A.L. Fracanzani

315 I148M PNPLA3 POLYMORPHISM IS ASSOCIATED WITH CLINICAL FEATURES IN PATIENTS WITH HEPATOCELLULAR CARCINOMA

315 I148M PNPLA3 POLYMORPHISM IS ASSOCIATED WITH CLINICAL FEATURES IN PATIENTS WITH HEPATOCELLULAR CARCINOMA L. Valenti, B. Motta, G. Soardo, C. Bertelli, A. Sangiovanni, R. Rametta, P. Dongiovanni, M. Colombo, S. Fargion, A.L. Fracanzani. Internal Medicine, Universita’ di Milano, Internale Medicine, Universita degli Studi di Milano, Milano, University of Udine, Udine, Gastroenterology, Universita degli Studi di Milano, Milano, Italy E-mail: luca.valenti@unimi.it

The rs2294918 E434K variant modulates PNPLA3 expression and liver damage

The patatin‐like phosholipase domain‐containing 3 (PNPLA3) rs738409 polymorphism (I148M) is a major determinant of hepatic fat and predisposes to the full spectrum of liver damage in nonalcoholic fatty liver disease (NAFLD). The aim of this study was to evaluate whether additional PNPLA3 coding variants contribute to NAFLD susceptibility, first in individuals with contrasting phenotypes (with early‐onset NAFLD vs. very low aminotransferases) and then in a large validation cohort. Rare PNPLA3 variants were not detected by sequencing coding regions and intron‐exon boundaries either in 142 patients with early‐onset NAFLD nor in 100 healthy individuals with alanine aminotransferase <22/20 IU/mL. Besides rs738409 I148M, the rs2294918 G>A polymorphism (E434K sequence variant) was over‐represented in NAFLD (adjusted P = 0.01). In 1,447 subjects with and without NAFLD, the 148M‐434E (P < 0.0001), but not the 148M‐434K, haplotype (P > 0.9), was associated with histological NAFLD and steatohepatitis. Both the I148M (P = 0.0002) and E434K variants (P = 0.044) were associated with serum ALT levels, by interacting with each other, in that the 434K hampered the association with liver damage of the 148M allele (P = 0.006). The E434K variant did not affect PNPLA3 enzymatic activity, but carriers of the rs2294918 A allele (434K) displayed lower hepatic PNPLA3 messenger RNA and protein levels (P < 0.05). Conclusions: Rare loss‐of‐function PNPLA3 variants were not detected in early‐onset NAFLD. However, PNPLA3 rs2294918 E434K decreased PNPLA3 expression, lessening the effect of the I148M variant on the predisposition to steatosis and liver damage. This suggests that the PNPLA3 I148M variant has a codominant negative effect on triglycerides mobilization from lipid droplets, mediated by inhibition of other lipases. (Hepatology 2016;63:787–798)

O071 : Telomerase reverse transcriptase mutations are associated with hepatocellular carcinoma in nash

O071 TELOMERASE REVERSE TRANSCRIPTASE MUTATIONS ARE ASSOCIATED WITH HEPATOCELLULAR CARCINOMA IN NASH B. Donati, E. Vanni, P. Dongiovanni, M. Iavarone, R. Rametta, C. Rosso, A. Carnelutti, S. Petta, A.L. Fracanzani, H.L. Reeves, J.F. Dofour, L. Miele, Q. Anstee, E. Bugianesi, G. Soardo, S. Fargion, L. Valenti. Pathophysiology and Transplantation, Universita degli Studi di Milano, Milano, Medical Sciences, University of Turin, Turin, Internal Medicine, Gastroenterology, Fondazione IRCCS Ca’ Granda, Milano, Internal Medicine, University of Udine, Udine, Gastroenterology, University of Palermo, Palermo, Italy; Medicine, Freeman Hospital, Newcastle Upon Tyne, United Kingdom; Clinical Research, University of Bern, Bern, Switzerland; Internal Medicine, Catholic University, Rome, Italy; Cellular Medicine, Newcastle University, Newcastle Upon Tyne, United Kingdom; Gastroenterology, University of Turin, Turin, Italy E-mail: donatibenedetta@gmail.com

Acquired hepatocerebral degeneration (AHD): a peculiar neurological impairment in advanced chronic liver disease

We discuss the case of a rare and often unrecognized neurologic syndrome, called Acquired Hepatocerebral Degeneration (AHD), observed in patients with advanced liver disease and portosystemic shunts. The clinical manifestations can be very heterogeneous and in our case included a combination of cerebellar and extrapyramidal signs, arisen in a period of few days. Brain Magnetic Resonance Imaging (MRI) showed, in T1-weighted images, diffuse bilateral hyper intensities in basal ganglia and biemispheric brain and cerebellar cortices, resembling paramagnetic deposits. No other neurological impairments, like stroke, infection or neoplasia, were found. It was excluded an episode of acute hepatic encephalopathy. We also ruled out Wilsonian degeneration, iron overload and autoimmune encephalitis and we lastly found high manganese levels as the possible cause of the brain paramagnetic deposits. Even though either serum Mn determination or its accumulation in the brain are not specific for AHD, however the chronic and progressively worsening of the neurological manifestations advocated a degenerative condition, possibly AHD. We finally opted for the early restoration of liver function by OLT, and we observed complete clinical symptoms’ resolution and partial MRI reversal after a follow up of 6 months.

P0166 : Anticoagulation does not increase portal hypertension related bleeding, but exposes patients with cirrhosis to a high risk of minor hemorrhages. Results from a comparative cohort study

V. La Mura1,2,∗, S. Braham3, F. Branchi4, M. Moia3, A.L. Fracanzani5, M. Colombo1, A. Tripodi3, M. Primignani1 1 U.O. Gastroenterologia-1, IRCCS-Ca’ Granda, Ospedale Maggiore Policlinico, Universita degli studi di Milano, Milan, Italy 2 U.O. Medicina Interna, IRCCS-San Donato, Dipartimento di Scienze Biomediche per la Salute, Universita degli studi di Milano, Milan, Italy 3 Centro Emofilia e Trombosi Angelo Bianchi Bonomi, IRCCS-Ca’ Granda, Ospedale Maggiore Policlinico, Universita degli studi di Milano, Milan, Italy 4 U.O. Gastroenterologia-2, IRCCS-Ca’ Granda, Ospedale Maggiore Policlinico, Universita degli studi di Milano, Milan, Italy 5 U.O. Medicina Interna, IRCCS-Ca’ Granda, Ospedale Maggiore Policlinico, Universita degli studi di Milano, Milan, Italy

P817 EARLY MENOPAUSAL STATUS IS ASSOCIATED WITH THE SEVERITY OF LIVER FIBROSIS IN ITALIAN PATIENTS WITH NON-ALCOHOLIC FATTY LIVER DISEASE

Methods: In 651 consecutive NAFLD patients (244 from Sicily, and 407 from Northern Italy), we assessed clinical, biochemical and histological features (Kleiner score). As controls, we evaluated 168 patients without clinical or histological evidence of steatosis. PNPLA3 rs738409 C>G and MERTK rs4374383 A>G SNPs were also assessed. Results: MERTK A>G SNP distribution was similar in cases compared to controls (p = 0.99). In the entire cohort, MERTK AA genotype (OR 0.25, 95%CI 0.10–0.58, p = 0.001) was independently associated with severe steatosis together with PNPLA3 GG status (OR 2.18, 95%CI 1.32–3.59, p = 0.002). In the high-risk group of PNPLA3 GG patients, severe steatosis was observed in none patients with MERTK AA (0/11) compared to 39% (33/84) with MERTK GG/GA genotype (p =0.01). The presence of fibrosis >F1 was independently linked to MERTK AA genotype in Sicilian cohort only (OR 0.28; 95%CI 0.11–0.69, p = 0.006), but not in the Northern Italy and in the entire cohorts. However, when excluding subjects with BMI > 40kg/m from the entire cohort F2–F4 fibrosis was observed in 19.2% patients with MERTK AA compared to 30.3% with MERTK GG/GA (p =0.04), being this data confirmed at multivariate analysis (OR 0.44; 95%CI 0.21–0.89, p = 0.02). Conclusions: MERTK AA genotype is protective against severe steatosis in patients with NAFLD, especially in those at high risk because of PNPLA3 GG genotype, while its effect on liver fibrosis needs to be further investigate.

Iron overload, hfe gene mutations and insulin resistance in non alcoholic fatty liver disease (NAFLD)

Ca.ssade#, E. Ferrnnninr’, M. Rtzetto’. ‘Division of Gostrwnterolog~ *Department OJ Internal Medicine, University of Turin, “Metabolism Unit, CNR Institute, Piss. Background and aims: The increaxd lipid peroxidation demonstrated in NASH might be related either to higher circtdadng levels of prooxidants and/or to a peculiar vulnerability of plasma lipids to &dative stress. Insulin resistance, a common feature in NASH, has been associated with increased oxidative stress. The aims of our srUdy were to establish whether the susceptibility of LDL-cholesteml pa&es to oxidation is increased in NASH oatients and whether this could be related to insulin resistance. Methods: We studied 11 non-obese, non diabetic patients with NASH (BMI=26.6+1.6), and 5 matched contmls. The following parameters were evaluated: 1) plasma lipid profile 2) total body lipid oxidation by indirect calorimetry 2) plasma LDGcholesteml vulnerability to oxidation as assessed by the lenght of the lag-phase during copper-catalyzed LDL oxidative modifications; 3) insulin sensitivity by hyperinsuliiemic (I mu/Kg min) euglycetnic clamp. Results: The basal lag-phase was significantly shorter in NASH patients compared to contmls (49+11 vs. 68+10 min, respectively; p=O.Ol). Plasma lipid pmtile was comparable in the hvo groups, with the exception of slightly higher triglycerides concentration in NASH (117+49 in NASH and 7l+ll m&IL in controls; p=O.O5). A slight inverse correlation was found between plasma triglycerides (t= -0.43) and lae chase and F’FA concentrations It= -0.521 and lae ohase in NASH patienis’bm not in controls. Total liiid oxidation w&‘1.13+0.25 and l.O+O.Zl micmmolrkg min in NASH and controls, respectively (p=ns) and inversely correlated with the lag-phase in both groups (r= -0.58.and 0.46). Insulin sensitivitv was deftitelv reduced in NASH oatients con&red to contmls (giucose inlitsion t&e = 4.49+1.48 vs. 7.67+0.54 mgkg mitt; p<O.Ol). The lag-phase did not change afta the euglycemic hyperinsulinemic clamp in both groups @IS) and did noOt corre& with insulin sensitivity. Conelusions: The increased susceptibility of LDLcholesterol particles contributes to enhanced lipid peroxidation in patients with NASY independendy from lipid levels and lipid oxidation. Tbe LDL oxidabilitv is not al&&d bv insulin adminisbation and does not appear to be &ed to insulin resi&nce