HSAR LELOSUTANSUB GASTROENTERO-HEPATOLOGI DEP. PENY. DALAM RSPAD GS JAKARTA 2006.

SIROSIS HATI

HEPATOMA

HEPATOSIT NORMAL

REVERSIBELFibrogenesis

Fibrosis : • Respons parenkim hati, berupa wound healing terhadap injury akut / kronik

Akumulasi matriks ekstraselular baru

menggantikan matriks lama Membentuk scar, menyelimuti daerah injury

Fibrogenesis hati,Fibrogenesis hati,

Pada dasarnya sama dengan fibrogenesis di tempat lain : Artherosklerosis Rhematoidartritis Glumerulosklerosis Fibrosis pankreas

Reaksi inflamatorik

Etiologi fibrosis hatiEtiologi fibrosis hati

• Infeksi kronik VHB• Infeksi kronik VHC• Alkoholisme• NASH• Obat

Tahap-tahap fibrosis hati Tahap-tahap fibrosis hati ( metavir)( metavir)

• Tahap 1 (F1) : zone 3 perivenulae, perisinusoid perisellular. Fokal /ekstensif• Tahap 2 (F2) : F1, diikuti fibrosis porta. Fokal/ekstensif• Tahap 3 (F3) : F2, diikuti bridging fibrosis• Tahap 4 (F4) : Sirosis hati (diikuti atau tidak dengan fibrosis residual peri- sinusoid

Fibrogenesis hati,Fibrogenesis hati,

• Dimulai dari aktivasi HSC• Aktivasi : transdifferentiasi 3 tahap Inisiasi

Perpetuasi Resolusi

InisiasiInisiasi

• Ditandai dengan perubahan ekspresi gen dan fenotip (transdeferensiasi) HSC• Fenotip baru menjadi lebih sensitif thd :

- Sitokin - stimuli

injury

Lekosit

hepatosit

platelet

endotel

Sel Kupffer

TGF 1IGF1PDGF EDFTNFFree radical

Act HSC

Q HSC

Proses inisiasi

PerpetuasiPerpetuasi• Mempertahankan efek stimuli yang mengaktifkan HSC • HSC mengalami perubahan biologik

Proliferasi HSCFibrogenesisChemotaksisKontraktilityKemoatraktan Produksi sitokinRetinoid menghilangDegradasi matriks

Akumulasi ECMfibrosis

ProliferasiProliferasi• Dipacu terutama oleh : - PDGF - Thrombin - EDGF - TGF - Angiotensin II - IGF 1 - Discoidin domain receptor (DDR2)• Selama injury proliferasi mengalahkan apoptosis

Proliferasi berakibat jumlah HSC didaerahInjury dan proses selanjutnya menjadi lebihbermakna

Fibrogenesis menjadiLebih hebat dan cepat

ContractilityContractility

• Pemacu - Thrombin - Angiotensin II - Vasopresin - Prostaglandin - ET ( paracrin dan autocrin)• HSC aktif mempunyai sifat seperti myofibroblast, dapat berkontraksi.

HSC mempunyai sifat dapat berkontraksi seperti myofibroblast mula-mula kontraksi disekitar sinusoid

Resistensi sistem porta meningkat

Hipertensi porta

FibrogenesisFibrogenesis

• Pemacu paling kuat TGF

• TGF• Peroksidasi lipid

Ekspresi gen kolagen

Sintesis ECM

Kemotaksis dan Kemotaksis dan penglepasan sitokinpenglepasan sitokin

• SC aktif menghasilkan - Monocyte chemotactic protein I - Chemoattractant - ICAM - NCAM lekosit ke daerah injury• Terjadi perubahan distribusi Th1/Th2 - Th2 memacu fibrogenesis

Lekosit bergerak kearah injury

menghasilkan ROS >> menghasilkan sitokin limfosit helper (Th) berdeferensiasi

Th1 : Inf , TNF, Il 2 Th2 : Il4, Il6 dan Il13

M-csfMCP-1 ICAMNCAM

imunnosit

Sitokinros

injury

Degradasi matriksDegradasi matriks

• HSC aktif menghasilkan : - MMPs (metalloproteinase) degradasi - TIMPs (Spesific tissue inhibitor) >< MMPs merupakan alat pengatur fibrotisasi

TIMP > MMPs fibrosis >> TIMP < MMPs fibrosis << • Hasil akhir Fibrotisasi adalah syntesis - degradasi

Resolusi aktivitas HSCResolusi aktivitas HSC

• Apoptosis • Dari aktif berubah menjadi quiscens jarang• Bila injury reda, pemacu aktifitas reda, apoptosis• Apoptosis dipacu : - soluble factor - komponen matriks

Diagnosis fibrosis hatiDiagnosis fibrosis hati

• Biopsi hati, invasif, dinilai dengan score metavir dan Knodell• Sulit dilaksanakan : penolakan besar sampling error perbedaan inter observer

SeromarkerSeromarker

• seromarker yang baik : spesifik untuk fibrosis hati dapat menerangkan tahap-tahap fibrosis• Yang dapat diperiksa : Mengukur produk break down ECM Mengukur enzim regulator produksi• Pada saat ini belum ada dipasaran

Fibrosis ditentukan secara klinik/laboratorium

Infeksi VHC :• 2 macroglobulin• Haptoglobin• GGT• globulin• Bilirubin total• Apolipoprotein.

Faktor peramal fibrosis Nash

• Usia > 50 tahun• Ast > Alt• Resistensi insulin• DM• Obesitas• Hipertensi• hipertrigliserida

Implikasi klinikImplikasi klinik

Etiologi dieradikasi

Mencegah inflamasi

Mencegah HSC menjadi aktifMenetralisasi pengaruh aktivasi HSCMemacu apoptosis

Anti fibrosis/meningkatkan degradasi

Injury

HSC aktif

Fibrosis

Viral Clearance

Seroconversion

Reduce inflammatory process

THE GOAL OF THERAPY ON CHRONIC VIRAL HEPATITIS

CIRRHOSIS

STOP

PILIHAN TERAPIPILIHAN TERAPI

NA

IFN

ImHepatoprotector / CAM (Antiinflammatory)

Immune tolerance Immune clearance Integration

COMPLEMENTARY AND COMPLEMENTARY AND ALTERNATIVE ALTERNATIVE MEDICINESMEDICINES

CAM: segala macam pengobatan di luar CAM: segala macam pengobatan di luar terapi konvensionalterapi konvensional

Alasan pemakaian CAM:Alasan pemakaian CAM:

- - terapi konvensional gagalterapi konvensional gagal

- - terapi konvensional tidak bisa terapi konvensional tidak bisa diberikandiberikan

Masih banyak kontroversiMasih banyak kontroversi

COMPLEMENTARY AND ALTERNATIVE COMPLEMENTARY AND ALTERNATIVE

MEDICINES (CAMMEDICINES (CAM))

Medical intervention not taught widely at medical Medical intervention not taught widely at medical school or generally available at hospitalsschool or generally available at hospitals

Not be tested with rigorous scientific Not be tested with rigorous scientific methodologies followed by critical review and methodologies followed by critical review and replicationreplication

Diagnostic procedures and treatments not based on Diagnostic procedures and treatments not based on current pathophysiology of disease and basic current pathophysiology of disease and basic biological sciences biological sciences

Rock CL. AGA Postgraduate Course May 19-20,2001

COMPLEMENTARY AND ALTERNATIVE COMPLEMENTARY AND ALTERNATIVE

MEDICINE (CAMMEDICINE (CAM)) NaturopathyNaturopathy HomeopathyHomeopathy AcupunctureAcupuncture ChiropracticChiropractic Herbal medicines / PhytopharmaceuticalHerbal medicines / Phytopharmaceutical MassageMassage Traditional or Chinese MedicineTraditional or Chinese Medicine AyurvedaAyurveda Special diets: Gerson therapy diet, dllSpecial diets: Gerson therapy diet, dll Dietery supplementDietery supplement

Rock CL. AGA Postgraduate Course May 19-20,2001

CAM PADA PENYAKIT HATI DI USACAM PADA PENYAKIT HATI DI USA

Dipakai 41% pasien penyakit hati Dipakai 41% pasien penyakit hati kronikkronik

Obat herbal pada 12 – 50 % : Obat herbal pada 12 – 50 % : Silymarin, Glycirrhyzin, GinsengSilymarin, Glycirrhyzin, Ginseng

National Center for Complementary National Center for Complementary and Alternative Medicine and Alternative Medicine (NCCAM) sejak 1998(NCCAM) sejak 1998

HERBAL ATAU DERIVATNYA HERBAL ATAU DERIVATNYA DI INDONESIADI INDONESIA

Schisandrin C Schisandrin C CurcumaCurcuma SilymarinSilymarin GlycirrhizynGlycirrhizyn EchinaceaEchinacea PhyllantusPhyllantus JamuJamu Dan lain lainDan lain lain

Sho Saiko ToSNMCZioparBiochosilHpProBuah merah

Drugs for which an antifibrotic effect has been Drugs for which an antifibrotic effect has been shown or disproven in vivoshown or disproven in vivo

Drug Antifobrotic effectDrug Antifobrotic effect Proposed mechanismProposed mechanismAnimalAnimal ManMan

ColchicineColchicine nono nono secretion of collagenase and cytokinessecretion of collagenase and cytokines

DD-Penicillamine-Penicillamine nono nono collagen cross-links (lysylhydroxylase )collagen cross-links (lysylhydroxylase )

CorticosteroidsCorticosteroids nono (no)(no) collagen synthesis , immunsuppressantcollagen synthesis , immunsuppressant

Prolyl hydroxylase inhibitorsProlyl hydroxylase inhibitors (no)(no) ?? Intracellular collagen degradation Intracellular collagen degradation

HOE 077HOE 077 (yes)(yes) ?? HSC proliferation HSC proliferation

Poly-unsaturated lecithinPoly-unsaturated lecithin (yes)(yes) ?? Collagenase activity Collagenase activity SilymarinSilymarin yesyes (yes)(yes) membrane modulation ?, anti-inflammatorymembrane modulation ?, anti-inflammatory

Ursodeoxycholic acidUrsodeoxycholic acid (no)(no) (?)(?) anticholestatic, anti-inflammatoryanticholestatic, anti-inflammatory

PentoxifylinePentoxifyline yesyes ?? Intracellular collagen, degradation , Intracellular collagen, degradation , collagen collagen

Prostaglandins EProstaglandins E11/E/E22 (yes)(yes) ?? Intracellular collagen, degradation ,Intracellular collagen, degradation ,collagen collagen

Drugs for which an antifibrotic effect has been Drugs for which an antifibrotic effect has been shown or disproven in vivoshown or disproven in vivo

Drugs for which an antifibrotic effect has been Drugs for which an antifibrotic effect has been shown or disproven in vivoshown or disproven in vivo

Drug Antifobrotic effectDrug Antifobrotic effect Proposed mechanismProposed mechanism

AnimalAnimal ManMan

Interferon Interferon yesyes ?? Collagenase , collagen , proliferation Collagenase , collagen , proliferation

Interferon Interferon // (yes)(yes) (yes)(yes) collagen , proliferationcollagen , proliferation

HGFHGF (yes)(yes) ?? Hepatocyte regenerationHepatocyte regeneration

Anti-TGF-Anti-TGF- monoclonal monoclonal (yes)(yes) ?? Stellate cell collagen Stellate cell collagen

antibodyantibody

ETAR antagonistsETAR antagonists ?? ?? Stellate cell matrix synthesis andStellate cell matrix synthesis and

proliferation (?)proliferation (?)

Retinoic acidRetinoic acid ?? ?? Stellate cell matrix synthesis and proli-Stellate cell matrix synthesis and proli-

feration (?)feration (?)

HGF = Hepatocyte growth factor; ETA = endothelin A.HGF = Hepatocyte growth factor; ETA = endothelin A.

THERAPEUTIC AGENTS TESTED IN HEPATIC FIBROSISTHERAPEUTIC AGENTS TESTED IN HEPATIC FIBROSIS

Effectiveness and Type of Injury*Effectiveness and Type of Injury*

HumanHuman Animal Animal

Type of Effecti-Type of Effecti- Type ofType of

AgentAgent Effectiveness Effectiveness injury veness injury veness injury injury MechanismMechanism

CorticosteroidsCorticosteroids ++ AIH, Alc hepAIH, Alc hep NDND -- -- Anti-inflammatory, ? CytoprotectiveAnti-inflammatory, ? Cytoprotective(possible effect on collagen synthesis)(possible effect on collagen synthesis)

ColchicineColchicine +/-+/- Alc hep. MiscAlc hep. Misc ++ MultipleMultiple Inhibits collagen releaseInhibits collagen release

Ursodeoxycholic acidUrsodeoxycholic acid +/-+/- PBC, PSC, CFPBC, PSC, CF ++ BiliaryBiliary Prevents lipid peroxidation; cytoprotectivePrevents lipid peroxidation; cytoprotective

Interferon-aInterferon-a ++ hepatitis Chepatitis C ++ MultipleMultiple Reduces viral-mediated inflammation; mayReduces viral-mediated inflammation; mayinhibit stellate cell actrivationinhibit stellate cell actrivation

PenicillaminePenicillamine -- PBCPBC +/-+/- ToxinToxin ? Cytoprotective? CytoprotectiveLamivudineLamivudine ++ Hepatitis BHepatitis B NDND -- Reduces viral-mediated inflammationReduces viral-mediated inflammationMalotilateMalotilate -- PBC, Alc hepPBC, Alc hep ++ MultipleMultiple Suppresses P-450; ? Antioxidant’?Suppresses P-450; ? Antioxidant’?

CytoprotectiveCytoprotective

SilymarinSilymarin +/-+/- Alc hep, miscAlc hep, misc ++ BiliaryBiliary Prevents lipid peroxidation; ? Antioxidant;Prevents lipid peroxidation; ? Antioxidant;? Cytoprotective? Cytoprotective

MethotrexateMethotrexate -- PBCPBC NDND -- Anti-inflammatory; ? CytoprotectiveAnti-inflammatory; ? CytoprotectiveVitamine EVitamine E +/-+/- Hepatitis CHepatitis C ++ Toxin, IronToxin, Iron Prevents lipid peroxidation; ? Antioxidan;Prevents lipid peroxidation; ? Antioxidan;

? Cytoprotectived? Cytoprotectived

*Studies are in either whole animals or humans.*Studies are in either whole animals or humans.AIH = autoimmune hepatitis; Alc hep = Alcoholic hepatitis; PHC = primary biliary cirrhosis; PSC = primary sclerosing cholangitisAIH = autoimmune hepatitis; Alc hep = Alcoholic hepatitis; PHC = primary biliary cirrhosis; PSC = primary sclerosing cholangitis

SUMMARYSUMMARY

1. Hepatic fibrosis was a problem from chronic all liver 1. Hepatic fibrosis was a problem from chronic all liver injuryinjury

2. Essential components :2. Essential components :a. fibrogenic cell type (stellate cell)a. fibrogenic cell type (stellate cell)b. extra cellular matrix (fibrosis scar = collagen)b. extra cellular matrix (fibrosis scar = collagen)c. role of cytokines (complexes and diverse)c. role of cytokines (complexes and diverse)

3. Altered Matrix synthesis and degradation = fibrosis result3. Altered Matrix synthesis and degradation = fibrosis result

SUMMARYSUMMARYSUMMARYSUMMARY

4. Tool and marker for hepatic fibrosis :4. Tool and marker for hepatic fibrosis :

liver biopsyliver biopsy

non commercial kit non commercial kit

Fibrosis ScannFibrosis Scann

5. Therapeutic strategy :5. Therapeutic strategy :

collagen synthesis inhibitioncollagen synthesis inhibition

hepatic stellate cell inhibitionhepatic stellate cell inhibition

6.6. CAM will be use as well as an antiimflammatory CAM will be use as well as an antiimflammatory phytopharmaceutical in the hepatic immune clearance and phytopharmaceutical in the hepatic immune clearance and integrated condition.integrated condition.

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