Diagnostic accuracy of non-invasive tests to screen for at-risk MASH-An individual participant data meta-analysis.

BACKGROUND & AIMS: There is a need to reduce the screen failure rate (SFR) in metabolic dysfunction-associated steatohepatitis (MASH) clinical trials (MASH+F2-3; MASH+F4) and identify people with high-risk MASH (MASH+F2-4) in clinical practice. We aimed to evaluate non-invasive tests (NITs) screening approaches for these target conditions. METHODS: This was an individual participant data meta-analysis for the performance of NITs against liver biopsy for MASH+F2-4, MASH+F2-3 and MASH+F4. Index tests were the FibroScan-AST (FAST) score, liver stiffness measured using vibration-controlled transient elastography (LSM-VCTE), the fibrosis-4 score (FIB-4) and the NAFLD fibrosis score (NFS). Area under the receiver operating characteristics curve (AUROC) and thresholds including those that achieved 34% SFR were reported. RESULTS: We included 2281 unique cases. The prevalence of MASH+F2-4, MASH+F2-3 and MASH+F4 was 31%, 24% and 7%, respectively. Area under the receiver operating characteristics curves for MASH+F2-4 were .78, .75, .68 and .57 for FAST, LSM-VCTE, FIB-4 and NFS. Area under the receiver operating characteristics curves for MASH+F2-3 were .73, .67, .60, .58 for FAST, LSM-VCTE, FIB-4 and NFS. Area under the receiver operating characteristics curves for MASH+F4 were .79, .84, .81, .76 for FAST, LSM-VCTE, FIB-4 and NFS. The sequential combination of FIB-4 and LSM-VCTE for the detection of MASH+F2-3 with threshold of .7 and 3.48, and 5.9 and 20 kPa achieved SFR of 67% and sensitivity of 60%, detecting 15 true positive cases from a theoretical group of 100 participants at the prevalence of 24%. CONCLUSIONS: Sequential combinations of NITs do not compromise diagnostic performance and may reduce resource utilisation through the need of fewer LSM-VCTE examinations.

A novel serum metabolomic panel distinguishes IgG4-related sclerosing cholangitis from primary sclerosing cholangitis.

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) and IgG4-related sclerosing cholangitis (IgG4-SC) are chronic fibro-inflammatory immune-mediated hepatobiliary conditions that are challenging to distinguish in a clinical setting. Accurate non-invasive biomarkers for discriminating PSC and IgG4-SC are important to ensure a correct diagnosis, prompt therapy and adequate cancer surveillance. METHODS: We performed nuclear magnetic resonance (NMR)-based metabolomic profiling using serum samples collected prospectively from patients with PSC (n = 100), IgG4-SC (n = 23) and healthy controls (HC; n = 16). RESULTS: Multivariate analysis of the serum metabolome discriminated PSC from IgG4-SC with greater accuracy (AUC 0.95 [95%CI 0.90-0.98]) than IgG4 titre (AUC 0.87 [95%CI 0.79-0.94]). When inflammatory bowel disease (IBD) was excluded as a comorbid condition (IgG4-SC n = 20, PSC n = 22), the diagnostic AUC increased to 1.0, suggesting that the metabolome differences identified are not a result of the increased prevalence of IBD in PSC relative to IgG4-SC patients. Serum lactate (p < .0001), glucose (p < .01) and glutamine (p < .01) metabolites were increased in IgG4-related disease (IgG4-RD) and IgG4-SC individuals compared to PSC, whereas mobile choline (p < .05), 3-hydroxybutyric acid (p < .01) and -CH3 lipoprotein resonances (p < .01) were decreased. CONCLUSIONS: Taken together, serum metabolomic profiling has the potential to be incorporated as a diagnostic criterion, independent of IgG4 titre, to improve the diagnosis of IgG4-RD and help distinguish IgG4-SC from PSC.

A Quantitative Magnetic Resonance Cholangiopancreatography Metric of Intrahepatic Biliary Dilatation Severity Detects High-Risk Primary Sclerosing Cholangitis.

Magnetic resonance imaging with magnetic resonance cholangiopancreatography (MRI-MRCP) in primary sclerosing cholangitis (PSC) is currently based on qualitative assessment and has high interobserver variability. We investigated the utility and performance of quantitative metrics derived from a three-dimensional biliary analysis tool in adult patients with PSC. MRI-MRCP, blood-based biomarkers, and FibroScan were prospectively performed in 80 participants with large-duct PSC and 20 healthy participants. Quantitative analysis was performed using MRCP+ (Perspectum Ltd., United Kingdom), and qualitative reads were performed by radiologists. Inter-reader agreements were compared. Patients were classified into high risk or low risk for disease progression, using Mayo risk score (MRS), Amsterdam-Oxford model (AOM), upper limit of normal (ULN) alkaline phosphatase (ALP), disease distribution, and presence of dominant stricture. Performance of noninvasive tools was assessed using binomial logistic regressions and receiver operating characteristic curve analyses. Quantitative biliary metrics performed well to distinguish abnormal from normal bile ducts (P < 0.0001). Interobserver agreements for MRCP+ dilatation metrics (intraclass correlation coefficient, 0.90-0.96) were superior to modified Amsterdam intrahepatic stricture severity score (κ = 0.74) and Anali score (κ = 0.38). MRCP+ intrahepatic dilatation severity showed excellent performance to classify patients into high-risk and low-risk groups, using predictors of disease severity as the reference (MRS, P < 0.0001; AOM, P = 0.0017; 2.2 × ULN ALP, P = 0.0007; 1.5 × ULN ALP, P = 0.0225; extrahepatic disease, P = 0.0331; dominant stricture, P = 0.0019). MRCP+ intrahepatic dilatation severity was an independent predictor of MRS >0 (odds ratio, 31.3; P = 0.035) in the multivariate analysis. Conclusion: Intrahepatic biliary dilatation severity calculated using MRCP+ is elevated in patients with high-risk PSC and may be used as an adjunct for risk stratification in PSC. This exploratory study has provided the groundwork for examining the utility of novel quantitative biliary metrics in multicenter studies.

Prognostic value of multiparametric magnetic resonance imaging, transient elastography and blood-based fibrosis markers in patients with chronic liver disease.

BACKGROUND & AIMS: Liver cT1 , liver T1 , transient elastography (TE) and blood-based biomarkers have independently been shown to predict clinical outcomes but have not been directly compared in a single cohort of patients. Our aim was to compare these tests' prognostic value in a cohort of patients with compensated chronic liver disease. METHODS: Patients with unselected compensated liver disease aetiologies had baseline assessments and were followed up for development of clinical outcomes, blinded to the imaging results. The prognostic value of non-invasive liver tests at prespecified thresholds was assessed for a combined clinical endpoint comprising ascites, variceal bleeding, hepatic encephalopathy, hepatocellular carcinoma, liver transplantation and mortality. RESULTS: One hundred and ninety-seven patients (61% male) with median age of 54 years were followed up for 693 patient-years (median (IQR) 43 (26-58) months). The main diagnoses were NAFLD (41%), viral hepatitis (VH, 25%) and alcohol-related liver disease (ArLD; 14%). During follow-up 14 new clinical events, and 11 deaths occurred. Clinical outcomes were predicted by liver cT1  > 825ms with HR 9.9 (95% CI: 1.29-76.4, P = .007), TE > 8kPa with HR 7.8 (95% CI: 0.97-62.3, P = .02) and FIB-4 > 1.45 with HR 4.09 (95% CI: 0.90-18.4, P = .05). In analysis taking into account technical failure and unreliability, liver cT1  > 825 ms could predict clinical outcomes (P = .03), but TE > 8kPa could not (P = .4). CONCLUSIONS: We provide further evidence that liver cT1 , TE and serum-based biomarkers can predict clinical outcomes, but when taking into account technical failure/unreliability, TE cut-offs perform worse than those of cT1 and blood biomarkers.

Evolving role of magnetic resonance techniques in primary sclerosing cholangitis.

Development of non-invasive methods to risk-stratify patients and predict clinical endpoints have been identified as one of the key research priorities in primary sclerosing cholangitis (PSC). In addition to serum and histological biomarkers, there has been much recent interest in developing imaging biomarkers that can predict disease course and clinical outcomes in PSC. Magnetic resonance imaging/magnetic resonance cholangiopancreatography (MRI/MRCP) continue to play a central role in the diagnosis and follow-up of PSC patients. Magnetic resonance (MR) techniques have undergone significant advancement over the last three decades both in MR data acquisition and interpretation. The progression from a qualitative to quantitative approach in MR acquisition techniques and data interpretation, offers the opportunity for the development of objective and reproducible imaging biomarkers that can potentially be incorporated as an additional endpoint in clinical trials. This review article will discuss how the role of MR techniques have evolved over the last three decades from emerging as an alternative diagnostic tool to endoscopic retrograde cholangiopancreatography, to being instrumental in the ongoing search for imaging biomarker of disease stage, progression and prognosis in PSC.