1. Non-invasive assessment of
NASH and fibrosis:
present and future
Salvatore Petta
Sezione di Gastroenterologia e Epatologia,
Di.Bi.M.I.S.,University of Palermo, Italy

2. Disclosures
Salvatore Petta participated at Advisory Boards and/or acted as Speaker for AbbVie, Bristol Myers Squibb, Gilead Sciences, Janssen, Polifarma, and Merck Sharp and Dohme.

3. NASH and Fibrosis in NAFLD
Why?

4. NAFL/NASH: Fibrosis Progression
Nel 70-80% dei casi, la NAFLD è caratterizzata dalla presenza di steatosi semplice. La steatoepatite si risocntra invece nel 20-30% dei casi, e, al contrario della semplice steatosi, può evolvere nel corso degli anni verso la cirrosi epatica e le sue complicanze
The annual fibrosis progression rate in patients with NAFL who had
stage 0 fibrosis at baseline was 0.07 stages
The annual fibrosis progression rate in patients with NAFL who had
stage 0 fibrosis at baseline was 0.14 stages
Singh et al, Clin Gastr Hep 2015

5. Fibrosis and NAFLD outcomes
Angulo et al, Gastroenterology 2015
Ekstedt et al, Hepatology 2014
Fibrosis stage predicted both overall and disease-specific mortality

6. NASH and Fibrosis in NAFLD
Why?
Main Outcomes in
Clinical Trials

7. Diagnosis of NASH and Fibrosis in NAFLD
Why?
How?

8. But! Liver Biopsy is the Gold Standard! Side effects Sampling error
Observer variation

9. Noninvasive Diagnosis of NASH in NAFLD
How?

10. NAFLD and Cytokeratin-18 Fragments
But!!!!
Lack of Standardization
and
Contrasting Results
Overall AUC 0.82, in 856 NAFLD
Patients from 9 validation studies
Musso et al, Ann of Med 2010
CK-18 Fragments also significantly associated with different stages of fibrosis
Feldstein A et al, Hepatology 2009

11. Can the genetic be useful for NASH Diagnosis?
PNPLA3 genotype, AST and fasting insulin
Hyysalo et al, J Hep 2013

12. 318 NAFLD patients (223 estimation, 95 validation)
Does combining clinical with lipidomic and metabolomic variables improves the diagnosis of NASH?
318 NAFLD patients (223 estimation, 95 validation)
Zhou et al, Clin Gastr Hep 2016

13. NAFLD and Metabolomic Approaches
535 Patients
Simple steatosis (N=353, 66%), NASH (N=182, 34%)
Alonso C et al, Gastroenterology 2017

14. Noninvasive Diagnosis of Fibrosis in NAFLD
How?

15. Non-invasive Diagnosis of Fibrosis in NAFLD
Non-invasive markers/scores
(NFS, FIB-4, etc)
Non-invasive Diagnosis of Fibrosis in NAFLD
Elastography

16. Non-invasive Diagnosis of Fibrosis in NAFLD
Non-invasive markers/scores
(NFS, FIB-4, etc)
Non-invasive Diagnosis of Fibrosis in NAFLD

17. Non-invasive Scores for Advanced Fibrosis in NAFLD
Castera, NRGE 2013

18. “Grey Area” for Noninvasive Staging of Fibrosis In NAFLD by Using Clinico-metabolic Scores
Boursier et al, J HEP 2016

19. Diagnostic Performance of NFS and FIB-4 fordiagnosis of F3-F4 Fibrosis
761 biopsy-proven
NAFLD patients
Accuracy (%)
Uncertainty
area (%)
Wrong
Classification (%)
False
positive (%)
negative (%)
NFS
398/761 (52.2)
294/761 (38.6)
69/761 (9.1)
16/526 (3.0)
53/235 (22.5)
FIB-4
454/761 (59.6)
223/761 (29.3)
84/761 (11.0)
15/526 (2.8)
69/235 (29.3)
Petta S et al, SUBMITTED

20. Non-invasive Diagnosis of Fibrosis in NAFLD
Elastography

21. Elastography and Fibrosis in NAFLD
Transient Elastography
(Fibroscan)
Acoustic radiation Force Impulse (ARFI)
Widely available
1 cm of liver explored
Less available
Integrated on ultrasound device
Sampling from different areas of liver
Supersonic Shear Imaging (SSI)
Magnetic Resonance
Elastography
Less available
Expensive
Assessment of whole liver 21 21

22. Liver Stiffness by Transient Elastography and NAFLD
Stiffness (Kpa)
Stages of Fibrosis
LSM 8.4 Kpa: Sensitivity 77.4%, specificity 77.6%, AUC for F3-F4 fibrosis
Petta S et al, HEP 2015

23. Liver Stiffness by Transient Elastography and NAFLD
TE has moderate accuracy for diagnosis F2-F4 fibrosis (Sens 79%, Spec 75%)
TE has good accuracy for diagnosis F3-F4 fibrosis (Sens 85%, Spec 82%)
Kwok et al, APT 2014

24. Liver Stiffness by Transient Elastography and NAFLD
TE has excellent accuracy for diagnosis F4 fibrosis (Sens 92%, Spec 92%)
Kwok et al, APT 2014

25. Fibroscan, ARFI and SSI in NAFLD: Are Always Reliable?
More reliable than M probe, but with a similar diagnostic performance
Obesity affects Failure and Reliability of Fibroscan, ARFI and SSI
Cassinotto et al, HEP 2016 25 25

26. Fibroscan, ARFI and SSI in NAFLD: Who is Better?
Fibrosis F2-F4
SSI better than ARFI
AUC 0.86
AUC 0.82
AUC 0.77
Obesity affects Failure and Reliability of Fibroscan, ARFI and SSI
Cassinotto et al, HEP 2016
Cassinotto et al, HEP 2016 26 26

27. Fibroscan, ARFI and SSI in NAFLD: Who is Better?
Fibrosis F3-F4
Fibrosis F4
AUC 0.89
AUC 0.88
AUC 0.86
AUC 0.87
AUC 0.84
AUC 0.84
Cassinotto et al, HEP 2016 27 27

28. Fibroscan, ARFI and MR Elastography in NAFLD: Who is Better?
In 142 NAFLD patients, MRe is more accurate than LSM for the diagnosis of F2-F4 fibrosis (AUC 0.91 vs 0.82, p<0.001) and Cirrhosis (AUC 0.97 vs 0.92, p=0.04) , not for F3-F4 fibrosis (AUC 0.89 vs 0.88, p=0.42)
Imajo K et al, Gastroenterology 2016
104 Patients
Park et al, Gastroenterology 2016

29. Confounders of Elastography in NAFLD
Stiffness values associated with obesity, inflammation, ballooning and steatosis,
other than fibrosis
High False Positive Results!!!!
n=761
Accuracy (%)
Uncertainty
area (%)
Wrong
Classification (%)
False
positive (%)
negative (%)
Fibroscan
517/761 (67.9)
122/761 (16)
122/761 (16.1%)
99/526 (18.8)
23/235 (9.7)
Petta S et al, APT 2011; Petta S et al Hepatology 2015; Palmeri ML et al, JHEP 2011;Cassinotto et al, HEP 2016; Petta et al, SUBMITTED 29 29

30. How can we improve the diagnostic accuracy for fibrosis of noninvasive tools?30 30

31. How can we improve the diagnostic accuracy for fibrosis of noninvasive tools?
Improving available noninvasive scores
Improving stiffness
Combining noninvasive scores with stiffness 31 31

32. Age as a Confounding Factor for the Accurate
Non-Invasive Diagnosis of Advanced NAFLD Fibrosis
Performance of current and proposed new cutoffs to exclude advanced fibrosis (stage F3–F4) in older patients (≥65 years) with biopsy-proven NAFLD (N=634, 74 ≥65 years) at different prevalence rates of advanced fibrosis
McPherson et al, AJG 2016

33. How can we improve the diagnostic accuracy for fibrosis of noninvasive tools?
Improving noninvasive scores
Improving stiffness
Combining noninvasive scores with stiffness 33 33

34. FibroScan and Improved Prediction of F3-F4 Fibrosis in NAFLD:
Use two Cut-off >90% PPV and NPV
Boursier et al, J HEP 2016

35. Controlled Attenuation Parameter and NAFLD
De Ledinghen V et al, J Gastr Hep 2015

36. Controlled Attenuation Parameter and LSM values
In F0-F2 patients LSM values were signficantly higher according to CAP tertiles
Petta S et al, Hepatology 2016

37. Controlled Attenuation Parameter and LSM values
Best LSM treshold for F3-F4 fibrosis 10.1 KPa
Petta S et al, Hepatology 2016

38. How can we improve the diagnostic accuracy for fibrosis of noninvasive tools?
Improving noninvasive scores
Improving stiffness
Combining noninvasive scores with stiffness 38 38

39. Paralell combination of LSM and Noninvasive Scores
Accuracy (%)
Uncertainty
area (%)
Wrong Classification (%)
False
positive (%)
negative (%)
Fibroscan + NFS
298/761 (39.1%)
443/761 (58.2%)
20/761 (2.6%)
11/526 (2.1%)
9/235 (3.8%)
Petta S et al, SUBMITTED

40. Serial combination of LSM and Noninvasive Scores
Accuracy (%)
Uncertainty
area (%)
Wrong Classification (%)
False
positive (%)
negative (%)
NFS  Fibroscan in NFS < or
ranging from to 0.676
531/761 (69.8%)
144/761 (18.9%)
86/761 (11.3%)
56/526 (10.6%)
30/235 (12.7%)
Petta S et al, SUBMITTED

41. Elastography and Noninvasive Scores Predict Outcomes in NAFLD
556 NAFLD patients with baseline LSM, followed for a median period of 6.4 yrs 83 pts died
Boursier et al, J HEP 2016 41 41

42. Thanks for Your Attention!!!
Take Home Messages
Thanks for
Your Attention!!!
Noninvasive diagnosis of NASH and severe fibrosis in NAFLD is useful for predicting outcomes
Noninvasive diagnosis of NASH in clinical practice is difficult, even if combining genetic and clinical variables, or metabolomic approaches are promising
Noninvasive scores and elastography for staging fibrosis in NAFLD are widely used, but they are affected by undeterminate results and errors
Combinations of noninvasive scores with elastography, as well as improving noninvasive scores and better reading elastography could improve the diagnostic accuracy for severe fibrosis
Noninvasive scores and elastography could also be useful for predicting mortality in NAFLD