Transcript 幻灯片 1 - yynet.cn

The advancement of liver fibrosis
Shi Guangfeng, M.D.,Ph.D
Huashan Hospital, Fudan University
Synopsis
• The etiology and pathogenisis of hepatic
fibrosis.
• The treatment strategies of hepatic fibrosis.
• The advancement of clinical pharmacal
research in hepatic fibrosis.
Hepatic fibrosis is a slow and dynamic process
which involving cells, cytokines and ECM
(extracellular matrix) and a series of
complicate changes among them.
• HSC (Hepatic stellate cell)---- the central
element
• Cytokines---TGF-b, PDGF, etc.
• TIMPs (The inhibitor of matrix
metalloproteinase )
The status quo of epidemiology
• The total number of hepatic fibrosis patients in China is
70 million.
35 million CHB (chronic hepatitis B)
20 million CHC (chronic hepatitis C)
13.5 million fatty liver
1.5 million alcohol liver
• There are 1 million people suffered from liver cirrhosis
per year , among which 110 thousand will die eventually.
One who can arrest or slow
down hepatic fibrosis will cure
liver disease as many as
possible.
----Hans
Hopper ( the deceased academic authority in the
field of international liver disease )
The etiology
• Chronic viral hepatitis, especially the hepatitis B is
one of the main causes in China
• Others : Schistosomiasis, alcoholic, cholestasis ,
the dysfunction of hepatic metabolism (Wilson’s
disease, hemachromatosis), congestion of the liver,
poisoning, etc.
The pathology
hepatic cell
the disappearance of
the hepatic microvilli
The mechanism of hepatic fibrosis
The cytokine / peroxidate stimulates HSC , and then
induces the priming of fibrosis.
The expression of collagenic gene prompts HSC to
secrete collagen which is result in the aggravation of
fibrosis.
Fibrosis is a process that is reversible.
Treatment of hepatic
fibrosis
The necessity and possibility
Liver diease

Inflammation and necrosis

Hepatic fibrosis

Reconstruction of hepatic lobule
and the psedlobule formation 
aggravate the inflammation
and necrosis of hepatocyte

portal hypertension
and ischemic of liver

liver cirrhosis
The therapeutic strategies
The involving factors of fibrosis
• Initiating agents : the necrosis of hepatocyte and the
aggregation of inflammatory cell
• Involving cells: sinusal endotheliocyte , Kuppfer cell ,
hepatic cell, fat storing cell (Ito’s cell, HSC)
• Central component: muscular fibroblast
• Mediating factor :
TGFa(transforming growth factor a)
TGF b(transforming growth factor b)
PDGF(platelet-derived growth factor)
EGF(epiderm growth factor)
• Ultimum consequence : the deposition of ECM
• While fibrogenesis, the catabolism of ECM is
taking place .
• The main enzyme involving in the catabolism of ECM :
The matrix protein enzyme
Type IV collagen
Stromelysin
Treatment of hepatic fibrosis
Anti-cytokine
Suppress the expression of
collagenous gene
Accelerate the degradation of
collagen that is paraplasm and
depositive
Prompt the apoptosis of HSC
the principal
measures
Anti-peroxidate
Anti-hepatic fibrosis’ strategies
1. Cure the priming disease
• Clear the infection of chronic virus
• Stop drinking and intaking toxins
• Shift excessive copper , ferrum and etc
( Wilson’s disease , Hemachrmatosis)
• Eliminate the infection of schistosoma
• Preclude the biliary tract’s obstruction
2. Relieve the inflammation and
immune response
INFa (interferon a)
PG (prostaglandin)
CTS(corticosteroid)
Penicillinamide
Antagon of cytokine (IL-1 , RGD peptide )
Transilast captopril
Malotilate
Sensitizer of IL-12 ( Schistosomiasis )
3. Inhibit the activation of HSC
Anti-oxidant : vitamin E、phosphatidyl
choline、legalon
Cytokine : INFr、HGF (hepatic growth factor)、
HOE077 Safironil
Endothelin antagonist
Celluar fibronectin antagonists
4. Neutralize the response of HSC
Neutralize the productive reaction :
PDGF, EGF and TGFa that can reject the
hyperplasy through inhibiting PTK receptor.
Studies have demonstrated that linoleic acid
and lipoxygenase inhibitor can restrain the
PTK receptor in HSC and then static the
hyperplasy.
5. Repress the formation of matrix
Which hitherto is also the most significant aim of
anti-fibrosis
HOE 077 traps the prolyl hydroxylase and then
inhibit the synthesis of collagen directly.
CLC(colchicina) restrains the intracellular
canaliculus formation, collagen secretion and
cuts down mRNA level of type 1 collagen.
6. Restrain the activity of TGFb1
• Which can achieve double purposes of both the inhibition of
matrix formation and the promption of matrix breakdown.
Decorin a peroteoglycan degradating TGFb1, but deserved to be
further studied to the effect to hepatic fibrosis.
LAP（Latency-associated peptide） a type of protein that is
associated to pre-TGFb, which has the similar effect of Decorin, can
anti-fibrosis in cultured cell, but its effect need studing futhermore in
vivo.
TGFβ1 soluble receptor antagonists Antisense oligonucleotides
The recombination of mannitose-6-orthophosphoric acid.
7. Inhance the fibrosis matrix degradation
TGF antagonists : neutralize the reaction of HSC , down
regulation TIMPs and increase the interstitial collagenase’s
activity.
Relaxin : raise the matrix degradation
CLC(colchicina) : reinforce the activity of collagenase
Penicillamine : prompt the collagenase’s activity and
repress the cross-linking of the collagen in empirical
study.
The therapeutic measure
to fibrosis
• Eliminate the etiopathogenisis inducing the
injury and inflammation of liver
Any causes leading to hepatic necrosis and inflammation can
activate HSC and induce hepatic fibrosis eventually, so controlling
the hepatic injury and annihilation inflammation actively can achieve
the purpose of antifibrosis.
• ALD （alcohol liver disease）go on the wagon severly
• PBC (primary biliary cirrhosis) : ursodeoxycholic acid
and corticosteroids
• HCH (hemachromatosis) : bloodletting therapy
• CHB/CHC (chronic hepatitis B/ chronic hepatitis C) :
antiviral therapy
• Hepatic fibrosis is always developing even
though the cause is removed.
• Machanism: the activated HSC can
restimulate the pathway of fibrosis through
autocrine or paracrine.
As a result , the therapy of antifibrosis has
become an essential link in holding the
progression of liver disease.
Summary
1 Hepatic fibrosis is the prelude and essential pathological process
of liver cirrhosis.
2 The proliferation and activation of HSC play a significant role in the
development and advancement of hepatic fibrosis.
3 Treatment involves treating the primary disease, regulating the
necrosis and inflammation in liver, repressing cytokine, restraining
the multiplication and activation of HSC, reinforcing the
collagenase activity and prompting the collagen fiber’s degradation.
4 The earlier period of hepatic fibrosis is reversible, and
what is more, the etiological treatment cann’t take place
the anti-fibrosis treatment.