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Objective The aim was to investigate the contribution of liver steatosis and significant fibrosis alone and in association [nonalcoholic fatty liver disease (NAFLD) with fibrosis] to frailty as a measure of biological age in people living with HIV (PLWH). Design This was a cross-sectional study of consecutive patients attending Modena HIV Metabolic Clinic in 2018-2019. Methods Patients with hazardous alcohol intake and viral hepatitis coinfection were excluded. Liver steatosis was diagnosed by controlled attenuation parameter (CAP), while liver fibrosis was diagnosed by liver stiffness measurement (LSM). NAFLD was defined as presence of liver steatosis (CAP ≥248 dB/m), while significant liver fibrosis or cirrhosis (stage ≥F2) as LSM at least 7.1 kPa. Frailty was assessed using a 36-Item frailty index. Logistic regression was used to explore predictors of frailty using steatosis and fibrosis as covariates. Results We analysed 707 PLWH (mean age 53.5 years, 76.2% men, median CD4 cell count 700 cells/μl, 98.7% with undetectable HIV RNA). NAFLD with fibrosis was present in 10.2%; 18.9 and 3.9% of patients were classified as frail and most-frail, respectively. Univariate analysis demonstrated that neurocognitive impairment [odds ratio (OR) = 5.1, 1.6-15], vitamin D insufficiency (OR = 1.94, 1.2-3.2), obesity (OR = 8.1, 4.4-14.6), diabetes (OR = 3.2, 1.9-5.6), metabolic syndrome (OR = 2.41, 1.47-3.95) and osteoporosis (OR = 0.37, 0.16-0.76) were significantly associated with NAFLD with fibrosis. Predictors of frailty index included steatosis (OR = 2.1, 1.3-3.5), fibrosis (OR = 2, 1-3.7), NAFLD with fibrosis (OR = 9.2, 5.2-16.8), diabetes (OR = 1.7, 1-2.7) and multimorbidity (OR = 2.5, 1.5-4). Conclusion Liver steatosis and NAFLD with fibrosis were associated with frailty. NAFLD with fibrosis exceeded multimorbidity in the prediction of frailty, suggesting the former as an indicator of metabolic age in PLWH.

Background: Achieving a reliable venous access in a particular subset of patients and/or in emergency settings can be challenging and time-consuming. Furthermore, many hospitalized patients do not meet the criteria for central venous catheter positioning, unless an upgrade of the treatment is further needed. The mini-midline catheter has already showed to be reliable and safe as a stand-alone device, since it is easily and rapidly inserted and can indwell up to 1 month. Methods: In this further case series, we retrospectively evaluated data from 63 patients where a previously inserted mini-midline catheter was upgraded to a central venous catheter (the devices inserted in the arm replaced by peripherally inserted central catheter and others inserted “off-label” in the internal jugular replaced by single lumen centrally inserted central catheter), being used as introducer for the Seldinger guidewire. Results: The guidewire replacement was been made even early (after 1 day) or late (more than 10 days), usually following a need for an upgrade in treatment. No early or late complications were reported. Conclusion: According to the preliminary data we collected, this converting procedure seems to be feasible and risk-free, since neither infectious nor thrombotic complications were reported.

Transjugular intrahepatic portosystemic shunt (TIPS) represents a very effective treatment of complications of portal hypertension. Established indications to TIPS in cirrhotic patients include portal hypertensive bleeding and refractory ascites. Over the years additional indications have been proposed, such as the treatment of vascular disease of the liver, hepatic hydrothorax, hepatorenal syndrome and bleeding from ectopic varices. Indications under evaluation include treatment of portal hypertension prior to major abdominal surgery and treatment of portal vein thrombosis. In spite of these advances, there are still uncertainties regarding the appropriate workup for patients to be scheduled for TIPS. Moreover, prevention and management of post-TIPS complications including hepatic encephalopathy and heart failure are still suboptimal. These issues are particularly relevant considering aging in TIPS candidates in Western countries. Correct selection of patients is mandatory to prevent complications which may eventually frustrate the good hemodynamic results and worsen the patient's quality of life or even life expectancy. The possible role of small diameter TIPS to prevent post-procedural complications is discussed.

BACKGROUND & AIMS: Portal hypertension is the strongest predictor of hepatic decompensation and death in patients with cirrhosis. However, its discriminatory accuracy in patients with nonalcoholic fatty liver disease (NAFLD) has been challenged because 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 included 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 Model for End-Stage Liver Disease score. 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 = .019) than in the aHCV group. For any of the HVPG cutoff analyzed (

Since the early 1970s several studies have reported distal splenic artery embolization, better known as partial spleen embolization (PSE), as an efficacious treatment of portal hypertensive variceal bleeding and hypersplenism in cirrhosis.(1, 2) However, the effect of PSE on portal pressure is secondary to the induction of splenic infarction. Depending on both the infarct volume and possible infection, PSE can induce serious complications including death.(2, 3) On the other hand, proximal splenic artery embolization (PSAE), which mimics surgical splenic artery ligation, prevents large infarction of the spleen, favoring collateral perfusion of its intact distal vasculature.(3) For this, PSAE has been extensively preferred over PSE for reducing portal hyperflow and treating refractory ascites (RA) after whole or partial liver transplantation (LT).(3, 4) We report here a case of PSAE used to treat RA in a patient with cirrhosis not eligible for transjugular intrahepatic portosystemic shunt (TIPS) and LT.

Background Transjugular Intrahepatic Portosystemic Shunt (TIPS) is a well-established treatment for complications of portal hypertension. Aims To analyze the impact of TIPS on virologic response and safety profile in patients treated with direct-acting antivirals (DAAs). Methods We analyzed data from HCV-positive cirrhotic patients treated with DAAs. Twenty-one patients with previous TIPS placement were compared with 42 matched subjects without TIPS. Logistic regression was used to identify predictors of hepatic function worsening and adverse events. Results No differences were found between the two groups in particular regarding sustained virologic response (92.5 and 97.6% in TIPS vs no-TIPS, p = 0.559). Model for End-stage Liver Disease (MELD) of both TIPS and no-TIPS groups declined from baseline to week 24 of follow-up (from 12.5 ± 3.5 to 10.8 ± 3.4 and from 11.1 ± 3.5 to 10.3 ± 3.4, p = 0.044 and 0.025). There were no differences in adverse event rates. At univariate analysis, age was associated with MELD increase from baseline to week 24 (OR 1.111, 95% CI 1.019-1.211, p = 0.017), and patients with higher baseline MELD developed serious adverse events more frequently (OR 0.815, 95% CI 0.658–1.010, p = 0.062). Patients with or without TIPS did not show differences in transplant-free survival. Conclusion TIPS placement does not affect virologic response and clinical outcome of patients receiving DAAs.

Background Cirrhosis leads to portal hypertension and to the consequent formation of spontaneous portosystemic shunts (SPSSs), leading to complications related to the diversion of portal blood into the systemic circulation, which is called portosystemic shunt syndrome. Purpose To investigate the characteristics of patients with cirrhosis and an SPSS and secondarily to assess the prognostic impact of SPSSs on portal hypertension-related complications and transplant-free survival. Materials and Methods A retrospective database review of patients with cirrhosis (observed from March 2015 to July 2019) was performed to identify patients with CT imaging and outcomes data. For each patient, clinical and biochemical data were collected, and the presence, types, and sizes of SPSSs were investigated with CT. Patients were followed for a mean of 27.5 months ± 22.8. Multivariable logistic analysis was used to identify the clinical characteristics associated with the presence of SPSSs (any size) and presence of SPSSs 1 cm or larger. Competitive risk analysis (Fine and Gray model) was used to identify the association between SPSSs and complications and mortality. Results Two hundred twenty-two patients with cirrhosis (157 male, 65 female; mean age, 62 years ± 12 [standard deviation]) were evaluated. An SPSS was found in 141 of 222 patients (63.5%), and 40 of 222 (18%) had a shunt diameter of at least 1 cm. At presentation, variables independently associated with the presence of SPSSs (any size) were portal vein thrombosis (odds ratio, 5.5

Key Points Three-day change in angiopoietin-2 levels predicts COVID-19 in-hospital mortality, whereas the 10-day trend is associated with chronic lung disability. Angiopoietin-2 may play an important pathogenic role in patients with COVID-19, and it could be a target for new treatments., This study examined the association between dynamic angiopoietin-2 assessment and COVID-19 short- and long-term clinical course. We included consecutive hospitalized patients from 1 February to 31 May 2020 with laboratory-confirmed COVID-19 from 2 Italian tertiary referral centers (derivation cohort, n = 187 patients; validation cohort, n = 62 patients). Serum biomarker levels were measured by sandwich enzyme-linked immunosorbent assay. Lung tissue from 9 patients was stained for angiopoietin-2, Tie2, CD68, and CD34. Cox model was used to identify risk factors for mortality and nonresolving pulmonary condition. Area under the receiver operating characteristic curve (AUROC) was used to assess the accuracy of 3- and 10-day angiopoietin-2 for in-hospital mortality and nonresolving pulmonary condition, respectively. Three-day angiopoietin-2 increase of at least twofold from baseline was significantly associated with in-hospital mortality by multivariate analysis (hazard ratio [HR], 6.69; 95% confidence interval [CI], 1.85-24.19; P = .004) with AUROC = 0.845 (95% CI, 0.725-0.940). Ten-day angiopoietin-2 of at least twofold from baseline was instead significantly associated with nonresolving pulmonary condition by multivariate analysis (HR, 5.33; 95% CI, 1.34-11.77; P ≤ .0001) with AUROC = 0.969 (95% CI, 0.919-1.000). Patients with persistent elevation of 10-day angiopoietin-2 levels showed severe reticular interstitial thickening and fibrous changes on follow-up computed tomography scans. Angiopoietin-2 and Tie2 were diffusely colocalized in small-vessel endothelia and alveolar new vessels and macrophages. Angiopoietin-2 course is strongly associated with COVID-19 in-hospital mortality and nonresolving pulmonary condition. Angiopoietin-2 may be an early and useful predictor of COVID-19 clinical course, and it could be a relevant part of disease pathogenesis. Angiopoietin-2 blockade may be a COVID-19 treatment option., Visual Abstract

Portopulmonary hypertension (PoPH) is a clinical condition associated with end-stage liver disease, described by the coexistence of pulmonary arterial hypertension (PAH) and portal hypertension. In PoPH patients, there is a right ventricle (RV) remodeling to compensate for the increased resistance in the lung circulation. There are no studies on the effects of the PAH-targeted pharmacological treatment on the RV dimension and function. The present study summarizes our experience in patients with PoPH treated with sildenafil in a period of 6 years (from 2013 to 2019). We enrolled 64 consecutive patients identified as PoPH, all treated with sildenafil (57.6% in monotherapy; in the other cases in association with macitentan; in 19.0% with initial combination therapy). A hemodynamic invasive cardiopulmonary study was performed at baseline and after 6 months of sildenafil treatment. In our population we showed a significative improvement in RV performance, with a significant increase in RV stroke volume (+33%), RV ejection fraction (+31%) and RV stroke work index (+17.5%). We registered the reduction of the RV cavity dimension over time in all patients treated with sildenafil (RV end diastolic diameter decreased by 15% after 6 months of follow-up). Regarding diastolic function, we highlighted a very significant reduction in RV end-diastolic pressure (-50% concerning baseline). Sildenafil was effective both when used as monotherapy and in combination with macitentan. In conclusion, Sildenafil had a positive impact on RV systolic and diastolic function in patients with PoPH and was able to conditionate the reverse remodeling of the RV.

INTRODUCTION Gastric antral vascular ectasia is a significant cause of gastrointestinal bleeding in patients with cirrhosis. AIM To assess safety/efficacy and cost/advantages of radiofrequency ablation for the treatment of gastric antral vascular ectasia in patients with cirrhosis. MATERIALS AND METHODS Patients with cirrhosis and severe gastric antral vascular ectasia who underwent radiofrequency ablation were enrolled. Clinical data, gastric antral vascular ectasia grade, and gastric antral vascular ectasia-related hospitalizations were collected. Primary outcome was defined as the absence of transfusion over the 6 months after radiofrequency. An economic analysis was performed in the same period. RESULTS Forty patients (50% Child B) were enrolled (80% refractory to argon plasma coagulation). Gastric antral vascular ectasia eradication was obtained in all patients and 65% of these patients achieved primary outcome. After radiofrequency, mean number of red blood cells transfusions dropped (from 25 to 0.9, P < 0.0001), with a parallel increase in hemoglobin (from 8 to 10.5 g/dL, P < 0.0001). No major complication occurred and liver function remained stable in all patients. The cost-analysis demonstrated a profound reduction of health care cost (from € 536.084 to € 189.044 in the 6 months before vs. after radiofrequency, respectively). These results were confirmed in the subgroup analysis in patients refractory to argon plasma coagulation. CONCLUSIONS Radiofrequency ablation is safe and effective for the treatment of gastric antral vascular ectasia in patients with cirrhosis, including those refractory to argon plasma coagulation. Although the cost of single radiofrequency ablation is relatively high, the cost-analysis demonstrated considerable saving.

Portal hypertension and ascites are two crucial events in the natural history of liver cirrhosis, whose appearance marks a downward shift in the prognosis of the disease. Over the years, several international and national societies have issued clinical practice guidelines for the diagnosis and management of portal hypertension and ascites. The present document addresses the needs of an updated guidance on the clinical management of these conditions. Accordingly, the AISF Governing Board appointed a multi-disciplinary committee of experts for drafting an update of the most recent EASL Clinical Practice Guidelines. The aim of this work was to adapt the EASL recommendations to national regulations and resources, local circumstances and settings, infrastructure, and cost/benefit strategies to avoid duplication of efforts and optimize resource utilization. The committee defined the objectives, the key issues and retrieved the relevant evidence by performing a systematic review of the literature. Finally, the committee members (chosen on the basis of their specific expertise) identified the guidelines’ key questions and developed them following the PICO format (Population, Intervention, Comparison, Outcomes). For each of the PICO questions, the systematic review of the literature was made on the most important scientific databases (Pubmed, Scopus, Embase)

Background Early after surgery, liver transplant (LT) recipients often develop weight gain. Metabolic disorders and cardiovascular disease represent main drivers of morbidity and mortality. Our aim was to identify predictors of atherosclerotic vascular events (AVE) and to assess the impact of AVE on the long-term outcome. Methods We retrospectively analyzed data from patients transplanted between 2000 and 2005 and followed-up in five Italian transplant clinics. Cox Regression analysis was performed to identify predictors of AVE, global mortality, and cardiovascular mortality. Survival analysis was performed using the Kaplan-Meier method. Results We analyzed data from 367 subjects during a median follow-up of 14 years. Thirty-seven post-LT AVE were registered. Patients with AVE more frequently showed pre-LT diabetes mellitus (DM) (48.6 vs 13.9%, p=0.000). In the post-LT period, patients with AVE satisfied criteria of metabolic syndrome in 83.8% vs. 36.7% of subjects without AVE (p=0.000). At multivariate analysis, pre-LT DM independently predicted AVE (HR 2.250, CI 4.848-10.440, p=0.038). Moreover, both pre-LT DM and AVE strongly predicted cardiovascular mortality (HR 5.418, CI 1.060-29.183, p=0.049, and HR 86.097, CI 9.510-779.480, p=0.000, respectively). Conclusions Pre-LT DM is the main risk factor for post-LT AVE. Pre-LT DM and post-LT AVE are strong, long-term predictors of cardiovascular mortality. Patients with pre-LT DM should obtain a personalized follow-up for prevention or early diagnosis of AVE.

Background & Aims: Acute-on-chronic liver failure (ACLF) is characterized by high short-term mortality and systemic inflammation (SI). Recently, different cardiodynamic states were shown to independently predict outcomes in cirrhosis. The relationship between cardiodynamic states, SI, and portal hypertension and their impact on ACLF development remains unclear. The aim of this study was therefore to evaluate the interplay of cardiodynamic state and SI on fatal ACLF development in cirrhosis. Results: At inclusion, hemodynamic measures including cardiac index (CI) and hepatic venous pressure gradient of 208 patients were measured. Patients were followed prospectively for fatal ACLF development (primary endpoint). SI was assessed by proinflammatory markers such as interleukins (ILs) 6 and 8 and soluble IL-33 receptor (sIL-33R). Patients were divided according to CI (4.2 L/min/m2) in hypo- (n = 84), normo- (n = 69) and hyperdynamic group (n = 55). After a median follow-up of 3 years, the highest risk of fatal ACLF was seen in hyperdynamic (35%) and hypodynamic patients (25%) compared with normodynamic (14%) (P =.011). Hyperdynamic patients showed the highest rate of SI. The detectable level of IL-6 was an independent predictor of fatal ACLF development. Conclusions: Cirrhotic patients with hyperdynamic and hypodynamic circulation have a higher risk of fatal ACLF. Therefore, the cardiodynamic state is strongly associated with SI, which is an independent predictor of development of fatal ACLF.

Background The burden of nonalcoholic fatty liver disease (NAFLD) is growing in people living with human immunodeficiency virus (HIV). NAFLD is associated with obesity; however, it can occur in normoweight (lean) patients. We aimed to investigate lean NAFLD in patients living with HIV. Methods We included patients living with HIV mono-infection from 3 prospective cohorts. NAFLD was diagnosed by transient elastography (TE) and defined as controlled attenuation parameter ≥248 dB/m, in absence of alcohol abuse. Lean NAFLD was defined when a body mass index was Results We included 1511 patients, of whom 57.4% were lean. The prevalence of lean NAFLD patients in the whole cohort was 13.9%. NAFLD affected 24.2% of lean patients. The proportions of lean NAFLD patients who were metabolically abnormal or had elevated alanine aminotransferase (ALT) were higher than among those who were lean patients without NAFLD (61.9% vs 48.9% and 36.7% vs 24.2%, respectively). Lean NAFLD patients had a higher prevalence of significant liver fibrosis than lean patients without NAFLD (15.7% vs 7.6%, respectively). After adjusting for sex, ethnicity, hypertension, CD4 cell count, nadir CD4 Conclusions NAFLD affects 1 in 4 lean patients living with HIV mono-infection. Investigations for NAFLD should be proposed in older patients with dyslipidemia and elevated ALT, even if normoweight.

Recent reports suggested that direct acting antivirals (DAAs) might favor hepatocellular carcinoma (HCC). In study 1, we studied the proangiogenic liver microenvironment in 242 DAA‐treated chronic hepatitis C patients with advanced fibrosis. Angiopoietin‐2 (ANGPT2) expression was studied in tissue (cirrhotic and/or neoplastic) from recurrent, de novo, nonrecurrent HCC, or patients never developing HCC. Circulating ANGPT2,vascular endothelial growth factor (VEGF), and C‐reactive protein (CRP) were also measured. In study 2, we searched for factors associated with de novo HCC in 257 patients with cirrhosis of different etiologies enrolled in a dedicated prospective study. Thorough biochemical, clinical, hemodynamic, endoscopic, elastographic, and echo‐Doppler work‐up was performed in both studies. In study 1, no patients without cirrhosis developed HCC. Of 183 patients with cirrhosis, 14 of 28 (50.0%) with previous HCC recurred whereas 21 of 155 (13.5%) developed de novo HCC. Patients with recurrent and de novo HCCs had significantly higher liver fibrosis (LF) scores, portal pressure, and systemic inflammation than nonrecurrent HCC or patients never developing HCC. In recurrent/de novo HCC patients, tumor and nontumor ANGPT2 showed an inverse relationship with portal vein velocity (PVv; r = –0.412, P = 0.037 and r = –0.409, P = 0.047 respectively) and a positive relationship with liver stiffness (r = 0.526, P = 0.007; r = 0.525, P = 0.003 respectively). Baseline circulating VEGF and cirrhotic liver ANGPT2 were significantly related (r = 0.414, P = 0.044). VEGF increased during DAAs, remaining stably elevated at 3‐month follow‐up, when it significantly related with serum ANGPT2 (r = 0.531, P = 0.005). ANGPT2 expression in the primary tumor or in cirrhotic tissue before DAAs was independently related with risk of HCC recurrence (odds ratio [OR], 1.137; 95% confidence interval [CI], 1.044‐1.137; P = 0.003) or occurrence (OR, 1.604; 95% CI, 1.080‐2.382; P = 0.019). In study 2, DAA treatment (OR, 4.770; 95% CI, 1.395‐16.316; P = 0.013) and large varices (OR, 3.857; 95% CI, 1.127‐13.203; P = 0.032) were independent predictors of de novo HCC. Conclusion: Our study indicates that DAA‐mediated increase of VEGF favors HCC recurrence/occurrence in susceptible patients, that is, those with more severe fibrosis and splanchnic collateralization, who already have abnormal activation in liver tissues of neo‐angiogenetic pathways, as shown by increased ANGPT2. (Hepatology 2018; 00:000‐000).

Objective Patients who have undergone transplantation often develop metabolic syndrome (MetS) and de-novo nonalcoholic fatty liver disease (NAFLD). Our aim was to evaluate the impact of metabolic disease on cardiovascular and neoplastic risk and survival. Patients and methods Data from patients who underwent transplantation between 2000 and 2005 in two Italian transplant centers were analyzed. Cox regression analysis was carried out for predictors of de-novo NAFLD and nonalcoholic steatohepatitis (NASH), cardiovascular events, de-novo extrahepatic cancers, and survival. Survival analysis was completed using the Kaplan-Meier method. A P value less than 0.05 was considered significant for all tests. Results De-novo NAFLD was found in one-fifth of 194 patients. Patients with de-novo NAFLD fulfilled the criteria of MetS in 74.4% of cases, while patients without de-novo NAFLD in 29.8% (P=0.000). On multivariate analysis, MetS correlated independently with de-novo NAFLD and this emerged as an independent predictor of cardiovascular events and as a relevant risk factor for solid extrahepatic cancer. Data on smoking habits, which represent a consolidated risk factor for cardiovascular events and cancer in both the general population and patients who have undergone transplantation, are not available. In the subset of histologically proven NASH, it was the strongest predictor of long-term survival (hazard ratio=4.133, 95% confidence interval: 1.385-12.331, P=0.011). Conclusion Post-transplant NAFLD represented a strong risk factor for cardiovascular atherosclerotic disease and solid extrahepatic cancer, whereas de novo histologically proven NASH was an independent predictor of long-term mortality.

Purpose of Review To revise experimental and clinical data supporting a less traditional role of anticoagulation for treating portal hypertension in patients with cirrhosis. Recent Findings Portal hypertension is the main driver of complications such as ascites, variceal hemorrhage, and hepatic encephalopathy, with inflammation as a key component. The traditional view of cirrhosis as a pro-hemorrhagic condition has recently changed, prothrombotic complications being recognized as frequently as the hemorrhagic ones. Several data indicate a close relationship between inflammation, prothrombotic status, worsening of hepatic fibrosis, and portal hypertension both in animal models and in patients with chronic liver disease. These findings indicate that anticoagulation may represent a potent tool to act on fibrogenesis and therefore consequently to treat portal hypertension. All anticoagulants have good to optimal safety profiles and can be used in patients with advanced chronic liver disease with confidence. Summary Anticoagulation has a role as a pleiotropic treatment of portal hypertension in cirrhosis.

Background & aims Anticoagulants are commonly indicated in cirrhotic patients due to high rate of (pro)thrombotic conditions. Low molecular weight heparin (LMWH) is safe in patients with esophageal varices. However, the safety of LMWH is unknown in patients undergoing prophylactic endoscopic variceal ligation (EVL). To define the 4-week risk of bleeding and death after prophylactic EVL in cirrhotic patients continuously treated with LMWH. Methods All EVLs performed at a tertiary Italian Center from 2009 to 2016 were retrospectively reviewed. Patients treated with LMWH were classified as on-LMWH; the remaining as no-LMWH. Endoscopic characteristics at first and index EVL (that preceding an endoscopy either showing a bleeding episode or the absence of further treatable varices) and clinical events within 4 weeks from the procedures were recorded. Results and conclusions Five hundred fifty-three EVLs were performed in 265 patients (in 215 as a primary prophylaxis): 169 EVLs in 80 on-LMWH and 384 in 185 no-LMWH (4.9 ± 1.1 vs 4.8 ± 1.0 bands/session, respectively; P = .796). Six patients bled (2.2%) without between-groups difference (3.8% on-LMWH vs 1.6% no-LMWH, Log-rank P = .291). Large varices with red marks (100% vs 51.4%, P = .032), number of bands (5.6 ± 0.5 vs 4.6 ± 1.2, P = .004), underlying portal vein thrombosis (66.7% vs 23.6%, P = .033), and creatinine (2.2 ± 2.7 vs 1.0 ± 0.8 mg/dL, P = .001) at index EVL were significantly different between bleeders and non-bleeders. Six patients died within 4-week from index EVL, without between-groups difference (2.5% on-LMWH vs 2.2% no-LMWH, Log-rank P = .863). LMWH does not increase the risk of post-procedural bleeding and does not affect survival of cirrhotic patients undergoing prophylactic EVL.

Non-alcoholic fatty liver disease (NAFLD) can be detected in up to 33.6% of inflammatory bowel disease (IBD) patients, often in absence of metabolic risk factors. Nevertheless, most of previous studies on such issue were conducted within the IBD population only. The primary aim of this study was to compare clinical and metabolic features of NAFLD in patients with and without IBD (w/o IBD) and to identify specific NAFLD phenotypes within the IBD population. Among 223 NAFLD patients, 78 patients with IBD were younger compared to 145 without (w/o) IBD, were less likely to have altered liver enzymes, had lower mean body weight, smaller waist circumference and lower body mass index (BMI); at the same time, MetS was more prevalent among patients w/o IBD (56.6 vs. 23.1%, p p = 0.01), compared to mild-to-moderate disease. Independent risk factors for S3 US steatosis in IBD patients at the multivariate logistic regression analysis were: more than 1 IBD relapse per year during disease history (OR 17.3, 95% CI 3.6–84), surgery for IBD (OR 15.1, 95% CI 3.1–73.7) and more extensive intestinal involvement (OR 19.4, 95% CI 3.4–110.9); the ongoing anti-Tumor Necrosis Factor alpha (antiTNFα) therapy was the only independent factor which protect toward the presence of altered liver enzymes (OR 0.15, 95% CI 0–0.8, p = 0.02). In conclusion, NAFLD in IBD patients is different from that in patients w/o IBD, who seem to develop different NAFLD phenotypes according to intestinal disease clinical course. More severe IBD seem to predict the presence of more severe steatosis. Therapy with antiTNFα antibodies could prevent alteration of liver enzymes in such population.

As the authors of the title paper [...]

Background: In patients with difficult peripheral venous access, alternative techniques require expertise and are invasive, expensive, and prone to serious adverse events. This brought us to designing a new venous catheter (JLB® Deltamed, Inc.) for the cannulation of medium and large bore veins; it is echogenic, and available in different lengths (60 / 70 / 80 mm) and Gauges (14 / 16 / 17 / 18). Methods: We led a multi-center observational convenience sampling study to evaluate safety and effectiveness of JLB. Data was collected from June 2015 to February 2018. Inclusion criteria were age ⩾ 18, difficulty in obtaining superficial venous access in the veins of the arm, need for rapid infusion, or patient’s preference. Results: We enrolled 1000 patients, mean age 66.8 years. In total, 951 (95.1%) had the device placed in internal jugular vein, 28 in basilic or cephalic vein, 15 in femoral vein, 5 in axillary vein (infra-clavicular tract), and 1 in the external jugular vein. The procedure was performed by attending physicians or emergency medicine residents under US guidance. Mean procedure time (from disinfection to securing) was approximately 240 s. Mean attempts number was 1.21. Early complications (Conclusion: According to preliminary data, the application of JLB appears to be safe, cost-effective, and rapid to place bedside.

Key Clinical Message Here, we report the unusual case of an ulcerative colitis female patient presenting together with cytomegalovirus infection, pyoderma gangrenosum and a noncaseating lung granuloma, both resistant to immunomodulatory drugs which dramatically obtained a clinical stable remission after restorative proctocolectomy.

In recent years, metabolomics has attracted great scientific attention. The metabolomics methodology might permit a view into transitional phases between healthy liver and nonalcoholic steatohepatitis. Metabolomics can help to analyze the metabolic alterations that play a main role in the progression of nonalcoholic steatohepatitis. Lipid, glucose, amino acid, and bile acid metabolism should be widely studied to understand the complex pathogenesis of nonalcoholic steatohepatitis. The discovery of new biomarkers would be important for diagnosis and staging of liver disease as well as for the assessment of efficacy of new drugs. Here, we review the metabolomics data regarding nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. We analyzed the main studies regarding the application of metabolomics methodology in the complex context of nonalcoholic steatohepatitis, trying to create a bridge from the basic to the clinical aspects.

Background & Aims The main stages of cirrhosis (compensated and decompensated) have been sub-staged based on clinical, endoscopic, and portal pressure (determined by the hepatic venous pressure gradient [HVPG]) features. Vasodilation leading to a hyperdynamic circulatory state is central in the development of a late decompensated stage, with inflammation currently considered a key driver. We aimed to assess hepatic/systemic hemodynamics and inflammation (by C-reactive protein [CRP]) among the different sub-stages of cirrhosis and to investigate their interrelationship and prognostic relevance. Methods A single center, prospective cohort of patients with cirrhosis undergoing per protocol hepatic and right-heart catheterization and CRP measurement, were classified into recently defined prognostic stages (PS) of compensated (PS1: HVPG ≥6 mmHg but 2 ) were created: relatively hypodynamic ( 4.2). Results Of 238 patients, 151 were compensated (PS1 = 25; PS2 = 36; PS3 = 90) and 87 were decompensated (PS4 = 48; PS5 = 39). Mean arterial pressure decreased progressively from PS1 to PS5, cardiac index increased progressively from PS1-to-PS4 but decreased in PS5. HVPG, model for end-stage liver disease (MELD), and CRP increased progressively from PS1-to-PS5. Among compensated patients, age, HVPG, relatively hypodynamic/hyperdynamic state and CRP were predictive of decompensation. Among patients with ascites, MELD, relatively hypodynamic/hyperdynamic state, post-capillary pulmonary hypertension, and CRP were independent predictors of death/liver transplant. Conclusions Our study demonstrates that, in addition to known parameters, cardiopulmonary hemodynamics and CRP are predictive of relevant outcomes, both in patients with compensated and decompensated cirrhosis. Lay summary There are two main stages in cirrhosis, compensated and decompensated, each with a main relevant outcome. In compensated cirrhosis the main relevant outcome is the development of ascites, while in decompensated cirrhosis it is death. Major roles of cardiac dysfunction and systemic inflammation have been hypothesized in the evolution of the disease in decompensated patients. In this study, we have shown that these factors were also involved in the progression from compensated to decompensated stage.

Cirrhosis represents the end stage of chronic liver disease and its transition from a compensated to a decompensated status is mainly driven by portal hypertension and systemic inflammation. Although relevant modifications in the evaluation of the coagulative balance in cirrhosis across its natural history have occurred and alterations in routine indices of hemostasis have lost their role as indicators of the hemorrhagic risk of patients with liver cirrhosis, these are still perceived as prone to bleed when admitted to invasive procedures. This view, which is still present in guidelines addressing the management of bleeding risk, makes preprocedural transfusion of plasma and platelets still an ongoing clinical practice. In this review, we describe the limitations of both bleeding risk assessment in cirrhotic patients admitted to radiologic and endoscopic invasive procedures and evaluate whether preventive strategies indicated by current guidelines can affect the procedure-related hemorrhagic events.

The article The Role of Anticoagulation in Treating Portal Hypertension, written by Laura Turco, Filippo Schepis and Erica Villa, was originally published electronically on the publisher’s internet portal (currently SpringerLink) on 18 June 2018 without open access.

Objective The biological heterogeneity of hepatocellular carcinoma (HCC) makes prognosis difficult. We translate the results of a genome-wide high-throughput analysis into a tool that accurately predicts at presentation tumour growth and survival of patients with HCC.Design Ultrasound surveillance identified HCC in 78 (training set) and 54 (validation set) consecutive patients with cirrhosis. Patients underwent two CT scans 6 weeks apart (no treatment in-between) to determine tumour volumes (V-0 and V-1) and calculate HCC doubling time. Baseline-paired HCC and surrounding tissue biopsies for microarray study (Agilent Whole Human Genome Oligo Microarrays) were also obtained. Predictors of survival were assessed by multivariate Cox model.Results Calculated tumour doubling times ranged from 30 to 621 days (mean, 107 +/- 91 days; median, 83 days) and were divided into quartiles: = 111 days (n= 19). Median survival according to doubling time was significantly lower for the first quartile versus the others (11 vs 41 months, 42, and 47 months, respectively) (p< 0.0001). A five-gene transcriptomic hepatic signature including angiopoietin-2 (ANGPT2), delta-like ligand 4 (DLL4), neuropilin (NRP)/tolloid (TLL)-like 2 (NETO2), endothelial cell-specific molecule-1 (ESM1), and nuclear receptor subfamily 4, group A, member 1 (NR4A1) was found to accurately identify rapidly growing HCCs of the first quartile (ROC AUC: 0.961; 95% CI 0.919 to 1.000; p< 0.0001) and to be an independent factor for mortality (HR: 3.987; 95% CI 1.941 to 8.193, p< 0.0001).Conclusions The hepatic five-gene signature was able to predict HCC growth in individual patient and the consequent risk of death. This implies a role of this molecular tool in the future therapeutic management of patients with HCC.

The Coiled-Coil Domain Containing 80 (CCDC80) gene has been identified as strongly induced in rat thyroid PC CL3 cells immortalized by the adenoviral E1A gene. In human, CCDC80 is a potential oncosoppressor due to its down-regulation in several tumor cell lines and tissues and it is expressed in almost all tissues. CCDC80 has homologous in mouse, chicken, and zebrafish. We cloned the zebrafish ccdc80 and analyzed its expression and function during embryonic development. The in-silico translated zebrafish protein shares high similarity with its mammalian homologous, with nuclear localization signals and a signal peptide. Gene expression analysis demonstrates that zebrafish ccdc80 is maternally and zygotically expressed throughout the development. In particular, ccdc80 is strongly expressed in the notochord and it is under the regulation of the Hedgehog pathway. In this work we investigated the functional effects of ccdc80-loss-of-function during embryonic development and verified its interaction with gadd45β2 in somitogenesis. J. Cell. Physiol. 230: 821–830, 2015. © 2014 Wiley Periodicals, Inc.

The trans jugular intrahepatic Porto systemic shunt (TIPS) is no longer viewed as a salvage therapy or a bridge to liver transplantation and is currently indicated for a number of conditions related to portal hypertension with positive results in survival. Moreover, the availability of self-expandable polytetrafluoroethylene (PTFE)-covered endoprostheses has dramatically improved the long-term patency of TIPS. However, since the last updated International guidelines have been published (year 2009) new evidence have come, which have open the field to new indications and solved areas of uncertainty. On this basis, the Italian Association of the Study of the Liver (AISF), the Italian College of Interventional Radiology—Italian Society of Medical Radiology (ICIR-SIRM), and the Italian Society of Anesthesia, Analgesia and Intensive Care (SIAARTI) promoted a Consensus Conference on TIPS. Under the auspices of the three scientific societies, the consensus process started with the review of the literature by a scientific board of experts and ended with a formal consensus meeting in Bergamo on June 4th and 5th, 2015. The final statements presented here were graded according to quality of evidence and strength of recommendations and were approved by an independent jury. By highlighting strengths and weaknesses of current indications to TIPS, the recommendations of AISF-ICIR-SIRM-SIAARTI may represent the starting point for further studies.

Background Guidelines recommend variceal screening in patients with cirrhosis to identify varices at high risk of bleeding requiring primary prophylaxis. Non-invasive criteria to rule out high-risk varices will avoid unnecessary endoscopies. Recent Baveno VI criteria define patients with compensated cirrhosis in whom endoscopy can be avoided as those with a liver stiffness by transient elastography 150 000/mm3. AIMS: To validate Baveno criteria in two cohorts with a different prevalence of high-risk varices and to determine whether alternate parameters not including liver stiffness would be equal/more accurate in ruling out high-risk varices. Methods Retrospective study evaluating patients with liver stiffness >10 kPa who had liver stiffness and endoscopy within 1 year of each other. Results This study included 161 patients from the US cohort (14 [9%] with high-risk varices) and 101 patients from an Italian cohort (17 [17%] with high-risk varices). Of patients meeting Baveno criteria (41 in the US, 16 in Italy), none had high-risk varices and therefore 26% (US) and 16% (Italy) endoscopies could have been avoided. Sensitivity and negative predictive value were 100%. A stepwise strategy using platelet count >150 000 and MELD=6, increased the number of endoscopies avoided to 54% (US) while maintaining a sensitivity and negative predictive value of 100%. Excellent sensitivity and negative predictive value were validated in the Italian cohort and in another cohort of patients with a clinical diagnosis of cirrhosis. Conclusions This study validates Baveno VI criteria, particularly in sites with a low prevalence of high-risk varices and describes a new accurate strategy that does not include liver stiffness.

Nonalcoholic fatty liver disease (NAFLD) is a common cause of hepatic abnormalities worldwide. Nonalcoholic steatohepatitis (NASH) is part of the spectrum of NAFLD and leads to progressive liver disease, such as cirrhosis and hepatocellular carcinoma. In NASH patient, fibrosis represents the major predictor of liver-related mortality; therefore, it is important to have an early and accurate diagnosis of NASH. The current gold standard for the diagnosis of NASH is still liver biopsy. The development of biomarkers able to predict disease severity, prognosis, as well as response to therapy without the need for a biopsy is the focus of most up-to-date genomic, transcriptomic, proteomic, and metabolomic research. In the future, patients might be diagnosed and treated according to their molecular signatures. In this short review, we discuss how information from genomics, proteomics, and metabolomics contribute to the understanding of NAFLD pathogenesis.

Cirrhosis recurrence is frequent after orthotopic liver transplantation for hepatitis C virus (HCV). Because transplantation causes liver denervation, we hypothesized that the response to propranolol might differ in transplant patients versus nontransplant patients with cirrhosis and portal hypertension. Twenty-one patients with cirrhosis recurrence after orthotopic liver transplantation with portal hypertension were compared to 20 nontransplant patients with cirrhosis, HCV, and portal hypertension, and they were matched by sex, age, presence of varices, and Child-Pugh score. The patients underwent systemic and hepatic hemodynamic measurements at the baseline and 20 minutes after intravenous propranolol (0.15 mg/kg). At the baseline, the transplant patients with cirrhosis had a lower hepatic venous pressure gradient (HVPG) than the nontransplant patients with cirrhosis (14.8 ± 2.9 versus 17.3 ± 4.4 mm Hg, P = 0.03) but a higher mean arterial pressure (MAP; 100.3 ± 12.3 versus 91.8 ± 11.6 mm Hg, P = 0.04) and higher systemic vascular resistance (2253 ± 573 versus 1883 ± 525 dyn/second/cm−5, P = 0.03). There were no differences in the cardiac index (CI). Propranolol significantly decreased HVPG to similar extents in transplant patients and nontransplant patients with cirrhosis (−14.1% ± 8.0% versus −16.9% ± 9.5%, P > 0.99). MAP tended to increase in transplant patients with cirrhosis, whereas it slightly decreased in nontransplant patients (5.1% ± 14.2% versus −4.8% ± 6.4%, P = 0.007); however, the reduction in CI was less marked in transplant patients with cirrhosis (−18.6% ± 7.6% versus −26.9% ± 9.0%, P = 0.005). In conclusion, patients with HCV-related cirrhosis and portal hypertension after orthotopic liver transplantation have lower baseline HVPG values but similar HVPG responses to propranolol infusions in comparison with nontransplant patients with cirrhosis. In contrast to nontransplant patients, propranolol increases the systemic vascular resistance and arterial pressure in transplant patients with cirrhosis and attenuates the fall in CI. Liver Transpl 19:450–456, 2013. © 2013 AASLD.

Patients with cirrhosis present with hemostatic alterations secondary to reduced availability of pro-coagulant and anti-coagulant factors. The net effect of these changes is a rebalanced hemostatic system. The Italian Association of the Study of the Liver (AISF) and the Italian Society of Internal Medicine (SIMI) promoted a consensus conference on the hemostatic balance in patients with cirrhosis. The consensus process started with the review of the literature by a scientific board of experts and ended with a formal consensus meeting in Rome in December 2014. The statements were graded according to quality of evidence and strength of recommendations, and approved by an independent jury. The statements presented here highlight strengths and weaknesses of current laboratory tests to assess bleeding and thrombotic risk in cirrhotic patients, the pathophysiology of hemostatic perturbations in this condition, and outline the optimal management of bleeding and thrombosis in patients with liver cirrhosis.

Background & Aims: Portosystemic encephalopathy (PSE) is a major complication of trans-jugular intrahepatic porto-systemic shunt (TIPS) placement. Most devices are self-expandable polytetrafluoroethylene-covered stent grafts (PTFE-SGs) that are dilated to their nominal diameter (8 or 10 mm). We investigated whether PTFE-SGs dilated to a smaller caliber (under-dilated TIPS) reduce PSE yet maintain clinical and hemodynamic efficacy. We also studied whether under-dilated TIPS self-expand to nominal diameter over time. Methods: We performed a prospective, non-randomized study of 42 unselected patients with cirrhosis who received under-dilated TIPS (7 and 6 mm) and 53 patients who received PTFE-SGs of 8 mm or more (controls) at referral centers in Italy. After completion of this study, dilation to 6 mm became the standard and 47 patients were included in a validation study. All patients were followed for 6 months; Doppler ultrasonography was performed 2 weeks and 3 months after TIPS placement and every 6 months thereafter. Stability of PTFE-SG diameter was evaluated by computed tomography analysis of 226 patients with cirrhosis whose stent grafts increased to 6, 7, 8, 9, or 10 mm. The primary outcomes were incidence of at least 1 episode of PSE grade 2 or higher during follow up, incidence of recurrent variceal hemorrhage or ascites, incidence of shunt dysfunction requiring TIPS recanalization, and reduction in porto-caval pressure gradient. Results: PSE developed in a significantly lower proportion of patients with under-dilated TIPS (27%) than controls (54%) during the first year after the procedure (P =.015), but the proportions of patients with recurrent variceal hemorrhage or ascites did not differ significantly between groups. No TIPS occlusions were observed. These results were confirmed in the validation cohort. In an analysis of self-expansion of stent grafts, during a mean follow-up period of 252 days after placement, none of the PTFE-SGs self-expanded to the nominal diameter in hemodynamically relevant sites (such as portal and hepatic vein vascular walls). Conclusions: In prospective, non-randomized study of patients with cirrhosis, we found under-dilation of PTFE-SGs during TIPS placement to be feasible, associated with lower rates of PSE, and effective.

We have previously reported that the expression of the CL2/CCDC80 gene is downregulated in human papillary thyroid carcinomas, particularly in follicular variants. We have also reported that the restoration of CL2/CCDC80 expression reverted the malignant phenotype of thyroid carcinoma cell lines and that CL2/CCDC80 positively regulated E-cadherin expression, an ability that likely accounts for the role of the CL2/CCDC80 gene in thyroid cancer progression. In order to validate the tumour suppressor role of the CL2/CCDC80 gene in thyroid carcinogenesis we generated cl2/ccdc80 knock-out mice. We found that embryonic fibroblasts from cl2/ccdc80 −/− mice showed higher proliferation rate and lower susceptibility to apoptosis. Furthermore, cl2/ccdc80 −/− mice developed thyroid adenomas and ovarian carcinomas. Finally, ret/PTC1 transgenic mice crossed with the cl2/ccdc80 knock-out mice developed more aggressive thyroid carcinomas compared with those observed in the single ret/PTC1 transgenic mice. Together, these results indicate CL2/CCDC80 as a putative tumour suppressor gene in human thyroid carcinogenesis.

Liver fibrosis and the mechanisms underlying its occurrence have gained increasing attention in recent years, in addition its the unexpected demonstration of its reversibility and of potential novel therapeutic interventions. The occurrence of fibrosis is the result of repeated rounds of liver damage occurring in relation with hepatitis C virus (HCV) and hepatitis B virus (HBV) infections, toxins/drugs, metabolic or autoimmune causes and of the consequent wound healing reactions. When an acute injury occurs in the liver, damaged epithelial and/or endothelial cells release inflammatory mediators