The advancement of liver fibrosis Shi Guangfeng, M.D.,Ph.D Huashan Hospital, Fudan University

1. The advancement of liver fibrosis Shi Guangfeng, M.D.,Ph.D Huashan Hospital, Fudan University

2. Synopsis • The etiology and pathogenisis of hepatic fibrosis. • The treatment strategies of hepatic fibrosis. • The advancement of clinical pharmacal research in hepatic fibrosis.

3. 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 )

4. 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.

5. 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 )

6. 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.

7. The pathology

8. the disappearance of the hepatic microvilli hepatic cell Disse diastema the static HSC Sinus hepaticus endothelial cell Kuppfer cell

9. 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.

10. Treatment of hepatic fibrosis

11. The necessity and possibility Liver diease  Inflammation and necrosis aggravate the inflammation and necrosis of hepatocyte   Hepatic fibrosisportal hypertension and ischemic of liver   Reconstruction of hepatic lobule and the psedlobule formationliver cirrhosis

12. The therapeutic strategies

13. 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

14. 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

15. 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 principal measures

16. 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

17. 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 )

18. 3. Inhibit the activation of HSC Anti-oxidant : vitamin E、phosphatidyl choline、legalon Cytokine : INFr、HGF (hepatic growth factor)、HOE077 SafironilEndothelin antagonistCelluar fibronectin antagonists

19. 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.

20. 5. Repress theformation of matrix Which hitherto is also the most significant aim of anti-fibrosis HOE 077traps 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.

21. 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 solublereceptor antagonists Antisense oligonucleotides The recombination of mannitose-6-orthophosphoric acid.

22. 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.

23. The therapeutic measure to fibrosis

24. 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 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

25. 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.

26. Summary • 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.