. Adult BA patients (with or without liver transplantation) report a quality of life similar to healthy peers. Young adults after pediatric liver transplantation do, however, show a delay in their developmental milestones in every dimension.

M3 - Thesis fully internal (DIV)

SN - 978-94-6299-423-2

PB - Rijksuniversiteit Groningen

CY - [Groningen]

ER -