Comparative efficacy of pharmacologic therapies for MASLD in improving fibrosis: systematic review and network meta-analysis.

Fibrosis impacts long-term outcomes among patients with nonalcoholic fatty liver disease (NAFLD). Due to well-documented flaws associated with liver biopsy, there has been a recent emphasis on prioritizing noninvasive testing over liver biopsy for the assessment of fibrosis. A comprehensive systematic review and frequentist random effects network meta-analysis was performed among randomized controlled trials reporting pharmacologic intervention in NAFLD. The primary endpoint was the absolute change in liver stiffness measurement (LSM) via elastography. Secondary endpoints included changes in noninvasive serologic tests including APRI, fibrosis-4 index, NAFLD fibrosis score, enhanced liver fibrosis (ELF) and FibroTest (FibroSure in the USA). Forty-five randomized controlled trials enrolling 6932 patients were identified for this network meta-analysis. Across the primary endpoint, firsocostat, semaglutide, montelukast, cilofexor plus firsocostat, obeticholic acid and diacerein (change in LSM via vibration controlled transient elastography), in addition to lubiprostone and pemafibrate (change in LSM via magnetic resonance elastography) were found to be the most effective and statistically significant treatment interventions. Similarly, the following interventions were determined to be most effective as compared to placebo among secondary endpoints: saroglitazar, lubiprostone, and obeticholic acid (change in APRI); saroglitazar, semaglutide, firsocostat and cilofexor plus firsocostat (change in ELF); obeticholic acid and belapectin [change in FibroTest/FibroSure]. This is the first systematic review and network meta-analysis reporting pharmacologic efficacy in the progression of fibrosis based on noninvasive testing among patients with NAFLD. Semaglutide, obeticholic acid, firsocostat, cilofexor plus firsocostat and lubiprostone were found to be the most effective treatments based on their consistent efficacy reproduced across multiple endpoints, both via elastography and noninvasive blood tests.

To the editor, We read with interest the study by Gidener et al.1 on the value of repeated liver stiffness measurements (LSMs) by magnetic resonance elastography (MRE) for prediction of outcomes in NAFLD. We congratulate the researchers on their statistically sound approach to capture dynamics in LSM and would like to discuss some important aspects of this study. First, the lack of knowledge on the reason for repeating the MRE‐LSM combined with the retrospective design of the study may have introduced selection, confirmation, and survival bias. For example, there is no knowledge of the clinical reason for repeating the MRE measurement, making those selected for and/or survived to have a second LSM an indeed selected cohort. Also, no data on the total number of NAFLD patients who were potentially eligible for a repeated MRE‐LSM are given. With this regard, an inception cohort would allow to compare the prognostic ability of baseline MRE‐LSM with serial changes. Second, the small sample size limits generalizability of the results: The 100% rate of hepatic decompensation was derived from 3 patients from a total of only 29 patients with compensated cirrhosis at last MRE‐LSM, including 2 patients who developed jaundice as an incident event. Similarly, associations of progression with “incident cirrhosis” were derived from 1 in 7 progressors who did not have cirrhosis at last MRE‐LSM. It could be suspected that patients with increasing LSMs are more likely to undergo further investigations and thereby get diagnosed with “incidence cirrhosis.” Therefore, larger studies are needed to validate the relevance of “progression” that go beyond the 19% increase cutoff. Although this cutoff has been derived from the repeatability coefficient in MRE2 and was proposed to be corresponding to a “true” change in LSM, its clinical significance remains to be validated. Third, whereas only hypertension was associated with changes in LSM, further elaboration/discussion of this finding could limit speculations about unmeasured confounders given the limited pathophysiological evidence for a causal connection between arterial hypertension and fibrosis progression. Fourth, although the researchers assessed longitudinal changes of MRE‐LSM in NAFLD, it would be interesting to see the results of the subgroup of patients with steatohepatitis being prone to fibrosis progression and liver‐related outcomes. Also, 24 patients with decompensated cirrhosis were included in this study, but neither separately analyzed nor further discussed. Finally, although MRE‐LSM showed a higher accuracy for fibrosis staging compared to vibration‐controlled transient elastography (VCTE), current guidelines do not recommend its routine nor repeated use because of limited availability and unfavorable cost‐effectiveness. With this regard, similar studies investigating the prognostic relevance of dynamics in VCTE‐based LSM are warranted.

Impact of 20% Change in Vibration-controlled Transient Elastography-measured Liver Stiffness on Liver-related Outcomes: A Systematic Review and Meta-analysis.

New treatments/targets for primary biliary cholangitis.

Increases and decreases in liver stiffness measurement are independently associated with the risk of liver-related events in NAFLD

Role of two-dimensional shear wave elastography in the assessment of chronic liver diseases.

Background & aimsIn primary biliary cholangitis (PBC), static liver stiffness measurement (LSM) has proven prognostic value. However, the added prognostic value of LSM time course in this disease remains uncertain. MethodsWe conducted an international retrospective cohort study among PBC patients treated with ursodeoxycholic acid (UDCA) and followed by vibration-controlled transient elastography (VCTE) between 2003 and 2022. Using joint modeling, the association of LSM trajectory and the incidence of serious clinical events (SCE), defined as cirrhosis complications, liver transplantation (LT) or death, was quantified using the hazard ratio (HR) and its confidence interval (CI). ResultsA total of 6,362 LSMs were performed in 3,078 patients (2,007 on UDCA alone; 13% with cirrhosis), in whom 316 SCE occurred over 14,445 person-years (median follow-up, 4.2 years; incidence rate, 21.9 per 1,000 person-years). LSM progressed in 59% of patients (mean 0.39 kPa/year). After adjusting for prognostic factors at baseline, including LSM, any relative change in LSM was associated with a significant variation in SCE risk (p<0.001). For example, the adjusted HRs (95% CI) associated with a 20% annual variation in LSM were 2.13 (1.89 – 2.45) for the increase and 0.40 (0.33 – 0.46) for the decrease. The association between LSM trajectory and SCE risk persisted regardless of treatment response or duration, when patients with cirrhosis were excluded, and when only death or LT was considered. ConclusionsTracking longitudinal changes in LSM using VCTE provides valuable insights into PBC prognosis, offering a robust predictive measure for the risk of SCE. LSM could be used as a clinically relevant surrogate endpoint in PBC clinical trials.

Magnetic resonance elastography (MRE) and vibration-controlled transient elastography (VCTE) have the potential to assess disease progression; however, repeatability data in people with cirrhosis are lacking. We aimed to assess the effect of disease severity on measurement variability and contribute to the evidentiary basis for the qualification of repeating liver stiffness measurements (LSM) in practice and research. This prospective study included 49 adult participants (58.3% female) with cirrhosis who underwent same-day repeat LSM examinations. The primary outcome was the same-day, same-operator repeatability coefficient% (RC%) and the within-case coefficient of variation (wCV) for each modality. Secondary outcomes include the intra-class correlation coefficient (ICC). The relationship between measurement variability (interquartile for VCTE, standard deviation for MRE) and disease severity (mean liver stiffness) was evaluated by linear regression with the coefficient of determination R2 reported. Same-day repeat MRE and VCTE exams were prospectively conducted in 33 and 45 participants, respectively. The RC% appeared 82% higher for VCTE versus MRE (38% vs. 21%), with consistent findings in head-to-head analyses. The wCV for VCTE and MRE was 14% and 8% respectively, indicating VCTE has 75% higher within-subject measurement variation than MRE. ICC was excellent for LSM by VCTE (0.92) and MRE (0.96). Measurement variability increased with mean liver stiffness for VCTE (R2 = 0.78) and MRE (R2 = 0.93). Both VCTE and MRE demonstrated increased measurement variability with disease severity. However, MRE outperformed VCTE in terms of technical repeatability in patients with cirrhosis. These repeatability estimates may improve the qualification of NITs in practice.

The availability of new drugs for the treatment of patients with metabolic dysfunction-associated steatotic liver disease (MASLD) underlines the need of early predictors of response to such therapies. This study evaluated the impact of 1-year changes in liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE), controlled attenuation parameters (CAP), and serum alanine aminotransferase (ALT) on liver outcomes in patients with MASLD. A large multicenter cohort of MASLD patients with LSM ≥8 kPa and prospective follow-up was enrolled. Liver-related events (LREs), including hepatocellular carcinoma (HCC) and liver decompensation (LD), were evaluated during follow-up. LSM, CAP, ALT, and Fibrosis-4 Index (FIB-4) were assessed at baseline and at 1-year follow-up. Cause-specific Cox regression analyses were performed to correlate 1-year variation in LSM, CAP, ALT, and FIB-4 with the risk of developing LRE, LD, and HCC, in terms of cause-specific hazard ratios (csHRs). We included 1744 patients with LSM ≥8 kPa (median age, 55 years; 52.1% male; 58.3% obese; 55.8% with diabetes) and 989 with LSM ≥10 kPa (median age, 56 years; 50.2% male; 54.7% obese; 51% with diabetes), followed for a median of 28.2 and 32 months, respectively. LREs occurred in 39 patients with LSM ≥8 kPa (26 LD, 22 HCC) and in 35 with LSM ≥10 kPa (25 LD, 19 HCC). A 1-year variation in LSM, but not in CAP, ALT, or FIB-4, was independently associated with LRE in patients with MASLD and LSM ≥8 kPa (csHR, 1.007; 95% confidence interval [CI], 1.001-1.014). Likewise, 1-year LSM variation (csHR, 1.009; 95% CI, 1.000-1.018) independently predicted LD in this population, whereas no 1-year changes in CAP, ALT, or FIB-4 were associated with LD risk. No independent associations were observed between 1-year changes in LSM, CAP, ALT, or FIB-4 and the risk of HCC. All findings were confirmed in patients with LSM ≥10 kPa and in those at high risk of progression with type 2 diabetes. In patients with MASLD and LSM ≥8 or ≥10 kPa, the % LSM reduction at 1 year was independently associated with lower risk of LRE and LD.

Needle-free Nonalcoholic Fatty Liver Disease Prognostication: Moving One Step Closer

To compare biliary stricture severity on magnetic resonance cholangiopancreatography (MRCP), magnetic resonance elastography (MRE), and vibration-controlled transient elastography (VCTE) liver stiffness (LS) for evaluation of risk stratification and prognostication in primary sclerosing cholangitis (PSC). Eighty-seven patients (31-61years; 34 female/53 male) prospectively underwent biochemical testing, VCTE, MRCP, and MRE between January 2014 and July 2016. Correlation between the MRCP grading of PSC based on biliary stricture severity, LS on MRE and VCTE, and the Mayo Risk Score as well as the Amsterdam Oxford Prognostic Index (AOPI) were evaluated and compared. Stricture severity was classified according to previous classification systems based on ERCP. Spearman's correlation and Kruskal-Wallis tests were performed. MRE-LS and intrahepatic stricture severity combined demonstrated higher discriminatory ability among risk categories based on Mayo Risk Score (AUROC = 0.8). MRE-LS alone demonstrated excellent discriminatory ability among risk categories based on AOPI using cutoffs of 1 and 2.7 and was superior to intrahepatic stricture severity (AUROC = 0.9, AUROC = 0.6-0.7). There was a weak correlation between intrahepatic stricture severity and MRE-LS (rho = 0.3; p = 0.011). VCTE-LS values were not correlated with stricture severity and were noncontributory to differentiate patients across risk groups. Intrahepatic stricture severity alone was a poor discriminator of advanced liver fibrosis on MRE (AUROC = 0.7); however, combining intra- and extrahepatic stricture severity and controlling for cholestasis and disease duration improved results (AUROC = 0.9). This study demonstrates a significant discriminatory ability of LS values on MRE to distinguish between early to moderate and advanced liver fibrosis. LS values on MRE may add value to risk prognostication and further studies including clinical outcomes are needed. • Risk stratification was excellent for liver stiffness measurements on MRE and poor for VCTE and biliary stricture severity. • Risk stratification was further improved when liver stiffness measured on MRE was combined with intrahepatic and extrahepatic stricture severity and indicators of cholestasis were controlled for. • Liver stiffness measurements on MRE correlated with prognostic scores better than measurements performed on VCTE.

In patients with metabolic dysfunction-associated steatotic liver disease (MASLD), there are limited data on how changes in FIB4 and liver stiffness measurement (LSM) correlate in non-biopsy cohorts. Our objective was to evaluate associations between changes in FIB4 and LSM in MASLD patients. We included MASLD patients with serial VCTE from 2015-2022. The primary predictors were change in FIB4 and presence of diabetes, obesity, and high alanine aminotransferase (ALT). The primary outcome, applied only to patients with LSM1 < 8kPa, was incident significant fibrosis (SF) defined as a ≥ 20% increase in LSM2 vs. LSM1 and LSM2 ≥ 8kPa. A secondary outcome was LSM progression with a similar definition but applied to all participants, not only those with LSM1 < 8kPa. Of 285 included patients, 216 had LSM1 < 8kPa and were included in the primary analysis; of these, 34 (16%) had incident SF. Changes in FIB4 correlated with changes in LSM (R = 0.16, p = 0.016). Independent predictors of incident SF included comorbid diabetes mellitus (OR 2.43, 95% CI 1.04-6.56), obesity (OR 3.88, 95% CI 1.63-9.25), and baseline ALT ≥ 30 (OR 8.55, 95% CI 1.10-66.29). A model including ALT, diabetes, and obesity outperformed a model with FIB4 change alone. Among patients with MASLD, changes in FIB4 correlated with changes in LSM but more significant correlates of incident significant fibrosis included diabetes mellitus, obesity, and high baseline ALT.

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). 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 ≥10kPa) 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 <10kPa or <20kPa with LSM decrease ≥20% ("cACLD decreasers"). In patients without cACLD, we defined follow-up LSM ≥10kPa as an LSM increase ("No cACLD increasers"). The remaining patients were considered LSM stable. We followed 536 patients for 3,008 patient-years-median age 57 years (IQR 49-63), baseline LSM 8.1kPa (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). LSM by transient elastography predicts decompensation and all-cause mortality in patients with compensated ALD both at diagnosis and when used for monitoring. 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.

Direct Comparison of US and MR Elastography for Staging Liver Fibrosis in Patients With Nonalcoholic Fatty Liver Disease

Obeticholic acid may increase the risk of gallstone formation in susceptible patients