Serum Ferritin Levels Lack Diagnostic Accuracy for Liver Fibrosis in Patients With Nonalcoholic Fatty Liver Disease

BACKGROUND & AIM: Series studies have associated increased serum levels of ferritin with liver fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). We aimed to determine the accuracy with which measurements of serum ferritin determine the presence and severity of liver fibrosis, and whether combining noninvasive scoring systems with serum ferritin analysis increases the accuracy of diagnosis of advanced liver fibrosis. METHODS: We performed a retrospective analysis of data from 1014 patients with liver biopsy-confirmed NAFLD. Three cut-points of serum ferritin level, adjusted for sex, were established based on receiver operating characteristics curve analysis: 1.0 (the upper limit of normal [ULN]), 1.5-fold ULN, and 2.0-fold ULN. Three multiple logistic regression models were created to determine the association of these cutoff values with liver fibrosis, adjusting for age, sex, race, diabetes, body mass index, and level of alanine aminotransferase. RESULTS: A greater proportion of patients with increased serum levels of ferritin had definitive NASH and more-advanced fibrosis than patients without increased levels. In all models, serum level of ferritin was significantly associated with the presence and severity of liver fibrosis. However, for all 3 cutoff values, area under the receiver operating characteristic curve values were low (less than 0.60) for the presence of fibrosis or any stage of liver fibrosis; ferritin level identified patients with fibrosis with 16%–41% sensitivity and 70%–92% specificity. The accuracy with which noninvasive scoring systems identified patients with advanced fibrosis did not change with inclusion of serum ferritin values. CONCLUSIONS: Although serum levels of ferritin correlate with more-severe liver fibrosis, based on adjusted multiple logistic regression analysis, serum ferritin levels alone have a low level of diagnostic accuracy for the presence or severity of liver fibrosis in patients with NAFLD

BIOCHRONOLOGY OF SELECTED MAMMALS, MOLLUSCS AND OSTRACODS FROM THE MIDDLE PLIOCENE TO THE LATE PLEISTOCENE IN ITALY. THE STATE OF THE ART

The Authors have elaborated four range charts of mammalian (large and micro), molluscs and fresh-water and brackish ostracodes faunas, for the selected Plio-Pleistocene fossiliferous localities of the Italy. A new Mammal Age (Aurelian) correlatable to late Middle and Late Pleistocene has been defined. Inside this age two Faunal Units (Torre in Pietra and Vitinia) have been defined as characteristic for Early and Middle Aurelian, while no gisements have been chosen for the late Aurelian. Biochronological units are calibrated on magnetostratigraphic and isotopic scales and by radiometric datings.   &nbsp

BIOCHRONOLOGY OF SELECTED MAMMALS, MOLLUSCS AND OSTRACODS FROM THE MIDDLE PLIOCENE TO THE LATE PLEISTOCENE IN ITALY. THE STATE OF THE ART

The Authors have elaborated four range charts of mammalian (large and micro), molluscs and fresh-water and brackish ostracodes faunas, for the selected Plio-Pleistocene fossiliferous localities of the Italy. A new Mammal Age (Aurelian) correlatable to late Middle and Late Pleistocene has been defined. Inside this age two Faunal Units (Torre in Pietra and Vitinia) have been defined as characteristic for Early and Middle Aurelian, while no gisements have been chosen for the late Aurelian. Biochronological units are calibrated on magnetostratigraphic and isotopic scales and by radiometric datings.   &nbsp

Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: A multicenter prospective study

107noNonalcoholic fatty liver disease (NAFLD) represents the hepatic manifestation of metabolic syndrome and may evolve into hepatocellular carcinoma (HCC). Only scanty clinical information is available on HCC in NAFLD. The aim of this multicenter observational prospective study was to assess the clinical features of patients with NAFLD-related HCC (NAFLD-HCC) and to compare them to those of hepatitis C virus (HCV)-related HCC. A total of 756 patients with either NAFLD (145) or HCV-related chronic liver disease (611) were enrolled in secondary care Italian centers. Survival was modeled according to clinical parameters, lead-time bias, and propensity analysis. Compared to HCV, HCC in NAFLD patients had a larger volume, showed more often an infiltrative pattern, and was detected outside specific surveillance. Cirrhosis was present in only about 50% of NAFLD-HCC patients, in contrast to the near totality of HCV-HCC. Regardless of tumor stage, survival was significantly shorter (P = 0.017) in patients with NAFLD-HCC, 25.5 months (95% confidence interval 21.9-29.1), than in those with HCV-HCC, 33.7 months (95% confidence interval 31.9-35.4). To eliminate possible confounders, a propensity score analysis was performed, which showed no more significant difference between the two groups. Additionally, analysis of patients within Milan criteria submitted to curative treatments did not show any difference in survival between NAFLD-HCC and HCV-HCC (respectively, 38.6 versus 41.0 months, P = nonsignificant) Conclusions: NAFLD-HCC is more often detected at a later tumor stage and could arise also in the absence of cirrhosis, but after patient matching, it has a similar survival rate compared to HCV infection; a future challenge will be to identify patients with NAFLD who require more stringent surveillance in order to offer the most timely and effective treatment. (Hepatology 2016;63:827-838)openopenPiscaglia F.; Svegliati-Baroni G.; Barchetti A.; Pecorelli A.; Marinelli S.; Tiribelli C.; Bellentani S.; Bernardi M.; Biselli M.; Caraceni P.; Domenicali M.; Garuti F.; Gramenzi A.; Lenzi B.; Magalotti D.; Cescon M.; Ravaioli M.; Del Poggio P.; Olmi S.; Rapaccini G.L.; Balsamo C.; Di Nolfo M.A.; Vavassori E.; Alberti A.; Benvegnau L.; Gatta A.; Giacomin A.; Vanin V.; Pozzan C.; Maddalo G.; Giampalma E.; Cappelli A.; Golfieri R.; Mosconi C.; Renzulli M.; Roselli P.; Dell'isola S.; Ialungo A.M.; Risso D.; Marenco S.; Sammito G.; Bruzzone L.; Bosco G.; Grieco A.; Pompili M.; Rinninella E.; Siciliano M.; Chiaramonte M.; Guarino M.; Camma C.; Maida M.; Costantino A.; Barcellona M.R.; Schiada L.; Gemini S.; Lanzi A.; Stefanini G.F.; Dall'aglio A.C.; Cappa F.M.; Suzzi A.; Mussetto A.; Treossi O.; Missale G.; Porro E.; Mismas V.; Vivaldi C.; Bolondi L.; Zoli M.; Granito A.; Malagotti D.; Tovoli F.; Trevisani F.; Venerandi L.; Brandi G.; Cucchetti A.; Bugianesi E.; Vanni E.; Mezzabotta L.; Cabibbo G.; Petta S.; Fracanzani A.; Fargion S.; Marra F.; Fani B.; Biasini E.; Sacco R.; Morisco F.; Caporaso N.; Colombo M.; D'ambrosio R.; Croce L.S.; Patti R.; Giannini E.G.; Loria P.; Lonardo A.; Baldelli E.; Miele L.; Farinati F.; Borzio M.; Dionigi E.; Soardo G.; Caturelli E.; Ciccarese F.; Virdone R.; Affronti A.; Foschi F.G.; Borzio F.Piscaglia, F.; Svegliati-Baroni, G.; Barchetti, A.; Pecorelli, A.; Marinelli, S.; Tiribelli, C.; Bellentani, S.; Bernardi, M.; Biselli, M.; Caraceni, P.; Domenicali, M.; Garuti, F.; Gramenzi, A.; Lenzi, B.; Magalotti, D.; Cescon, M.; Ravaioli, M.; Del Poggio, P.; Olmi, S.; Rapaccini, G. L.; Balsamo, C.; Di Nolfo, M. A.; Vavassori, E.; Alberti, A.; Benvegnau, L.; Gatta, A.; Giacomin, A.; Vanin, V.; Pozzan, C.; Maddalo, G.; Giampalma, E.; Cappelli, A.; Golfieri, R.; Mosconi, C.; Renzulli, M.; Roselli, P.; Dell'Isola, S.; Ialungo, A. M.; Risso, D.; Marenco, S.; Sammito, G.; Bruzzone, L.; Bosco, G.; Grieco, A.; Pompili, M.; Rinninella, E.; Siciliano, M.; Chiaramonte, M.; Guarino, M.; Camma, C.; Maida, M.; Costantino, A.; Barcellona, M. R.; Schiada, L.; Gemini, S.; Lanzi, A.; Stefanini, G. F.; Dall'Aglio, A. C.; Cappa, F. M.; Suzzi, A.; Mussetto, A.; Treossi, O.; Missale, G.; Porro, E.; Mismas, V.; Vivaldi, C.; Bolondi, L.; Zoli, M.; Granito, A.; Malagotti, D.; Tovoli, F.; Trevisani, F.; Venerandi, L.; Brandi, G.; Cucchetti, A.; Bugianesi, E.; Vanni, E.; Mezzabotta, L.; Cabibbo, G.; Petta, S.; Fracanzani, A.; Fargion, S.; Marra, F.; Fani, B.; Biasini, E.; Sacco, R.; Morisco, F.; Caporaso, N.; Colombo, M.; D'Ambrosio, R.; Croce, L. S.; Patti, R.; Giannini, E. G.; Loria, P.; Lonardo, A.; Baldelli, E.; Miele, L.; Farinati, F.; Borzio, M.; Dionigi, E.; Soardo, G.; Caturelli, E.; Ciccarese, F.; Virdone, R.; Affronti, A.; Foschi, F. G.; Borzio, F

Interferon-λ rs12979860 genotype and liver fibrosis in viral and non-viral chronic liver disease

Tissue fibrosis is a core pathologic process that contributes to mortality in ~45% of the population and is likely to be influenced by the host genetic architecture. Here we demonstrate, using liver disease as a model, that a single-nucleotide polymorphism (rs12979860) in the intronic region of ​interferon-λ4 (​IFNL4) is a strong predictor of fibrosis in an aetiology-independent manner. In a cohort of 4,172 patients, including 3,129 with chronic hepatitis C (CHC), 555 with chronic hepatitis B (CHB) and 488 with non-alcoholic fatty liver disease (NAFLD), those with rs12979860CC have greater hepatic inflammation and fibrosis. In CHC, those with rs12979860CC also have greater stage-constant and stage-specific fibrosis progression rates (P<0.0001 for all). The impact of rs12979860 genotypes on fibrosis is maximal in young females, especially those with HCV genotype 3. These findings establish rs12979860 genotype as a strong aetiology-independent predictor of tissue inflammation and fibrosis

A variant in the MICA gene is associated with liver fibrosis progression in chronic hepatitis C through TGF-β1 dependent mechanisms.

Hepatocarcinogenesis is tightly linked to liver fibrosis. Recently, two GWAS variants, MICA rs2596542 and DEPDC5 rs1012068 were identified as being associated with the development of HCV-induced hepatocellular carcinoma (HCC) in Japanese patients. The role of these variants on hepatic inflammation and fibrosis that are closely associated with HCC development is not known, nor are the biological mechanisms underlying their impact on the liver. Here, we demonstrate in 1689 patients with chronic hepatitis C (CHC) (1,501 with CHC and 188 with HCV-related HCC), that the MICA (T) allele, despite not being associated with HCC susceptibility, is associated with increased fibrosis stage (OR: 1.47, 95% CI: 1.05-2.06, p = 0.02) and fibrosis progression rate (hazards ratio: 1.41, 95% CI: 1.04-1.90, p = 0.02). The DEPDC5 variant was not associated with any of these phenotypes. MICA expression was down-regulated in advanced fibrosis stages. Further, (T) allele carriage was associated with lower MICA expression in liver and serum. Transforming growth factor-β1 (TGF-β1) expression suppresses MICA expression in hepatic stellate cells. Our findings suggest a novel mechanism linking susceptibility to advanced fibrosis and subsequently indirectly to HCC, to the level of MICA expression through TGF-β1-dependent mechanisms

Accounting and Taxation of Intangibles with particular reference to IP

The aim of this Chapter is to provide an overview of the complex issues and various rules and approaches regarding accounting for, and reporting on, IP and intangibles. In particular, the analysis will delineate the issues linked to the recognition, measure, and disclosure both within and outside the traditional financial statements, which are posed by the intangible economy to private sector organizations. In this respect, there will be a section devoted to traditional accounting for intangibles and IP followed by a section illustrating some of the alternative methods to represent these critical resources