Hepatofugal portal flow is highly predictive of acute-on-chronic liver failure: A new hemodynamic patho-physiological hypothesis.

BACKGROUND AND AIMS: Acute-on-chronic liver failure (ACLF) is a severe complication of advanced liver disease. A significant number of ACLF patients have not clear precipitating factors. The aim of the study was to investigate the role of alterations in porto-hepatic hemodynamics, especially non-forward portal flow (NFPF), in ACLF and liver-related mortality. METHODS: 233 cirrhotic patients were included in the study with a median follow-up of 24 months. Color-Doppler ultrasound was used to assess portal vein patency, flow direction and significant porto-systemic collaterals (>8 mm). Patients with active cancer, both at baseline and during follow-up and severe non liver-related comorbidities were excluded. ACLF and liver-related mortality were recorded during follow-up. RESULTS: Fifty-six patients (24%) developed ACLF; 24 (10,3%) had baseline NFPF. In survival analysis, NFPF, but not portal vein thrombosis, was independently associated with ACLF development (HR 2.85 95% C.I. [1.49-5.42], p = 0.001) and liver-related mortality (HR 2.24 95% C.I. [1.16-4.28], p = 0.015), even after adjustment for liver disease severity scores, age and etiology of liver disease. CONCLUSION: NFPF is independently associated with ACLF development and liver-related mortality, regardless of etiology, severity disease scores and portal vein thrombosis. Although there is no specific measure to reverse NFPF, patients with NFPF should receive prompt intensive management and urgent prioritization for liver transplantation. CLINICAL TRIAL NUMBER: 2730 CESC.

Cholestatic HCV Cryoglobulinemia: A New Clinical and Pathological Entity before and after Direct-Acting Antiviral Therapies-A Case-Control Study.

Twenty-nine patients with HCV infection (HCV+) and mixed cryoglobulinemia (MC+) were retrospectively selected and matched for age and sex with 31 HCV+ MC- patients. Biomarkers of cholestasis (direct bilirubin, alkaline phosphatase, and gamma-glutamyl transferase), HCV-RNA and genotype, and plasma cryoprecipitates were measured before and after virus eradication; liver histology and plasma cells (aggregation and distribution), observed blinded by two pathologists, were analyzed. Sixty participants (mean age: 56.5; range: 35-77, males: 50%) with HCV infection were enrolled. Cholestasis (≥2 pathologically increased cholestasis biomarkers) was significantly higher in the MC group (p = 0.02) and correlated with cryoglobulinemia (OR 6.52; p = 0.02). At liver histological assessment, plasma cells were significantly increased in the MC+ group (p = 0.004) and tended to form aggregates more than the control group (p = 0.05). At multivariate analysis with MC, age, HCV-RNA, HBV diabetes, and cirrhosis, cholestasis was only significantly correlated to MC (OR 8.30; p < 0.05). In 25% patients, MC persisted after virus eradication with new antiviral treatment. Our study identified for the first time an association between MC, cholestasis, and an increased number of intrahepatic plasma cells in chronic hepatitis C (CHC) patients before virus eradication. Future studies are required to understand how MC contributes to liver damage and how its persistence affects the patients' follow-up after antiviral therapies.

Serological response and breakthrough infection after COVID-19 vaccination in patients with cirrhosis and post-liver transplant.

BACKGROUND: Vaccine hesitancy and lack of access remain major issues in disseminating COVID-19 vaccination to liver patients globally. Factors predicting poor response to vaccination and risk of breakthrough infection are important data to target booster vaccine programs. The primary aim of the current study was to measure humoral responses to 2 doses of COVID-19 vaccine. Secondary aims included the determination of factors predicting breakthrough infection. METHODS: COVID-19 vaccination and Biomarkers in cirrhosis And post-Liver Transplantation is a prospective, multicenter, observational case-control study. Participants were recruited at 4-10 weeks following first and second vaccine doses in cirrhosis [n = 325; 94% messenger RNA (mRNA) and 6% viral vaccine], autoimmune liver disease (AILD) (n = 120; 77% mRNA and 23% viral vaccine), post-liver transplant (LT) (n = 146; 96% mRNA and 3% viral vaccine), and healthy controls (n = 51; 72% mRNA, 24% viral and 4% heterologous combination). Serological end points were measured, and data regarding breakthrough SARS-CoV-2 infection were collected. RESULTS: After adjusting by age, sex, and time of sample collection, anti-Spike IgG levels were the lowest in post-LT patients compared to cirrhosis (p < 0.0001), AILD (p < 0.0001), and control (p = 0.002). Factors predicting reduced responses included older age, Child-Turcotte-Pugh B/C, and elevated IL-6 in cirrhosis; non-mRNA vaccine in AILD; and coronary artery disease, use of mycophenolate and dysregulated B-call activating factor, and lymphotoxin-α levels in LT. Incident infection occurred in 6.6%, 10.6%, 7.4%, and 15.6% of cirrhosis, AILD, post-LT, and control, respectively. The only independent factor predicting infection in cirrhosis was low albumin level. CONCLUSIONS: LT patients present the lowest response to the SARS-CoV-2 vaccine. In cirrhosis, the reduced response is associated with older age, stage of liver disease and systemic inflammation, and breakthrough infection with low albumin level.

Spur cells in liver cirrhosis are predictive of acute-on-chronic liver failure and liver-related mortality regardless of severe anaemia.

Chronic anaemia in advanced liver disease is a frequent finding. The aim was to explore the clinical impact of spur cell anaemia, a rare entity typically associated with end-stage of the disease. One-hundred and nineteen patients (73.9% males) with liver cirrhosis of any etiology were included. Patients with bone marrow diseases, nutrients deficiencies and hepatocellular carcinoma were excluded. In all patients, a blood sample was collected to check for the presence of spur cells on blood smear. A complete blood biochemical panel was recorded together with Child-Pugh (CP) score and Model for End-Stage Liver Disease (MELD) score. For each patients, clinically relevant events, such as acute-on-chronic liver failure (ACLF) and 1 year liver-related mortality, were registered. Patients were then grouped according to the percentage of spur cells at smear (> 5%, 1-5%, < 1%). Severe anaemia was defined as haemoglobin levels lower than 8 g/dL. 9.2% of subjects had > 5% spur cells, only 2 had evidence of haemolysis. In patients with > 5% spur cells, haemoglobin and albumin were lower compared with the other sub-group, while MELD score, CP score, International Normalized Ratio, ferritin, creatinine and unconjugated bilirubin were higher. Patients with more spur cells were more decompensated and developed more frequently ACLF. ACLF and liver-related mortality were significantly and independently associated with the presence of > 5% spur cells but not with baseline severe anaemia. Cirrhotic patients have a fairly high prevalence of spur cells, not always associated with severe haemolytic anaemia. The presence of spur red cells is per se associated with a worse prognosis and, therefore, should be always evaluated to prioritize patients for intensive management and eventually liver transplantation.

Chronic anaemia is a frequent finding in liver cirrhosis and spur cell anaemia has been shown to be an uncommon non-immune haemolytic disease typically related to advanced-liver disease. In our study, spur cell anaemia (spur cells >5%) was found in almost 10% of outpatient cirrhotics and was significantly related to more decompensated disease, higher incidence of ACLF and 1 year liver-related mortality. More importantly, the vast majority of patients with high percentage of spur cells did not have severe anaemia. Therefore, spur cells should be searched for in patients with advanced liver disease by a simple blood smear evaluation, even in the absence of significant anaemia, because of relevant prognostic impact and in order to prioritize patients to intensive management and possibly liver transplantation.

The multi-drug resistant organisms infections decrease during the antimicrobial stewardship era in cirrhotic patients: An Italian cohort study.

BACKGROUND AND PURPOSE: Bacterial infections represent a major cause of morbidity and mortality in cirrhotic patients. Our aim was to assess the incidence of bacterial infections, in particular due to multidrug-resistant organisms (MDROs) before and after the introduction of the antimicrobial stewardship program, "Stewardship Antimicrobial in VErona" (SAVE). In addition, we also analysed the liver complications and the crude mortality during the whole follow up. METHODS: We analysed 229 cirrhotic subjects without previous hospitalization for infections enrolled at the University Verona Hospital from 2017 to 2019 and followed up until December 2021 (mean follow-up 42.7 months). RESULTS: 101 infections were recorded and 31.7% were recurrent. The most frequent were sepsis (24.7%), pneumonia (19.8%), spontaneous bacterial peritonitis (17.8%). 14.9% of infections were sustained by MDROs. Liver complications occurred more frequently in infected patients, and in case of MDROs infections with a significantly higher MELD and Child-Pugh score. In Cox regression analysis, mortality was associated with age, diabetes and bacterial infections episodes (OR 3.30, CI 95%: (1.63-6.70). Despite an increase in total infections over the past three years, a decrease in the incidence rate in MDROs infections was documented concurrently with the introduction of SAVE (IRD 28.6; 95% CI: 4.6-52.5, p = 0.02). CONCLUSIONS: Our study confirms the burden of bacterial infections in cirrhotic patients, especially MDROs, and the strong interconnection with liver complications. The introduction of SAVE decreased MDROs infections. Cirrhotic patients require a closer clinical surveillance to identify colonized patients and avoid the horizontal spread of MDROs in this setting.

Effects of direct-acting antiviral agents on lipid and glucose profile in HCV patients with type 2 diabetes: A real-life Italian experience.

OBJECTIVES: Hepatitis C virus (HCV) infection is associated with an increased risk of type 2 diabetes mellitus (T2DM) and cardiovascular diseases. The impact of HCV eradication on the metabolic profile in diabetic patients treated with direct-acting antiviral agents (DAAs) is not well defined. The aim of our study was to evaluate the effects of DAAs on a lipid and glucose profile in a cohort of diabetic patients with different liver fibrotic stages. METHODS: T2DM patients with active HCV infection were consecutively enrolled in this prospective trial. Glycolipidic status was assessed, before starting DAA treatment (T0) and at 12 months after the beginning of treatment (T1). Liver fibrotic stage was assessed by FibroScan. RESULTS: In all, 131 patients were enrolled and all of them achieved a sustained virologic response. At baseline, no significant differences were found in lipid and glucose profiles in subgroup analysis by liver fibrosis, HCV genotype, and cardiovascular risk factors. At T1, total cholesterol and low-density lipoprotein cholesterol, but not triglycerides, significantly increased irrespective of liver fibrotic stage and baseline anthropometric and clinical profiles, while glycated hemoglobin significantly decreased only in F4 patients. CONCLUSIONS: HCV eradication in diabetic patients is associated with a worsening lipid profile that could impact future cardiovascular risk. A careful global monitoring of cardiovascular risk factors in all diabetic patients after HCV eradication is needed.

Beneficial effects of DAAs on cardiac function and structure in hepatitis C patients with low-moderate liver fibrosis.

Hepatitis C virus (HCV)-related chronic infection has been associated with a higher incidence of cardiovascular diseases. An altered morphology and function of both left and right heart have been described in HCV patients; however, the causality of the association is still debated. Ninety-eight nonobese and nondiabetic HCV patients (59.5 ± 12.0 years; males 52%) with Fibroscan-Transient Elastography assessed low-moderate liver fibrosis that achieved sustained viral response at 12 and 24 weeks after DAAs (direct-acting antivirals) participated. 56 were matched with 52 control subjects for age, sex and cardiovascular risk factors at baseline. A trans-thoracic echocardiography was performed in each subject at baseline (T0) and repeated in all HCV patients after eradication (6 months later eligibility, T1). TNF-α and IL-10 were measured at baseline and at T1. A concentric remodelling of the left heart in HCV participants was identified, whereas tricuspidal annular plane systolic excursion, right indexed atrial volume, right basal ventricular diameter, inferior vena cava diameter and pulmonary arterial pressure were higher in HCV participants compared to matched controls. After virus eradication, left indexed atrial volume and all right cardiac chambers measures were lower than baseline. A significant reduction of TNF-α was shown at T1, while IL-10 did not change. This study shows a concentric remodelling of the left ventricle and structural modifications in the right sections in HCV patients compared to controls. Virus eradication with DAAs was associated with a reduction of the main right atrioventricular parameters indicating a direct involvement of the HCV in cardiac changes.

Real-life effectiveness and safety of sofosbuvir/velpatasvir/voxilaprevir in hepatitis C patients with previous DAA failure.

BACKGROUND & AIMS: Sofosbuvir/velpatasivr/voxilaprevir (SOF/VEL/VOX) is approved for retreatment of patients with HCV and a previous failure on direct-acting antivirals (DAAs), however real-life data are limited. The aim of this study was to assess the effectiveness and safety of SOF/VEL/VOX in a real-life setting. METHODS: All consecutive patients with HCV receiving SOF/VEL/VOX between May-October 2018 in 27 centers in Northern Italy were enrolled. Bridging fibrosis (F3) and cirrhosis (F4) were diagnosed by liver stiffness measurement: >10 and >13 kPa respectively. Sustained virological response (SVR) was defined as undetectable HCV-RNA 4 (SVR4) or 12 (SVR12) weeks after the end-of-treatment. RESULTS: A total of 179 patients were included: median age 57 (18-88) years, 74% males, median HCV-RNA 1,081,817 (482-25,590,000) IU/ml. Fibrosis stage was F0-F2 in 32%, F3 in 21%, F4 in 44%. HCV genotype was 1 in 58% (1b 33%, 1a 24%, 1nc 1%), 2 in 10%, 3 in 23% and 4 in 9%; 82% of patients carried resistance-associated substitutions in the NS3, NS5A or NS5B regions. Patients received SOF/VEL/VOX for 12 weeks, ribavirin was added in 22% of treatment schedules. Undetectable HCV-RNA was achieved by 74% of patients at week 4 and by 99% at week 12. Overall, 162/179 (91%) patients by intention to treat analysis and 162/169 (96%) by per protocol analysis achieved SVR12, respectively; treatment failures included 6 relapsers and 1 virological non-responder. Cirrhosis (p = 0.005) and hepatocellular carcinoma (p = 0.02) were the only predictors of treatment failure. Most frequent adverse events included fatigue (6%), hyperbilirubinemia (6%) and anemia (4%). CONCLUSIONS: SOF/VEL/VOX is an effective and safe retreatment for patients with HCV who have failed on a previous DAA course in a real-life setting. LAY SUMMARY: This is the largest European real-life study evaluating effectiveness and safety of sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) in a large cohort of consecutive patients with hepatitis C virus infection and a prior direct-acting antiviral failure, who were treated within the NAVIGATORE Lombardia and Veneto Networks, in Italy. This study demonstrated excellent effectiveness (98% and 96% sustained virological response rates at week 4 and 12, respectively) and an optimal safety profile of SOF/VEL/VOX. Cirrhosis and hepatocellular carcinoma onset were the only features associated with treatment failure.