HSAR LELOSUTAN

SUB GASTROENTERO-HEPATOLOGI DEP. PENY. DALAM RSPAD GS

JAKARTA 2006.

HEPATOSIT NORMAL

Fibrogenesis

SIROSIS HATI
HEPATOMA

REVERSIBEL

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

Reaksi
inflamatorik

Etiologi fibrosis hati

Infeksi kronik VHB
Infeksi kronik VHC
Alkoholisme
NASH
Obat

Tahap-tahap fibrosis hati

( 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 perisinusoid

Fibrogenesis hati,
Dimulai dari aktivasi HSC
Aktivasi : transdifferentiasi
3 tahap

Inisiasi
Perpetuasi
Resolusi

Inisiasi
Ditandai dengan perubahan ekspresi gen dan
fenotip (transdeferensiasi) HSC
Fenotip baru menjadi lebih sensitif thd :
- Sitokin
- stimuli

injury

Q HSC

hepatosit
platelet
Lekosit

TGF 1
IGF1
PDGF
EDF
TNF

Free
radical

Act HSC

endotel
Sel Kupffer

Proses inisiasi

Perpetuasi
Mempertahankan efek stimuli yang mengaktifkan
HSC
HSC mengalami perubahan biologik
Proliferasi HSC
Fibrogenesis
Chemotaksis
Kontraktility
Kemoatraktan
Produksi sitokin
Retinoid menghilang
Degradasi matriks

Akumulasi ECM
fibrosis

Proliferasi
Dipacu terutama oleh :
- PDGF
- Thrombin
- EDGF
- TGF
- Angiotensin II
- IGF 1
- Discoidin domain receptor (DDR2)

Selama injury proliferasi mengalahkan

apoptosis

Proliferasi berakibat jumlah HSC didaerah

Injury dan proses selanjutnya menjadi lebih
bermakna

Fibrogenesis menjadi
Lebih hebat dan cepat

Contractility
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

Fibrogenesis
Pemacu paling kuat TGF
TGF
Peroksidasi
lipid

Ekspresi gen kolagen

Sintesis
ECM

Kemotaksis dan
penglepasan 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-csf
MCP-1
ICAM
NCAM

Sitokin
ros

imunnosit
injury

Degradasi 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 HSC

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

Diagnosis fibrosis hati

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

Seromarker
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 klinik
Injury

Etiologi dieradikasi
Mencegah inflamasi

HSC aktif

Mencegah HSC menjadi aktif

Menetralisasi pengaruh
aktivasi
HSC
Memacu apoptosis

Fibrosis

Anti fibrosis/meningkatkan
degradasi

THE GOAL OF THERAPY ON

CHRONIC VIRAL HEPATITIS

Seroconversion
Viral Clearance
Reduce
inflammatory
process
STOP

CIRRHOSIS

PILIHAN TERAPI
Immune tolerance Immune clearance

NA
IFN
Im
Hepatoprotector / CAM
(Antiinflammatory)

Integration

COMPLEMENTARY AND ALTERNATIVE

MEDICINES

CAM: segala macam pengobatan di luar

terapi konvensional
Alasan pemakaian CAM:
- terapi konvensional gagal
- terapi konvensional tidak bisa
diberikan
Masih banyak kontroversi

COMPLEMENTARY AND ALTERNATIVE

MEDICINES (CAM)

Medical intervention not taught widely at medical

school or generally available at hospitals
Not be tested with rigorous scientific
methodologies followed by critical review and
replication
Diagnostic procedures and treatments not based on
current pathophysiology of disease and basic
biological sciences
Rock CL. AGA Postgraduate Course May 19-20,2001

COMPLEMENTARY AND ALTERNATIVE

MEDICINE (CAM)

Naturopathy
Homeopathy
Acupuncture
Chiropractic
Herbal medicines / Phytopharmaceutical
Massage
Traditional or Chinese Medicine
Ayurveda
Special diets: Gerson therapy diet, dll
Dietery supplement
Rock CL. AGA Postgraduate Course May 19-20,2001

CAM PADA PENYAKIT HATI DI USA

Dipakai 41% pasien penyakit hati

kronik
Obat herbal pada 12 50 % :
Silymarin, Glycirrhyzin, Ginseng
National Center for Complementary
and Alternative Medicine
(NCCAM) sejak 1998

HERBAL ATAU DERIVATNYA DI

INDONESIA

Schisandrin C
Curcuma
Silymarin
Glycirrhizyn
Echinacea
Phyllantus
Jamu
Dan lain lain

Sho Saiko To
SNMC
Ziopar
Biochosil
HpPro
Buah merah

Drugs for which an antifibrotic effect has been

shown or disproven in vivo
Drug
Animal

Antifobrotic effect Proposed mechanism

Man

Colchicine

no

no

secretion of collagenase and cytokines

D-Penicillamine

no

no

collagen cross-links (lysylhydroxylase )

Corticosteroids

no

(no)

collagen synthesis , immunsuppressant

Prolyl hydroxylase inhibitors

(no)

Intracellular collagen degradation

HOE 077

(yes)

HSC proliferation

Poly-unsaturated lecithin
Silymarin

(yes)
yes

?
(yes)

Collagenase activity
membrane modulation ?, anti-inflammatory

Ursodeoxycholic acid

(no)

(?)

anticholestatic, anti-inflammatory

Pentoxifyline
collagen

yes

Intracellular collagen, degradation ,

Prostaglandins E1/E2
collagen

(yes)

Intracellular collagen, degradation ,

Drugs for which an antifibrotic effect has been

shown or disproven in vivo
Drug
Animal

Antifobrotic effect Proposed mechanism

Man

Interferon

yes

Collagenase , collagen , proliferation

Interferon /

(yes)

(yes)

collagen , proliferation

HGF

(yes)

Hepatocyte regeneration

Anti-TGF- monoclonal
antibody

(yes)

Stellate cell collagen

ETAR antagonists
proliferation (?)

Stellate cell matrix synthesis and

Retinoic acid
feration (?)

Stellate cell matrix synthesis and proli-

HGF = Hepatocyte growth factor; ETA = endothelin A.

THERAPEUTIC AGENTS TESTED IN HEPATIC FIBROSIS

Effectiveness and Type of Injury*
Human
Type of

Agent

Animal
Effecti- Type of
Effectiveness

injury

Mechanism

injury

veness

Corticosteroids
+
(possible effect on collagen synthesis)

AIH, Alc hep

ND

Colchicine

+/-

Alc hep. Misc

Multiple

Inhibits collagen release

Ursodeoxycholic acid

+/-

PBC, PSC, CF

Biliary

Prevents lipid peroxidation; cytoprotective

Interferon-a
+
inhibit stellate cell actrivation

hepatitis C

Multiple

Reduces viral-mediated inflammation; may

Penicillamine
Lamivudine
Malotilate
Cytoprotective

+
-

PBC
Hepatitis B
PBC, Alc hep

+/ND
+

Toxin
Multiple

? Cytoprotective
Reduces viral-mediated inflammation
Suppresses P-450; ? Antioxidant?

Silymarin
? Cytoprotective

+/-

Alc hep, misc

Biliary

Prevents lipid peroxidation; ? Antioxidant;

Methotrexate
Vitamine E
? Cytoprotectived

+/-

PBC
Hepatitis C

ND
+

Toxin, Iron

Anti-inflammatory; ? Cytoprotective
Prevents lipid peroxidation; ? Antioxidan;

--

Anti-inflammatory, ? Cytoprotective

*Studies are in either whole animals or humans.

AIH = autoimmune hepatitis; Alc hep = Alcoholic hepatitis; PHC = primary biliary cirrhosis; PSC = primary sclerosing cholangitis

SUMMARY
1. Hepatic fibrosis was a problem from chronic all liver
injury
2. Essential components :
a. fibrogenic cell type (stellate cell)
b. extra cellular matrix (fibrosis scar = collagen)
c. role of cytokines (complexes and diverse)
3. Altered Matrix synthesis and degradation = fibrosis result

SUMMARY
4. Tool and marker for hepatic fibrosis :
liver biopsy
non commercial kit
Fibrosis Scann
5. Therapeutic strategy :
collagen synthesis inhibition
hepatic stellate cell inhibition
6. CAM will be use as well as an antiimflammatory
phytopharmaceutical in the hepatic immune clearance and
integrated condition.

Terima kasih