Dr.ssa Federica Calvo Prof. Elisabetta Bugianesi ‘Diagnostic accuracy and prognostic significance of non-invasive fibrosis tests in NAFLD’ Journal Club 11.12.2017 Dr.ssa Federica Calvo Prof. Elisabetta Bugianesi

Worldwide prevalence of NAFLD Younossi & Bugianesi Nat Gastro Rev 2017 in press

Global NAFLD/NASH epidemic Diehl and Day. NEJM 2017

“The need for NAFLD screening in the community has been questioned given the high direct and indirect costs of testing, the low predictive value of non-invasive tests, the risks of liver biopsy and the lack of effective treatments “ “However, the progressive form of NAFLD (i.e. NASH), particularly when associated with advanced fibrosis, should be identified in patients at risk (age > 50 years, type 2 diabetes mellitus (T2DM) or MetS), because of its prognostic implications”

Fibrosis, not NASH, predicts survival

Non-invasive markers in NAFLD: what we need? Fare esempio HbA1c

Molti studi hanno valutato l’accuratezza diagnostica di numerosi test/score di fibrosi. Il migliore marcatore è quello che ha più alta SE, SP, PPV, NPV e AUROC > 0.80. NPV per escludere la fibrosi avanzata è più alto del PPV. Inoltre questi studi suggeriscono che i biomarkers sono marcatori prognostici predittivi di overall mortality, mortalità da complicanze epato-relate e da cause extra-epatiche.

Fare esempio HbA1c EASL-EASD-EASO CPG for the management of non-alcoholic fatty liver diasease, 2016

Fibroscan e test bioumorali di fibrosi richiedono successive valutazioni in NAFLD, con un confronto diretto della loro accuratezza diagnostica e con la valutazione del significato prognostico in un ampia popolazione di paziente con NAFLD.

Aims Evaluate and directly compare the accuracy of eight blood tests and FibroScan for the non-invasive diagnosis of liver fibrosis in a large population of NALFD patients and develop fibrosis classifications that allow a precise estimation of the histological fibrosis stage, without the need for liver biopsy (Cross-sectional study) Validate the clinical relevance of fibrosis classifications by evaluating their prognostic accuracy (Longitudinal study).

Cross-sectional study Biopsy-proven NAFLD were included from 2004 to 2014 at Angers and Bordeaux University Hositals Biopsy-proven NALFD included from 2004 to 2014 at Angers and Bordeaux University Hospitals

Blood fibrosis tests AST/platelet ratio index (APRI) FIB-4 score AST (IU/L)/ (ULN) /platelet count (x109/L) x 100; Score > 1 associated with cirrhosis FIB-4 score age x AST (IU/L)/platelet count (x109/L) x √ ALT (IU/L); Score < 1.3 to exclude advanced fibrosis; Score > 3.25 to diagnose advanced fibrosis BARD score AST/ALT ratio ≥0.8 = 2 points; BMI ≥28 = 1 point; diabetes = 1 point. Range: from 0 to 4 points. NAFLD Fibrosis Score (NFS) -1.675 + 0.037 x Age (years) + 0.094 x BMI (kg/m2) + 1.13 x IFG/diabetes (yes = 1, no = 0) + 0.99 x AST/ALT ratio - 0.013 x platelet (x109/l) - 0.66 x Albumin (g/dl). Score < -1.455 to exclude advanced fibrosis; Score > 0.676 to diagnose advanced fibrosis Commercial Panels including : Fibrotest, FibroMeterNAFLD, FibroMeter V2G, Hepascore

Comparison of the diagnostic accuracy of non-invasive fibrosis tests Per la diagnosi di fribrosi avanzata, target diagnostico primario dello studio, il Fibrometer V2G e il Fibroscan hanno valori di AUROC significativamente più elevati rispetto agli altri test. Obukovsky index: valuta la capacità dei test di fibrosi di discriminare gli stadi di fibrosi

Comparison of the diagnostic accuracy of non-invasive fibrosis tests

Fibrosis Classifications Fibrosis classifications of FibroScan and FibroMeter V2G: estimation of the pathological fibrosis stage from the fibrosis tests results (diagnostic accuracy, respectively 80.8% vs 77.4%, p=0.190). LSM and FM V2G had the highest Obuchowsky index (ability of fibrosis tests to discriminate individual fibrosis stage). Sono state poi sviluppate due classificazioni della fibrosi che ci forniscono una stima precisa dello stadio istologico di fibrosi dai risultati ottenuti da Fibrometer e fibroscan, senza biopsia epatica. Sono stati scelti questi due test perché sono i più accurati; in particolare l’Obuchiwski index suggerisce che essi hanno la maggiore capacità discriminante tra i vari stadi di fibrosi.

Longitudinal study: outcome prediction From January 2005 to December 2009 360 NAFLD patients with blood sampling and LSM at baseline followed for a median period of 6.4 yrs 83 pts died (causes of death: 20% liver-related complications, CVD 23%, malignacy 34%) E’stata valutata l’accuratezza prognostica di 4 test bioumorali e del fibroscan. Il fibroscan ha la maggiore accuratezza nel predire la mortalità per complicanze epatorelate, mentre il fibrometer per l’overall mortality (anche se AUROC <0.8).

Elastography and Outcome Prediction

FibroMeterV2G and Outcome Prediction

Conclusions Fibroscan and FibroMeterV2G were the two most accurate tests fot the non invasive diagnosis of liver fibrosis in NAFLD. The fibrosis classifications are very relevant for clinical practice because, in addition to accurately estimate the liver fibrosis stage, they can be categorise patients into subgroups with significantly different prognosis, without the need for any liver biopsy.

Non-invasive markers in NAFLD: what we need?

5 year programme 47 EU Partners Academic and Industry 34 milion Euro Start: Nov 2017