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1. Starvation hepatitis and refeeding-induced hepatitis: mechanism, diagnosis, and treatment

Author

Biolato, Marco, Terranova, Rosy, Policola, Caterina, Pontecorvi, Alfredo, Gasbarrini, Antonio, Grieco, Antonio, Pontecorvi, Alfredo (ORCID:0000-0003-0570-6865), Gasbarrini, Antonio (ORCID:0000-0002-7278-4823), Grieco, Antonio (ORCID:0000-0002-0544-8993), Biolato, Marco, Terranova, Rosy, Policola, Caterina, Pontecorvi, Alfredo, Gasbarrini, Antonio, Grieco, Antonio, Pontecorvi, Alfredo (ORCID:0000-0003-0570-6865), Gasbarrini, Antonio (ORCID:0000-0002-7278-4823), and Grieco, Antonio (ORCID:0000-0002-0544-8993)

Abstract

Anorexia nervosa (AN) is one of the most common psychiatric disorders among young adults and is associated with a substantial risk of death from suicide and medical complications. Transaminase elevations are common in patients with AN at the time of hospital admission and have been associated with longer lengths of hospital stay. Multiple types of hepatitis may occur in these patients, including two types that occur only in patients with AN: starvation hepatitis and refeeding-induced hepatitis. Starvation hepatitis is characterized by severe transaminase elevation in patients in the advanced phase of protein-energy deprivation and is associated with complications of severe starvation, such as hypoglycaemia, hypothermia, and hypotension. Refeeding-induced hepatitis is characterized by a milder increase in transaminases that occurs in the early refeeding phase and is associated with hypophosphatemia, hypokalemia, and hypomagnesaemia. Among the most common forms of hepatitis, drug-induced liver injury is particularly relevant in this patient cohort, given the frequent use and abuse of methamphetamines, laxatives, antidepressants, and antipsychotics. In this review, we provided an overview of the different forms of anorexic-associated hepatitis, a diagnostic approach that can help the clinician to correctly frame the problem, and indications on their management and treatment.

Published
2024

2. Serum ferritin levels can predict long-term outcomes in patients with metabolic dysfunction-associated steatotic liver disease

Author

Armandi, Angelo, Sanavia, Tiziana, Younes, Ramy, Caviglia, Gian Paolo, Rosso, Chiara, Govaere, Olivier, Liguori, Antonio, Francione, Paolo, Gallego-Duràn, Rocìo, Ampuero, Javier, Pennisi, Grazia, Aller, Rocio, Tiniakos, Dina, Burt, Alastair, David, Ezio, Vecchio, Fabio Maria, Maggioni, Marco, Cabibi, Daniela, Mcleod, Duncan, Pareja, Maria Jesu, Zaki, Marco Y W, Grieco, Antonio, Stål, Per, Kechagias, Stergio, Fracanzani, Anna Ludovica, Valenti, Luca, Miele, Luca, Fariselli, Piero, Eslam, Mohammed, Petta, Salvatore, Hagström, Hanne, George, Jacob, Schattenberg, Jörn M, Romero-Gómez, Manuel, Anstee, Quentin Mark, Bugianesi, Elisabetta, Vecchio, Fabio (ORCID:0000-0002-9197-2264), Grieco, Antonio (ORCID:0000-0002-0544-8993), Miele, Luca (ORCID:0000-0003-3464-0068), Armandi, Angelo, Sanavia, Tiziana, Younes, Ramy, Caviglia, Gian Paolo, Rosso, Chiara, Govaere, Olivier, Liguori, Antonio, Francione, Paolo, Gallego-Duràn, Rocìo, Ampuero, Javier, Pennisi, Grazia, Aller, Rocio, Tiniakos, Dina, Burt, Alastair, David, Ezio, Vecchio, Fabio Maria, Maggioni, Marco, Cabibi, Daniela, Mcleod, Duncan, Pareja, Maria Jesu, Zaki, Marco Y W, Grieco, Antonio, Stål, Per, Kechagias, Stergio, Fracanzani, Anna Ludovica, Valenti, Luca, Miele, Luca, Fariselli, Piero, Eslam, Mohammed, Petta, Salvatore, Hagström, Hanne, George, Jacob, Schattenberg, Jörn M, Romero-Gómez, Manuel, Anstee, Quentin Mark, Bugianesi, Elisabetta, Vecchio, Fabio (ORCID:0000-0002-9197-2264), Grieco, Antonio (ORCID:0000-0002-0544-8993), and Miele, Luca (ORCID:0000-0003-3464-0068)

Abstract

Objective Hyperferritinaemia is associated with liver fibrosis severity in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), but the longitudinal implications have not been thoroughly investigated. We assessed the role of serum ferritin in predicting long-term outcomes or death. Design We evaluated the relationship between baseline serum ferritin and longitudinal events in a multicentre cohort of 1342 patients. Four survival models considering ferritin with confounders or non-invasive scoring systems were applied with repeated five-fold cross-validation schema. Prediction performance was evaluated in terms of Harrell's C-index and its improvement by including ferritin as a covariate. Results Median follow-up time was 96 months. Liver-related events occurred in 7.7%, hepatocellular carcinoma in 1.9%, cardiovascular events in 10.9%, extrahepatic cancers in 8.3% and all-cause mortality in 5.8%. Hyperferritinaemia was associated with a 50% increased risk of liver-related events and 27% of all-cause mortality. A stepwise increase in baseline ferritin thresholds was associated with a statistical increase in C-index, ranging between 0.02 (lasso-penalised Cox regression) and 0.03 (ridge-penalised Cox regression); the risk of developing liver-related events mainly increased from threshold 215.5 mu g/L (median HR=1.71 and C-index=0.71) and the risk of overall mortality from threshold 272 mu g/L (median HR=1.49 and C-index=0.70). The inclusion of serum ferritin thresholds (215.5 mu g/L and 272 mu g/L) in predictive models increased the performance of Fibrosis-4 and Non-Alcoholic Fatty Liver Disease Fibrosis Score in the longitudinal risk assessment of liver-related events (C-indices>0.71) and overall mortality (C-indices>0.65). Conclusions This study supports the potential use of serum ferritin values for predicting the long-term prognosis of patients with MASLD.

Published
2024

3. Branched chain amino acids in hepatic encephalopathy and sarcopenia in liver cirrhosis: Evidence and uncertainties

Author

Marrone, Giuseppe, Serra, Amato, Miele, Luca, Biolato, Marco, Liguori, Antonio, Grieco, Antonio, Gasbarrini, Antonio, Miele, Luca (ORCID:0000-0003-3464-0068), Grieco, Antonio (ORCID:0000-0002-0544-8993), Gasbarrini, Antonio (ORCID:0000-0002-7278-4823), Marrone, Giuseppe, Serra, Amato, Miele, Luca, Biolato, Marco, Liguori, Antonio, Grieco, Antonio, Gasbarrini, Antonio, Miele, Luca (ORCID:0000-0003-3464-0068), Grieco, Antonio (ORCID:0000-0002-0544-8993), and Gasbarrini, Antonio (ORCID:0000-0002-7278-4823)

Abstract

Liver cirrhosis is commonly associated with nutritional alterations, reported in 20% of patients with compensated disease and over 60% of patients with decompensated cirrhosis. Nutritional disturbances are associated with a worse prognosis and increased risk of complication. Serum levels of branched-chain amino acids (BCAAs) are decreased in patients with liver cirrhosis. The imbalance of amino acids levels has been suggested to be associated with the development of complications, such as hepatic encephalopathy and sarcopenia, and to affect the clinical presentation and prognosis of these patients. Several studies investigated the efficacy of BCAAs supplementation as a therapeutic option in liver cirrhosis, but uncertainties remain about the real efficacy, the best route of administration, and dosage.

Published
2023

4. Urinary lithogenic profile of patients with non-alcoholic fatty liver disease

Author

Bargagli, Matteo, Liguori, Antonio, Napodano, Cecilia, Baroni, Silvia, Tomasello, Lidia, Pizzolante, Fabrizio, De Matthaeis, Nicoletta, De Ninno, Grazia, Grieco, Antonio, Gasbarrini, Antonio, Gambaro, Giovanni, Ferraro, Pietro Manuel, Miele, Luca, Napodano, Cecilia (ORCID:0000-0002-8720-6284), Baroni, Silvia (ORCID:0000-0002-3410-2617), Grieco, Antonio (ORCID:0000-0002-0544-8993), Gasbarrini, Antonio (ORCID:0000-0002-7278-4823), Gambaro, Giovanni (ORCID:0000-0001-5733-2370), Ferraro, Pietro Manuel (ORCID:0000-0002-1379-022X), Miele, Luca (ORCID:0000-0003-3464-0068), Bargagli, Matteo, Liguori, Antonio, Napodano, Cecilia, Baroni, Silvia, Tomasello, Lidia, Pizzolante, Fabrizio, De Matthaeis, Nicoletta, De Ninno, Grazia, Grieco, Antonio, Gasbarrini, Antonio, Gambaro, Giovanni, Ferraro, Pietro Manuel, Miele, Luca, Napodano, Cecilia (ORCID:0000-0002-8720-6284), Baroni, Silvia (ORCID:0000-0002-3410-2617), Grieco, Antonio (ORCID:0000-0002-0544-8993), Gasbarrini, Antonio (ORCID:0000-0002-7278-4823), Gambaro, Giovanni (ORCID:0000-0001-5733-2370), Ferraro, Pietro Manuel (ORCID:0000-0002-1379-022X), and Miele, Luca (ORCID:0000-0003-3464-0068)

Abstract

N/A

Published
2023

5. Dynamics of liver stiffness predicts complications in patients with HCV related cirrhosis treated with direct-acting antivirals

Author

Nicoletti, Alberto, Ainora, Maria Elena, Cintoni, Marco, Garcovich, Matteo, Funaro, Barbara, Pecere, Silvia, De Siena, Martina, Santopaolo, Francesco, Ponziani, Francesca Romana, Riccardi, Laura, Grieco, Antonio, Pompili, Maurizio, Gasbarrini, Antonio, Zocco, Maria Assunta, Cintoni, Marco (ORCID:0000-0002-9610-0748), Ponziani, Francesca Romana (ORCID:0000-0002-5924-6238), Grieco, Antonio (ORCID:0000-0002-0544-8993), Pompili, Maurizio (ORCID:0000-0001-6699-7980), Gasbarrini, Antonio (ORCID:0000-0002-7278-4823), Zocco, Maria Assunta (ORCID:0000-0002-0814-9542), Nicoletti, Alberto, Ainora, Maria Elena, Cintoni, Marco, Garcovich, Matteo, Funaro, Barbara, Pecere, Silvia, De Siena, Martina, Santopaolo, Francesco, Ponziani, Francesca Romana, Riccardi, Laura, Grieco, Antonio, Pompili, Maurizio, Gasbarrini, Antonio, Zocco, Maria Assunta, Cintoni, Marco (ORCID:0000-0002-9610-0748), Ponziani, Francesca Romana (ORCID:0000-0002-5924-6238), Grieco, Antonio (ORCID:0000-0002-0544-8993), Pompili, Maurizio (ORCID:0000-0001-6699-7980), Gasbarrini, Antonio (ORCID:0000-0002-7278-4823), and Zocco, Maria Assunta (ORCID:0000-0002-0814-9542)

Abstract

Background: Direct acting antivirals(DAAs) are effective in reducing inflammatory ant fibrotic markers in patients with chronic hepatitis C virus(HCV) infection and to prevent liver-related complications. Two-dimensional shear wave elastography(2D-SWE) is an effective technique for the assessment of liver fibrosis. Aim: To evaluate changes in liver stiffness(LS) in HCV cirrhotic patients undergoing DAA therapy and to identify non-invasive parameters that predict the occurrence of liver-related events. Methods: We enrolled 229 patients who received DAAs between January 2015 and October 2018. Ultrasound parameters and laboratory data were assessed before treatment and 24(T1) and 48(T2) weeks after end of treatment. Patients were followed up every 6 months to evaluate the development of HCC and other liver related complications. Multiple Cox regression analysis was used to determine parameters associated with the development of complications. Results: Model for End-stage Liver Disease(MELD) score(HR 1.16; CI 95% 1.01-1.33; p = 0.026) and a change in LS at T2(1-year Delta LS) < 20%(HR 2.98; CI 95% 1.01-8.1; p = 0.03) were independently associated with HCC risk. One-year Delta-LS <20% was independently associated with the development of ascites(HR 5.08; CI 95% 1.03 - 25.14; p = 0.04). Conclusions: Dynamic changes of 2D-SWE-measured LS after DAA therapy may be a useful tool to identify patients who are at higher risk of liver related complications.

Published
2023

6. Minimum platelet count threshold before invasive procedures in cirrhosis: Evolution of the guidelines

Author

Biolato, Marco, Vitale, Federica, Galasso, Tiziano, Gasbarrini, Antonio, Grieco, Antonio, Gasbarrini, Antonio (ORCID:0000-0002-7278-4823), Grieco, Antonio (ORCID:0000-0002-0544-8993), Biolato, Marco, Vitale, Federica, Galasso, Tiziano, Gasbarrini, Antonio, Grieco, Antonio, Gasbarrini, Antonio (ORCID:0000-0002-7278-4823), and Grieco, Antonio (ORCID:0000-0002-0544-8993)

Abstract

Cirrhotic patients with severe thrombocytopenia are at increased risk of bleeding during invasive procedures. The need for preprocedural prophylaxis aimed at reducing the risk of bleeding in cirrhotic patients with thrombocytopenia who undergo scheduled procedures is assessed via the platelet count; however, establishing a minimum threshold considered safe is challenging. A platelet count >= 50000/mu L is a frequent target, but levels vary by provider, procedure, and specific patient. Over the years, this value has changed several times according to the different guidelines proposed in the literature. According to the latest guidelines, many procedures can be performed at any level of platelet count, which should not necessarily be checked before the procedure. In this review, we aim to investigate and describe how the guidelines have evolved in recent years in the evaluation of the minimum platelet count threshold required to perform different invasive procedures, according to their bleeding risk.

Published
2023

7. The role of antiplatelet therapies on incidence and mortality of hepatocellular carcinoma

Author

Lai, Quirino, De Matthaeis, Nicoletta, Finotti, Michele, Galati, Giovanni, Marrone, Giuseppe, Melandro, Fabio, Morisco, Filomena, Nicolini, Daniele, Pravisani, Riccardo, Giannini, Edoardo G, Aglitti, A, Aliberti, C, Baccarani, U, Bhoori, S, Borzio, M, Brancaccio, G, Burra, P, Cabibbo, G, Casadei Gardini, A, Carrai, P, Cillo, U, Conti, F, Cucchetti, A, D'Ambrosio, R, Dell'Unto, C, Di Costanzi, Gg, Di Sandro, S, Foschi, Fg, Fucilli, F, Gambato, M, Gasbarrini, Antonio, Giuliante, Felice, Ghinolfi, D, Grieco, Antonio, Gruttaduria, S, Guarino, M, Kostandini, A, Iavarone, M, Lenci, I, Levi Sandri, Gb, Losito, F, Lupo, Lg, Manzia, Tm, Mazzocato, S, Mescoli, C, Miele, Luca, Muley, M, Persico, M, Plaz Torres, Mc, Pompili, Maurizio, Ponziani, Francesca Romana, Rapaccini, Gian Ludovico, Rendina, M, Renzulli, M, Rossi, Marco, Rreka, E, Russo, Fp, Sacco, R, Sangiovanni, A, Sessa, A, Simonetti, N, Sposito, C, Tortora, R, Trevisani, F, Viganò, L, Viganò, M, Villa, E, Vincenzi, V, Violi, P, Vitale, A, Gasbarrini, A (ORCID:0000-0002-7278-4823), Giuliante, F (ORCID:0000-0001-9517-8220), Grieco, A (ORCID:0000-0002-0544-8993), Miele, L (ORCID:0000-0003-3464-0068), Pompili, M (ORCID:0000-0001-6699-7980), Ponziani, FR (ORCID:0000-0002-5924-6238), Rapaccini, GL (ORCID:0000-0002-6467-857X), Rossi, M (ORCID:0000-0002-4539-5670), Lai, Quirino, De Matthaeis, Nicoletta, Finotti, Michele, Galati, Giovanni, Marrone, Giuseppe, Melandro, Fabio, Morisco, Filomena, Nicolini, Daniele, Pravisani, Riccardo, Giannini, Edoardo G, Aglitti, A, Aliberti, C, Baccarani, U, Bhoori, S, Borzio, M, Brancaccio, G, Burra, P, Cabibbo, G, Casadei Gardini, A, Carrai, P, Cillo, U, Conti, F, Cucchetti, A, D'Ambrosio, R, Dell'Unto, C, Di Costanzi, Gg, Di Sandro, S, Foschi, Fg, Fucilli, F, Gambato, M, Gasbarrini, Antonio, Giuliante, Felice, Ghinolfi, D, Grieco, Antonio, Gruttaduria, S, Guarino, M, Kostandini, A, Iavarone, M, Lenci, I, Levi Sandri, Gb, Losito, F, Lupo, Lg, Manzia, Tm, Mazzocato, S, Mescoli, C, Miele, Luca, Muley, M, Persico, M, Plaz Torres, Mc, Pompili, Maurizio, Ponziani, Francesca Romana, Rapaccini, Gian Ludovico, Rendina, M, Renzulli, M, Rossi, Marco, Rreka, E, Russo, Fp, Sacco, R, Sangiovanni, A, Sessa, A, Simonetti, N, Sposito, C, Tortora, R, Trevisani, F, Viganò, L, Viganò, M, Villa, E, Vincenzi, V, Violi, P, Vitale, A, Gasbarrini, A (ORCID:0000-0002-7278-4823), Giuliante, F (ORCID:0000-0001-9517-8220), Grieco, A (ORCID:0000-0002-0544-8993), Miele, L (ORCID:0000-0003-3464-0068), Pompili, M (ORCID:0000-0001-6699-7980), Ponziani, FR (ORCID:0000-0002-5924-6238), Rapaccini, GL (ORCID:0000-0002-6467-857X), and Rossi, M (ORCID:0000-0002-4539-5670)

Abstract

Aim To evaluate the impact of antiplatelet therapy (APT)on the incidence of hepatocellular carcinoma (HCC) and mortality following its treatment. Methods A systematic literature search was performed using PubMed and Cochrane Central Register of Controlled Trials Databases. Two HCC clinical settings were explored: (i) incidence, and (ii) death after any HCC treatment. Odds ratios (OR) and 95% confidence intervals (95%CI) were calculated to compare the pooled data between patients who received or did not receive APT. Results A total of 20 studies were identified, of whom 15 focused on HCC incidence, including 2,685,009 patients, and five on post-treatment death, including 3281 patients. APT was associated with an overall reduced risk of HCC incidence (OR: 0.63; 95%CI = 0.51-0.79; p < 0.001) as well as of post-treatment mortality (OR: 0.54; 95%CI = 0.35-0.83; p = 0.006). Conclusions Current data suggest that APT correlated with higher HCC incidence and poor overall survival following tumour treatment.

Published
2023

8. Fib-4 score is able to predict intra-hospital mortality in 4 different SARS-COV2 waves

Author

Miele, Luca, Dajko, Marianxhela, Savino, Mariachiara, Capocchiano, Nicola D, Calvez, Valentino, Liguori, Antonio, Masciocchi, Carlotta, Vetrone, Lorenzo, Mignini, Irene, Schepis, Tommaso, Marrone, Giuseppe, Biolato, Marco, Cesario, Alfredo, Patarnello, Stefano, Damiani, Andrea, Grieco, Antonio, Valentini, Vincenzo, Gasbarrini, Antonio, Miele, Luca (ORCID:0000-0003-3464-0068), Savino, Maria Chiara, Cesario, Alfredo (ORCID:0000-0003-4687-0709), Grieco, Antonio (ORCID:0000-0002-0544-8993), Valentini, Vincenzo (ORCID:0000-0003-4637-6487), Gasbarrini, Antonio (ORCID:0000-0002-7278-4823), Miele, Luca, Dajko, Marianxhela, Savino, Mariachiara, Capocchiano, Nicola D, Calvez, Valentino, Liguori, Antonio, Masciocchi, Carlotta, Vetrone, Lorenzo, Mignini, Irene, Schepis, Tommaso, Marrone, Giuseppe, Biolato, Marco, Cesario, Alfredo, Patarnello, Stefano, Damiani, Andrea, Grieco, Antonio, Valentini, Vincenzo, Gasbarrini, Antonio, Miele, Luca (ORCID:0000-0003-3464-0068), Savino, Maria Chiara, Cesario, Alfredo (ORCID:0000-0003-4687-0709), Grieco, Antonio (ORCID:0000-0002-0544-8993), Valentini, Vincenzo (ORCID:0000-0003-4637-6487), and Gasbarrini, Antonio (ORCID:0000-0002-7278-4823)

Abstract

Increased values of the FIB-4 index appear to be associated with poor clinical outcomes in COVID-19 patients. This study aimed to develop and validate predictive mortality models, using data upon admission of hospitalized patients in four COVID-19 waves between March 2020 and January 2022. A single-center cohort study was performed on consecutive adult patients with Covid-19 admitted at the Fondazione Policlinico Gemelli IRCCS (Rome, Italy). Artificial intelligence and big data processing were used to retrieve data. Patients and clinical characteristics of patients with available FIB-4 data derived from the Gemelli Generator Real World Data (G2 RWD) were used to develop predictive mortality models during the four waves of the COVID-19 pandemic. A logistic regression model was applied to the training and test set (75%:25%). The model's performance was assessed by receiver operating characteristic (ROC) curves. A total of 4936 patients were included. Hypertension (38.4%), cancer (12.15%) and diabetes (16.3%) were the most common comorbidities. 23.9% of patients were admitted to ICU, and 12.6% had mechanical ventilation. During the study period, 762 patients (15.4%) died. We developed a multivariable logistic regression model on patient data from all waves, which showed that the FIB-4 score > 2.53 was associated with increased mortality risk (OR = 4.53, 95% CI 2.83-7.25; p & LE; 0.001). These data may be useful in the risk stratification at the admission of hospitalized patients with COVID-19.

Published
2023

9. Balloon-Occluded Radiofrequency Ablation as Bridge to TACE in the Treatment of Advanced HCC with Arterioportal Shunt

Author

Iezzi, Roberto, Posa, Alessandro, Santoro, Marco, Tanzilli, Alessandro, Cerrito, Lucia, Ponziani, Francesca Romana, Pompili, Maurizio, Grieco, Antonio, Rapaccini, Gian Ludovico, Gasbarrini, Antonio, Manfredi, Riccardo, Iezzi, Roberto (ORCID:0000-0002-2791-481X), Ponziani, Francesca Romana (ORCID:0000-0002-5924-6238), Pompili, Maurizio (ORCID:0000-0001-6699-7980), Grieco, Antonio (ORCID:0000-0002-0544-8993), Rapaccini, Gian Ludovico (ORCID:0000-0002-6467-857X), Gasbarrini, Antonio (ORCID:0000-0002-7278-4823), Manfredi, Riccardo (ORCID:0000-0002-4972-9500), Iezzi, Roberto, Posa, Alessandro, Santoro, Marco, Tanzilli, Alessandro, Cerrito, Lucia, Ponziani, Francesca Romana, Pompili, Maurizio, Grieco, Antonio, Rapaccini, Gian Ludovico, Gasbarrini, Antonio, Manfredi, Riccardo, Iezzi, Roberto (ORCID:0000-0002-2791-481X), Ponziani, Francesca Romana (ORCID:0000-0002-5924-6238), Pompili, Maurizio (ORCID:0000-0001-6699-7980), Grieco, Antonio (ORCID:0000-0002-0544-8993), Rapaccini, Gian Ludovico (ORCID:0000-0002-6467-857X), Gasbarrini, Antonio (ORCID:0000-0002-7278-4823), and Manfredi, Riccardo (ORCID:0000-0002-4972-9500)

Abstract

Background: Transarterial chemoembolization is the most widely used palliative treatment for unresectable hepatocellular carcinoma; however, arterioportal shunt represents a contraindication to this treatment. Objective: The study aims to assess the feasibility of balloon-occluded radiofrequency ablation in the transitory resolution of an extensive arterioportal shunt in patients with advanced hepatocellular carcinoma as a bridge to safe and effective transarterial chemoembolization. Methods: 12 consecutive patients advanced multinodular unilobar unresectable hepatocellular carcinoma with a target lesion larger than 5 cm (mean diameter 7.7 +/- 1.4 cm), not suitable to transarterial chemoembolization due to extensive arterioportal shunt, were recruited. Balloon-occluded radiofrequency ablation of the hepatic area surrounding the shunt during occlusion of the artery supplying the shunt was performed, followed by lobar conventional chemoembolization. Intra/periprocedural complications were evaluated. Technical success was defined by the result of radiofrequency ablation in terms of immediate disappearance, reduction, or persistence of the shunt. Local efficacy of chemoembolization was evaluated at 1-month computed tomography according to m-RECIST criteria. Results: Technical success was achieved in all patients. No major complications were observed. 1-month follow-up showed a mean necrotic diameter of 6.3 cm (range: 3.8-8.7 cm), with an acceptable procedural result and persistence of the shunt. An overall response rate was obtained in all patients, with 25% complete response and 75% partial response. Conclusion: Balloon-occluded radiofrequency ablation of an arterioportal shunt in patients with advanced hepatocellular carcinoma can temporarily reduce shunting, allowing to perform safe and therapeutically useful chemoembolization, with satisfactory control of tumor growth.

Published
2022

10. Liver transplantation for severe alcoholic hepatitis: A multicenter Italian study

Author

Germani, Giacomo, Angrisani, Debora, Addolorato, Giovanni, Merli, Manuela, Mazzarelli, Chiara, Tarli, Claudia, Lattanzi, Barbara, Panariello, Adelaide, Prandoni, Paola, Craxì, Lucia, Forza, Giovanni, Feltrin, Alessandra, Ronzan, Andrea, Feltracco, Paolo, Grieco, Antonio, Agnes, Salvatore, Gasbarrini, Antonio, Rossi, Massimo, De Carlis, Luciano, Francesco, D'Amico, Cillo, Umberto, Belli, Luca S, Burra, Patrizia, Addolorato, Giovanni (ORCID:0000-0002-1522-9946), Grieco, Antonio (ORCID:0000-0002-0544-8993), Agnes, Salvatore (ORCID:0000-0002-3341-4221), Gasbarrini, Antonio (ORCID:0000-0002-7278-4823), Germani, Giacomo, Angrisani, Debora, Addolorato, Giovanni, Merli, Manuela, Mazzarelli, Chiara, Tarli, Claudia, Lattanzi, Barbara, Panariello, Adelaide, Prandoni, Paola, Craxì, Lucia, Forza, Giovanni, Feltrin, Alessandra, Ronzan, Andrea, Feltracco, Paolo, Grieco, Antonio, Agnes, Salvatore, Gasbarrini, Antonio, Rossi, Massimo, De Carlis, Luciano, Francesco, D'Amico, Cillo, Umberto, Belli, Luca S, Burra, Patrizia, Addolorato, Giovanni (ORCID:0000-0002-1522-9946), Grieco, Antonio (ORCID:0000-0002-0544-8993), Agnes, Salvatore (ORCID:0000-0002-3341-4221), and Gasbarrini, Antonio (ORCID:0000-0002-7278-4823)

Abstract

There is increasing evidence that early liver transplantation (eLT), performed within standardized protocols can improve survival in severe alcoholic hepatitis (sAH). The aim of the study was to assess outcomes after eLT for sAH in four Italian LT centers and to compare them with non-responders to medical therapy excluded from eLT. Patients admitted for sAH (2013-2019), according to NIAAA criteria, were included. Patients not responding to medical therapy were placed on the waiting list for eLT after a strict selection. Histological features of explanted livers were evaluated. Posttransplant survival and alcohol relapse were evaluated. Ninety-three patients with severe AH were evaluated (65.6% male, median [IQR] age: 47 [42-56] years). Forty-five of 93 patients received corticosteroids, 52 of 93 were non-responders and among these, 20 patients were waitlisted. Sixteen patients underwent LT. Overall, 6-, 12-, and 24-month survival rates were 100% significantly higher compared with non-responders to medical therapy who were denied LT (45%, 45%, and 36%; p < .001). 2/16 patients resumed alcohol intake, one at 164 days and one at 184 days. Early LT significantly improves survival in sAH non-responding to medical therapy, when a strict selection process is applied. Further studies are needed to properly assess alcohol relapse rates.

Published
2022

11. A single course of lusutrombopag for multiple invasive procedures in cirrhosis-associated thrombocytopenia: A case series

Author

Biolato, Marco, Vitale, Federica, Marrone, Giuseppe, Miele, Luca, Grieco, Antonio, Miele, Luca (ORCID:0000-0003-3464-0068), Grieco, Antonio (ORCID:0000-0002-0544-8993), Biolato, Marco, Vitale, Federica, Marrone, Giuseppe, Miele, Luca, Grieco, Antonio, Miele, Luca (ORCID:0000-0003-3464-0068), and Grieco, Antonio (ORCID:0000-0002-0544-8993)

Abstract

Rationale: Lusutrombopag is a thrombopoietin receptor agonist which reduces the need for platelet transfusions before planned invasive procedures. A post hoc analysis of data from the registration trials observed that lusutrombopag-treated patients who achieved a platelet count > 50 x 10(9)/L (responder patients) did so in a median of 6 days and the effect on platelet count lasted for nearly 3 weeks in total. Since patients with cirrhosis often require repeat invasive procedures, this kind of response-time trend sheds light on the possibility of placing more than one invasive procedure within a single course of lusutrombopag treatment. Patient concerns: Platelet transfusion represents the gold standard in this setting, but is limited by the risk of adverse events and limited availability. Diagnoses: We describe our experience with lusutrombopag in three patients with severe cirrhosis-associated thrombocytopenia who underwent multiple invasive procedures after a single course of treatment. Interventions: The treatment schedule is lusutrombopag orally 3 mg/daily for 7 days and then a time window of 6 days (day 9-14) for the elective invasive procedure. Outcomes: All three patients achieved good response to lusutrombopag treatment and were able to undergone more invasive procedures in the same course of treatment without need of platelet transfusion. Lessons: our preliminary experience supports the safety and the effectiveness of lusutrombopag in patients with severe cirrhosis-associated thrombocytopenia who underwent multiple invasive elective procedures after a single course.

Published
2022

12. Two elective invasive procedures after a single avatrombopag treatment in a patient with liver cirrhosis and severe thrombocytopenia

Author

Biolato, Marco, Vitale, Federica, Marrone, Giuseppe, Miele, Luca, Grieco, Antonio, Miele, Luca (ORCID:0000-0003-3464-0068), Grieco, Antonio (ORCID:0000-0002-0544-8993), Biolato, Marco, Vitale, Federica, Marrone, Giuseppe, Miele, Luca, Grieco, Antonio, Miele, Luca (ORCID:0000-0003-3464-0068), and Grieco, Antonio (ORCID:0000-0002-0544-8993)

Abstract

N/A

Published
2022

13. Noninvasive Evaluation of Clinically Significant Portal Hypertension in Patients with Liver Cirrhosis: The Role of Contrast-Enhanced Ultrasound Perfusion Imaging and Elastography

Author

Zocco, Maria Assunta, Cintoni, Marco, Ainora, Maria Elena, Garcovich, Matteo, Lupascu, Andrea, Iezzi, Roberto, Annichiarico, Brigida Eleonora, Siciliano, Massimo, Riccardi, Laura, Rapaccini, Gian Ludovico, Grieco, Antonio, Pompili, Maurizio, Gasbarrini, Antonio, Zocco, Maria Assunta (ORCID:0000-0002-0814-9542), Cintoni, Marco (ORCID:0000-0002-9610-0748), Iezzi, Roberto (ORCID:0000-0002-2791-481X), Rapaccini, Gian Ludovico (ORCID:0000-0002-6467-857X), Grieco, Antonio (ORCID:0000-0002-0544-8993), Pompili, Maurizio (ORCID:0000-0001-6699-7980), Gasbarrini, Antonio (ORCID:0000-0002-7278-4823), Zocco, Maria Assunta, Cintoni, Marco, Ainora, Maria Elena, Garcovich, Matteo, Lupascu, Andrea, Iezzi, Roberto, Annichiarico, Brigida Eleonora, Siciliano, Massimo, Riccardi, Laura, Rapaccini, Gian Ludovico, Grieco, Antonio, Pompili, Maurizio, Gasbarrini, Antonio, Zocco, Maria Assunta (ORCID:0000-0002-0814-9542), Cintoni, Marco (ORCID:0000-0002-9610-0748), Iezzi, Roberto (ORCID:0000-0002-2791-481X), Rapaccini, Gian Ludovico (ORCID:0000-0002-6467-857X), Grieco, Antonio (ORCID:0000-0002-0544-8993), Pompili, Maurizio (ORCID:0000-0001-6699-7980), and Gasbarrini, Antonio (ORCID:0000-0002-7278-4823)

Abstract

Background: Hepatic venous pressure gradient (HVPG) is the gold standard for assessing the degree of portal hypertension (PH), but it is not suitable for routine clinical use. The recently developed ultrasonography techniques, dynamic contrast-enhanced ultrasound (D-CEUS) and liver stiffness (LS), have expanded the possibilities for noninvasive evaluation. Aims: To investigate the usefulness of D-CEUS and elastographic parameters in assessing the presence and degree of PH. Methods: This is a prospective monocentric study. Patients with liver cirrhosis referred for HVPG measurements underwent hepatic Doppler ultrasound, LS measurement, and D-CEUS with a second-generation contrast agent. Pearson's correlation and a receiver operating characteristic (ROC) curve analysis were performed to assess the role of noninvasive findings in predicting clinically significant PH (CSPH) and severe PH (SPH). Results: 46 consecutive patients (31 men; mean age±SD: 57±11 years) were enrolled. A significant positive correlation was noted between LS and HVPG (r = 0.809, p<0.0001) with an area under the ROC curve of 0.923. A cut-off value of 24.2 kPa best predicted CSPH with a positive predictive value of 85%. Among the D-CEUS features, the area under the ROC curves of liver parenchyma peak intensity (PI-LP) was greater than the other indices both for CSPH and SPH (1.000 and 0.981, respectively). A PI-LP under 23.3 arbitrary units indicated the presence of CSPH with a sensitivity and a specificity of 100%. Conclusion: A multimodal ultrasound approach based on D-CEUS and LS might become a reliable predictor of CSPH and SPH and a useful alternative to HVPG.

Published
2022

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

Author

Younes, R., Govaere, O., Petta, S., Miele, Luca, Tiniakos, D., Burt, A., David, E., Vecchio, Fabio Maria, Maggioni, M., Cabibi, D., Mcleod, D., Pareja, M. J., Fracanzani, A. L., Aller, R., Rosso, C., Ampuero, J., Gallego-Duran, R., Armandi, A., Caviglia, G. P., Zaki, M. Y. W., Liguori, Antonio, Francione, P., Pennisi, G., Grieco, Antonio, Birolo, G., Fariselli, P., Eslam, M., Valenti, L., George, J., Romero-Gomez, M., Anstee, Q. M., Bugianesi, E., Miele L. (ORCID:0000-0003-3464-0068), Vecchio F. M. (ORCID:0000-0002-9197-2264), Liguori A., Grieco A. (ORCID:0000-0002-0544-8993), Younes, R., Govaere, O., Petta, S., Miele, Luca, Tiniakos, D., Burt, A., David, E., Vecchio, Fabio Maria, Maggioni, M., Cabibi, D., Mcleod, D., Pareja, M. J., Fracanzani, A. L., Aller, R., Rosso, C., Ampuero, J., Gallego-Duran, R., Armandi, A., Caviglia, G. P., Zaki, M. Y. W., Liguori, Antonio, Francione, P., Pennisi, G., Grieco, Antonio, Birolo, G., Fariselli, P., Eslam, M., Valenti, L., George, J., Romero-Gomez, M., Anstee, Q. M., Bugianesi, E., Miele L. (ORCID:0000-0003-3464-0068), Vecchio F. M. (ORCID:0000-0002-9197-2264), Liguori A., and Grieco A. (ORCID:0000-0002-0544-8993)

Abstract

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) 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 PNPLA3 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.

Published
2022

15. Non-alcoholic fatty liver disease and the risk of fibrosis in Italian primary care services: GPS-NAFLD Study

Author

Miele, Luca, Grattagliano, I., Lapi, F., Dajko, M., De Magistris, A., Liguori, Antonio, De Matthaeis, Nicoletta, Rossi, A., Gasbarrini, Antonio, Cricelli, Claudio, Grieco, Antonio, Miele L. (ORCID:0000-0003-3464-0068), Liguori A., De Matthaeis N., Gasbarrini A. (ORCID:0000-0002-7278-4823), Cricelli C., Grieco A. (ORCID:0000-0002-0544-8993), Miele, Luca, Grattagliano, I., Lapi, F., Dajko, M., De Magistris, A., Liguori, Antonio, De Matthaeis, Nicoletta, Rossi, A., Gasbarrini, Antonio, Cricelli, Claudio, Grieco, Antonio, Miele L. (ORCID:0000-0003-3464-0068), Liguori A., De Matthaeis N., Gasbarrini A. (ORCID:0000-0002-7278-4823), Cricelli C., and Grieco A. (ORCID:0000-0002-0544-8993)

Abstract

Background and aims: The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing globally. This study aimed to determine the prevalence of NAFLD and the probability of liver fibrosis in Italian primary care services. Methods: We carried out a population-based and nested case–control study including all individuals aged 18 years and above registered at Italian primary care services. Data were collected from the general practitioners' network from 2010 to 2017. NAFLD cases were identified via the ICD-9-CM and Hepatic Steatosis Index score > 36 and were matched each up to 10 controls. Other causes of liver diseases were excluded. The risk of fibrosis was assessed using the FIB-4 and NAFLD fibrosis scores (NFS). Results: NAFLD was present in 9% of the primary care population with high regional variability. Among NAFLD subjects: 25% had diabetes, 10% had chronic kidney disease, 11% had cardiovascular disease and 28% were obese. Furthermore, 30% had at least two comorbidities and 13% had cirrhosis. Once cirrhosis was excluded, the risk of any degree of fibrosis was 13.8% with NFS and 20.5% with FIB-4 in subjects <65 years. Conclusions: Even if there is an identification gap in primary care, recorded cases with NAFLD have a high frequency of associated comorbidities. Despite regional variability, a close relation between cirrhosis and NAFLD exists (OR: 3.48, 95% CI: 3.23–3.76). Therefore, the use of non-invasive tests should be promoted in primary care as a useful tool for the early identification of fibrosis risk, independently of evidence of steatosis.

Published
2022

16. Project for interventional Oncology LArge-database in liveR Hepatocellular carcinoma - Preliminary CT-based radiomic analysis (POLAR Liver 1.1)

Author

Iezzi, Roberto, Casà, C, Posa, Alessandro, Cornacchione, Patrizia, Carchesio, F, Boldrini, Luca, Tanzilli, A, Cerrito, Lucia, Fionda, B, Longo, V, Miele, Luca, Lancellotta, V, Cellini, Francesco, Tran, H E, Ponziani, Francesca Romana, Giuliante, Felice, Rapaccini, Gian Ludovico, Grieco, Antonio, Pompili, Maurizio, Gasbarrini, Antonio, Valentini, Vincenzo, Gambacorta, Maria Antonietta, Tagliaferri, Luca, Manfredi, Riccardo, Iezzi, R (ORCID:0000-0002-2791-481X), Posa, A, Cornacchione, P, Boldrini, L, Cerrito, L, Miele, L (ORCID:0000-0003-3464-0068), Cellini, F (ORCID:0000-0002-2145-2300), Ponziani, F R (ORCID:0000-0002-5924-6238), Giuliante, F (ORCID:0000-0001-9517-8220), Rapaccini, G L (ORCID:0000-0002-6467-857X), Grieco, A (ORCID:0000-0002-0544-8993), Pompili, M (ORCID:0000-0001-6699-7980), Gasbarrini, A (ORCID:0000-0002-7278-4823), Valentini, V (ORCID:0000-0003-4637-6487), Gambacorta, M A (ORCID:0000-0001-5455-8737), Tagliaferri, L (ORCID:0000-0003-2308-0982), Manfredi, R (ORCID:0000-0002-4972-9500), Iezzi, Roberto, Casà, C, Posa, Alessandro, Cornacchione, Patrizia, Carchesio, F, Boldrini, Luca, Tanzilli, A, Cerrito, Lucia, Fionda, B, Longo, V, Miele, Luca, Lancellotta, V, Cellini, Francesco, Tran, H E, Ponziani, Francesca Romana, Giuliante, Felice, Rapaccini, Gian Ludovico, Grieco, Antonio, Pompili, Maurizio, Gasbarrini, Antonio, Valentini, Vincenzo, Gambacorta, Maria Antonietta, Tagliaferri, Luca, Manfredi, Riccardo, Iezzi, R (ORCID:0000-0002-2791-481X), Posa, A, Cornacchione, P, Boldrini, L, Cerrito, L, Miele, L (ORCID:0000-0003-3464-0068), Cellini, F (ORCID:0000-0002-2145-2300), Ponziani, F R (ORCID:0000-0002-5924-6238), Giuliante, F (ORCID:0000-0001-9517-8220), Rapaccini, G L (ORCID:0000-0002-6467-857X), Grieco, A (ORCID:0000-0002-0544-8993), Pompili, M (ORCID:0000-0001-6699-7980), Gasbarrini, A (ORCID:0000-0002-7278-4823), Valentini, V (ORCID:0000-0003-4637-6487), Gambacorta, M A (ORCID:0000-0001-5455-8737), Tagliaferri, L (ORCID:0000-0003-2308-0982), and Manfredi, R (ORCID:0000-0002-4972-9500)

Abstract

N/A

Published
2022

17. Long-term outcomes and predictive ability of non-invasive scoring systems in patients with non-alcoholic fatty liver disease

Author

Younes, Ramy, Caviglia, Gian Paolo, Govaere, Olivier, Rosso, Chiara, Armandi, Angelo, Sanavia, Tiziana, Pennisi, Grazia, Liguori, Antonio, Francione, Paolo, Gallego-Durán, Rocío, Ampuero, Javier, Garcia Blanco, Maria J, Aller, Rocio, Tiniakos, Dina, Burt, Alastair, David, Ezio, Vecchio, Fabio Maria, Maggioni, Marco, Cabibi, Daniela, Pareja, María Jesú, Zaki, Marco Y W, Grieco, Antonio, Fracanzani, Anna L, Valenti, Luca, Miele, Luca, Fariselli, Piero, Petta, Salvatore, Romero-Gomez, Manuel, Anstee, Quentin M, Bugianesi, Elisabetta, Vecchio, Fabio M (ORCID:0000-0002-9197-2264), Grieco, Antonio (ORCID:0000-0002-0544-8993), Miele, Luca (ORCID:0000-0003-3464-0068), Younes, Ramy, Caviglia, Gian Paolo, Govaere, Olivier, Rosso, Chiara, Armandi, Angelo, Sanavia, Tiziana, Pennisi, Grazia, Liguori, Antonio, Francione, Paolo, Gallego-Durán, Rocío, Ampuero, Javier, Garcia Blanco, Maria J, Aller, Rocio, Tiniakos, Dina, Burt, Alastair, David, Ezio, Vecchio, Fabio Maria, Maggioni, Marco, Cabibi, Daniela, Pareja, María Jesú, Zaki, Marco Y W, Grieco, Antonio, Fracanzani, Anna L, Valenti, Luca, Miele, Luca, Fariselli, Piero, Petta, Salvatore, Romero-Gomez, Manuel, Anstee, Quentin M, Bugianesi, Elisabetta, Vecchio, Fabio M (ORCID:0000-0002-9197-2264), Grieco, Antonio (ORCID:0000-0002-0544-8993), and Miele, Luca (ORCID:0000-0003-3464-0068)

Abstract

Background & Aims: Non-invasive scoring systems (NSS) are used to identify patients with non-alcoholic fatty liver disease (NAFLD) who are at risk of advanced fibrosis, but their reliability in predicting long-term outcomes for hepatic/extrahepatic complications or death and their concordance in cross-sectional and longitudinal risk stratification remain uncertain.Methods: The most common NSS (NFS, FIB-4, BARD, APRI) and the Hepamet fibrosis score (HFS) were assessed in 1,173 European patients with NAFLD from tertiary centres. Performance for fibrosis risk stratification and for the prediction of long-term hepatic/extrahepatic events, hepatocarcinoma (HCC) and overall mortality were evaluated in terms of AUC and Harrell's c-index. For longitudinal data, NSS-based Cox proportional hazard models were trained on the whole cohort with repeated 5-fold cross-validation, sampling for testing from the 607 patients with all NSS available.Results: Cross-sectional analysis revealed HFS as the best performer for the identification of significant (F0-1 vs. F2-4, AUC = 0.758) and advanced (F0-2 vs. F3-4, AUC = 0.805) fibrosis, while NFS and FIB-4 showed the best performance for detecting histological cirrhosis (range AUCs 0.85-0.88). Considering longitudinal data (follow-up between 62 and 110 months), NFS and FIB-4 were the best at predicting liver-related events (c-indices>0.7), NFS for HCC (c-index = 0.9 on average), and FIB-4 and HFS for overall mortality (c-indices >0.8). All NSS showed limited performance (c-indices <0.7) for extrahepatic events.Conclusions: Overall, NFS, HFS and FIB-4 outperformed APRI and BARD for both cross-sectional identification of fibrosis and prediction of long-term outcomes, confirming that they are useful tools for the clinical management of patients with NAFLD at increased risk of fibrosis and liver-related complications or death.Lay summary: Non-invasive scoring systems are increasingly being used in patients with non-alcoholic fatty

Published
2021

18. The histone variant macroh2a1 impacts circadian gene expression and cell phenotype in an in vitro model of hepatocellular carcinoma

Author

Carbone, A., De Santis, E., Cela, O., Giambra, V., Miele, Luca, Marrone, G., Grieco, Antonio, Buschbeck, M., Capitanio, N., Mazza, T., Mazzoccoli, G., Miele L. (ORCID:0000-0003-3464-0068), Grieco A. (ORCID:0000-0002-0544-8993), Carbone, A., De Santis, E., Cela, O., Giambra, V., Miele, Luca, Marrone, G., Grieco, Antonio, Buschbeck, M., Capitanio, N., Mazza, T., Mazzoccoli, G., Miele L. (ORCID:0000-0003-3464-0068), and Grieco A. (ORCID:0000-0002-0544-8993)

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer‐related death worldwide. A foremost risk factor for HCC is obesity/metabolic syndrome‐related non‐alcoholic fatty liver disease (NAFLD) and non‐alcoholic steatohepatitis (NASH), which is prompted by remarkable changes in transcription patterns of genes enriching metabolic, immune/inflammatory, and circadian pathways. Epigenetic mechanisms play a role in NAFLD‐associated HCC, and macroH2A1, a variant of histone H2A, is involved in the pathogenesis modulating the expression of oncogenes and/or tumor suppressor genes and interacting with SIRT1, which crucially impacts the circadian clock circuitry. Hence, we aimed to appraise if and how macroH2A1 regulated the expression patterns of circadian genes in the setting of NAFLD‐associated HCC. We took advantage of an in vitro model of liver cancer represented by HepG2 (human hepatocarcinoma) cells stably knocked down for macroH2A1 and conducted whole transcriptome profiling and deep phenotyping analysis. We found up‐regulation of PER1 along with several deregulated circadian genes, enriching several important pathways and functions related to cancer onset and progression, such as epithelial‐to‐mesenchymal transition, cell cycle deregulation, and DNA damage. PER1 silencing partially mitigated the malignant phenotype induced by the loss of macroH2A1 in HCC cells. In conclusion, our findings suggest a modulatory role for the core circadian protein PER1 in liver carcinogenesis in the context of a lack of the macroH2A1 epigenetic and transcriptional landscape.

Published
2021

19. Nonalcoholic fatty liver disease (Nafld) as model of gut–liver axis interaction: From pathophysiology to potential target of treatment for personalized therapy

Author

Fianchi, Francesca, Liguori, Antonio, Gasbarrini, Antonio, Grieco, Antonio, Miele, Luca, Fianchi F., Liguori A., Gasbarrini A. (ORCID:0000-0002-7278-4823), Grieco A. (ORCID:0000-0002-0544-8993), Miele L. (ORCID:0000-0003-3464-0068), Fianchi, Francesca, Liguori, Antonio, Gasbarrini, Antonio, Grieco, Antonio, Miele, Luca, Fianchi F., Liguori A., Gasbarrini A. (ORCID:0000-0002-7278-4823), Grieco A. (ORCID:0000-0002-0544-8993), and Miele L. (ORCID:0000-0003-3464-0068)

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of liver disease worldwide, affecting both adults and children and will result, in the near future, as the leading cause of end-stage liver disease. Indeed, its prevalence is rapidly increasing, and NAFLD is becoming a major public health concern. For this reason, great efforts are needed to identify its pathogenetic factors and new therapeutic approaches. In the past decade, enormous advances understanding the gut–liver axis—the complex network of cross-talking between the gut, microbiome and liver through the portal circulation—have elucidated its role as one of the main actors in the pathogenesis of NAFLD. Indeed, evidence shows that gut microbiota is involved in the development and progression of liver steatosis, inflammation and fibrosis seen in the context of NAFLD, as well as in the process of hepatocarcinogenesis. As a result, gut microbiota is currently emerging as a non-invasive biomarker for the diagnosis of disease and for the assessment of its severity. Additionally, to its enormous diagnostic potential, gut microbiota is currently studied as a therapeutic target in NAFLD: several different approaches targeting the gut homeostasis such as antibiotics, prebiotics, probiotics, symbiotics, adsorbents, bariatric surgery and fecal microbiota transplantation are emerging as promising therapeutic options.

Published
2021

20. The role of elastography in non-Alcoholic fatty liver disease

Author

Liguori, Antonio, Ainora, Maria Elena, Riccardi, Laura, Dematthaeis, N., Pizzolante, Fabrizio, Gasbarrini, Antonio, Zocco, Maria Assunta, Grieco, Antonio, Rapaccini, Gian Ludovico, Miele, Luca, Liguori A., Ainora M. E., Riccardi L., Pizzolante F., Gasbarrini A. (ORCID:0000-0002-7278-4823), Zocco M. A. (ORCID:0000-0002-0814-9542), Grieco A. (ORCID:0000-0002-0544-8993), Rapaccini G. (ORCID:0000-0002-6467-857X), Miele L. (ORCID:0000-0003-3464-0068), Liguori, Antonio, Ainora, Maria Elena, Riccardi, Laura, Dematthaeis, N., Pizzolante, Fabrizio, Gasbarrini, Antonio, Zocco, Maria Assunta, Grieco, Antonio, Rapaccini, Gian Ludovico, Miele, Luca, Liguori A., Ainora M. E., Riccardi L., Pizzolante F., Gasbarrini A. (ORCID:0000-0002-7278-4823), Zocco M. A. (ORCID:0000-0002-0814-9542), Grieco A. (ORCID:0000-0002-0544-8993), Rapaccini G. (ORCID:0000-0002-6467-857X), and Miele L. (ORCID:0000-0003-3464-0068)

Abstract

Non-Alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide and its prevalence is even higher in patients with risk factors such as type 2 diabetes and obesity. Liver biopsy is the gold standard for diagnosis of non-Alcoholic steatohepatitis (NASH), particularly for the assessment of fibrosis stage that is a key prognostic factor. Noninvasive methods for assessment of liver fibrosis are a huge need in contemporary hepatology in order to stratify patient s risk of advanced and progressive liver disease. In this perspective different imaging techniques have been developed in last decades and showed high performance in liver fibrosis evaluation. Strengths and weaknesses of all imaging methods are summarized in this review. (Cite this article as: Liguori A, Ainora ME, Riccardi L, De Matthaeis N, Pizzolante F, Gasbarrini A, et al. The role of elastography in non-Alcoholic fatty liver disease. Minerva Gastroenterol.

Published
2021

21. The Disease-Modifying Therapies of Relapsing-Remitting Multiple Sclerosis and Liver Injury: A Narrative Review

Author

Biolato, Marco, Bianco, Assunta, Lucchini, Matteo, Gasbarrini, Antonio, Mirabella, Massimiliano, Grieco, Antonio, Lucchini, Matteo (ORCID:0000-0002-0447-2297), Gasbarrini, Antonio (ORCID:0000-0002-7278-4823), Mirabella, Massimiliano (ORCID:0000-0002-7783-114X), Grieco, Antonio (ORCID:0000-0002-0544-8993), Biolato, Marco, Bianco, Assunta, Lucchini, Matteo, Gasbarrini, Antonio, Mirabella, Massimiliano, Grieco, Antonio, Lucchini, Matteo (ORCID:0000-0002-0447-2297), Gasbarrini, Antonio (ORCID:0000-0002-7278-4823), Mirabella, Massimiliano (ORCID:0000-0002-7783-114X), and Grieco, Antonio (ORCID:0000-0002-0544-8993)

Abstract

In this narrative review, we analyze pre-registration and post-marketing data concerning hepatotoxicity of all disease-modifying therapies (DMTs) available for the treatment of relapsing-remitting multiple sclerosis, including beta interferon, glatiramer acetate, fingolimod, teriflunomide, dimethyl fumarate, cladribine, natalizumab, alemtuzumab, and ocrelizumab. We review the proposed causal mechanisms described in the literature and we also address issues like use of DMTs in patients with viral hepatitis or liver cirrhosis. Most data emerged in the post-marketing phase by reports to national pharmacovigilance agencies and published case reports or case series. Serious liver adverse events are rare, but exact incidence is largely unknown, as are predictive factors. Unfortunately, none of the DMTs currently available for the treatment of multiple sclerosis is free of potential hepatic toxic effects. Cases of acute liver failure have been reported for beta-interferon, fingolimod, natalizumab, alemtuzumab, and ocrelizumab by different mechanisms (idiosyncratic reaction, autoimmune hepatitis, or viral reactivation). Patients with multiple sclerosis should be informed about possible hepatic side effects of their treatment. Most cases of liver injury are idiosyncratic and unpredictable. The specific monitoring schedule for each DMT has been reviewed and the clinician should be ready to recognize clinical symptoms suggestive for liver injury. Not all DMTs are indicated in cirrhotic patients. For some DMTs, screening for hepatitis B virus and hepatitis C virus is required before starting treatment and a monitoring or antiviral prophylaxis schedule has been established. Beta interferon, glatiramer acetate, natalizumab, and alemtuzumab are relatively contraindicated in autoimmune hepatitis due to the risk of disease exacerbation.Plain Language Summary Many disease-modifying therapies (DMTs) are approved for multiple sclerosis treatment, but liver injury is a concern. Patients

Published
2021

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

Author

Miele, Luca, Alberelli, M. A., Martini, Maurizio, Liguori, Antonio, Marrone, Giuseppe, Cocomazzi, Alessandra, Vecchio, Fabio Maria, Landolfi, Raffaele, Gasbarrini, Antonio, Grieco, Antonio, De Candia, Erica, Miele L. (ORCID:0000-0003-3464-0068), Martini M. (ORCID:0000-0002-6260-6310), Liguori A., Marrone G., Cocomazzi A., Vecchio F. M. (ORCID:0000-0002-9197-2264), Landolfi R. (ORCID:0000-0002-7913-8576), Gasbarrini A. (ORCID:0000-0002-7278-4823), Grieco A. (ORCID:0000-0002-0544-8993), De Candia E. (ORCID:0000-0003-0942-2819), Miele, Luca, Alberelli, M. A., Martini, Maurizio, Liguori, Antonio, Marrone, Giuseppe, Cocomazzi, Alessandra, Vecchio, Fabio Maria, Landolfi, Raffaele, Gasbarrini, Antonio, Grieco, Antonio, De Candia, Erica, Miele L. (ORCID:0000-0003-3464-0068), Martini M. (ORCID:0000-0002-6260-6310), Liguori A., Marrone G., Cocomazzi A., Vecchio F. M. (ORCID:0000-0002-9197-2264), Landolfi R. (ORCID:0000-0002-7913-8576), Gasbarrini A. (ORCID:0000-0002-7278-4823), Grieco A. (ORCID:0000-0002-0544-8993), and De Candia E. (ORCID:0000-0003-0942-2819)

Abstract

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.

Published
2021

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

Author

Buzova, D., Maugeri, A., Liguori, Antonio, Napodano, Cecilia, Lo Re, O., Oben, J., Alisi, A., Gasbarrini, Antonio, Grieco, Antonio, Cerveny, J., Miele, Luca, Vinciguerra, Maria, Liguori A., Napodano C. (ORCID:0000-0002-8720-6284), Gasbarrini A. (ORCID:0000-0002-7278-4823), Grieco A. (ORCID:0000-0002-0544-8993), Miele L. (ORCID:0000-0003-3464-0068), Vinciguerra M., Buzova, D., Maugeri, A., Liguori, Antonio, Napodano, Cecilia, Lo Re, O., Oben, J., Alisi, A., Gasbarrini, Antonio, Grieco, Antonio, Cerveny, J., Miele, Luca, Vinciguerra, Maria, Liguori A., Napodano C. (ORCID:0000-0002-8720-6284), Gasbarrini A. (ORCID:0000-0002-7278-4823), Grieco A. (ORCID:0000-0002-0544-8993), Miele L. (ORCID:0000-0003-3464-0068), and Vinciguerra M.

Abstract

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.

Published
2020

24. Mediterranean diet and the prevention of non-alcoholic fatty liver disease: Results from a case-control study

Author

Giraldi, Luca, Miele, Luca, Aleksovska, K., Manca, F., Leoncini, Emanuele, Biolato, Marco, Arzani, D., Pirro, Maria Antonia, Marrone, Giuseppe, Cefalo, Chiara Maria Assunta, Racco, S., Liguori, Antonio, Rapaccini, Gian Ludovico, Miggiano, G. A., Gasbarrini, Antonio, Boccia, Stefania, Grieco, Antonio, Giraldi L., Miele L. (ORCID:0000-0003-3464-0068), Leoncini E., Biolato M., Pirro M. A., Marrone G., Cefalo C., Liguori A., Rapaccini G. (ORCID:0000-0002-6467-857X), Gasbarrini A. (ORCID:0000-0002-7278-4823), Boccia S. (ORCID:0000-0002-1864-749X), Grieco A. (ORCID:0000-0002-0544-8993), Giraldi, Luca, Miele, Luca, Aleksovska, K., Manca, F., Leoncini, Emanuele, Biolato, Marco, Arzani, D., Pirro, Maria Antonia, Marrone, Giuseppe, Cefalo, Chiara Maria Assunta, Racco, S., Liguori, Antonio, Rapaccini, Gian Ludovico, Miggiano, G. A., Gasbarrini, Antonio, Boccia, Stefania, Grieco, Antonio, Giraldi L., Miele L. (ORCID:0000-0003-3464-0068), Leoncini E., Biolato M., Pirro M. A., Marrone G., Cefalo C., Liguori A., Rapaccini G. (ORCID:0000-0002-6467-857X), Gasbarrini A. (ORCID:0000-0002-7278-4823), Boccia S. (ORCID:0000-0002-1864-749X), and Grieco A. (ORCID:0000-0002-0544-8993)

Abstract

OBJECTIVE: Few studies report that Mediterranean dietary (MD) pattern has a beneficial role in the progression of non-alcoholic fatty liver disease (NAFLD). Evidence on its potential effect on the onset of disease are, however, scanty. With our study, we evaluated whether MD affects the risk of NAFLD with a large case-control study performed in Italy. PATIENTS AND METHODS: Three hundred and seventy-one cases of NAFLD and 444 controls were questioned on the demographic data and their dietary habits before diagnosis. Additionally, information about lifestyles and other related diseases, such as hypertension and diabetes mellitus were collected. The MD adherence was assessed using a pre-defined Mediterranean Diet Score (MDS). Odds ratios (OR) and 95% confidence intervals (CI) were obtained using a multiple logistic regression model. RESULTS: A high adherence to the MD is significantly associated with decreased risk of NAFLD (OR: 0.83 95% CI: 0.71-0.98). When the different MD components were examined separately, higher legumes consumption (OR: 0.62 95% CI: 0.38-0.99) and high fish consumption (OR 0.38 95% CI: 0.17-0.85) were reported to be protective against NAFLD. CONCLUSIONS: Our study shows that a high adherence to the MD decreases the risk of NAFLD.

Published
2020

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

Author

Miele, Luca, Giorgio, Valentina, Liguori, Antonio, Petta, S., Pastorino, Roberta, Arzani, D., Alberelli, M. A., Cefalo, Chiara Maria Assunta, Marrone, Giuseppe, Biolato, Marco, Rapaccini, Gian Ludovico, Boccia, Stefania, Gasbarrini, Antonio, Craxi, A., Grieco, Antonio, Miele L. (ORCID:0000-0003-3464-0068), Giorgio V., Liguori A., Pastorino R. (ORCID:0000-0001-5013-0733), Cefalo C., Marrone G., Biolato M., Rapaccini G. (ORCID:0000-0002-6467-857X), Boccia S. (ORCID:0000-0002-1864-749X), Gasbarrini A. (ORCID:0000-0002-7278-4823), Grieco A. (ORCID:0000-0002-0544-8993), Miele, Luca, Giorgio, Valentina, Liguori, Antonio, Petta, S., Pastorino, Roberta, Arzani, D., Alberelli, M. A., Cefalo, Chiara Maria Assunta, Marrone, Giuseppe, Biolato, Marco, Rapaccini, Gian Ludovico, Boccia, Stefania, Gasbarrini, Antonio, Craxi, A., Grieco, Antonio, Miele L. (ORCID:0000-0003-3464-0068), Giorgio V., Liguori A., Pastorino R. (ORCID:0000-0001-5013-0733), Cefalo C., Marrone G., Biolato M., Rapaccini G. (ORCID:0000-0002-6467-857X), Boccia S. (ORCID:0000-0002-1864-749X), Gasbarrini A. (ORCID:0000-0002-7278-4823), and Grieco A. (ORCID:0000-0002-0544-8993)

Abstract

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.

Published
2020

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

Author

Ponziani, Francesca Romana, Valenza, Venanzio, Nure, Erida, Bianco, Giuseppe, Marrone, Giuseppe, Grieco, Antonio, Pompili, Maurizio, Gasbarrini, Antonio, Agnes, Salvatore, Sganga, Gabriele, Ponziani, Francesca Romana (ORCID:0000-0002-5924-6238), Valenza, Venanzio (ORCID:0000-0002-0023-6625), Grieco, Antonio (ORCID:0000-0002-0544-8993), Pompili, Maurizio (ORCID:0000-0001-6699-7980), Gasbarrini, Antonio (ORCID:0000-0002-7278-4823), Agnes, Salvatore (ORCID:0000-0002-3341-4221), Sganga, Gabriele (ORCID:0000-0001-5079-0395), Ponziani, Francesca Romana, Valenza, Venanzio, Nure, Erida, Bianco, Giuseppe, Marrone, Giuseppe, Grieco, Antonio, Pompili, Maurizio, Gasbarrini, Antonio, Agnes, Salvatore, Sganga, Gabriele, Ponziani, Francesca Romana (ORCID:0000-0002-5924-6238), Valenza, Venanzio (ORCID:0000-0002-0023-6625), Grieco, Antonio (ORCID:0000-0002-0544-8993), Pompili, Maurizio (ORCID:0000-0001-6699-7980), Gasbarrini, Antonio (ORCID:0000-0002-7278-4823), Agnes, Salvatore (ORCID:0000-0002-3341-4221), and Sganga, Gabriele (ORCID:0000-0001-5079-0395)

Published
2020

27. Contrast-enhanced ultrasound in the short-term evaluation of hepatocellular carcinoma after locoregional treatment

Author

Ainora, Maria Elena, Iezzi, Roberto, Ponziani, Francesca Romana, Garcovich, Matteo, Di Stasio, Enrico, Riccardi, Laura, Annicchiarico, Brigida Eleonora, Abbate, Valeria, De Gaetano, Anna Maria, Siciliano, Massimo, Grieco, Antonio, Rapaccini, Gian Ludovico, Gasbarrini, Antonio, Pompili, Maurizio, Zocco, Maria Assunta, Iezzi, Roberto (ORCID:0000-0002-2791-481X), Ponziani, Francesca Romana (ORCID:0000-0002-5924-6238), Di Stasio, Enrico (ORCID:0000-0003-1047-4261), De Gaetano, Anna Maria (ORCID:0000-0002-7493-9462), Grieco, Antonio (ORCID:0000-0002-0544-8993), Rapaccini, Gian Ludovico (ORCID:0000-0002-6467-857X), Gasbarrini, Antonio (ORCID:0000-0002-7278-4823), Pompili, Maurizio (ORCID:0000-0001-6699-7980), Zocco, Maria Assunta (ORCID:0000-0002-0814-9542), Ainora, Maria Elena, Iezzi, Roberto, Ponziani, Francesca Romana, Garcovich, Matteo, Di Stasio, Enrico, Riccardi, Laura, Annicchiarico, Brigida Eleonora, Abbate, Valeria, De Gaetano, Anna Maria, Siciliano, Massimo, Grieco, Antonio, Rapaccini, Gian Ludovico, Gasbarrini, Antonio, Pompili, Maurizio, Zocco, Maria Assunta, Iezzi, Roberto (ORCID:0000-0002-2791-481X), Ponziani, Francesca Romana (ORCID:0000-0002-5924-6238), Di Stasio, Enrico (ORCID:0000-0003-1047-4261), De Gaetano, Anna Maria (ORCID:0000-0002-7493-9462), Grieco, Antonio (ORCID:0000-0002-0544-8993), Rapaccini, Gian Ludovico (ORCID:0000-0002-6467-857X), Gasbarrini, Antonio (ORCID:0000-0002-7278-4823), Pompili, Maurizio (ORCID:0000-0001-6699-7980), and Zocco, Maria Assunta (ORCID:0000-0002-0814-9542)

Abstract

BACKGROUND: Contrast-enhanced ultrasound (CEUS) with second-generation contrast agents performed 1-month after 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 of CEUS for the assessment of tumour response shortly after locoregional therapy in patients with unresectable HCC. METHODS: Ninety-four patients with 104 HCC lesions who were scheduled to receive PEI, RFA, TACE or combined treatment were enrolled in this study. With CECT at 1-month as the reference standard, the diagnostic accuracy of CEUS performed 48-hours 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-hours after treatment detected residual tumor in 34/43 nodules with treatment failure at CECT with a sensitivity, specificity, PPV, NPV 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). An 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 hours CEUS had a significantly longer mean overall survival and time to progression compared to non-responders. CONCLUSION: CEUS performed 48 hours 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 hepatocellular carcinoma.

Published
2020

28. A Role for the Biological Clock in Liver Cancer

Author

Mazzoccoli, Gianluigi, Miele, Luca, Marrone, Giuseppe, Mazza, Tommaso, Vinciguerra, Manlio, Grieco, Antonio, Miele, Luca (ORCID:0000-0003-3464-0068), Grieco, Antonio (ORCID:0000-0002-0544-8993), Mazzoccoli, Gianluigi, Miele, Luca, Marrone, Giuseppe, Mazza, Tommaso, Vinciguerra, Manlio, Grieco, Antonio, Miele, Luca (ORCID:0000-0003-3464-0068), and Grieco, Antonio (ORCID:0000-0002-0544-8993)

Abstract

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.

Published
2019

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

Author

Biolato, Marco, Tarli, Claudia, Marrone, Giuseppe, Barbaro, Brunella, Liguori, Antonio, Gasbarrini, Antonio, Grieco, Antonio, Barbaro, Brunella (ORCID:0000-0002-9638-543X), Gasbarrini, Antonio (ORCID:0000-0002-7278-4823), Grieco, Antonio (ORCID:0000-0002-0544-8993), Biolato, Marco, Tarli, Claudia, Marrone, Giuseppe, Barbaro, Brunella, Liguori, Antonio, Gasbarrini, Antonio, Grieco, Antonio, Barbaro, Brunella (ORCID:0000-0002-9638-543X), Gasbarrini, Antonio (ORCID:0000-0002-7278-4823), and Grieco, Antonio (ORCID:0000-0002-0544-8993)

Abstract

N/A

Published
2019

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

Author

Nicoletti, Alberto, Ponziani, Francesca Romana, Biolato, Marco, Valenza, Venanzio, Marrone, Giuseppe, Sganga, Gabriele, Gasbarrini, Antonio, Miele, Luca, Grieco, Antonio, Ponziani, Francesca Romana (ORCID:0000-0002-5924-6238), Valenza, Venanzio (ORCID:0000-0002-0023-6625), Sganga, Gabriele (ORCID:0000-0001-5079-0395), Gasbarrini, Antonio (ORCID:0000-0002-7278-4823), Miele, Luca (ORCID:0000-0003-3464-0068), Grieco, Antonio (ORCID:0000-0002-0544-8993), Nicoletti, Alberto, Ponziani, Francesca Romana, Biolato, Marco, Valenza, Venanzio, Marrone, Giuseppe, Sganga, Gabriele, Gasbarrini, Antonio, Miele, Luca, Grieco, Antonio, Ponziani, Francesca Romana (ORCID:0000-0002-5924-6238), Valenza, Venanzio (ORCID:0000-0002-0023-6625), Sganga, Gabriele (ORCID:0000-0001-5079-0395), Gasbarrini, Antonio (ORCID:0000-0002-7278-4823), Miele, Luca (ORCID:0000-0003-3464-0068), and Grieco, Antonio (ORCID:0000-0002-0544-8993)

Abstract

N/A

Published
2019

31. Platelets and Hepatocellular Cancer: Bridging the Bench to the Clinics

Author

Lai, Quirino, Vitale, Alessandro, Manzia, Tommaso M, Foschi, Francesco G, Levi Sandri, Giovanni B, Gambato, Martina, Melandro, Fabio, Russo, Francesco P, Miele, Luca, Viganò, Luca, Burra, Patrizia, Giannini, Edoardo G, Aglitti, A13, Aliberti, C13, Baccarani, U13, Bhoori, S13, Borzio, M13, Brancaccio, G13, Cabibbo, G13, Casadei Gardini, A13, Carrai, P13, Cillo, U13, Conti, F13, Cucchetti, A13, D’Ambrosio, R13, Dell’Unto, C13, Dematthaeis, N13, Di Costanzo, Gg13, Di Sandro, S13, Fucilli, F13, Galati, G13, Gasbarrini, Antonio, Giuliante, F13, Ghinolfi, D13, Grieco, Antonio, Gruttaduria, S13, Guarino, M13, Kostandini, A13, Iavarone, M13, Lenci, I13, Losito, F13, Lupo, Lg13, Mazzocato, S13, Mescoli, C13, Miele, L13, Morisco, F13, Muley, M13, Nicolini, D13, Persico, M13, Pompili, M13, Ponziani, Fr13, Pravisani, R13, Rapaccini, Gl13, Rendina, M13, Renzulli, M13, Rossi, M13, Rreka, E13, Sacco, R13, Sangiovanni, A13, Sessa, A13, Simonetti, N13, Sposito, C13, Tortora, R13, Trevisani, F13, Viganò, M13, Villa, E13, Vincenzi, V13, Violi, P13., Miele, Luca (ORCID:0000-0003-3464-0068), Gasbarrini A (ORCID:0000-0002-7278-4823), Grieco A13 (ORCID:0000-0002-0544-8993), Lai, Quirino, Vitale, Alessandro, Manzia, Tommaso M, Foschi, Francesco G, Levi Sandri, Giovanni B, Gambato, Martina, Melandro, Fabio, Russo, Francesco P, Miele, Luca, Viganò, Luca, Burra, Patrizia, Giannini, Edoardo G, Aglitti, A13, Aliberti, C13, Baccarani, U13, Bhoori, S13, Borzio, M13, Brancaccio, G13, Cabibbo, G13, Casadei Gardini, A13, Carrai, P13, Cillo, U13, Conti, F13, Cucchetti, A13, D’Ambrosio, R13, Dell’Unto, C13, Dematthaeis, N13, Di Costanzo, Gg13, Di Sandro, S13, Fucilli, F13, Galati, G13, Gasbarrini, Antonio, Giuliante, F13, Ghinolfi, D13, Grieco, Antonio, Gruttaduria, S13, Guarino, M13, Kostandini, A13, Iavarone, M13, Lenci, I13, Losito, F13, Lupo, Lg13, Mazzocato, S13, Mescoli, C13, Miele, L13, Morisco, F13, Muley, M13, Nicolini, D13, Persico, M13, Pompili, M13, Ponziani, Fr13, Pravisani, R13, Rapaccini, Gl13, Rendina, M13, Renzulli, M13, Rossi, M13, Rreka, E13, Sacco, R13, Sangiovanni, A13, Sessa, A13, Simonetti, N13, Sposito, C13, Tortora, R13, Trevisani, F13, Viganò, M13, Villa, E13, Vincenzi, V13, Violi, P13., Miele, Luca (ORCID:0000-0003-3464-0068), Gasbarrini A (ORCID:0000-0002-7278-4823), and Grieco A13 (ORCID:0000-0002-0544-8993)

Abstract

N/A

Published
2019

32. Acute HEV hepatitis: clinical and laboratory diagnosis

Author

Marrone, Giuseppe, Biolato, Marco, Mercurio, Giovanna, Capobianchi, M R, Garbuglia, A R, Liguori, Antonio, Vassallo, G, Gasbarrini, Antonio, Miele, Luca, Grieco, Antonio, Marrone, G, Biolato, M, Mercurio, G, Gasbarrini, A (ORCID:0000-0002-7278-4823), Miele, L (ORCID:0000-0003-3464-0068), Grieco, A (ORCID:0000-0002-0544-8993), Marrone, Giuseppe, Biolato, Marco, Mercurio, Giovanna, Capobianchi, M R, Garbuglia, A R, Liguori, Antonio, Vassallo, G, Gasbarrini, Antonio, Miele, Luca, Grieco, Antonio, Marrone, G, Biolato, M, Mercurio, G, Gasbarrini, A (ORCID:0000-0002-7278-4823), Miele, L (ORCID:0000-0003-3464-0068), and Grieco, A (ORCID:0000-0002-0544-8993)

Abstract

OBJECTIVE: Hepatitis E Virus (HEV) is probably the most common cause of acute hepatitis worldwide. It has been regarded for a long time as a disease limited to developing countries. Recently, the refinement of diagnostic techniques, on the one hand, and migratory flows, on the other hand, have also led to the identification of an increased number of HEV infections in industrialized countries. Four HEV genotypes have been identified across the world, with different epidemiological burdens and a wide range of clinical presentations. Here, we report a case series of acute HEV hepatitis observed in the last three years in our hospital. PATIENTS AND METHODS: We performed a search for HEV IgM and IgG in all subjects admitted for acute hepatitis without evidence of other possible infectious, toxic or metabolic causes of liver damage. In subjects with HEV IgM positivity, the search for HEV-RNA was performed. RESULTS: We diagnosed eight acute HEV infections: 2 epidemic and 6 sporadic forms. HEV-RNA was detected in serum in 2 cases. CONCLUSIONS: HEV infection appears to be a cause of acute hepatitis that we must keep in mind even in developed countries.

Published
2019

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

Author

Biolato, Marco, Manca, Fiorella, Marrone, Giuseppe, Cefalo, Consuelo, Racco, Simona, Miggiano, Giacinto Abele Donato, Valenza, Venanzio, Gasbarrini, Antonio, Miele, Luca, Grieco, Antonio, Miggiano, Giacinto A (ORCID:0000-0002-8627-5528), Valenza, Venanzio (ORCID:0000-0002-0023-6625), Gasbarrini, Antonio (ORCID:0000-0002-7278-4823), Miele, Luca (ORCID:0000-0003-3464-0068), Grieco, Antonio (ORCID:0000-0002-0544-8993), Biolato, Marco, Manca, Fiorella, Marrone, Giuseppe, Cefalo, Consuelo, Racco, Simona, Miggiano, Giacinto Abele Donato, Valenza, Venanzio, Gasbarrini, Antonio, Miele, Luca, Grieco, Antonio, Miggiano, Giacinto A (ORCID:0000-0002-8627-5528), Valenza, Venanzio (ORCID:0000-0002-0023-6625), Gasbarrini, Antonio (ORCID:0000-0002-7278-4823), Miele, Luca (ORCID:0000-0003-3464-0068), and Grieco, Antonio (ORCID:0000-0002-0544-8993)

Abstract

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, P = 0.003), mean waist circumference (-7.9 ± 4.9 cm, P = 0.001), and mean transaminase levels [alanine aminotransferase (ALT) -28.3 ± 11.9 IU/L, P = 0.0001; aspartate aminotransferase (AST) -6.4 ± 56.3 IU/L, P = 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 over

Published
2019

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

Author

Pelusi, Serena, Baselli, Guido, Pietrelli, Alessandro, Dongiovanni, Paola, Donati, Maria Benedetta, Mccain, Misti Vanette, Meroni, Marica, Fracanzani, Anna Ludovica, Romagnoli, Renato, Petta, Salvatore, Grieco, Antonio, Miele, Luca, Soardo, Giorgio, Bugianesi, Elisabetta, Fargion, Silvia, Aghemo, Alessio, D'Ambrosio, Roberta, Xing, Chao, Romeo, Stefano, De Francesco, Raffaele, Reeves, Helen Louise, Valenti, Luca Vittorio Carlo, Donati, Benedetta, Grieco, Antonio (ORCID:0000-0002-0544-8993), Miele, Luca (ORCID:0000-0003-3464-0068), Pelusi, Serena, Baselli, Guido, Pietrelli, Alessandro, Dongiovanni, Paola, Donati, Maria Benedetta, Mccain, Misti Vanette, Meroni, Marica, Fracanzani, Anna Ludovica, Romagnoli, Renato, Petta, Salvatore, Grieco, Antonio, Miele, Luca, Soardo, Giorgio, Bugianesi, Elisabetta, Fargion, Silvia, Aghemo, Alessio, D'Ambrosio, Roberta, Xing, Chao, Romeo, Stefano, De Francesco, Raffaele, Reeves, Helen Louise, Valenti, Luca Vittorio Carlo, Donati, Benedetta, Grieco, Antonio (ORCID:0000-0002-0544-8993), and Miele, Luca (ORCID:0000-0003-3464-0068)

Abstract

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*10-6), 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*10-16), 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.

Published
2019

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

Author

Calvaruso, Vincenza, Mazzarelli, Chiara, Milazzo, Laura, Badia, Lorenzo, Pasulo, Luisa, Guaraldi, Giovanni, Lionetti, Raffaella, Villa, Erica, Borghi, Vanni, Carrai, Paola, Alberti, Alfredo, Biolato, Marco, Piai, Guido, Persico, Marcello, Santantonio, Teresa, Felder, Martina, Angelico, Mario, Montalbano, Marzia, Mancusi, Rossella Letizia, Grieco, Antonio, Angeli, Elena, D'Offizi, Gianpiero, Fagiuoli, Stefano, Belli, Luca, Verucchi, Gabriella, Puoti, Massimo, Craxì, Antonio, Grieco, Antonio (ORCID:0000-0002-0544-8993), Calvaruso, Vincenza, Mazzarelli, Chiara, Milazzo, Laura, Badia, Lorenzo, Pasulo, Luisa, Guaraldi, Giovanni, Lionetti, Raffaella, Villa, Erica, Borghi, Vanni, Carrai, Paola, Alberti, Alfredo, Biolato, Marco, Piai, Guido, Persico, Marcello, Santantonio, Teresa, Felder, Martina, Angelico, Mario, Montalbano, Marzia, Mancusi, Rossella Letizia, Grieco, Antonio, Angeli, Elena, D'Offizi, Gianpiero, Fagiuoli, Stefano, Belli, Luca, Verucchi, Gabriella, Puoti, Massimo, Craxì, Antonio, and Grieco, Antonio (ORCID:0000-0002-0544-8993)

Abstract

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.

Published
2019

36. Economic Consequences of Investing in Anti-HCV Antiviral Treatment from the Italian NHS Perspective: A Real-World-Based Analysis of PITER Data

Author

Marcellusi, Andrea, Viti, Raffaella, Kondili, Loreta A., Rosato, Stefano, Vella, Stefano, Mennini, Francesco Saverio, Kondili, L. A., Vella, S., Quaranta, M. G., Rosato, S., Tosti, M. E., Weimer, L. E., Ferrigno, L., D’Angelo, F., Falzano, L., Benedetti, A., Schiadà, L., Cucco, M., Giacometti, A., Brescini, L., Castelletti, S., Drenaggi, D., Mazzaro, C., Angarano, G., Milella, M., Di&nbsp, Leo, A., Rendina, M., Contaldo, A., Iannone, A., La Fortezza, F., Rizzi, M., Cologni, G., Bolondi, L., Benevento, F., Serio, I., Andreone, P., Caraceni, P., Guarneri, V., Margotti, M., Simonetti, G., Mazzella, G., Verucchi, G., Donati, V., Mian, Peter, Rimenti, G., Rossini, A., Contessi, G. B., Castelli, Fulvio, Zaltron, S., Spinetti, A., Odolini, S., Leandro, G., Cozzolongo, R., Zappimbulso, M., Russello, M., Benigno, R., Coco, C., Torti, C., Costa, C., Greco, G., Mazzitelli, M., Pisani, V., Cosco, Lucia, Quintieri, F., De Siena, Martina, Giancotti, F., Vecchiet, J., Falasca, K., Mastroianni, A., Apuzzo, G., Chidichimo, L., Foschi, F. G., Dall’Aglio, A. C., Libanore, M., Segala, D., Sighinolfi, L., Bartolozzi, D., Salomoni, E., Blanc, P., Baragli, F., Del&nbsp, Pin, B., Mariabelli, E., Mazzotta, F., Poggi, A., Zignego, A. L., Monti, M., Madia, Francesca, Xheka, A., Cela, E. M., Santantonio, T. A., Bruno, S. R., Viscoli, C., Alessandrini, A. I., Curti, C., Biagio, A., Nicolini, L. A., Balletto, E., Mastroianni, Chiara, Blerta, K., Prati, D., Raffaele, L., Andreoletti, M., Perboni, G., Costa, P., Manzini, L., Raimondo, G., Filomia, R., Lazzarin, A., Morsica, G., Salpietro, S., Puoti, M., Baiguera, C., Vassalli, S., Rumi, M. G., Labanca, S., Zuin, M., Giorgini, A., Orellana, D., D’Arminio&nbsp, Monforte, A., Debona, A., Solaro, S., Fargion, S., Valenti, L., Periti, G., Pelusi, S., Galli, M., Calvi, E., Milazzo, L., Peri, A., Lampertico, P., Borghi, Margherita, D’Ambrosio, R., Degasperi, E., Vinci, Maria Rosaria, Villa, E., Bernabucci, V., Bristot, Luca, Pereira, F., Chessa, L., Pasetto, M. C., Loi, M., Gori, A., Beretta, I., Pastore, V., Soria, A., Strazzabosco, M., Ciaccio, A., Gemma, M., Borgia, G., Foggia, A., Zappulo, E., Gentile, I., Buonomo, A. R., Abrescia, N., Maddaloni, A., Caporaso, N., Morisco, F., Camera, S., Donnarumma, L., Coppola, C., Amoruso, D. C., Staiano, L., Saturnino, M. R., Coppola, N., Martini, S., Monari, C., Federico, Alex, Dallio, M., Loguercio, C., Gaeta, G. B., Brancaccio, G., Nardone, G., Sgamato, C., D’Adamo, G., Alberti, A., Gonzo, M., Piovesan, S., Chemello, L., Buggio, A., Cavalletto, L., Barbaro, F., Castelli, Enrico, Floreani, A., Cazzagon, N., Franceschet, I., Russo, F. P., Zanetto, A., Franceschet, E., Madonia, S., Cannizzaro, Maria Chiara, Montalto, G., Licata, A., Capitano, A. R., Craxì, A., Petta, S., Calvaruso, V., Rini, F., Ferrari, C., Negri, E., Orlandini, A., Pesci, M., Bruno, R., Lombardi, A., Zuccaro, V., Gulminetti, R., Asti, A., Villaraggia, M., Mondelli, M., Ludovisi, S., Baldelli, F., Di Candilo, F., Parruti, G., Di Stefano, Paolo, Sozio, F., Gizzi, M. C., Brunetto, M. R., Colombatto, P., Coco, B., Surace, L., Foti, G., Pellicano, S., Fornaciari, G., Schianchi, S., Vignoli, P., Massari, M., Corsini, R., Garlassi, E., Ballardini, G., Andreoni, M., Cerva, C., Angelico, M., Gasbarrini, Antonio, Siciliano, M., Nosotti, L., Taliani, G., Biliotti, E., Santori, M., Spaziante, M., Tamburini, F., Vullo, V., D’Ettorre, G., Cavallari, E. N., Gebremeskel, T. S., Pavone, P., Cauda, Roberto, Cingolani, Antonella, Lamonica, S., D’Offizi, G., Lionetti, R., Visco Comandini, U., Grieco, Antonio, D’Aversa, F., Picardi, A., De Vincentis, A., Galati, G., Gallo, Patrizia, Dell’Unto, C., Aghemo, A., Gatti Comini, A., Persico, M., Masarone, M., Anselmo, M., De Leo, P., Marturano, Monia, Brunelli, E., Ridolfi, F., Schimizzi, A. M., Ayoubi Khajekini, M., Framarin, L., Di Perri, G., Cariti, G., Boglione, L., Cardellino, C., Marinaro, L., Saracco, G. M., Ciancio, A., Toniutto, P., Alterini, G., Capra, F., Ieluzzi, D., De Siena, M., Madia, F., Mastroianni, C., Vinci, M., Federico, A., Gasbarrini, A. (ORCID:0000-0002-7278-4823), Cauda, R. (ORCID:0000-0002-1498-4229), Cingolani, A. (ORCID:0000-0002-3793-2755), Grieco, A. (ORCID:0000-0002-0544-8993), Marturano, M., Marcellusi, Andrea, Viti, Raffaella, Kondili, Loreta A., Rosato, Stefano, Vella, Stefano, Mennini, Francesco Saverio, Kondili, L. A., Vella, S., Quaranta, M. G., Rosato, S., Tosti, M. E., Weimer, L. E., Ferrigno, L., D’Angelo, F., Falzano, L., Benedetti, A., Schiadà, L., Cucco, M., Giacometti, A., Brescini, L., Castelletti, S., Drenaggi, D., Mazzaro, C., Angarano, G., Milella, M., Di&nbsp, Leo, A., Rendina, M., Contaldo, A., Iannone, A., La Fortezza, F., Rizzi, M., Cologni, G., Bolondi, L., Benevento, F., Serio, I., Andreone, P., Caraceni, P., Guarneri, V., Margotti, M., Simonetti, G., Mazzella, G., Verucchi, G., Donati, V., Mian, Peter, Rimenti, G., Rossini, A., Contessi, G. B., Castelli, Fulvio, Zaltron, S., Spinetti, A., Odolini, S., Leandro, G., Cozzolongo, R., Zappimbulso, M., Russello, M., Benigno, R., Coco, C., Torti, C., Costa, C., Greco, G., Mazzitelli, M., Pisani, V., Cosco, Lucia, Quintieri, F., De Siena, Martina, Giancotti, F., Vecchiet, J., Falasca, K., Mastroianni, A., Apuzzo, G., Chidichimo, L., Foschi, F. G., Dall’Aglio, A. C., Libanore, M., Segala, D., Sighinolfi, L., Bartolozzi, D., Salomoni, E., Blanc, P., Baragli, F., Del&nbsp, Pin, B., Mariabelli, E., Mazzotta, F., Poggi, A., Zignego, A. L., Monti, M., Madia, Francesca, Xheka, A., Cela, E. M., Santantonio, T. A., Bruno, S. R., Viscoli, C., Alessandrini, A. I., Curti, C., Biagio, A., Nicolini, L. A., Balletto, E., Mastroianni, Chiara, Blerta, K., Prati, D., Raffaele, L., Andreoletti, M., Perboni, G., Costa, P., Manzini, L., Raimondo, G., Filomia, R., Lazzarin, A., Morsica, G., Salpietro, S., Puoti, M., Baiguera, C., Vassalli, S., Rumi, M. G., Labanca, S., Zuin, M., Giorgini, A., Orellana, D., D’Arminio&nbsp, Monforte, A., Debona, A., Solaro, S., Fargion, S., Valenti, L., Periti, G., Pelusi, S., Galli, M., Calvi, E., Milazzo, L., Peri, A., Lampertico, P., Borghi, Margherita, D’Ambrosio, R., Degasperi, E., Vinci, Maria Rosaria, Villa, E., Bernabucci, V., Bristot, Luca, Pereira, F., Chessa, L., Pasetto, M. C., Loi, M., Gori, A., Beretta, I., Pastore, V., Soria, A., Strazzabosco, M., Ciaccio, A., Gemma, M., Borgia, G., Foggia, A., Zappulo, E., Gentile, I., Buonomo, A. R., Abrescia, N., Maddaloni, A., Caporaso, N., Morisco, F., Camera, S., Donnarumma, L., Coppola, C., Amoruso, D. C., Staiano, L., Saturnino, M. R., Coppola, N., Martini, S., Monari, C., Federico, Alex, Dallio, M., Loguercio, C., Gaeta, G. B., Brancaccio, G., Nardone, G., Sgamato, C., D’Adamo, G., Alberti, A., Gonzo, M., Piovesan, S., Chemello, L., Buggio, A., Cavalletto, L., Barbaro, F., Castelli, Enrico, Floreani, A., Cazzagon, N., Franceschet, I., Russo, F. P., Zanetto, A., Franceschet, E., Madonia, S., Cannizzaro, Maria Chiara, Montalto, G., Licata, A., Capitano, A. R., Craxì, A., Petta, S., Calvaruso, V., Rini, F., Ferrari, C., Negri, E., Orlandini, A., Pesci, M., Bruno, R., Lombardi, A., Zuccaro, V., Gulminetti, R., Asti, A., Villaraggia, M., Mondelli, M., Ludovisi, S., Baldelli, F., Di Candilo, F., Parruti, G., Di Stefano, Paolo, Sozio, F., Gizzi, M. C., Brunetto, M. R., Colombatto, P., Coco, B., Surace, L., Foti, G., Pellicano, S., Fornaciari, G., Schianchi, S., Vignoli, P., Massari, M., Corsini, R., Garlassi, E., Ballardini, G., Andreoni, M., Cerva, C., Angelico, M., Gasbarrini, Antonio, Siciliano, M., Nosotti, L., Taliani, G., Biliotti, E., Santori, M., Spaziante, M., Tamburini, F., Vullo, V., D’Ettorre, G., Cavallari, E. N., Gebremeskel, T. S., Pavone, P., Cauda, Roberto, Cingolani, Antonella, Lamonica, S., D’Offizi, G., Lionetti, R., Visco Comandini, U., Grieco, Antonio, D’Aversa, F., Picardi, A., De Vincentis, A., Galati, G., Gallo, Patrizia, Dell’Unto, C., Aghemo, A., Gatti Comini, A., Persico, M., Masarone, M., Anselmo, M., De Leo, P., Marturano, Monia, Brunelli, E., Ridolfi, F., Schimizzi, A. M., Ayoubi Khajekini, M., Framarin, L., Di Perri, G., Cariti, G., Boglione, L., Cardellino, C., Marinaro, L., Saracco, G. M., Ciancio, A., Toniutto, P., Alterini, G., Capra, F., Ieluzzi, D., De Siena, M., Madia, F., Mastroianni, C., Vinci, M., Federico, A., Gasbarrini, A. (ORCID:0000-0002-7278-4823), Cauda, R. (ORCID:0000-0002-1498-4229), Cingolani, A. (ORCID:0000-0002-3793-2755), Grieco, A. (ORCID:0000-0002-0544-8993), and Marturano, M.

Abstract

Objective: We estimated the cost consequence of Italian National Health System (NHS) investment in direct-acting antiviral (DAA) therapy according to hepatitis C virus (HCV) treatment access policies in Italy. Methods: A multistate, 20-year time horizon Markov model of HCV liver disease progression was developed. Fibrosis stage, age and genotype distributions were derived from the Italian Platform for the Study of Viral Hepatitis Therapies (PITER) cohort. The treatment efficacy, disease progression probabilities and direct costs in each health state were obtained from the literature. The break-even point in time (BPT) was defined as the period of time required for the cumulative costs saved to recover the Italian NHS investment in DAA treatment. Three different PITER enrolment periods, which covered the full DAA access evolution in Italy, were considered. Results: The disease stages of 2657 patients who consecutively underwent DAA therapy from January 2015 to December 2017 at 30 PITER clinical centres were standardized for 1000 patients. The investment in DAAs was considered to equal €25 million, €15 million, and €9 million in 2015, 2016, and 2017, respectively. For patients treated in 2015, the BPT was not achieved, because of the disease severity of the treated patients and high DAA prices. For 2016 and 2017, the estimated BPTs were 6.6 and 6.2 years, respectively. The total cost savings after 20 years were €50.13 and €55.50 million for 1000 patients treated in 2016 and 2017, respectively. Conclusions: This study may be a useful tool for public decision makers to understand how HCV clinical and epidemiological profiles influence the economic burden of HCV.

Published
2019

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

Author

Vassallo, Ga, Tarli, Claudia, Rando, Mm, Mosoni, Carolina, Mirijello, A, Agyei-Nkansah, A, Antonelli, Massimo, Sestito, Luisa, Perotti, Germano, Di Giuda, Daniela, Agnes, Salvatore, Grieco, Antonio, Gasbarrini, Antonio, Addolorato, Giovanni, Tarli, C, Mosoni, C, Antonelli, M (ORCID:0000-0003-3007-1670), Sestito, L, Perotti, G, Di Giuda, D (ORCID:0000-0002-5758-3986), Agnes, S (ORCID:0000-0002-3341-4221), Grieco, A (ORCID:0000-0002-0544-8993), Gasbarrini, A (ORCID:0000-0002-7278-4823), Addolorato, G (ORCID:0000-0002-1522-9946), Vassallo, Ga, Tarli, Claudia, Rando, Mm, Mosoni, Carolina, Mirijello, A, Agyei-Nkansah, A, Antonelli, Massimo, Sestito, Luisa, Perotti, Germano, Di Giuda, Daniela, Agnes, Salvatore, Grieco, Antonio, Gasbarrini, Antonio, Addolorato, Giovanni, Tarli, C, Mosoni, C, Antonelli, M (ORCID:0000-0003-3007-1670), Sestito, L, Perotti, G, Di Giuda, D (ORCID:0000-0002-5758-3986), Agnes, S (ORCID:0000-0002-3341-4221), Grieco, A (ORCID:0000-0002-0544-8993), Gasbarrini, A (ORCID:0000-0002-7278-4823), and Addolorato, G (ORCID:0000-0002-1522-9946)

Abstract

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 complicatio

Published
2018

38. Impact of new DAA therapy on real clinical practice: A multicenter region-wide cohort study

Author

Lanini, Simone, Scognamiglio, Paola, Mecozzi, Alessandra, Lombardozzi, Lorella, Vullo, Vincenzo, Angelico, Mario, Gasbarrini, Antonio, Taliani, Gloria, Attili, Adolfo Francesco, Perno, Carlo Federico, De Santis, Adriano, Puro, Vincenzo, Cerqua, Fabio, D'Offizi, Gianpiero, Pellicelli, Adriano, Armignacco, Orlando, Mennini, Francesco Saverio, Siciliano, Massimo, Girardi, Enrico, Panella, Vincenzo, Ippolito, Giuseppe, Sarrecchia, C., Di Paolo, M. D., Francioso, S., Brega, A., Lenci, I., Sarmati, L., Pompili, Maurizio, Grieco, Antonio, Tamburrini, Enrica, Apaccini, R., Miele, Luca, D'Ettorre, G., Mezzaroma, I., Furlan, C., Accapezzato, D., Paoletti, F., Merili, M., Corradini, S., Sereno, S., Fimiani, C., Mastropietro, C., Labbadia, G., Gentile, Giuseppe, Pasquazzi, C., Marignani, M., Guarisco, R., Puoti, C., Spilabotti, L., Montalbano, M., Boumis, E., Visco-Comandini, U., Zaccarelli, M., Ammassari, A., Lionetti, R., Murachelli, S., Loiacono, L., Antinori, Armando, Noto, P., Palmieri, F., Cicalini, S., Cerilli, S., Sampaolesi, A., Vincenzi, L., Bellagamba, R., Galati, V., Abdeddaim, A., Iacomi, F., Iannicelli, G., Mastroianni, Chiara, Lichtner, M., Ridola, L., Coluzzi, T., Mercurio, V., Del Borgo, C., Fondacaro, L., Cerasari, G., Guarascio, P., D'Ambrosio, C., Starnini, G., Caterini, A., Villani, Emanuele Rocco, Sarracino, L., Casinelli, K., Moretti, A., Vespasiani, U., Galati, G., Cecere, R., Bonaventura, M., Scudieri, M., Gasbarrini, Antonio (ORCID:0000-0002-7278-4823), Pompili, M. (ORCID:0000-0001-6699-7980), Grieco, A. (ORCID:0000-0002-0544-8993), Tamburrini, E. (ORCID:0000-0003-4930-426X), Miele, L. (ORCID:0000-0003-3464-0068), Gentile, G., Antinori, A. (ORCID:0000-0002-6019-2417), Mastroianni, C., Villani, R., Lanini, Simone, Scognamiglio, Paola, Mecozzi, Alessandra, Lombardozzi, Lorella, Vullo, Vincenzo, Angelico, Mario, Gasbarrini, Antonio, Taliani, Gloria, Attili, Adolfo Francesco, Perno, Carlo Federico, De Santis, Adriano, Puro, Vincenzo, Cerqua, Fabio, D'Offizi, Gianpiero, Pellicelli, Adriano, Armignacco, Orlando, Mennini, Francesco Saverio, Siciliano, Massimo, Girardi, Enrico, Panella, Vincenzo, Ippolito, Giuseppe, Sarrecchia, C., Di Paolo, M. D., Francioso, S., Brega, A., Lenci, I., Sarmati, L., Pompili, Maurizio, Grieco, Antonio, Tamburrini, Enrica, Apaccini, R., Miele, Luca, D'Ettorre, G., Mezzaroma, I., Furlan, C., Accapezzato, D., Paoletti, F., Merili, M., Corradini, S., Sereno, S., Fimiani, C., Mastropietro, C., Labbadia, G., Gentile, Giuseppe, Pasquazzi, C., Marignani, M., Guarisco, R., Puoti, C., Spilabotti, L., Montalbano, M., Boumis, E., Visco-Comandini, U., Zaccarelli, M., Ammassari, A., Lionetti, R., Murachelli, S., Loiacono, L., Antinori, Armando, Noto, P., Palmieri, F., Cicalini, S., Cerilli, S., Sampaolesi, A., Vincenzi, L., Bellagamba, R., Galati, V., Abdeddaim, A., Iacomi, F., Iannicelli, G., Mastroianni, Chiara, Lichtner, M., Ridola, L., Coluzzi, T., Mercurio, V., Del Borgo, C., Fondacaro, L., Cerasari, G., Guarascio, P., D'Ambrosio, C., Starnini, G., Caterini, A., Villani, Emanuele Rocco, Sarracino, L., Casinelli, K., Moretti, A., Vespasiani, U., Galati, G., Cecere, R., Bonaventura, M., Scudieri, M., Gasbarrini, Antonio (ORCID:0000-0002-7278-4823), Pompili, M. (ORCID:0000-0001-6699-7980), Grieco, A. (ORCID:0000-0002-0544-8993), Tamburrini, E. (ORCID:0000-0003-4930-426X), Miele, L. (ORCID:0000-0003-3464-0068), Gentile, G., Antinori, A. (ORCID:0000-0002-6019-2417), Mastroianni, C., and Villani, R.

Abstract

Background: Management of chronic hepatitis C (CHC) has significantly accelerated in the last few years. Currently, second generation direct acting antivirals (DAAs) promise clearance of infection in most of patients. Here we present the results of the first analysis carried out on data of Lazio clinical network for DAAs. Methods: The study was designed as a multicenter cohort: a) to assess the evolution of treatment during the first 24 months of the activity of the Clinical Network; b) to report overall efficacy of treatments; c) to analyze potential factors associated with lack of virological response at 12 weeks after therapy (SVR12); d) to evaluate the variation of ALT at baseline and 12 weeks after therapy in those who achieved SVR12 in comparison to those who did not. Analyses of efficacy were carried out with multilevel mixed effect logistic regression model. ALT temporal variation was assessed by mixed effect model mixed models with random intercept at patient's level and random slope at the level of the time; i.e. either before or after therapy. Results: Between 30 December 2014 and 31 December 2016 5279 patients started a DAA treatment; of those, 5127 (in 14 clinical centers) had completed the 12-week follow-up. Overall proportion of SVR12 was 93.41% (N = 4780) with no heterogeneity between the 14 clinical centers. Interruption as the consequence of severe side effect was very low (only 23 patients). Unadjusted analysis indicates that proportion of SVR12 significantly changes according to patient's baseline characteristics, however after adjusting for potential confounders only adherence to current guidelines, stage of liver diseases, gender, transplant and HIV status were independently associated with the response to therapy. Analysis of ALT temporal variation showed that ALT level normalized in most, but not, all patients who achieved SVR12. Conclusion: Our study confirmed the extraordinary efficacy of DAAs outside clinical trials. The advantage of DAAs

Published
2018

39. Pretreatment prediction of response to ursodeoxycholic acid in primary biliary cholangitis: development and validation of the UDCA Response Score

Author

Carbone, Marco, Nardi, Alessandra, Flack, Steve, Carpino, Guido, Varvaropoulou, Nikoletta, Gavrila, Caiu, Spicer, Ann, Badrock, Jonathan, Bernuzzi, Francesca, Cardinale, Vincenzo, Ainsworth, Holly F, Heneghan, Michael A, Thorburn, Dougla, Bathgate, Andrew, Jones, Rebecca, Neuberger, James M, Battezzati, Pier Maria, Zuin, Massimo, Taylor-Robinson, Simon, Donato, Maria F, Kirby, John, Mitchell-Thain, Robert, Floreani, Annarosa, Sampaziotis, Fotio, Muratori, Luigi, Alvaro, Domenico, Marzioni, Marco, Miele, Luca, Marra, Fabio, Giannini, Edoardo, Gaudio, Eugenio, Ronca, Vincenzo, Bonato, Giulia, Cristoferi, Laura, Malinverno, Federica, Gerussi, Alessio, Stocken, Deborah D, Cordell, Heather J, Hirschfield, Gideon M, Alexander, Graeme J, Sandford, Richard N, Jones, David E, Invernizzi, Pietro, Mells, George F, Thomas, Caradog, Rahman, Meshbah, Yapp, Tom, Lye Ch'ng, Chin, Harrison, Melanie, Sturgess, Richard, Galaska, Roman, Healey, Chri, Whiteman, Jessica, Czaijkowski, Marek, Gray, Catherine, Gunasekera, Anton, Gyawli, Pranab, Premchand, Purushothaman, Mann, Steven, Elliott, Keith, Kapur, Kapil, Watson, Alan, Foster, Graham, Trembling, Paul, Subhani, Javaid, Harvey, Rory, Mccorry, Roger, Adgey, Carolyn, Hobson, Lucie, Mulvaney-Jones, Caroline, Evans, Richard, Mathialahan, Thiriloganathan, Ramanaden, David, Gasem, Jaber, Van Duyvenvoorde, Greta, Shorrock, Christopher, Seward, Katie, Southern, Paul, Tibble, Jeremy, Penn, Ruth, Gorard, David, Maiden, Jane, Damant, Rose, Palegwala, Altaf, Jones, Susan, Alexander, Graeme, Mells, George, Sandford, Richard, Dolwani, Sunil, Prince, Martin, Silvestre, Valeria, Foxton, Matthew, Dungca, Eleanor, Mitchison, Harriet, Wheatley, Natalie, Gooding, Ian, Doyle, Helen, Karmo, Mazn, Kent, Melanie, Saksena, Sushma, Braim, Delyth, Patel, Minesh, Lord, Susan, Ede, Roland, Paton, Alison, Austin, Andrew, Lancaster, Nicola, Sayer, Joanna, Gibbins, Andrew, Hogben, Karen, Hovell, Chri, Fisher, Neil, Carter, Martyn, Koss, Konrad, Musselwhite, Janine, Muscariu, Florin, Piotreowicz, Andrzej, Mckay, Alexandra, Grimley, Charle, Neal, David, Ting Tan, Lai, Lim, Guan, Brighton, Jacqueline, Foale, Carole, Ala, Aftab, Saeed, Athar, Flahive, Kerry, Wood, Gordon, Townshend, Paula, Ford, Chri, Brown, Jonathan, Kordula, Jean, Bowles, Jane, Wilkinson, Mark, Palmer, Caroline, Ramage, John, Gordon, Harriet, Featherstone, Jame, Ridpath, Jo, Ngatchu, Theodore, Levi, Sa, Shaukat, Syed, Sadeghian, Joy, Shidrawi, Ray, Williams, Bronwen, Abouda, George, Jones, Sarah, Duggan, Claire, Hynes, Abigail, Narain, Mark, Rees, Ian, Salam, Imroz, Crossey, Mary, Brown, Ashley, Macnicol, Carolyn, Williams, Simon, Wilhelmsen, Elva, Banim, Paul, Raymode, Parizade, Chilton, Andrew, Das, Debasish, Lee, Hye-Jeong, Curtis, Howard, Heneghan, Michael, Gess, Marku, Durant, Emma, Drake, I. M., Bishop, Rebecca, Davies, Mervyn, Aldersley, Mark, Ncube, Noma, Mcnair, Alistair, Srirajaskanthan, Raj, Sen, Sambit, Casey, Rebecca, Bird, George, Mendall, Mike, Cowley, Caroline, Barnardo, Adrian, Kitchen, Paul, Yoong, Kevin, Amore, Kelly, Sirdefield, Dawn, Orpe, Jacky, Mathew, Ray, Macfaul, George, Wrigth, Aruna, Shah, Amir, Evans, Chri, Keggans, Janie, Bird, Bridget, Baxter, Gwen, Saha, Subrata, Pollock, Katharine, Hughes, Maggie, Bramley, Peter, Grieve, Emma, Young, Karin, Fraser, Andrew, Mukhopadhya, Ashi, Ocker, Kate, Mills, Peter, Hines, Franci, Shallcross, Chri, Wilkins, Joy, Grellier, Leonie, Campbell, Stewart, Martin, Kirsty, Innes, Caron, Shepherd, Alan, Rushbrook, Simon, Valliani, Talal, Przemioslo, Robert, Fairlamb, Helen, Macdonald, Chri, Eastick, Anne, Metcalf, Jane, Tanqueray, Elizabeth, Shmueli, Udi, Holbrook, Becky, Davis, Andrew, Browning, Julie, Naqvi, Asifabba, Walker, Kirsten, Lee, Tom, Verheyden, Juliette, Slininger, Susan, Ryder, Stephen D, Chapman, Roger, Collier, Jane, O'Donnell, Denise, Stafford, Lizzie, Williamson, Kate, Kent, Linda, Klass, Howard, Ninkovic, Mary, March, Linda, Cramp, Matthew, Simpson, Diane, Dickson, Christine, Sharer, Nichola, Hayes, Maria, Goggin, Patrick, Quinne, Mary, Pearson, Sallyanne, Hoeroldt, Barbara, Jones, Linda, Wright, Alice, Booth, Jonathan, Loftus, Alison, Lipscomb, George, Dewhurst, Hannah, Gunter, Emma, Williams, Earl, Fouracres, Anna, Farrington, Liz, Graves, Lyn, Hussaini, Hyder, Stableforth, Bill, Marriott, Suzie, Ayres, Reuben, Leoni, Marina, Burroughs, Andrew, Marshall, Eileen, Tyrer, David, Martin, Kate, Lombard, Martin, Patanwala, Imran, Dali-Kemmery, Lola, Lambourne, Victoria, Maltby, Julia, Vyas, Samir, Colley, Julie, Shinder, Bal, Singhal, Saket, Jones, Jayne, Mills, Marisa, Gleeson, Dermot, Carnahan, Mandy, Butterworth, Jeff, Boulton, Kerenza, Taylor, Natalie, George, Keith, Harding, Tim, Tregonning, Julie, Douglass, Andrew, Brown, Carly, Clifford, Gayle, Panter, Simon, Gocher, Denise, Shearman, Jeremy, Bray, Gary, Hamilton, Maria, Butcher, Graham, Forton, Daniel, Mclindon, John, Curtis, Janette, Das, Debashi, Shewan, Tracey, Cowan, Matthew, Whatley, Gregory, Nasseri, Mariam, Grover, Bob, Sivaramakrishnan, Nurani, Ducker, Samantha, Houghton, Kathryn, Jones, David, Griffiths, Laura, Tripoli, Sherill, Pitcher, Maxton, Shpuza, Ervin, White, Nikki, Ghosh, Deb, Douds, Andrew, Green, Marie, Brookes, Matthew, Cumlat, Lourde, Wong, Voi Shim, Warner, Karen, Netherton, Kimberley, Mandal, Adtya, Jain, Snjiv, Gupta, Hemant, Sanghi, Pradeep, Pereira, Steve, Neuberger, Jame, Gunson, Bridget, Hirschfield, Gideon, Lim, Reina Teegan, Gallagher, Susan, Clement, Darren, Brind, Alison, Watts, Gill, Mupudzi, Mcdonald, Wright, Mark, Gitahi, Jane, Gordon, Fiona, Gocher, Deni, Unitt, Esther, Pateman, Hilary, Batham, Sally, Delahooke, Toby, Grant, Allister, Conder, Jill, Higham, Andrew, Cox, Mark, O'Donohoe, Lynn, Currie, Lynn, King, Alistair, Oblak, Metod, Collins, Carole, Whalley, Simon, Quinn, Marie, Baird, Yolanda, Amey, Isobel, Fraser, Jocelyn, Li, Andy, Cotterill, Donna, Bell, Andrew, Singhal, Amit, Gee, Ian, Greer, Sandra, Ang, Yeng, Ransford, Rupert, Allison, Joanna, Gotto, Jame, Dyer, Simon, Sweeting, Helen, Millson, Charle, Labbadia, Giancarlo, Bragazzi, Maria Consiglia, Andreone, Pietro, Azzaroli, Francesco, Galli, Andrea, Tarocchi, Mirko, Gasbarrini, Antonio, Grieco, Antonio, Marrone, Giuseppe, Donato, Maria Francesca, Valenti, Luca, Maroni, Luca, Rigamonti, Cristina, Picciotto, Antonino, Miele, Luca (ORCID:0000-0003-3464-0068), Gasbarrini, Antonio (ORCID:0000-0002-7278-4823), Grieco, Antonio (ORCID:0000-0002-0544-8993), Carbone, Marco, Nardi, Alessandra, Flack, Steve, Carpino, Guido, Varvaropoulou, Nikoletta, Gavrila, Caiu, Spicer, Ann, Badrock, Jonathan, Bernuzzi, Francesca, Cardinale, Vincenzo, Ainsworth, Holly F, Heneghan, Michael A, Thorburn, Dougla, Bathgate, Andrew, Jones, Rebecca, Neuberger, James M, Battezzati, Pier Maria, Zuin, Massimo, Taylor-Robinson, Simon, Donato, Maria F, Kirby, John, Mitchell-Thain, Robert, Floreani, Annarosa, Sampaziotis, Fotio, Muratori, Luigi, Alvaro, Domenico, Marzioni, Marco, Miele, Luca, Marra, Fabio, Giannini, Edoardo, Gaudio, Eugenio, Ronca, Vincenzo, Bonato, Giulia, Cristoferi, Laura, Malinverno, Federica, Gerussi, Alessio, Stocken, Deborah D, Cordell, Heather J, Hirschfield, Gideon M, Alexander, Graeme J, Sandford, Richard N, Jones, David E, Invernizzi, Pietro, Mells, George F, Thomas, Caradog, Rahman, Meshbah, Yapp, Tom, Lye Ch'ng, Chin, Harrison, Melanie, Sturgess, Richard, Galaska, Roman, Healey, Chri, Whiteman, Jessica, Czaijkowski, Marek, Gray, Catherine, Gunasekera, Anton, Gyawli, Pranab, Premchand, Purushothaman, Mann, Steven, Elliott, Keith, Kapur, Kapil, Watson, Alan, Foster, Graham, Trembling, Paul, Subhani, Javaid, Harvey, Rory, Mccorry, Roger, Adgey, Carolyn, Hobson, Lucie, Mulvaney-Jones, Caroline, Evans, Richard, Mathialahan, Thiriloganathan, Ramanaden, David, Gasem, Jaber, Van Duyvenvoorde, Greta, Shorrock, Christopher, Seward, Katie, Southern, Paul, Tibble, Jeremy, Penn, Ruth, Gorard, David, Maiden, Jane, Damant, Rose, Palegwala, Altaf, Jones, Susan, Alexander, Graeme, Mells, George, Sandford, Richard, Dolwani, Sunil, Prince, Martin, Silvestre, Valeria, Foxton, Matthew, Dungca, Eleanor, Mitchison, Harriet, Wheatley, Natalie, Gooding, Ian, Doyle, Helen, Karmo, Mazn, Kent, Melanie, Saksena, Sushma, Braim, Delyth, Patel, Minesh, Lord, Susan, Ede, Roland, Paton, Alison, Austin, Andrew, Lancaster, Nicola, Sayer, Joanna, Gibbins, Andrew, Hogben, Karen, Hovell, Chri, Fisher, Neil, Carter, Martyn, Koss, Konrad, Musselwhite, Janine, Muscariu, Florin, Piotreowicz, Andrzej, Mckay, Alexandra, Grimley, Charle, Neal, David, Ting Tan, Lai, Lim, Guan, Brighton, Jacqueline, Foale, Carole, Ala, Aftab, Saeed, Athar, Flahive, Kerry, Wood, Gordon, Townshend, Paula, Ford, Chri, Brown, Jonathan, Kordula, Jean, Bowles, Jane, Wilkinson, Mark, Palmer, Caroline, Ramage, John, Gordon, Harriet, Featherstone, Jame, Ridpath, Jo, Ngatchu, Theodore, Levi, Sa, Shaukat, Syed, Sadeghian, Joy, Shidrawi, Ray, Williams, Bronwen, Abouda, George, Jones, Sarah, Duggan, Claire, Hynes, Abigail, Narain, Mark, Rees, Ian, Salam, Imroz, Crossey, Mary, Brown, Ashley, Macnicol, Carolyn, Williams, Simon, Wilhelmsen, Elva, Banim, Paul, Raymode, Parizade, Chilton, Andrew, Das, Debasish, Lee, Hye-Jeong, Curtis, Howard, Heneghan, Michael, Gess, Marku, Durant, Emma, Drake, I. M., Bishop, Rebecca, Davies, Mervyn, Aldersley, Mark, Ncube, Noma, Mcnair, Alistair, Srirajaskanthan, Raj, Sen, Sambit, Casey, Rebecca, Bird, George, Mendall, Mike, Cowley, Caroline, Barnardo, Adrian, Kitchen, Paul, Yoong, Kevin, Amore, Kelly, Sirdefield, Dawn, Orpe, Jacky, Mathew, Ray, Macfaul, George, Wrigth, Aruna, Shah, Amir, Evans, Chri, Keggans, Janie, Bird, Bridget, Baxter, Gwen, Saha, Subrata, Pollock, Katharine, Hughes, Maggie, Bramley, Peter, Grieve, Emma, Young, Karin, Fraser, Andrew, Mukhopadhya, Ashi, Ocker, Kate, Mills, Peter, Hines, Franci, Shallcross, Chri, Wilkins, Joy, Grellier, Leonie, Campbell, Stewart, Martin, Kirsty, Innes, Caron, Shepherd, Alan, Rushbrook, Simon, Valliani, Talal, Przemioslo, Robert, Fairlamb, Helen, Macdonald, Chri, Eastick, Anne, Metcalf, Jane, Tanqueray, Elizabeth, Shmueli, Udi, Holbrook, Becky, Davis, Andrew, Browning, Julie, Naqvi, Asifabba, Walker, Kirsten, Lee, Tom, Verheyden, Juliette, Slininger, Susan, Ryder, Stephen D, Chapman, Roger, Collier, Jane, O'Donnell, Denise, Stafford, Lizzie, Williamson, Kate, Kent, Linda, Klass, Howard, Ninkovic, Mary, March, Linda, Cramp, Matthew, Simpson, Diane, Dickson, Christine, Sharer, Nichola, Hayes, Maria, Goggin, Patrick, Quinne, Mary, Pearson, Sallyanne, Hoeroldt, Barbara, Jones, Linda, Wright, Alice, Booth, Jonathan, Loftus, Alison, Lipscomb, George, Dewhurst, Hannah, Gunter, Emma, Williams, Earl, Fouracres, Anna, Farrington, Liz, Graves, Lyn, Hussaini, Hyder, Stableforth, Bill, Marriott, Suzie, Ayres, Reuben, Leoni, Marina, Burroughs, Andrew, Marshall, Eileen, Tyrer, David, Martin, Kate, Lombard, Martin, Patanwala, Imran, Dali-Kemmery, Lola, Lambourne, Victoria, Maltby, Julia, Vyas, Samir, Colley, Julie, Shinder, Bal, Singhal, Saket, Jones, Jayne, Mills, Marisa, Gleeson, Dermot, Carnahan, Mandy, Butterworth, Jeff, Boulton, Kerenza, Taylor, Natalie, George, Keith, Harding, Tim, Tregonning, Julie, Douglass, Andrew, Brown, Carly, Clifford, Gayle, Panter, Simon, Gocher, Denise, Shearman, Jeremy, Bray, Gary, Hamilton, Maria, Butcher, Graham, Forton, Daniel, Mclindon, John, Curtis, Janette, Das, Debashi, Shewan, Tracey, Cowan, Matthew, Whatley, Gregory, Nasseri, Mariam, Grover, Bob, Sivaramakrishnan, Nurani, Ducker, Samantha, Houghton, Kathryn, Jones, David, Griffiths, Laura, Tripoli, Sherill, Pitcher, Maxton, Shpuza, Ervin, White, Nikki, Ghosh, Deb, Douds, Andrew, Green, Marie, Brookes, Matthew, Cumlat, Lourde, Wong, Voi Shim, Warner, Karen, Netherton, Kimberley, Mandal, Adtya, Jain, Snjiv, Gupta, Hemant, Sanghi, Pradeep, Pereira, Steve, Neuberger, Jame, Gunson, Bridget, Hirschfield, Gideon, Lim, Reina Teegan, Gallagher, Susan, Clement, Darren, Brind, Alison, Watts, Gill, Mupudzi, Mcdonald, Wright, Mark, Gitahi, Jane, Gordon, Fiona, Gocher, Deni, Unitt, Esther, Pateman, Hilary, Batham, Sally, Delahooke, Toby, Grant, Allister, Conder, Jill, Higham, Andrew, Cox, Mark, O'Donohoe, Lynn, Currie, Lynn, King, Alistair, Oblak, Metod, Collins, Carole, Whalley, Simon, Quinn, Marie, Baird, Yolanda, Amey, Isobel, Fraser, Jocelyn, Li, Andy, Cotterill, Donna, Bell, Andrew, Singhal, Amit, Gee, Ian, Greer, Sandra, Ang, Yeng, Ransford, Rupert, Allison, Joanna, Gotto, Jame, Dyer, Simon, Sweeting, Helen, Millson, Charle, Labbadia, Giancarlo, Bragazzi, Maria Consiglia, Andreone, Pietro, Azzaroli, Francesco, Galli, Andrea, Tarocchi, Mirko, Gasbarrini, Antonio, Grieco, Antonio, Marrone, Giuseppe, Donato, Maria Francesca, Valenti, Luca, Maroni, Luca, Rigamonti, Cristina, Picciotto, Antonino, Miele, Luca (ORCID:0000-0003-3464-0068), Gasbarrini, Antonio (ORCID:0000-0002-7278-4823), and Grieco, Antonio (ORCID:0000-0002-0544-8993)

Abstract

Background: Treatment guidelines recommend a stepwise approach to primary biliary cholangitis: all patients begin treatment with ursodeoxycholic acid (UDCA) monotherapy and those with an inadequate biochemical response after 12 months are subsequently considered for second-line therapies. However, as a result, patients at the highest risk can wait the longest for effective treatment. We determined whether UDCA response can be accurately predicted using pretreatment clinical parameters. Methods: We did logistic regression analysis of pretreatment variables in a discovery cohort of patients in the UK with primary biliary cholangitis to derive the best-fitting model of UDCA response, defined as alkaline phosphatase less than 1·67 times the upper limit of normal (ULN), measured after 12 months of treatment with UDCA. We validated the model in an external cohort of patients with primary biliary cholangitis and treated with UDCA in Italy. Additionally, we assessed correlations between model predictions and key histological features, such as biliary injury and fibrosis, on liver biopsy samples. Findings: 2703 participants diagnosed with primary biliary cholangitis between Jan 1, 1998, and May 31, 2015, were included in the UK-PBC cohort for derivation of the model. The following pretreatment parameters were associated with lower probability of UDCA response: higher alkaline phosphatase concentration (p<0·0001), higher total bilirubin concentration (p=0·0003), lower aminotransferase concentration (p=0·0012), younger age (p<0·0001), longer interval from diagnosis to the start of UDCA treatment (treatment time lag, p<0·0001), and worsening of alkaline phosphatase concentration from diagnosis (p<0·0001). Based on these variables, we derived a predictive score of UDCA response. In the external validation cohort, 460 patients diagnosed with primary biliary cholangitis were treated with UDCA, with follow-up data until May 31, 2016. In this validation cohort, the area under the re

Published
2018

40. Safety and efficacy of ombitasvir/paritaprevir/ritonavir/dasabuvir plus ribavirin in patients over 65 years with HCV genotype 1 cirrhosis

Author

Ascione, Antonio, De Luca, Massimo, Melazzini, Mario, Montilla, Simona, Trotta, Maria Paola, Petta, Salvatore, Puoti, Massimo, Sangiovanni, Vincenzo, Messina, Vincenzo, Bruno, Savino, Izzi, Antonio, Villa, Erica, Aghemo, Alessio, Zignego, Anna Linda, Orlandini, Alessandra, Fontanella, Luca, Gasbarrini, Antonio, Marzioni, Marco, Giannini, Edoardo G., Craxì, Antonio, Abbati, Giuseppe, Alberti, Alfredo, Andreone, Pietro, Andreoni, Massimo, Angeli, Paolo, Angelico, Mario, Angarano, Gioacchino, Angrisani, Debora, Antinori, Andrea, Antonini, Cinzia, Avancini, Ivo, Barone, Michele, Bruno, Raffaele, Benedetti, Antonio, Bernabucci, Veronica, Blanc, Pier, Boarini, Chiara, Boffa, Nicola, Boglione, Lucio, Borghi, Vanni, Borgia, Guglielmo, Brancaccio, Giuseppina, Brunetto, Maurizia, Cacciola, Irene, Calabrese, Paolo, Calvaruso, Vincenza, Campagnolo, Davide, Canovari, Benedetta, Caporaso, Nicola, Capra, Franco, Carolo, Giada, Cassola, Giovanni, Castelli, Francesco, Cauda, Roberto, Silberstein, Francesca Ceccherini, Cecere, Roberto, Chessa, Luchino, Chiodera, Alessandro, Chirianni, Antonio, Ciancio, Alessia, Cima, Serena, Coco, Barbara, Colombo, Massimo, Coppola, Nicola, Corti, Giampaolo, Cosco, Lucio, Corradori, Silvia, Cozzolongo, Raffaele, Cristaudo, Antonio, Danieli, Elena, Monforte, Antonella D’Arminio, Monache, Marco delle, Del Poggio, Paolo, de Luca, Andrea, Dentone, Chiara, Di Biagio, Antonio, Di Leo, Alfredo, Di Perri, Giovanni, Di Stefano, Marco, D’Offizi, Giampiero, Donato, Francesca, Durante, Emanuele, Erne, Elke, Fagiuoli, Stefano, Falasca, Katia, Federico, Alessandro, Felder, Martina, Ferrari, Carlo, Gaeta, Giovanni Battista, Ganga, Roberto, Gatti, Pietro, Giacomet, Vania, Giacometti, Andrea, Gianstefani, Alice, Giordani, Maria, Giorgini, Alessia, Grieco, Antonio, Guerra, Michele, Gulminetti, Roberto, Ieluzzi, Donatella, Imparato, Michele, Iodice, Valentina, La Monica, Silvia, Lazzarin, Adriano, Lenzi, Marco, Levrero, Massimo, Lichtner, Myriam, Lionetti, Raffaella, Guercio, Carmela Lo, Madonna, Salvatore, Magnani, Silvia, Maida, Ivana, Marignani, Massimo, Marrone, Aldo, Marsetti, Fabio, Martini, Silvia, Masarone, Mario, Maserati, Renato, Mastroianni, Claudio Maria, Memoli, Massimo, Menzaghi, Barbara, Merli, Manuela, Miele, Luca, Milella, Michele, Mondelli, Mario, Montalbano, Marzia, Monti, Monica, Morelli, Olivia, Morisco, Filomena, Nardone, Gaetano, Novara, Sergio, Onnelli, Giovanna, Onofrio, Mirella, Paganin, Simona, Pani, Luca, Parisi, Maria Rita, Parruti, Giustino, Pasquazzi, Caterina, Pasulo, Luisa, Perno, Carlo Federico, Persico, Marcello, Piai, Guido, Picciotto, Antonino, Pigozzi, Grazielle Marie, Piovesan, Sara, Piras, Maria Chiara, Pirisi, Massimo, Piscaglia, Anna Maria, Ponti, Laura, Potenza, Domenico, Pravadelli, Cecilia, Quartini, Mariano, Quirino, Tiziana, Raimondo, Giovanni, Rapaccini, Gian Ludovico, Rendina, Maria, Rizzardini, Giuliano, Rizzetto, Mario, Rizzo, Salvatore, Romagnoli, Dante, Romano, Antonietta, Rossi, Cristina, Rumi, Maria Grazia, Russello, Maurizio, Russo, Francesca Paolo, Russo, Maria Luisa, Sansonno, Domenico Ettore, Santantonio, Teresa Antonia, Saracco, Giorgio, Schimizzi, Anna Maria, Serviddio, Gaetano, Simeone, Filomena, Solinas, Attilio, Soria, Alessandro, Tabone, Marco, Taliani, Gloria, Tarantino, Giuseppe, Tarquini, Pierluigi, Tavio, Marcello, Termite, Antonio, Teti, Elisabetta, Toniutto, Pierluigi, Torti, Carlo, Tundi, Paolo, Vecchiet, Giacomo, Verucchi, Gabriella, Gentilucci, Umberto Vespasiani, Vinci, Maria, Vullo, Vincenzo, Zolfino, Teresa, Zuin, Massimo, Gasbarrini, Antonio (ORCID:0000-0002-7278-4823), Cauda, Roberto (ORCID:0000-0002-1498-4229), de Luca, Andrea (ORCID:0000-0002-8311-6935), Grieco, Antonio (ORCID:0000-0002-0544-8993), Miele, Luca (ORCID:0000-0003-3464-0068), Rapaccini, Gian Ludovico (ORCID:0000-0002-6467-857X), Ascione, Antonio, De Luca, Massimo, Melazzini, Mario, Montilla, Simona, Trotta, Maria Paola, Petta, Salvatore, Puoti, Massimo, Sangiovanni, Vincenzo, Messina, Vincenzo, Bruno, Savino, Izzi, Antonio, Villa, Erica, Aghemo, Alessio, Zignego, Anna Linda, Orlandini, Alessandra, Fontanella, Luca, Gasbarrini, Antonio, Marzioni, Marco, Giannini, Edoardo G., Craxì, Antonio, Abbati, Giuseppe, Alberti, Alfredo, Andreone, Pietro, Andreoni, Massimo, Angeli, Paolo, Angelico, Mario, Angarano, Gioacchino, Angrisani, Debora, Antinori, Andrea, Antonini, Cinzia, Avancini, Ivo, Barone, Michele, Bruno, Raffaele, Benedetti, Antonio, Bernabucci, Veronica, Blanc, Pier, Boarini, Chiara, Boffa, Nicola, Boglione, Lucio, Borghi, Vanni, Borgia, Guglielmo, Brancaccio, Giuseppina, Brunetto, Maurizia, Cacciola, Irene, Calabrese, Paolo, Calvaruso, Vincenza, Campagnolo, Davide, Canovari, Benedetta, Caporaso, Nicola, Capra, Franco, Carolo, Giada, Cassola, Giovanni, Castelli, Francesco, Cauda, Roberto, Silberstein, Francesca Ceccherini, Cecere, Roberto, Chessa, Luchino, Chiodera, Alessandro, Chirianni, Antonio, Ciancio, Alessia, Cima, Serena, Coco, Barbara, Colombo, Massimo, Coppola, Nicola, Corti, Giampaolo, Cosco, Lucio, Corradori, Silvia, Cozzolongo, Raffaele, Cristaudo, Antonio, Danieli, Elena, Monforte, Antonella D’Arminio, Monache, Marco delle, Del Poggio, Paolo, de Luca, Andrea, Dentone, Chiara, Di Biagio, Antonio, Di Leo, Alfredo, Di Perri, Giovanni, Di Stefano, Marco, D’Offizi, Giampiero, Donato, Francesca, Durante, Emanuele, Erne, Elke, Fagiuoli, Stefano, Falasca, Katia, Federico, Alessandro, Felder, Martina, Ferrari, Carlo, Gaeta, Giovanni Battista, Ganga, Roberto, Gatti, Pietro, Giacomet, Vania, Giacometti, Andrea, Gianstefani, Alice, Giordani, Maria, Giorgini, Alessia, Grieco, Antonio, Guerra, Michele, Gulminetti, Roberto, Ieluzzi, Donatella, Imparato, Michele, Iodice, Valentina, La Monica, Silvia, Lazzarin, Adriano, Lenzi, Marco, Levrero, Massimo, Lichtner, Myriam, Lionetti, Raffaella, Guercio, Carmela Lo, Madonna, Salvatore, Magnani, Silvia, Maida, Ivana, Marignani, Massimo, Marrone, Aldo, Marsetti, Fabio, Martini, Silvia, Masarone, Mario, Maserati, Renato, Mastroianni, Claudio Maria, Memoli, Massimo, Menzaghi, Barbara, Merli, Manuela, Miele, Luca, Milella, Michele, Mondelli, Mario, Montalbano, Marzia, Monti, Monica, Morelli, Olivia, Morisco, Filomena, Nardone, Gaetano, Novara, Sergio, Onnelli, Giovanna, Onofrio, Mirella, Paganin, Simona, Pani, Luca, Parisi, Maria Rita, Parruti, Giustino, Pasquazzi, Caterina, Pasulo, Luisa, Perno, Carlo Federico, Persico, Marcello, Piai, Guido, Picciotto, Antonino, Pigozzi, Grazielle Marie, Piovesan, Sara, Piras, Maria Chiara, Pirisi, Massimo, Piscaglia, Anna Maria, Ponti, Laura, Potenza, Domenico, Pravadelli, Cecilia, Quartini, Mariano, Quirino, Tiziana, Raimondo, Giovanni, Rapaccini, Gian Ludovico, Rendina, Maria, Rizzardini, Giuliano, Rizzetto, Mario, Rizzo, Salvatore, Romagnoli, Dante, Romano, Antonietta, Rossi, Cristina, Rumi, Maria Grazia, Russello, Maurizio, Russo, Francesca Paolo, Russo, Maria Luisa, Sansonno, Domenico Ettore, Santantonio, Teresa Antonia, Saracco, Giorgio, Schimizzi, Anna Maria, Serviddio, Gaetano, Simeone, Filomena, Solinas, Attilio, Soria, Alessandro, Tabone, Marco, Taliani, Gloria, Tarantino, Giuseppe, Tarquini, Pierluigi, Tavio, Marcello, Termite, Antonio, Teti, Elisabetta, Toniutto, Pierluigi, Torti, Carlo, Tundi, Paolo, Vecchiet, Giacomo, Verucchi, Gabriella, Gentilucci, Umberto Vespasiani, Vinci, Maria, Vullo, Vincenzo, Zolfino, Teresa, Zuin, Massimo, Gasbarrini, Antonio (ORCID:0000-0002-7278-4823), Cauda, Roberto (ORCID:0000-0002-1498-4229), de Luca, Andrea (ORCID:0000-0002-8311-6935), Grieco, Antonio (ORCID:0000-0002-0544-8993), Miele, Luca (ORCID:0000-0003-3464-0068), and Rapaccini, Gian Ludovico (ORCID:0000-0002-6467-857X)

Abstract

Purpose: To analyse safety and efficacy of treatment based on ombitasvir/paritaprevir/ritonavir/dasabuvir plus ribavirin in the sub-group of GT1 patients older than 65 years. Methods: We collected data extracted from the ABACUS compassionate-use nationwide Italian programme, in patients with cirrhosis due to hepatitis C virus (HCV) Genotype-1 (GT1) or 4 and at high risk of decompensation. GT1-HCV-infected patients received once-daily ombitasvir/paritaprevir, with the pharmacokinetic enhancer ritonavir (25/150/100 mg) and twice-daily dasabuvir (250 mg) plus Ribavirin (RBV) (OBV/PTV/r + DSV + RBV) for 12 (GT1b) or 24 (GT1a) weeks. Endpoints were to evaluate safety and efficacy, the latter defined as HCV RNA negative 12 weeks after the end of treatment (SVR12). Results: Patients who suffered any adverse event (AE) were 74/240 (30.8%); 13/240 (5.4%) discontinued the treatment. A multivariate analysis found albumin < 3.5 g/dL (OR 2.04: 95% CI 1.0–4.2, p < 0.05) and hypertension (OR 4.6: 95% CI 2.3–9.2, p < 0.001) as variables independently associated with AE occurrence. The SVR12 was 95% (228/240). Multivariate analysis identified baseline bilirubin < 2 mg/dL (OR 4.9: 95% CI 1.17–20.71, p = 0.029) as the only variable independently associated with SVR12. Conclusion: Our findings suggest that OBV/PTV/r + DSV + RBV is safe and effective in real-life use in patients with compensated cirrhosis, HCV-GT1 infection, and age over 65.

Published
2018

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

Author

Porcu, Cristiana, Antonucci, Laura, Barbaro, Barbara, Illi, Barbara, Nasi, Sergio, Martini, Maurizio, Licata, Anna, Miele, Luca, Grieco, Antonio, Balsano, Clara, Martini, Maurizio (ORCID:0000-0002-6260-6310), Miele, Luca (ORCID:0000-0003-3464-0068), Grieco, Antonio (ORCID:0000-0002-0544-8993), Porcu, Cristiana, Antonucci, Laura, Barbaro, Barbara, Illi, Barbara, Nasi, Sergio, Martini, Maurizio, Licata, Anna, Miele, Luca, Grieco, Antonio, Balsano, Clara, Martini, Maurizio (ORCID:0000-0002-6260-6310), Miele, Luca (ORCID:0000-0003-3464-0068), and Grieco, Antonio (ORCID:0000-0002-0544-8993)

Abstract

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 overexpressed 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.

Published
2018

42. Liver transplantation in patients with alcoholic liver disease: A retrospective study

Author

Vassallo, Gabriele A., Tarli, Claudia, Rando, Maria M., Mosoni, Carolina, Mirijello, Antonio, Agyei-Nkansah, Adwoa, Antonelli, Mariangela, Sestito, Luisa, Perotti, Germano, Di Giuda, Daniela, Agnes, Salvatore, Grieco, Antonio, Gasbarrini, Antonio, Addolorato, Giovanni, Abbate, Valeria, Ainora, Maria Elena, Annicchiarico, Eleonora, Avolio, Alfonso Wolfango, Biolato, Marco, Calia, Rosaria, de Matthaeis, Nicoletta, Cristina d'Angelo, Null, Ferrarese, Daniele, Ferrulli, Anna, Garcovich, Matteo, Frongillo, Francesco, Marrone, Giuseppe, Miele, Luca, Nure, Eda, Pietrogiacomi, Paola, Pizzolante, Fabrizio, Pompili, Maurizio, Ponziani, Francesca Romana, Rapaccini, Gian Ludovico, Riccardi, Laura, Rinninella, Emanuele, Sganga, Gabriele, Siciliano, Massimo, Zocco, Maria Assunta, Di Giuda, Daniela (ORCID:0000-0002-5758-3986), Agnes, Salvatore (ORCID:0000-0002-3341-4221), Grieco, Antonio (ORCID:0000-0002-0544-8993), Gasbarrini, Antonio (ORCID:0000-0002-7278-4823), Addolorato, Giovanni (ORCID:0000-0002-1522-9946), Avolio, Alfonso Wolfango (ORCID:0000-0003-2491-7625), Calia, Rosaria (ORCID:0000-0003-1060-7554), Miele, Luca (ORCID:0000-0003-3464-0068), Pompili, Maurizio (ORCID:0000-0001-6699-7980), Ponziani, Francesca Romana (ORCID:0000-0002-5924-6238), Rapaccini, Gian Ludovico (ORCID:0000-0002-6467-857X), Rinninella, Emanuele (ORCID:0000-0002-9165-2367), Sganga, Gabriele (ORCID:0000-0001-5079-0395), Zocco, Maria Assunta (ORCID:0000-0002-0814-9542), Vassallo, Gabriele A., Tarli, Claudia, Rando, Maria M., Mosoni, Carolina, Mirijello, Antonio, Agyei-Nkansah, Adwoa, Antonelli, Mariangela, Sestito, Luisa, Perotti, Germano, Di Giuda, Daniela, Agnes, Salvatore, Grieco, Antonio, Gasbarrini, Antonio, Addolorato, Giovanni, Abbate, Valeria, Ainora, Maria Elena, Annicchiarico, Eleonora, Avolio, Alfonso Wolfango, Biolato, Marco, Calia, Rosaria, de Matthaeis, Nicoletta, Cristina d'Angelo, Null, Ferrarese, Daniele, Ferrulli, Anna, Garcovich, Matteo, Frongillo, Francesco, Marrone, Giuseppe, Miele, Luca, Nure, Eda, Pietrogiacomi, Paola, Pizzolante, Fabrizio, Pompili, Maurizio, Ponziani, Francesca Romana, Rapaccini, Gian Ludovico, Riccardi, Laura, Rinninella, Emanuele, Sganga, Gabriele, Siciliano, Massimo, Zocco, Maria Assunta, Di Giuda, Daniela (ORCID:0000-0002-5758-3986), Agnes, Salvatore (ORCID:0000-0002-3341-4221), Grieco, Antonio (ORCID:0000-0002-0544-8993), Gasbarrini, Antonio (ORCID:0000-0002-7278-4823), Addolorato, Giovanni (ORCID:0000-0002-1522-9946), Avolio, Alfonso Wolfango (ORCID:0000-0003-2491-7625), Calia, Rosaria (ORCID:0000-0003-1060-7554), Miele, Luca (ORCID:0000-0003-3464-0068), Pompili, Maurizio (ORCID:0000-0001-6699-7980), Ponziani, Francesca Romana (ORCID:0000-0002-5924-6238), Rapaccini, Gian Ludovico (ORCID:0000-0002-6467-857X), Rinninella, Emanuele (ORCID:0000-0002-9165-2367), Sganga, Gabriele (ORCID:0000-0001-5079-0395), and Zocco, Maria Assunta (ORCID:0000-0002-0814-9542)

Abstract

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 complic

Published
2018

43. Liver injury after pulsed methylprednisolone therapy in multiple sclerosis patients

Author

Nociti, Viviana, Biolato, Marco, De Fino, Chiara, Bianco, Assunta, Losavio, Francesco Antonio, Lucchini, Matteo, Marrone, Giuseppe, Grieco, Antonio, Mirabella, Massimiliano, Nociti, Viviana (ORCID:0000-0002-4607-3948), Lucchini, Matteo (ORCID:0000-0002-0447-2297), Grieco, Antonio (ORCID:0000-0002-0544-8993), Mirabella, Massimiliano (ORCID:0000-0002-7783-114X), Nociti, Viviana, Biolato, Marco, De Fino, Chiara, Bianco, Assunta, Losavio, Francesco Antonio, Lucchini, Matteo, Marrone, Giuseppe, Grieco, Antonio, Mirabella, Massimiliano, Nociti, Viviana (ORCID:0000-0002-4607-3948), Lucchini, Matteo (ORCID:0000-0002-0447-2297), Grieco, Antonio (ORCID:0000-0002-0544-8993), and Mirabella, Massimiliano (ORCID:0000-0002-7783-114X)

Abstract

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.

Published
2018

44. Prognostic ability of BCLC-B subclassification in patients with hepatocellular carcinoma undergoing transarterial chemoembolization

Author

Biolato, Marco, Gallusi, Giulia, Iavarone, Massimo, Cabibbo, Giuseppe, Racco, Simona, De Santis, Adriano, Corte, Cristina Della, Maida, Marcello, Attili, Adolfo Francesco, Sangiovanni, Angelo, Cammà, Calogero, La Torre, Giuseppe, Gasbarrini, Antonio, Grieco, Antonio, Gasbarrini, Antonio (ORCID:0000-0002-7278-4823), Grieco Antonio (ORCID:0000-0002-0544-8993), Gasbarrini Antonio (ORCID:0000-0002-7278-4823), Biolato, Marco, Gallusi, Giulia, Iavarone, Massimo, Cabibbo, Giuseppe, Racco, Simona, De Santis, Adriano, Corte, Cristina Della, Maida, Marcello, Attili, Adolfo Francesco, Sangiovanni, Angelo, Cammà, Calogero, La Torre, Giuseppe, Gasbarrini, Antonio, Grieco, Antonio, Gasbarrini, Antonio (ORCID:0000-0002-7278-4823), Grieco Antonio (ORCID:0000-0002-0544-8993), and Gasbarrini Antonio (ORCID:0000-0002-7278-4823)

Abstract

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.

Published
2018

45. Liver transplantation for drug-induced acute liver failure

Author

Biolato, Marco, Araneo, C, Marrone, Giuseppe, Liguori, A, Miele, Luca, Ponziani, F. R, Gasbarrini, Antonio, Grieco, Antonio, Miele, Luca (ORCID:0000-0003-3464-0068), Gasbarrini, Antonio (ORCID:0000-0002-7278-4823), Grieco, Antonio (ORCID:0000-0002-0544-8993), Biolato, Marco, Araneo, C, Marrone, Giuseppe, Liguori, A, Miele, Luca, Ponziani, F. R, Gasbarrini, Antonio, Grieco, Antonio, Miele, Luca (ORCID:0000-0003-3464-0068), Gasbarrini, Antonio (ORCID:0000-0002-7278-4823), and Grieco, Antonio (ORCID:0000-0002-0544-8993)

Abstract

n/a

Published
2017

46. Liver Resection versus Radiofrequency Ablation plus Transcatheter Arterial Chemoembolization in Cirrhotic Patients with Solitary Large Hepatocellular Carcinoma

Author

Saviano, Angela, Iezzi, Roberto, Giuliante, Felice, Salvatore, L., Mele, C., Posa, Alessandro, Ardito, Francesco, De Gaetano, Anna Maria, Pompili, Maurizio, Rinninella, Emanuele, Zocco, Maria Assunta, Riccardi, Laura, Annicchiarico, Brigida Eleonora, Siciliano, M., De Matthaeis, Nicoletta, Grieco, Antonio, Rapaccini, Gian Ludovico, Gasbarrini, Antonio, Saviano A. (ORCID:0000-0002-2820-7180), Iezzi R. (ORCID:0000-0002-2791-481X), Giuliante F. (ORCID:0000-0001-9517-8220), Posa A., Ardito F. (ORCID:0000-0003-1596-2862), De Gaetano A. M. (ORCID:0000-0002-7493-9462), Pompili M. (ORCID:0000-0001-6699-7980), Rinninella E. (ORCID:0000-0002-9165-2367), Zocco M. A. (ORCID:0000-0002-0814-9542), Riccardi L., Annicchiarico B. E., De Matthaeis N., Grieco A. (ORCID:0000-0002-0544-8993), Rapaccini G. L. (ORCID:0000-0002-6467-857X), Gasbarrini A. (ORCID:0000-0002-7278-4823), Saviano, Angela, Iezzi, Roberto, Giuliante, Felice, Salvatore, L., Mele, C., Posa, Alessandro, Ardito, Francesco, De Gaetano, Anna Maria, Pompili, Maurizio, Rinninella, Emanuele, Zocco, Maria Assunta, Riccardi, Laura, Annicchiarico, Brigida Eleonora, Siciliano, M., De Matthaeis, Nicoletta, Grieco, Antonio, Rapaccini, Gian Ludovico, Gasbarrini, Antonio, Saviano A. (ORCID:0000-0002-2820-7180), Iezzi R. (ORCID:0000-0002-2791-481X), Giuliante F. (ORCID:0000-0001-9517-8220), Posa A., Ardito F. (ORCID:0000-0003-1596-2862), De Gaetano A. M. (ORCID:0000-0002-7493-9462), Pompili M. (ORCID:0000-0001-6699-7980), Rinninella E. (ORCID:0000-0002-9165-2367), Zocco M. A. (ORCID:0000-0002-0814-9542), Riccardi L., Annicchiarico B. E., De Matthaeis N., Grieco A. (ORCID:0000-0002-0544-8993), Rapaccini G. L. (ORCID:0000-0002-6467-857X), and Gasbarrini A. (ORCID:0000-0002-7278-4823)

Abstract

Purpose To compare liver resection (LR) with single-step, balloon-occluded radiofrequency (RF) ablation plus drug-eluting embolics transarterial chemoembolization in cirrhotic patients with single hepatocellular carcinoma (HCC) ≥ 3 cm. Materials and Methods From 2010 to 2014, 25 patients with compensated cirrhosis and single HCC ≥ 3 cm (median size 4.5 cm; range, 3.0–6.8 cm) not suitable for LR or liver transplantation were treated with RF ablation plus transarterial chemoembolization in a prospective observational single-center pilot study; all patients had complete tumor necrosis after treatment. A retrospective control group included 29 patients (median HCC size 4.0 cm; range, 3.0–7.4 cm) who underwent LR. RF ablation plus transarterial chemoembolization group included more patients with severe portal hypertension (65.5% vs 35.0%, P =.017). Primary endpoints were overall survival (OS) and tumor recurrence (TR) rates. Results One death and 1 major complication (4%) were observed in LR group. No major complications were reported in RF ablation plus transarterial chemoembolization group (P =.463). OS rates at 1 and 3 years were 91.8% and 79.3% in LR group and 89.4% and 48.2% in RF ablation plus transarterial chemoembolization group (P = 0.117). TR rates at 1 and 3 years were 29.5% and 45.0% in LR group and 42.4% and 76.0% in RF ablation plus transarterial chemoembolization group (P =.034). Local tumor progression (LTP) rates at 3 years were significantly lower in LR group (21.8% vs 58.1%, P =.005). Similar results were found in patients with HCC ≤ 5 cm (TR rates 35.4% vs 75.1%, P =.016; LTP 16.0% vs 55.7%, P =.013). Conclusions LR achieved lower TR and LTP rates than RF ablation plus transarterial chemoembolization, but 3-years OS rates were not statistically different between the 2 groups. RF ablation plus transarterial chemoembolization is an effective treatment option in patients with compensated cirrhosis and solitary HCC ≥ 3 cm unsuitable for LR.

Published
2017

47. Editorial - Drug-induced hepatotoxicity

Author

Busardo, F. P., Grieco, Antonio, Grieco A. (ORCID:0000-0002-0544-8993), Busardo, F. P., Grieco, Antonio, and Grieco A. (ORCID:0000-0002-0544-8993)

Abstract

NO ABSTRACT

Published
2017

48. Editorial - Drug-induced hepatotoxicity

Author

Busardò, F P, Grieco, Antonio, Grieco, A (ORCID:0000-0002-0544-8993), Busardò, F P, Grieco, Antonio, and Grieco, A (ORCID:0000-0002-0544-8993)

Abstract

No abstract

Published
2017

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

Author

Donati, Maria Benedetta, Pietrelli, Alessandro, Pingitore, Piero, Dongiovanni, Paola, Caddeo, Andrea, Walker, Lucy, Baselli, Guido, Pelusi, Serena, Rosso, Chiara, Vanni, Ester, Daly, Ann, Mancina, Rosellina Margherita, Grieco, Antonio, Miele, Luca, Grimaudo, Stefania, Craxi, Antonio, Petta, Salvatore, De Luca, Laura, Maier, Silvia, Soardo, Giorgio, Bugianesi, Elisabetta, Colli, Fabio, Romagnoli, Renato, Anstee, Quentin M., Reeves, Helen L., Fracanzani, Anna Ludovica, Fargion, Silvia, Romeo, Stefano, Valenti, Luca, Donati, Benedetta, Grieco, Antonio (ORCID:0000-0002-0544-8993), Miele, Luca (ORCID:0000-0003-3464-0068), Donati, Maria Benedetta, Pietrelli, Alessandro, Pingitore, Piero, Dongiovanni, Paola, Caddeo, Andrea, Walker, Lucy, Baselli, Guido, Pelusi, Serena, Rosso, Chiara, Vanni, Ester, Daly, Ann, Mancina, Rosellina Margherita, Grieco, Antonio, Miele, Luca, Grimaudo, Stefania, Craxi, Antonio, Petta, Salvatore, De Luca, Laura, Maier, Silvia, Soardo, Giorgio, Bugianesi, Elisabetta, Colli, Fabio, Romagnoli, Renato, Anstee, Quentin M., Reeves, Helen L., Fracanzani, Anna Ludovica, Fargion, Silvia, Romeo, Stefano, Valenti, Luca, Donati, Benedetta, Grieco, Antonio (ORCID:0000-0002-0544-8993), and Miele, Luca (ORCID:0000-0003-3464-0068)

Abstract

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.

Published
2017

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

Author

Donati, Maria Benedetta, Dongiovanni, Paola, Romeo, Stefano, Meroni, Marica, Mccain, Misti, Miele, Luca, Petta, Salvatore, Maier, Silvia, Rosso, Chiara, De Luca, Laura, Vanni, Ester, Grimaudo, Stefania, Romagnoli, Renato, Colli, Fabio, Ferri, Flaminia, Mancina, Rosellina Margherita, Iruzubieta, Paula, Craxi, Antonio, Fracanzani, Anna Ludovica, Grieco, Antonio, Corradini, Stefano Ginanni, Aghemo, Alessio, Colombo, Massimo, Soardo, Giorgio, Bugianesi, Elisabetta, Reeves, Helen, Anstee, Quentin M, Fargion, Silvia, Valenti, Luca, Donati, Benedetta, Miele, Luca (ORCID:0000-0003-3464-0068), Grieco, Antonio (ORCID:0000-0002-0544-8993), Donati, Maria Benedetta, Dongiovanni, Paola, Romeo, Stefano, Meroni, Marica, Mccain, Misti, Miele, Luca, Petta, Salvatore, Maier, Silvia, Rosso, Chiara, De Luca, Laura, Vanni, Ester, Grimaudo, Stefania, Romagnoli, Renato, Colli, Fabio, Ferri, Flaminia, Mancina, Rosellina Margherita, Iruzubieta, Paula, Craxi, Antonio, Fracanzani, Anna Ludovica, Grieco, Antonio, Corradini, Stefano Ginanni, Aghemo, Alessio, Colombo, Massimo, Soardo, Giorgio, Bugianesi, Elisabetta, Reeves, Helen, Anstee, Quentin M, Fargion, Silvia, Valenti, Luca, Donati, Benedetta, Miele, Luca (ORCID:0000-0003-3464-0068), and Grieco, Antonio (ORCID:0000-0002-0544-8993)

Abstract

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.

Published
2017

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