The need of

ANTI HEPATIC FIBROSIS CIRRHOSIS

Treatment
for Chronic Hepatitis
(CHB, CHC, ASH, NASH, etc)
including for those with normal ALT
 Fibrosis hati
akumulasi/penumpukan jaringan parut didalam hati

Pembentukan jaringan parut

merupakan respon normal tubuh terhadap kerusakan sel hati,
tetapi dalam fibrosis ini proses penyembuhan berjalan menyimpang

ketika hepatosit rusak akibat infeksi dan peradangan

dengan berbagai penyebab seperti : virus, konsumsi alkohol berat, racun, trauma, atau faktor lain
maka sistem imun akan diaktifkan
untuk memperbaiki kerusakan sel

Kerusakan hati oleh sebab apapun

akan menginduksi nekrosis hepatosit dan apoptosis
Nekrosis melibatkan sinyal inflamasi dan menyebabkan peradangan klasik dan
sinyal fibrogenik dan fibrogenik klasik
 Cirrhosis is
REVERSIBLE
Friedmann SL (Shanghai)

Cirrhosis
the most advanced stage of fibrosis
connotes not only more scar than fibrosis alone,
but also distortion of the liver parenchyma associated with
septae and nodule formation, altered blood flow, and risk of liver failure.

However,
cirrhosis still remains a dynamicand evolving state, such that
Interventions even at these advanced stages
could regress scar and improve clinical outcomes

Scott L. Friedman
GASTROENTEROLOGY 2008;134:1655–1669
Terapi Causal seringkali tidak berhasil memenuhi harapan
….. diperlukan upaya optimal untuk mencegah komplikasi

Protect
Mitochondrial
Dysfunction

Immune Regulator
Stop Nekroinflamasi

Stop Fibrosis &

Stop Fibrosis
Stop Nekroinflamasi

Terapi Sirosis –

Tingkatkan
Kualitas Hidup
Masalah Primary
TARGET
TERAPI ETIOLOGI ETIOLOGI
1) Chronic Hepatitis B: cccDNA
2) Chronic Hepatitis C: Mutasi
3) Efektifitas
4) Resistensi
5) Efek samping
6) Biaya Secondary
TARGET
Stop Nekroinflamasi NEKROINFLAMASI
Stop Fibrosis FIBROSIS

Fibrosis & Sirosis

 “ANYONE
WHO CAN STOP OR DELAY
LIVER FIBROSIS

WOULD BE ABLE TO CURE MOST

CHRONIC LIVER DISEASES.”

PROFESSOR HANS POPPER

A FAMOUS HEPATOLOGIST IN THE U.S.

GASTROENTEROLOGY RESEARCH AND PRACTICE, VOLUME 2012

prevent the development of decompensated cirrhosis
and hepatocellular carcinoma (HCC)
Hepatitis Kronik dgn ALT normal
juga perlu diobati
High prevalence of significant liver fibrosis and cirrhosis in
chronic hepatitis B patients with normal ALT
in central Europe. Thomas Göbel,
The indication for antiviral treatment of patients with chronic hepatitis B is based on serum HBV DNA levels, transaminases, and
histological grade and stage. The relation of liver fibrosis and inflammation to ALT activity in chronic hepatitis B infection was
investigated in a non-endemic, European setting.

A total of 253 patients with CHB who had undergone liver biopsy at the Clinic of Gastroenterology, Hepatology, and
Infectious Diseases, Düsseldorf, Germany over the past 19 years (1990–2009) were evaluated.
39 had persistently normal ALT, 86 had ALT 1–2 × ULN, and 128 had ALT >2 × ULN.

Liver fibrosis or inflammation was defined as significant for stages or grades ≥ 2 according to the Desmet/Scheuer score.
Significant liver fibrosis (F ≥ 2) was found in 36%, cirrhosis in 18%, and significant inflammation (G ≥ 2) in
27%, of patients with normal ALT. There was no difference in the stage of liver fibrosis and the frequency of cirrhosis
between patients with normal and elevated ALT. The most important factor associated with the presence of cirrhosis in multivariate
analysis was age ≥40 years (P < 0.003). If concomitant factors like elevated GGT or male sex were furthermore present high
prevalences of significant liver disease were found.
The data indicate that, in a European setting, patients with chronic hepatitis B infection, and normal ALT
frequently have significant liver fibrosis or cirrhosis. Therefore, liver biopsy or liver stiffness measurement (LSM)
should be performed in these patients to determine the stage of liver fibrosis.

J. Med. Virol. 83:968–973, 2011.

Need anti-fibrosis treatment

(Fibroles, HpPro PLUS, AHFC
 World J Gastroenterol 2013
Chronic Hepatitis C Patients
n = 232, no antiviral therapy, with normal ALT (< 40 IU/L)

The Incidence of Disease Progression

as defined by the occurrence of an increase of ≥ 2 points in the Child-Pugh score, spontaneous bacterial peritonitis, bleeding gastric
or esophageal varices, hepatic encephalopathy, development of HCC, or death related to liver disease

The best predictive

cutoff baseline Experienced
ALT Mean Annual Rate (%) ALT Elevation 5 year
serum ALT (IU/L) (> 41 IU/L) Cumulative Incidence
for disease progress.

low-normal low-normal
1.2%
≤ 25 0%
male high-normal
high-normal
VS
3.9% 47.7%
> 26 high-normal
VS
8.3%
low-normal low-normal
1.4% VS
≤ 22 27.9%
ALT elevation
female high-normal
p=0.002
34.3%
4.8%
> 23 P<0.001
A “high normal” ALT level in CHC Patients
was associated with disease progression
 Protect
Telah Ada di Indonesia
Mitochondrial
Dysfunction
Carnico Q
Immune Regulator
Stop Nekroinflamasi ImReg
Hp Pro

Stop Fibrosis &

Stop Fibrosis
Stop Nekroinflamasi
Fibroles
Hp Pro Plus

Terapi Sirosis –
AHFC

Tingkatkan
KualitasHidup
BRM
 FOKUS TERAPI
1) Regulasi Sistem Imun

2)Hentikan Nekroinflamasi
3) Hentikan Fibrosis
4) Terapi Sirosis
5) Terapi Kanker???

Effectiveness of Hp Pro
in treatment of liver diseases:
an experience in Indonesian patients
Chinese Medical Journal 1998 :

Nurul Akbar, Rino Alvani Gani Taher, Widayat Djoko Santoso, Soemarno
Sumaryono, H M Sjaifoelah Noer, Liu Geng Tao
 content

Hp Pro - Mechanism of Actions

1) MAINTAIN MEMBRANE STABILITY OF HEPATOCYTES
through inhibiting lipid peroxidation and covalent binding of toxic metabolite of CCl4 to
lipid and proteins of liver microsomes

2) INCREASES THE DETOXIFICATION FUNCTION OF LIVER

by increasing the liver microsomal cytochrome P-450 content

3) INCREASES RESISTANCE OF THE BODY TO HARMFUL STIMULI

by modifying the pattern of metabolic activation and metabolite-DNA complex profile in
liver microsomes of carcinogenic substance (benzopyrene)

4) INHIBITS HEPATOCARCINOGENESIS INDUCED BY AFLATOXIN B1

as indicated in less and smaller y-GT foci and inhibition of a-FP production in rats after
Hp Pro treatment

5) PROMOTES LIVER CELL REGENERATION

as indicated in increase of RNA and glycogen content, ATPase and cytochrome oxidase in
hepatocyte mitochondria.

Liu Gengtao, Chinese Academy of Medical Sciences, Beijing Chine

 is a series of progressive stages
Cirrhosis (not a single stage)

Fibroles
HpProPlus

AHFC prevent the development of decompensated cirrhosis

and hepatocellular carcinoma (HCC)
cpd 861 (AHFC)
• an aqueous extract of
10 defined herbs based on TCM

• The chief herbs used in cpd 861 are :

‐ Salvia miltiorrhiza (FIBROLES)
‐ Astragalus membranaceous
‐ Spatholobus suberectus
‐ Bupleurum sinens

• The aim of TCM

is resolution of :
- blood stasis and
- liver stagnation
two conditions that form the basis of
liver pathology and patient discomfort

Hepatology, October 1999

Herbal Products for Liver Diseases:
A Therapeutic Challenge for the New Millennium.
D Schuppan, Ji-Dong Jia
AHFC ; The Mechanisms
leading to The Reversal of Fibrosis

Significantly inhibit LX-2 cell proliferation

Suppression of fibrogenesis and Concurrent

Enhancement of ECM degradation
• reduced the mRNA levels of
collagen type Ⅲ, MMP-2 and TGF-β1
• enhanced the MMP-1 mRNA levels
• down-regulated the TIMP-1 mRNA expression
increasing the ratio of MMP-1 to TIMP-1
REF
- World J Gastroenterol 2004;10(19): 2831-2835
- World J Gastroenterol 2008 March 21; 14(11): 1790-1794
 Cpd 861 (AHFC)
is proved to be
an effective anti-fibrotic herbal compound

1. Animal Experiment
Efficacy Confirmed by
2. Open Clinical Trial Liver Biopsies
3. Double Blind Cinical Trial GOLD STANDARD
 double-blind
The
AH F C (n= 50) , 52% REVERSAL
100 Rate
78.6% Fibrosis
75 SCORE
53.3%
50
≥2
38.9%

25 Confirmed by
0%
0
S1 (n=3) S2 (n=18) S3 (n=15) S4 (n=14) (Liver Biopsies)

AFTER 6 (SIX) MONTHS TREATMENT

The Overall Reversal Rate
C ontrol (n=50), 20%
100
AHFC 52% vs Control 20% 75 41.7%
50 14.3% 25.0%
p<0.05 25
0
0.0%

S1 S2 S3 S4
(n=12) (n=14) (n=12) (n=12)
YIN Shan -shan et al. Chin J Hepatol, August 2004
Penelitian di Indonesia
Evaluasi Fibrosis hati secara non invasif
dengan Fibroscan pada
Terapi Anti-Fibrosis
Prof.Dr.Nurul.Akbar,SpPD-KGEH

Bagian Ilmu Penyakit Dalam

FKUI/RSCM. Jakarta
F0: < 5, F1: 5 -7, F2: 7.1-9.4, F3: 9.5-12.4, F4: 12.5-20, Sirosis > 20
KESIMPULAN:

Terapi Hepatitis Kronik

1) Terapi Causal

Hepatitis Virus
 Terapi Imun (+ anti virus, sesuai pedoman)

Hepatitis Non-Virus
 Terapi Etiologi (Obesitas, DM, Alkohol, dll)

2) Stop Dysfungsi Mitochondria

 Cegah Hepatic Fat Infiltrasi & Nekroinflamasi

3) Stop Nekroinflamasi
 Cegah Fibrosis

4) Stop Fibrosis
 Cegah Sirosis

5) Terapi Sirosis
 Cegah Sirosis Dekompensata & Kanker Hati
 Stop Nekroinflamasi & Fibrosis
Cegah Sirosis dan Kanker Hati

Stop Fibrosis
Hepatitis Kronik ALT = Normal

Stop Nekroinflamasi & Fibrosis

Hepatitis Kronik ALT > Normal

Fibroles Hp Pro Plus

Salvianolic Acid B
and its metabolite SMND-309
FIBROLES
Mechanisms of Action
and Therapeutic Effects
1) Ameliorated liver function
2) Decreased the elevation of
• Serum HA, LN, PIIIP
• Hydroxyproline content in liver tissue
• MDA
3) Restored the decrease of
• Superoxide dismutase (SOD)
• Glutathione peroxidase (GSH-PX) activities
4) Reduced liver damage and liver fibrosis grade.
5) Powerfully down-regulated the expression of CTGF rather
than TGF-B1

Therapeutic effects of SMND-309, a new metabolite of salvianolic acid B, on experimental liver fibrosis.
Jian Hou et al. European Journal of Pharmacology 650 (2011) 390-395
Terima Kasih
prevent the development of
decompensated cirrhosis and HCC