Development, validation, and prognostic evaluation of a risk score for long-term liver-related outcomes in the general population: a multicohort study.

BACKGROUND: Liver cirrhosis is a major cause of death worldwide. Cirrhosis develops after a long asymptomatic period of fibrosis progression, with the diagnosis frequently occurring late, when major complications or cancer develop. Few reliable tools exist for timely identification of individuals at risk of cirrhosis to allow for early intervention. We aimed to develop a novel score to identify individuals at risk for future liver-related outcomes. METHODS: We derived the LiverRisk score from an international prospective cohort of individuals from six countries without known liver disease from the general population, who underwent liver fibrosis assessment by transient elastography. The score included age, sex, and six standard laboratory variables. We created four groups: minimal risk, low risk, medium risk, and high risk according to selected cutoff values of the LiverRisk score (6, 10, and 15). The model's discriminatory accuracy and calibration were externally validated in two prospective cohorts from the general population. Moreover, we ascertained the prognostic value of the score in the prediction of liver-related outcomes in participants without known liver disease with median follow-up of 12 years (UK Biobank cohort). FINDINGS: We included 14 726 participants: 6357 (43·2%) in the derivation cohort, 4370 (29·7%) in the first external validation cohort, and 3999 (27·2%) in the second external validation cohort. The score accurately predicted liver stiffness in the development and external validation cohorts, and was superior to conventional serum biomarkers of fibrosis, as measured by area under the receiver-operating characteristics curve (AUC; 0·83 [95% CI [0·78-0·89]) versus the fibrosis-4 index (FIB-4; 0·68 [0·61-0·75] at 10 kPa). The score was effective in identifying individuals at risk of liver-related mortality, liver-related hospitalisation, and liver cancer, thereby allowing stratification to different risk groups for liver-related outcomes. The hazard ratio for liver-related mortality in the high-risk group was 471 (95% CI 347-641) compared with the minimal risk group, and the overall AUC of the score in predicting 10-year liver-related mortality was 0·90 (0·88-0·91) versus 0.84 (0·82-0·86) for FIB-4. INTERPRETATION: The LiverRisk score, based on simple parameters, predicted liver fibrosis and future development of liver-related outcomes in the general population. The score might allow for stratification of individuals according to liver risk and thus guide preventive care. FUNDING: European Commission under the H20/20 programme; Fondo de Investigación Sanitaria de Salud; Instituto de Salud Carlos III; Spanish Ministry of Economy, Industry, and Competitiveness; the European Regional Development Fund; and the German Ministry of Education and Research (BMBF).

Assessment of clinically significant portal hypertension by two-dimensional shear wave elastography.

BACKGROUND AND AIMS: To evaluate two-dimensional shear wave elastography (2DSWE) in parallel with transient elastography (TE) for diagnosing clinically significant portal hypertension (CSPH) and high-risk varices (HRV) in patients with chronic liver disease. PATIENTS AND METHODS: Consecutive patients with suspicion of compensated advanced chronic liver disease (cACLD) [liver stiffness measurement (LSM) ≥ 10 kPa by TE, or morphological signs suggestive of cACLD on imaging], with no history of liver decompensation, underwent hepatic venous pressure gradient (HVPG) measurement, transjugular liver biopsy and esophagogastroduodenoscopy, which served as the reference methods for diagnosing CSPH, cACLD and HRV. All patients underwent LSM and spleen stiffness measurements (SSM) by 2DSWE and TE. RESULTS: Seventy-six (76) patients were included (78% men, mean age 62 years, body mass index 28.3 kg/m2 , 36.8% alcoholic, 30.3% non-alcoholic fatty liver disease, 14.5% viral hepatitis). Of them, 80.3%, 69.7%, 52.6% and 22.4% had cACLD, cirrhosis, CSPH and HRV respectively. LSM performed better than SSM in diagnosing CSPH and HRV. For CSPH, AUROCs (0.926 vs. 0.866), optimal cut-offs (20.1 vs. 20.2 kPa) and sensitivity/specificity (80.5%/94.3% vs. 77.5% /86.1%) were comparable for 2DSWE and TE. Ruling-out of CSPH by 2DSWE (LSM at cut-off with ≥90% sensitivity (13.5 kPa) and platelets ≥ 150 x 109 /L) performed comparably to TE, with 1/24 cases falsely classified as negative. For HRV, AUROCs were similar (0.875 2DSWE, 0.851 TE) with similar optimal LSM cut-offs enabling 100% sensitivity and ruling-out HRV. CONCLUSION: Liver stiffness measurement by 2DSWE appears to perform equally well as TE for diagnosing CSPH and ruling-out HRV in compensated chronic liver disease.

Validation of the New Diagnostic Criteria for Clinically Significant Portal Hypertension by Platelets and Elastography.

BACKGROUND AND AIMS: We aimed to validate newly proposed noninvasive criteria for diagnosing clinically significant portal hypertension (CSPH) using liver stiffness measurements (LSM) by transient elastography (TE) and platelet count. METHODS: Diagnostic performance of these new criteria for CSPH (LSM ≥ 25 kPa to rule in and Plt ≥ 150 × 109/L + LSM ≤ 15 kPa to rule out CSPH) were retrospectively tested in an independent cohort of consecutive patients who underwent hepatic venous pressure gradient (HVPG) measurements and liver biopsy due to suspicion of compensated advanced chronic liver disease. Suspicion of cACLD was based on LSM ≥ 10 kPa by TE or results of liver imaging, without overt signs of CSPH. Patients with conditions known to affect results of LSM (ALT > 5 × ULN, liver congestion, extrahepatic biliary obstruction, infiltrative liver neoplasms) were excluded. RESULTS: Seventy six (76) patients were included: 78.9% males, mean age 62 years, 36.8% suffered from alcoholic, 30.3% nonalcoholic fatty liver disease, 14.5% chronic viral hepatitis, 30.3% were obese, 52.6% had HVPG ≥ 10 mmHg, 56.6% had platelet count ≥ 150 × 109/L. LSM ≥ 25 kPa had 88.9% specificity (95% CI 73.9-96.9) to rule in, whereas Plt ≥ 150 + LSM ≤ 15 kPa had 100% sensitivity (95% CI 91.1-100) to rule out CSPH. CONCLUSION: By using these simple noninvasive criteria 49/76 (64.5%) patients could be classified correctly for the presence/absence of CSPH, thus obviating the need for HVPG measurements.

LiverScreen project: study protocol for screening for liver fibrosis in the general population in European countries.

BACKGROUND: The development of liver cirrhosis is usually an asymptomatic process until late stages when complications occur. The potential reversibility of the disease is dependent on early diagnosis of liver fibrosis and timely targeted treatment. Recently, the use of non-invasive tools has been suggested for screening of liver fibrosis, especially in subjects with risk factors for chronic liver disease. Nevertheless, large population-based studies with cost-effectiveness analyses are still lacking to support the widespread use of such tools. The aim of this study is to investigate whether non-invasive liver stiffness measurement in the general population is useful to identify subjects with asymptomatic, advanced chronic liver disease. METHODS: This study aims to include 30,000 subjects from eight European countries. Subjects from the general population aged ≥ 40 years without known liver disease will be invited to participate in the study either through phone calls/letters or through their primary care center. In the first study visit, subjects will undergo bloodwork as well as hepatic fat quantification and liver stiffness measurement (LSM) by vibration-controlled transient elastography. If LSM is ≥ 8 kPa and/or if ALT levels are ≥1.5 x upper limit of normal, subjects will be referred to hospital for further evaluation and consideration of liver biopsy. The primary outcome is the percentage of subjects with LSM ≥ 8kPa. In addition, a health economic evaluation will be performed to assess the cost-effectiveness and budget impact of such an intervention. The project is funded by the European Commission H2020 program. DISCUSSION: This study comes at an especially important time, as the burden of chronic liver diseases is expected to increase in the coming years. There is consequently an urgent need to change our current approach, from diagnosing the disease late when the impact of interventions may be limited to diagnosing the disease earlier, when the patient is asymptomatic and free of complications, and the disease potentially reversible. Ultimately, the LiverScreen study will serve as a basis from which diagnostic pathways can be developed and adapted to the specific socio-economic and healthcare conditions in each country. TRIAL REGISTRATION: This study is registered on Clinicaltrials.gov ( NCT03789825 ).

Epidemiological and clinical features of primary biliary cholangitis in two Croatian regions: a retrospective study.

AIM: To assess the measures of disease frequency and determine the clinical features of primary biliary cholangitis (PBC) in two Croatian regions. METHODS: Databases of two tertiary hospitals, one located in the continental and one in the coastal region of Croatia, were retrospectively searched for PBC patients diagnosed from 2007 to 2018. Epidemiologic data analysis was restricted to patients from each hospital's catchment area. We analyzed factors related to response to therapy and event-free survival (EFS), defined as absence of ascites, variceal bleeding, encephalopathy, hepatocellular carcinoma, liver transplantation (LT), or death. In addition, we determined clinical and demographic data of transplanted PBC patients. RESULTS: Out of 83 PBC patients, 86.7% were female, with a median age at diagnosis of 55 years. Average PBC incidence for the 11-year period was 0.79 and 0.89 per 100000 population, whereas the point prevalence on December 31, 2017 was 11.5 and 12.5 in the continental and coastal region, respectively. Of 76 patients with complete medical records, 21% had an advanced disease stage, 31.6% had an associated autoimmune condition, and all received ursodeoxycholic acid. EFS rate at 5 years was 95.8%. In an age and sex-adjusted multivariate Cox regression model, the only factor significantly associated with inferior EFS was no response to therapy (HR=18.4; P=0.018). Of all Croatian patients who underwent LT, 3.8% had PBC, with the survival rate at 5 years after LT of 93.4%. CONCLUSION: This study gives pioneer insights into the epidemiological and clinical data on PBC in Croatia, thus complementing the PBC map of Southeast Europe.

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.

Improved Applicability and Diagnostic Accuracy of the Novel Spleen-Dedicated Transient Elastography Device for High-Risk Esophageal Varices.

Spleen stiffness measurement (SSM) by transient elastography (TE) has been repeatedly demonstrated as the reliable way to rule out the presence of high-risk esophageal varices (HRV). We aimed to evaluate and compare novel vs. standard TE-SSM module performance in diagnosing HRV in patients with compensated advanced chronic liver disease (cACLD). This retrospective study included patients with cACLD; blood data, upper digestive endoscopy performed within 3 months of TE, SSM@50Hz and SSM@100Hz were collected. Overall, 112 patients with cACLD were analyzed (75.9% males, average age of 66, 43.7% alcohol-related chronic liver disease, 22.3% metabolic-associated steatotic liver disease, 6.2% viral hepatitis). Reliable SSM was possible in 80.3% and 93.8% of patients by using SSM@50Hz and SSM@100Hz probe, respectively. At the cut-off 41.8 kPa and 40.9 kPa (Youden), SSM@50Hz and SSM@100Hz had AUROCs of 0.746 and 0.752, respectively, for diagnosing HRV (p = 0.71). At the respective cut-offs, sensitivities for HRV were 92.9% and 100%, resulting in misclassification rates of 7.1% and 0% by using SSM@50Hz and SSM@100Hz. SSM reliably excludes HRV in cACLD patients, with measurements below 41 kPa potentially avoiding EGD in around 50% of cases, with minimal risk of HRV omission. SSM@100Hz demonstrated less measurement failures and no HRV misclassification.

Validation of Baveno VII criteria for clinically significant portal hypertension by two-dimensional shear wave elastography.

BACKGROUND: The Baveno VII consensus proposed criteria for the non-invasively diagnosis of clinically significant portal hypertension (CSPH) in patients with compensated advanced chronic liver disease (cACLD). The performance of Baveno VII criteria for assessing CSPH by two-dimensional shear wave elastography (2D-SWE) had not been well validated. We aimed to validate the performance of Baveno VII criteria for rule-in and rule-out CSPH by 2D-SWE. METHOD: This is an international multicenter study including cACLD patients from China and Croatia with paired liver stiffness measurement (LSM), spleen stiffness measurement (SSM) by 2D-SWE, and hepatic venous pressure gradient (HVPG) were included. CSPH was defined as HVPG ≥ 10 mmHg. RESULT: A total of 146 patients with cACLD were enrolled, and finally 118 patients were included in the analysis. Among them, CSPH was documented in 79 (66.9%) patients. Applying the Baveno VII criteria for rule-out CSPH by 2D-SWE, [LSM ≤ 15 kPa and platelet count ≥ 150 × 109/L] OR SSM < 21 kPa, could exclude CSPH with sensitivity > 90% (93.5 or 98.7%) but negative predictive value < 90% (74.1 or 85.7%). Using the Baveno VII criteria for rule-in CSPH by 2D-SWE, LSM ≥ 25 kPa OR SSM ≥ 50 kPa, could diagnose CSPH with 100% specificity and 100% positive predictive values. CONCLUSION: Baveno VII criteria by 2D-SWE showed a good diagnostic performance for ruling in but not for ruling out CSPH, which might become an emerging non-invasive elastography tool to select the patients who needed non-selective beta blocker therapy.

Use of biochemical parameters for non-invasive screening of oesophageal varices in comparison to elastography-based approach in patients with compensated advanced chronic liver disease.

Introduction: Oesophageal varices are routinely diagnosed by esophagogastroduodenoscopy (EGD), and their bleeding has high mortality. We aimed to evaluate diagnostic performance of biochemical tests in comparison to elastography-based approaches, as non-invasive alternatives to EGD, for ruling-out high risk oesophageal varices (HRV). Material and methods: Retrospective analysis of patients (N = 861) who underwent liver stiffness measurement (LSM) by transient elastography (TE) in a single centre over 5-year period, with available results of EGD (within 3 months from LSM). Only patients with suspicion of compensated advanced chronic liver disease (cACLD) defined by LSM ≥ 10 kPa were included comprising the final cohort of 73 subjects. Original and expanded Baveno VI criteria (B6C), controlled attenuation parameter (CAP), platelet count (PLT), aspartate aminotransferase to PLT ratio index (APRI), Fibrosis-4 index (FIB4), model for end stage liver disease (MELD) score were evaluated against the results of EGD that served as the reference method. Results: Analysed patients had median age 62 years, 59/73 (0.81) were males, 54/73 (0.74) had alcoholic/non-alcoholic fatty liver disease, and 21/73 (0.29) had HRV. In multivariate logistic regression analysis only LSM and PLT were independently associated with HRV. The best performing tests for ruling-out HRV (% of spared EGD; % of missed HRV) were respectively: LSM < 20 kPa (53.4%; 0%), B6C (38%; 0%), Expanded B6C (47.9%; 4.8%); PLT > 214x109/L (21.9%; 0%); FIB4 ≤ 1.8 (21.4%; 0%), APRI ≤ 0.34 (12.3%; 0%). CAP, MELD = 6 alone or combined with PLT > 150(x109/L) did not show acceptable performance. Conclusion: The best performing biochemical tests for ruling-out HRV in our cohort of patients were PLT and FIB-4, but they were still outperformed by elastography-based approaches.

Prognostic Factors in Primary Biliary Cholangitis: A Retrospective Study of Joint Slovak and Croatian Cohort of 249 Patients.

OBJECTIVE: To identify pretreatment laboratory parameters associated with treatment response and to describe the relationship between treatment response and liver decompensation in patients with primary biliary cholangitis treated with ursodeoxycholic acid. METHODS: We defined treatment response as both ALP ≤ 1.67 × ULN and total bilirubin ≤ 2 × ULN. Multiple logistic regression analyses were performed to adjust for confounding effects of sociodemographic variables. RESULTS: Pretreatment total bilirubin ((TB); OR = 0.3388, 95%CI = 0.1671-0.6077), ALT (OR = 0.5306, 95%CI = 0.3830-0.7080), AST (OR = 0.4065, 95%CI = 0.2690-0.5834), ALP (OR = 0.3440, 95%CI = 0.2356-0.4723), total cholesterol ((TC); OR = 0.7730, 95%CI = 0.6242-0.9271), APRI (OR = 0.3375, 95%CI = 0.1833-0.5774), as well as pretreatment albumin (OR = 1.1612, 95%CI = 1.0706-1.2688) and ALT/ALP (OR = 2.4596, 95%CI = 1.2095-5.5472) were associated with treatment response after six months of treatment. Pretreatment TB (OR = 0.2777, 95%CI = 0.1288-0.5228), ALT (OR = 0.5968, 95%CI = 0.4354-0.7963), AST (OR = 0.4161, 95%CI = 0.2736-0.6076), ALP (OR = 0.4676, 95%CI = 0.3487-0.6048), APRI (OR = 0.2838, 95%CI = 0.1433-0.5141), as well as pretreatment albumin (OR = 1.2359, 95%CI = 1.1257-1.3714) and platelet count (OR = 1.0056, 95%CI = 1.0011-1.0103) were associated with treatment response after 12 months of treatment. Treatment response after 6 months of UDCA therapy is significantly associated with treatment response after 12 months of UDCA therapy (OR = 25.2976, 95% CI = 10.5881-68.4917). Treatment responses after 6 and 12 months of UDCA therapy decrease the risk of an episode of liver decompensation in PBC patients (OR = 12.1156, 95%CI = 3.7192-54.4826 and OR = 21.6000, 95%CI = 6.6319-97.3840, respectively). CONCLUSIONS: There are several pretreatment laboratory parameters associated with treatment response in patients with primary biliary cholangitis. Treatment response after six months is significantly associated with treatment response after 12 months of ursodeoxycholic acid (UDCA) therapy. Treatment responses after 6 and 12 months of UDCA decrease the risk of an episode of liver decompensation.

FibroScan-AST Score Predicts 30-Day Mortality or Need for Mechanical Ventilation among Patients Hospitalized with COVID-19.

BACKGROUND: Liver involvement in Coronavirus disease 2019 (COVID-19) has been recognised. We aimed to investigate the correlation of non-invasive surrogates of liver steatosis, fibrosis and inflammation using transient elastography (TE) and FibroScan-AST (FAST) score with (a) clinical severity and (b) 30-day composite outcome of mechanical ventilation (MV) or death among patients hospitalized due to COVID-19. METHOD: Patients with non-critical COVID-19 at admission were included. Liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) were assessed by TE. Clinical severity of COVID-19 was assessed by 4C Mortality Score (4CMS) and need for high-flow nasal cannula (HFNC) oxygen supplementation. RESULTS: 217 patients were included (66.5% males, median age 65 years, 4.6% with history of chronic liver disease). Twenty-four (11.1%) patients met the 30-day composite outcome. Median LSM, CAP and FAST score were 5.2 kPa, 274 dB/m and 0.31, respectively, and neither was associated with clinical severity of COVID-19 at admission. In multivariate analysis FAST > 0.36 (OR 3.19, p = 0.036), 4CMS (OR 1.68, p = 0.002) and HFNC (OR 7.03, p = 0.001) were independent predictors of adverse composite outcome. CONCLUSION: Whereas LSM and CAP failed to show correlation with COVID-19 severity and outcomes, FAST score was an independent risk factor for 30-day mortality or need for MV.

Natural History of Nonalcoholic Fatty Liver Disease: Implications for Clinical Practice and an Individualized Approach.

Nonalcoholic fatty liver disease (NAFLD) is becoming the most prevalent liver disease worldwide, associated with epidemics of overweight and resulting metabolic syndrome (MetS). Around 20-30% of patients with NAFLD develop progressive liver fibrosis, which is the most important predictor of liver-related and overall morbidity and mortality. In contrast to classical understanding, no significant association has been demonstrated between the inflammatory component of NAFLD, i.e., nonalcoholic steatohepatitis (NASH), and the adverse clinical outcomes. Older age (>50 years) and presence of type 2 diabetes mellitus, in addition to some genetic variants, are most consistently reported indicators of increased risk of having liver fibrosis. However, critical driving force for the progression of fibrosis and risk factors for this have still not been fully elucidated. Apart from the genetic profile, gut dysbiosis, weight gain, worsening of insulin resistance, and worsening of liver steatosis represent candidate factors associated with unfavourable development of liver disease. Cardiovascular events, extrahepatic malignancies, and liver-related deaths are the leading causes of mortality in NAFLD. As patients with advanced fibrosis are under highest risk of adverse clinical outcomes, efforts should be made to recognize individuals under risk and rule out the presence of this stage of fibrosis, preferably by using simple noninvasive tools. This process should start at the primary care level by using validated biochemical tests, followed by direct serum tests for fibrosis or elastography in the remaining patients. Patients with advanced fibrosis should be referred to hepatologists for aggressive lifestyle modification and correction of the components of MetS, and cirrhotic patients should be screened for hepatocellular carcinoma and oesophageal varices.

Infection as a predictor of mortality in decompensated liver cirrhosis: exploring the relationship to severity of liver failure.

BACKGROUND: Infections are common in patients with liver cirrhosis and increase mortality. We explored the relationship between infection and liver dysfunction in their effects on mortality. METHODS: Single-center data on decompensated liver cirrhosis patients hospitalized between March 2014 and December 2017 (index period) were reviewed until death, liver transplantation or 31 December 2018. Infections were classified as community-acquired infection (CAi) or hospital/healthcare associated infection (HCAi). Child-Pugh, model for the end-stage liver disease (MELD) and chronic liver failure-organ failure (CLiF-OF) scores indicated liver (dys)function. RESULTS: We enrolled 155 patients (85% alcoholic liver disease), 65 without infection at first hospitalization, 48 with CAi and 42 with HCAi. Multidrug resistant agents were confirmed in 2/48 (4.2%) CAi and 10/42 (23.8%) HCAi patients. At first hospitalization, infection was independently associated with worse liver dysfunction and vice versa, and with higher 30-day mortality [odds ratio (OR) = 2.73, 95% confidence interval (CI) 1.07-6.94]. The association was reduced with adjustment for MELD/CLiF-OF scores, but mediation analysis detected an indirect (via liver dysfunction) association. Twenty-eight patients were repeatedly hospitalized, 11 with new HCAi. HCAi was independently associated with twice higher risk of medium-term mortality and added an additional risk to any level of liver dysfunction, considering all or patients who survived the first 30 days. In those repeatedly hospitalized, HCAi appeared independently associated with a higher probability of infection and higher MELD scores at subsequent hospitalizations. CONCLUSION: Infection (particularly HCAi) adds mortality risk to any level of liver dysfunction in decompensated liver cirrhosis patients. Mechanisms of long(er)-term effects (in acute episode survivors) seemingly include enhanced deterioration of liver function.

Hepatitis C is now curable, but what happens with cirrhosis and portal hypertension afterwards?

Results from the interferon era have demonstrated reversibility of cirrhosis following viral eradication, but only for patients in the initial stage of cirrhosis. Although direct-acting antivirals (DAA) represent revolutionary treatment of hepatitis C, there are currently no studies showing histological effects of therapy on a large number of cirrhotic patients. However, studies involving transient elastography demonstrated a rapid decrease in liver stiffness after successful DAA therapy, probably due to resolution of inflammation, rather than fibrosis regression, as the latter requires a longer period of time. Reversal of fibrosis and cirrhosis upon viral eradication is a prerequisite for the reduction of portal pressure, but this effect has only been observed for the subclinical stage of portal hypertension (PH). On the other hand, the majority of patients with clinically significant PH remain at risk of decompensation and death, despite hepatitis C virus cure, as PH remains high in this setting. This calls for novel therapeutic approaches.