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 Nekroinflamasi
Terapi Sirosis –
Tingkatkan Kualitas Hidup
Stop Fibrosis
Masalah TERAPI ETIOLOGI 1) Chronic Hepatitis B: cccDNA 2) Chronic Hepatitis C: Mutasi 3) Efektifitas 4) Resistensi 5) Efek samping 6) Biaya Stop Nekroinflamasi Stop Fibrosis
Primary TARGET
ETIOLOGI
Secondary TARGET
NEKROINFLAMASI 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
ALT
serum ALT
(IU/L)
Mean Annual Rate (%)
for disease progress.
male
female
low-normal ≤ 25
1.2%
high-normal > 26
3.9%
low-normal ≤ 22
1.4%
high-normal > 23
4.8%
Experienced ALT Elevation (> 41 IU/L)
high-normal 47.7% VS low-normal 27.9% p=0.002
5 year Cumulative Incidence
low-normal 0% VS high-normal 8.3% VS ALT elevation 34.3%
A “high normal” ALT level in CHC Patients
was associated with disease progression
P<0.001
Telah Ada di Indonesia
Protect Mitochondrial Dysfunction
Carnico Q Stop Nekroinflamasi Hp Pro
Stop Fibrosis & Stop Nekroinflamasi Hp Pro Plus
Terapi Sirosis – AHFC
Tingkatkan KualitasHidup BRM
Immune Regulator ImReg
Stop Fibrosis Fibroles
FOKUS TERAPI 1)
Regulasi Sistem Imun
2)Hentikan Nekroinflamasi 3) 4) 5)
Hentikan Fibrosis Terapi Sirosis 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
Cirrhosis
is a series of progressive stages (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 2. Open Clinical Trial 3. Double Blind Cinical Trial
Efficacy Confirmed by
Liver Biopsies
GOLD STANDARD
double-blind
The
AH F C
(n= 50) ,
52%
REVERSAL
100 75
SCORE ≥2
53.3% 50
38.9%
25 0
Confirmed by
0%
(Liver Biopsies)
S1 (n=3) S2 (n=18) S3 (n=15) S4 (n=14)
AFTER 6 (SIX) MONTHS TREATMENT The Overall Reversal Rate
AHFC 52% vs Control 20%
p<0.05 YIN Shan -shan et al.
Rate
Fibrosis
78.6%
Chin J Hepatol, August 2004
C ontrol (n=50), 20% 100 75 50 25 0
0.0% S1 (n=12)
14.3% 25.0% S2 (n=14)
S3 (n=12)
41.7%
S4 (n=12)
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) 2)
3)
4) 5)
Ameliorated liver function Decreased the elevation of • Serum HA, LN, PIIIP • Hydroxyproline content in liver tissue • MDA Restored the decrease of • Superoxide dismutase (SOD) • Glutathione peroxidase (GSH-PX) activities Reduced liver damage and liver fibrosis grade. 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
