Publications by authors named "Antonio Grieco"

113 Publications

Caucasian lean subjects with non-alcoholic fatty liver disease share long-term prognosis of non-lean: time for reappraisal of BMI-driven approach?

Gut 2021 Feb 4. Epub 2021 Feb 4.

Department of Medical Sciences, Division of Gastroenterology and Hepatology, A.O. Città della Salute e della Scienza di Torino, Università degli Studi di Torino, Torino, Italy

Objective: The full phenotypic expression of non-alcoholic fatty liver disease (NAFLD) in lean subjects is incompletely characterised. We aimed to investigate prevalence, characteristics and long-term prognosis of Caucasian lean subjects with NAFLD.

Design: The study cohort comprises 1339 biopsy-proven NAFLD subjects from four countries (Italy, UK, Spain and Australia), stratified into lean and non-lean (body mass index (BMI)
Results: Lean patients represented 14.4% of the cohort and were predominantly of Italian origin (89%). They had less severe histological disease (lean vs non-lean: non-alcoholic steatohepatitis 54.1% vs 71.2% p<0.001; advanced fibrosis 10.1% vs 25.2% p<0.001), lower prevalence of diabetes (9.2% vs 31.4%, p<0.001), but no significant differences in the prevalence of the I148M variant (p=0.57). During a median follow-up of 94 months (>10 483 person-years), 4.7% of lean vs 7.7% of non-lean patients reported liver-related events (p=0.37). No difference in survival was observed compared with non-lean NAFLD (p=0.069).

Conclusions: Caucasian lean subjects with NAFLD may progress to advanced liver disease, develop metabolic comorbidities and experience cardiovascular disease (CVD) as well as liver-related mortality, independent of longitudinal progression to obesity and genotype. These patients represent one end of a wide spectrum of phenotypic expression of NAFLD where the disease manifests at lower overall BMI thresholds.

Lay Summary: NAFLD may affect and progress in both obese and lean individuals. Lean subjects are predominantly males, have a younger age at diagnosis and are more prevalent in some geographic areas. During the follow-up, lean subjects can develop hepatic and extrahepatic disease, including metabolic comorbidities, in the absence of weight gain. These patients represent one end of a wide spectrum of phenotypic expression of NAFLD.
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http://dx.doi.org/10.1136/gutjnl-2020-322564DOI Listing
February 2021

Cumulative incidence of solid and hematological De novo malignancy after liver transplantation in a multicentre cohort.

Ann Hepatol 2021 Jan 20;24:100309. Epub 2021 Jan 20.

Gastroenterology, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy. Electronic address:

Background: Recent innovations in the field of liver transplantation have led to a wealth of new treatment regimes, with potential impact on the onset of de novo malignancies (DNM). The aim of this multicenter cohort study was to provide contemporary figures for the cumulative incidences of solid and hematological DNM after liver transplantation.

Methods: We designed a retrospective cohort study including patients undergoing LT between 2000 and 2015 in three Italian transplant centers. Cumulative incidence was calculated by Kaplan-Meyer analysis.

Results: The study included 789 LT patients with a median follow-up of 81 months (IQR: 38-124). The cumulative incidence of non-cutaneous DNM was 6.2% at 5-years, 11.6% at 10-years and 16.3% at 15-years. Post-Transplant Lymphoproliferative Disorders (PTLD) were demonstrated to have a cumulative incidence of 1.0% at 5-years, 1.6% at 10-years and 2.2% at 15-years. Solid Organ Tumors (SOT) demonstrated higher cumulative incidences - 5.3% at 5-years, 10.3% at 10-years and 14.4% at 15-years. The most frequently observed classifications of SOT were lung (rate 1.0% at 5-years, 2.5% at 10-years) and head & neck tumors (rate 1.3% at 5-years, 1.9% at 10-years).

Conclusions: Lung tumors and head & neck tumors are the most frequently observed SOT after LT.
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http://dx.doi.org/10.1016/j.aohep.2021.100309DOI Listing
January 2021

Clinical characteristics of metabolic associated fatty liver disease (MAFLD) in subjects with myotonic dystrophy type 1 (DM1).

Dig Liver Dis 2021 Jan 9. Epub 2021 Jan 9.

Department of Neuroscience, Fondazione Policlinico Gemelli IRCCS, Università Cattolica del S. Cuore, Roma, Italy.

Background: Myotonic dystrophy type 1 (DM1) is a rare inherited neuromuscular disease associated with insulin resistance, and its association with metabolically associated fatty liver disease (MAFLD) has never been explored in prospective studies. The aim of this study was to assess the clinical features of MAFLD in DM1 patients.

Methods: We investigated the prevalence and the diagnostic features of MAFLD in a cohort of 29 outpatient fully characterized DM1 patients; afterward, we compared the selected cohort of DM1-MAFLD individuals with a propensity-matched cohort of non-DM1-MAFLD RESULTS: 13/29 (44.83%) DM1 patients received a clinical diagnosis of MAFLD. Compared to DM1 patients with normal liver, DM1-MAFLD individuals showed a higher male prevalence (p = 0.008), BMI (p = 0.014), HOMA score (p = 0.012), and GGT levels (p = 0.050). The statistical comparison showed that the DM1-MAFLD group had a more severe MAFLD according to the FIB4 score than non-DM1-MAFLD patients. This association of a more severe form of liver disease with DM1 remained significant after logistic regression analysis (OR: 6.12, 95% CI 1.44- 26.55).
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http://dx.doi.org/10.1016/j.dld.2020.12.010DOI Listing
January 2021

Nonalcoholic fatty liver disease (NAFLD) severity is associated to a nonhemostatic contribution and proinflammatory phenotype of platelets.

Transl Res 2020 Nov 7. Epub 2020 Nov 7.

Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del S. Cuore, Roma, Italy; UOSD Malattie Emorragiche e Trombotiche, Dipartimento di Diagnostica per immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy. Electronic address:

Nonalcoholic fatty liver disease (NAFLD) is the main cause of chronic liver disease and ranges from simple steatosis to nonalcoholic steatohepatitis. Recently, a platelet role in NAFLD pathogenesis and progression has been reported in mouse models and in patients. We investigated whether platelets are involved in liver and systemic inflammation processes in NAFLD. In this exploratory study we recruited 24 consecutive patients with biopsy-proven diagnosis of NAFLD and 17 healthy volunteers. We measured plasma levels of inflammatory markers by ELISA. We investigated hemostatic and inflammatory transcripts in circulating platelets and leukocytes from NAFLD patients. We analyzed platelet and neutrophil extracellular traps (NET) accumulations in liver sinusoids using CD42 and H3 citrullinated histones immunohistochemical staining on liver biopsies. NAFLD patients had increased inflammation markers and lipolysaccharides plasma levels. We found significant increase of inflammatory transcripts in circulating platelets and not in leukocytes of NAFLD subjects compared with healthy controls. We demonstrated increased intrahepatic platelet accumulation that correlated with NAFLD activity score (NAS) score and intrahepatic neutrophil extracellular traps (NET) formation in liver biopsies of NAFLD patients. NET formation was higher in livers with higher NAS and inflammation scores. The presence of low-grade systemic inflammation and proinflammatory changes of circulating platelets indicate that platelets participate on systemic inflammatory changes associated with NAFLD. Liver platelet accumulation and liver NET formation, together with low-grade endotoxemia, suggest that platelets may act to protect the liver from invading microorganisms by favoring local NET formation.
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http://dx.doi.org/10.1016/j.trsl.2020.11.003DOI Listing
November 2020

Use of imaging techniques for non-invasive assessment in the diagnosis and staging of non-alcoholic fatty liver disease.

Metabolism 2020 Sep 9;112:154355. Epub 2020 Sep 9.

Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Gemelli IRCCS, Università Cattolica del S. Cuore, Roma, Italy; Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del S. Cuore, Roma. Italy.

Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease and represent a common finding in highly prevalent metabolic disorders (i.e. type 2 diabetes, metabolic syndrome, obesity). Non-alcoholic steatohepatitis (NASH) requires liver biopsy for grading and staging the liver damage by the assessment of steatosis, inflammation and fibrosis. In parallel with the development of numerous 'liquid' biomarkers and algorithms that combine anthropometric and laboratory parameters, innovative hepatic imaging techniques have increasingly been developed to attempt to overcome the need for biopsy, both in diagnosis and staging of NAFLD, and in possible use in the follow-up of the disease. In this review, we focused on the different imaging techniques trying to highlight the strengths and disadvantages of different approaches, particularly for ultrasound techniques, in stratifying liver injury and fibrosis in patients with NAFLD / NASH.
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http://dx.doi.org/10.1016/j.metabol.2020.154355DOI Listing
September 2020

Circulating histone signature of human lean metabolic-associated fatty liver disease (MAFLD).

Clin Epigenetics 2020 08 20;12(1):126. Epub 2020 Aug 20.

International Clinical Research Center, St Anne's University Hospital, Brno, Czech Republic.

Background: Although metabolic associate fatty liver disease (MAFLD) is associated with obesity, it can also occur in lean patients. MAFLD is more aggressive in lean patients compared to obese patients, with a higher risk of mortality. Specific biomarkers to diagnose differentially lean or overweight MAFLD are missing. Histones and nucleosomes are released in the bloodstream upon cell death. Here, we propose a new, fast, imaging and epigenetics based approach to investigate the severity of steatosis in lean MAFLD patients.

Results: A total of 53 non-obese patients with histologically confirmed diagnosis of MAFLD were recruited. Twenty patients displayed steatosis grade 1 (0-33%), 24 patients with steatosis grade 2 (34-66%) and 9 patients with steatosis grade 3 (67-100%). The levels of circulating nucleosomes were assayed using enzyme-linked immunosorbent assay, while individual histones or histone dimers were assayed in serum samples by means of a new advanced flow cytometry ImageStream(X)-adapted method. Circulating nucleosome levels associated poorly with MAFLD in the absence of obesity. We implemented successfully a multi-channel flow methodology on ImageStream(X), to image single histone staining (H2A, H2B, H3, H4, macroH2A1.1 and macroH2A1.2). We report here a significant depletion of the levels of histone variants macroH2A1.1 and macroH2A1.2 in the serum of lean MAFLD patients, either individually or in complex with H2B.

Conclusions: In summary, we identified a new circulating histone signature able to discriminate the severity of steatosis in individuals with lean MAFLD, using a rapid and non-invasive ImageStream(X)-based imaging technology.
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http://dx.doi.org/10.1186/s13148-020-00917-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441674PMC
August 2020

Genetic susceptibility of increased intestinal permeability is associated with progressive liver disease and diabetes in patients with non-alcoholic fatty liver disease.

Nutr Metab Cardiovasc Dis 2020 10 27;30(11):2103-2110. Epub 2020 Jun 27.

University Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy; Department of Medicine and Surgery, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.

Background And Aim: Increased intestinal permeability plays a key role in the pathogenesis of fat deposition in the liver. The aim of our study was to assess whether a single nucleotide polymorphism of protein tyrosine phosphatase non-receptor type 2 (PTPN2) (rs2542151 T→G), involved in intestinal permeability, may be associated with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM).

Methods And Results: We recruited a prospective cohort of NAFLD subjects and matched controls. Clinical data, PTPN2 genotype and laboratory data were collected for each patient. Results were stratified according to liver histology and diabetes. We enrolled 566 cases and 377 controls. PTPN2 genotype distribution did not significantly differ between patients and controls. In the entire population, patients with PTPN2 rs2542151 T→G (dominant model) have a higher prevalence of diabetes; 345 patients (60.9%) underwent liver biopsy: 198 (57.4%) had steatohepatitis and 75 (21.7%) had advanced fibrosis. At multiple logistic regression analysis PTPN2 rs2542151 T→G was associated with T2DM (OR 2.14, 95% CI 1.04-4.40, P = 0.03). Patients who underwent liver biopsy, rs2542151 T→G of PTPN2 was independently associated with severe steatosis (OR 2.00, 95% CI 1.17-3.43, p = 0.01) and severe fibrosis (OR 2.23, 95% CI 1.06-4.72, P = 0.03).

Conclusion: Our study shows that NAFLD patients with rs2542151 T→G of PTPN2 have a higher severity of fatty liver disease and a higher prevalence of T2DM. These results suggest that individual genetic susceptibility to intestinal permeability could play a role in liver disease progression.
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http://dx.doi.org/10.1016/j.numecd.2020.06.013DOI Listing
October 2020

Neurotensin up-regulation is associated with advanced fibrosis and hepatocellular carcinoma in patients with MAFLD.

Biochim Biophys Acta Mol Cell Biol Lipids 2020 10 11;1865(10):158765. Epub 2020 Jul 11.

General Medicine and Metabolic Diseases, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy; Departments of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy. Electronic address:

Background & Aims: Neurotensin (NTS), a 13-aminoacid peptide localized in central nervous system and gastrointestinal tract, is involved in lipid metabolism and promotes various cancers onset mainly by binding to neurotensin receptor 1 (NTSR1). Increased plasma levels of pro-NTS, the stable NTS precursor, have been associated with type 2 diabetes (T2D), cardiovascular diseases and metabolic associated fatty liver disease (MAFLD). We aimed to evaluate 1) the impact of NTS rs1800832 and NTSR1 rs6090453 genetic variants on liver damage in 1166 MAFLD European individuals, 2) the relation between NTS variant and circulating pro-NTS and 3) the hepatic NTS expression by RNAseq transcriptomic analysis in 125 bariatric patients.

Results: The NTS rs1800832 G allele was associated with hepatic fibrosis (OR 1.27, 95% confidence interval (CI). 1.02-1.58; p = 0.03), even more in carriers of both NTS and NTSR1 G risk alleles (OR 1.17, 95% CI. 1.03-1.34; p = 0.01), with cirrhosis (OR 1.58, 95% CI. 1.07-2.34; p = 0.02) and HCC (OR 1.98, 95% CI. 1.24-3.2; p = 0.004). Pro-NTS circulating levels were correlated with T2D (p = 0.005), BMI, (p = 0.04), age (p = 0.0016), lobular inflammation (p = 0.0025), fibrosis>2 (p < 0.0001), cirrhosis (p = 0.0009) and HCC (p < 0.0001) and more so after stratification for the NTS G allele. Transcriptomic data showed that hepatic NTS expression correlated with that of fibrogenic genes (p < 0.05).

Conclusions: NTS rs1800832 variant is associated with advanced fibrosis and HCC in MAFLD patients likely affecting NTS protein activity. The rs6090453 NTSR1 gene variant synergizes with NTS rs1800832 mutation to promote liver damage. Prospective studies are necessary to confirm NTS role in liver disease progression.
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http://dx.doi.org/10.1016/j.bbalip.2020.158765DOI Listing
October 2020

High Prevalence and Gender-Related Differences of Gastrointestinal Manifestations in a Cohort of DM1 Patients: A Perspective, Cross-Sectional Study.

Front Neurol 2020 12;11:394. Epub 2020 Jun 12.

Institute of Neurology, Università Cattolica del Sacro Cuore, Rome, Italy.

Myotonic dystrophy type 1 (DM1, MIM #160900), the most common muscular dystrophy among adults, is a multisystem disorder, which affects, besides the skeletal muscle, several other tissues and/or organs, including the gastrointestinal apparatus, with manifestations that frequently affect the quality of life of DM1 patients. So far, only few, mainly retrospective studies evaluated this specific topic in DM1, so we performed a perspective study, enrolling 61 DM1 patients who underwent an extensive diagnostic protocol, including administration of the Gastrointestinal Symptom Rating Scale (GSRS), a validated patient-reported questionnaire about GI symptoms, laboratory tests, liver US scan, and an intestinal permeability assay, in order to characterize frequency and assess correlations regarding specific gastrointestinal manifestations with demographic or other DM1-related features. Our results in our DM1 cohort confirm the high frequency of various gastrointestinal manifestations, with the most frequent being constipation (45.9%). γGT levels were pathologically increased in 65% of DM1 patients and GPT in 29.82%; liver ultrasound studies showed steatosis in 34.4% of patients. Significantly, 91.22% of DM1 patients showed signs of altered intestinal permeability at the specific assay. We documented a gender-related prevalence and severity of gastrointestinal manifestations in DM1 females compared to DM1 males, while males showed higher serum GPT and γGT levels than females. Correlation studies documented a direct correlation between severity of muscle weakness estimated by MIRS score and γGT and alkaline phosphatase levels, suggesting their potential use as biomarkers of muscle disease severity in DM1.
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http://dx.doi.org/10.3389/fneur.2020.00394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303304PMC
June 2020

Effect of liver transplantation on intestinal permeability and correlation with infection episodes.

PLoS One 2020 26;15(6):e0235359. Epub 2020 Jun 26.

Emergency Surgery-Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.

Background: Liver cirrhosis has been known to be associated with increased intestinal permeability (IP); however, little is known about the modification of IP after liver transplantation (LT). The present study was aimed to assess IP after LT and evaluated its association with laboratory tests and clinical parameters, as well as with the development of infections.

Methods: LT recipients were consecutively enrolled and compared with an equal number of patients with liver cirrhosis and healthy subjects. IP was assessed by urinary excretion of chromium-51 ethylenediaminetetraacetic acid (51Cr-EDTA).

Results: The median 51Cr-EDTA excretion was found to be higher in 35 LT recipients as compared with that in the healthy controls [4.77% (2.79-6.03) vs. 2.07% (1.57-2.42), p<0.0001], and comparable to that in the cirrhotic patients [3.69% (2.34-6.57), p = 0.445]. 51Cr-EDTA excretion was not associated with clinical variables, the type of immunosuppressive therapy, donor-related factors, comorbidities and incidence of infections [infection/no infection: 4.97% (3.14-7.03) vs 4.62% (2.79-5.82), p = 0.938].

Conclusion: LT recipients show an increased IP, similar to that in patients with liver cirrhosis. However, it is not associated with a high risk of infections. Further investigations into the pathogenesis of this persistent impairment of the intestinal barrier are warranted.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235359PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319319PMC
September 2020

Presence of Serum Antinuclear Antibodies Does Not Impact Long-Term Outcomes in Nonalcoholic Fatty Liver Disease.

Am J Gastroenterol 2020 08;115(8):1289-1292

Department of Medical Sciences, Division of Gastroenterology and Hepatology, A.O. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy.

Introduction: We investigated the longitudinal impact of antinuclear antibody (ANA) on clinical outcomes and survival in nonalcoholic fatty liver disease (NAFLD).

Methods: ANA were found in 16.9% of 923 biopsy-proven NAFLD patients, but none of them had histologic autoimmune hepatitis (AIH) or developed AIH after a mean follow-up of 106±50 months.

Results: Although ANA-positive cases had a higher prevalence of nonalcoholic steatohepatitis at baseline, the occurrence of liver-related events, hepatocellula carcinoma, cardiovascular events, extrahepatic malignancy, and overall survival were similar to ANA-negative.

Discussion: Once AIH has been ruled out, the long-term outcomes and survival are unaffected by the presence of ANA in patients with NAFLD.
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http://dx.doi.org/10.14309/ajg.0000000000000676DOI Listing
August 2020

Contrast-Enhanced Ultrasound in the Short-Term Evaluation of Hepatocellular Carcinoma after Locoregional Treatment.

Dig Dis 2020 13;38(6):522-533. Epub 2020 Feb 13.

Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Catholic University of Rome, Rome, Italy,

Background: Contrast-enhanced ultrasound (CEUS) with second-generation contrast agents performed 1 month after hepatocellular carcinoma (HCC) treatment is almost as sensitive as contrast-enhanced computed tomography (CECT) in depicting the residual tumor. However, the efficacy of CEUS performed early after the procedure is still debated.

Aim: We evaluated the diagnostic accuracy (DA) of CEUS for the assessment of tumor response shortly after locoregional therapy in patients with unresectable HCC.

Methods: Ninety-four patients with 104 HCC lesions who were scheduled to receive percutaneous ethanol injection, radiofrequency ablation, transcatheter arterial chemoembolization, or combined treatment were enrolled in this study. With CECT at 1-month as the reference standard, the DA of CEUS performed 48-h after the procedure was evaluated. Patients were followed-up to look for tumor or disease progression.

Results: Based on CECT findings, 43/104 lesions were diagnosed as having residual viability after 1 month. CEUS performed 48 h after treatment detected residual tumor in 34/43 nodules with treatment failure at CECT with a sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 79.1, 96.7, 94.4, 86.8, and 89%, respectively. There was a high degree of concordance between CEUS and CECT (kappa coefficient = 0.78). A hyperemic halo was detectable in 35 lesions without a statistically significant difference between concordant and discordant cases. In patients with uninodular disease responders according to 48 h CEUS had a significantly longer mean overall survival and time to progression compared to nonresponders.

Conclusion: CEUS performed 48 h after treatment can be considered a reliable modality for the evaluation of the real extent of necrosis and has prognostic value in the assessment of HCC.
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http://dx.doi.org/10.1159/000506455DOI Listing
November 2020

Outcomes of Liver Transplant for Adults With Wilson's Disease.

Liver Transpl 2020 04 23;26(4):507-516. Epub 2020 Feb 23.

Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padua University Hospital, Padua, Italy.

Wilson's disease (WD) is a rare genetic disorder with protean manifestations. Even if liver transplantation (LT) could represent an effective therapeutic option for patients with end-stage liver disease, it has remained controversial in the presence of neuropsychiatric involvement. This study aimed to examine the frequency of adult LT for WD in Italy, focusing on the disease phenotype at the time of LT. A retrospective, observational, multicenter study was conducted across Italy exploring the frequency and characteristics of adults transplanted for WD between 2006 and 2016. A total of 29 adult WD patients underwent LT during the study period at 11 Italian LT centers (accounting for 0.4% of all LTs performed), and 27 of them were considered in this analysis (male/female, n = 9/18; age at LT, 29 years [19-60 years]; median Model for End-Stage Liver Disease score at LT, 27 [6-49]). Isolated hepatic phenotype was the indication for LT in 17 (63%) patients, whereas 2 (7%) patients underwent LT for neurological impairment on compensated liver disease. Overall 1- and 5-year patient survival was excellent (88% and 83%, respectively). Neuropsychiatric symptoms early after LT completely recovered in only a few patients. In conclusion, WD remains an uncommon, unusual indication for LT in Italy, displaying good post-LT graft and patient survival. Because isolated neuropsychiatric involvement represents a rare indication to LT, more data are needed to properly assess the value of LT for WD in this subset of patients.
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http://dx.doi.org/10.1002/lt.25714DOI Listing
April 2020

A Role for the Biological Clock in Liver Cancer.

Cancers (Basel) 2019 Nov 11;11(11). Epub 2019 Nov 11.

Fondazione Policlinico Universitario A Gemelli-IRCCS- Catholic University of the Sacred Heart, 00168 Rome, Italy.

The biological clock controls at the molecular level several aspects of mammalian physiology, by regulating daily oscillations of crucial biological processes such as nutrient metabolism in the liver. Disruption of the circadian clock circuitry has recently been identified as an independent risk factor for cancer and classified as a potential group 2A carcinogen to humans. Hepatocellular carcinoma (HCC) is the prevailing histological type of primary liver cancer, one of the most important causes of cancer-related death worldwide. HCC onset and progression is related to B and C viral hepatitis, alcoholic and especially non-alcoholic fatty liver disease (NAFLD)-related milieu of fibrosis, cirrhosis, and chronic inflammation. In this review, we recapitulate the state-of-the-art knowledge on the interplay between the biological clock and the oncogenic pathways and mechanisms involved in hepatocarcinogenesis. Finally, we propose how a deeper understanding of circadian clock circuitry-cancer pathways' crosstalk is promising for developing new strategies for HCC prevention and management.
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http://dx.doi.org/10.3390/cancers11111778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895918PMC
November 2019

Intestinal permeability in the pathogenesis of liver damage: From non-alcoholic fatty liver disease to liver transplantation.

World J Gastroenterol 2019 Sep;25(33):4814-4834

Fondazione Policlinico Universitario A Gemelli IRCCS, Rome 00168, Italy.

The intimate connection and the strict mutual cooperation between the gut and the liver realizes a functional entity called gut-liver axis. The integrity of intestinal barrier is crucial for the maintenance of liver homeostasis. In this mutual relationship, the liver acts as a second firewall towards potentially harmful substances translocated from the gut, and is, in turn, is implicated in the regulation of the barrier. Increasing evidence has highlighted the relevance of increased intestinal permeability and consequent bacterial translocation in the development of liver damage. In particular, in patients with non-alcoholic fatty liver disease recent hypotheses are considering intestinal permeability impairment, diet and gut dysbiosis as the primary pathogenic trigger. In advanced liver disease, intestinal permeability is enhanced by portal hypertension. The clinical consequence is an increased bacterial translocation that further worsens liver damage. Furthermore, this pathogenic mechanism is implicated in most of liver cirrhosis complications, such as spontaneous bacterial peritonitis, hepatorenal syndrome, portal vein thrombosis, hepatic encephalopathy, and hepatocellular carcinoma. After liver transplantation, the decrease in portal pressure should determine beneficial effects on the gut-liver axis, although are incompletely understood data on the modifications of the intestinal permeability and gut microbiota composition are still lacking. How the modulation of the intestinal permeability could prevent the initiation and progression of liver disease is still an uncovered area, which deserves further attention.
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http://dx.doi.org/10.3748/wjg.v25.i33.4814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737313PMC
September 2019

Gallbladder perforation without cholecystitis in a patient awaiting liver transplantation: a peculiar case report of anaemia in cirrhosis.

BMC Gastroenterol 2019 Jun 27;19(1):112. Epub 2019 Jun 27.

Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy.

Background: Acute anaemia in decompensated liver cirrhosis is commonly caused due to gastrointestinal bleeding; however, sometimes, detecting the site of blood loss is challenging. A patient on waitlist for orthotopic liver transplantation because of decompensated liver cirrhosis was admitted with acute anaemia and recurrence of ascites. Their abdomen CT showed migration of gallbladder stones in the pelvis while paracentesis documented hemoperitoneum. A diagnosis of gallbladder perforation was performed.

Conclusion: Challenging choice of a "wait and see" strategy with conservative therapy, avoiding high-risk cholecystectomy, resulted in a successful liver transplant.
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http://dx.doi.org/10.1186/s12876-019-1018-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598236PMC
June 2019

Rare Pathogenic Variants Predispose to Hepatocellular Carcinoma in Nonalcoholic Fatty Liver Disease.

Sci Rep 2019 03 6;9(1):3682. Epub 2019 Mar 6.

Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Nonalcoholic fatty liver disease (NAFLD) is a rising cause of hepatocellular carcinoma (HCC). We examined whether inherited pathogenic variants in candidate genes (n = 181) were enriched in patients with NAFLD-HCC. To this end, we resequenced peripheral blood DNA of 142 NAFLD-HCC, 59 NAFLD with advanced fibrosis, and 50 controls, and considered 404 healthy individuals from 1000 G. Pathogenic variants were defined according to ClinVar, likely pathogenic as rare variants predicted to alter protein activity. In NAFLD-HCC patients, we detected an enrichment in pathogenic (p = 0.024), and likely pathogenic variants (p = 1.9*10), particularly in APOB (p = 0.047). APOB variants were associated with lower circulating triglycerides and higher HDL cholesterol (p < 0.01). A genetic risk score predicted NAFLD-HCC (OR 4.96, 3.29-7.55; p = 5.1*10), outperforming the diagnostic accuracy of common genetic risk variants, and of clinical risk factors (p < 0.05). In conclusion, rare pathogenic variants in genes involved in liver disease and cancer predisposition are associated with NAFLD-HCC development.
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http://dx.doi.org/10.1038/s41598-019-39998-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6403344PMC
March 2019

Intestinal permeability after Mediterranean diet and low-fat diet in non-alcoholic fatty liver disease.

World J Gastroenterol 2019 Jan;25(4):509-520

Department of Gastroenterological, Endocrine-Metabolic and Nefro-Urological Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome 00168, Italy.

Background: In non-alcoholic fatty liver disease (NAFLD), a high-fat or high-fructose diet increases intestinal permeability and promotes derangement of the gut-liver axis. We hypothesize that, diet could be able to modulate intestinal permeability in patients with NAFLD.

Aim: To detect diet-induced modification of intestinal permeability in patients with NAFLD undergoing a Mediterranean diet or a low-fat diet.

Methods: The current study was a dietary intervention for non-diabetic, patients with biopsy-verified NAFLD and increased transaminases. A crossover design was employed: participants underwent 16 weeks of Mediterranean diet, 16 wk of free wash-out, and 16 weeks of low-fat diet. Both diets were hypocaloric and no consumption of supplements was allowed. All patients were followed bimonthly by a dietitian. Evaluations of clinical and metabolic parameters were completed at baseline and at the end of each dietary period. Intestinal permeability was assessed by chromium-51 ethylene diamine tetraacetate excretion testing (51Cr-EDTA).

Results: Twenty Caucasian patients, 90% male, median age 43 years, body mass index (BMI) 30.9, with biopsy-verified NAFLD were enrolled. At the end of 16 weeks of a Mediterranean diet, a significant reduction in mean body weight (-5.3 ± 4.1 kg, = 0.003), mean waist circumference (-7.9 ± 4.9 cm, = 0.001), and mean transaminase levels [alanine aminotransferase (ALT) -28.3 ± 11.9 IU/L, = 0.0001; aspartate aminotransferase (AST) -6.4 ± 56.3 IU/L, = 0.01] were observed. These benefits were maintained after 16 wk of wash-out and also after 16 wk of low-fat diet, without further improvements. Fourteen of the 20 patients had intestinal permeability alteration at baseline (mean percentage retention of 51Cr-EDTA = 5.4%), but no significant changes in intestinal permeability were observed at the end of the 16 wk of the Mediterranean diet or 16 wk of the low-fat diet.

Conclusion: Mediterranean diet is an effective strategy for treating overweight, visceral obesity and serum transaminase in patients with NAFLD. If the Mediterranean diet can improve intestinal permeability in patients with NAFLD, it deserves further investigation.
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http://dx.doi.org/10.3748/wjg.v25.i4.509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350174PMC
January 2019

Daclatasvir-based regimens in HCV cirrhosis: experience from the Italian early access program.

Sci Rep 2019 01 24;9(1):585. Epub 2019 Jan 24.

Gastroenterology and Hepatology Unit, Dipartimento Biomedico di Medicina Interna e Specialistica, University of Palermo, Palermo, Italy.

We reported the efficacy and safety data for daclatasvir (DCV)-based all-oral antiviral therapy in patients treated in the Italian compassionate-use program. 275 patients were included (202 male-73.5%, mean age: 57.4 years, 62 HIV-coinfected, 94 with recurrence of hepatitis C post-OLT). Forty-nine patients (17.8%) had Child-Pugh B, Genotype(G) distribution was: G1a:72 patients (26.2%), G1b:137 (49.8%); G3:40 (14.5%) and G4:26 (9.5%). Patients received DCV with sofosbuvir(SOF) (n = 221, 129 with ribavirin(RBV) or with simeprevir (SMV) or asunaprevir (ASU) (n = 54, 19 with RBV) for up to 24 weeks. Logistic regression was used to identify baseline characteristics associated with sustained virological response at week 12 post-treatment (SVR12). Liver function changes between baseline and follow up were assessed in 228 patients. 240 patients achieved SVR12 (87.3%), post transplant and HIV co-infected patients were equally distributed among SVR and no SVR (35% vs 34.3%; p = 0.56 and 24.2% vs 11.4%, p = 0.13, respectively). SVR rate was significantly higher with the combination DCV + SOF compared with DCV + SIM or ASU (93.2% vs 63.0%, p < 0.0001). Bilirubin value (OR: 0.69, CI95%: 0.54-0.87, p = 0.002) and regimen containing SOF (OR: 9.99, CI95%: 4.09-24.40; p < 0.001) were independently related with SVR. Mean albumin and bilirubin values significantly improved between baseline and follow-up week 12. DCV-based antiviral therapy was well tolerated and resulted in a high SVR when combined with SOF either in pre-transplant and in OLT patients and in "difficult to treat" HCV genotypes. Regimens containing DCV in combination with NS3 protease inhibitors obtained suboptimal results.
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http://dx.doi.org/10.1038/s41598-018-36734-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345835PMC
January 2019

Liver injury after pulsed methylprednisolone therapy in multiple sclerosis patients.

Brain Behav 2018 06 4;8(6):e00968. Epub 2018 May 4.

Multiple Sclerosis Center, Neuroscience Area, Neuroscience, Aging, Head and Neck and Orthopaedics Sciences Department, Fondazione Policlinico Universitario Gemelli, Catholic University of Sacred Heart, Rome, Italy.

Objectives: High-dose pulsed methylprednisolone-related liver injury cases have been reported in the literature, but a prospective study in patients with multiple sclerosis (MS) has never been performed. The aim of this study was to evaluate the prevalence and severity of liver injury in patients with MS after pulsed methylprednisolone therapy.

Methods: We performed a prospective observational single-center study on patients with MS treated with i.v. methylprednisolone 1,000 mg/day for 5 days. We tested the liver functionality before and 2 weeks after the treatment. In case of severe liver injury, defined according to "Hy's law," a comprehensive hepatologic workup was performed.

Results: During a 12-month observation period, we collected data on 251 cycles of i.v. steroid treatment of 175 patients with MS. After excluding eight cycles presenting a basal alteration of the biochemical liver tests, we observed a prevalence of 8.6% of liver injury in MS patients treated with pulsed methylprednisolone for clinical and neuroradiological relapses. In 2.5% of the patients, the liver injury was severe according to Hy's law; after a comprehensive hepatologic workup, three of them received a diagnosis of drug-induced liver injury and the other three of autoimmune hepatitis.

Conclusions: Liver injury after pulsed methylprednisolone therapy in patients with MS is not infrequent, and a close monitoring of aminotransferase level before treatment and 2 weeks later seems advisable.
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http://dx.doi.org/10.1002/brb3.968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5991562PMC
June 2018

Copper/MYC/CTR1 interplay: a dangerous relationship in hepatocellular carcinoma.

Oncotarget 2018 Feb 20;9(10):9325-9343. Epub 2018 Jan 20.

MESVA Department, University of L'Aquila, L'Aquila, Italy.

Free serum copper correlates with tumor incidence and progression of human cancers, including hepatocellular carcinoma (HCC). Copper extracellular uptake is provided by the transporter CTR1, whose expression is regulated to avoid excessive intracellular copper entry. Inadequate copper serum concentration is involved in the pathogenesis of Non Alcoholic Fatty Liver Disease (NAFLD), which is becoming a major cause of liver damage progression and HCC incidence. Finally, MYC is over-expressed in most of HCCs and is a critical regulator of cellular growth, tumor invasion and metastasis. The purpose of our study was to understand if higher serum copper concentrations might be involved in the progression of NAFLD-cirrhosis toward-HCC. We investigated whether high exogenous copper levels sensitize liver cells to transformation and if it exists an interplay between copper-related proteins and MYC oncogene. NAFLD-cirrhotic patients were characterized by a statistical significant enhancement of serum copper levels, even more evident in HCC patients. We demonstrated that high extracellular copper concentrations increase cell growth, migration, and invasion of liver cancer cells by modulating MYC/CTR1 axis. We highlighted that MYC binds a specific region of the CTR1 promoter, regulating its transcription. Accordingly, CTR1 and MYC proteins expression were progressively up-regulated in liver tissues from NAFLD-cirrhotic to HCC patients. This work provides novel insights on the molecular mechanisms by which copper may favor the progression from cirrhosis to cancer. The Cu/MYC/CTR1 interplay opens a window to refine HCC diagnosis and design new combined therapies.
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http://dx.doi.org/10.18632/oncotarget.24282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5823635PMC
February 2018

Reverse time-dependent effect of alphafetoprotein and disease control on survival of patients with Barcelona Clinic Liver Cancer stage C hepatocellular carcinoma.

World J Hepatol 2017 Dec;9(36):1322-1331

Department of Internal Medicine, Gastroenterology and Hepatology, Agostino Gemelli Hospital, Rome 00168, Italy.

Aim: To characterize the survival of cirrhotic patients with Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC) and to ascertain the factors predicting the achievement of disease control (DC).

Methods: The cirrhotic patients with BCLC stage C HCC evaluated by the Hepatocatt multidisciplinary group were subjected to the investigation. Demographic, clinical and tumor features, along with the best tumor response and overall survival were recorded.

Results: One hundred and ten BCLC stage C patients were included in the analysis; the median overall survival was 13.4 mo (95%CI: 10.6-17.0). Only alphafetoprotein (AFP) serum level > 200 ng/mL and DC could independently predict survival but in a time dependent manner, the former was significantly associated with increased risk of mortality within the first 6 mo of follow-up (HR = 5.073, 95%CI: 2.159-11.916, = 0.0002), whereas the latter showed a protective effect against death after one year (HR = 0.110, 95%CI: 0.038-0.314, < 0.0001). Only patients showing microvascular invasion and/or extrahepatic spread recorded lower chances of achieving DC (OR = 0.263, 95%CI: 0.111-0.622, = 0.002).

Conclusion: The BCLC stage C HCC includes a wide heterogeneous group of cirrhotic patients suitable for potentially curative treatments. The reverse and time dependent effect of AFP serum level and DC on patients' survival confers them as useful predictive tools for treatment management and clinical decisions.
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http://dx.doi.org/10.4254/wjh.v9.i36.1322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5756721PMC
December 2017

Prognostic ability of BCLC-B Subclassification in Patients with Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization.

Ann Hepatol 2018 January-February;17(1):110-118

Department of Internal Medicine, Fondazione Policlinico Gemelli Catholic University of the Sacred Heart, Rome, Italy.

Prognostic ability of BCLC-B Subclassification in Patients with Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization Background and aims. A subclassification system for intermediate hepatocellular carcinoma (HCC) was recently proposed to optimize treatment allocation. The aim of this study was to assess the prognostic ability of that substaging proposal.

Patients And Methods: This is a retrospective multicenter cohort study including patients with intermediate HCC treated with transarterial chemoembolization (TACE). Predictors of survival were identified using the Cox proportional regression model.

Results: 289 Barcelona Clinic Liver Cancer (BCLC) B patients were included. Median overall survival of the whole cohort was 23 months (C.I. 95% 20.2- 25.8). Child A status (H.R. 1.35, C.I. 95% 1.02-1.78) and tumour burden beyond the up-to-seven criterion (H.R. 1.39, C.I. 95% 1.07- 1.80) were independent prognostic factors for overall survival on multivariate analysis. Analysis of the substages showed that median survival was 33.0 months for B1 stage (n = 81), 20.8 months for B2 stage (n = 106), 16.1 months for B3 stage (n = 24), 22.2 months for B4 stage (n = 42) and 15.0 months for quasi-C stage (n = 36). Regarding the discriminatory ability of the substaging proposal, the log rank test showed a significant survival difference for B1vs. B4 (p = 0.003) and B1 vs. Quasi-C (p = 0.039) and a trend for B1 vs. B2 (p = 0.05) and B1 vs. B3 (p = 0.05).

Conclusions: Apart from substage B1, BCLC-B subclassification does not discriminate perfectly patients treated with TACE. Also some patients in substage B4 can benefit from TACE.
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http://dx.doi.org/10.5604/01.3001.0010.7542DOI Listing
October 2018

Liver Transplantation in Patients with Alcoholic Liver Disease: A Retrospective Study.

Alcohol Alcohol 2018 Mar;53(2):151-156

Department of Internal Medicine, Gastroenterology and Hepatology, Catholic University of the Sacred Heart, Foundation A. Gemelli Hospital, Largo Gemelli 8, 00168 Rome, Italy.

Aim: Alcoholic liver disease (ALD) is the most common liver disease in the Western World. Liver transplantation (LT) is the treatment for end-stage ALD. However, many transplant centers are still reluctant to transplant these patients because of the risk of alcohol relapse, recurrence of the primary liver disease and associated post-transplant complications. We examined survival rate, prevalence of primary liver disease recurrence, re-transplantation and post-transplant complications among transplanted patients for alcoholic cirrhosis compared with those transplanted for viral cirrhosis.

Methods: data about patients transplanted for alcoholic and viral cirrhosis at the Gemelli Hospital from January 1995 to April 2016 were retrospectively collected. Survival rate was evaluated according to the Kaplan-Meier method. Recurrence was defined as histological evidence of primary liver disease. Data on the onset of complication, causes of death and graft failure after liver transplant were analyzed.

Results: There was no statistically significant difference regarding survival rate between the two groups. Only patients transplanted for viral cirrhosis presented with primary liver disease recurrence. There was a higher rate of cancer development in patients transplanted for alcoholic cirrhosis. Cancer was the major cause of death in this population. Risk factors associated with the onset of cancer were a high MELD score at the transplant time and smoking after transplantation.

Conclusion: ALD is a good indication for LT. Patients transplanted for alcoholic cirrhosis should receive regular cancer screening and should be advised against smoking.

Short Summary: No difference was found between patients transplanted for alcoholic cirrhosis and viral cirrhosis in term of survival rate. Only patients transplanted for viral cirrhosis presented primary liver disease recurrence. A higher rate of cancer development was found in patients transplanted for alcoholic cirrohosis. This complication was associated with post-trasplant smoking.
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http://dx.doi.org/10.1093/alcalc/agx097DOI Listing
March 2018

Enhanced liver fibrosis test as a reliable tool for assessing fibrosis in nonalcoholic fatty liver disease in a clinical setting.

Int J Biol Markers 2017 Oct 31;32(4):e397-e402. Epub 2017 Oct 31.

Department of Internal Medicine and Gastroenterology, Gemelli University Hospital, Catholic University of Sacred Heart, Rome - Italy.

Background: Liver fibrosis is the main determinant and predictor of the clinical course of nonalcoholic fatty liver disease (NAFLD). To date, a liver biopsy is still considered the gold standard for staging fibrosis. The aim of this study was to investigate the diagnostic accuracy of the commercial enhanced liver fibrosis (ELF) test manufacturer's cutoff value (≥9.8) in identifying severe fibrosis for adult patients with histologically confirmed NAFLD.

Methods: We tested the ELF test in a clinical practice, prospective cohort of 82 consecutive patients who consecutively underwent percutaneous liver biopsy.

Results: All stages of liver fibrosis were represented in our cohort, and severe fibrosis was present in 15 of 82 patients (18.3%). The stage of fibrosis was significantly associated with ELF score (Spearman's rho = 0.483, p<0.001). The commercial ELF test manufacturer's cutoff identified severe fibrosis with good sensitivity (86.7%; 95% confidence interval [95% CI], 0.69-1.04) and high specificity (92.5%; 95% CI, 0.86-0.99), with a positive predictive value of 72% and negative predictive value of 97%.

Conclusions: Our data could support the use of the ELF test in clinical practice.
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http://dx.doi.org/10.5301/ijbm.5000292DOI Listing
October 2017

Elevated Hemoglobin Level Is Associated With Advanced Fibrosis in Pediatric Nonalcoholic Fatty Liver Disease.

J Pediatr Gastroenterol Nutr 2017 08;65(2):150-155

*Department of Pediatrics, Fondazione Policlinico Universitario Agostino Gemelli, Università Cattolica del Sacro Cuore †Hepatometabolic Disease Unit, Bambino Gesù Children Hospital, Rome, Italy.

Objectives: Hemoglobin (Hb) and red blood cell distribution width (RDW) have been reported to be a risk marker of metabolic syndrome and nonalcoholic fatty liver disease (NAFLD). No study exists on pediatric populations. We aimed to determine the association between hematological parameters, and the severity of disease in children with biopsy-proven NAFLD.

Methods: A total of 117 children (85 boys, mean age 12 years) with ultrasound evidence of NAFLD undergoing liver biopsy for diagnosis of nonalcoholic steatohepatitis (NASH), were prospectively enrolled between January 2011 and May 2013 in the setting of a tertiary care center. Children were screened for routine hematological and metabolic parameters, and causes of liver steatosis other than nonalcoholic were excluded, before liver biopsy was performed.

Results: A total of 41 NAFLD (boys 29, mean age 11.2 years) and 76 NASH (boys 56, mean age 12.8 years) children were studied. Alanine transaminase levels were significantly higher in NASH group compared with NAFLD group (P = 0.05), and homeostatic model assessment of insulin resistance and triglycerides levels (P = 0.03 and 0.02, respectively). Regarding hematological components: red cell count, Hb, hematocrit, and RDW values were all significantly higher in NASH group compared with NAFLD group (P < 0.05 for each parameter).

Conclusions: Children with NASH were more likely to have high levels of RDW compared to those with steatosis only. Moreover, NASH was associated with higher red cell count, Hb, and hematocrit. If confirmed in future follow-up studies, hematological parameters may be introduced in algorithms for NASH risk prediction.
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http://dx.doi.org/10.1097/MPG.0000000000001614DOI Listing
August 2017

Telomerase reverse transcriptase germline mutations and hepatocellular carcinoma in patients with nonalcoholic fatty liver disease.

Cancer Med 2017 Aug 4;6(8):1930-1940. Epub 2017 Jul 4.

Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, 20122, Italy.

In an increasing proportion of cases, hepatocellular carcinoma (HCC) develops in patients with nonalcoholic fatty liver disease (NAFLD). Mutations in telomerase reverse transcriptase (hTERT) are associated with familial liver diseases. The aim of this study was to examine telomere length and germline hTERT mutations as associated with NAFLD-HCC. In 40 patients with NAFLD-HCC, 45 with NAFLD-cirrhosis and 64 healthy controls, peripheral blood telomere length was evaluated by qRT-PCR and hTERT coding regions and intron-exon boundaries sequenced. We further analyzed 78 patients affected by primary liver cancer (NAFLD-PLC, 76 with HCC). Enrichment of rare coding mutations (allelic frequency <0.001) was evaluated by Burden test. Functional consequences were estimated in silico and by over-expressing protein variants in HEK-293 cells. We found that telomere length was reduced in individuals with NAFLD-HCC versus those with cirrhosis (P = 0.048) and healthy controls (P = 0.0006), independently of age and sex. We detected an enrichment of hTERT mutations in NAFLD-HCC, that was confirmed when we further considered a larger cohort of NAFLD-PLC, and was more marked in female patients (P = 0.03). No mutations were found in cirrhosis and local controls, and only one in 503 healthy Europeans from the 1000 Genomes Project (allelic frequency = 0.025 vs. <0.001; P = 0.0005). Mutations with predicted functional impact, including the frameshift Glu113Argfs*79 and missense Glu668Asp, cosegregated with liver disease in two families. Three patients carried missense mutations (Ala67Val in homozygosity, Pro193Leu and His296Pro in heterozygosity) in the N-terminal template-binding domain (P = 0.037 for specific enrichment). Besides Glu668Asp, the Ala67Val variant resulted in reduced intracellular protein levels. In conclusion, we detected an association between shorter telomeres in peripheral blood and rare germline hTERT mutations and NAFLD-HCC.
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http://dx.doi.org/10.1002/cam4.1078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5548883PMC
August 2017

MBOAT7 rs641738 variant and hepatocellular carcinoma in non-cirrhotic individuals.

Sci Rep 2017 07 3;7(1):4492. Epub 2017 Jul 3.

Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122, Milano, Italy.

Nonalcoholic fatty liver disease (NAFLD) represents an emerging cause of hepatocellular carcinoma (HCC), especially in non-cirrhotic individuals. The rs641738 C > T MBOAT7/TMC4 variant predisposes to progressive NAFLD, but the impact on hepatic carcinogenesis is unknown. In Italian NAFLD patients, the rs641738 T allele was associated with NAFLD-HCC (OR 1.65, 1.08-2.55; n = 765), particularly in those without advanced fibrosis (p < 0.001). The risk T allele was linked to 3'-UTR variation in MBOAT7 and to reduced MBOAT7 expression in patients without severe fibrosis. The number of PNPLA3, TM6SF2, and MBOAT7 risk variants was associated with NAFLD-HCC independently of clinical factors (p < 0.001), but did not significantly improve their predictive accuracy. When combining data from an independent UK NAFLD cohort, in the overall cohort of non-cirrhotic patients (n = 913, 41 with HCC) the T allele remained associated with HCC (OR 2.10, 1.33-3.31). Finally, in a combined cohort of non-cirrhotic patients with chronic hepatitis C or alcoholic liver disease (n = 1121), the T allele was independently associated with HCC risk (OR 1.93, 1.07-3.58). In conclusion, the MBOAT7 rs641738 T allele is associated with reduced MBOAT7 expression and may predispose to HCC in patients without cirrhosis, suggesting it should be evaluated in future prospective studies aimed at stratifying NAFLD-HCC risk.
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http://dx.doi.org/10.1038/s41598-017-04991-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5495751PMC
July 2017

Liver transplantation for intermediate hepatocellular carcinoma: An adaptive approach.

World J Gastroenterol 2017 May;23(18):3195-3204

Marco Biolato, Giuseppe Marrone, Luca Miele, Antonio Gasbarrini, Antonio Grieco, Liver Transplant Medicine, Gastroenterological Area, Gastroenterological and Endocrino-Metabolical Sciences Department, Fondazione Policlinico Universitario Gemelli, Universita' Cattolica del Sacro Cuore, 00168 Roma, Italy.

Hepatocellular carcinoma is becoming an increasing indication for liver transplantation, but selection and allocation of patients are challenging because of organ shortages. Conventional Milan criteria are the reference for the selection of patients worldwide, but many expanded criteria, like University of California San Francisco criteria and up-to-7 criteria, have demonstrated that survival and recurrence results are lower than those for restricted indications. Correct staging is crucial and should include surrogate markers of biological aggressiveness (α-fetoprotein, response to loco-regional treatments). Successful down-staging can select between patients with tumor burden initially beyond transplantation criteria those with a more favorable biology, provided a 3-mo stability in meeting the transplantation criteria. Allocation rules are constantly adjusted to minimize the imbalance between the priorities of candidates with and without hepatocellular carcinoma, and take into account local donor rate and waitlist dynamics. Recently, Mazzaferro et al proposed a benefit-oriented "adaptive approach", in which the selection and allocation of patients are based on their response to non-transplantation treatments: low priority for transplantation in case of complete response, high priority in case of partial response or recurrence, and no listing in case of progression beyond transplantation criteria.
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http://dx.doi.org/10.3748/wjg.v23.i18.3195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5434425PMC
May 2017

Watery stools and metabolic acidosis.

Intern Emerg Med 2017 Jun 5;12(4):487-492. Epub 2017 Apr 5.

Institute of Internal Medicine and Gastroenterology Area, Fondazione Policlinico Universitario A. Gemelli, Università Cattolica del S. Cuore, Largo Gemelli, 00168, Rome, Italy.

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http://dx.doi.org/10.1007/s11739-017-1656-2DOI Listing
June 2017