Publications by authors named "Giulia Tosetti"

26 Publications

  • Page 1 of 1

Decompensation in advanced non-alcoholic fatty liver disease may occur at lower hepatic venous pressure gradient levels that in patients with viral disease.

Clin Gastroenterol Hepatol 2021 Oct 21. Epub 2021 Oct 21.

Division of Gastroenterology, Azienda Ospedaliero-Universitaria di Modena and University of Modena and Reggio Emilia, Modena, Italy.

Background & Aims: Portal hypertension (PH) is the strongest predictor of hepatic decompensation and death in patients with cirrhosis. However, its discriminatory accuracy in patients with non-alcoholic fatty liver disease (NAFLD) has been challenged as hepatic vein catheterization may not reflect the real portal vein pressure as accurately as in patients with other etiologies. We aimed to evaluate the relationship between hepatic venous pressure gradient (HVPG) and presence of portal hypertension related decompensation in patients with advanced NAFLD (aNAFLD).

Methods: Multicenter cross-sectional study including 548 patients with aNAFLD and 444 with advanced RNA-positive hepatitis C (aHCV) who had detailed portal hypertension evaluation (HVPG measurement, gastroscopy, and abdominal imaging). We examined the relationship between etiology, HVPG, and decompensation by logistic regression models. We also compared the proportions of compensated/decompensated patients at different HVPG levels.

Results: Both cohorts, aNAFLD and aHVC, had similar baseline age, gender, Child-Pugh score, and MELD. Median HVPG was lower in the aNAFLD cohort (13 vs 15 mmHg) despite similar liver function and higher rates of decompensation in aNAFLD group (32% vs 25% p=0.019) than in the aHCV group. For any of the HVPG cutoff analyzed (<10, 10-12 or 12 mmHg) the prevalence of decompensation was higher in the aNAFLD than in the aHCV group.

Conclusion: Patients with aNAFLD have higher prevalence of portal hypertension related decompensation at any value of HVPG as compared to aHCV patients. Longitudinal studies aiming to identify HVPG thresholds able to predict decompensation and long-term outcomes in aNAFLD population are strongly needed.
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http://dx.doi.org/10.1016/j.cgh.2021.10.023DOI Listing
October 2021

Incidence of liver and non-liver-related outcomes in patients with HCV-cirrhosis after SVR.

J Hepatol 2021 Sep 27. Epub 2021 Sep 27.

Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, Milan, Italy; CRC "A. M. and A. Migliavacca" Center for Liver Disease, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.

Background And Aim: As the long-term benefits of a sustained virological response (SVR) in hepatitis C virus (HCV) cirrhosis following direct-acting antivirals (DAA) remain undefined, we assessed the incidence and predictors of liver-related events (LRE), non-liver related events (NLRE) and mortality in DAA-treated cirrhotics.

Methods: Consecutive SVR cirrhotics were enrolled in a longitudinal, single-center study, and divided into 3 cohorts: Cohort A (CPT-A without previous LRE), Cohort B (CPT-B or CPT-A with prior non-HCC LRE), Cohort C (previous HCC).

Results: 636 cirrhotics (65 years-old, 58% males, 89% CPT-A) were followed for 51 (8-68) months [Cohort A n=480, Cohort B n=89, Cohort C n=67]. The 5-year estimated cumulative incidences of LRE were 10.4% in Cohort A vs. 32.0% in Cohort B [HCC 7.7% vs. 19.7%; ascites 1.4% vs. 8.6%; variceal bleeding 1.3% vs. 7.8%; encephalopathy 0 vs. 2.5%] vs. 71% in Cohort C [HCC only] (p<0.0001). The corresponding figures for NLRE were 11.7% in Cohort A vs. 17.9% in Cohort B vs. 17.5% in Cohort C (p=0.32). The 5-year estimated probabilities of liver-related vs. non-liver related deaths were 0.5% vs. 4.5% in Cohort A, 16.2% vs. 8.8% in Cohort B and 12.1% vs. 7.7% in Cohort C. All-cause mortality rate in Cohort A was similar to the rate expected for the general population stratified by age, gender and calendar year according to the Human Mortality Database, while it was significantly higher in Cohort B.

Conclusions: Cirrhotic patients with an SVR to DAA face risks of liver-related and non-liver related events and mortality; however, their incidence is strongly influenced by pre-DAA patient history.

Lay Summary: • In this large single-center study enrolling HCV cirrhotic patients cured by direct-acting antivirals, pre-treatment liver disease history strongly influenced long-term outcomes. • In HCV cirrhotic patients, hepatocellular carcinoma accounted for the most frequent liver-related complication after viral cure. • Due to improved long-term outcomes, cirrhotic patients after HCV cure are exposed to a significant proportion of non-liver related events and mortality.
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http://dx.doi.org/10.1016/j.jhep.2021.09.013DOI Listing
September 2021

Performance of the model for end-stage liver disease score for mortality prediction and the potential role of etiology.

J Hepatol 2021 Jul 30. Epub 2021 Jul 30.

Gastroenterology Unit, ASL Latina, Department of Translational and Precision Medicine, "Sapienza" University of Rome, Italy.

Background & Aims: Although the discriminative ability of the model for end-stage liver disease (MELD) score is generally considered acceptable, its calibration is still unclear. In a validation study, we assessed the discriminative performance and calibration of 3 versions of the model: original MELD-TIPS, used to predict survival after transjugular intrahepatic portosystemic shunt (TIPS); classic MELD-Mayo; and MELD-UNOS, used by the United Network for Organ Sharing (UNOS). We also explored recalibrating and updating the model.

Methods: In total, 776 patients who underwent elective TIPS (TIPS cohort) and 445 unselected patients (non-TIPS cohort) were included. Three, 6 and 12-month mortality predictions were calculated by the 3 MELD versions: discrimination was assessed by c-statistics and calibration by comparing deciles of predicted and observed risks. Cox and Fine and Grey models were used for recalibration and prognostic analyses.

Results: In the TIPS/non-TIPS cohorts, the etiology of liver disease was viral in 402/188, alcoholic in 185/130, and non-alcoholic steatohepatitis in 65/33; mean follow-up±SD was 25±9/19±21 months; and the number of deaths at 3-6-12 months was 57-102-142/31-47-99, respectively. C-statistics ranged from 0.66 to 0.72 in TIPS and 0.66 to 0.76 in non-TIPS cohorts across prediction times and scores. A post hoc analysis revealed worse c-statistics in non-viral cirrhosis with more pronounced and significant worsening in the non-TIPS cohort. Calibration was acceptable with MELD-TIPS but largely unsatisfactory with MELD-Mayo and -UNOS whose performance improved much after recalibration. A prognostic analysis showed that age, albumin, and TIPS indication might be used to update the MELD.

Conclusions: In this validation study, the performance of the MELD score was largely unsatisfactory, particularly in non-viral cirrhosis. MELD recalibration and candidate variables for an update to the MELD score are proposed.

Lay Summary: While the discriminative performance of the model for end-stage liver disease (MELD) score is credited to be fair to good, its calibration, the correspondence of observed to predicted mortality, is still unsettled. We found that application of 3 different versions of the MELD in 2 independent cirrhosis cohorts yielded largely imprecise mortality predictions particularly in non-viral cirrhosis. Thus, we propose a recalibration and suggest candidate variables for an update to the model.
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http://dx.doi.org/10.1016/j.jhep.2021.07.018DOI Listing
July 2021

Combined approach for embolization of otherwise unmanageable gastric varices.

Ann Gastroenterol 2021 Jul-Aug;34(4):510-515. Epub 2021 Mar 23.

Radiology Department, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan (Anna Maria Ierardi, Gianpaolo Carrafiello).

Background: This study aimed to determine the feasibility, safety and effectiveness of combined percutaneous transhepatic obliteration (PTO) and balloon-occluded retrograde transvenous obliteration (BRTO) therapy for the treatment of patients with high-risk bleeding gastric varices.

Methods: Ten patients were retrospectively reviewed. All the patients presented gastric varices, according to the Sarin classification, at high risk of bleeding, and not otherwise manageable. Patients with portal vein thrombosis were excluded. All patients were treated with a combination of PTO and BRTO. In all cases the gastric varices were embolized with glue, combined with coils or not, with an occlusion balloon inflated into the shunt. In 7 cases, embolization was immediate; in the remaining 3 the balloon remained inflated for 4 h and in 2 of them embolization of the shunt was required. Technical success was defined as complete obliteration of the gastric varices observed during a contrast-enhanced computed tomography study and endoscopy within 1 month following treatment. Clinical success was defined as absence of bleeding of gastric varices during the follow-up period. Major and minor complications during the follow up were recorded.

Results: Twelve sessions of combined PTO and BRTO procedures were performed in 10 patients; in 2 patients a new combined treatment was required during the follow up. Technical and clinical success was 100%. Neither major nor minor procedure-related complications were observed.

Conclusion: Combined PTO and BRTO therapy is safe and effective for the treatment of gastric varices that cannot be managed otherwise.
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http://dx.doi.org/10.20524/aog.2021.0616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8276367PMC
March 2021

Response to Sharma and Saraya.

Am J Gastroenterol 2021 08;116(8):1756-1757

Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, Milan, Italy.

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http://dx.doi.org/10.14309/ajg.0000000000001290DOI Listing
August 2021

Decompensation in Direct-Acting Antiviral Cured Hepatitis C Virus Compensated Patients With Clinically Significant Portal Hypertension: Too Rare to Warrant Universal Β-Blocker Therapy.

Am J Gastroenterol 2021 06;116(6):1342-1344

Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, Milan, Italy.

Nonselective β-blockers improve decompensation-free survival in viremic hepatitis C virus compensated cirrhotic patients with clinically significant portal hypertension, but their protective role after sustained virological response by direct-acting antiviral (DAA) is undefined. We evaluated the incidence of decompensation in DAA-cured Child-A patients without high-risk varices. During the 49-month (12-60) follow-up, only one of 148 patients decompensated (ascites), with a 4-year cumulative risk of 1%, but decompensation was associated with hepatocellular carcinoma. The risk of decompensation in DAA cured hepatitis C virus compensated Child-A cirrhotic patients with clinically significant portal hypertension but without high-risk varices is negligible; thus, questioning the need for nonselective β-blocker treatment in this setting (see Visual abstract, Supplemental Digital Content, 1, http://links.lww.com/AJG/B861). JOURNAL/ajgast/04.03/00000434-202106000-00035/inline-graphic1/v/2021-05-28T144026Z/r/image-tiff.
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http://dx.doi.org/10.14309/ajg.0000000000001158DOI Listing
June 2021

Post-banding ulcer bleeding in the elective setting: Are there any risk factors?

Dig Liver Dis 2021 May 2;53(5):658-660. Epub 2021 Feb 2.

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico - UOC Gastroenterologia ed Epatologia, Milano, Italia. Electronic address:

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http://dx.doi.org/10.1016/j.dld.2021.01.016DOI Listing
May 2021

High-dose pre-endoscopic intravenous proton pump inhibitors in upper gastrointestinal bleeding: Utility or futility?

Dig Liver Dis 2021 03 4;53(3):387-388. Epub 2021 Jan 4.

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico - UOC Gastroenterologia ed Epatologia, Milano, Italia.

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http://dx.doi.org/10.1016/j.dld.2020.12.007DOI Listing
March 2021

Coronavirus disease 2019 and transplantation: tackling the challenges of SARS-CoV-2 infection in waiting list candidates.

Transpl Int 2020 12 28;33(12):1830-1832. Epub 2020 Sep 28.

General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

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http://dx.doi.org/10.1111/tri.13742DOI Listing
December 2020

The Role of Spleen and Liver Elastography and Color-Doppler Ultrasound in the Assessment of Transjugular Intrahepatic Portosystemic Shunt Function.

Ultrasound Med Biol 2020 07 8;46(7):1641-1650. Epub 2020 May 8.

Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, UOC Gastroenterologia ed Endoscopia, Milan, Italy. Electronic address:

The reference standard for assessing transjugular intrahepatic portosystemic shunt (TIPS) function is venography with portosystemic pressure gradient (PPG) measurement. This procedure is invasive and expensive; thus, we assessed the feasibility, reproducibility and diagnostic accuracy of color-Doppler ultrasound (CDUS) and spleen and liver stiffness (LS) measurements for identifying TIPS dysfunction. Twenty-four patients (15 undergoing TIPS placement and nine undergoing TIPS revision) consecutively underwent CDUS examination and LS and spleen stiffness (SS) determination by transient elastography (TE) and point shear-wave elastography (pSWE). All parameters were taken before TIPS placement/revision (1-15 d before) and 24 h after, just before revision by venography. pSWE inter-observer agreement was assessed by intra-class correlation coefficient (ICC). CDUS and elastographic data were correlated (Pearson coefficient) with pressure gradients (hepatic venous pressure gradient [HVPG], PPG). Main determinants of TIPS dysfunction were investigated by linear regression. Forty-nine paired examinations were performed in total: 49 (100%) SS reliable measurements by pSWE and 38 (88%) by TE. The ICC for pSWE values was 0.90 (95% confidence interval [CI] 0.81‒0.94). SS values significantly correlated with HVPG and PPG (R = 0.51, p = 0.01). The area under the Receiver-Operating Characteristic (AUROC) curve of SS for diagnosing TIPS dysfunction was 0.86 (95% CI 0.70‒0.96) using a 25 kPa cutoff. At multivariate analysis, the flow direction of the intrahepatic portal vein branches and SS values were independently associated to TIPS dysfunction. The intrahepatic portal vein branches flow direction and SS value are two simple, highly sensitive parameters accurately excluding TIPS dysfunction. SS measurement by pSWE is feasible, reproducible and both positively and significantly correlates with HVPG and PPG values.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2020.04.007DOI Listing
July 2020

AB0, von Willebrand factor/factor VIII and portal vein thrombosis in decompensated cirrhosis: Too late to unmask the culprit?

Liver Int 2020 07 18;40(7):1788-1789. Epub 2020 May 18.

Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, CRC "A. M. and A. Migliavacca" Center for Liver Disease, Milan, Italy.

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http://dx.doi.org/10.1111/liv.14493DOI Listing
July 2020

Letter to the Editor: Thromboelastography-Guided Blood Product Transfusion in Cirrhosis With Coagulopathy: Real Saving or Just Less Waste?

Hepatology 2020 09;72(3):1158-1159

Foundation IRCCS Ca' Granda, Ospedale Maggiore Policlinico, "Angelo Bianchi Bonomi" Hemophilia and Thrombosis Center, Milan, Italy.

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http://dx.doi.org/10.1002/hep.31263DOI Listing
September 2020

Etiology of non-cirrhotic portal vein thrombosis in children: Few or many causes?

Dig Liver Dis 2020 01 14;52(1):118-120. Epub 2019 Oct 14.

CRC "A. M. e A. Migliavacca" Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.

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http://dx.doi.org/10.1016/j.dld.2019.09.006DOI Listing
January 2020

Plasma miRNA-based signatures in CRC screening programs.

Int J Cancer 2020 02 5;146(4):1164-1173. Epub 2019 Aug 5.

Tumor Genomics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Colorectal cancer (CRC) screening programs help diagnose cancer precursors and early cancers and help reduce CRC mortality. However, currently recommended tests, the fecal immunochemical test (FIT) and colonoscopy, have low uptake. There is therefore a pressing need for screening strategies that are minimally invasive and consequently more acceptable to patients, most likely blood based, to increase early CRC identification. MicroRNAs (miRNAs) released from cancer cells are detectable in plasma in a remarkably stable form, making them ideal cancer biomarkers. Using plasma samples from FIT-positive (FIT+) subjects in an Italian CRC screening program, we aimed to identify plasma circulating miRNAs that detect early CRC. miRNAs were initially investigated by quantitative real-time PCR in plasma from 60 FIT+ subjects undergoing colonoscopy at Fondazione IRCCS Istituto Nazionale dei Tumori, then tested on an internal validation cohort (IVC, 201 cases) and finally in a large multicenter prospective series (external validation cohort [EVC], 1121 cases). For each endoscopic lesion (low-grade adenoma [LgA], high-grade adenoma [HgA], cancer lesion [CL]), specific signatures were identified in the IVC and confirmed on the EVC. A two-miRNA-based signature for CL and six-miRNA signatures for LgA and HgA were selected. In a multivariate analysis including sex and age at blood collection, the areas under the receiver operating characteristic curve (95% confidence interval) of the signatures were 0.644 (0.607-0.682), 0.670 (0.626-0.714) and 0.682 (0.580-0.785) for LgA, HgA and CL, respectively. A miRNA-based test could be introduced into the FIT+ workflow of CRC screening programs so as to schedule colonoscopies only for subjects likely to benefit most.
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http://dx.doi.org/10.1002/ijc.32573DOI Listing
February 2020

Congenital Extrahepatic Portosystemic Shunts (Abernethy Malformation): An International Observational Study.

Hepatology 2020 02 19;71(2):658-669. Epub 2019 Aug 19.

Aparato Digestivo, Hospital Universitario Central de Asturias HUCA, Asturias, España.

Congenital extrahepatic portosystemic shunt (CEPS) or Abernethy malformation is a rare condition in which splanchnic venous blood bypasses the liver draining directly into systemic circulation through a congenital shunt. Patients may develop hepatic encephalopathy (HE), pulmonary hypertension (PaHT), or liver tumors, among other complications. However, the actual incidence of such complications is unknown, mainly because of the lack of a protocolized approach to these patients. This study characterizes the clinical manifestations and outcome of a large cohort of CEPS patients with the aim of proposing a guide for their management. This is an observational, multicenter, international study. Sixty-six patients were included; median age at the end of follow-up was 30 years. Nineteen patients (28%) presented HE. Ten-, 20-, and 30-year HE incidence rates were 13%, 24%, and 28%, respectively. No clinical factors predicted HE. Twenty-five patients had benign nodular lesions. Ten patients developed adenomas (median age, 18 years), and another 8 developed HCC (median age, 39 years). Of 10 patients with dyspnea, PaHT was diagnosed in 8 and hepatopulmonary syndrome in 2. Pulmonary complications were only screened for in 19 asymptomatic patients, and PaHT was identified in 2. Six patients underwent liver transplantation for hepatocellular carcinoma or adenoma. Shunt closure was performed in 15 patients with improvement/stability/cure of CEPS manifestations. Conclusion: CEPS patients may develop severe complications. Screening for asymptomatic complications and close surveillance is needed. Shunt closure should be considered both as a therapeutic and prophylactic approach.
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http://dx.doi.org/10.1002/hep.30817DOI Listing
February 2020

Body mass index reduction improves the baseline procoagulant imbalance of obese subjects.

J Thromb Thrombolysis 2019 Jul;48(1):52-60

IRCCS Cà Granda Maggiore Hospital Foundation, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and Fondazione Luigi villa, Via Pace 9, 20122, Milano, Italy.

Obesity is a risk factor for cardiovascular diseases. The latter being dependent (at least in part) on plasma procoagulant imbalance (i.e., hypercoagulability). Information on hypercoagulability associated with obesity is scanty and mainly based on global traditional coagulation tests or on the measurement of individual components of coagulation (i.e., pro- and anticoagulants). Plasma from 33 obese subjects was investigated soon before endoscopic balloon placement and after removal (6 months later) by thrombin-generation procedures that are thought to represent much better than any other in vitro test the coagulation process occurring in vivo. We found that obese subjects possess a state of hypercoagulability as demonstrated by the modification of the main parameters of thrombin-generation. In particular, the median value (min-max) of the endogenous thrombin potential (ETP) of obese subjects at baseline was higher than that of controls [1968 (1335-2533) vs. 1710 (1010-2119), p < 0.001]. Endoscopic balloon placement achieved a BMI reduction from 38.9 (31.7-62.3) to 31.6 (21.9-53.3), p < 0.001 and a parallel reduction of thrombin-generation as demonstrated by the following findings. The ETP measured soon after balloon removal was significantly smaller than that measured at baseline [1783 (1224-2642) vs. 1968 (1335-2533), p < 0.01]. The other parameters of thrombin-generation, including lag-time, peak-thrombin, time-to-reach the peak and velocity index showed a pattern consistent with the ETP, both at baseline and soon after balloon removal. Endoscopic balloon placement achieves concomitant reduction of BMI and thrombin-generation in subjects with obesity.
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http://dx.doi.org/10.1007/s11239-019-01818-9DOI Listing
July 2019

Evaluation of three "beyond Baveno VI" criteria to safely spare endoscopies in compensated advanced chronic liver disease.

Dig Liver Dis 2019 08 11;51(8):1135-1140. Epub 2019 Jan 11.

CRC "A. M. e A. Migliavacca" Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.

Background: Liver stiffness measurement (LSM) <20 kPa and platelet count >150,000/mm exclude varices needing treatment (VNT) in viral compensated advanced chronic liver disease (cACLD), saving-up to 20-25% endoscopies (Baveno VI criteria). Refinements of such criteria to further reduce endoscopies and an approach without LSM (Platelet 150/MELD 6) were later proposed.

Aims: To assess LSM 25/platelet 125, LSM 25/platelet 110 (Expanded-Baveno VI) and Platelet 150/MELD 6 accuracy versus Baveno VI criteria, and the impact of platelet count variability on criteria accuracy in all-etiologies cACLD.

Methods: cACLD patients undergoing screening endoscopy with laboratory data within 6 months and LSM within one year.

Results: Of 442 patients, 31% had varices (7% with VNT). Baveno VI criteria had 100% sensitivity (Se) and negative predictive value (NPV) and spared 19.5% endoscopies. "LSM 25/platelet 125" and "Expanded-Baveno VI" criteria maintained such accuracy, sparing 15% and 24% more endoscopies, respectively (p < 0.001). Platelet 150/MELD 6 was less accurate, misclassifying 10% VNT. Platelet count variability exceeded 8% and one VNT patient was misclassified with both "Expanded-Baveno VI" and "LSM 25/platelet 125" criteria considering the previous platelet count.

Conclusions: Both "Expanded-Baveno VI" and "LSM 25/platelet 125" criteria are accurate in cACLD, but the former are more advantageous. Platelet 150/MELD 6 proved inadequate.
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http://dx.doi.org/10.1016/j.dld.2018.12.025DOI Listing
August 2019

Harmful and Beneficial Effects of Anticoagulants in Patients With Cirrhosis and Portal Vein Thrombosis.

Clin Gastroenterol Hepatol 2018 07 21;16(7):1146-1152.e4. Epub 2017 Oct 21.

A. M. and A. Migliavacca-Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy.

Background & Aims: Vitamin K antagonists (VKAs) promote recanalization of portal vein thrombosis (PVT) in patients with cirrhosis. However, the benefit of PVT recanalization might be offset by major and minor bleeding associated with use of anticoagulants. We evaluated harmful and beneficial effects of VKA in patients with PVT and cirrhosis.

Methods: We performed a retrospective study of 63 consecutive patients with cirrhosis given anticoagulants for the first detection of non-neoplastic PVT from 2003 to 2015 in Italy. We collected data on bleeding events in these patients and compared them with those from patients without cirrhosis with venous thromboembolism (VTE) (n = 160) for up to 4 years. Time in the therapeutic range, based on the international normalized ratio, was used to determine the quality of anticoagulation. We also collected data from 139 patients with cirrhosis who did not receive VKAs (controls), to analyze portal hypertension-related events. We performed survival analyses to determine the effects of VKA in patients with PVT vs controls.

Results: The group with VTE and the group with PVT were comparable in age, sex, and time in the therapeutic range, but patients with VTE received VKAs for a longer time period (31.1 ± 16.9 mo vs 23.3 ± 16.2 mo; P = .002). The incidence of major or minor bleeding was higher in patients with PVT than patients with VTE (major, 24% vs 7%; P = .012; minor, 29% vs 19%; P = .024). Patients with PVT had a higher rate of major bleeding from the upper-gastrointestinal tract than patients with VTE (P = .019), but there were no significant differences in other types of major bleeding (P = .376). Patients with PVT and controls had the same rate of upper-gastrointestinal bleeding. Complete recanalization in patients with PVT receiving VKA (n = 31) was independently associated with increased portal hypertension-related event-free and transplantation-free survival times.

Conclusions: In a retrospective analysis of 63 patients with cirrhosis given anticoagulants for PVT, we found VKA use to increase risk of minor bleeding, compared with patients without cirrhosis given VKA. However, this risk is offset by the ability of VKA to increase portal hypertension-related, event-free, and transplantation-free survival of patients with PVT recanalization. Portal hypertension, rather than anticoagulants, could account for the difference in risk of major bleeding between patients with PVT vs patients with VTE.
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http://dx.doi.org/10.1016/j.cgh.2017.10.016DOI Listing
July 2018

Evaluation of coagulation during treatment with directly acting antivirals in patients with hepatitis C virus related cirrhosis.

Liver Int 2017 09 23;37(9):1295-1303. Epub 2017 Feb 23.

IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy.

Background & Aims: The effect of direct-acting-antivirals (DAA) on coagulation of hepatitis-C-virus (HCV)-related cirrhosis is unknown.

Methods: We investigated 28 patients on DAA treatment and performed prothrombin-time, thrombin generation with and without thrombomodulin, whole-blood thromboelastometry, as well as the individual procoagulants (II, VIII, XIII, von Willebrand) and anticoagulants, antithrombin and protein-C.

Results: Patients had undetectable HCV-RNA at the end-of- treatment and at 12-weeks after end-of-treatment (sustained virological response). Transaminases were significantly decreased at both end-of-treatment and at 12-weeks. Prothrombin-time declined at 12-weeks, but did not reach statistical significance. Factor-II, protein-C and antithrombin increased significantly at end-of-treatment (P<.001) and persisted at 12-weeks. Factor-VIII decreased at end-of-treatment and to a greater extent at 12-weeks when reached statistical significance (P<.05). Factor-VIII/protein-C ratio decreased sharply, reached statistical significance at end-of-treatment (P<.01) and persisted at 12-weeks. Von-Willebrand decreased at end-of-treatment and reached statistical significance at 12-weeks (P<.001). Endogenous-thrombin-potential without thrombomodulin increased significantly at end-of-treatment (P<.01) and persisted at 12-weeks. No changes were observed after addition of thrombomodulin. Endogenous-thrombin-potential ratio (with/without thrombomodulin) decreased and reached statistical significance at 12-weeks (P<.05). Thromboelastometry clotting time decreased sharply, reached statistical significance at end-of treatment (P<.001) and persisted at 12-weeks.

Conclusions: Treatment with DAAs in HCV-related cirrhosis results in improvement of the individual pro- and anticoagulants. It can be hypothesised that the net effect does not substantially modify their balance (as shown by the unchanged thrombin generation in the presence of thrombomodulin) but makes it more stable and less amenable to be perturbed as presumably occurs before treatment when there is a partial deficiency for both.
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http://dx.doi.org/10.1111/liv.13374DOI Listing
September 2017

Portal hypertensive gastropathy after variceal eradication: more bleeding risk or just more reddening?

Hepatol Int 2016 Nov 9;10(6):847-850. Epub 2016 Jun 9.

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

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http://dx.doi.org/10.1007/s12072-016-9750-5DOI Listing
November 2016

Pediatric Tuberculosis in Italian Children: Epidemiological and Clinical Data from the Italian Register of Pediatric Tuberculosis.

Int J Mol Sci 2016 Jun 17;17(6). Epub 2016 Jun 17.

Institute of Pediatrics, Università Cattolica del Sacro Cuore, Rome 00168, Italy.

Tuberculosis (TB) is one of the leading causes of death worldwide. Over the last decades, TB has also emerged in the pediatric population. Epidemiologic data of childhood TB are still limited and there is an urgent need of more data on very large cohorts. A multicenter study was conducted in 27 pediatric hospitals, pediatric wards, and public health centers in Italy using a standardized form, covering the period of time between 1 January 2010 and 31 December 2012. Children with active TB, latent TB, and those recently exposed to TB or recently adopted/immigrated from a high TB incidence country were enrolled. Overall, 4234 children were included; 554 (13.1%) children had active TB, 594 (14.0%) latent TB and 3086 (72.9%) were uninfected. Among children with active TB, 481 (86.8%) patients had pulmonary TB. The treatment of active TB cases was known for 96.4% (n = 534) of the cases. Overall, 210 (39.3%) out of these 534 children were treated with three and 216 (40.4%) with four first-line drugs. Second-line drugs where used in 87 (16.3%) children with active TB. Drug-resistant strains of Mycobacterium tuberculosis were reported in 39 (7%) children. Improving the surveillance of childhood TB is important for public health care workers and pediatricians. A non-negligible proportion of children had drug-resistant TB and was treated with second-line drugs, most of which are off-label in the pediatric age. Future efforts should concentrate on improving active surveillance, diagnostic tools, and the availability of antitubercular pediatric formulations, also in low-endemic countries.
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http://dx.doi.org/10.3390/ijms17060960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4926492PMC
June 2016

Resistance to thrombomodulin is associated with de novo portal vein thrombosis and low survival in patients with cirrhosis.

Liver Int 2016 09 31;36(9):1322-30. Epub 2016 Mar 31.

Division of Gastroenterology and Hepatology, IRCCS Ca' Granda Maggiore Hospital Foundation, University of Milan, Milan, Italy.

Background & Aims: Portal vein thrombosis (PVT) is frequently observed in cirrhosis and may be a clinically important complication. In vitro assays for endogenous thrombin potential (ETP) demonstrated that in cirrhosis plasma has intrinsic resistance to the anticoagulant action of thrombomodulin (TM-R). This study retrospectively explores the association of TM-R with de novo PVT and its clinical impact on cirrhosis.

Methods: Fifty-three patients with cirrhosis were tested for ETP-ratio with/without thrombomodulin. Clinical, endoscopic variables, presence/absence of PVT by Doppler-US and/or CT examination were collected at baseline and up to 4 years from baseline. The de novo PVT was the primary clinical end-point. Portal hypertension (PHT)-related complications and transplantation free survival were secondary end-points. ETP-ratio higher than the 95° percentile of the distribution in 173 healthy controls defined TM-R.

Results: During 48 months of follow-up, 11 patients developed de novo PVT, with preference for the 36 patients with TM-R after adjusting for Child-Pugh class (HR: 8.354; 90%CI:1.475 - 47.305; P = 0.009). Seventeen patients experienced PHT-related complications, 23 either died or underwent liver transplantation. PHT complications and transplantation free survival were associated with TM-R, but were independently predicted by Child-Pugh class, only. Same results were obtained by considering the MELD score.

Conclusions: Owing to PVT results from the pro-coagulant imbalance occurring in patients with advanced cirrhosis, TM-R might serve as a predictor and could possibly be a biological mediator of adverse outcome in patients with advanced cirrhosis.
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http://dx.doi.org/10.1111/liv.13087DOI Listing
September 2016

Therapeutic and clinical aspects of portal vein thrombosis in patients with cirrhosis.

World J Hepatol 2015 Dec;7(29):2906-12

Massimo Primignani, Giulia Tosetti, U.O. Gastroenterologia ed Epatologia, IRCCS-Ca' Granda, Ospedale Maggiore Policlinico, 20122 Milano, Italy.

Portal vein thrombosis (PVT) is a frequent complication in cirrhosis, particularly in advanced stages of the disease. As for general venous thromboembolism, risk factors for PVT are slow blood flow, vessel wall damage and hypercoagulability, all features of advanced cirrhosis. Actually, the old dogma of a hemorrhagic tendency in cirrhosis has been challenged by new laboratory tools and the clinical evidence that venous thrombosis also occurs in cirrhosis. The impaired hepatic synthesis of both pro- and anticoagulants leads to a rebalanced hemostasis, more liable to be tipped towards thrombosis or even bleeding. Conventional anticoagulant drugs (low molecular weight heparin or vitamin K antagonists) may be used in cirrhosis patients with PVT, particularly in those eligible for liver transplantation, to prevent thrombosis progression thus permitting/facilitating liver transplant. However, several doubts exist on the level of anticoagulation achieved as estimated by coagulation tests, on the efficacy of treatment monitoring and on the correct timing for discontinuation in non-transplant candidates, while in transplant candidates there is expert consensus on continuing anticoagulation until transplantation. The recent introduction of direct acting oral anticoagulant drugs (DOACs) in other clinical settings generates much interest on their possible application in patients with cirrhosis and PVT. However, DOACs were not evaluated yet in patients with liver disease and cannot be recommended for the present time.
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http://dx.doi.org/10.4254/wjh.v7.i29.2906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678377PMC
December 2015

Cirrhosis and portal hypertension: The importance of risk stratification, the role of hepatic venous pressure gradient measurement.

World J Hepatol 2015 Apr;7(4):688-95

Vincenzo La Mura, Antonio Nicolini, Giulia Tosetti, Massimo Primignani, Fondazione IRCCS, Ca' Granda, Ospedale Maggiore Policlinico, 20100 Milano, Italy.

Portal hypertension is the main prognostic factor in cirrhosis. The recent emergence of potent antiviral drugs and new algorithm of treatment for the management of complications due to portal hypertension have sensibly changed our perception of cirrhosis that can be now considered as a multistage liver disease whose mortality risk can be reduced by a tailored approach for any stage of risk. Experts recommend to move toward a pathophysiological classification of cirrhosis that considers both structural and functional changes. The hepatic venous pressure gradient HVPG, is the reference gold standard to estimate the severity of portal hypertension in cirrhosis. It correlates with both structural and functional changes that occur in cirrhosis and carries valuable prognostic information to stratify the mortality risk. This article provides a general overview of the pathophysiology and natural course of cirrhosis and portal hypertension. We propose a simplified classification of cirrhosis based on low, intermediate and high mortality stage. The prognostic information provided by HVPG is presented according to each stage. A comparison with prognostic models based on clinical and endoscopic variables is discussed in order to evidence the additional contribute given by HVPG on top of other clinical and instrumental variables widely used in clinical practice.
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http://dx.doi.org/10.4254/wjh.v7.i4.688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4388996PMC
April 2015

Use of non-selective beta blockers in cirrhosis: the evidence we need before closing (or not) the window.

World J Gastroenterol 2015 Feb;21(8):2265-8

Vincenzo La Mura, Francesco Salerno, U.O. Medicina Interna, IRCCS-San Donato, Dipartimento di Scienze Biomediche per la Salute, Università degli studi di Milano, 20097 Milan, Italy.

Non selective beta blockers (NSBBs) are used in primary and secondary prophylaxis of portal hypertension-related bleeding in patients with cirrhosis. The efficacy of NSBBs treatment is predicted by hemodynamic response in term of reduction of the hepatic venous pressure gradient (HVPG) below 12 mmHg or at least 20% of the basal value. Nevertheless a relevant number of patients who do not achieve this HVPG reduction during NSBBs therapy do not bleed during follow up; this evidence suggests an additional non-hemodynamic advantage of NSBBs treatment to modify the natural history of cirrhosis. Recent studies have questioned the efficacy and safety of NSBBs in patients with advanced stage of liver disease characterized by refractory ascites and/or spontaneous bacterial peritonitis. These studies have suggested the existence of a defined and limited period to modify the natural history of cirrhosis by NSBBs: the "window hypothesis". According with this hypothesis, patients with cirrhosis benefit from the use of NSBBs from the appearance of varices up to the development of an advanced stage of cirrhosis. Indeed, in patients with refractory ascites and/or spontaneous bacterial peritonitis the hemodynamic effects of NSBBs may expose to a high risk of further complications such as renal insufficiency and/or death. Methodological concerns and contrasting results counterbalance the evidence produced up to now on this issue and are the main topic of this editorial.
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http://dx.doi.org/10.3748/wjg.v21.i8.2265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342901PMC
February 2015
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