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Galioto, Alessandra (2009) L'evoluzione clinica della gammopatia monoclonale di incerto significato nel trapianto di fegato. [Tesi di dottorato]

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Abstract (inglese)

Background - A monoclonal gammopathy of undetermined significance (MGUS) can develop in patients with liver cirrhosis as well as in liver transplant recipients. Few data are available today on the prevalence of MGUS in patients who underwent liver transplantation (LT) and on its impact on the outcome of LT. In particular there are no data relating to the potential progression of MGUS to B cell malignant disorder in subjects who underwent organ transplantation.
Aim - The main aim of our study was to define the prevalence of MGUS in a population of patients with advanced chronic liver diseases who referred to our Centre for LT and the prevalence of MGUS “de novo” after LT. The secondary aim was to evaluate the evolution of MGUS after LT. In particular it has been considered the possibility of MGUS turning to myeloma or lymphoma and its possible contribution in the pathogenesis of other complications after LT.
Study population and methods - One hundred and fifty liver transplant recipients with a follow-up longer than twelve months were included in the study. The inclusion in the transplant list has been performed in accordance with AISF-AALSD guidelines. After LT patients underwent a follow-up including medical examination, laboratory screening and if necessary in-depth instrumental examination. Blood serum proteins electrophoresis has been measured every six months. In presence of a monoclonal gammopathy, MGUS diagnosis was made on the basis of the absence of clinical manifestation, a concentration of circulating IgG monoclonal protein lower than 3g/dl or a concentration of circulating IgG monoclonal component higher than 3 g/dl and any amount of IgA, IgM with a percentage of plasma cells in the bone marrow lower than 10%.
Results – One hundred and fifty liver transplant patients were included in the study. Their median age at the time of transplantation was 52,5 years (21-65 years). The median follow-up was of 84.7 ± 6,23 months (range 12-192months). Eighteen out of 150 patients had a MGUS before LT (prevalence 12%); in 10 of them the MGUS disappeared during the follow-up post LT (“transient”MGUS). MGUS developed after LT (MGUS “de novo”) in 49 patients out of 132 (prevalence 37%). The prevalence of MGUS “de novo” after LT is quite higher than what reported in patients with chronic liver disease waiting for transplant (12%, p < 0.05) and in people older than 50 years (3.2%, p < 0.05). In 28 of 49 patients with MGUS “de novo”, MGUS did not disappear during the follow-up (“permanent MGUS”). Eighty-three liver transplant recipients never had a MGUS. No patient with MGUS developed a lymphoproliferative disease, one patient with MGUS pre-OLT developed a smouldering myeloma.
Comparing patients who had permanent MGUS (n°=36) developed before and after LT and patient with transient MGUS or without MGUS, the first group of patients showed a higher rate of severe infections (30,56% versus 13%, p= 0,01), chronic renal failure (75% versus 45%, p= 0,001) and mortality (33% versus 17%, p<0.05).
Patients with permanent MGUS and patients with transient MGUS or without MGUS showed no significant differences about aetiology of liver disease, CHILD and MELD at the time of LT, immunosuppressive therapy, liver graft function, development of rejection, diabetes and EBV and CMV infections and recurrence of the primary liver disease after LT. Patients with “de novo” MGUS were older than patients without MGUS (55 vs 50 years, p= 0,04) as well as patients with permanent MGUS than patients with a transient or without MGUS (57 versus 51 years, p= 0,6).
Conclusions - MGUS is frequent in patients with advanced chronic liver and in liver transplant recipients. The progression of a permanent MGUS after LT to myeloma is uncommon and a permanent MGUS is not associated with a progression to other lymphoproliferative diseases. Nevertheless, its development and persistence after LT are associated with a higher risk of complications, in particular severe infections, chronic renal failure and with a higher rate of mortality.

Abstract (italiano)

Premessa: La gammopatia monoclonale di incerto significato (MGUS) può svilupparsi sia in pazienti con cirrosi epatica che in pazienti sottoposti a trapianto di fegato (LT). Esistono pochi dati relativi alla prevalenza di MGUS nei pazienti sottoposti a trapianto di fegato e al suo impatto sull’esito di trapianto. In particolare non sono presenti dati rilevanti per ciò che riguarda la progressione di una MGUS verso un disordine maligno a cellule B nei soggetti sottoposti a trapianto di organo solido.
Scopo: Lo scopo principale del nostro studio è stato di definire la prevalenza della MGUS in un gruppo di pazienti con patologie croniche avanzate del fegato, che si sono rivolti al nostro Centro per trapianto di fegato e stabilire la prevalenza di una MGUS “de novo” dopo trapianto di fegato. Scopo secondario è stato di valutare l’evoluzione della MGUS dopo trapianto di fegato. In particolare è stata considerata sia la possibile progressione di MGUS a mieloma multiplo od a linfoma, che il suo possibile contributo nella patogenesi di altre complicanze insorte dopo il trapianto di fegato.
Materiali e Metodi: Nel nostro studio sono stati inclusi 150 pazienti sottoposti a trapianto epatico con un follow-up superiore a dodici mesi. L’iter di valutazione per l’inserimento in lista d’attesa per trapianto è stato effettuato secondo le linee guida AISF-AASLD. Dopo il trapianto i pazienti sono stati sottoposti a follow-up che prevedeva esame clinico, screening di laboratorio ed eventuali esami strumentali di approfondimento. L’elettroforesi delle proteine plasmatiche è stata eseguita almeno ogni 6 mesi. Nei casi in cui l’elettroforesi proteica evidenziasse una componente monoclonale, la diagnosi di MGUS è stata posta sulla base dell’assenza di manifestazioni cliniche, del riscontro di una concentrazione di proteina monoclonale IgG circolante inferiore a 3 g/dl, del riscontro di una concentrazione di componente monoclonale IgG maggiore o uguale a 3 g/dl e di una qualsiasi quantità di IgA o IgM con quantità percentuale di plasmacellule nel midollo osseo inferiore al 10%.
Risultati: L’età dei pazienti al momento del trapianto, espressa come mediana, e di 52,5 anni (21-65 anni) e la durata media del follow-up è pari a 84.7 ± 6,23 mesi (range 12-192). Diciotto pazienti su 150 avevano una MGUS prima del trapianto. In dieci di questi pazienti la MGUS è scomparsa dopo il trapianto di fegato (MGUS “transitoria”). Una MGUS si è sviluppata dopo trapianto di fegato (MGUS “de novo”) in 49 pazienti su 132. La prevalenza di MGUS “de novo” è risultata pari al 37%. Questo valore è molto più alto di quello osservato nei pazienti con malattie croniche del fegato in attesa di trapianto (12%, p < 0.05) e nella popolazione generale dei pazienti di età superiore ai 50 anni (3.2%, p<0.05). Quarantanove pazienti hanno sviluppano MGUS “de novo” dopo trapianto; in 21 di questi pazienti l’MGUS è stata transitoria, in 28 la MGUS non è scomparsa durante il follow-up (MGUS “permanente”). Un paziente con MGUS presente già prima del trapianto ha sviluppato un mieloma micromolecolare. Nessun paziente con MGUS permanente ha sviluppato un linfoma. Confrontando complessivamente i pazienti con MGUS permanente (n° = 36 pazienti) e i pazienti che non hanno mai sviluppato una MGUS (n° = 83) insieme a quelli che hanno sviluppato una MGUS transitoria (n° = 31), si è stata riscontrata nel primo gruppo una percentuale maggiore di infezioni opportunistiche severe (30,56% vs 13%, p= 0,01), di insufficienza renale (75% vs 45%, p= 0,001) e di mortalità (33% vs 17%, p<0.05).
Nel confronto tra i due gruppi di pazienti non sono state riscontrate differenze significative per quanto riguarda le caratteristiche di base prima del trapianto (sesso, eziologia, gravità dell’epatopatia) ad eccezione dell’età risultata tendenzialmente maggiore nei pazienti con MGUS permanente. Non sono state riscontrate differenze significative neanche per quanto riguarda la funzionalità del graft al termine del follow up, le caratteristiche della terapia immunosoppressiva e lo sviluppo di altre complicanze quali il rigetto, le recidive di malattia, complicanze cardiovascolari, infezioni di CMV e EBV.
Conclusioni: La MGUS è frequente in pazienti con malattie epatiche croniche avanzate e la prevalenza di MGUS aumenta ulteriormente dopo il trapianto. Una MGUS permanente dopo trapianto di fegato si associa raramente a progressione a mieloma e sembra non associarsi a progressione verso altri disordini linfoproliferativi a cellule B. Tuttavia, il suo sviluppo e la sua persistenza dopo il trapianto di fegato sono associate ad un rischio maggiore di complicanze, soprattutto di infezioni severe ed insufficienza renale e, probabilmente come conseguenza di ciò, e ad un tasso maggiore di mortalità.


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Tipo di EPrint:Tesi di dottorato
Relatore:Angeli, Paolo
Dottorato (corsi e scuole):Ciclo 21 > Scuole per il 21simo ciclo > SCIENZE MEDICHE, CLINICHE E SPERIMENTALI > EPATOLOGIA CLINICA
Data di deposito della tesi:NON SPECIFICATO
Anno di Pubblicazione:20 Dicembre 2009
Parole chiave (italiano / inglese):MGUS, trapianto di fegato
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/09 Medicina interna
Struttura di riferimento:Dipartimenti > Dipartimento di Medicina Clinica e Sperimentale
Codice ID:2264
Depositato il:29 Nov 2010 09:16
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