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PATHOLOGY OF NAFLD
Pierre BedossaDepartement of Pathology
Hpital BeaujonUniversity Paris-Diderot
Paris - FRANCE
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PHC, Paris, 30th Jan 2017
NAFLD: a chronic liver disease with a wide range of tissue lesions
Liver biopsy allows an integrated evaluation of tissue damages related to various pathophysiological mechanisms
Histology is central for disease definitions and prognosis in NAFLD
Non invasive biomarkers are still unmet need
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PATHOLOGY OF NAFLD
CLASSIFICATIONS OF NAFLD :
INTEGRATED APPROACH (NASH CRN)
ANALYTICAL APPROACH (SAF)
HISTOLOGY IN CLINICAL TRIALS
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OUTLINES
STEATOSIS(NAFL)
STEATOHEPATITIS
(NASH)
HISTORICAL LANDMARK Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed
disease. Ludwig J, et al. Mayo Clin Proc. 1980
THE CLASSICAL VIEW : A DICHOTOMOUS CLASSIFICATION
Non Alcoholic Fatty Liver Diseases (NAFLD)
STEATOHEPATITIS
(NASH) FIBROSIS
CIRRHOSIS
HCC
STEATOSIS (NAFL)
THE NATURAL HISTORY OF NAFLD
STEATOHEPATITIS
(NASH) FIBROSIS
CIRRHOSIS
HCC
STEATOSIS (NAFL)
NASH : ASSOCIATION OF HISTOLOGICAL PATTERNS
STEATOSIS+
BALLOONING+
INFLAMMATION+
Perisinusoidal fibrosis+
Location in zone 3
STEATOSIS(NAFL)
STEATOHEPATITIS
(NASH)
THE LIMIT OF A DICHOTOMOUS CLASSIFICATION
BO
RD
ERL I
NE
STEATOSIS(NAFL)
STEATOHEPATITIS
(NASH)
THE LIMIT OF A DICHOTOMOUS CLASSIFICATION
BO
RD
ERL I
NE
+ BALLONING
1 2
+ INFLAMMATION
1 2 3
NAFLD Activity Score (NAS, 0-8)
STEATOSIS
1 2 3
NASH CRN, Hepatology 2005
Correlation between NAS and histologic diagnosis of NASH
< 3: no NASH 3-4 : GREY ZONE
>5 : definitively NASH
NAS = Sum of lesions related to different mechanisms and with different clinical relevance (steatosis vs hepatocellular injury)
Ballooning (0-2) underweighted vs steatosis (0-3) or inflammation (0-3)
NAS has not been shown as a prognostic factor
NAFLD Activity Score (NAS, 0-8)
CLASSIFICATIONS OF NAFLD :
INTEGRATED APPROACH (NASH CRN)
ANALYTICAL APPROACH (SAF)
HISTOLOGY IN CLINICAL TRIALS
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OUTLINES
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STEATOSIS
FIBROSIS
FLIP consortium, Hepatology 2012, Hepatology 2014
THE MARKER
ACTIVITYTHE DRIVER
THE KILLER
UNDER THE LENS : THE 3 HISTOLOGICAL COMPONENTS OF NAFLD
Steatosis (0-3) as for NASH CRN ACTIVITY (0-4) = BALLOONING (0-2) + LOBULAR
INFLAMMATION (0-2)
Fibrosis (0 4) as for NASH CRNS0-3A0-4F0-4
The S.A.F. score(Steatosis-Activity-Fibrosis)
Histopathological algorithm and scoring system for evaluation of liver lesions in morbidly obese patients. Bedossa P, Poitou C, Veyrie N, Bouillot JL, Basdevant A, Paradis V, Tordjman J, Clement K. Hepatology. 2012 Nov;56(5):1751-9
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STEATOSISTHE MARKER
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Ballooning
Inflammation
ACTIVITYTHE DRIVER
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HEPATOCELLULAR BALLOONING: THE HALLMARK OF NASH SHAPE + COLOR + SIZE
Ballooning 1 Ballooning 2
NORMAL LIVER CK18
Histopathological algorithm and scoring system for evaluation of liver lesions in morbidly obese patients. Bedossa P, Poitou C, Veyrie N, Bouillot JL, Basdevant A, Paradis V, Tordjman J, Clement K. Hepatology. 2012 Nov;56(5):1751-9
The FLIP algorithm
NAFL NAFLNAFL
NAFLNASHNASHNAFL NASHNASH
40 biopsies (Steatosis, NASH) 1st session(unsupervised)
2nd session (with classifier)
Liver Pathologists (n=6) score 0.54 (moderate) 0.66 (substantial) Nbr of biopsies with agreement
between all pathologists 26/40 (65 %) 34/40 (85 %)
General Pathologists (n=10) score 0.35 (fair) 0.70 (substantial) Nbr of biopsies with agreement
between all pathologists 18/40 (45 %) 34/40 (85 %)
REPRODUCIBILITY OF DIAGNOSIS OF NASH WITH FLIP ALGORITHM
The definition of NASH by an association of 3 features and a clear definition of each of them make the diagnosis of NASH strongly reproducible
The FLIP Pathology consortium, Hepatology 2014
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FIBROSISTHE KILLER
Younossi ZM, Stepanova M, Rafiq N, et al.. Hepatology 2011 Ekstedt M, Hagstrm H, Nasr P et al, Hepatology 2015
LIVER FIBROSIS : MAJOR PROGNOSTIC FACTOR
Overal survival according to stage of fibrosis in index biopsy
Liver Related Mortality
Overal survival according to fibrosis stage and compared to
control population
Stage of Fibrosis (Kleiner et al, Hepatology 2005) 1
2 3
0
4
STAGE OF FIBROSIS: ROOM FOR IMPROVEMENT
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STAGE OF FIBROSIS: ROOM FOR IMPROVEMENT
STAGE 3 / SEPTAL FIBROSIS
OUTLINES
CLASSIFICATION OF NAFLD : INTEGRATED APPROACH ANALYTICAL APPROACH
HISTOLOGY IN CLINICAL TRIALS Histology is a validated surrogate endpoint
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PATHOLOGY OF NAFLD
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ACTIVITY
FIBR
OS
IS
MANY SHADES OF NAFLD
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ACTIVITY
FIBR
OS
IS
MANY SHADES OF NAFLD
A0F1
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ACTIVITY
FIBR
OS
IS
MANY SHADES OF NAFLD
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ACTIVITY
FIBR
OS
IS
MANY SHADES OF NAFLD
A3F1
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ACTIVITY
FIBR
OS
IS
MANY SHADES OF NAFLD
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ACTIVITY
FIBR
OS
IS
MANY SHADES OF NAFLD
A0F4
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ACTIVITY
FIBR
OS
IS
MANY SHADES OF NAFLD
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ACTIVITY
FIBR
OS
IS
MANY SHADES OF NAFLD
A3F4
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ACTIVITY
FIBR
OS
IS
MANY SHADES OF NAFLD
A3F4A0F4
A3F1A0F1
STEATOSIS +
A0 A1 A2 A3 A4
F0 A0F0 A1F0 A2F0 A3F0 A4F0
F1 A0F1 A1F1 A2F1 A3F1 A4F1
F2 A0F2 A1F2 A2F2 A3F2 A4F2
F3 A0F3 A1F3 A2F3 A3F3 A4F3
F4 A0F4 A1F4 A2F4 A3F4 A4F4
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HISTOLOGY IN NAFLD CLINICAL TRIALS
STEATOSIS +
A0 A1 A2 A3 A4
F0 A0F0 A1F0 A2F0 A3F0 A4F0
F1 A0F1 A1F1 A2F1 A3F1 A4F1
F2 A0F2 A1F2 A2F2 A3F2 A4F2
F3 A0F3 A1F3 A2F3 A3F3 A4F3
F4 A0F4 A1F4 A2F4 A3F4 A4F4
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HISTOLOGY IN NAFLD CLINICAL TRIALS
STEATOSIS +
A0 A1 A2 A3 A4
F0 A0F0 A1F0 A2F0 A3F0 A4F0
F1 A0F1 A1F1 A2F1 A3F1 A4F1
F2 A0F2 A1F2 A2F2 A3F2 A4F2
F3 A0F3 A1F3 A2F3 A3F3 A4F3
F4 A0F4 A1F4 A2F4 A3F4 A4F4
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HISTOLOGY IN NAFLD CLINICAL TRIALS
STEATOSIS +
A0 A1 A2 A3 A4
F0 A0F0 A1F0 A2F0 A3F0 A4F0
F1 A0F1 A1F1 A2F1 A3F1 A4F1
F2 A0F2 A1F2 A2F2 A3F2 A4F2
F3 A0F3 A1F3 A2F3 A3F3 A4F3
F4 A0F4 A1F4 A2F4 A3F4 A4F4
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HISTOLOGY IN NAFLD CLINICAL TRIALS
STEATOSIS +
A0 A1 A2 A3 A4
F0 A0F0 A1F0 A2F0 A3F0 A4F0
F1 A0F1 A1F1 A2F1 A3F1 A4F1
F2 A0F2 A1F2 A2F2 A3F2 A4F2
F3 A0F3 A1F3 A2F3 A3F3 A4F3
F4 A0F4 A1F4 A2F4 A3F4 A4F4
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RESOLUTION OF NASH WITHOUT WORSENING OF FIBROSIS
RE
GR
ES
SIO
N O
F FIBR
OS
IS W
ITHO
UT
WO
RS
EN
ING
OF N
AS
H
CURING THE DISEASE
ENDPOINT IN CLINICAL TRIALS
PATHOLOGY OF NAFLD Take-home messages
NAFLD is the combination of several features of variable intensity and of different prognostic values.
The dichotomous classification NAFL vs NASH is an oversimplification which is no more relevant in clinical practice. New proposals have been formulated.
NASH is defined by histological criteria. Therefore, biopsy is needed if diagnosis and evaluation of severity are required.
Histology is the only accepted surrogate marker in clinical trials
Non invasive markers are urgently needed
THANK YOU FOR YOUR ATTENTION !
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Slide 1Slide 2Slide 3Slide 4Slide 5Slide 6Slide 7Slide 8NAFLD Activity Score (NAS, 0-8)NAFLD Activity Score (NAS, 0-8)Slide 11Slide 12The S.A.F. score (Steatosis-Activity-Fibrosis)Slide 14Slide 15Slide 16Slide 17REPRODUCIBILITY OF DIAGNOSIS OF NASH WITH FLIP ALGORITHMSlide 19LIVER FIBROSIS : MAJOR PROGNOSTIC FACTORSlide 21Slide 22Slide 23OUTLINESSlide 25Slide 26Slide 27Slide 28Slide 29Slide 30Slide 31Slide 32Slide 33Slide 34Slide 35Slide 36Slide 37Slide 38PATHOLOGY OF NAFLD Take-home messagesSlide 40