Simple blood tests to diagnose compensated advanced chronic liver disease and stratify the risk of clinically significant portal hypertension.

BACKGROUND AND AIMS: Compensated advanced chronic liver disease (cACLD) identifies patients at risk for clinically significant portal hypertension (CSPH), and thus, for liver-related complications. The limited availability of liver stiffness measurements (LSM) impedes the identification of patients at risk for cACLD/CSPH outside of specialized clinics. We aimed to develop a blood-based algorithm to identify cACLD by fibrosis-4 (FIB-4) and CSPH by von Willebrand factor/platelet count ratio (VITRO). APPROACH AND RESULTS: Patients with (suspected) compensated chronic liver disease undergoing FIB-4+LSM were included in the LSM/FIB-4 cohorts from Vienna and Salzburg. The HVPG/VITRO cohorts included patients undergoing HVPG-measurement + VITRO from Vienna and Bern.LSM/FIB-4-derivation-cohort: We included 6143 patients, of whom 211 (3.4%) developed hepatic decompensation. In all, 1724 (28.1%) had LSM ≥ 10 kPa, which corresponded to FIB-4 ≥ 1.75. Importantly, both LSM (AUROC:0.897 [95% CI:0.865-0.929]) and FIB-4 (AUROC:0.914 [95% CI:0.885-0.944]) were similarly accurate in predicting hepatic decompensation within 3 years. FIB-4 ≥ 1.75 identified patients at risk for first hepatic decompensation (5 y-cumulative incidence:7.6%), while in those <1.75, the risk was negligible (0.3%).HVPG/VITRO-derivation cohort: 247 patients of whom 202 had cACLD/FIB-4 ≥ 1.75 were included. VITRO exhibited an excellent diagnostic performance for CSPH (AUROC:0.889 [95% CI:0.844-0.934]), similar to LSM (AUROC:0.856 [95% CI:0.801-0.910], p = 0.351) and the ANTICIPATE model (AUROC:0.910 [95% CI:0.869-0.952], p = 0.498). VITRO < 1.0/ ≥ 2.5 ruled-out (sensitivity:100.0%)/ruled-in (specificity:92.4%) CSPH. The diagnostic performance was comparable to the Baveno-VII criteria.LSM/FIB-4-derivation cohort findings were externally validated in n = 1560 patients, while HVPG/VITRO-derivation-cohort findings were internally (n = 133) and externally (n = 55) validated. CONCLUSIONS: Simple, broadly available laboratory tests (FIB-4/VITRO) facilitate cACLD detection and CSPH risk stratification in patients with (suspected) liver disease. This blood-based approach is applicable outside of specialized clinics and may promote early intervention.

Dynamics in Liver Stiffness Measurements Predict Outcomes in Advanced Chronic Liver Disease.

BACKGROUND & AIMS: Liver stiffness measurements (LSMs) provide an opportunity to monitor liver disease progression and regression noninvasively. We aimed to determine the prognostic relevance of LSM dynamics over time for liver-related events and death in patients with chronic liver disease. METHODS: Patients with chronic liver disease undergoing 2 or more reliable LSMs at least 180 days apart were included in this retrospective cohort study and stratified at baseline (BL) as nonadvanced chronic liver disease (non-ACLD, BL-LSM < 10 kPa), compensated ACLD (cACLD; BL-LSM ≥ 10 kPa), and decompensated ACLD. Data on all consecutive LSMs and clinical outcomes were collected. RESULTS: There were 2508 patients with 8561 reliable LSMs (3 per patient; interquartile range, 2-4) included: 1647 (65.7%) with non-ACLD, 757 (30.2%) with cACLD, and 104 (4.1%) with decompensated ACLD. Seven non-ACLD patients (0.4%) and 83 patients with cACLD (10.9%) developed hepatic decompensation (median follow-up, 71 months). A 20% increase in LSM at any time was associated with an approximately 50% increased risk of hepatic decompensation (hazard ratio, 1.58; 95% CI, 1.41-1.79; P < .001) and liver-related death (hazard ratio, 1.45; 95% CI, 1.28-1.68; P < .001) in patients with cACLD. LSM dynamics yielded a high accuracy to predict hepatic decompensation in the following 12 months (area under the receiver operating characteristics curve = 0.933). The performance of LSM dynamics was numerically better than dynamics in Fibrosis-4 score (0.873), Model for End-Stage Liver Disease (0.835), and single time-point LSM (BL-LSM: 0.846; second LSM: 0.880). Any LSM decrease to <20 kPa identified patients with cACLD with a substantially lower risk of hepatic decompensation (hazard ratio, 0.13; 95% CI, 0.07-0.24). If reliable, LSM also confers prognostic information in decompensated ACLD. CONCLUSIONS: Repeating LSM enables an individual and updated risk assessment for decompensation and liver-related mortality in ACLD.

Diagnostic and prognostic performance of the LiverRisk score in tertiary care.

Background & Aims: The LiverRisk score has been proposed as a blood-based tool to estimate liver stiffness measurement (LSM), thereby stratifying the risk of compensated advanced chronic liver disease (cACLD, LSM ≥10 kPa) and liver-related events in patients without known chronic liver disease (CLD). We aimed to evaluate its diagnostic/prognostic performance in tertiary care. Methods: Patients referred to two hepatology outpatient clinics (cohort I, n = 5,897; cohort II, n = 1,558) were retrospectively included. Calibration/agreement of the LiverRisk score with LSM was assessed, and diagnostic accuracy for cACLD was compared with that of fibrosis-4 (FIB-4)/aspartate aminotransferase-to-platelet ratio index (APRI). The prediction of hepatic decompensation and utility of proposed cut-offs were evaluated. Results: In cohort I/II, mean age was 48.3/51.8 years, 44.2%/44.7% were female, predominant etiologies were viral hepatitis (51.8%)/metabolic dysfunction-associated steatotic liver disease (63.7%), median LSM was 6.9 (IQR 5.1-10.9)/5.8 (IQR 4.5-8.8) kPa, and 1,690 (28.7%)/322 (20.7%) patients had cACLD.Despite a moderate correlation (Pearson's r = 0.325/0.422), the LiverRisk score systematically underestimated LSM (2.93/1.80 points/kPa lower), and range of agreement was wide, especially at higher values.The diagnostic accuracy of the LiverRisk score for cACLD (area under the receiver operator characteristics curve [AUROC] 0.757/0.790) was comparable to that of FIB-4 (AUROC 0.769/0.813) and APRI (AUROC 0.747/0.765). The proposed cut-off of 10 points yielded an accuracy of 74.2%/81.2%, high specificity (91.9%/93.4%), but low negative predictive value (76.6%/84.5%, Cohen's κ = 0.260/0.327).In cohort I, 208 (3.5%) patients developed hepatic decompensation (median follow-up 4.7 years). The LiverRisk score showed a reasonable accuracy for predicting hepatic decompensation within 1-5 years (AUROC 0.778-0.832). However, it was inferior to LSM (AUROC 0.847-0.901, p <0.001) and FIB-4 (AUROC 0.898-0.913, p <0.001). Similar to the strata of other non-invasive tests, the proposed LiverRisk groups had distinct risks of hepatic decompensation. Conclusions: The LiverRisk score did not improve the diagnosis of cACLD or prediction of hepatic decompensation in the tertiary care setting. Impact and implications: The LiverRisk score has been proposed as a non-invasive tool to estimate liver stiffness measurement and thus the risk of compensated advanced chronic liver disease and liver-related events. As automatic implementation into lab reports is being discussed, the question of its applicability outside of opportunistic screening in the general population arises. In two large cohorts of patients referred to hepatology outpatient clinics, the LiverRisk score did not accurately predict liver stiffness, did not improve cACLD identification, and had a lower predictive performance for hepatic decompensation as compared with FIB-4. Although it represents a major step forward for screening patients without known liver disease in primary care, our findings indicate that the LiverRisk score does not improve patient management outside the primary care setting, that is, in cohorts with a higher pre-test probability of cACLD.