A Nutraceutical Rich in Docosahexaenoic Acid Improves Portal Hypertension in a Preclinical Model of Advanced Chronic Liver Disease.
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ABSTRACT:
SUBMITTER: Boyer-Diaz Z
PROVIDER: S-EPMC6835927 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundRotational thromboelastometry (ROTEM) has been studied in patients with advanced chronic liver disease (ACLD) without considering the impact of portal hypertension. We evaluated the influence of the hepatic venous pressure gradient (HVPG) on ROTEM results in patients with ACLD.MethodsCross-sectional study; ACLD patients undergoing HVPG measurement within the prospective Vienna Cirrhosis Study (NCT03267615) underwent concomitant ROTEM testing.ResultsAmong 159 patients (68% male; Child-Pugh-A: 53%, Child-Pugh-B: 34%, Child-Pugh-C: 13%), 21 patients (13%) had a HVPG between 6 and 10 mmHg, 84 patients (53%) between 10 and 19 mmHg, and 54 patients (34%) ≥ 20 mmHg. Child-Pugh-C patients (vs. Child-Pugh-A and vs. Child-Pugh-B patients, respectively) showed longer clot formation time (CFT: median 187 s vs. 122 s vs. 122 s, p = 0.007) and lower maximum clot firmness (MCF: median: 45 mm vs. 56 mm vs. 56 mm, p = 0.002) in extrinsic thromboelastometry (EXTEM), while platelet counts were similar across Child-Pugh stages. In the overall cohort, ROTEM parameters did not differ by severity of portal hypertension. However, among compensated Child-Pugh-A patients, MCF decreased with increasing portal pressure, i.e. in higher HVPG strata (HVPG 9-10 mmHg: median MCF: 59 mm vs. HVPG 10-19 mmHg: 56 mm vs HVPG ≥ 20 mmHg: 54 mm, p = 0.023). Furthermore, patients with short CFT and high MCF in EXTEM had higher levels of lipopolysaccharide-binding protein, C-reactive protein, and procalcitonin, as well as higher leukocyte counts (all p < 0.05).ConclusionsPortal hypertension seems to impact ROTEM results only in compensated Child-Pugh-A patients. Bacterial translocation and systemic inflammation may trigger a procoagulant state in patients with ACLD.
| S-EPMC7803675 | biostudies-literature
Project description:BackgroundLiver stiffness (LS) measured by vibration-controlled transient elastography (VCTE) is influenced by liver fibrosis and hepatic perfusion pressure. VCTE-based controlled attenuation parameter (CAP) is a noninvasive marker for hepatic steatosis (HS).AimsTo investigate the diagnostic performance of CAP in patients with advanced chronic liver disease (ACLD)/portal hypertension (PHT: hepatic venous pressure gradient (HVPG)???6 mmHg).MethodsEighty-eight patients with LS???10 kPa and/or HVPG???6 mmHg who underwent simultaneous liver biopsy, CAP, and HVPG measurement were included. HS was histologically graded according to the modified Brunt classification.ResultsPatient characteristics: Mean MELD:11 (standard derivation [SD]?±?4), median HVPG:16 (interquartile range [IQR]10-19) mmHg, median LS:27.4 (IQR 16.2-48.9) kPa, and mean CAP:221 (SD?±?75) dB/m. According to histology, 47 (53.4%) patients had no HS (S0), 28 (31.8%) had S1, 11 (12.5%) had S2, and 2 (2.3%) had S3. The area under the receiver operating characteristic curve (AUROC) of CAP for diagnosing any HS (S0 vs.???S1) was 0.692 (95% confidence interval [95% CI] 0.582-0.802) in the overall cohort, 0.830 (95% CI 0.637-1.0) in patients with HVPG?<?10 mmHg, and 0.629 (95% CI 0.497-0.761) in patients with clinically significant portal hypertension (CSPH; HVPG???10 mmHg; n?=?69). Using the established cutoff for any HS (248 dB/m), the sensitivity/specificity of CAP was only 48.8%/76.6%, respectively. In contrast, the AUROC and sensitivity/specificity (cutoff 268 dB/m) for diagnosing HS???S2 were 0.842 (95% CI 0.747-0.936) and 84.6%/81.3%, respectively. CAP correlated with the percentage of steatotic hepatocytes (Spearman's ??=?0.402; p???0.001) and showed a weak correlation with liver stiffness (??=?0.225; p?=?0.035).ConclusionsThe diagnostic performance of CAP for any HS seems to be limited in patients with ACLD, if CSPH is present.
| S-EPMC6858384 | biostudies-literature
Project description:IntroductionPortal hypertension (PH) drives the progression of liver cirrhosis to decompensation and death. Hepatic venous pressure gradient (HVPG) measurement is the standard of PH quantification, and HVPG≥10 mmHg defines clinically significant PH (CSPH). We performed proteomics-based serum profiling to search for a proteomic signature of CSPH in patients with compensated advanced chronic liver disease (cACLD).Materials and methodsConsecutive patients with histologically confirmed cACLD and results of HVPG measurements were prospectively included. Serum samples were pooled according to the presence/absence of CSPH and analysed by liquid chromatography-mass spectrometry. Gene set enrichment analysis was performed, followed by comprehensive literature review for proteins identified with the most striking difference between the groups.ResultsWe included 48 patients (30 with, and 18 without CSPH). Protein CD44, involved in the inflammatory response, vascular endothelial growth factor C (VEGF-C) and lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1), both involved in lymphangiogenesis were found solely in the CSPH group. Although identified in both groups, proteins involved in neutrophil extracellular traps (NET) formation, as well as tenascin C, autotaxin and nephronectin which mediate vascular contractility and lymphangiogenesis were more abundant in CSPH.Discussion and conclusionWe propose that altered inflammatory response, including NET formation, vascular contractility and formation of new lymph vessels are key steps in PH development. Proteins such as CD44, VEGF-C, LYVE-1, tenascin C, Plasminogen activator inhibitor 1, Nephronectin, Bactericidal permeability-increasing protein, Autotaxin, Myeloperoxidase and a disintegrin and metalloproteinase with thrombospondin motifs-like protein 4 might be considered for further validation as potential therapeutic targets and candidate biomarkers of CSPH in cACLD.
| S-EPMC11008873 | biostudies-literature
Project description:Study aim: To compare proteomic profiles of patients with compensated advanced liver disease with and without clinically significant portal hypertension (CSPH) and by analyzing differently expressed proteins to identify potential new serum biomarkers for the early diagnosis of CSPH. Subjects and methods: Patients with compensated advanced liver disease will be included in the study. Two groups will be separated based on the presence of CSPH assessed by hepatic vein pressure gradient. High performance liquid chromatography and mass spectrometry will be used to determine the protein composition of the pooled samples. Bioinformatic tools and literature review will be used to analyze the significance and biologic role of the identified proteins. Expected scientific yield: We expect by analyzing differently expressed proteins and biological processes to identify potential biomarkers of CPSH and to provide additional insight to the pathogenesis of CSPH.
2024-02-01 | PXD040807 | Pride
Project description:Background and study aims? Assessment of endoscopic ultrasonography (EUS)-elastography of the liver and spleen may identify patients with portal hypertension secondary to chronic liver disease. We aimed to evaluate use of EUS-elastography of the liver and spleen in identification of portal hypertension in patients with chronic liver disease. Patients and methods? This was a single-center, diagnostic cohort study. Consecutive patients with liver cirrhosis and portal hypertension underwent EUS-elastography of the liver and spleen. Patients without a history of liver disease were enrolled as controls. The primary outcome was diagnostic yield of liver and spleen stiffness measurement via EUS-elastography in prediction of portal hypertension secondary to chronic liver cirrhosis. Cutoff values were defined through Youden's index. Overall accuracy was calculated for parameters with an area under the receiver operating characteristic (AUROC) curve ??80?%. Results? Among the 61 patients included, 32 had cirrhosis of the liver. Liver and spleen stiffness was measured by the strain ratio and strain histogram, with sensitivity/(1 - specificity) AUROC values ??80?%. For identification of patients with cirrhosis and portal hypertension, the liver strain ratio (SR) had a sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 84.3?%, 82.8 %, 84.4?%, and 82.8?%, respectively; the liver strain histogram (SH) had values of 87.5?%, 69.0?%, 75.7?%, and 83.3 %, respectively. EUS elastography of the spleen via the SR reached a sensitivity, specificity, PPV, and NPV of 87.5?%, 69.0?%, 75.7?%, and 83.3?%, respectively, whereas the values of SH were 56.3?%, 89.7?%, 85.7?%, and 65.0?%, respectively. Conclusion? Endoscopic ultrasonographic elastography of the liver and spleen is useful for diagnosis of portal hypertension in patients with cirrhosis.
| S-EPMC7581480 | biostudies-literature
Project description:Portal hypertension (PHT) in advanced chronic liver disease (ACLD) results from increased intrahepatic resistance caused by pathologic changes of liver tissue composition (structural component) and intrahepatic vasoconstriction (functional component). PHT is an important driver of hepatic decompensation such as development of ascites or variceal bleeding. Dysbiosis and an impaired intestinal barrier in ACLD facilitate translocation of bacteria and pathogen-associated molecular patterns (PAMPs) that promote disease progression via immune system activation with subsequent induction of proinflammatory and profibrogenic pathways. Congestive portal venous blood flow represents a critical pathophysiological mechanism linking PHT to increased intestinal permeability: The intestinal barrier function is affected by impaired microcirculation, neoangiogenesis, and abnormal vascular and mucosal permeability. The close bidirectional relationship between the gut and the liver has been termed "gut-liver axis". Treatment strategies targeting the gut-liver axis by modulation of microbiota composition and function, intestinal barrier integrity, as well as amelioration of liver fibrosis and PHT are supposed to exert beneficial effects. The activation of the farnesoid X receptor in the liver and the gut was associated with beneficial effects in animal experiments, however, further studies regarding efficacy and safety of pharmacological FXR modulation in patients with ACLD are needed. In this review, we summarize the clinical impact of PHT on the course of liver disease, discuss the underlying pathophysiological link of PHT to gut-liver axis signaling, and provide insight into molecular mechanisms that may represent novel therapeutic targets.
| S-EPMC6815800 | biostudies-literature
Project description:Non-alcoholic steatohepatitis (NASH) is a common chronic liver disorder in developed countries, with the associated clinical complications driven by portal hypertension (PH). PH may precede fibrosis development, probably due to endothelial dysfunction at early stages of the disease. Our aim was to characterize liver sinusoidal endothelial cell (LSEC) dedifferentiation/capillarization and its contribution to PH in NASH, together with assessing statins capability to revert endothelial function improving early NASH stages. Sprague-Dawley rats were fed with high fat glucose-fructose diet (HFGFD), or control diet (CD) for 8 weeks and then treated with simvastatin (sim) (10 mg·kg-1·day-1), atorvastatin (ato) (10 mg·kg-1·day-1) or vehicle during 2 weeks. Biochemical, histological and hemodynamic determinations were carried out. Sinusoidal endothelial dysfunction was assessed in individualized sorted LSEC and hepatic stellate cells (HSC) from animal groups and in whole liver samples. HFGFD rats showed full NASH features without fibrosis but with significantly increased portal pressure compared with CD rats (10.47 ± 0.37 mmHg vs 8.30 ± 0.22 mmHg; p < 0.001). Moreover, HFGFD rats showed a higher percentage of capillarized (CD32b-/CD11b-) LSEC (8% vs 1%, p = 0.005) showing a contractile phenotype associated to HSC activation. Statin treatments caused a significant portal pressure reduction (sim: 9.29 ± 0.25 mmHg, p < 0.01; ato: 8.85 ± 0.30 mmHg, p < 0.001), NASH histology reversion, along with significant recovery of LSEC differentiation and a regression of HSC activation to a more quiescent phenotype. In an early NASH model without fibrosis with PH, LSEC transition to capillarization and HSC activation are reverted by statin treatment inducing portal pressure decrease and NASH features improvement.
| S-EPMC6934751 | biostudies-literature
Project description:Background and aimsKinin B1 receptors (B1Rs) are implicated in the pathogenesis of fibrosis. This study examined the anti-fibrotic effects of B1R blockade with BI 113823 in two established mouse models of hepatic fibrosis induced by intraperitoneal carbon tetrachloride (CCl4) injection or bile duct ligation (BDL). The mechanisms underlying the protection afforded by B1R inhibition were examined using human peripheral blood cells and LX2 human hepatic stellate cells (HSCs).MethodsFibrotic liver diseases were induced in mice by intraperitoneal carbon tetrachloride (CCl4) injection for 6 weeks, and by bile duct ligation (BDL) for 3 weeks, respectively. Mice received daily treatment of vehicle or BI 113823 (B1R antagonist) from onset of the experiment until the end of the study.ResultsB1Rs were strongly induced in fibrotic mouse liver. BI 113823 significantly attenuated liver fibrosis and portal hypertension (PH), and improved survival in both CCl4 and BDL mice. BI 113823 significantly reduced the expression of fibrotic proteins α-SMA, collagens 1, 3, 4, and profibrotic growth factors PDGF, TGFβ, CTGF, VEGF, proliferating cell nuclear antigen; and reduced hepatic Akt phosphorylation in CCl4- and BDL-induced liver fibrosis. BI 113823 also reduced expression of Cytokines IL-1, IL-6; chemokines MCP-1, MCP-3 and infiltration of inflammatory cells; and inhibited human monocyte and neutrophil activation, transmigration, TNF-α & MPO production in vitro. BI 113823 inhibited TGF-β and B1R agonist-stimulated human-HSC activation, contraction, proliferation, migration and fibrosis protein expression, and inhibited activation of PI3K/Akt signalling pathway.ConclusionsB1Rs merits consideration as a novel therapeutic target for chronic liver fibrosis and PH.
| S-EPMC9746183 | biostudies-literature
Project description:Background and Aims:Angiogenesis is critically involved in the development of liver fibrosis, portal hypertension (PHT) and hepatocellular carcinoma (HCC). Regorafenib is a novel second-line therapy for HCC, but might also be beneficial in fibrosis and PHT even in absence of HCC. This study investigated the effects of regorafenib in experimental models without HCC. Methods:Fibrosis (in vivo and in vitro), inflammation, liver damage (aminotransferases), angiogenesis (matrigel implantation) and in vivo systemic and portal hemodynamics were assessed in different mouse and rat models (bile duct ligation, CCl4, partial portal vein ligation) after acute and chronic treatment with regorafenib. Results:Long-term treatment with regorafenib improved portal hypertension most likely due to blunted angiogenesis, without affecting fibrosis progression or regression. Interestingly, acute administration of regorafenib also ameliorated portal hemodynamics. Although regorafenib treatment led to hepatotoxic side effects in long-term treated fibrotic animals, in partial portal vein ligated rats, no liver toxicity due to regorafenib was observed. Discussion:Regorafenib might be especially suitable as therapy in patients with PHT and preserved liver function.
| S-EPMC6281422 | biostudies-literature
Project description:BackgroundKeratins (Ks) represent tissue-specific proteins. K18 is produced in hepatocytes while K19, the most widely used ductular reaction (DR) marker, is found in cholangiocytes and hepatic progenitor cells. K18-based serum fragments are commonly used liver disease predictors, while K19-based serum fragments detected through CYFRA21-1 are established tumor but not liver disease markers yet. Since DR reflects the severity of the underlying liver disease, we systematically evaluated the usefulness of CYFRA21-1 in different liver disease severities and etiologies.MethodsHepatic expression of ductular keratins (K7/K19/K23) was analyzed in 57 patients with chronic liver disease (cohort i). Serum CYFRA21-1 levels were measured in 333 Austrians with advanced chronic liver disease (ACLD) of various etiologies undergoing hepatic venous pressure gradient (HVPG) measurement (cohort ii), 231 French patients with alcoholic cirrhosis (cohort iii), and 280 hospitalized Germans with decompensated cirrhosis of various etiologies (cohort iv).Results(i) Hepatic K19 levels were comparable among F0-F3 fibrosis stages, but increased in cirrhosis. Hepatic K19 mRNA strongly correlated with the levels of other DR-specific keratins. (ii) In ACLD, increased serum CYFRA21-1 associated with the presence of clinically significant portal hypertension (CSPH; HVPG ≥ 10 mmHg) (OR = 5.87 [2.95-11.68]) and mortality (HR = 3.02 [1.78-5.13]; median follow-up 22 months). (iii) In alcoholic cirrhosis, elevated serum CYFRA21-1 indicated increased risk of death/liver transplantation (HR = 2.59 [1.64-4.09]) and of HCC (HR = 1.74 [1.02-2.96]) over the long term (median follow-up 73 months). (iv) In decompensated cirrhosis, higher serum CYFRA21-1 predicted 90-day mortality (HR = 2.97 [1.92-4.60]) with a moderate accuracy (AUROC 0.64), independently from established prognostic scores.ConclusionsHepatic K19 mRNA and serum CYFRA21-1 levels rise in cirrhosis. Increased CYFRA21-1 levels associate with the presence of CSPH and reliably indicate mortality in the short and long term independently of conventional liver biochemistry markers or scoring systems. Hence, the widely available serum CYFRA21-1 constitutes a novel, DR-related marker with prognostic implications in patients with different settings of advanced liver disease.
| S-EPMC7661160 | biostudies-literature