Fibrosis Hati
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Transcript of Fibrosis Hati
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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