DOTT. CLAUDIO PUOTI - 3° Giornata Master ECM in Gastroenterologia 2016 (25/11/2016) - Fondazione Santa Lucia - Sala Congressi - Roma Sito: www.asmad.net Canale Youtube: https://youtu.be/tz9PBGvk7aY

1. Claudio PuotiClaudio Puoti
Liver UnitLiver Unit
INI Research Institute and Clinics, Grottaferrata, Rome, andINI Research Institute and Clinics, Grottaferrata, Rome, and
““Regina Elena” Nat’l Cancer Institute, RomeRegina Elena” Nat’l Cancer Institute, Rome

2. The spectrum of CLD
Chronic liver disease due to :Chronic liver disease due to :
HBV, HCVHBV, HCV
HCCHCC
Alcoholic Liver DiseaseAlcoholic Liver Disease
SteatosisSteatosis, NASH, diabetes, NASH, diabetes
HemochromatosisHemochromatosis
PBC, PSCPBC, PSC
Wilson’ diseaseWilson’ disease
How new paradigms will impactHow new paradigms will impact
on clinical practice ?on clinical practice ?
• Treatment of chronic viral hepatitis : an updateTreatment of chronic viral hepatitis : an update
• New paradigms in liver cirrhosisNew paradigms in liver cirrhosis
• Portal Hypertension : the undiscovered countryPortal Hypertension : the undiscovered country
• Liver fibrosis : a reversible process ?Liver fibrosis : a reversible process ?

3. cccDNAcccDNA

5. End-point of therapyEnd-point of therapy
1.1. to reduce HBV DNA to as low a level as possible, ideally below theto reduce HBV DNA to as low a level as possible, ideally below the
lower limit of detection of real-time PCR assays (10-15 IU/mL).lower limit of detection of real-time PCR assays (10-15 IU/mL).
2.2. to allow HBsAgto allow HBsAg HBsAb seroconversionHBsAb seroconversion
3.3. to ensure a degree of viral suppression that will then lead toto ensure a degree of viral suppression that will then lead to
biochemical remission, histological improvement and prevention ofbiochemical remission, histological improvement and prevention of
complications.complications.
Treatment of CHBTreatment of CHB

6. HBV DNA suppressionHBV DNA suppression
– Weak surrogate end-pointWeak surrogate end-point
– Achievable in the majority of the patients in the short-term periodAchievable in the majority of the patients in the short-term period
– Lost in the majority of the patients in the long-term periodLost in the majority of the patients in the long-term period
Indicates pharmacologicalpharmacological control of the infection
TrueTrue end-pointsend-points
1.1. HBeAgHBeAg  HBeAb seroconversionHBeAb seroconversion
2.2. HBsAgHBsAg  HBsAb seroconversionHBsAb seroconversion
– True end-pointsTrue end-points
– Sustained in the long-term periodSustained in the long-term period
– Achievable in a minority of casesAchievable in a minority of cases
IndicateIndicate immune-controlimmune-control of the infectionof the infection

7. AdvantagesAdvantages DisadvantagesDisadvantages
IFNIFN Finite duration (6-12 mo)Finite duration (6-12 mo)
No resistanceNo resistance
Sustained and durable response (ALTSustained and durable response (ALT
normal, HBV DNA clearance)normal, HBV DNA clearance)
InjectionInjection
Poor tolerabilityPoor tolerability
ExpensiveExpensive
No role in decompensed cirrhosisNo role in decompensed cirrhosis
Low rates of SVRLow rates of SVR (HBsAg loss : 0-7%,(HBsAg loss : 0-7%,
HBV DNA undetectable 7-19%)HBV DNA undetectable 7-19%)
Nucleos(t)idesNucleos(t)ides OralOral
Negligible side effectsNegligible side effects
Potent viral inhibitionPotent viral inhibition
Less expensiveLess expensive
Long/ indefinite treatment to achieve HBVLong/ indefinite treatment to achieve HBV
suppression (HBV DNA neg)suppression (HBV DNA neg)
Drug resistanceDrug resistance
Potential for multi-drug resistancePotential for multi-drug resistance
Expensive if long termExpensive if long term
Two therapeutic Options for CHB :Two therapeutic Options for CHB :
advantages and disadvantagesadvantages and disadvantages
PEG IFN alfa 2aPEG IFN alfa 2a
PEG IFN alfa 2bPEG IFN alfa 2b
LamivudineLamivudine
AdefovirAdefovir
TelbivudineTelbivudine
EntecavirEntecavir
TenofovirTenofovir

12. • HBV vaccineHBV vaccine
• Disposable syringesDisposable syringes
• 1st generation treatments1st generation treatments
• Decreased PT HBV infectionDecreased PT HBV infection
• Non hepatic deathsNon hepatic deaths
(elderly inactive carriers)(elderly inactive carriers)
The ‘90sThe ‘90s
PrevalencePrevalence
3%3%  0.8%-1%0.8%-1%
The futureThe future

13. Antiviral treatment of HCV CLDAntiviral treatment of HCV CLD
in the new erain the new era

15. - previr- previr - asvir- asvir - buvir- buvir

16. Antivirals now available in ItalyAntivirals now available in Italy
Sofosbuvir (Sovaldi Gilead)Sofosbuvir (Sovaldi Gilead) HCV 1, 2, 3, 4HCV 1, 2, 3, 4
Simeprevir (Simeprevir (OlysioOlysio Janssen Cilag)Janssen Cilag) HCV 1- 4HCV 1- 4
Ombitasvir (Ombitasvir (Viekirax AbbVie)Viekirax AbbVie) HCV 4HCV 4
Dasabuvir (Dasabuvir (Exviera AbbVie)Exviera AbbVie) HCV 1HCV 1
Daclatasvir (Daclatasvir (Daklinza BMSDaklinza BMS)) HCV 1, 3, 4HCV 1, 3, 4
Ledipasvir + SOF (Ledipasvir + SOF (Harvoni GileadHarvoni Gilead) HCV 1, 3, 4) HCV 1, 3, 4
PEG IFN + RBVPEG IFN + RBV

19. Eradicheremo del tuttoEradicheremo del tutto
l’ epatite C con i nuovi farmaci ?l’ epatite C con i nuovi farmaci ?
SISI
Se si considera l’eradicazione dell’ HCV nei singoli pazientiSe si considera l’eradicazione dell’ HCV nei singoli pazienti
FORSEFORSE
Se riusciremo a trattare anche i portatori “sani” di HCV (fibrosi F0) ed iSe riusciremo a trattare anche i portatori “sani” di HCV (fibrosi F0) ed i
pazienti con danno minimo/lieve (F1-F2) per eliminare la circolazione delpazienti con danno minimo/lieve (F1-F2) per eliminare la circolazione del
virus nella popolazionevirus nella popolazione
NONO
Se non riusciremo a raggiungere anche i migranti da aree ad alta prevalenzaSe non riusciremo a raggiungere anche i migranti da aree ad alta prevalenza
di HCV, che non accedono alle strutture sanitarie, e che possonodi HCV, che non accedono alle strutture sanitarie, e che possono
interfacciarsi in vario modo con la popolazione “stanziale” (prostituzione,interfacciarsi in vario modo con la popolazione “stanziale” (prostituzione,
tossicodipendenza, ecc)tossicodipendenza, ecc)

20. Hyperkinetic syndromeHyperkinetic syndrome
A multiorgan failureA multiorgan failure
Liver cirrhosis +Liver cirrhosis +
PORTAL HYPERTENSIONPORTAL HYPERTENSION
BLEEDINGBLEEDING
HRSHRS HEHE HPSHPS
CirrhoticCirrhotic
Cardio-Cardio-
miopathymiopathy
AscitesAscites

22. 2011; 31: 75-822011; 31: 75-82

24. Hemodynamic Factors in the PathophysiologyHemodynamic Factors in the Pathophysiology
ofof CirrhoticCirrhotic Portal HypertensionPortal Hypertension
∆ Portal Pressure = Blood Flow x Resistance
Increased Portal PressureIncreased Portal Pressure
Increased
resistance
Increased
blood flow
Ohm’s lawOhm’s law

26. Extrahepatic (splanchnic) NO signalingExtrahepatic (splanchnic) NO signaling
in cirrhotic portal hypertensionin cirrhotic portal hypertension
Liver cirrhosisLiver cirrhosis
Portal HypertensionPortal Hypertension

30. Statins : a new approachStatins : a new approach
to portal hypertension ?to portal hypertension ?

31. Courtesy of prof. J Bosch, mod.5, mod.5, mod.5Courtesy of prof. J Bosch, mod.5, mod.5, mod.5
HEPARINEHEPARINE
ANTI FIBROTICSANTI FIBROTICS

32. HSCs migrateHSCs migrate
andand
accumulate inaccumulate in
the site ofthe site of
tissue repairtissue repair
Activate HSC (myofibroblast-like cells)Activate HSC (myofibroblast-like cells)
 Enhanced cell migration and proliferation
 Recruitment of inflammatory cells
 Proinflammatory properties
 Contractibility
 Acquisition of fibrogenic capacity
 Loss of retinoic storing ability

33. CTGF, connective tissue GF
FGF, fibroblast growth factor
PDGF, platelet-derived GF
TGF, transforming growth factor
TLR, toll like receptors
TRAIL, TNF-related
apoptosis-inducing factor
VEGF, vascular endothelial GF

34. HBVHBV
HCVHCV
alcoholalcohol
……..
fibrogenesis
ECM
Fibrogenesis and fibrolysis mechanisms
Activated HSCsActivated HSCs
CTGF, connective tissue GF
FGF, fibroblast growth factor
PDGF, platelet-derived GF
TGF, transforming growth factor
TLR, toll like receptors
TRAIL, TNF-related
apoptosis-inducing factor
VEGF, vascular endothelial GF
The process of breaking down or degrading collagen is impaired.The process of breaking down or degrading collagen is impaired.
In a healthy liver, the synthesis (fibrogenesis) and breakdownIn a healthy liver, the synthesis (fibrogenesis) and breakdown
(fibrolysis) of matrix tissue are in balance.(fibrolysis) of matrix tissue are in balance.
Fibrosis occurs when excessive scar tissue builds up faster than itFibrosis occurs when excessive scar tissue builds up faster than it
can be broken down and removed from the livercan be broken down and removed from the liver

38. • Liver fibrosis is dynamic, active and reversible process, often resulting in cirrhosis,Liver fibrosis is dynamic, active and reversible process, often resulting in cirrhosis,
liver failure, and portal hypertension.liver failure, and portal hypertension.
• Chronically damaged hepatocytes release inflammatory cytokines, with recruitmentChronically damaged hepatocytes release inflammatory cytokines, with recruitment
of activated T cells and activation of Kuppfer cells and HSCs, with development ofof activated T cells and activation of Kuppfer cells and HSCs, with development of
contractile and fibrogenic phenotype (myofibroblasts).contractile and fibrogenic phenotype (myofibroblasts).
• Myofibroblasts proliferate and produce large amounts of ECM, leading to fibrosis.Myofibroblasts proliferate and produce large amounts of ECM, leading to fibrosis.
Apoptosis of damaged hepatocytes further stimulates the fibrogenic actions of HSCs.Apoptosis of damaged hepatocytes further stimulates the fibrogenic actions of HSCs.
• ECM degradation is inhibited by TIMPs, resulting an unbalance between the synthesisECM degradation is inhibited by TIMPs, resulting an unbalance between the synthesis
(fibrogenesis) and breakdown (fibrolysis) of ECM.(fibrogenesis) and breakdown (fibrolysis) of ECM.
Take home
messages 1

39. • Therapeutic strategies have been designed to target each step of this process,
including removal of liver injury, promotion of HSCs and hepatocyte apoptosis,
suppression of inflammation, down regulation of HSCs activation, promotion of ECM
degradation.
• Regression occurs if changes are reversible.
• What is not reversible?
 Extensive scar with elastosisExtensive scar with elastosis
 Parenchymal extinctionParenchymal extinction
 Cirrhotic nodulesCirrhotic nodules
 Non-degradable forms of highly complexed collagen (such as Type II)Non-degradable forms of highly complexed collagen (such as Type II)
 Extensive vascular remodelingExtensive vascular remodeling
Take home
messages 2

40. Liver cellsLiver cells
SinusoidsSinusoids
FibrosisFibrosis
Grazie per la pazienza e la cortese attenzioneGrazie per la pazienza e la cortese attenzione