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

\ua9 2024 The Authors. Liver International published by John Wiley & Sons Ltd.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 Screen against Leishmania Intracellular Amastigotes: Comparison to a Promastigote Screen and Identification of a Host Cell-Specific Hit

The ability to screen compounds in a high-throughput manner is essential in the process of small molecule drug discovery. Critical to the success of screening strategies is the proper design of the assay, often implying a compromise between ease/speed and a biologically relevant setting. Leishmaniasis is a major neglected disease with limited therapeutic options. In order to streamline efforts for the design of productive drug screens against Leishmania, we compared the efficiency of two screening methods, one targeting the free living and easily cultured promastigote (insect–infective) stage, the other targeting the clinically relevant but more difficult to culture intra-macrophage amastigote (mammal-infective) stage. Screening of a 909-member library of bioactive compounds against Leishmania donovani revealed 59 hits in the promastigote primary screen and 27 in the intracellular amastigote screen, with 26 hits shared by both screens. This suggested that screening against the promastigote stage, although more suitable for automation, fails to identify all active compounds and leads to numerous false positive hits. Of particular interest was the identification of one compound specific to the infective amastigote stage of the parasite. This compound affects intracellular but not axenic parasites, suggesting a host cell-dependent mechanism of action, opening new avenues for anti-leishmanial chemotherapy

Stratification of disease severity in patients with liver fibrosis, cirrhosis and portal hypertension using novel multiparametric magnetic resonance imaging techniques

Chronic liver diseases (CLDs) affect millions worldwide and are a major cause of mortality. Recently, multiparametric magnetic resonance (MR) methods have been proposed as a non-invasive, quantitative biomarker for assessment of CLD. CLD traverses a spectrum of severity, and the aim of this thesis was to apply MR methods across this spectrum for a quantitative assessment of disease severity. The primary variable of interest was the iron and field strength corrected T1 (cT1), generated by LiverMultiScanTM software from T1 and T2* mapping techniques. Liver cT1 was found to predict liver-related clinical outcomes in patients with CLD (p825ms having a negative predictive value (NPV) of 100%. Liver cT1 quantitatively assessed changes in fibroinflammation in 15 patients with chronic hepatitis C virus (HCV) undergoing treatment by direct acting antiviral (DAA) therapy. Liver cT1 showed significant decreases from baseline to 24 weeks after end of treatment (EoT) (876 vs 806 ms, p=0.002), from baseline to 48 weeks EoT (876 vs 788 ms, p=0.0002) and from 24 weeks EoT to 48 weeks EoT (806 vs 788ms, p=0.016). Spleen cT1 had good diagnostic accuracy for presence of portal hypertension in both an adult cohort with CLD and a paediatric cohort with autoimmune liver disease (area under the receiver operating curve (AUC) of 0.85 and 0.81 respectively). In another adult cohort, spleen cT1 was predictive of future episodes of variceal bleeding (AUC: 0.74), especially in those on non-selective beta-blocker treatments (AUC: 0.97). A reference range for spleen T1 and cT1 was established using data from the United Kingdom Biobank population health study and healthy volunteers from our centre. Higher spleen T1 /cT1 was observed in women vs men and in children vs adults. This thesis provided further evidence that multiparametric MR methods combining T1 and T2* relaxometry can be used across the spectrum of CLD for stratification of disease severity

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 noninvasive liver tests at pre‐specified 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=0.007), TE>8kPa with HR 7.8 (95% CI: 0.97‐62.3, p=0.02) and FIB‐4>1.45 with HR 4.09 (95% CI: 0.90‐18.4, p=0.05). In analysis taking into account technical failure and unreliability, liver cT1>825 ms could predict clinical outcomes (p=0.03), but TE>8kPa could not (p=0.4). 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 cutoffs perform worse than those of cT1 and blood biomarkers.</p

Diagnostic accuracy of non-invasive tests for advanced fibrosis in patients with NAFLD: an individual patient data meta-analysis

Objective Liver biopsy is still needed for fibrosis staging in many patients with non-alcoholic fatty liver disease. The aims of this study were to evaluate the individual diagnostic performance of liver stiffness measurement by vibration controlled transient elastography (LSM-VCTE), Fibrosis-4 Index (FIB-4) and NAFLD (non-alcoholic fatty liver disease) Fibrosis Score (NFS) and to derive diagnostic strategies that could reduce the need for liver biopsies. Design Individual patient data meta-analysis of studies evaluating LSM-VCTE against liver histology was conducted. FIB-4 and NFS were computed where possible. Sensitivity, specificity and area under the receiver operating curve (AUROC) were calculated. Biomarkers were assessed individually and in sequential combinations. Results Data were included from 37 primary studies (n=5735; 45% women; median age: 54 years; median body mass index: 30 kg/m2; 33% had type 2 diabetes; 30% had advanced fibrosis). AUROCs of individual LSM-VCTE, FIB-4 and NFS for advanced fibrosis were 0.85, 0.76 and 0.73. Sequential combination of FIB-4 cut-offs (<1.3; ≥2.67) followed by LSM-VCTE cut-offs (<8.0; ≥10.0 kPa) to rule-in or rule-out advanced fibrosis had sensitivity and specificity (95% CI) of 66% (63–68) and 86% (84–87) with 33% needing a biopsy to establish a final diagnosis. FIB-4 cut-offs (<1.3; ≥3.48) followed by LSM cut-offs (<8.0; ≥20.0 kPa) to rule out advanced fibrosis or rule in cirrhosis had a sensitivity of 38% (37–39) and specificity of 90% (89–91) with 19% needing biopsy. Conclusion Sequential combinations of markers with a lower cut-off to rule-out advanced fibrosis and a higher cut-off to rule-in cirrhosis can reduce the need for liver biopsies