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BACKGROUND AND AIM: Type 2 Diabetes mellitus (T2DM), age, and obesity are risk factors for metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to assess the performance of non-invasive tests (NITs) for the diagnosis of metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis in high-risk subjects. METHODS: Multicentre cross-sectional study that included 124 biopsy-proven MASLD in more than 50 years-old patients with overweight/obesity and T2DM. Vibration-controlled transient elastography, Fibrosis-4 index (FIB-4), Non-alcoholic fatty liver disease fibrosis score (NFS), OWLiver Panel (OWLiver DM2 + Metabolomics-Advanced Steatohepatitis Fibrosis Score -MASEF) and FibroScan-AST were performed. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and area under the receiver operating characteristic curve (AUC) were calculated. NITs were assessed individually and in sequential/parallel combinations. RESULTS: 35 (28.2%) patients had early MASH and 66 (53.2%) had MASH with significant fibrosis (at-risk MASH). The OWLiver Panel correctly classified 86.1% as MASH, showing an accuracy, sensitivity, specificity, PPV, and NPV of 0.77, 0.86, 0.35, 0.85, and 0.36, respectively. Class III obesity, diabetes control, or gender did not impact on the performance of the OWLiver Panel (p > 0.1). NITs for at-risk MASH showed an AUC > 0.70 except for NFS. MASEF showed the highest accuracy and NPV for at-risk MASH (AUC 0.77 [0.68-0.85], NPV 72%) and advanced fibrosis (AUC 0.80 [0.71-0.88], NPV 92%). Combinations of NITs for the identification of at-risk MASH did not provide any additional benefit over using MASEF alone. CONCLUSION: One-step screening strategy with the OWLiver Panel has high accuracy to detect MASH and at-risk MASH in high-risk subjects for MASLD.
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BACKGROUND & AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of advanced chronic liver disease (ACLD). Portal hypertension drives hepatic decompensation and is best diagnosed by hepatic venous pressure gradient (HVPG) measurement. Here, we investigate the prognostic value of HVPG in MASLD-related compensated ACLD (MASLD-cACLD). METHODS: This European multicentre study included patients with MASLD-cACLD characterised by HVPG at baseline. Hepatic decompensation (variceal bleeding/ascites/hepatic encephalopathy) and liver-related mortality were considered the primary events of interest. RESULTS: A total of 340 patients with MASLD-cACLD (56.2% male; median age 62 [55-68] years, median MELD 8 [7-9], 71.2% with diabetes) were included. Clinically significant portal hypertension (CSPH: i.e., HVPG ≥10 mmHg) was found in 209 patients (61.5%). During a median follow-up of 41.5 (27.5-65.8) months, 65 patients developed hepatic decompensation with a cumulative incidence of 10.0% after 2 years (2Y) and 30.7% after 5 years (5Y) in those with MASLD-cACLD with CSPH, compared to 2.4% after 2Y and 9.4% after 5Y in patients without CSPH. Variceal bleeding did not occur without CSPH. CSPH (subdistribution hazard ratio [SHR] 5.13; p <0.001) was associated with an increased decompensation risk and a higher HVPG remained an independent risk factor in the multivariable model (adjusted SHR per mmHg: 1.12, p <0.001). Liver-related mortality occurred in 37 patients at a cumulative incidence of 3.3% after 2Y and 21.4% after 5Y in CSPH. Without CSPH, the incidence after 5Y was 0.8%. Accordingly, a higher HVPG was also independently associated with a higher risk of liver-related death (adjusted SHR per mmHg: 1.20, p <0.001). CONCLUSION: HVPG measurement is of high prognostic value in MASLD-cACLD. In patients with MASLD-cACLD without CSPH, the short-term risk of decompensation is very low and liver-related mortality is rare, while the presence of CSPH substantially increases the risk of both. IMPACT AND IMPLICATIONS: While the incidence of compensated advanced chronic liver disease (cACLD) due to metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing worldwide, insights into the impact of clinically significant portal hypertension (CSPH) on the risk of liver-related events in MASLD-cACLD remain limited. Based on the findings of this European multicentre study including 340 MASLD-cACLD patients, we could show that increasing HVPG values and the presence of CSPH in particular were associated with a significantly higher risk of first hepatic decompensation and liver-related mortality. In contrast, the short-term incidence of decompensation in patients with MASLD-cACLD without CSPH was low and the risk of liver-mortality remained negligible. Thus, HVPG measurements can provide important prognostic information for individualised risk stratification in MASLD-cACLD and may help facilitate the study of novel and promising treatment possibilities for MASLD.
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BACKGROUND: Early identification of those with NAFLD activity score ≥ 4 and significant fibrosis (≥F2) or at-risk metabolic dysfunction-associated steatohepatitis (MASH) is a priority as these patients are at increased risk for disease progression and may benefit from therapies. We developed and validated a highly specific metabolomics-driven score to identify at-risk MASH. METHODS: We included derivation (n = 790) and validation (n = 565) cohorts from international tertiary centers. Patients underwent laboratory assessment and liver biopsy for metabolic dysfunction-associated steatotic liver disease. Based on 12 lipids, body mass index, aspartate aminotransferase, and alanine aminotransferase, the MASEF score was developed to identify at-risk MASH and compared to the FibroScan-AST (FAST) score. We further compared the performance of a FIB-4 + MASEF algorithm to that of FIB-4 + liver stiffness measurements (LSM) by vibration-controlled transient elastography (VCTE). RESULTS: The diagnostic performance of the MASEF score showed an area under the receiver-operating characteristic curve, sensitivity, specificity, and positive and negative predictive values of 0.76 (95% CI 0.72-0.79), 0.69, 0.74, 0.53, and 0.85 in the derivation cohort, and 0.79 (95% CI 0.75-0.83), 0.78, 0.65, 0.48, and 0.88 in the validation cohort, while FibroScan-AST performance in the validation cohort was 0.74 (95% CI 0.68-0.79; p = 0.064), 0.58, 0.79, 0.67, and 0.73, respectively. FIB-4+MASEF showed similar overall performance compared with FIB-4 + LSM by VCTE ( p = 0.69) to identify at-risk MASH. CONCLUSION: MASEF is a promising diagnostic tool for the assessment of at-risk MASH. It could be used alternatively to LSM by VCTE in the algorithm that is currently recommended by several guidance publications.
Subject(s)
Elasticity Imaging Techniques , Non-alcoholic Fatty Liver Disease , Humans , Liver/diagnostic imaging , Liver/pathology , Liver Cirrhosis/pathology , Non-alcoholic Fatty Liver Disease/pathology , Fibrosis , Predictive Value of Tests , Biopsy/adverse effectsABSTRACT
BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is characterized by severe systemic inflammation, multi-organ failure and high mortality rates. Its treatment is an urgent unmet need. DIALIVE is a novel liver dialysis device that aims to exchange dysfunctional albumin and remove damage- and pathogen-associated molecular patterns. This first-in-man randomized-controlled trial was performed with the primary aim of assessing the safety of DIALIVE in patients with ACLF, with secondary aims of evaluating its clinical effects, device performance and effect on pathophysiologically relevant biomarkers. METHODS: Thirty-two patients with alcohol-related ACLF were included. Patients were treated with DIALIVE for up to 5 days and end points were assessed at Day 10. Safety was assessed in all patients (n = 32). The secondary aims were assessed in a pre-specified subgroup that had at least three treatment sessions with DIALIVE (n = 30). RESULTS: There were no significant differences in 28-day mortality or occurrence of serious adverse events between the groups. Significant reduction in the severity of endotoxemia and improvement in albumin function was observed in the DIALIVE group, which translated into a significant reduction in the CLIF-C (Chronic Liver Failure consortium) organ failure (p = 0.018) and CLIF-C ACLF scores (p = 0.042) at Day 10. Time to resolution of ACLF was significantly faster in DIALIVE group (p = 0.036). Biomarkers of systemic inflammation such as IL-8 (p = 0.006), cell death [cytokeratin-18: M30 (p = 0.005) and M65 (p = 0.029)], endothelial function [asymmetric dimethylarginine (p = 0.002)] and, ligands for Toll-like receptor 4 (p = 0.030) and inflammasome (p = 0.002) improved significantly in the DIALIVE group. CONCLUSIONS: These data indicate that DIALIVE appears to be safe and impacts positively on prognostic scores and pathophysiologically relevant biomarkers in patients with ACLF. Larger, adequately powered studies are warranted to further confirm its safety and efficacy. IMPACT AND IMPLICATIONS: This is the first-in-man clinical trial which tested DIALIVE, a novel liver dialysis device for the treatment of cirrhosis and acute-on-chronic liver failure, a condition associated with severe inflammation, organ failures and a high risk of death. The study met the primary endpoint, confirming the safety of the DIALIVE system. Additionally, DIALIVE reduced inflammation and improved clinical parameters. However, it did not reduce mortality in this small study and further larger clinical trials are required to re-confirm its safety and to evaluate efficacy. CLINICAL TRIAL NUMBER: NCT03065699.
Subject(s)
Acute-On-Chronic Liver Failure , End Stage Liver Disease , Humans , Acute-On-Chronic Liver Failure/therapy , Acute-On-Chronic Liver Failure/complications , Standard of Care , Prognosis , Renal Dialysis/adverse effects , Liver Cirrhosis/complications , Biomarkers , Inflammation/complicationsABSTRACT
BACKGROUND & AIMS: Alcohol-related hepatitis (AH) encompasses a high mortality. AH might be a concomitant event in patients with acute variceal bleeding (AVB). The current study aimed to assess the prevalence of AH in patients with AVB and to compare the clinical outcomes of AH patients to other alcohol-related liver disease (ALD) phenotypes and viral cirrhosis. METHODS: Multicentre, observational study including 916 patients with AVB falling under the next categories: AH (n = 99), ALD cirrhosis actively drinking (d-ALD) (n = 285), ALD cirrhosis abstinent from alcohol (a-ALD) (n = 227) and viral cirrhosis (n = 305). We used a Cox proportional hazards model to calculate adjusted hazard ratio (HR) of death adjusted by MELD. RESULTS: The prevalence of AH was 16% considering only ALD patients. AH patients exhibited more complications. Forty-two days transplant-free survival was worse among AH, but statistical differences were only observed between AH and d-ALD groups (84 vs. 93%; p = 0.005), when adjusted by MELD no differences were observed between AH and the other groups. At one-year, survival of AH patients (72.7%) was similar to the other groups; when adjusted by MELD mortality HR was better in AH compared to a-ALD (0.48; 0.29-0.8, p = 0.004). Finally, active drinkers who remained abstinent presented better survival, independently of having AH. CONCLUSIONS: Contrary to expected, AH patients with AVB present no worse one-year survival than other patients with different alcohol-related phenotypes or viral cirrhosis. Abstinence influences long-term survival and could explain these counterintuitive results.
Subject(s)
Esophageal and Gastric Varices , Hepatitis, Alcoholic , Humans , Esophageal and Gastric Varices/complications , Gastrointestinal Hemorrhage , Liver Cirrhosis/complications , Hepatitis, Alcoholic/complications , PhenotypeABSTRACT
OBJECTIVE: Non-cirrhotic portal vein cavernoma (PVC) is a cause of portal hypertension (PH) frequently affecting women of childbearing age. Cavernous transformation of the portal vein is frequently associated with prothrombotic disorders and often entails multiple hemodynamic changes, porto-collateral shunt development and thrombopenia, all of which can affect the course of pregnancy. Our aim was to evaluate the risk of PH-related complications and pregnancy outcomes in patients with PVC. METHODS: Retrospective case series study of patients with PVC undergoing pregnancy in a tertiary care hospital. RESULTS: Eight pregnancies fulfilled the eligibility criteria. All patients had a predisposing factor for PVC. One episode of variceal bleeding was reported at week 28. Six cesarean sections were scheduled to avoid labor while two urgent surgeries were indicated due to fetal distress and intrauterine growth restriction (IUGR). In all but one case, anticoagulation was prescribed after delivery. No hemorrhagic or thrombotic complications were reported. There were four cases of IUGR with no case of miscarriage or stillbirth. CONCLUSION: Pregnancy in patients with PVC has an overall favorable outcome albeit a higher risk of PH-derived complications, and IUGR may be expected. Hence, PVC must not be considered a contraindication for pregnancy although larger prospective studies are necessary.
Subject(s)
Esophageal and Gastric Varices , Hypertension, Portal , Hypertension , Pregnancy Complications , Venous Thrombosis , Pregnancy , Humans , Female , Pregnancy Outcome , Portal Vein , Esophageal and Gastric Varices/complications , Retrospective Studies , Venous Thrombosis/etiology , Prospective Studies , Gastrointestinal Hemorrhage/complications , Hypertension, Portal/complications , Hypertension, Portal/surgery , Hypertension/complicationsABSTRACT
Acute renal failure (ARF) development is likely the most relevant event in the natural history of severely decompensated cirrhosis. It is a common complication affecting 20-49% of inpatients with decompensated cirrhosis. Also, its presence is associated with a notable increase in morbidity and mortality, and hampers management of classical cirrhosis decompensations such as ascites or hepatic encephalopathy.
Subject(s)
Hepatic Encephalopathy , Hepatorenal Syndrome , Humans , Hepatorenal Syndrome/diagnosis , Hepatorenal Syndrome/etiology , Hepatorenal Syndrome/therapy , Ascites/etiology , Ascites/therapy , Hepatic Encephalopathy/etiology , Hepatic Encephalopathy/therapy , Inpatients , Liver Cirrhosis/complicationsABSTRACT
Background & Aims: Clinically significant portal hypertension (CSPH) is a landmark in the natural history of cirrhosis, influencing clinical decisions in patients with hepatocellular carcinoma (HCC). Previous small series suggested that splanchnic volume measurements may predict portal hypertension. We aimed to evaluate whether volumetry obtained by standard multidetector computerised tomography (MDCT) can predict CSPH in patients with HCC. Methods: We included 175 patients with HCC, referred for hepatic venous pressure gradient (HVPG) evaluation, in whom contemporary MDCT was available. Liver volume, spleen volume (SV) and liver segmental volume ratio (LSVR: volume of the segments I-III/volume of the segments IV-VIII) were calculated semi-automatically from MDCT. Other non-invasive tests (NITs) were also employed. Results: Volume parameters could be measured in almost 100% of cases with an excellent inter-observer agreement (intraclass correlation coefficient >0.950). SV and LSVR were independently associated with CSPH (HVPG ≥10 mmHg) and did not interact with aetiology. The volume Index (VI), calculated as the product of SV and LSVR, predicted CSPH (AUC 0.83; 95% CI 0.77-0.89). Similar results were observed in an external cohort (n = 23) (AUC 0.87; 95% CI 0.69-1.00). Setting a sensitivity and specificity of 98%, VI could have avoided 35.9% of HVPG measurements. The accuracy of VI was similar to that of other NITs. VI also accurately predicted HVPG greater than 12, 14, 16 and 18 mmHg (AUC 0.81 [95% CI 0.74-0.88], 0.84 [95% CI 0.77-0.91], 0.85 [95% CI 0.77-0.92] and 0.87 [95% CI 0.79-0.94], respectively). Conclusions: Quantification of liver and spleen volumes by MDCT is a simple, accurate and reliable method of CSPH estimation in patients with compensated cirrhosis and HCC. Impact and implications: An increase in portal pressure strongly impacts outcomes after surgery in patients with early hepatocellular carcinoma (HCC). Direct measurement through hepatic vein catheterization remains the reference standard for portal pressure assessment, but its invasiveness limits its application. Therefore, we evaluated the ability of CT scan-based liver and spleen volume measurements to predict portal hypertension in patients with HCC. Our results indicate that the newly described index, based on quantification of liver and spleen volume, accurately predicts portal hypertension. These results suggest that a single imaging test may be used to diagnose and stage HCC, while providing an accurate estimation of portal hypertension, thus helping to stratify surgical risks.
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The aim of this study was to evaluate potential criteria for defining hyperdynamic circulation in patients with cirrhosis according to the severity of ascites and its association with the activation of vasoactive systems and markers of systemic inflammation. Cross-sectional study of patients with cirrhosis and right heart catheter measurement from two different academic centers. We evaluated systemic vascular resistance (SVR)/cardiac output (CO) according to ascites severity. The first substudy evaluated the possible definition, the second validated the findings, and the third evaluated the possible mechanisms. Comparisons were performed by means of t test, Mann-Whitney U test, and analysis of variance. Finally, linear regression curves were adjusted to evaluate the relationship between CO and SVR according to the severity of ascites and compensated or decompensated stage of cirrhosis. The study included 721 patients (substudy 1, n = 437; substudy 2, n = 197; substudy 3, n = 87). Hyperdynamic circulation (HC), defined by absolute cutoffs, had no association with the presence or severity of ascites in the first two cohorts. No association was observed between HC with renin, aldosterone, or markers of bacterial translocation. Comparison of linear regression curves showed a shift of the CO-SVR relationship to the left in patients with refractory ascites (p < 0.001) compared to patients without ascites as well as to patients with decompensated cirrhosis (p = 0.002). Conclusion: HC according to the traditional concept of high CO and low SVR is not always present in ascites. Evaluation of the CO-SVR relationship according to the severity of ascites shows a shift to the left, suggesting that the presence of HC would be defined by this shift, independent of absolute values.
Subject(s)
Ascites , Hemodynamics , Humans , Ascites/diagnosis , Cross-Sectional Studies , Hemodynamics/physiology , Liver Cirrhosis/complications , Vascular Resistance/physiology , BiomarkersABSTRACT
BACKGROUND & AIMS: Non-invasive tests (NITs) for clinically significant portal hypertension (CSPH; hepatic venous pressure gradient [HVPG] ≥10 mmHg) have predominantly been studied in patients with active HCV infection. Investigations after HCV cure are limited and have yielded conflicting results. We conducted a pooled analysis to determine the diagnostic/prognostic utility of liver stiffness measurement (LSM)/platelet count (PLT) in this setting. METHODS: A total of 418 patients with pre-treatment HVPG ≥6 mmHg who achieved sustained virological response (SVR) and underwent post-treatment HVPG measurement were assessed, of whom 324 (HVPG/NIT-cohort) also had paired data on pre-/post-treatment LSM/PLT. The derived LSM/PLT criteria were then validated against the direct endpoint decompensation in 755 patients with compensated advanced chronic liver disease (cACLD) with SVR (cACLD-validation-cohort). RESULTS: HVPG/NIT-cohort: Among patients with cACLD, the pre-/post-treatment prevalence of CSPH was 80%/54%. The correlation between LSM/HVPG increased from pre- to post-treatment (r = 0.45 vs. 0.60), while that of PLT/HVPG remained unchanged. For given LSM/PLT values, HVPG tended to be lower post- vs. pre-treatment, indicating the need for dedicated algorithms. Combining post-treatment LSM/PLT yielded a high diagnostic accuracy for post-treatment CSPH in cACLD (AUC 0.884; 95% CI 0.843-0.926). Post-treatment LSM <12 kPa & PLT >150 G/L excluded CSPH (sensitivity: 99.2%), while LSM ≥25 kPa was highly specific for CSPH (93.6%). cACLD-validation-cohort: the 3-year decompensation risk was 0% in the 42.5% of patients who met the LSM <12 kPa & PLT >150 G/L criteria. In patients with post-treatment LSM ≥25 kPa (prevalence: 16.8%), the 3-year decompensation risk was 9.6%, while it was 1.3% in those meeting none of the above criteria (prevalence: 40.7%). CONCLUSIONS: NITs can estimate the probability of CSPH after HCV cure and predict clinical outcomes. Patients with cACLD but LSM <12 kPa & PLT>150 G/L may be discharged from portal hypertension surveillance if no co-factors are present, while patients with LSM ≥25 kPa require surveillance/treatment. LAY SUMMARY: Measurement of liver stiffness by a specific ultrasound device and platelet count (a simple blood test) are broadly used for the non-invasive diagnosis of increased blood pressure in the veins leading to the liver, which drives the development of complications in patients with advanced liver disease. The results of our pooled analysis refute previous concerns that these tests are less accurate after the cure of hepatitis C virus (HCV) infection. We have developed diagnostic criteria that facilitate personalized management after HCV cure and allow for a de-escalation of care in a high proportion of patients, thereby decreasing disease burden.
Subject(s)
Hepatitis C , Hypertension, Portal , Humans , Hepacivirus , Hypertension, Portal/diagnosis , Hypertension, Portal/etiology , Portal Pressure , Sustained Virologic ResponseABSTRACT
OBJECTIVES: The current study aimed to assess the impact of HIV on the production of anti-HCV antibodies in HCV-infected individuals with advanced HCV-related cirrhosis before and 36 weeks after the sustained virological response (SVR) induced by direct-acting antivirals (DAAs) therapy. METHODS: Prospective study on 62 patients (50 HIV/HCV-coinfected and 12 HCV-monoinfected). Plasma anti-E2 and HCV-nAbs were determined respectively by ELISA and microneutralization assays. RESULTS: At baseline, the HCV-group had higher anti-E2 levels against Gt1a (p = 0.012), Gt1b (p = 0.023), and Gt4a (p = 0.005) than the HIV/HCV-group. After SVR, anti-E2 titers against Gt1a (p < 0.001), Gt1b (p = 0.001), and Gt4a (p = 0.042) were also higher in the HCV-group than HIV/HCV-group. At 36 weeks post-SVR, plasma anti-E2 titers decreased between 1.3 and 1.9-fold in the HIV/HCV-group (p < 0.001) and between 1.5 and 1.8-fold in the HCV-group (p ≤ 0.001). At baseline, the HCV-group had higher titers of HCV-nAbs against Gt1a (p = 0.022), Gt1b (p = 0.002), Gt2a (p < 0.001), and Gt4a (p < 0.001) than the HIV/HCV-group. After SVR, HCV-nAbs titers against Gt1a (p = 0.014), Gt1b (p < 0.001), Gt2a (p = 0.002), and Gt4a (p = 0.004) were also higher in the HCV-group. At 36 weeks post-SVR, HCV-nAbs decreased between 2.6 and 4.1-fold in the HIV/HCV-group (p < 0.001) and between 1.9 and 4.0-fold in the HCV-group (p ≤ 0.001). CONCLUSIONS: HIV/HCV-coinfected patients produced lower levels of broad-spectrum anti-HCV antibodies than HCV-monoinfected patients.
Subject(s)
Coinfection , HIV Infections , Hepatitis C, Chronic , Antibodies, Neutralizing/therapeutic use , Antiviral Agents/therapeutic use , Broadly Neutralizing Antibodies , HIV Infections/complications , HIV Infections/drug therapy , Hepacivirus , Hepatitis C Antibodies/therapeutic use , Hepatitis C, Chronic/drug therapy , Humans , Liver Cirrhosis/drug therapy , Prospective StudiesABSTRACT
BACKGROUND: Patients with a significant decrease in hepatic venous pressure gradient (HVPG) have a considerable reduction of liver complications and higher survival after HCV eradication. OBJECTIVES: To evaluate the association between the baseline blood microbiome and the changes in HVPG after successful direct-acting antiviral (DAA) therapy in patients with HCV-related cirrhosis. METHODS: We performed a prospective study in 32 cirrhotic patients (21 HIV positive) with clinically significant portal hypertension (HVPG ≥10 mmHg). Patients were assessed at baseline and 48 weeks after HCV treatment completion. The clinical endpoint was a decrease in HVPG of ≥20% or HVPG <12 mmHg at the end of follow-up. Bacterial 16S ribosomal DNA was sequenced using MiSeq Illumina technology, inflammatory plasma biomarkers were investigated using ProcartaPlex immunoassays and the metabolome was investigated using GC-MS. RESULTS: During the follow-up, 47% of patients reached the clinical endpoint. At baseline, those patients had a higher relative abundance of Corynebacteriales and Diplorickettsiales order, Diplorickettsiaceae family, Corynebacterium and Aquicella genus and Undibacterium parvum species organisms and a lower relative abundance of Oceanospirillales and Rhodospirillales order, Halomonadaceae family and Massilia genus organisms compared with those who did not achieve the clinical endpoint according to the LEfSe algorithm. Corynebacteriales and Massilia were consistently found within the 10 bacterial taxa with the highest differential abundance between groups. Additionally, the relative abundance of the Corynebacteriales order was inversely correlated with IFN-γ, IL-17A and TNF-α levels and the Massilia genus with glycerol and lauric acid. CONCLUSIONS: Baseline-specific bacterial taxa are related to an HVPG decrease in patients with HCV-related cirrhosis after successful DAA therapy.
Subject(s)
Hepatitis C, Chronic , Hypertension, Portal , Microbiota , Antiviral Agents/therapeutic use , Hepatitis C, Chronic/complications , Hepatitis C, Chronic/drug therapy , Humans , Hypertension, Portal/drug therapy , Hypertension, Portal/etiology , Liver Cirrhosis/complications , Prospective StudiesABSTRACT
BACKGROUND AND PURPOSE: Hepatitis C virus (HCV) infection is associated with neuropsychiatric disturbances that impact on functioning and health-related quality of life (HRQoL). Reversibility at different liver disease stages is unknown, particularly in cirrhosis. We aimed to evaluate cognition, functioning, and HRQoL following HCV eradication at different liver disease stages. METHODS: A random sample (n = 152) of consecutive patients treated with direct-acting antiviral agents (DAAs) between April 2015 and March 2017 were included. A comprehensive neuropsychological assessment, functioning and HRQoL questionnaires were applied at baseline, and 12 and 48 weeks after the end of antivirals. RESULTS: One-hundred thirty-five patients who achieved virological response completed the follow-up, of whom 44 had cirrhosis (27% decompensated). Twenty-one percent had cognitive impairment before starting DAAs (34.1% cirrhotic vs. 14.4% noncirrhotic, p < 0.011). Viral eradication was associated with a decrease in cognitive impairment to 23% of cirrhotic and 6% of noncirrhotic patients (p < 0.05). Interestingly, older patients (B = 0.11, 95% confidence interval [CI] = 0.03-0.19) with baseline cognitive impairment (B = 3.58, 95% CI = 1.54-5.62) were those with higher cognitive benefit, regardless of liver disease. Persistent cognitive impairment was associated with having higher cardiovascular risk, cirrhosis, lower education, and higher anxiety and depression scores. Functioning and HRQoL also improved after eradication but remained worse in the cirrhotic group. CONCLUSIONS: Viral eradication decreases the prevalence of cognitive impairment and improves functioning and HRQoL. Patients with lower brain reserve (older patients) and baseline cognitive impairment may benefit the most. Identification and treatment of HCV patients through screening programs may reduce the burden of cognitive disturbances beyond the prevention of liver disease progression.
Subject(s)
Hepatitis C, Chronic , Hepatitis C , Antiviral Agents/therapeutic use , Cognition , Hepacivirus , Hepatitis C/complications , Hepatitis C/drug therapy , Hepatitis C, Chronic/complications , Hepatitis C, Chronic/drug therapy , Humans , Liver Cirrhosis/complications , Prospective Studies , Quality of LifeABSTRACT
Hepatitis C virus (HCV) cure after all-oral direct-acting antiviral (DAA) therapy greatly improves the liver and immune system. We aimed to assess the impact of this HCV clearance on immune system-related markers in plasma and the gene expression profile in human immunodeficiency virus (HIV)/HCV-coinfected patients with advanced cirrhosis. We performed a prospective study on 33 HIV/HCV-coinfected patients at baseline and 36 weeks after the sustained virological response. Gene expression was evaluated by RNA-seq analysis on peripheral blood mononuclear cells (PBMCs) and plasma biomarkers by multiplex immunoassays. We found a decrease in plasma biomarkers (PD1, PDL1, CXCL10, CXCL8, IL12p70, IL10, and TGFß) and liver disease markers (stiffness measurement (LSM), hepatic venous pressure gradient (HVPG), and transaminases, among others). Furthermore, decreased plasma levels of CXCL8, CXCL10, IL10, and PD1 were associated with reduced LSM values. We also found two upregulated (HAS1 and IRG1) and 15 downregulated (CXCL11, CCL8, CCL7, CCL2, ADARB2, RRAD, MX1, SIGLEC1, IFI44L, IFI44, IFI27, IFI6, IFIT3, IFIT1B, and IFIT1) genes at the end of follow-up, all interferon-stimulated genes (ISGs) grouped into four pathways ("cytokine-cytokine receptor interaction", "viral protein interaction with cytokine and cytokine receptor", "chemokine signaling pathway", and "hepatitis C"). Additionally, the decrease in most of these ISGs was significantly related to reduced LSM and HVPG values. In conclusion, HIV/HCV-coinfected patients with advanced-HCV-related cirrhosis who eradicated HCV following DAA therapy exhibited an improvement in liver disease markers and a significant decrease in plasma biomarkers and gene expression related to antiviral/inflammatory response, particularly in levels of several chemokines and ISGs.
Subject(s)
Antiviral Agents/therapeutic use , Biomarkers/blood , Hepacivirus/genetics , Hepatitis C/drug therapy , Liver Cirrhosis/diagnosis , Aged , Chemokines/blood , Coinfection/drug therapy , Female , Gene Expression , HIV Infections/drug therapy , Hepatitis C/complications , Hepatitis C/virology , Humans , Interferons/blood , Liver Cirrhosis/blood , Liver Cirrhosis/etiology , Liver Function Tests , Male , Middle Aged , Prospective Studies , Sustained Virologic ResponseABSTRACT
BACKGROUND & AIMS: Antibiotic prophylaxis reduces the risk of infection and mortality in patients with cirrhosis and acute variceal bleeding (AVB). This study examines the incidence of, and risk factors for, bacterial infections during hospitalization in patients with AVB on antibiotic prophylaxis. METHODS: A post hoc analysis was performed using the database of an international, multicenter, observational study designed to examine the role of pre-emptive transjugular intrahepatic portosystemic shunts in patients with cirrhosis and AVB. Data were collected on patients with cirrhosis hospitalized for AVB (n = 2,138) from a prospective cohort (October 2013-May 2015) at 34 referral centers, and a retrospective cohort (October 2011-September 2013) at 19 of these centers. The primary outcome was incidence of bacterial infection during hospitalization. RESULTS: A total of 1,656 patients out of 1,770 (93.6%) received antibiotic prophylaxis; third-generation cephalosporins (76.2%) and quinolones (19.0%) were used most frequently. Of the patients on antibiotic prophylaxis, 320 patients developed bacterial infection during hospitalization. Respiratory infection accounted for 43.6% of infections and for 49.7% of infected patients, and occurred early after admission (median 3 days, IQR 1-6). On multivariate analysis, respiratory infection was independently associated with Child-Pugh C (odds ratio [OR] 3.1; 95% CI 1.4-6.7), grade III-IV encephalopathy (OR 2.8; 95% CI 1.8-4.4), orotracheal intubation for endoscopy (OR 2.6; 95% CI 1.8-3.8), nasogastric tube placement (OR 1.7; 95% CI 1.2-2.4) or esophageal balloon tamponade (OR 2.4; 95% CI 1.2-4.9). CONCLUSION: Bacterial infections develop in almost one-fifth of patients with AVB despite antibiotic prophylaxis. Respiratory infection is the most frequent, is an early event after admission, and is associated with advanced liver failure, severe hepatic encephalopathy and use of nasogastric tube, orotracheal intubation for endoscopy or esophageal balloon tamponade. LAY SUMMARY: Bacterial infections develop during hospitalization in close to 20% of patients with acute variceal bleeding despite antibiotic prophylaxis. Respiratory bacterial infections are the most frequent and occur early after admission. Respiratory infection is associated with advanced liver disease, severe hepatic encephalopathy and a need for a nasogastric tube, orotracheal intubation for endoscopy or esophageal balloon tamponade.
Subject(s)
Antibiotic Prophylaxis/standards , Bacterial Infections/etiology , Esophageal and Gastric Varices/complications , Hemorrhage/etiology , Aged , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Antibiotic Prophylaxis/methods , Antibiotic Prophylaxis/statistics & numerical data , Bacterial Infections/drug therapy , Bacterial Infections/epidemiology , Cephalosporins/pharmacology , Cephalosporins/therapeutic use , Esophageal and Gastric Varices/epidemiology , Female , Hemorrhage/epidemiology , Humans , Incidence , Logistic Models , Male , Middle Aged , Multivariate Analysis , Odds Ratio , Quinolones/pharmacology , Quinolones/therapeutic use , Risk FactorsABSTRACT
Background: Eradication of hepatitis C virus (HCV) promotes an improvement in liver disease and the deactivation of the immune system. Here, we aimed to evaluate the changes in liver disease scores and plasma biomarkers following HCV clearance with direct-acting antivirals (DAAs) in HIV-infected patients with advanced HCV-related cirrhosis. Methods: We performed an observational study of 50 patients with advanced cirrhosis who received DAAs therapy. Variables were assessed at baseline and 48 weeks after HCV treatment completion. Epidemiological and clinical data were collected through an online form. Liver stiffness measurement (LSM), hepatic venous pressure gradient (HVPG), and Child-Pugh-Turcotte (CTP) were evaluated by physicians. Plasma biomarkers were measured by multiplex immunoassay. Results: We found significant decreases in severity scores of liver disease [LSM (q-value < 0.001), HVPG (q-value = 0.011), and CTP (q-value = 0.045)] and plasma biomarkers [LBP (q-value < 0.001), IP-10 (q-value < 0.001), IL-8 (q-value < 0.001), IL-18 (q-value < 0.001), IL-1RA (q-value = 0.013), OPG (q-value < 0.001), sVCAM-1 (q-value < 0.001), sICAM-1 (q-value < 0.001), PAI-1 (q-value = 0.001), and VEGF-A (q-value = 0.006)]. We also found a significant direct association between the change in LSM values and the change in values of LBP (q-value < 0.001), IP-10 (q-value < 0.001), MCP-1 (q-value = 0.008), IL-8 (q-value < 0.001), IL-18 (q-value < 0.001), OPG (q-value = 0.004), sVCAM-1 (q-value < 0.001), sICAM-1 (q-value < 0.001), and PAI-1 (q-value = 0.002). For CTP values, we found significant positive associations with IP-10 (q-value = 0.010), IL-6 (q-value = 0.010), IL-1RA (q-value = 0.033), and sICAM-1 (q-value = 0.010). Conclusion: The HCV eradication with all-oral DAAs in HIV/HCV-coinfected patients with advanced cirrhosis promoted an improvement in the severity of advanced cirrhosis and plasma biomarkers (inflammation, coagulopathy, and angiogenesis). The decrease in plasma biomarkers was mainly related to the reduction in LSM values.