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MASSIMO PINZANI, M.D., Ph.D.
DIPARTIMENTO DI MEDICINA INTERNA – CENTER FOR RESEARCH, TRANSFER AND HIGH EDUCATION “DENOTHE” –
UNIVERSITA’ DI FIRENZE, FLORENCE, ITALY
CORSO UNIGASTRO
RIVA DEGLI ETRUSCHI 4-6 MAGGIO 2008
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OBESITY
DIABETES
METABOLIC SYNDROME
NAFLDNASH
FIBROSIS
NASH, A FIBROGENIC CHRONIC LIVER DISEASE
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15-50% FIBROSIS OR CIRRHOSIS AT PRESENTATION
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DIABETES
METABOLIC SYNDROME
NAFLDNASH
FIBROSIS
NASH, A FIBROGENIC CHRONIC LIVER DISEASE
OBESITY
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A B
C D
Pinzani M, and Rombouts K., Dig Liv Dis 2004; 36:231-242Patterns of Hepatic Fibrosis Development
Biliary TypePost-necrotic
Vascular Type
Pericellular “Chicken Wire”
ASH/NASH
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A B
C D
Pinzani M, and Rombouts K., Dig Liv Dis 2004; 36:231-242Patterns of Hepatic Fibrosis Development
Biliary TypePost-necrotic
Vascular Type
Pericellular “Chicken Wire”
ASH/NASH
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FIBROSIS PATTERN
EARLY PORTAL TO CENTRAL
SEPTA
NEO ANGIOGENESIS
REVERSIBILITY
POST-NECROTIC ++++ ++++ +
BILIARY + ++ ++++
CENTROLOBULAR - + ++++
PERICELLULAR -PERISINUSOIDAL
- + +++
REVERSIBILITY OF LIVER FIBROSIS ACCORDING TO THE PATTERN
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EXPANDED FAT MASS
INSULIN RESISTANCE
FATTY LIVER NASH
FFA INFLUX
HYPERINSULINEMIA
(HEPATIC IRON ?)
PRODUCTS OF FFA OXIDATION
MITOCHONDRIAL DYSFUNCTION
LIPID PEROXIDATION
OXIDATIVE STRESS
INFLAMMATION
FIBROGENESIS & ANGIOGENESIS
ACTIVATION IKK-β/NF-κB
TNF-α
HEPATOCELLULAR DAMAGE/APOPTOSIS
CB1-R
ANGIOTENSIN II (INCREASE) LEPTIN/RESISTIN (INCREASE) VEGF (INCREASE) ADIPONECTIN (DECREASE) NOREPINEPHRINE (DECREASE)
TWO HITS OR JUSTPREDISPOSITION
(GENERAL/GENETIC?)
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Prevalent Mechanism of Fibrogenesis in Different CLD
Chronic direct/indirect damage (Viral, Autoimmune)
Chronic activation of the wound healing process
Chronic Toxic Damage and/or metabolic overload (ETOH Abuse, metals, steatohepatitis)
Oxidative stress
Bile duct proliferation / chronic cholestasis
Epithelial/mesenchymal interaction and Oxidative Stress
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Reactive Aldehydes Induce Procollagen Type I mRNA Expression in Human HSC
C HOE HUE
- 5.7- 4.7
α1(I)
- 1.4 36B4
C 3h 6h
HNE
- 5.7- 4.7
α1(I)
- 1.4 36B4
Parola M. et al. Biochem.Biophys.Res.Comm. 1996; 222:261-264
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Reactive Aldehydes Induce Procollagen Type I mRNA Expression in Human HSC
C HOE HUE
- 5.7- 4.7
α1(I)
- 1.4 36B4
C 3h 6h
HNE
- 5.7- 4.7
α1(I)
- 1.4 36B4
Parola M. et al. Biochem.Biophys.Res.Comm. 1996; 222:261-264
ROI, Reactive Aldehydes, Acetaldehyde (ETOH)
OXIDATIVE STRESS AND MEMBRANE
LIPID PEROXIDATION
Up-regulation of pro-fibrogenic genes
Accumulation of fibrillar ECM in the space of Disse independent of
cell damage and inflammation
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EMERGING MECHANISMSOF HEPATIC FIBROGENESIS
1.- Sympathetic neurotransmitters2.- Viral proteins3.- Renin-angiotensin-aldosterone system4.- Apoptosis products5.- Adipokines
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ADIPOKINES LINKED TO INFLAMMATION AND TO THE INFLAMMATORY RESPONSE
resistin
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FAT- DERIVED FACTORS REGULATE HEPATIC INFLAMMATORY
RESPONSE AND FIBROGENESIS
LEPTIN
RESISTIN
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Uygun A. et al.,Am J Gastroenterol 2000; 95:3584
LEPTIN LEVELS IN NASH
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LEPTIN UPREGULATES LIVER DAMAGE AND REPAIR
Ikejima K et al., Hepatology 2001;34:288-297
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LEPTIN DEFICIENCY BLOCKS THEDEVELOPMENT OF FIBROSIS
Ikejima K et al., Gastroenterology. 2002;122:1399-1410
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Proliferation
Apoptosis
Collagen synthesis
TIMP-1 expression
Oxidative stress
Norepinephrine
Pro-inflammatory cytokines (via NF-kB)
Angiogenic cytokines (via HIF-1α)
LEPTIN AND HEPATIC STELLATE CELLS
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Leptin Induces the Expression of HIF1αand VEGF in human HSC
Aleffi S et al., Hepatology 2005;42:1339-1348
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Normoxia Hypoxia
HIF-1HIF-2 HIF-3
α β
O2
Hypoxia Responsive Element (HRE)
VEGF
Angiogenesis
Oxygen Sensors PHD 1,2,3
OHHIF-1 HIF-2 HIF-3
α β
OH
Vascular Stability and Quiescence
HRE
Angiogenesis is a Biological Response to Hypoxia
LEPTIN
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EXPRESSION OF RESISTIN IN HUMAN CLDS
AAE
NHL
HCV
AAE NASH
RESISTIN
CD43
α−SMA
COLLAGEN I
Bertolani C., et al., Am J Pathol 2006
RESISTIN CD43 MERGE
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RESISTIN ENHANCES THE PRO-INFLAMMATORY ACTION OF HUMAN HSC
Bertolani C., et al., Am J Pathol 2006
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Brun P., et al., Am J Physiol Gastrointest Liver Physiol 2005; 289:G571-G578
EXPOSURE TO BACTERIAL CELL WALL PRODUCTS TRIGGERS AN INFLAMMATOTY PHENOTYPE IN HEPATIC STELLATE CELLS
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Brun P., et al., Am J Physiol Gastrointest Liver Physiol 2007; 292:G518-G525
INCREASED INTESTINAL PERMEABILITY IN OBESE MICE: NEW EVIDENCE IN THE PATHOGENESIS ON NONALCOHOLIC
STEATOHEPATITIS
Ob/Ob (ipoleptin)& Db/Db (iperleptin: lacking leptin receptor)
Altered intestinal mucosal barrier function (Ussing chamber)
Profoundly modified distribution of occludin and zonula occludens-1 in the intestinal mucosa
Higher circulating levels of inflammatory cytokines and portal endotoxemia
HSCs with higher membrane CD14 mRNA levels and more pronounced lipopolysaccharide-induced proinflammatory and fibrogenic responses
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Histological Scoring of NAFLDsBrunt E.M., Sem Liv Dis 2001; 21:3-16
Steatosis1. 0-33% fatty inflitration2. 34-66% fatty inflitration3. 67-100% fatty inflitration
Necroinflammation0. Absent1. Occasional balooning and no or very mild inflammation2. Balooning and mild-to-moderate portal inflammation3. Intra-acinar and moderate portal inflammation
Fibrosis0. Absent1. Perisinusoidal/pericellular fibrosis2. Periportal fibrosis3. Bridging fibrosis4. Cirrhosis
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Steatosis (0-3)Lobular inflammation (0-2)Hepatocellular ballooning (0-2)Fibrosis (0-4)
NAFLD activity score (NAS) = steatosis + lobular inflammation + hepatocellular ballooning
NASH if NAS≥5‘NO NASH’ if NAS<3
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Steatosis (0-3)Lobular inflammation (0-2)Hepatocellular ballooning (0-2)Fibrosis (0-4)
NAFLD activity score (NAS) = steatosis + lobular inflammation + hepatocellular ballooning
NASH if NAS≥5‘NO NASH’ if NAS<3
Consensus means that a lot of people saycollectively what no one believes individually
Abba Eban
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THE NAS SCORE IS BASED ON THE ASSUMPTION THAT THE EXTENT FIBROSIS IS AN EXCLUSIVE CONSEQUENCE OF HEPATOCELLULAR DAMAGE AND INFLAMMATION
THIS ASSUMPTION IS NOT PROVEN IN ANY CLD AND PARTICULARLY IN NASH
A. OXIDATIVE STRESS DIRECTLY AFFECTS COLLAGEN GENE EXPRESSION AND SYNTHESIS
B. INDIVIDUAL DIFFERENCES IN THE ABILITY OF DEGRADING FIBRILLAR MATRIX IN CAPILLARIZED SINUSOIDS
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DIAGNOSIS OF NASH AND RELATED ISSUES
1. – DIFFERENTIATE FATTY LIVER FROM NASH
2. – DEFINE THE SEVERITY OF NASH
3. – PREDICT AND MONITOR THE FIBROGENIC EVOLUTION OF NASH TOWARDS CIRRHOSIS
4. – DIFFERENTIATE NASH FROM ASH
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TO BIOPSY OR NOT TO BIOPSY (AND WHOM) ?
Reasons to perform a liver biopsy
Unknown disease
DIAGNOSIS
Patients with unexplained
alterations of liver enzymes
Known disease
SEVERITY
Patients with a “bright liver”
pattern at the US scan
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1.- Reliability of the fibrosis rate (stages treated as linear variables)
2.- Sampling error
3.- Adequacy of biopsy sample
4.- Time between biopsies
LIVER BIOPSY IN NAFLD/NASH
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Non-invasive tests may help to identify patients with steatosis in large population studies.
A test differentiating bland steatosis from NASH would be the most useful in this setting.
Several algorythms identify advanced fibrosis in NASH with a good performance.
We need DISCRIMINANT and PROGNOSTIC INDEXES
DIAGNOSIS OF NASH AND RELATED ISSUES
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Pinzani et al., Nat Clin Pract Gastroenterol Hepatol. 2008;5:95
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Dixon et al., 2001(26 severely obese pts.)
Predictors of advanced fibrosis:Insulin resistanceHypertensionALT levels
Ratziu et al., 2000(93 overweight pts.)
Predictors of septal (F≥2) fibrosis:BMI AgeALTTriglycerides
Bugianesi et al., 2004(167 NAFLD pts. with no
diabetes)
Predictors of septal fibrosis after adjustment for age, and BMI:
Insulin resistanceFerritin (NOT iron overload)
Angulo et al., 1999(144 NASH pts.)
Predictors of severe fibrosis:Older ageObesityDiabetes mellitusAST/ALT ratio >1
How to Predict Fibrosis: Cross-sectional studies
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Adams L et al., J Hepatol 2005;42:132
Predictors of fibrosis rate bymultivariate analysis
BMIDiabetesEarlier fibrosis stage
103 patients
Biopsy interval
<24 Months 24–48 Months >48 Months
Progressors 11 (34%) 18 (36%) 9 (43%)
Stable 13 (41%) 13 (26%) 9 (43%)
Regressors 8 (25%) 19 (38%) 3 (14%)
No correlation with changes in ALT or AST
Improvement in ALT correlateswith improvement in steatosis or inflammation but NOT fibrosis
How to Predict Fibrosis: Longitudinal studies
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1.- In at least 1/3 of NASH patients fibrosis progresses
2.- No clear parameters at baseline allow to identify patients that will progress
3.- Fibrosis progression occurs even in presence of a decrease in necro-inflammatory activity and/or steatosis
4.- Improvement of transaminases is NOT a surrogate marker for improvement of fibrosis
Messages from Paired-Biopsy Studies
Fassio et al., Hepatology 2004;40:820 Harrison et al., Am J Gastroenterol 2003;98:2042Adams et al., J Hepatol 2005;42:132
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Noninvasive Model for the Prediction of Fibrosis in Patients with NAFLD
1-Specificity
Sens
itivi
ty
0.0 0.2 0.4 0.6 0.8 1.0
0.0
0.2
0.4
0.6
0.8
1.0
Model Building Data
1-Specificity
Sen
sitiv
ity
0.0 0.2 0.4 0.6 0.8 1.0
0.0
0.2
0.4
0.6
0.8
1.0
Validation Data
Angulo P. et al,HEPATOLOGY, in press
Variable OR 95% CI p ValueAge ≥ 45 years 2.3 1.2, 4.3 0.01Obese (BMI ≥ 30) 2.6 1.4, 4.9 0.004AST/ALT ratio > 1 6.7 3.4, 13.2 < 0.0001Low platelet count (< 150x103/dL) 8.3 3.8, 18.3 < 0.0001AST/platelet > 1 2.4 1.3, 4.5 0.007Diabetes mellitus (yes) 4.7 2.5, 8.8 < 0.0001Hypertriglyceridemia (> 150 mg/dL) 0.5 0.3, 0.8 < 0.02
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ELF Study: Algorythm Performance in Different Diagnostic Subgroups
Diagnosis Pts (n) Sensitivity Specificity NPV
NAFLD/NASH 60 92.3 91.7
59.6 66.7
96.6 97.0
HCC & Iron Overload
15 100100
84.676.9
100 100
Disease Post OLT
33 100 100
41.7 33.3
100100
HCV or HBV or Both
289 60.060.7
72.0 72.0
70.271.6
PBC or PSC 33 78.978.9
71.4 78.9
71.4 71.4
SCHEUER ISHAK
Detection of Scheuer Stage 0,1,2 versus 3,4
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Ancona – Clinica di GastroenterologiaGrosseto – Divisione di Gastroenterologia Modena e Trieste - Amici del Fegato Napoli – Gastroenterologia II UniversitàNovara - Dipartimento Scienze MedichePadova – Clinica di Gastroenterologia Padova - Dipartimento Medicina Clinica e
SperimentaleRoma – Università Cattolica Savona - UO Semplice di
Gastroenterologia-EpatologiaTorino – Gastroenterologia
209 campioni
AISF-FAT STUDY, Validation of the ELF panel in an Italian NAFLD cohort
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PERFORMANCE OF ELF SERUM MARKERS IN PREDICTING FIBROSIS STAGE IN CHILDREN WITH NON ALCOHOLIC FATTY LIVER DISEASEValerio Nobili, Julie Parkes, Gianfranco Bottazzo, Matilde Marcellini, Richard Cross, Daniel Newman, Massimo Pinzani, and William Rosenberg (2008 Submitted)
43210
12.
10.
8.
*
*#
#
EL
F S
co
re
Fibrosis Stage (Kleiner)
112 pts with biopsy proven NAFLD (64 M and 48 F, mean age 13.8± 3.3, age range 3-17 yrs)
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PERFORMANCE OF ELF SERUM MARKERS IN PREDICTING FIBROSIS STAGE IN CHILDREN WITH NON ALCOHOLIC FATTY LIVER DISEASEValerio Nobili, Julie Parkes, Gianfranco Bottazzo, Matilde Marcellini, Richard Cross, Daniel Newman, Massimo Pinzani, and William Rosenberg (2008 Submitted)
43210
12.
10.
8.
*
*#
#
EL
F S
co
re
Fibrosis Stage (Kleiner)
0%
10%20%
30%40%
50%
60%70%
80%90%
100%
“any” fibrosis
“any”fibrosis
1c-4 2-4 3-4
cannot be allocated
avoid biopsy incorrectly
avoid biopsy correctly
8.84+9.54 9.54 9.54 10.3 10.3
112 pts with biopsy proven NAFLD (64 M and 48 F, mean age 13.8± 3.3, age range 3-17 yrs)
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ACCURACY AND REPRODUCIBILITY OF TRANSIENT ELASTOGRAPHY FOR THE DIAGNOSIS OF FIBROSIS IN PEDIATRIC NON-ALCOHOLIC
STEATOHEPATITISValerio Nobili, Francesco Vizzutti, Umberto Arena, Juan G. Abraldes, Fabio Marra, Andrea
Pietrobattista, Rodolfo Fruhwirth, Matilde Marcellini, and Massimo PinzaniHEPATOLOGY 2008 (IN PRESS)
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When should intervention begin?
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Are study endpoints consistent and complementary to clinical goals and actual outcomes?
1. – EFFECT ON MORTALITY (NOT REALISTIC)
3. – EFFECT ON INSULIN RESISTANCE (NOT NECESSARILY ASSOCIATED WITH LIVER CHANGES IN THE SHORT TERM)
4. – EFFECT ON HISTOLOGY: DOWNSTAGING NAS SCORE.
2. – EFFECT ON LIVER FUNCTION TESTS (NOT RELIABLE)
5.- EFFECT ON HISTOLOGY: DOWNSTAGING FIBROSIS.
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How does the stage of NAFLD/NASH influence the option of intervention, therapeutic target, and clinical outcomes and goals?
1. – NO FIBROSIS OR MILD PERISINUSOIDAL FIBROSIS
2. - SIGNIFICANT FIBROSIS WITHOUT BRIDGING AND ANGIOGENESIS
3. ADVANCED FIBROSIS (ALSO PERIPORTAL)
4. HISTOLOGICAL CIRRHOSIS
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What features of a NAFLD/NASH study could be required to test efficacy?
1.- Histology
2.- Metabolic parameters
3.- Cardiovascular risk
4.- Adipokine levels (Adiponectin increase)
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Potential therapeutic approaches
BW REDUCTIONSIBUTRAMINE
ORLISTATSURGERY
METFORMINTHIAZOLIDINEDIONESGLP1-R AGONISTS
(EXENDIN-4)
BOWEL DECONT & PRE-PROBIOTICS
ANTI-TNF (PTFYLLIN)IKK-β INHIBITORS
SAMeBETAINE
SYLIBININ
HEPATIC ACETYLCoA
CARBOXILASES 1-2 INHIBITORS
ACE INHIB/ATII RBANTI-VEGF?
CB1-RB
CHEMOKINERECEPTOR
BLOCKERS (CCR2)
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DIAGNOSIS OF NASH AND RELATED ISSUES
1. – DIFFERENTIATE FATTY LIVER FROM NASH
2. – DEFINE THE SEVERITY OF NASH
3. – PREDICT AND MONITOR THE FIBROGENIC EVOLUTION OF NASH TOWARDS CIRRHOSIS
4. – DIFFERENTIATE NASH FROM ASH
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Alcohol Consumption by Country, Adults aged 15 years and above, 2001, Europe
0.0
2.0
4.0
6.0
8.0
10.0
12.0
14.0
16.0
18.0
20.0
litre
s/pe
rson
/yea
r
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Under-reported or surreptitious alcohol consumption (the “desperate house wife syndrome”)
The “gourmet business man syndrome”
ASH vs. NASH
How do NASH studies relate to the Country’s average alcohol consumption and drinking habits?
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MCV + AST/ALT + BMI + GENDER = ANI (ALD/NAFLD INDEX)
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ACCURACY OF ANI IN DISTINGUISHING ALD FROM NAFLD COMPARED TO STANDARD
METHODS
DISTRIBUTION OF ANI IN NAFLD COMPARED TO ABSTINENT OR ACTIVE ALCOHOLICS