Hepatic Venous Pressure Gradient Measurement Research Articles

Predicting response to non-selective beta-blockers with liver-spleen stiffness and heart rate in patients with liver cirrhosis and high-risk varices.

Non-selective beta-blockers (NSBB) are used for primary prophylaxis in patients with liver cirrhosis and high-risk varices (HRVs). Assessing therapeutic response is challenging due to the invasive nature of hepatic venous pressure gradient (HVPG) measurement. This study aims to define anoninvasive machine-learning basedapproach to determine response to NSBB in patients with liver cirrhosis and HRVs. We conducted a prospective study on a cohort of cirrhotic patients with documented HRVs receiving NSBB treatment. Patients were followed-up with clinical and elastography appointments at 3, 6, and 12months after NSBB treatment initiation. NSBB response was defined as stationary or downstaging variceal grading at the 12-month esophagogastroduodenoscopy (EGD). In contrast, non-response was defined as upstaging variceal grading at the 12-month EGD or at least one variceal hemorrhage episode during the 12-month follow-up. We chose cut-off values for univariate and multivariate model with 100% specificity. According to least absolute shrinkage and selection operator (LASSO) regression, spleen stiffness (SS) and liver stiffness (LS) percentual decrease, along with changes in heart rate (HR) at 3months were the most significant predictors of NSBB response. A decrease > 11.5% in SS, > 16.8% in LS, and > 25.3% in HR was associated with better prediction of clinical response to NSBB. SS percentual decrease showed the highest accuracy (86.4%) with high sensitivity (78.8%) when compared to LS and HR. The multivariate model incorporating SS, LS, and HR showed the highest discrimination and calibration metrics (AUROC = 0.96), with the optimal cut-off of 0.90 (sensitivity 94.2%, specificity 100%, PPV 95.7%, NPV 100%, accuracy 97.5%).

Serum proteomic profiling of patients with compensated advanced chronic liver disease with and without clinically significant portal hypertension.

Portal 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). Consecutive 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. We 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. We 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.

The clinical value of the hepatic venous pressure gradient in patients undergoing hepatic resection for hepatocellular carcinoma with or without liver cirrhosis.

The role of hepatic venous pressure gradient (HVPG) measurement in risk stratification before liver resection is an ongoing area of debate. This study examines the impact of preoperative HVPG levels on overall survival (OS)/time to recurrence (TTR) and postoperative complications after hepatic resection of hepatocellular carcinoma (HCC). Thirty-eight HCC patients undergoing HVPG measurement before liver resection at Cambridge University Hospitals NHS Foundation Trust between January 2014 and April 2022 were retrospectively analysed. Statistical analysis comprised univariable/multivariable Cox/logistic regression to identify risk factors of reduced OS/TTR or 90-day post-resection complications and Kaplan-Meier estimator, log-rank, chi-squared, Fisher's exact, and Mann-Whitney U test, or Student's t-test for survival/subgroup analysis. The median HPVG was 6 (range: 0-14) mmHg. The HVPG was an independent risk factor for poorer TTR in the overall cohort (cut-off: ≥7.5 mmHg (17.18/43.81 months; P = 0.009)). In the subgroup analysis of cirrhotic patients (N = 29 (76%)), HVPG was additionally an independent risk factor for lower OS (cut-off: ≥8.5 mmHg [44.39/76.84 months; P = 0.012]). The HVPG had no impact on OS/TTR in non-cirrhotic patients (N = 9 (24%)), nor was it associated with postoperative complications in any cohort. In conclusion, preoperative HVPG levels are useful predictors for TTR and OS in cirrhotic HCC patients undergoing hepatic resection.

CT perfusion imaging of the liver and the spleen can identify severe portal hypertension.

To determine if hepatic and splenic perfusion parameters are useful in identifying severe portal hypertension (SPH). The study enrolled 52 patients who underwent perfusion CT scan within one week before the hepatic venous pressure gradient (HVPG) measurement. A commercial software package was used for post-processing to generate hepatic and splenic perfusion parameters. Correlations were assessed using Pearson and Spearman rank correlation coefficients. Logistic regression was used to screen predictive parameters of SPH. The cut-off values of parameters for severe portal hypertension were calculated, as well as the sensitivity and specificity. There was a significant difference between SPH and non-severe portal hypertension (NSPH) in blood volume of liver (BVLiver), hepatic arterial fraction (HAF), hepatic arterial perfusion (HAP), portal venous perfusion (PVP), mean slope of increase in spleen (MSISpleen), BVSpleen, blood flow of spleen (BFSpleen), BVSpleen/Liver, and BVSpleen/Liver(P) (p < 0.05). The Spearman correlation coefficient was - 0.541 (p < 0.001) between BVSpleen/Live and HVPG and - 0.568 (p < 0.001) between BVSpleen/Liver(P) and HVPG. Using a BVSpleen/Liver value of 0.780 or BVSpleen/Liver(P) value of 1.061 as the cut-off value for the detection of SPH, the sensitivity and specificity were 94.7% and 72.7%, 100%, and 63.6% respectively. There was a moderate correlation between CT perfusion parameters BVSpleen/Liver, BVSpleen/Liver(P), and HVPG, which may be used to detect severe portal hypertension.

One‐year status of hepatic venous pressure gradient measurement from 85 hospitals in China

AbstractAimsSurveys and research on the applications of the hepatic venous pressure gradient (HVPG) are important for understanding the current status and future development of this technology in China. This article aimed to investigate the status of hepatic venous pressure gradient measurement in China in 2022.MethodsWe investigated the overall status of HVPG technology in China—including hospital distribution, hospital level, annual number of cases, catheters used, average cost, indications, and current challenges by using online questionnaire. By counting the number and percentages of cases of these results, we hope to clarify the current status of HVPG measurements in China.ResultsAccording to the survey, 85 hospitals in China used HVPG technology in 2022 distributed across 29 provinces. A total of 4989 HVPG measurements were performed in all of the surveyed hospitals in 2022, of which 2813 cases (56.4%) were measured alone. The average cost of HVPG measurement was 5646.8 ± 2327.9 CNY. Of the clinical teams who performed the measurements (sometimes multiple per hospital), 94.3% (82/87) used the balloon method, and the majority of the teams (72.4%, 63/87) used embolectomy catheters.ConclusionsThis survey clarified the clinical application status of HVPG in China and confirmed that some medical institutions in China have established a foundation for this technology. It is still necessary to continue promoting and popularizing this technology in the future.

A283 HETEROGENEITY OF TREATMENT RESPONSE TO BETA-BLOCKERS IN THE TREATMENT OF PORTAL HYPERTENSION RELATED TO CIRRHOSIS

Abstract Background Non-selective beta-blockers (BB) improve clinical outcomes in patients with cirrhosis and portal hypertension. However, it has been suggested that only a proportion of patients treated with BB benefit from them. Indeed, patients who achieve a ampersand:003E20% reduction in Hepatic Venous Pressure Gradient (HVPG) with BB have an excellent prognosis, but only 30-50% achieve such response. This has been suggested as a reason for not using BB where no HVPG measurements are available. Aims In this study we aimed to quantify how heterogeneous is the response to BB in patients with cirrhosis, by analyzing trials in which the effects of BB on HVPG were compared with those of placebo. Methods For assessing the potential heterogeneity of treatment response to BB we conducted a meta-analysis of differences in variance between trial arms. The degree of heterogeneity of HVPG response to BB was quantified with the pooled variability ratio (VR) (SD of the HVPG at the end of the trial in the BB group divided by that in the placebo group). Results Our systematic search yielded 18 studies. Figure 1 shows a forest plot with the meta-analysis of the variability ratios (VR) in final HVPG. Pooled VR was 0.99 (95% CI 0.87-1.14). This indicates that there was no evidence for a higher average variability in the final HVPG in the beta-blocker treatment groups as compared to placebo groups, and hence there was no evidence to support that patients with cirrhosis exhibit a heterogeneous response to beta-blockers (i.e. there is no evidence to support that some patients responded to beta-blockers and others did not). Conclusions In conclusion, the analysis of RCTs comparing the HVPG response of beta-blockers with placebo in patients with cirrhosis does not suggest a heterogeneous hemodynamic response to beta-blockers. This, together with the fact that in most RCTs demonstrating the clinical benefits of beta-blockers treatment was not adjusted based on HVPG response, further supports the concept that there is no need to perform portal pressure measurements to guide treatment with beta-blockers. Funding Agencies None

FXR-FGF19 signaling in the gut–liver axis is dysregulated in patients with cirrhosis and correlates with impaired intestinal defence

Background and aimsExperimental 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.MethodsPatients 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.ResultsSystemic 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.ConclusionsFXR-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: NCT03267615Graphical abstractPhysiology of enterohepatic FXR-FGF19 signaling and its regulation in patients with advanced chronic liver disease (ACLD). (FXR) farnesoid X receptor; (FGF19) fibroblast growth factor 19; (BA) bile acids; (c/dACLD) compensated/decompensated advanced chronic liver disease; (FXR) farnesoid X receptor; (SHP) small heterodimer partner; (OST-α/-β) organic solute transporter subunit alpha/beta; (CYP7A1) cholesterol 7 alpha-hydroxylase; (NTCP) Na+-taurocholate cotransporting polypeptide; (CYP8B1) sterol 12-alpha-hydroxylase; (HVPG) hepatic venous pressure gradient; (TJ) tight junctions; (AMP) antimicrobial peptides; (ASBT) Apical Sodium Dependent Bile Acid Transporter; (ZO 1) zonula occludens-1; (OCLN) occluding; (DEFA5) alpha-5-defensin.

Hepatic hemodynamic study: More than just HVPG measurement

Evaluation and staging of liver disease is essential in the clinical decision-making process of liver tumors. The severity of portal hypertension (PH) is the main prognostic factor in advanced liver disease. Performing an accurate hepatic venous pressure gradient (HVPG) measurement is not always possible, especially when veno-venous communications are present. In those complex cases, a refinement in HVPG measurement with a thorough evaluation of each of the components of PH is mandatory. We aimed at describing how some technical modifications and complementary procedures may contribute to an accurate and complete clinical evaluation to improve therapeutic decisions.

Portal hypertension in patients with nonalcoholic fatty liver disease: Current knowledge and challenges.

Portal hypertension (PH) has traditionally been observed as a consequence of significant fibrosis and cirrhosis in advanced non-alcoholic fatty liver disease (NAFLD). However, recent studies have provided evidence that PH may develop in earlier stages of NAFLD, suggesting that there are additional pathogenetic mechanisms at work in addition to liver fibrosis. The early development of PH in NAFLD is associated with hepatocellular lipid accumulation and ballooning, leading to the compression of liver sinusoids. External compression and intra-luminal obstacles cause mechanical forces such as strain, shear stress and elevated hydrostatic pressure that in turn activate mechanotransduction pathways, resulting in endothelial dysfunction and the development of fibrosis. The spatial distribution of histological and functional changes in the periportal and perisinusoidal areas of the liver lobule are considered responsible for the pre-sinusoidal component of PH in patients with NAFLD. Thus, current diagnostic methods such as hepatic venous pressure gradient (HVPG) measurement tend to underestimate portal pressure (PP) in NAFLD patients, who might decompensate below the HVPG threshold of 10 mmHg, which is traditionally considered the most relevant indicator of clinically significant portal hypertension (CSPH). This creates further challenges in finding a reliable diagnostic method to stratify the prognostic risk in this population of patients. In theory, the measurement of the portal pressure gradient guided by endoscopic ultrasound might overcome the limitations of HVPG measurement by avoiding the influence of the pre-sinusoidal component, but more investigations are needed to test its clinical utility for this indication. Liver and spleen stiffness measurement in combination with platelet count is currently the best-validated non-invasive approach for diagnosing CSPH and varices needing treatment. Lifestyle change remains the cornerstone of the treatment of PH in NAFLD, together with correcting the components of metabolic syndrome, using nonselective beta blockers, whereas emerging candidate drugs require more robust confirmation from clinical trials.

HVPG minimally invasive era: exploration based on forearm venous approach

Objective: The transjugular or transfemoral approach is used as a common method for hepatic venous pressure gradient (HVPG) measurement in current practice. This study aims to confirm the safety and effectiveness of measuring HVPG via the forearm venous approach. Methods: Prospective recruitment was conducted for patients with cirrhosis who underwent HVPG measurement via the forearm venous approach at six hospitals in China and Japan from September 2020 to December 2020. Patients' clinical baseline information and HVPG measurement data were collected. The right median cubital vein or basilic vein approach for all enrolled patients was selected. The HVPG standard process was used to measure pressure. Research data were analyzed using SPSS 22.0 statistical software. Quantitative data were used to represent medians (interquartile ranges), while qualitative data were used to represent frequency and rates. The correlation between two sets of data was analyzed using Pearson correlation analysis. Results: A total of 43 cases were enrolled in this study. Of these, 41 (95.3%) successfully underwent HVPG measurement via the forearm venous approach. None of the patients had any serious complications. The median operation time for HVPG detection via forearm vein was 18.0 minutes (12.3~38.8 minutes). This study confirmed that HVPG was positively closely related to Child-Pugh score (r = 0.47, P = 0.002), albumin-bilirubin score (r = 0.37, P = 0.001), Lok index (r = 0.36, P = 0.02), liver stiffness (r = 0.58, P = 0.01), and spleen stiffness (r = 0.77, P = 0.01), while negatively correlated with albumin (r = -0.42, P = 0.006). Conclusion: The results of this multi-centre retrospective study suggest that HVPG measurement via the forearm venous approach is safe and feasible.

Novel serum biomarker of Golgi protein 73 for the diagnosis of clinically significant portal hypertension in patients with compensated cirrhosis.

Hepatic venous pressure gradient (HVPG) is the gold standard for evaluating clinically significant portal hypertension (CSPH). However, reliable noninvasive methods are limited. Our study aims to investigate the diagnostic value of serum Golgi protein 73 (GP73) for CSPH in patients with compensated cirrhosis. The study enrolled 262 consecutive patients with compensated cirrhosis from three centers in China from February 2021 to September 2023, who underwent both serum GP73 tests and HVPG measurements. CSPH was defined as HVPG ≥ 10 mmHg. Diagnostic accuracy was evaluated using the areas under the receiver operating characteristic curve (AUC). The prevalence of CSPH was 56.9% (n = 149). There were significant differences between the CSPH and non-CSPH groups in the median serum GP73 level (126.8 vs. 73.1 ng/mL, p < 0.001). GP73 level showed a significant positive linear correlation with HVPG (r = 0.459, p < 0.001). The AUC for the diagnosis of CSPH using serum GP73 alone was 0.75 (95% confidence interval [CI] 0.68-0.81). Multivariate logistic regression analysis determined that the levels of GP73, platelets and international normalized ratio were independently associated with CSPH. The combination of these three markers was termed "IP73" score with an AUC value of 0.85 (95% CI 0.80-0.89) for CSPH. Using 0 as a cut-off value, the specificity and sensitivity of IP73 score were 77.9% and 81.9%, respectively. The IP73 score offers a novel, simple and noninvasive method of assessing CSPH in patients with compensated cirrhosis. A cut-off value of the IP73 score at 0 can distinguish patients with or without CSPH.

Correlation Between Portal Vein Diameter and Clinical Prognostic Scores in Patients with Liver Cirrhosis: A Cross-sectional Study

Introduction: Patients with liver cirrhosis develop portal hypertension, which leads to complications like splenomegaly, ascites, and oesophageal varices. Hepatic Venous Pressure Gradient (HVPG) measurement, the best available method to measure portal hypertension, is invasive and difficult to perform. Some studies suggest that an increased Portal Vein Diameter (PVD) on ultrasonography indicates portal hypertension and correlates with oesophageal varices. Studies correlating PVD with other complications of portal hypertension, like ascites and spleen size, are scarce. Aim: To correlate ultrasonographically measured PVD with clinical prognostic models: Child-Turcotte-Pugh (CTP) score and Model for End-stage Liver Disease (MELD), as well as with platelet count, in patients with liver cirrhosis. Materials and Methods: This was a cross-sectional study conducted in the Department of General Medicine in collaboration with the Department of Radiodiagnosis at Government Medical Collge, Chandigarh, India, from February 2021 to September 2021 over an eight-month period in a tertiary healthcare centre in North India. A total of 97 patients with cirrhosis, identified based on clinical features supported by laboratory tests and ultrasonography, were included in the study. A 6 mL of blood sample was collected from each patient for haemogram, biochemical tests (liver function tests and renal function tests), and coagulogram. Ultrasonography assessment of PVD, spleen size, and ascites was performed in a supine position using a right subcostal approach, after overnight fasting. The collected data were analysed using relevant statistical tests. Results: The mean age of the study population was 47.39 ± 12.64 years, with 73 (75.3%) males and 24 (24.7%) females. The most common aetiological factor for liver cirrhosis was alcohol, present in 52 (53.6%) patients. The mean PVD was found to be 12.31±2.71 mm. The correlation coefficient of PVD with spleen size was 0.3 with a p-value of 0.004, suggesting a positive correlation. The correlation coefficient of parameters like thrombocytopenia, CTP score, and MELD score was -0.2 (p-value=0.066), 0.1 (p-value=0.463), and 0.0 (p-value=0.725), respectively. Conclusion: Sonographically measured PVD cannot be used as a substitute for the clinical grading and staging of cirrhosis. Only a weak positive correlation was found between PVD and spleen size.

Decreased platelet activation predicts hepatic decompensation and mortality in patients with cirrhosis.

Patients with cirrhosis show alterations in primary haemostasis, 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. We prospectively included 107 cirrhotic patients 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 (aHR 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 (aHR per 100 MFI:0.93 [95%CI:0.87-0.99]; p=0.040). Thromboembolic events occurred in 8 patients (75% non-tumoral 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. 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.

Consensus on clinical application of hepatic venous pressure gradient in China (2023 edition)

Hepatic venous pressure gradient (HVPG) is considered the gold standard for diagnosing clinically significant portal hypertension (CSPH). To further standardize the application of HVPG measurement, the Chinese Portal Hypertension Alliance (CHESS) and the Minimally Invasive Interventional Collaboration Group of the Chinese Society of Gastroenterology have updated the "Consensus on clinical application of hepatic venous pressure gradient in China (2023 edition)". This consensus provides 10 recommendations, with the aim of effectively promoting standardized measurement and the regulated application of HVPG in the field of cirrhotic portal hypertension in China.

Comparison of Inflammatory Cytokine Levels in Hepatic and Jugular Veins of Patients with Cirrhosis

Background. Systemic inflammation with elevated inflammatory cytokines is a hallmark in patients with cirrhosis and the main driver of decompensation. There is insufficient data on whether inflammatory cytokine levels differ between hepatic and jugular veins, which may have implications for further immunological studies. Methods. Blood from the hepatic and jugular veins of 40 patients with cirrhosis was collected during hepatic venous pressure gradient (HVPG) measurements. Serum levels of 13 inflammatory cytokines (IL-1β, Int-α2, Int-γ, TNF-α, MCP-1, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IL-18, IL-23, and IL-33) were quantified by cytometric bead array. Results. Cytokine levels of IFN-α2, IFN-γ, TNF-α, IL-6, IL-8, IL-10, IL-17A, IL-18, IL-23, and IL-33 were significantly elevated in patients with decompensated cirrhosis compared to patients with compensated cirrhosis. When comparing patients with clinically significant portal hypertension (CSPH, HVPG ≥ 10 mmHg) to patients without CSPH, there were significantly enhanced serum levels of IL-6 and IL-18 in the former group. There was no significant difference between cytokine serum levels between blood obtained from the jugular versus hepatic veins. Even in subgroup analyses stratified for an early cirrhosis stage (Child-Pugh (CP) A) or more decompensated stages (CP B/C), cytokine levels were similar. Conclusion. Cytokine levels increase with decompensation and increasing portal hypertension in patients with cirrhosis. There is no relevant difference in cytokine levels between hepatic and jugular blood in patients with cirrhosis.

Methods for assessing portal hypertension

Many researchers and clinicians have taken the value of hepatic venous pressure gradient (HVPG) as an essential prognostic factor in subjects with chronic liver diseases. HVPG ≥ 10 mmHg indicates the presence of clinically significant portal hypertension, the main predictor of the risk of variceal bleeding, hepatic decompensation, and mortality. However, HVPG measurement is invasive and requires high expertise, so its routine use outside tertiary care centers or clinical trials is limited. Clinically significant portal hypertension also might be detected using non-invasive options such as ultrasonography, elastography, magnetic resonance imaging, and indices derived from laboratory parameters. Our review aims to present the feasibility and applicability of HVPG in modern clinical practice in patients with liver cirrhosis, including invasive and non-invasive methods, based on literary sources from the MEDLINE database.

Lower free triiodothyronine (fT3) levels in cirrhosis are linked to systemic inflammation, higher risk of acute-on-chronic liver failure, and mortality

Advanced chronic liver disease (ACLD) may affect thyroid hormone homeostasis. We aimed to analyze the pituitary-thyroid axis in ACLD and the prognostic value of free triiodothyronine (fT3). Patients with ACLD (liver stiffness measurement [LSM] ≥10kPa) undergoing hepatic venous pressure gradient (HVPG) measurement between June 2009 and September 2022 and available fT3 levels were included. Clinical stages of ACLD were defined as follows: probable ACLD (pACLD; LSM ≥10kPa and HVPG ≤5mmHg), S0 (mild portal hypertension [PH]; HVPG6-9mmHg), S1 (clinically significant PH), S2 (clinically significant PH with varices), S3 (past variceal bleeding), S4(past/current non-bleeding hepatic decompensation), and S5 (further decompensation). Among 297 patients with ACLD, 129 were compensated (pACLD, n= 10; S0, n= 33; S1, n= 42; S2, n= 44), whereas 168 were decompensated (S3, n= 12; S4, n= 97; S5, n= 59). Median levels of thyroid-stimulating hormone (TSH) numerically increased with progressive ACLD stage (from 1.2 μIU/ml [pACLD] to 1.5 μIU/ml [S5]; p= 0.152), whereas fT3 decreased (from 3.2pg/ml [pACLD] to 2.5pg/ml [S5]; p <0.001). Free thyroxin levels remained unchanged (p= 0.338). TSH (aB 0.45; p= 0.046) and fT3 (aB -0.17; p= 0.048) were independently associated with systemic C-reactive protein levels. Lower fT3 was linked to higher risk of (further) decompensation (adjusted subdistribution hazard ratio [asHR] 0.60; 95% CI 0.37-0.97; p= 0.037), acute-on-chronic liver failure (asHR 0.19; 95% CI 0.08-0.49; p <0.001) and liver-related death (asHR 0.14; 95% CI 0.04-0.51; p=0.003). Increasing TSH and declining fT3 levels are observed with progressive ACLD stages. The association of TSHand fT3 with systemic inflammation suggests a liver disease-associated non-thyroidal illness syndrome. Lower fT3 levels in patients with ACLD indicate increased risk for decompensation, acute-on-chronic liver failure, and liver-related death. In a large well-characterized cohort of patients with advanced chronic liver disease (ACLD), we found a decline of free triiodothyronine (fT3) throughout the clinical stages of ACLD, paralleled by a numerical increase of thyroid-stimulating hormone (TSH). This suggests a progressive development of a non-thyroidal illness syndrome in association with ACLD severity. Importantly, C-reactive protein independently correlated with TSH and fT3, linking thyroid dysbalance in ACLD to systemic inflammation. Lower fT3 indicated an increased risk for subsequent development of hepatic decompensation, acute-on-chronic liver failure, and liver-related death. Vienna Cirrhosis Study (VICIS; NCT: NCT03267615).

Recent Advances in the Pathogenesis and Clinical Evaluation of Portal Hypertension in Chronic Liver Disease.

In chronic liver disease, hepatic stellate cell activation and degeneration of liver sinusoidal endothelial cells lead to structural changes, which are secondary to fibrosis and the presence of regenerative nodules in the sinusoids, and to functional changes, which are related to vasoconstriction. The combination of such changes increases intrahepatic vascular resistance and causes portal hypertension. The subsequent increase in splanchnic and systemic hyperdynamic circulation further increases the portal blood flow, thereby exacerbating portal hypertension. In clinical practice, the hepatic venous pressure gradient is the gold-standard measure of portal hypertension; a value of ≥10 mm Hg is defined as clinically significant portal hypertension, which is severe and is associated with the risk of liver-related events. Hepatic venous pressure gradient measurement is somewhat invasive, so evidence on the utility of risk stratification by elastography and serum biomarkers is needed. The various stages of cirrhosis are associated with different outcomes. In viral hepatitis-related cirrhosis, viral suppression or elimination by nucleos(t)ide analog or direct-acting antivirals results in recompensation of liver function and portal pressure. However, careful follow-up should be continued, because some cases have residual clinically significant portal hypertension even after achieving sustained virologic response. In this study, we reviewed the current and future prospects for portal hypertension.

Spleen stiffness: a new tool to predict high-risk varices in cirrhotic patients.

Cirrhosis is one of the major causes of morbidity and mortality worldwide. Portal hypertension is the major contributor of cirrhosis-related complications and is defined as a hepatic venous pressure gradient (HVPG)>5mmHg. Measurement of HVPG is an invasive, difficult, and costly procedure. Therefore, it is only performed in specialized centers. Liver stiffness measured with transient elastography is one of the most studied noninvasive markers of portal hypertension, and spleen elastography has recently emerged as an important adjuvant tool. The development of a new probe (100Hz) that more reliably reflect the grade of portal hypertension evaluated by spleen stiffness measurement has improved the accuracy of this technique. The aim of this work was to evaluate the accuracy of spleen stiffness with the new dedicated probe to predict the presence of high-risk varices, as well as to determine the ideal cutoff to predict it. Prospective study of cirrhotic patients admitted to upper endoscopy that were also submitted to liver and spleen elastography with the 100-Hz probe by the same blinded operator in a tertiary center. We included 209 cirrhotic patients, with mean age of 61.9years (±9.9), 77.0% male. The most common etiology was alcoholic liver disease (72.7%). The median value of liver elastography was 25.3 [4.5-75] kPa, and the median value of spleen elastography was 42.4 [7.6-100] kPa. At the cutoff of 53.25kPa, we obtained sensitivity of 100% and specificity of 72.6% to predict high-risk varices, and, according to this cutoff, 133/175 of esophagogastroduodenoscopy could have been spared (76.0%), while according to Baveno guidelines, only 51/175 would have been spared (29.1%). In the era of noninvasive exams, spleen elastography with the 100-Hz probe emerges as an excellent tool for prediction of presence of high-risk varices. At the cutoff of 53.25kPa, spleen elastography avoids upper endoscopy for screening for high-risk varices, promising to be become part of the hepatologists' daily routine.

The impact of transmembrane 6 superfamily 2 (TM6SF2) rs58542926 on liver-related events in patients with advanced chronic liver disease.

Genetic factors such as the transmembrane 6 superfamily 2 (TM6SF2) rs58542926 single nucleotide variant(SNV) modulate the susceptibility for (advanced) chronic liver disease ([A]CLD). However, the impact of this variant in patients who have already progressed to ACLD is unknown. The association between TM6SF2-rs58542926 genotype and liver-related events was evaluated in 938 ACLD patients undergoing hepatic venous pressure gradient (HVPG) measurement. Mean HVPG was 15±7 mmHg and mean UNOS MELD (2016) 11±5 points. Viral hepatitis (n=495, 53%) was the most common cause of ACLD, followed by alcohol-related (ARLD; n=342, 37%) and non-alcoholic fatty liver disease (NAFLD; n=101, 11%). While 754 (80%) patients harboured the TM6SF2 wild-type (C/C), 174 (19%) and 10 (1%) patients had one or two T-alleles. At baseline, patients with at least one TM6SF2 T-allele had more pronounced portal hypertension (HVPG: 16±7 vs. 15±7 mmHg; p=0.031), higher gamma-glutamyl transferase levels (123 [63-229] vs. 97 [55-174] UxL-1; p=0.002), and more commonly hepatocellular carcinoma (17% vs. 12%; p=0.049). Harbouring the TM6SF2 T-allele was associated with the composite endpoint hepatic decompensation/liver transplantation/liver-related death (SHR: 1.44 [95%CI: 1.14-1.83]; p=0.003). This was confirmed in multivariable competing risk regression analyses that were adjusted for severity of portal hypertension and hepatic dysfunction at baseline. The TM6SF2 variant modulates liver disease progression beyond the development of ACLD, as it modifies the risks of hepatic decompensation and liver-related death, independently of baseline liver disease severity.