Using liver stiffness to predict and monitor the risk of decompensation and mortality in patients with alcohol-related liver disease.

BACKGROUND & AIMS: Liver stiffness measurement (LSM) is recommended for disease prognostication and monitoring. We evaluated if LSM, using transient elastography, and LSM changes predict decompensation and mortality in patients with alcohol-related liver disease (ALD). METHODS: We performed an observational cohort study of compensated patients at risk of ALD from Denmark and Austria. We evaluated the risk of decompensation and all-cause mortality, stratified for compensated advanced chronic liver disease (cACLD: baseline LSM ≥10 kPa) and LSM changes after a median of 2 years. In patients with cACLD, we defined LSM changes as (A) LSM increase ≥20% ("cACLD increasers") and (B) follow-up LSM <10 kPa or <20 kPa with LSM decrease ≥20% ("cACLD decreasers"). In patients without cACLD, we defined follow-up LSM ≥10 kPa as an LSM increase ("No cACLD increasers"). The remaining patients were considered LSM stable. RESULTS: We followed 536 patients for 3,008 patient-years-median age 57 years (IQR 49-63), baseline LSM 8.1 kPa (IQR 4.9-21.7)-371 patients (69%) had follow-up LSM after a median of 25 months (IQR 17-38), 41 subsequently decompensated and 55 died. Of 125 with cACLD at baseline, 14% were "cACLD increasers" and 43% "cACLD decreasers", while 13% of patients without cACLD were "No cACLD increasers" (n = 33/246). Baseline LSM, follow-up LSM and LSM changes accurately predicted decompensation (C-index: baseline LSM 0.85; follow-up LSM 0.89; LSM changes 0.85) and mortality (C-index: baseline LSM 0.74; follow-up LSM 0.74; LSM changes 0.70). When compared to "cACLD decreasers", "cACLD increasers" had significantly lower decompensation-free survival and higher risks of decompensation (subdistribution hazard ratio 4.39, p = 0.004) and mortality (hazard ratio 3.22, p = 0.01). CONCLUSION: LSM by transient elastography predicts decompensation and all-cause mortality in patients with compensated ALD both at diagnosis and when used for monitoring. IMPACT AND IMPLICATIONS: Patients at risk of alcohol-related liver disease (ALD) are at significant risk of progressive disease and adverse outcomes. Monitoring is essential for optimal disease surveillance and patient guidance, but non-invasive monitoring tools are lacking. In this study we demonstrate that liver stiffness measurement (LSM), using transient elastography, and LSM changes after a median of 2 years, can predict decompensation and all-cause mortality in patients at risk of ALD with and without compensated advanced chronic liver disease. These findings are in line with results from non-alcoholic fatty liver disease, hepatitis C and primary sclerosing cholangitis, and support the clinical utility of LSM, using transient elastography, for disease prognostication and monitoring in chronic liver diseases including ALD, as recommended by the Baveno VII.

Liver Stiffness Measurement and Risk Prediction of Hepatocellular Carcinoma After HCV Eradication in Veterans With Cirrhosis.

BACKGROUND & AIMS: Patients with cirrhosis secondary to chronic hepatitis C virus (HCV) are at risk for hepatocellular carcinoma (HCC) despite a sustained virological response (SVR). We examined whether post-SVR liver stiffness measurement (LSM) could be used to stratify HCC risk. METHODS: This was a retrospective cohort study of 1850 participants identified from the Veterans Health Administration, with HCV cirrhosis and SVR, followed up over 5099 person-years, from the time of post-SVR elastography until death, HCC, or the end of the study. RESULTS: The risk of HCC increased by 3% with every 1-kPa increase in LSM (adjusted hazard ratio [aHR], 1.03, 95% confidence interval [CI], 1.01-1.04; P < .001) and decreased with the number of years from SVR (aHR, 0.79; 95% CI, 0.70-0.90; P = .0003). The adjusted annual risk of HCC was 2.03% among participants with post-SVR LSM <10 kPa, 2.48% in LSM 10-14.9 kPa (aHR, 1.71; 95% CI, 1.01-2.88; P = .046), 3.22% for LSM 15-19.9 kPa (aHR, 1.59; 95% CI, 0.78-3.20; P = .20), 5.07% among LSM 20-24.9 kPa (aHR, 2.55; 95% CI, 1.30-5.01; P = .01), and 5.44% in LSM ≥25 kPa (aHR, 3.03; 95% CI, 1.74-5.26; P < .0001). The adjusted annual risk of HCC was < 0.4% in participants with LSM <5 kPa and without diabetes mellitus. CONCLUSIONS: LSM predicts rates of HCC in patients with HCV cirrhosis after SVR at multiple cutoff levels and offers a single test to predict portal hypertension-related complications and HCC. Patients with LSM <5 kPa in the absence of diabetes mellitus had a low risk of HCC in which surveillance could be discontinued.

Baveno VII algorithm outperformed other models in ruling out high-risk varices in individuals with HBV-related cirrhosis.

BACKGROUND & AIMS: The Baveno VII consensus recommends that spleen stiffness measurement (SSM) ≤40 kPa is safe for ruling out high-risk varices (HRVs) and avoiding endoscopic screening in patients who do not meet the Baveno VI criteria. This study aimed to validate the performance of the Baveno VII algorithm in individuals with HBV-related cirrhosis. METHODS: Consecutive individuals with HBV-related cirrhosis who underwent liver stiffness measurement (LSM) and SSM - using a 50 Hz shear wave frequency, spleen diameter measurement, and esophagogastroduodenoscopy (EGD) were prospectively enrolled from June 2020. A 100 Hz probe has been adopted for additional SSM assessment since July 2021. RESULTS: From June 2020 to January 2022, 996 patients were screened and 504 were enrolled for analysis. Among the 504 patients in whom SSM was assessed using a 50 Hz probe, the Baveno VII algorithm avoided more EGDs (56.7% vs. 39.1%, p <0.001) than Baveno VI criteria, with a comparable missed HRV rate (3.8% vs. 2.5%). Missed HRV rates were >5% for all other measures: 11.3% for LSM-longitudinal spleen diameter to platelet ratio score, 20.0% for platelet count/longitudinal spleen diameter ratio, and 8.8% for Rete Sicilia Selezione Terapia-hepatitis. SSM@100 Hz was assessed in 232 patients, and the Baveno VII algorithm with SSM@100 Hz spared more EGDs (75.4% vs. 59.5%, p <0.001) than that with SSM@50 Hz, both with a missed HRV rate of 3.0% (1/33). CONCLUSIONS: We validated the Baveno VII algorithm, demonstrating the excellent performance of SSM@50 Hz and SSM@100 Hz in ruling out HRV in individuals with HBV-related cirrhosis. Furthermore, the Baveno VII algorithm with SSM@100 Hz could safely rule out more EGDs than that with SSM@50 Hz. CLINICAL TRIAL NUMBER: NCT04890730. IMPACT AND IMPLICATIONS: The Baveno VII guideline proposed that for patients who do not meet the Baveno VI criteria, SSM ≤40 kPa could avoid further unnecessary endoscopic screening. The current study validated the Baveno VII algorithm using 50 Hz and 100 Hz probes, which both exhibited excellent performance in ruling out HRVs in individuals with HBV-related cirrhosis. Compared with the Baveno VII algorithm with SSM@50 Hz, SSM@100 Hz had a better capability to safely rule out unnecessary EGDs. Baveno VII algorithm will be a practical tool to triage individuals with cirrhosis in future clinical practice.

The Sequential Application of Baveno VII Criteria and VITRO Score Improves Diagnosis of Clinically Significant Portal Hypertension.

BACKGROUND & AIMS: Baveno VII proposed liver stiffness measurement (LSM)/platelet count (PLT)-based criteria ('ruled out,' LSM ≤15 kPa plus PLT ≥150 G/L; 'ruled in': LSM ≥25 kPa) for clinically significant portal hypertension (CSPH) in compensated advanced chronic liver disease (cACLD). However, a substantial proportion of patients remains 'unclassified.' METHODS: Patients with evidence of cACLD (LSM ≥10 kPa) undergoing hepatic venous pressure gradient (HVPG) measurement at the Vienna General Hospital 2004 to 2021 (derivation [2004-2016], n = 221; validation [2017-2021], n = 81) were included. The performance of noninvasive tests (NITs) including von Willebrand factor antigen to PLT ratio (VITRO) for the detection of CSPH (HVPG ≥10 mmHg) were evaluated. RESULTS: Overall, viral hepatitis was the predominant (50.7%) etiology, followed by alcoholic liver disease (15.2%) and nonalcoholic steatohepatitis (13.2%); CSPH prevalence was 62.3%. In the derivation cohort, 45.7% were 'unclassified' according to Baveno VII criteria; in this group, VITRO showed an excellent diagnostic performance for the detection of CSPH (area under the receiver operating curve, 0.909; 95% confidence interval, 0.823-0.965). VITRO ≤1.5 and ≥2.5 ruled out (sensitivity, 97.7%; negative predictive value, 97.5%) and ruled in (specificity, 94.7%; positive predictive value, 91.2%), respectively, CSPH in patients who were 'unclassifiable' by Baveno VII criteria. The application of a sequential Baveno VII-VITRO algorithm reallocated 73% and 70% of 'unclassified' patients to the 'ruled in' and 'ruled out' group, respectively, while maintaining high sensitivity and negative predictive value and specificity and positive predictive value in the derivation and validation cohort, respectively. No patient allocated to the 'CSPH ruled out' group by the Baveno VII-VITRO algorithm developed decompensation within 5 years, whereas 5-year decompensation rates were negligible (4%) and substantial (23.9%) among 'unclassified' and 'CSPH ruled in' patients, respectively. CONCLUSIONS: The sequential application of VITRO in patients with cACLD who were 'unclassifiable' with regard to CSPH by Baveno VII criteria substantially decreased the number of 'unclassifiable' patients to <15% and refined prognostication.

Hepatic recompensation according to Baveno VII criteria via transjugular intrahepatic portosystemic shunt.

Transjugular intrahepatic portosystemic shunt is a therapeutic modality done through interventional radiology. It is aimed to decrease portal pressure in special situations for patients with decompensated liver disease with portal hypertension. It represents a potential addition to the therapeutic modalities that could achieve hepatic recompensation in those patients based on Baveno VII criteria.

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.

Transjugular intrahepatic portosystemic shunt for recompensating decompensated cirrhosis?

Transjugular intrahepatic portosystemic shunt (TIPS) is a medical procedure that has been used to manage variceal bleeding and ascites in patients with cirrhosis. It can prevent further decompensation and improve the survival of high-risk decompensated patients. Recent research indicates that TIPS could increase the possibility of recompensation of decompensated cirrhosis when it is combined with adequate suppression of the causative factor of liver disease. However, the results of the studies have been based on retrospective analysis, and further validation is required by conducting randomized controlled studies. In this context, we highlight the limitations of the current studies and emphasize the issues that must be addressed before TIPS can be recommended as a potential recompensating tool.

Advancing hepatic recompensation: Baveno VII criteria and therapeutic innovations in liver cirrhosis management.

The Baveno VII criteria redefine the management of decompensated liver cirrhosis, introducing the concept of hepatic recompensation marking a significant departure from the conventional view of irreversible decline. Central to this concept is addressing the underlying cause of cirrhosis through tailored therapies, including antivirals and lifestyle modifications. Studies on alcohol, hepatitis C virus, and hepatitis B virus-related cirrhosis demonstrate the efficacy of these interventions in improving liver function and patient outcomes. Transjugular intrahepatic portosystemic shunt (TIPS) emerges as a promising intervention, effectively resolving complications of portal hypertension and facilitating recompensation. However, optimal timing and patient selection for TIPS remain unresolved. Despite challenges, TIPS offers renewed hope for hepatic recompensation, marking a significant advancement in cirrhosis management. Further research is needed to refine its implementation and maximize its benefits. In conclusion, TIPS stands as a promising avenue for improving hepatic function and patient outcomes in decompensated liver cirrhosis within the framework of the Baveno VII criteria.

Evaluation of potential hepatic recompensation criteria in patients with PBC and decompensated cirrhosis.

BACKGROUND: Aetiological therapy improves liver function and may enable hepatic recompensation in decompensated cirrhosis. AIMS: We explored the potential for recompensation in patients with decompensated primary biliary cholangitis (PBC) - considering a biochemical response to ursodeoxycholic acid (UDCA) according to Paris-II criteria as a surrogate for successful aetiological treatment. METHODS: Patients with PBC were retrospectively included at the time of first decompensation. Recompensation was defined as (i) resolution of ascites and hepatic encephalopathy (HE) despite discontinuation of diuretic/HE therapy, (ii) absence of variceal bleeding and (iii) sustained liver function improvement. RESULTS: In total, 42 patients with PBC with decompensated cirrhosis (age: 63.5 [IQR: 51.9-69.2] years; 88.1% female; MELD-Na: 13.5 [IQR: 11.0-15.0]) were included and followed for 41.9 (IQR: 11.0-70.9) months after decompensation. Seven patients (16.7%) achieved recompensation. Lower MELD-Na (subdistribution hazard ratio [SHR]: 0.90; p = 0.047), bilirubin (SHR per mg/dL: 0.44; p = 0.005) and alkaline phosphatase (SHR per 10 U/L: 0.67; p = 0.001) at decompensation, as well as variceal bleeding as decompensating event (SHR: 4.37; p = 0.069), were linked to a higher probability of recompensation. Overall, 33 patients were treated with UDCA for ≥1 year and 12 (36%) achieved Paris-II response criteria. Recompensation occurred in 5/12 (41.7%) and in 2/21 (9.5%) patients with vs. without UDCA response at 1 year, respectively. Recompensation was linked to a numerically improved transplant-free survival (HR: 0.46; p = 0.335). Nonetheless, 4/7 recompensated patients presented with liver-related complications after developing hepatic malignancy and/or portal vein thrombosis and 2 eventually died. CONCLUSIONS: Patients with PBC and decompensated cirrhosis may achieve hepatic recompensation under UDCA therapy. However, since liver-related complications still occur after recompensation, patients should remain under close follow-up.

Transjugular intrahepatic portosystemic shunt: A promising therapy for recompensation in cirrhotic patients.

This is a retrospective study focused on recompensation after transjugular intrahepatic portosystemic shunt (TIPS) procedure. The authors confirmed TIPS could be a treatment for recompensation of patients with cirrhosis according to Baveno VII. The paper identified age and post-TIPS portal pressure gradient as independent predictors of recompensation in patients with decompensated cirrhosis after TIPS. These results need to be validated in a larger prospective cohort.

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.

Risk and predictors of hepatic decompensation in grey zone patients by the Baveno VII criteria: A competing risk analysis.

BACKGROUND: Baveno VII was proposed for non-invasive identification of clinically significant portal hypertension. However, a substantial proportion of patients is classified in the grey zone (i.e., liver stiffness 15-24.9 kPa and/or platelet count <150 × 109 /L). AIMS: To evaluate the risk and predictors of hepatic decompensation in patients in the grey zone, and to determine the prognostic role of spleen stiffness measurement. METHODS: We included prospective cohorts (from Hong Kong, Korea and France) of patients who had undergone transient elastography examination for chronic liver disease. We estimated risk of hepatic decompensation using competing risk regression with hepatocellular carcinoma and non-liver-related death as competing events. RESULTS: We identified 2763 patients with compensated advanced chronic liver disease (cACLD). There were 1243 (44.9%) and 536 (19.4%) patients in the Baveno VII grey zone and high-risk groups, respectively. The cumulative incidence of decompensation at 5 years was significantly different among low-risk (0.6% [95% CI: 0.2%-1.3%]), grey zone 4.2% (95% CI: 3.1%-5.4%) and high-risk groups (11.4% [95% CI: 8.7%-14.6%]). By competing risk analysis, aetiology of liver disease (alcohol-related liver disease), albumin-bilirubin score and alkaline phosphatase level were independently associated with decompensation among patients in the grey zone. The combination of Baveno VII and spleen stiffness significantly reduced patients classified into grey zone (12.8% in cACLD patients), while maintaining high discrimination of decompensation in low- and high-risk groups. CONCLUSIONS: Patients in grey zone of Baveno VII criteria remain at high risk of hepatic decompensation. Clinical risk factors and spleen stiffness can further stratify the risk in such patients.

Lymphatic drainage dysfunction via narrowing of the lumen of cisterna chyli and thoracic duct after luminal dilation.

BACKGROUND: The chronological pattern of extrahepatic lymphatic vessel progression in the course of chronic liver disease has not been clarified. This study aimed to clarify the chronological changes in lymphatic vessels with liver disease progression. METHODS: This was a prospective cross-sectional study that enrolled a total of 199 patients. The maximum diameter of the cisterna chyli (CC) or terminal thoracic duct (tTD) was measured using computed tomography or ultrasonography, respectively. Changes in the maximum diameters of the CC and tTD were evaluated with patients with chronic liver disease as the pilot set (n = 138). Subsequently, we examined whether CC/tTD could be used to re-allocate unclassified patients by the Baveno-VII criteria to appropriately diagnose clinically significant portal hypertension (CSPH) in the pilot and validation sets. RESULTS: In the pilot set, a scatter-plot showed that both CC and tTD were narrowed as terminal features in chronic liver disease after dilation. Because there was a significant correlation between the CC diameter and hepatic venous pressure gradient (r = 0.724) in unclassified patients, the diagnostic value of CC and tTD for CSPH was good (AUC: 0.961 and 0.913, respectively). After re-allocation, 68 and 27 unclassified patients were reduced to 4 and 5 in the pilot and validation sets, respectively. CONCLUSION: Both the CC and tTD narrow in the course of liver disease after dilation. Moreover, the maximum diameter of the CC and tTD can be used to re-allocate patients who are unclassified according to the Baveno-VII criteria. CLINICAL TRIAL NUMBER: UMIN trial no. 000044857.