Liver cirrhosis represents the final common pathway for a multitude of chronic liver diseases and is a major cause of morbidity and mortality worldwide [1]. The primary driver of clinical complications in cirrhosis is the development of portal hypertension (PHT), a syndrome defined by a pathological increase in pressure within the portal venous system [2]. The consequences of PHT, including the formation of gastroesophageal varices, ascites, and hepatic encephalopathy, mark the transition from a compensated to a decompensated state, which is associated with a dramatically worsened prognosis [3]. The accurate quantification of portal pressure is therefore fundamental to the management of cirrhotic patients. The hepatic venous pressure gradient (HVPG), determined by the difference between the wedged hepatic venous pressure (WHVP) and the free hepatic venous pressure (FHVP), is recognized as the gold-standard method for assessing the severity of portal hypertension in patients with cirrhosis [4]. This minimally invasive procedure provides a precise and reproducible measurement that directly reflects the sinusoidal portal pressure. Specific HVPG thresholds have been established as critical prognostic markers. An HVPG of ≥5 mmHg defines the presence of portal hypertension, while a value of ≥10 mmHg indicates clinically significant portal hypertension (CSPH), the point at which complications such as varices begin to develop [5]. Higher thresholds, such as ≥12 mmHg and ≥16 mmHg, are associated with an increased risk of variceal hemorrhage and mortality, respectively [6]. Beyond its role in staging, HVPG is a vital tool for assessing therapeutic response. A reduction in HVPG by ≥20% from baseline or to a value <12 mmHg following the initiation of non-selective beta-blockers (NSBBs) is termed a "hemodynamic response" and is strongly associated with a reduced risk of variceal bleeding and improved survival [7]. This makes HVPG an invaluable surrogate endpoint in clinical trials and a guide for personalized medicine in hepatology. In recent years, the focus has shifted towards non-invasive tests (NITs) like transient elastography (FibroScan) and various serum biomarker panels to estimate liver fibrosis and predict PHT [8]. While these NITs offer convenience and safety, they provide an indirect measure of portal pressure and lack the precision of HVPG, especially in monitoring therapeutic interventions [9]. Thus, HVPG measurement retains its unique and indispensable position in the hepatologist's armamentarium. However, much of the foundational evidence supporting the clinical utility of HVPG originates from studies conducted in North American and European populations, where the etiological spectrum of cirrhosis may differ from that in other parts of the world. In India, for instance, alcohol and non-alcoholic fatty liver disease (NAFLD) are increasingly dominant causes of cirrhosis, alongside viral hepatitis [10]. A research gap exists in prospectively validating the established HVPG thresholds for staging and prognosis within this specific demographic. Therefore, the aim of this study was to prospectively investigate the clinical implications of baseline HVPG measurement in a cohort of patients with liver cirrhosis and portal hypertension We sought to correlate HVPG values with established markers of disease severity and to evaluate its power to predict the incidence of clinical decompensation and all-cause mortality over a one-year follow-up period.

Study Design and Setting This was a prospective, single-center, observational cohort study conducted at the Department of Gastroenterology and Hepatology of a tertiary care academic hospital in Mumbai, Maharashtra, India. Study Population and Duration A total of 120 consecutive patients were enrolled between January 2022 and January 2023. All enrolled patients were followed for a fixed period of 12 months, with the final follow-up concluding in January 2024. Inclusion Criteria: 1. Age between 18 and 70 years. 2. A diagnosis of liver cirrhosis, established on the basis of clinical signs, biochemical tests, and/or imaging findings (ultrasonography or CT showing a nodular liver contour, splenomegaly, and/or ascites). 3. Evidence of portal hypertension (esophageal/gastric varices on endoscopy or clinical/radiological evidence of ascites). Exclusion Criteria: 1. Presence of hepatocellular carcinoma (HCC) outside the Milan criteria or with macroscopic vascular invasion. 2. Previous liver transplantation or scheduled for transplant within 3 months. 3. Portal or hepatic vein thrombosis (Budd-Chiari syndrome or extrahepatic portal venous obstruction). 4. Active, uncontrolled bacterial infection or sepsis at the time of enrollment. 5. Severe cardiopulmonary disease or other comorbidities limiting one-year survival. 6. Pregnancy. 7. Refusal or inability to provide informed consent. Procedures and Data Collection At baseline, all patients underwent a comprehensive evaluation including a detailed medical history, physical examination, and standard laboratory investigations (complete blood count, liver function tests, renal function tests, and coagulation profile). The Model for End-Stage Liver Disease (MELD) and Child-Turcotte-Pugh (CTP) scores were calculated for each patient. All patients underwent an upper gastrointestinal endoscopy to assess for the presence and grade of esophageal varices. HVPG Measurement: HVPG measurement was performed for all patients by a single experienced interventional radiologist blinded to the detailed clinical status of the patient. The procedure was conducted after an overnight fast. Under local anesthesia and sterile conditions, the right internal jugular vein was accessed. A 7-Fr balloon-tipped catheter (Edwards Lifesciences) was advanced under fluoroscopic guidance into a large-caliber hepatic vein, typically the right or middle. The free hepatic venous pressure (FHVP) was recorded. Subsequently, the balloon was inflated with a sufficient volume of a C02/contrast mixture to occlude the vein, and the wedged hepatic venous pressure (WHVP) was measured. The correct occlusive position was confirmed by the absence of reflux of contrast into the inferior vena cava. HVPG was calculated as the difference between the mean WHVP and the mean FHVP (HVPG = WHVP – FHVP). At least three separate, consistent measurements were obtained and averaged. Follow-up and Endpoints: Patients were followed up in the outpatient clinic at 3, 6, 9, and 12 months. The primary endpoints were: (1) the first episode of clinical decompensation, defined as new or worsening ascites requiring an increase in diuretic dose or paracentesis, any episode of variceal hemorrhage confirmed by endoscopy, or the development of overt hepatic encephalopathy (West Haven grade ≥2); and (2) all-cause mortality. Statistical Analysis Data were entered into a database and analyzed using SPSS Statistics Version 26.0 (IBM Corp., Armonk, NY). Continuous variables were presented as mean ± standard deviation (SD), and categorical variables as frequencies and percentages (%). The relationship between baseline HVPG and CTP class was assessed using a one-way analysis of variance (ANOVA) with post-hoc Tukey tests. An independent samples t-test was used to compare mean HVPG between patients who did and did not reach an endpoint. Survival and decompensation-free survival were analyzed using Kaplan-Meier curves, and groups were compared using the log-rank test. A multivariate Cox proportional hazards model was constructed to identify independent predictors of decompensation and mortality, including HVPG (as a categorical variable, ≥16 vs. <16 mmHg), MELD score, CTP class, and serum albumin. A p-value of <0.05 was considered statistically significant.

Baseline Characteristics of the Study Cohort The study cohort comprised 120 patients, with a mean age of 51.6 ± 10.8 years; 81.7% (n=98) were male. The most common etiology of cirrhosis was alcohol-related liver disease (52.5%, n=63), followed by non-alcoholic steatohepatitis (NASH) (25.0%, n=30), and viral hepatitis (HCV or HBV) (15.8%, n=19). At baseline, 40 patients (33.3%) were in CTP Class A, 55 (45.8%) in Class B, and 25 (20.8%) in Class C. The mean MELD score was 14.5 ± 4.6. The overall mean baseline HVPG for the cohort was 15.8 ± 5.5 mmHg. Detailed baseline characteristics are presented in Table 1. Table 1. Baseline Demographic and Clinical Characteristics of the Study Population (N=120) Characteristic Value Age (years), mean ± SD 51.6 ± 10.8 Gender (Male), n (%) 98 (81.7%) Etiology of Cirrhosis, n (%) Alcohol 63 (52.5%) NASH 30 (25.0%) Viral (HBV/HCV) 19 (15.8%) Other/Cryptogenic 8 (6.7%) Laboratory Parameters, mean ± SD Serum Bilirubin (mg/dL) 2.4 ± 1.9 Serum Albumin (g/dL) 2.9 ± 0.6 INR 1.5 ± 0.4 MELD Score, mean ± SD 14.5 ± 4.6 Child-Pugh (CTP) Class, n (%) Class A 40 (33.3%) Class B 55 (45.8%) Class C 25 (20.8%) Baseline Ascites (any grade), n (%) 68 (56.7%) Large Esophageal Varices, n (%) 59 (49.2%) Mean Baseline HVPG (mmHg), mean ± SD 15.8 ± 5.5 Correlation of HVPG with Disease Severity A strong, statistically significant correlation was observed between baseline HVPG and the severity of liver dysfunction. The mean HVPG progressively increased with worsening CTP class, from 8.5 ± 2.1 mmHg in CTP Class A to 14.2 ± 3.5 mmHg in Class B, and 19.8 ± 4.2 mmHg in Class C (p<0.001 for ANOVA). Patients with baseline ascites had a significantly higher mean HVPG compared to those without ascites (18.1 ± 4.1 mmHg vs. 12.8 ± 5.3 mmHg, p<0.001). Similarly, patients with large esophageal varices had a higher mean HVPG than those with small or no varices (18.9 ± 4.5 mmHg vs. 12.9 ± 4.7 mmHg, p<0.001). These findings are summarized in Table 2. Table 2. Correlation of Baseline HVPG with Clinical and Endoscopic Parameters of Severity Parameter Group N Mean HVPG (mmHg) ± SD p-value Child-Pugh Class Class A 40 8.5 ± 2.1 <0.001* Class B 55 14.2 ± 3.5 Class C 25 19.8 ± 4.2 Baseline Ascites Absent 52 12.8 ± 5.3 <0.001† Present 68 18.1 ± 4.1 Esophageal Varices No/Small 61 12.9 ± 4.7 <0.001† Large 59 18.9 ± 4.5 *p-value from one-way ANOVA. †p-value from independent samples t-test. HVPG as a Predictor of Clinical Outcomes Over the 12-month follow-up period, 41 patients (34.2%) developed their first or a new type of clinical decompensation, and 19 patients (15.8%) died. Patients who experienced decompensation had a significantly higher mean baseline HVPG (19.1 ± 3.9 mmHg) than those who remained compensated (13.7 ± 4.8 mmHg, p<0.001). We stratified the cohort based on the established prognostic threshold of HVPG ≥16 mmHg. Fifty-four patients (45.0%) had a baseline HVPG ≥16 mmHg. As shown in Table 3, the incidence of all primary outcome events was significantly higher in this high-risk group. The 1-year rate of clinical decompensation was 56.9% in the HVPG ≥16 mmHg group compared to only 14.3% in the HVPG <16 mmHg group (p<0.001). Variceal hemorrhage occurred in 22.2% vs. 3.0% (p=0.002), and all-cause mortality was 25.9% vs. 4.8% (p=0.002), respectively. Kaplan-Meier survival analysis confirmed a significantly lower probability of both decompensation-free survival and overall survival in the high-HVPG group (log-rank p<0.001 and p=0.001, respectively). In the multivariate Cox proportional hazards model, after adjusting for MELD score and serum albumin, an HVPG ≥16 mmHg remained a strong and independent predictor of both clinical decompensation (Hazard Ratio [HR]: 4.2, 95% CI: 2.1-8.5, p<0.001) and all-cause mortality (HR: 5.1, 95% CI: 1.4-18.2, p=0.012). Table 3. Incidence of 1-Year Clinical Outcomes Based on Baseline HVPG Threshold (≥16 mmHg) Outcome HVPG <16 mmHg (n=66) HVPG ≥16 mmHg (n=54) p-value Any Clinical Decompensation, n (%) 9 (14.3%) 31 (56.9%) <0.001 New/Worsening Ascites, n (%) 7 (10.6%) 22 (40.7%) <0.001 Variceal Hemorrhage, n (%) 2 (3.0%) 12 (22.2%) 0.002 Hepatic Encephalopathy, n (%) 3 (4.5%) 10 (18.5%) 0.018 All-Cause Mortality, n (%) 3 (4.8%) 14 (25.9%) 0.002

This prospective study, conducted in a large tertiary care center in Maharashtra, India, robustly demonstrates the profound clinical implications of HVPG measurement in patients with liver cirrhosis. Our findings confirm, in this specific demographic, that baseline HVPG not only serves as an excellent objective marker for staging the severity of liver disease but also acts as a powerful, independent predictor of adverse clinical outcomes over a one-year period. The strong, graded correlation we observed between HVPG and both the Child-Pugh and MELD scores is a cornerstone finding. This confirms that as liver function deteriorates and fibrosis progresses, the resultant increase in intrahepatic vascular resistance is accurately and quantitatively captured by the HVPG measurement [11]. This objective parameter moves beyond the semi-quantitative nature of clinical scoring systems, providing a direct physiological readout of the severity of portal hypertension, which is the engine of clinical decompensation [4]. The significant difference in HVPG between patients with and without ascites or large varices further solidifies its role as a surrogate for the presence of established, clinically significant complications. The most compelling result of our study is the strong prognostic value of a single baseline HVPG measurement. Our data clearly show that patients with a baseline HVPG ≥16 mmHg face a drastically higher risk of clinical decompensation and death within one year. The 1-year mortality rate of 25.9% in this group, compared to just 4.8% in those with HVPG <16 mmHg, aligns remarkably well with seminal studies from Western cohorts that established this threshold as a harbinger of poor prognosis [6, 12]. The fact that HVPG remained an independent predictor of both decompensation (HR: 4.2) and mortality (HR: 5.1) even after adjusting for powerful prognostic tools like the MELD score underscores its unique and non-redundant contribution to risk stratification. While MELD score predicts mortality across a spectrum of liver diseases, HVPG specifically quantifies the risk driven by portal hypertension-related complications [13]. Our study is particularly relevant in the current era of expanding non-invasive tests (NITs). While liver stiffness measurement by transient elastography has been validated to predict CSPH (HVPG ≥10 mmHg), its accuracy diminishes at higher pressure levels, and it cannot reliably predict specific prognostic thresholds like 16 mmHg or quantify the response to therapy [14, 15]. Our findings reinforce the Baveno consensus guidelines, which continue to position HVPG as the reference standard for portal pressure measurement in clinical research and for complex management decisions where precision is paramount [11]. The etiologies in our cohort, with a predominance of alcohol and NAFLD-related cirrhosis, reflect the changing epidemiology of liver disease in India [10]. The validation of HVPG's prognostic power in this population confirms that its physiological relevance transcends the underlying cause of cirrhosis. This is crucial for clinical practice in India and similar regions, providing clinicians with a robust tool to identify high-risk patients who may benefit from more aggressive management, such as earlier consideration for pre-emptive TIPS, closer surveillance, or priority listing for liver transplantation [16]. Several limitations of our study merit consideration. First, as a single-center study, its findings may not be fully generalizable to other regions of India with different healthcare infrastructures or patient characteristics. Second, the one-year follow-up period is relatively short and does not capture the full natural history of the disease. Third, we did not perform serial HVPG measurements to assess hemodynamic response to therapy, which is another key application of the technique. Finally, the invasive nature and cost of HVPG measurement inherently limit its application to specialized centers and preclude its use as a routine screening tool.

In this prospective study of Indian patients with liver cirrhosis, the hepatic venous pressure gradient demonstrated exceptional utility as an objective tool for staging disease severity and as a powerful, independent predictor of 1-year clinical decompensation and mortality. A baseline HVPG of ≥16 mmHg effectively identifies a subgroup of patients at very high risk for adverse outcomes, independent of conventional clinical scores. These findings validate the clinical importance of HVPG in this specific demographic and support its continued use for precise risk stratification and for guiding critical management decisions in patients with advanced portal hypertension.

1. GBD 2017 Cirrhosis Collaborators. The global, regional, and national burden of cirrhosis by cause in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol. 2020;5(3):245-266. DOI: 10.1016/S2468-1253(19)30349-8. 2. Bosch J, Abraldes JG, Berzigotti A, Garcia-Pagan JC. The clinical use of HVPG measurements in chronic liver disease. Nat Rev Gastroenterol Hepatol. 2009;6(10):573-82. DOI: 10.1038/nrgastro.2009.149. 3. D'Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol. 2006;44(1):217-31. DOI: 10.1016/j.jhep.2005.10.013. 4. Groszmann RJ, Wongcharatrawee S. The hepatic venous pressure gradient: anything worth doing should be done right. Hepatology. 2004;39(2):280-2. DOI: 10.1002/hep.20062. 5. Garcia-Tsao G, Abraldes JG, Berzigotti A, Bosch J. Portal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases. Hepatology. 2017;65(1):310-335. DOI: 10.1002/hep.28906. 6. Ripoll C, Groszmann R, Garcia-Tsao G, et al. Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis. Gastroenterology. 2007;133(2):481-8. DOI: 10.1053/j.gastro.2007.05.024. 7. Abraldes JG, Villanueva C, Bañares R, et al. Hepatic venous pressure gradient identifies patients with compensated cirrhosis at risk of developing clinical decompensation. J Hepatol. 2020;73(5):1098-1107. DOI: 10.1016/j.jhep.2020.04.032. 8. Castera L, Pinzani M, Bosch J. Non-invasive evaluation of portal hypertension using transient elastography. J Hepatol. 2012;56(3):696-703. DOI: 10.1016/j.jhep.2011.07.005. 9. Thabut D, Bureau C, Valla DC. Assessment of portal hypertension and its complications: the role of invasive and non-invasive measurements. Liver Int. 2019;39 Suppl 1:11-20. DOI: 10.1111/liv.14059. 10. Kumar A, Abbas Z, Anania F, et al. The Baveno VI recommendations for management of portal hypertension: A critical appraisal. J Gastroenterol Hepatol. 2017;32(1):11-22. DOI: 10.1111/jgh.13508. 11. de Franchis R, Bosch J, Garcia-Tsao G, et al. Baveno VII - Renewing consensus in portal hypertension. J Hepatol. 2022;76(4):959-974. DOI: 10.1016/j.jhep.2021.12.022. 12. Merkel C, Bolognesi M, Sacerdoti D, et al. The prognostic value of the hepatic venous pressure gradient in patients with cirrhosis. Curr Opin Gastroenterol. 2005;21(3):286-92. DOI: 10.1097/01.mog.0000159897.87325.29. 13. Jalal P, Kumar A, Sahu MK. Comparison of model for end-stage liver disease and hepatic venous pressure gradient in predicting survival in patients with cirrhosis of liver. J Clin Exp Hepatol. 2019;9(4):460-466. DOI: 10.1016/j.jceh.2018.11.004. 14. Berzigotti A. Non-invasive evaluation of portal hypertension: the clinical impact. Dig Liver Dis. 2017;49(10):1068-1074. DOI: 10.1016/j.dld.2017.05.011. 15. Rodrigues SG, C-FN, Llop E, et al. Noninvasive prediction of the hemodynamic response to nonselective beta-blockers in patients with cirrhosis and portal hypertension: a systematic review. J Gastroenterol Hepatol. 2021;36(1):15-26. DOI: 10.1111/jgh.15174. 16. Monescillo A, Martinez-Lagares F, Ruiz-del-Arbol L, et al. Influence of portal hypertension and its early decompression by TIPS on outcome of liver transplantation for cirrhosis. Gastroenterology. 2004;127(4):1317-25. DOI: 10.1053/j.gastro.2004.07.014.