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POCI, CARLO (2008) DANNI ISTOLOGICI E ALTERAZIONI METABOLICHEIN PAZIENTI EPATOTRAPIANTATI PER CIRROSI HCV CON RECIDIVA DI MALATTIA VIRALE. [Ph.D. thesis]

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Abstract (english)

Summary
Introduction: Terminal liver cirrhosis secondary to hepatitis C virus (HCV) infection represents one of the main indications to liver transplantation. Reactivation of the infection following the transplantation is the rule, and histological flares are greater than 90% after one year. It is known that progression of HCV liver disease is more rapid in immunossuppressed patients compared to immunocompetent individuals, approximating 30% in 5 years.
The metabolic syndrome is characterized by insulin resistance associated, according to the ATPIII criteria, with visceral obesity, hypertriglyceridemia, low levels of HDL cholesterol, diabetes mellitus and hypertension. From the histological standpoint, simple steatosis or non-alcoholic steatohepatitis (NASH) can be present with features ranging from simple fat liver infiltration (>5%) up to lobular inflammation with possible evolution towards fibrosis or cirrhosis.
Leptin is protein hormone coded by the obesity gene (OB) involved in the regulation of lipid metabolism and energy homeostasis. Several studies reported increased serum levels of leptin in patients with steatosis and/or NASH, suggesting that this protein may be promoting progression to NASH.
Methods: In the present investigation, we evaluated metabolic characteristics, histological patterns of liver biopsies and plasma levels of leptin in a cohort of patients followed at the Clinica Medica 1 of the University of Padua, who underwent liver transplantation for HCV-related terminal liver cirrhosis.
Results: The new onset of typical clinical features of the metabolic syndrome was observed in our patients compared to their pre-transplant status: diabetes mellitus (39%), hypertension (58%), hypertriglyceridemia (32%), HDL-hypercholesterolemia (32%), and obesity (39%). Liver histology showed presence of disease reactivation in all studied patients, with variable levels of inflammation and fibrosis ranging from mild to severe. These findings were associated with the time-from-transplantation rather than with a specific viral genotype. In addition, besides the histological features related to the viral hepatic disease, we detected typical lesions of nonalcoholic fatty liver disease (NAFLD) in zone 3, such as steatosis (55%) and pericellular fibrosis (45%). Leptin was previously shown to be elevated in subjects with HCV liver disease not yet transplanted. In our cohort, higher plasma levels of leptin were significantly associated with the presence and severity of steatosis in the liver.
Conclusion: This study shows that the typical features of the metabolic syndrome tend to manifest in patients following liver transplantation, and that leptin levels are significantly elevated in subjects with liver steatosis. Since leptin can induce insulin resistance, our findings suggest that in liver transplant patients it may function as an initial trigger for metabolic liver damage. We suggest that this protein may represent a additional biomarker of the ongoing metabolic damage to the hepatocytes, and therefore may be useful to identify those patients who will benefit from an earlier diagnostic liver biopsy.

Abstract (italian)

Introduzione: la cirrosi, epatica in stadio terminale, secondaria all’infezione cronica da virus dell’epatite C, rappresenta una delle principali indicazioni al trapianto di fegato. La recidiva dell’infezione dopo trapianto è la regola e la recidiva istologica supera il 90% dopo un anno. E’ noto inoltre che la progressione dell’epatopatia causata dal virus C nei soggetti immunosoppressi procede più rapidamente verso la cirrosi rispetto ai soggetti immunocompetenti, raggiungendo il 30% a cinque anni.
La sindrome metabolica è una condizione clinica caratterizzata dalla presenza di un’insulino-resistenza, associata, secondo i criteri dell’ATPIII, ad obesità viscerale, ipertrigliceridemia, bassi livelli di colesterolo-HDL, diabete mellito ed ipertensione arteriosa. Dal punto di vista istologico può essere presente un quadro di semplice steatosi o di steatoepatite non alcolica con quadri istologici che vanno dalla semplice infiltrazione grassa del fegato (>5%) fino alla presenza di infiammazione lobulare con possibile evoluzione verso la fibrosi o la cirrosi.
La leptina è un ormone di natura proteica che viene codificato dal gene dell’obesità (OB), ed è coinvolto nella regolazione del metabolismo lipidico e del consumo energetico. Diversi studi hanno riportato un aumento dei livelli sierici di leptina nei pazienti con steatosi e/o NASH e hanno proposto che questo rialzo possa promuovere la steatosi epatica e la progressione a NASH.
Abbiamo valutato le caratteristiche metaboliche, istologiche e i livelli plasmatici di leptina in una coorte di pazienti sottoposti a trapianto di fegato, per cirrosi epatica terminale secondaria ad un’infezione cronica da virus dell’epatite C, senza altre cause eziologiche documentate, e seguiti presso la Clinica Medica 1 dell’Università di Padova,
Risultati: si è assistito nei pazienti, rispetto alle condizioni pre-trapianto, alla comparsa ex novo di alcuni quadri patologici caratteristici della sindrome metabolica quali: il diabete mellito, nel 39%, l’ipertensione arteriosa, nel 58%, l’ipertrigliceridemia, nel 32%, l’ipocolesterolemia-HDL, nel 32%, l’obesità nel 39%.
La valutazione istologica evidenziava in tutti i pazienti una recidiva di malattia, con gradi di attività infiammatoria e di fibrosi variabile da lieve ad elevata. La flogosi e la fibrosi non dipendevano dal genotipo virale, quanto piuttosto dal tempo trascorso dal trapianto.
Oltre alle alterazioni istologiche tipiche della malattia epatica virale, erano presenti anche alterazioni istologiche caratteristiche della NAFLD in zona 3, quali la steatosi (55%) e la fibrosi pericellulare (45%).
I livelli plasmatici di leptina, che già erano stati dimostrati elevati in pazienti non sottoposti a trapianto di fegato, ma con epatopatia HCV correlata, risultavano significativamente aumentati sia in relazione alla presenza che alla severità della steatosi all’esame istologico.
Conclusioni: dopo il trapianto di fegato, nei nostri pazienti si manifestano le caratteristiche cliniche della sindrome metabolica non evidenti prima del trapianto come il diabete mellito (39%), l’ipertensione arteriosa (58%), l’ipertrigliceridemia (32%), l’ipocolesterolemia-HDL (32%), l’obesità (39%) ed istologiche quali la statosi (55%) e la fibrosi pericellulare (45%).
I livelli di leptina sono risultati significativamente più elevati nei pazienti con statosi epatica.
Considerando che la leptina può indurre insulino-resistenza e quindi contribuire al primo “hit” del processo di danno metabolico epatico, i risultati da noi trovati, potrebbero confermare il suo ruolo patogenetico anche nei pazienti epatotrapiantati. Inoltre dal momento che i livelli di leptina non correlavano con le caratteristiche cliniche-bioumorali della sindrome metabolica riteniamo che possa rappresentare un marker aggiuntivo per individuare quei pazienti che dovrebbero essere sottoposti a biopsia epatica per valutare l’iniziale danno metabolico cellulare.

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EPrint type:Ph.D. thesis
Tutor:OSSI , ELENA
Ph.D. course:Ciclo 20 > Scuole per il 20simo ciclo > SCIENZE MEDICHE, CLINICHE E SPERIMENTALI > FISIOPATOLOGIA CLINICA
Data di deposito della tesi:01 February 2009
Anno di Pubblicazione:2008
Key Words:NASH, NAFLD, TRAPAINTO DI FEGATO, LEPTINA
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/09 Medicina interna
Struttura di riferimento:Dipartimenti > pre 2012 - Dipartimento di Scienze Mediche e Chirurgiche
Codice ID:1762
Depositato il:01 Feb 2009
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