1. THE NEED OF A NEW PATHOPHYSIOLOGICAL CLASSIFICATION OF CIRRHOSIS
PINZANI M- 2012
THE NEED OF A NEW PATHOPHYSIOLOGICAL CLASSIFICATION OF CIRRHOSIS
MASSIMO PINZANI, M.D., Ph.D., FRCP
Sheila Sherlock Chair of Hepatology
UCL Institute for Liver and Digestive Health
Royal Free Hospital, London, UK

2. The Current Perception of Chronic Liver Disease
PINZANI M- 2012
The Current Perception of Chronic Liver Disease
Towards CIRRHOSIS F0 F1 F2 F3 F4
Beyond CIRRHOSIS
CIRRHOSIS

3. >12 Decompensated Compensated Non-cirrhotic Clinical
PINZANI M- 2012
Decompensated
Compensated
Non-cirrhotic
Clinical
Ascites, VH, Encephalopathy
None (varices present)
None (no varices)
None
Symptoms
Stages 3,4,5*
Stage 2
Stage 1 -
Sub-stage
Insoluble scar
Thick (acellular) scar and nodules
Scar and
X-linking
Fibrogenesis and Angiogenesis
Biological
Hemodynamic (HVPG, mmHg)
Histological
F1-F3
F4 (Cirrhosis)
>6
>10
>12
*G. D’Amico, AASLD 2011 PGC

4. CIRRHOSIS: IN SEARCH OF A PATHOPHYSIOLOGICAL CLASSIFICATION, WHY?
PINZANI M- 2012
CIRRHOSIS: IN SEARCH OF A PATHOPHYSIOLOGICAL CLASSIFICATION, WHY?
1.- Cirrhosis cannot be simply considered an “end-stage”.
2.- The evaluation of the cirrhotic patient is based on the observation of clinical and biochemical events often unpredictable and characterized by a rough and insufficient pathophysiological framing.
3.- The biology of hepatic fibrogenesis evolves in cirrhotic liver and it is tightly correlated with disease progression in “compensated” cirrhosis.
4.- Very limited diagnostic/prognostic resources are available to frame the stage of “Compensated” cirrhosis.
5.- “Decompensated” cirrhosis is based on the occurrence of clinical complications but not on other potentially relevant biological events (i.e. altered tissue regeneration, loss of specific liver functions, transition to a systemic disease, etc).

5. The Diversity of Chronic Liver Diseases
PINZANI M- 2012
The Diversity of Chronic Liver Diseases
Etiology has a relevant impact on disease progression (fibrogenesis) and regression (fibrolysis)
Different etiologies result in different patterns of fibrosis development
Etiology influences the prevailing pro-fibrogenic mechanism(s)
ETIOLOGY !!

6. Hall A. et al., Histopathology 2012; 60:270-277
PINZANI M- 2012
Fibrosis Quantity and Distribution in Explanted Cirrhotic Liver Depending on Etiology
Hall A. et al., Histopathology 2012; 60:
Measurement of Collagen Proportionate Area (CPA)

7. The Progression of Chronic Hepatitis C and the METAVIR Score
PINZANI M- 2012
The Progression of Chronic Hepatitis C and the METAVIR Score F1
PORTAL FIBROSIS
Mild fibrous expansion of portal tracts F2
PERIPORTAL FIBROSIS
Rare portal-portal septa F3
SEPTAL FIBROSIS
Portal-portal linkage F4
CIRRHOSIS
Bridging fibrosis and nodular regeneration
F4 is WRONGLY considered an END-STAGE

8. PINZANI M- 2012 A B C

9. PINZANI M- 2012

10. PINZANI M- 2012
Morphology and Collagen Proportionate Area Correlate with Portal Hypertension
Nagula S et al., J. Hepatol. 2006; 44:
Calvaruso V et al., Hepatology 2009; 49:

11. Liver biopsy: 1 yr after OLT Staging: Ishak’s
PINZANI M- 2012
Liver biopsy: 1 yr after OLT Staging: Ishak’s

12. Measuring Collagen Content: What Are We Missing?
PINZANI M- 2012
Measuring Collagen Content: What Are We Missing?
Hepatocyte necrosis/apoptosis,inflammatory infiltration
All potential targets for bio-imaging and functional imaging
Neoangiogenesis and microthrombosis
Activation of the stem cell compartment
Ductular reaction and “reactive” cholangiocytes
Increasing tissue hypoxia and endothelial dysfunction
Unbalanced vasoconstrictors and scar contraction

13. Biological Events in the Natural History of CLD
PINZANI M- 2012
Biological Events in the Natural History of CLD
Contribution of hepatic stem cell compartment R E G N A T I O
HBV
HCV
GENETIC
INSTABILITY
AND
MUTATIONS
ABERRANT
ACTIVATION OF
SIGNALLING
PATHWAYS
HCC
CHRONIC TISSUE
DAMAGE
CHRONIC WOUND
HEALING
FIBROGENESIS
ANGIOGENESIS
ALTERED
MICRO-
ENVIRONMENT
ASH
NASH
IRON
OXIDATIVE
STRESS 13 13

14. Cytochrome C oxidase positive: regenerating hepatocytes
PINZANI M- 2012
Cytochrome C oxidase positive: regenerating hepatocytes
Cytochrome C oxidase negative (MtDNA mutation): progenitor cells
Mixed population

15. >12 Decompensated Compensated Non-cirrhotic Clinical
PINZANI M- 2012
Decompensated
Compensated
Non-cirrhotic
Clinical
Ascites, VH, Encephalopathy
None (varices present)
None (no varices)
None
Symptoms
Stages 3.4,5*
Stage 2
Stage 1 -
Sub-stage
Insoluble scar
Thick (acellular) scar and nodules
Scar and
X-linking
Fibrogenesis and Angiogenesis
Biological
Hemodynamic (HVPG, mmHg)
Histological
F1-F3
F4 (Cirrhosis)
>6
>10
>12
REVERSIBLE PARTIALLY REVERSIBLE IRREVERSIBLE

16. Biochemical and Biological Evolution of Fibrillar Extracellular Matrix
PINZANI M- 2012
Biochemical and Biological Evolution of Fibrillar Extracellular Matrix
EARLY FIBROSIS
Inter-fiber filaments (type VI)
MMP-1
Fibrillar Collagen
(type I,III, V)
COLLAGEN CROSS-LINKING
PRESENCE OF ELASTIN
ACELLULAR FIBROSIS
DOWNREGULATION OF MMP-1 AND UPREGULATION OF TIMP-1
INCREASE IN TISSUE RIGIDITY AND TENSION
ESTABLISHED FIBROSIS

17. Hepatocellular Carcinoma
PINZANI M- 2012
The Natural History of Cirrhosis: a Summary
HVPG > 12 mm Hg
Stage 3
Bleeding ?
“Decompensating Event”
SEPSIS
Renal
Failure
HVPG: 5-12 mm Hg
Stage 1
Stage 2
No Varices
No Ascites
Varices
Stage 4
First non
bleeding
decompensation
Death or
OLT
Stage 5
Second
decompensation
Hepatocellular Carcinoma
Compensated Cirrhosis
Decompensated Cirrhosis
Modified from Arvaniti V. et al., Gastroenterology 2010; 139:

18. Hepatocellular Carcinoma
PINZANI M- 2012
Compensated Cirrhosis a Clinical Stage with Very Limited Diagnostic Resources
Stage 3
Bleeding ?
“Decompensating Event”
SEPSIS
Renal
Failure
Stage 1
Stage 2
No Varices
No Ascites
Varices
Stage 4
First non
bleeding
decompensation
Death or
OLT
Years
Months
Stage 5
Second
decompensation
Hepatocellular Carcinoma
Compensated Cirrhosis ?
Decompensated Cirrhosis
Modified from Arvaniti V. et al., Gastroenterology 2010; 139:

19. Measurement of portal pressure (HVPG) and liver tissue stiffness
PINZANI M- 2012
Clinical observation, tissue morphology: an “expectant” algorithm that treats complications
Measurement of portal pressure (HVPG) and liver tissue stiffness
Bio-imaging, functional imaging?

20. Cinically Significant
PINZANI M- 2012
Diagnostic performance of transient elastography for the detection of clinically significant portal hypertension (HVPG 10 mm Hg)
Authors
Carrion et al. (35)
Vizzutti et al. (36)
Sanchez-Condé et al. (39)
Lemoine et al. (38)
Bureau et al. (37)
AUC
0.92
0.99
0.80
0.76
0.94 Se
(%) 90 97 94 93 83 63 Sp 81 92 50 67 70 88
Etiologies
HCV-LT
HCV
HIV-HCV
Alcohol
CLD
* Hepatic Venous Pressure Gradient (HVPG) ≥6 mm Hg; ** severe portal hypertension HVPG ≥12 mm Hg
Patients
(n)
124 61 38 44 48
150
+LR
4.7
13.7
4.9
3.5
2.5
2.1
7.5
12.8
-LR
0.12
0.02
0.08
0.62
0.49
0.53
0.13
0.10
AUC: area under ROC curve; Se sensitivity; Sp specificity; +LR positive likelihood ratio; -LR negative likelihood ratio;
HCV chronic hepatitis C; HCV-LT Liver transplant for hepatitis C; CLD chronic liver diseases;
Study design
Prospective monocentric
Prospective
monocentric
Retrospective monocentric
Cut-offs
HVPG 10 mm Hg
(kPa)
8.7*
13.6
17.6**
14.0
23.0**
20.5
34.9
21.0
Prevalence of
Cinically Significant
Portal hypertension
21%
77%
74%
83%
51%
PPV 86 84 79
NPV 91 71 35 64
Castera L, Pinzani M, Bosch J, J Hepatology 2012

21. Hypertrophy and Hyperplasia
PINZANI M- 2012
The Spleen in the Assessment of Advanced Chronic Liver Disease
Congestion
Hypertrophy and Hyperplasia
Fibrosis

22. INCREASE IN SPLEEN STIFFNESS ?? Hypertrophy and Hyperplasia
PINZANI M- 2012
The Spleen in the Assessment of Advanced Chronic Liver Disease
INCREASE IN SPLEEN STIFFNESS ??
Congestion
Hypertrophy and Hyperplasia
Fibrosis

23. “Compensated” Cirrhosis
PINZANI M- 2012
Spleen Stiffness (SS), a Promising Diagnostic Parameter in Cirrhosis
Spleen Stiffness (SS), a Promising Diagnostic Parameter in Cirrhosis
Colecchia A. et al., Gastroenterology 2012 ; 143(3):646-54
HVPG (mm Hg)
HVPG (mm Hg)
“Compensated” Cirrhosis
Liver Stiffness (kPa)
Spleen Stiffness (kPa)
Esophageal Varices: NO
Esophageal Varices: YES

24. Colecchia A. et al., Gastroenterology 2012 ; 143(3):646-54
PINZANI M- 2012
Liver and Spleen Stiffness for the Prediction of the Presence of Esophageal Varices
Colecchia A. et al., Gastroenterology 2012 ; 143(3):646-54
EV: NO
EV: YES
EV: NO
EV: YES

25. Hepatocellular Carcinoma
PINZANI M- 2012
Compensated Cirrhosis a Clinical Stage with Very Limited Diagnostic Resources
Stage 3
Bleeding ?
“Decompensating Event”
SEPSIS
Renal
Failure
Stage 1
Stage 2
No Varices
No Ascites
Varices
Stage 4
First non
bleeding
decompensation
Death or
OLT
Years
Months
Stage 5
Second
decompensation
Hepatocellular Carcinoma
Compensated Cirrhosis ?
Decompensated Cirrhosis
Modified from Arvaniti V. et al., Gastroenterology 2010; 139:

26. >12 LS (kPa) 6-7 9-12 13.6 17.6 20-60 Decompensated Compensated
PINZANI M- 2012
LS (kPa)
Decompensated
Compensated
Non-cirrhotic
Clinical
Ascites, VH, Encephalopathy
None (varices present)
None (no varices)
None
Symptoms
Stage 2
Stage 1 -
Sub-stage
Insoluble scar
Thick (acellular) scar and nodules
Scar and
X-linking
Fibrogenesis and Angiogenesis
Biological
Hemodynamic (HVPG, mmHg)
Histological
F1-F3
F4 (Cirrhosis)
>6
>10
>12
Stages 3.4,5*
REVERSIBLE PARTIALLY REVERSIBLE IRREVERSIBLE

27. PINZANI M- 2012
FIBROSCAN
FIBROTEST

28. Hepatocellular Carcinoma
PINZANI M- 2012
Compensated Cirrhosis a Clinical Stage with Very Limited Diagnostic Resources
Stage 3
Bleeding ?
“Decompensating Event”
SEPSIS
Renal
Failure
Stage 1
Stage 2
No Varices
No Ascites
Varices
Stage 4
First non
bleeding
decompensation
Death or
OLT
Years
Months
Stage 5
Second
decompensation
Hepatocellular Carcinoma
Compensated Cirrhosis ?
Decompensated Cirrhosis
Modified from Arvaniti V. et al., Gastroenterology 2010; 139:

29. PINZANI M- 2012
Cirrhosis Causes Structural and Functional Changes in the Mucosa of the Small Intestine
Changes in Microbiota Bacterial Overgrowth
Decreased Bile Acids
Immunosuppression
Mesenteric Vein Congestion
Mucosal Injury (ETOH)
CIRRHOSIS
Obesity/Overweight High Fat Diet
Optical density at 540 nm
Bacterial adherence to BBM
Urinary excretion of DTPA (%)
Intestinal permeability
Control
Cirrhosis
Ramachandran A. et al. Hepatology 2002
Chiva M. et al. Eur J Gastroenterol Hepatol 2003
Perez-Páramo M et al. Hepatology 2003
Natarajan SK et al. Hepatology 2006
Functional abnormalities of the mucosa of the small intestine of rats with cirrhosis:
• oxidative stress, ↑ xanthine oxidase activity
• lipid peroxidation of brush border membrane
• ↑ sugar content of brush border membrane
• abnormal intestinal transport
P<0.01
Increased Pathogen-Associated Molecular Patterns “PAMPs” (i.e. LPS) in the portal circulation 29 29

30. PINZANI M- 2012

31. Clinico-pathological
PINZANI M- 2012
Beyond Cirrhosis…………
Advanced CLD without clinically evident complications (compensated cirrhosis)
Clinical Workup
Pathology
Clinico-pathological
Correlation
Assessment or re-assessment of ETIOLOGY, co-factors and co-morbidities
ASSESSMENT OF SEVERITY: biochemistry, non invasive (Transient Elastography), HVPG, Upper GI endoscopy, imaging
Morphological (distribution) and quantitative (CPA) assessment of tissue fibrosis
Inflammatory activity, angiogenesis, histological correlates with co-factors (e.g. metabolic, alcohol, iron, etc)
Features of REGRESSION
Features predicting MALIGNANCY (HCC)
Final Diagnosis
Etiology +
Stage:
Advanced Stage with no complications
Advanced Stage with complications (e.g. varices)
Advanced Stage with features of regression
End stage +
Disease Activity +
Risk for HCC

32. UCL Institute for Liver and Digestive Health
Royal Free Hospital, London, United Kingdom