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Medici, Valentina (2009) S-adenosylmethionine and methionine metabolism in Alcoholic Liver Disease (ALD). [Tesi di dottorato]

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Abstract (inglese)

BACKGROUND: Prior experimental studies found associations of alcoholism and alcoholic liver disease (ALD) with abnormal methionine metabolism. Aberrant methionine metabolism
may play a central role in the pathogenesis of ALD. AIM: To establish profiles of plasma methionine metabolites in ALD patients compared to those found in healthy control subjects and alcoholics without clinical or biochemical evidence of liver disease, and to define the relationship of these profiles to clinical and pathological severity of ALD. PATIENTS AND
METHODS: Serum levels of S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH),homocysteine (Hcy), methionine, dimethylglycine (DMG), cysteine, and cystathionine were measured by GCMS and LCMS in 32 patients with ALD (group A), 20 chronic alcoholics without liver disease (group B), and 20 healthy control subjects (group C). Liver biopsies were performed in 20 ALD patients. Patients with creatinine ? 1.4 were excluded. RESULTS: The
mean age of all subjects was 47 ± 9.7 years (range 28-67), with 27.8 % women. No age or gender difference between the 3 groups. The mean duration of abstinence was 71 days for group A, and 1.3 days for group B. AST, Bilirubin, Alkaline Phosphatase, and INR were significantly higher in group A compared to the other 2 groups (all p< 0.0001). SAM, SAH, and DMG were significantly higher in group A compared to groups B and C, while Hcy was significantly higher in group A and B vs group C. Increased DMG is consistent with activation of betaine hydoxymethyltransferase in response to elevated Hcy. Methionine was similar in the three groups. SAM was significantly correlated with cysteine serum level (r= 0.34, p= 0.02), indicating a possible effect of diminished kidney function on SAM serum levels. Liver histology showed 5 patients with no steatosis, 3 grade 1, 4 had grade 2, and 8 grade 4; one patient did not 2 have fibrosis, 4 had stage 1, 4 stage 2, 5 stage 3 and 6 stage 4. On bivariate analysis, the duration of abstinence correlated significantly with the severity of steatosis (p= 0.02). On multivariate
analysis, predictors of steatosis severity were AST, bilirubin, creatinine, albumin, and serum Hcy (p=0.0002); predictors of stage of fibrosis were hispanic ethnicity, ALT, SAM/SAH, and Hcy (p= 0.001). CONCLUSIONS: Serum Hcy is elevated in alcoholics, with the highest levels in those with ALD. The original correlation between Hcy and severity of histopathology score emphasizes the link between methionine metabolism and clinical ALD.

Abstract (italiano)

BACKGROUND: precedenti studi hanno indicato la correlazione tra l’epatopatia alcolica ed alterazioni del metabolismo della metionina. SCOPI: Il primo scopo (Aim 1) e’ di definire i profili sierici dei componenti del metabolismo della metionina in pazienti con epatopatia alcolica, in alcolisti senza epatopatia ed in soggetti sani e definire la loro relazione con parametri bioumorali ed istologici di severita’ di epatopatia alcolica. Il secondo scopo (Aim 2) e’ di definire l’effetto della somministrazione orale di S-adenosilmetionina (SAM) verso placebo in soggetti con epatopatia alcolica. Il trial clinico e’ ancora in corso, dunque vengono qui presentati
i risultati del Aim 1. PAZIENTI E METODI: i livelli sierici di SAM, S-adenosilomocisteina (SAH), omocisteina (HCY), metionina, dimetilglicina, cisteina e cistationina sono stati misurati mediante GCMS e LCMS in 32 pazienti con epatopatia alcolica (grupp A), 20 alcolisti senza evidenza di malattia epatica (gruppo B), e 20 soggetti sani (gruppo C). Le biopsie epatiche sono state eseguite al tempo 0 e dopo 6 mesi di trial. I pazienti con creatinina > 1.4 sono stati esclusi
dallo studio. RISULTATI: L’eta’ media dell’intero gruppo e’ 47 ± 9.7 anni (range 28-67). Il 27.8 % sono donne. Non si e’ rilevata nessuna significativa differenza di eta’ tra i 3 gruppi. La durata media dell’astinenza e’ di 71 giorni per il gruppo A e di 1.3 giorni per il gruppo B. I parametri bioumorali di epatopatia alcolica erano tutti significativamente alterati nel gruppo A rispetto agli altri 2 gruppi. SAM, SAH e DMG erano significativamente elevati nel gruppo A rispetto al
gruppo B e C, mentre HCY era significativamente elevata nel gruppo A e B rispetto al gruppo C. L’aumento di DMG e’ spiegabile dall’attivazione della salvage pathway che porta alla sintesi di metionina in caso di uso di alcol. L’istologia epatica ha dimostrato 5 pazienti senza steatosi, 3
con grado 1, 4 con grado 2, e 8 con grado 4; un paziente non ha dimostrato fibrosi epatica, 4 hanno dimostrato stage 1, 4 stage 2, 5 stage 3 e 6 stage 4. Secondo la correlazione bivariata, la durata dell’astinenza alcolica e’ correlata postivamente con la severita’ della steatosi (p=0.02).
L’analisi multivariata, fattori predittivi di steatosi sono risultati essere i livelli di AST, bilirubina, creatinina, albumina, e HCY (p=0.0002). Fattori predittivi di fibrosis sono risultati essere l’etnia ispanica, ALT, SAM/SAH e HCY (p=0.001). CONCLUSIONI PRELIMINARI: I livelli sierici di HCY sono elevati nell’epatopatia alcolica e rivestono un ruolo importante nel predire la severita’ della steatosi e della fibrosi.

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Tipo di EPrint:Tesi di dottorato
Relatore:Sturniolo, Giacomo Carlo
Dottorato (corsi e scuole):Ciclo 21 > Scuole per il 21simo ciclo > BIOLOGIA E MEDICINA DELLA RIGENERAZIONE > SCIENZE EPATOLOGICHE E GASTROENTEROLOGICHE
Data di deposito della tesi:18 Gennaio 2009
Anno di Pubblicazione:Gennaio 2009
Parole chiave (italiano / inglese):Alcoholic liver disease, S-adenosylmethionine, homocysteine,
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/12 Gastroenterologia
Struttura di riferimento:Dipartimenti > pre 2012 - Dipartimento di Scienze Chirurgiche Gastroenterologiche "Pier Giuseppe Cevese"
Codice ID:1334
Depositato il:18 Gen 2009
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