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Summary: Background: One of the unmet needs in patients with type 2 diabetes mellitus (T2DM) is the prediction of non‐alcoholic liver disease by non‐invasive blood tests, for each of the three main histological features, fibrosis, non‐alcoholic steatohepatitis (NASH) and steatosis. Aims: To validate externally the performances of a recent panel, Nash‐FibroTest, for the assessment of the severity of fibrosis stages, NASH grades and steatosis grades. Methods: We prospectively analysed 272 patients with T2DM. Standard definitions of stages and grades were used, and analyses were centralised and blinded. The performances of the FibroTest, NashTest‐2 and SteatoTest‐2 were assessed using the Obuchowski measure (OM), the main outcome recommended as a summary measure of accuracy includeing all pairwise stages and grades comparisons, which is not provided par the extensively used binary area under the ROC curve. Results: The diagnostic performance of each component of the panel was significant. OM (SE; significance) of the FibroTest, the NashTest‐2 and the SteatoTest‐2 was 0.862 (0.012; P < 0.001), 0.827 (0.015; P < 0.001) and 0.794 (0.020; P < 0.01), respectively. For ballooning and lobular inflammation, OM was 0.794 (0.021; P < 0.001) and 0.821 (0.017; P < 0.001), respectively. In a post hoc analysis the FibroTest outperformed VCTE by 4.1% (2.5‐6.5; P < 0.001) for reliability, with a non‐significant difference for OM for fibrosis staging, 0.859 (0.012) for FibroTest vs 0.870 (0.009) for VCTE. Conclusions: From a single blood sample, the panel provides non‐invasive diagnosis of the stages of fibrosis, and the grades of NASH and steatosis in patients with T2DM. Trial registration number: NCT03634098. [ABSTRACT FROM AUTHOR]

Abstract Background FibroTest (FT) is a validated biomarker of fibrosis. To assess the applicability rate and to reduce the risk of false positives/negatives (RFPN), security algorithms were developed. The aims were to estimate the prevalence of RFPN and of proven failures, and to identify factors associated with their occurrences. Methods Four populations were studied: 954 blood donors (P1), 7,494 healthy volunteers (P2), 345,695 consecutive worldwide sera (P3), including 24,872 sera analyzed in a tertiary care centre (GHPS) (P4). Analytical procedures of laboratories with RFPN > 5% and charts of P4 patients in with RFPN were reviewed. Results The prevalence of RFPN was 0.52% (5/954; 95%CI 0.17-1.22) in P1, 0.51% (38/7494; 0.36-0.70) in P2, and 0.97% (3349/345695; 0.94-1.00) in P3. Three a priori high-risk populations were confirmed: 1.97% in P4, 1.77% in HIV centre and 2.61% in Sub-Saharan origin subjects. RFPN was mostly associated with low haptoglobin (0.46%), and high apolipoproteinA1 (0.21%). A traceability study of a P3 laboratory with RFPFN > 5% permitted to correct analytical procedures. Conclusion The mean applicability rate of Fibrotest was 99.03%. Independent factors associated with the high risk of false positives/negatives were HIV center, subSaharan origin, and a tertiary care reference centre, although the applicability rate remained above 97%.

Abstract Background FibroTest and elastography have been validated as biomarkers of liver fibrosis in the most frequent chronic liver diseases and in the fibrosis screening of patients with diabetes. One challenge was to use them for estimating the prevalence of fibrosis, identifying independent risk factors and to propose screening strategies in the general population. Methods We prospectively studied 7,463 consecutive subjects aged 40 years or older. Subjects with presumed advanced fibrosis (FibroTest greater than 0.48) were re-investigated in a tertiary center. Results The sample characteristics were similar to those of the French population. FibroTest was interpretable in 99.6%. The prevalence of presumed fibrosis was 2.8%, (209/7,463), including cirrhosis in 0.3% (25/7,463); 105/209 (50%) subjects with presumed fibrosis accepted re-investigation. Fibrosis was confirmed in 50, still suspected in 27, indeterminate in 25 and not confirmed with false positive FibroTest or false negative elastography in 3 subjects. False negative rate of FibroTest estimated using elastography was 0.4% (3/766). The attributable causes for confirmed fibrosis were both alcoholic and nonalcoholic fatty liver disease (NAFLD) in 66%, NAFLD in 13%, alcohol in 9%, HCV in 6%, and other in 6%. Factors independently associated (all P < 0.003) with confirmed fibrosis were age, male gender, waist circumference, HCV antibody and alcohol consumption estimated using carbohydrate-deficient transferrin, enabling efficient screening-oriented strategies to be compared and proposed. Conclusions Biomarkers have permitted to estimate prevalence of advanced fibrosis around 2.8% in a general population aged 40 years or older, and several risk factors which may be used for the validation of selective or non-selective screening strategies.

Summary: Background: No blood test has been shown to be effective in the prediction of primary liver cancer in patients without cirrhosis. Aim: To construct and internally validate two sequential tests for early prediction of liver cancer. These tests enable an algorithm which could improve the performance of the standard surveillance protocol recommended (imaging with or without AFP), limited to patients with cirrhosis. Methods: We performed a retrospective analysis in prospectively collected specimens from an ongoing cohort. We designed an early sensitive high‐risk test (LCR1) that combined (using Cox model) hepatoprotective proteins (apolipoproteinA1, haptoglobin) with known risk factors (gender, age, gammaglutamyltranspeptidase), and a marker of fibrosis (alpha2‐macroglobulin). To increase the specificity, we then combined (LCR2) these components with alpha‐fetoprotein. Results: A total of 9892 patients, 85.9% without cirrhosis, were followed up for 5.9 years [IQR: 4.3‐9.4]. LCR1 and LCR2 time‐dependent AUROCs were not different in construction and validation randomised subsets. Among 2027 patients with high‐LCR1 then high‐LCR2, 167 cancers (113 with cirrhosis, 54 without cirrhosis) were detected, that is 12 patients needed to screen one cancer. The negative predictive value was 99.5% (95% CI 99.0‐99.7) in the 2026 not screened patients (11 cancers without cirrhosis) higher than the standard surveillance, which detected 113 cancers in 755 patients screened, that is seven patients needed to screen one cancer, but with a lower negative predictive value 98.0% (97.5‐98.5; Z = 4.3; P < 0.001) in 3298 not screened patients (42 cancers without cirrhosis). Conclusions: In patients with chronic liver disease the LCR1 and LCR2 tests identify those with a high risk of liver cancer, including in those without cirrhosis. NCT01927133. [ABSTRACT FROM AUTHOR]