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BACKGROUND AND AIMS: The role of histamine in advanced chronic liver disease (ACLD) is poorly understood. We investigated plasma histamine levels across ACLD stages and their prognostic value. METHODS: We included patients with evidence of ACLD, defined by portal hypertension (hepatic venous pressure gradient [HVPG] ≥6 mmHg) and/or a liver stiffness measurement by transient elastography ≥10 kPa, who underwent HVPG measurement between 2017 and 2020. Acute-on-chronic liver failure (ACLF) and/or liver-related death were defined as composite endpoint. RESULTS: Of 251 patients, 82.5% had clinically significant portal hypertension (median HVPG: 17 mmHg [interquartile range (IQR) 12-21]) and 135 patients (53.8%) were decompensated at baseline. Median plasma histamine was 8.5 nmol/L (IQR: 6.4-11.5), 37.1% of patients showed elevated values (>9.9 nmol/L). Histamine levels did not differ significantly across Child-Turcotte-Pugh (CTP) stages nor strata of model for end-stage liver disease (MELD) or HVPG. Histamine levels correlated with markers of circulatory dysfunction (i.e. sodium, renin and aldosterone). During a median follow-up of 29.2 months, 68 patients developed ACLF or liver-related death. In univariate as well as in multivariate analysis (adjusting for age, sex, HVPG as well as either MELD, clinical stage, and serum albumin or CTP and serum sodium), elevated histamine levels remained associated with the composite endpoint. CTP-based multivariate model adjusted sub-distribution hazard ratio (asHR): 1.010 (95% CI: 1.004-1.021), p < .001; MELD-based multivariate model asHR: 1.030 (95% CI: 1.017-1.040), p < .001. CONCLUSION: High levels of histamine were linked to circulatory dysfunction in ACLD patients and independently associated with increased risks of ACLF or liver-related death. Further mechanistic studies on the link between histamine signalling and development of hyperdynamic circulation and ACLF are warranted.
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BACKGROUND AND AIMS: Zinc and selenium are essential trace elements involved in important (patho)physiological processes. The prevalence and prognostic implications of zinc and selenium deficiency in patients with advanced chronic liver disease (ACLD) remain unknown. METHODS: We determined serum zinc and selenium concentrations in 309 patients with ACLD undergoing hepatic venous pressure gradient (HVPG) measurement between 2019 and 2022. We evaluated the prevalence of zinc/selenium deficiency and assessed its association with severity of ACLD and liver-related events (LRE, i.e. first/further hepatic decompensation/liver-related death). RESULTS: Among 309 ACLD patients (median: age: 57 [IQR: 50-64], MELD: 11 [IQR: 9-16], HVPG: 17 [IQR: 11-20]), 73% (227) and 63% (195) were deficient in zinc and selenium, respectively. Decompensated (dACLD) patients showed significantly lower serum zinc (median: 48 [IQR: 38-59] vs. compensated, cACLD: 65 [IQR: 54-78], p < 0.001) and selenium levels (median: 4.9 [IQR 4.0-6.2] vs. cACLD: 6.1 [IQR 5.1-7.3], p < 0.001). Significant correlations of zinc/selenium levels were found with MELD (zinc: ρ = -0.498, p < 0.001; selenium: ρ = -0.295, p < 0.001), HVPG (zinc: ρ = -0.400, p < 0.001; selenium: ρ = -0.157, p = 0.006) and liver disease-driving mechanisms (IL6, bile-acid homeostasis). On multivariable analysis, low zinc/selenium levels, age and MELD remained independently associated with LRE. CONCLUSION: Zinc and selenium deficiencies are common in ACLD patients especially with higher MELD and HVPG. Low zinc and selenium levels independently predicted hepatic decompensation and liver-related death. The effect of zinc/selenium supplementation in ACLD should be investigated in future trials.
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BACKGROUND: Obesity impacts the diagnostic accuracy of shear wave elastography (SWE). A deep abdominal ultrasound transducer (DAX) capable of point (pSWE) and two-dimensional (2D)-SWE has recently been introduced to address this issue. METHODS: We performed a prospective study in a cohort of mostly patients with obesity undergoing liver biopsy with a high prevalence of metabolic dysfunction-associate steatotic liver disease (MASLD). Liver stiffness measurement (LSM) was measured using vibration-controlled transient elastography (VCTE), as well as pSWE and 2D SWE on the standard (5C1) and the DAX transducers. RESULTS: We included 129 patients with paired LSM and liver biopsy: median age 44.0 years, 82 (63.6%) women, median BMI: 43.2 kg/m2. Histologic fibrosis stages: F0: N = 55 (42.6%), F1: N = 14 (10.9%), F2: N = 50 (38.8%), F3: N = 2 (1.6%), F4: N = 8 (6.2%). VCTE-LSM failed (N = 13) or were unreliable (IQR/median ≤30% in ≥7.1 kPa, N = 14) in 20.9% of patients. The Pearson correlation of reliable VCTE-LSM with both pSWE and 2D SWE was strong (all >0.78). The diagnostic accuracy for all LSM techniques was poor for significant fibrosis (≥F2, AUC: 0.54-0.63); however, it was good to excellent for advanced fibrosis (≥F3, AUC: 0.87-0.99) and cirrhosis (F4, AUC: 0.86-1.00). In intention-to-diagnose analysis, pSWE on DAX was significantly superior to VCTE-LSM. CONCLUSIONS: pSWE- and 2D-SWE enable the non-invasive identification of advanced fibrosis and cirrhosis in patients with obese MASLD. The use of the DAX transducer for acoustic radiation force imaging (ARFI)-LSM avoids technical failures in an obese population and subsequently offers advantages over VCTE-LSM for the evaluation of fibrosis in an obese MASLD population at risk for fibrosis.
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Técnicas de Imagem por Elasticidade , Cirrose Hepática , Obesidade , Humanos , Técnicas de Imagem por Elasticidade/métodos , Feminino , Masculino , Estudos Prospectivos , Cirrose Hepática/diagnóstico por imagem , Adulto , Pessoa de Meia-Idade , Obesidade/complicações , Biópsia/métodos , Fígado/diagnóstico por imagem , Fígado/patologia , TransdutoresRESUMO
Persistent liver injury triggers a fibrogenic program that causes pathologic remodeling of the hepatic microenvironment (i.e., liver fibrosis) and portal hypertension. The dynamics of gene regulation during liver disease progression and early regression remain understudied. Here, we generated hepatic transcriptome profiles in two well-established liver disease models at peak fibrosis and during spontaneous regression after the removal of the inducing agents. We linked the dynamics of key disease readouts, such as portal pressure, collagen area, and transaminase levels, to differentially expressed genes, enabling the identification of transcriptomic signatures of progressive vs. regressive liver fibrosis and portal hypertension. These candidate biomarkers (e.g., Tcf4, Mmp7, Trem2, Spp1, Scube1, Islr) were validated in RNA sequencing datasets of patients with cirrhosis and portal hypertension, and those cured from hepatitis C infection. Finally, deconvolution identified major cell types and suggested an association of macrophage and portal hepatocyte signatures with portal hypertension and fibrosis area.
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BACKGROUND AND AIMS: The prognostic performance of von Willebrand factor (VWF) may vary across clinical stages of advanced chronic liver disease (ACLD). Therefore, we investigated the evolution of VWF and other biomarkers throughout the full ACLD spectrum and evaluated their stage-specific prognostic utility. METHODS: We retrospectively included Viennese ACLD patients with available information on hepatic venous pressure gradient (HVPG), C-reactive protein (CRP)/VWF levels and outcomes. ACLD stages were defined according to D'Amico et al. We included an external validation cohort from Padua. RESULTS: We observed gradual increases in VWF throughout ACLD stages. In contrast, HVPG levelled off in decompensated ACLD (dACLD), whereas MELD showed only minor changes in the early stages and CRP did not increase until stage 3. VWF was associated with hepatic decompensation/liver-related death in compensated ACLD (cACLD) in a fully adjusted model, while it was not independently predictive of ACLF/liver-related death in dACLD. After backward selection, HVPG/CRP/VWF remained the main predictors of hepatic decompensation/liver-related death in cACLD. Notably, the performance of the non-invasive CRP/VWF-based model was comparable to invasive HVPG-based models (C-index:0.765 ± 0.034 vs. 0.756 ± 0.040). The discriminative ability of the CRP/VWF-based model was confirmed in an external validation cohort using another VWF assay which yielded systematically lower values. CONCLUSION: VWF is the only biomarker that gradually increases across all ACLD stages. It is of particular prognostic value in cACLD, where a CRP/VWF-based model is equivalent to an invasive HVPG-based model. Systematic differences in VWF underline the importance of interlaboratory surveys. Moreover, our findings reinforce the notion that, already in cACLD, inflammation is a key disease-driving mechanism.
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Biomarcadores , Proteína C-Reativa , Fator de von Willebrand , Humanos , Fator de von Willebrand/metabolismo , Fator de von Willebrand/análise , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Biomarcadores/sangue , Proteína C-Reativa/análise , Prognóstico , Idoso , Hepatopatias/sangue , Hepatopatias/mortalidade , Doença Crônica , Adulto , Índice de Gravidade de Doença , Valor Preditivo dos TestesRESUMO
BACKGROUND AND AIMS: Experimental studies linked dysfunctional Farnesoid X receptor (FXR)-fibroblast growth factor 19 (FGF19) signaling to liver disease. This study investigated key intersections of the FXR-FGF19 pathway along the gut-liver axis and their link to disease severity in patients with cirrhosis. METHODS: Patients with cirrhosis undergoing hepatic venous pressure gradient measurement (cohort-I n = 107, including n = 53 with concomitant liver biopsy; n = 5 healthy controls) or colonoscopy with ileum biopsy (cohort-II n = 37; n = 6 controls) were included. Hepatic and intestinal gene expression reflecting FXR activation and intestinal barrier integrity was assessed. Systemic bile acid (BA) and FGF19 levels were measured. RESULTS: Systemic BA and FGF19 levels correlated significantly (r = 0.461; p < 0.001) and increased with cirrhosis severity. Hepatic SHP expression decreased in patients with cirrhosis (vs. controls; p < 0.001), indicating reduced FXR activation in the liver. Systemic FGF19 (r = -0.512, p < 0.001) and BA (r = -0.487, p < 0.001) levels correlated negatively with hepatic CYP7A1, but not SHP or CYP8B1 expression, suggesting impaired feedback signaling in the liver. In the ileum, expression of FXR, SHP and FGF19 decreased in patients with cirrhosis, and interestingly, intestinal FGF19 expression was not linked to systemic FGF19 levels. Intestinal zonula occludens-1, occludin, and alpha-5-defensin expression in the ileum correlated with SHP and decreased in patients with decompensated cirrhosis as compared to controls. CONCLUSIONS: FXR-FGF19 signaling is dysregulated at essential molecular intersections along the gut-liver axis in patients with cirrhosis. Decreased FXR activation in the ileum mucosa was linked to reduced expression of intestinal barrier proteins. These human data call for further mechanistic research on interventions targeting the FXR-FGF19 pathway in patients with cirrhosis. CLINICAL TRIAL NUMBER: NCT03267615.
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Fatores de Crescimento de Fibroblastos , Cirrose Hepática , Fígado , Receptores Citoplasmáticos e Nucleares , Transdução de Sinais , Humanos , Fatores de Crescimento de Fibroblastos/metabolismo , Masculino , Feminino , Cirrose Hepática/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Pessoa de Meia-Idade , Fígado/metabolismo , Ácidos e Sais Biliares/metabolismo , Mucosa Intestinal/metabolismo , Adulto , Idoso , Íleo/metabolismoRESUMO
BACKGROUND AND AIMS: Patients with cirrhosis show alterations in primary hemostasis, yet prognostic implications of changes in platelet activation remain controversial, and assay validity is often limited by thrombocytopenia. We aimed to study the prognostic role of platelet activation in cirrhosis, focusing on bleeding/thromboembolic events, decompensation, and mortality. APPROACH AND RESULTS: We prospectively included 107 patients with cirrhosis undergoing a same-day hepatic venous pressure gradient (HVPG) and platelet activation measurement. Platelet activation was assessed using flow cytometry after protease-activated receptor (PAR)-1, PAR-4, or epinephrine stimulation. Over a follow-up of 25.3 (IQR: 15.7-31.2) months, first/further decompensation occurred in 29 patients and 17 died. More pronounced platelet activation was associated with an improved prognosis, even after adjusting for systemic inflammation, HVPG, and disease severity. Specifically, higher PAR-4-inducible platelet activation was independently linked to a lower decompensation risk [adjusted HR per 100 MFI (median fluorescence intensity): 0.95 (95% CI: 0.90-0.99); p =0.036] and higher PAR-1-inducible platelet activation was independently linked to longer survival [adjusted HR per 100 MFI: 0.93 (95% CI: 0.87-0.99); p =0.040]. Thromboembolic events occurred in eight patients (75% nontumoral portal vein thrombosis [PVT]). Higher epinephrine-inducible platelet activation was associated with an increased risk of thrombosis [HR per 10 MFI: 1.07 (95% CI: 1.02-1.12); p =0.007] and PVT [HR per 10 MFI: 1.08 (95% CI: 1.02-1.14); p =0.004]. In contrast, of the 11 major bleedings that occurred, 9 were portal hypertension related, and HVPG thus emerged as the primary risk factor. CONCLUSIONS: Preserved PAR-1- and PAR-4-inducible platelet activation was linked to a lower risk of decompensation and death. In contrast, higher epinephrine-inducible platelet activation was a risk factor for thromboembolism and PVT.
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BACKGROUND & AIMS: In individuals with compensated advanced chronic liver disease (cACLD), the severity of portal hypertension (PH) determines the risk of decompensation. Invasive measurement of the hepatic venous pressure gradient (HVPG) is the diagnostic gold standard for PH. We evaluated the utility of machine learning models (MLMs) based on standard laboratory parameters to predict the severity of PH in individuals with cACLD. METHODS: A detailed laboratory workup of individuals with cACLD recruited from the Vienna cohort (NCT03267615) was utilised to predict clinically significant portal hypertension (CSPH, i.e., HVPG ≥10 mmHg) and severe PH (i.e., HVPG ≥16 mmHg). The MLMs were then evaluated in individual external datasets and optimised in the merged cohort. RESULTS: Among 1,232 participants with cACLD, the prevalence of CSPH/severe PH was similar in the Vienna (n = 163, 67.4%/35.0%) and validation (n = 1,069, 70.3%/34.7%) cohorts. The MLMs were based on 3 (3P: platelet count, bilirubin, international normalised ratio) or 5 (5P: +cholinesterase, +gamma-glutamyl transferase, +activated partial thromboplastin time replacing international normalised ratio) laboratory parameters. The MLMs performed robustly in the Vienna cohort. 5P-MLM had the best AUCs for CSPH (0.813) and severe PH (0.887) and compared favourably to liver stiffness measurement (AUC: 0.808). Their performance in external validation datasets was heterogeneous (AUCs: 0.589-0.887). Training on the merged cohort optimised model performance for CSPH (AUCs for 3P and 5P: 0.775 and 0.789, respectively) and severe PH (0.737 and 0.828, respectively). CONCLUSIONS: Internally trained MLMs reliably predicted PH severity in the Vienna cACLD cohort but exhibited heterogeneous results on external validation. The proposed 3P/5P online tool can reliably identify individuals with CSPH or severe PH, who are thus at risk of hepatic decompensation. IMPACT AND IMPLICATIONS: We used machine learning models based on widely available laboratory parameters to develop a non-invasive model to predict the severity of portal hypertension in individuals with compensated cirrhosis, who currently require invasive measurement of hepatic venous pressure gradient. We validated our findings in a large multicentre cohort of individuals with advanced chronic liver disease (cACLD) of any cause. Finally, we provide a readily available online calculator, based on 3 (platelet count, bilirubin, international normalised ratio) or 5 (platelet count, bilirubin, activated partial thromboplastin time, gamma-glutamyltransferase, choline-esterase) widely available laboratory parameters, that clinicians can use to predict the likelihood of their patients with cACLD having clinically significant or severe portal hypertension.
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Técnicas de Imagem por Elasticidade , Hipertensão Portal , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/diagnóstico , Hipertensão Portal/complicações , Hipertensão Portal/diagnóstico , Pressão na Veia Porta , Contagem de Plaquetas , BilirrubinaRESUMO
Nonselective beta-blockers are used as prophylaxis for variceal bleeding in patients with advanced chronic liver disease (ACLD). The acute hemodynamic response to intravenous propranolol (i.e., ≥10% reduction in hepatic venous pressure gradient [HVPG]) is linked to a decreased risk of variceal bleeding. In this study, we aimed to investigate the overall prognostic value of an acute response in compensated and decompensated ACLD. We analyzed the long-term outcome of prospectively recruited patients with ACLD following a baseline HVPG measurement with an intraprocedural assessment of the acute hemodynamic response to propranolol. Overall, we included 98 patients with ACLD (mean ± SD age, 56.4 ± 11.5 years; 72.4% decompensated; 88.8% varices; mean ± SD HVPG, 19.9 ± 4.4 mm Hg) who were followed for a median of 9.6 (interquartile range, 6.5-18.2) months. Fifty-seven patients (58.2%) demonstrated an acute hemodynamic response to propranolol that was associated with a decreased risk of variceal bleeding (at 12 months, 3.6% vs. 15% in nonresponder; log-rank, p = 0.038) and hepatic decompensation (at 12 months, 23% vs. 33% in nonresponder; log-rank, p = 0.096). On multivariate analysis, the acute response was an independent predictor of first/further hepatic decompensation (adjusted hazards ratio, 0.31; 95% confidence interval [CI], 0.13-0.70; p = 0.005). Importantly, there was a tendency toward a prolonged transplant-free survival in acute responders compared to nonresponders (34.2; 95% CI, 29.2-39.2 vs. 25.2; 95% CI, 19.8-30.6 months; log-rank, p = 0.191). Conclusions: Patients with ACLD who achieve an acute hemodynamic response to intravenous propranolol experience a lower risk of variceal bleeding and nonbleeding hepatic decompensation events compared to nonresponders. An assessment of the acute hemodynamic response to intravenous propranolol provides important prognostic information in ACLD.
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Varizes Esofágicas e Gástricas , Varizes , Adulto , Idoso , Varizes Esofágicas e Gástricas/tratamento farmacológico , Hemorragia Gastrointestinal/tratamento farmacológico , Hemodinâmica , Humanos , Cirrose Hepática/complicações , Pessoa de Meia-Idade , Propranolol/uso terapêutico , Varizes/complicaçõesRESUMO
Background: Congestion and plasma volume expansion are important features of heart failure, whose prognostic significance has been investigated in a range of surgical and non-surgical settings. The aim of this study was to evaluate the value of the estimated plasma volume status (ePVS) in patients undergoing isolated tricuspid valve surgery. Methods: This study included patients who underwent isolated tricuspid valve surgery at the Vienna General Hospital (Austria) between July 2008 and November 2018. The PVS cut-off was calculated using ROC analysis and Youden's Index. Results: Eighty eight patients (median age: 58 [IQR: 35-70] years; 44.3% male; 75.6% NYHA III/IV; median EuroSCORE II 2.65 [IQR: 1.70-5.10]; 33.0% endocarditis-related regurgitation; 60.2% isolated repair; 39.8% isolated replacement) were included in this study. Patients who died within 1 year following surgery had significantly higher baseline ePVS values than survivors (median ePVS 5.29 [IQR: -1.55-13.55] vs. -3.68 [IQR: -10.92-4.22]; p = 0.005). During a median actuarial follow-up of 3.02 (IQR: 0.36-6.80) years, patients with a preoperative ePVS ≥ -4.17 had a significantly increased mortality (log-rank p = 0.006). Conclusions: ePVS is an easily obtainable risk parameter for patients undergoing isolated tricuspid valve surgery capable of predicting mid- and long-term outcomes after isolated tricuspid valve surgery.
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BACKGROUND AND AIMS: Portal hypertension (PH) and sarcopenia are common in patients with advanced chronic liver disease (ACLD). However, the interaction between PH and sarcopenia and their specific and independent impact on prognosis and mortality has yet to be systematically investigated in patients with ACLD. METHODS: Consecutive patients with ACLD and hepatic venous pressure gradient (HVPG) ≥10 mm Hg with available CT/MRI imaging were included. Sarcopenia was defined by transversal psoas muscle thickness (TPMT) at <12 mm/m in men and <8 mm/m in women at the level of the third lumbar vertebrae. Hepatic decompensation and mortality was recorded during follow-up. RESULTS: Among 203 patients (68% male, age: 55 ± 11, model for end-stage liver disease [MELD]: 12 [9-15]), sarcopenia was observed in 77 (37.9%) and HVPG was ≥20 mm Hg in 98 (48.3%). There was no correlation between TPMT and HVPG (r = .031, P = .66), median HVPG was not different between patients with vs without sarcopenia (P = .211). Sarcopenia was significantly associated with first/further decompensation both in compensated (SHR: 3.05, P = .041) and in decompensated patients (SHR: 1.86, P = .021). Furthermore, sarcopenia (SARC) was a significant predictor of mortality irrespective of HVPG (HVPG < 20-SARC: SHR: 2.25, P = .021; HVPG ≥ 20-SARC: SHR: 3.33, P = .001). On multivariate analysis adjusted for age, HVPG and MELD, sarcopenia was an independent risk factor for mortality (aHR: 1.99, 95% confidence interval: 1.2-3.3, P = .007). CONCLUSION: Sarcopenia has a major impact on clinical outcomes both in compensated and in decompensated ACLD patients. The presence of sarcopenia doubled the risk for mortality independently from the severity of PH.