Alcohol-related liver disease is a leading cause of liver-related mortality. The effect of alcohol abstinence on the natural history of alcohol-related cirrhosis across distinct stages of portal hypertension has not been thoroughly investigated. In this study, we assessed the clinical implications of abstinence in patients with alcohol-related cirrhosis and clinically significant portal hypertension. Alcohol abstinence, hepatic decompensation, and mortality were assessed in patients with alcohol-related cirrhosis who underwent a baseline hepatic venous pressure gradient (HVPG) measurement and were diagnosed with clinically significant portal hypertension (HVPG ≥10 mm Hg). A total of 320 patients with alcohol-related cirrhosis (median age: 57 [interquartile range (IQR), 49.7-63.1] years; 75.6% male; 87.5% decompensated) and a median HVPG of 20 (IQR, 17-23) mm Hg were followed up for a median of 36 (IQR, 14-80) months. Overall, 241 (75.3%) patients remained abstinent, while 79 (24.7%) patients had active alcohol consumption. Alcohol abstinence was linked to a significantly reduced risk of hepatic decompensation (adjusted hazard ratio [aHR], 0.391; P < .001), as well as liver-related (aHR, 0.428; P < .001) and all-cause (aHR, 0.453; P < .001) mortality, after adjusting for baseline HVPG, MELD, and previous decompensation. Importantly, alcohol abstinence significantly reduced the cumulative incidence of hepatic decompensation in both groups with HVPG 10-19 mm Hg (P < .001) and HVPG ≥20 mm Hg (P = .002). The 3-year decompensation probability was 32.4% vs 60.0% in HVPG 10-19 mm Hg and 57.5% vs 82.6% in HVPG ≥20 mm Hg for abstinent patients vs active drinkers, respectively. Alcohol abstinence improves prognosis across all stages of portal hypertension in alcohol-related cirrhosis, including in patients who have already progressed to high-risk portal hypertension. (ClinicalTrials.gov, Number: NCT03267615).

Background & Aims: Removing the primary aetiological factor in decompensated cirrhosis may lead to a restoration of hepatic function. In this study, we investigated the clinical implications of recompensation and the subsequent survival in patients with decompensated alcohol‐related cirrhosis.Methods: The rate of recompensation was evaluated in patients with decompensated alcohol‐related cirrhosis and persistent alcohol abstinence undergoing a hepatic venous pressure gradient (HVPG) measurement. Recompensation was defined according to Baveno VII criteria as resolution of ascites and hepatic encephalopathy, absence of variceal bleeding and improvement in liver function.Results: Two hundred and four abstinent patients with decompensated alcohol‐related cirrhosis (age: 57.2 [IQR:50.1–63.7] years; 75.0% male; median MELD: 15 [IQR:11–19]) and a median HVPG of 20 (IQR:18–24) mmHg were included. During a median follow‐up of 24.4 (IQR:10.9–50.4) months, 37 patients (18.1%) achieved abstinence‐induced recompensation. Lower baseline HVPG, lower Child‐Pugh score, lower BMI, higher albumin and higher mean arterial pressure were linked to a higher probability of recompensation. After adjusting for age, disease severity, portal hypertension and systemic inflammation, achieving recompensation resulted in a significant and considerable reduction in liver‐related mortality (adjusted HR: 0.091 [95% CI: 0.012–0.677]; p = .019). Only 13 patients (6.4%) developed hepatocellular carcinoma, with a tendency towards a lower risk upon recompensation (HR: 0.398 [95% CI: 0.084–1.878]; p = .245), yet this finding did not reach statistical significance and requires further investigation.Conclusions: Alcohol abstinence led to recompensation in 18.1% of our cohort of HVPG‐characterised patients with decompensated alcohol‐related cirrhosis. Achieving hepatic recompensation resulted in a >90% risk reduction in liver‐related mortality.

Traditionally, the progression from compensated to decompensated cirrhosis has been regarded as a point of no return in the natural history of the disease. However, this point of view is increasingly being challenged by new evidence on disease regression and hepatic recompensation upon suppression/cure of the underlying aetiology. In order to create a uniform definition of recompensated cirrhosis, standardised criteria have been set out by the Baveno VII consensus, which include the removal of the primary aetiological factor, the resolution of any decompensating events and a sustained improvement in hepatic function. Initial insights into the concept of hepatic recompensation come from previous studies, which have demonstrated that a cure/suppression of the underlying aetiology in patients with prior decompensation leads to significant clinical improvements and favourable outcomes and can even enable the delisting of transplant candidates. Nevertheless, future studies are required to shed light on the natural history of hepatic recompensation, assess modifying factors and potential non-invasive biomarkers of recompensation and explore the molecular mechanisms of disease regression.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of advanced chronic liver disease (ACLD). Portal hypertension drives hepatic decompensation and is best diagnosed by hepatic venous pressure gradient (HVPG) measurement. Here we investigate the prognostic value of HVPG in compensated (cACLD) MASLD. This European multicentre study included MASLD-cACLD patients characterised by HVPG at baseline. Hepatic decompensation (variceal bleeding/ ascites/hepatic encephalopathy) and liver-related mortality were considered the primary events of interest. 340 MASLD-cACLD patients [56.2% men; age: 62 (55-68) years; MELD: 8 (7-9); 71.2% diabetes] were included. Clinically significant portal hypertension (CSPH; i.e., HVPG ≥10 mmHg) was found in 209 patients (61.5%). During a median follow-up of 41.5 (27.5-65.8) months, 65 patients developed hepatic decompensation with a cumulative incidence of 10.0% after 2 years (2Y) and 30.7% after 5 years (5Y) in MASLD-cACLD with CSPH, compared to 2.4% after 2Y and 9.4% after 5Y in patients without CSPH. Variceal bleeding did not occur without CSPH. CSPH (subdistribution hazard ratio, SHR:5.13; p<0.001) was associated with an increased decompensation risk and a higher HVPG remained an independent risk factor in the multivariable model (aSHR per mmHg:1.12; p<0.001). Liver-related mortality occurred in 37 patients with a cumulative incidence of 3.3% after 2Y and 21.4% after 5Y in CSPH. Without CSPH, the incidence after 5Y was 0.8%. Accordingly, a higher HVPG was also independently associated with a higher risk of liver-related death (aSHR per mmHg:1.20; p<0.001). HVPG measurement is of high prognostic value in MASLD-cACLD. While MASLD-cACLD patients without CSPH show a very low short-term risk of decompensation and liver-related mortality is rare, the presence of CSPH substantially increases both risks. While the incidence of compensated advanced chronic liver disease (cACLD) due to metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing worldwide, insights into the impact of clinically significant portal hypertension (CSPH) on the risk of liver-related events in MASLD-cACLD remain limited. Based on the findings of this European multicentre study including 340 MASLD-cACLD, we could show that increasing HVPG values and the presence of CSPH in particular were associated with a significantly higher risk of first hepatic decompensation and liver-related mortality. In contrast, the short-term incidence of decompensation in MASLD-cACLD patients without CSPH was low and the risk of liver-mortality remained negligible. Thus, HVPG measurements can provide important prognostic information for individualised risk-stratification in MASLD-cACLD and may help facilitate the study of novel and promising treatment possibilities for MASLD.

Although ascites is the most frequent first decompensating event in cirrhosis, the clinical course after ascites as the single index decompensation is not well defined. The aim of this multicentre study was thus to systematically investigate the incidence and type of further decompensation after ascites as the first decompensating event and to assess risk factors for mortality. A total of 622 patients with cirrhosis presenting with grade 2/3 ascites as the single index decompensating event at 2 university hospitals (Padova and Vienna) between 2003 and 2021 were included. Events of further decompensation, liver transplantation, and death were recorded. The mean age was 57 ± 11 years, and most patients were male (n = 423, 68%) with alcohol-related (n = 366, 59%) and viral (n = 200,32%) liver disease as the main aetiologies. In total, 323 (52%) patients presented with grade 2 and 299 (48%) with grade 3 ascites. The median Child–Pugh score at presentation was 8 (IQR 7–9), and the mean model for end-stage liver disease (MELD) was 15 ± 6. During a median follow-up period of 49 months, 350 (56%) patients experienced further decompensation: refractory ascites (n = 130, 21%), hepatic encephalopathy (n = 112, 18%), spontaneous bacterial peritonitis (n = 32, 5%), hepatorenal syndrome–acute kidney injury (n = 29, 5%). Variceal bleeding as an isolated further decompensation event was rare (n = 18, 3%), whereas non-bleeding further decompensation (n = 161, 26%) and ≥2 concomitant further decompensation events (n = 171, 27%) were frequent. Transjugular intrahepatic portosystemic shunt was used in only 81 (13%) patients. In patients presenting with grade 2 ascites, MELD ≥15 indicated a considerable risk for further decompensation (subdistribution hazard ratio [SHR] 2.18; p <0.001; 1-year incidences: <10: 10% vs. 10–14: 13% vs. ≥15: 28%) and of mortality (SHR 1.89; p = 0.004; 1-year incidences: <10: 3% vs. 10–14: 6% vs. ≥15: 14%). Importantly, mortality was similarly high throughout MELD strata in grade 3 ascites (p = n.s. for different MELD strata; 1-year incidences: <10: 14% vs. 10–14: 15% vs. ≥15: 20%). Further decompensation is frequent in patients with ascites as a single index decompensation event and only rarely owing to bleeding. Although patients with grade 2 ascites and MELD <15 seem to have a favourable prognosis, those with grade 3 ascites are at a high risk of mortality across all MELD strata. Decompensation (the development of symptoms as a result of worsening liver function) marks a turning point in the disease course for patients with cirrhosis. Ascites (i.e. , the accumulation of fluid in the abdomen) is the most common first decompensating event, yet little is known about the clinical course of patients who develop ascites as a single first decompensating event. Herein, we show that the severity of ascites is associated with mortality and that in patients with moderate ascites, the widely used prognostic MELD score can predict patient outcomes.

In individuals with compensated advanced chronic liver disease (cACLD), the severity of portal hypertension (PH) determines the risk of decompensation. Invasive measurement of the hepatic venous pressure gradient (HVPG) is the diagnostic gold standard for PH. We evaluated the utility of machine learning models (MLMs) based on standard laboratory parameters to predict the severity of PH in individuals with cACLD. A detailed laboratory workup of individuals with cACLD recruited from the Vienna cohort (NCT03267615) was utilised to predict clinically significant portal hypertension (CSPH, i.e., HVPG ≥10 mmHg) and severe PH (i.e., HVPG ≥16 mmHg). The MLMs were then evaluated in individual external datasets and optimised in the merged cohort. Among 1,232 participants with cACLD, the prevalence of CSPH/severe PH was similar in the Vienna (n = 163, 67.4%/35.0%) and validation (n = 1,069, 70.3%/34.7%) cohorts. The MLMs were based on 3 (3P: platelet count, bilirubin, international normalised ratio) or 5 (5P: +cholinesterase, +gamma-glutamyl transferase, +activated partial thromboplastin time replacing international normalised ratio) laboratory parameters. The MLMs performed robustly in the Vienna cohort. 5P-MLM had the best AUCs for CSPH (0.813) and severe PH (0.887) and compared favourably to liver stiffness measurement (AUC: 0.808). Their performance in external validation datasets was heterogeneous (AUCs: 0.589-0.887). Training on the merged cohort optimised model performance for CSPH (AUCs for 3P and 5P: 0.775 and 0.789, respectively) and severe PH (0.737 and 0.828, respectively). Internally trained MLMs reliably predicted PH severity in the Vienna cACLD cohort but exhibited heterogeneous results on external validation. The proposed 3P/5P online tool can reliably identify individuals with CSPH or severe PH, who are thus at risk of hepatic decompensation. We used machine learning models based on widely available laboratory parameters to develop a non-invasive model to predict the severity of portal hypertension in individuals with compensated cirrhosis, who currently require invasive measurement of hepatic venous pressure gradient. We validated our findings in a large multicentre cohort of individuals with advanced chronic liver disease (cACLD) of any cause. Finally, we provide a readily available online calculator, based on 3 (platelet count, bilirubin, international normalised ratio) or 5 (platelet count, bilirubin, activated partial thromboplastin time, gamma-glutamyltransferase, choline-esterase) widely available laboratory parameters, that clinicians can use to predict the likelihood of their patients with cACLD having clinically significant or severe portal hypertension.