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Psychometric Hepatic Encephalopathy Score (PHES) and EEG are used to detect minimal hepatic encephalopathy (MHE). We aimed at standardizing PHES in Italy and comparing Italian, German and Spanish norms in EEG characterized cirrhotic patients.PHES was standardized on 228 normal individuals. Repeatability was studied in 128 individuals. One hundred patients with liver cirrhosis underwent EEG and PHES which was computed on the Spanish, German and the Italian norms.Age and education levels were predictors of psychometric tests; therefore, adjusted Z scores were calculated. Practice effect (p0.01) was detected. In the patients, the Italian norms were closer to the Spanish norms (difference -0.14+/-1.32, p=0.29) than to the Germans ones (difference 1.97+/-2.07, p0.001). The PHES calculated on the Italian norms was correlated with the EEG mean dominant frequency more closely than the ones calculated on the German and Spanish norms (r=0.38, r=0.31, r=0.33, respectively -p0.01). The detection of MHE on the basis of PHES and EEG showed limited agreement (73%, Cohen's K=0.32).(i) Valid norms for PHES were produced, (ii) clues for the use of common norms in Latin Countries were found, (iii) different findings between PHES and EEG possibly reflect various features of MHE.

Background/Aims : The electroencephalogram (EEG) is frequently altered in cirrhotic patients. We, therefore, performed a study to ascertain the features and the prognosis of cirrhotic patients without current overt hepatic encephalopathy (OHE) who have EEG alterations. Methods : A series of 296 consecutive cirrhotic patients who had undergone quantified-EEG was studied. The median follow-up was 442 days, 128 patients had bouts of OHE and 78 patients died from liver-related causes. Another group of 124 cirrhotic patients with a median follow-up of 223 days was examined to validate the prognostic model. Results : EEG alterations were detected in 38% of the patients. The prevalence of EEG alterations was associated with the severity of cirrhosis (class B: odds ratio (OR)=2.3, 95% confidence interval (CI)=1.2–4.7; class C: OR=3.5, 95% CI=1.6–7.7), but not with the aetiology (alcoholic vs. non-alcoholic: OR=0.9; 95% CI=0.5–1.5). The EEG predicted the occurrence of OHE ( χ 2 =26; P 0.001) and mortality ( χ 2 =34; P 0.001), also adjusting for Child–Pugh class by a multivariate analysis. In the patients with a Child–Pugh score of ≥ 8, the EEG discriminated between those patients with a higher 1-year risk of OHE (hazard ratio (HR)=3.3, 95% CI=1.8–6.1) and death (HR=3.1, 95% CI=1.7–5.6). Conclusions : In conclusion, quantified-EEG had a prognostic value for the occurrence of bouts of OHE and mortality in cirrhotic patients.

Background : Chronic hepatitis C virus (HCV) infection is associated with a variety of extrahepatic disorders that may relate to direct or indirect effects of virus infection. Increased levels of soluble forms of tumor necrosis factor (TNF) receptors I and II, found in lymphoproliferative and infectious diseases, can interfere with TNF induced apoptotic cell death. The aim of the present study was to evaluate soluble TNF family receptors levels in lymphoproliferative disorders associated with HCV infection. Methods : One hundred and forty-nine subjects were studied, including 120 anti-HCV positive patients (60 without lymphoproliferative manifestations, 47 with type II cryoglobulinemia and 13 with low-grade B-cell non-Hodgkin's lymphoma (B-NHL)) and 29 anti-HCV negative subjects (19 with low-grade B-NHLs and ten normal controls). Results : Soluble forms of TNF receptor I, TNF receptor II and Fas were significantly higher in HCV positive patients compared with normal controls. The highest levels were found in patients affected by type II cryoglobulinemia or HCV positive lymphoplasmacytoid lymphomas (LP-NHLs), while HCV positive patients without type II cryoglobulinemia or with other B-NHLs had lower values ( P Conclusions : Among HCV infected individuals, very high levels of soluble TNF receptors are significantly associated with type II cryoglobulinemia and LP-NHLs, suggesting that they may be involved in these proliferative disorders.

Background/Aims: In chronic hepatitis C, interferon-alpha (α-IFN) and ribavirin combination therapy improves sustained response compared to α-IFN monotherapy, both in naive patients and in previous α-IFN relapsers, but the efficacy of such therapy remains limited in non-responder cases. The aim of this study was to assess whether the pattern of response to α-IFN alone may predict sustained response to combination therapy during retreatment. Methods: Fifty previous α-IFN relapsers and 50 previous α-IFN non-responders were retreated with a high α-IFN dose (6 MU/thrice weekly for 2 months; induction phase) and then randomised to continue with α-IFN alone (3 MU/thrice weekly) or to receive combination therapy (3 MU/thrice weekly of α-IFN and 1000–1200 mg/daily of ribavirin) for an additional 6 months according to the biochemical response to α-IFN shown after the induction phase. All patients were also evaluated for virological and histological response. Results: Eleven of 25 (44%) relapsers treated with combination therapy and 4/25 (16%) treated with α-IFN alone achieved a sustained response. The corresponding figures among non-responders were 1/25 (4%) and 0/25, respectively. Among 26 patients with a complete ALT and HCV-RNA response after 2 months of α-IFN, sustained response was seen in 11/14 (79%) treated with combination therapy and in 4/12 (33%) treated with α-IFN alone ( p =0.05). On the other hand, of 74 cases still HCV-RNA positive after 2 months of α-IFN alone, biochemical and virological end of therapy response was better with combination therapy (11/36; 30.5%) compared to α-IFN alone (4/38; 10.5%), but only one patient developed a sustained response (1/36; 3%). Conclusions: The retreatment with a 6-month combination therapy was associated with a high rate of sustained response only in patients showing a complete biochemical and virological response to α-IFN alone. Longer retreatment with combination therapy may be needed to achieve a sustained response in patients without a prompt virological response to α-IFN.

Background & Aims Heme oxygenase (HO) catabolizes heme into biliverdin, carbon monoxide (CO), and free iron. CO generated in endothelial and smooth muscle layers of blood vessels modulates vascular tone by inducing relaxation of vascular smooth muscle cells. The aim of this study was to verify the role played by HO in regulating renal arterial resistance and Na + excretion in cirrhosis. Methods Twenty control rats and 20 rats with CCl 4 − induced cirrhosis, 10 of which were chronically treated with the HO inducer cobalt-protoporphyrin (CoPP), were studied. Pressurized renal interlobar arteries were challenged with increasing doses of phenylephrine (PE) and acetylcholine (ACh). Dose–response curves were evaluated under basal conditions and after inhibition of HO with chromium-mesoporphyrin (CrMP). HO-1 (inducible form) and HO-2 (constitutive form) expression was measured in the main and interlobar renal arteries. Serum and urinary levels of Na + and creatinine were also evaluated. Results In renal interlobar arteries from cirrhotic rats, the response to PE was increased, while that to ACh was blunted. After HO inhibition, the responsiveness to these vasoactive substances was comparable in the two groups. In cirrhotic rats, HO-1 expression was impaired in the main and the interlobar renal arteries. Chronic HO induction normalized the response to the vasoconstrictor, but not to the vasodilator. Cirrhotic rats treated with CoPP showed higher urinary Na + concentration and fractional Na + excretion, compared to both untreated cirrhotic and control rats. Conclusions In cirrhotic rats, an impaired HO-1 expression promotes vasoconstriction of renal interlobar arteries. Chronic HO induction normalizes the sensitivity to PE and promotes Na + excretion.

Thirty-two patients with non-cirrhotic portal system obstruction and oesophageal varices of non-malignant etiology were recruited over 13 years. Diagnosis was based on the presence of oesophageal varices at endoscopy, minor alterations in liver function tests and liver histology, a low hepatic venous pressure gradient, and pertinent angiographic patterns. Twenty-three had portal vein thrombosis, nine had splenic vein thrombosis. Twenty-one had idiopathic portal vein obstruction, 11 had secondary obstruction. The outcome was compared with a group of 32 patients with cirrhosis and portal hypertension, matched for age, Child-Pugh class, previous history of gastrointestinal bleeding, and size of oesophageal varices. Patients with non-cirrhotic obstruction of the portal system were followed for up to 171 months (mean 94 months). During follow-up ten patients had gastrointestinal bleeding, and eight died (five of gastrointestinal bleeding). After 6 years of follow-up, the cumulative risk of gastrointestinal bleeding was 24%, the cumulative risk of death was 17%, and the cumulative risk of death from gastrointestinal bleeding was 14%. Cumulative probability of death by any cause and the probability of gastrointestinal bleeding were significantly lower in patients with non-cirrhotic obstruction of the portal system than in patients with cirrhosis comparable for liver function and portal hypertension ( p = 0.04 for both). The cumulative probability of death by gastrointestinal bleeding was not significantly different. In conclusion, the prognosis for non-eirrhotic obstruction of the portal system is significantly better than for patients with cirrhosis with comparable levels of liver function impairment and severity of portal hypertension.

223 COST-EFFECTIVENESS OF A NEW MODEL OF SPECIALISTIC CAREGIVING FOR OUTPATIENTS WITH CIRRHOSIS AND ASCITES; A PROSPECTIVE STUDY F. Morando, G. Maresio, S.S. Piano, S. Fasolato, M. Cavallin, A. Romano, S. Rosi, E. Gola, A. Sticca, A.C. Frigo, M. Stanco, C. Destro, G. Rupolo, D. Mantoan, P. Angeli, A. Gatta. Department of Medicine, Department of Cardiac, Thoracic and Vascular Sciences, University of Padova, Medical Direction, University and General Hospital of Padova, Direction of Health System of Veneto Region, Department of Medicine, Unit of Hepatic Emergencies and Liver Transplantation, University of Padova, Padova, Italy E-mail: filippo.morando@alice.it

Results: The MTHFR C677T homozygote mutation (TT) was found in 28 (21%) patients, while the remaining 107 (79%) were wild types or heterozygotes (C/*). TT as compared to C/* patients had significantly higher DMELD-score (0.329±0.093 vs 0.146±0.096 means±SE, respectively; p < 0.01) before LT. At multivariate analysis, TT genotype was independently associated with MELD-score worsening during the waiting list (OR 5.21, lower 95% C.L 1.33, upper 95% C.L 20.31, p = 0.018), after adjustment for patient age, PL-MELD score, sex, portal vein thrombosis and cirrhosis aetiology. Post-transplant patient survival was significantly (Log-Rank test p = 0.007) lower in TT (median follow-up 27 months; range 0.1–85 months) than in C/* (median follow-up 33 months; range 0.1– 102 months) recipients. At Cox regression analysis, recipient TT genotype was independently associated with post-transplant patient survival (OR 2.44, lower 95% C.L 1.22, upper 95% C.L 4.84, p = 0.011), after adjustment for recipient age, LT-MELD score, sex, HCV status, and donor risk index. Conclusions: Cirrhotic patients with the MTHFR C677T homozygous mutation have faster disease progression before LT and worse survival after LT.

Cirrhosis was induced in Wistar-Kyoto rats by intragastric administration of carbon tetrachloride. Microsomes were obtained from the renal cortex and outer medulla and incubated with [ 14 C]arachidonic acid (AA) (0.2–0.4 μCi) in the presence or absence of indomethacin, NADPH, and SKF-525A. Cytochrome P -450-dependent AA metabolites (those whose formation required NADPH, were inhibited by SKF-525A, but not by indomethacin) were separated by thin-layer chromatography and high-pressure liquid chromatography (HPLC). Compared to controls, total synthesis of cytochrome P -450-dependent AA metabolites was reduced in cirrhotic rats (renal cortex: cirrhotics 380 ± 52 vs. controls 493 ± 68 pg/mg protein per 30 min; p p P -450-dependent AA metabolites were composed of three peaks separated by HPLC. Peak I, which had a retention time of 16.3 ± 0.3 min and comigrated with 11,12-dihydroxyeicosatrienoic acid, and peak II, which had a retention time of 18.7 ± 0.4 min and comigrated with 19- and 20-hydroxyeicosatetraenoic acid, were not different in cirrhotics and controls. Peak III, which had a retention time of 26.8 ± 0.3 min, and comigrated with 11,12-epoxyeicosatrienoic acid, was significantly decreased in the renal cortex of cirrhotic rats compared to controls (cirrhotics 316 ± 40 vs. controls 473 ± 89 pg/mg protein per 30 min; p P -450-dependent activity, was increased in the renal cortex of cirrhotic rats (AHH cirrhotics: 40.1 ± 15.7 pmol/mg per min vs. controls: 20.0 ± 9.3 pmol/mg per min; p P -450-dependent pathway. Reduced synthesis of these AA metabolites may contribute in the pathogenesis of renal failure associated with cirrhosis.