The advancement of liver fibrosis

Shi Guangfeng, M.D.,Ph.D

Huashan Hospital, Fudan University

SynopsisSynopsis

• 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 ele

ment• Cytokines---TGF-b, PDGF, etc.• TIMPs (The inhibitor of matrix metalloprotei

nase )

• 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 p

er year , among which 110 thousand will die eventually.

The status quo of epidemiologyThe status quo of epidemiology

One who can arrest or slow One who can arrest or slow down hepatic fibrosis will cure down hepatic fibrosis will cure liver disease as many as liver disease as many as possible.possible.

----Hans Hopper ( the deceased academic authority in the field of international liver disease )

The etiologyThe 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 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.

The mechanism of hepatic fibrosisThe mechanism of hepatic fibrosis

Treatment of hepatic fibrosis

The necessity and possibilityThe necessity and possibility

　 Liver diease

Inflammation and necrosis aggravate the inflammation

and necrosis of hepatocyte

Hepatic fibrosis portal hypertension

and ischemic of liver

Reconstruction of hepatic lobule

and the psedlobule formation liver cirrhosis

　

The therapeutic strategiesThe therapeutic strategies

The involving factors of fibrosisThe 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

Anti-peroxidate Suppress the expression of collagenous gene

Accelerate the degradation of collagen that is paraplasm and depositive

Prompt the apoptosis of HSC

the p

rincip

al m

easures

Anti-hepatic fibrosis’ strategiesAnti-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 ( Wilso

n’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) 、 H

OE077 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 fur

ther studied to the effect to hepatic fibrosis.

LAP （ Latency-associated peptide ） a type of protein that is asso

ciated 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 liverAny 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 pur

pose of antifibrosis. 　• ALD （ alcohol liver disease ） go on the wagon severly• PBC (primary biliary cirrhosis) : ursodeoxycholic acid an

d corticosteroids • HCH (hemachromatosis) : bloodletting therapy• CHB/CHC (chronic hepatitis B/ chronic hepatitis C) : anti

viral 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.

SummarySummary

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.