Effect of Fuzheng Huayu formula and its actions against liver fibrosis
© Liu et al; licensee BioMed Central Ltd. 2009
Received: 09 September 2008
Accepted: 29 June 2009
Published: 29 June 2009
Liver fibrosis is a common histological process to develop into cirrhosis in various chronic liver diseases including chronic hepatitis and fatty liver. Therefore anti-liver fibrosis is very important strategy to treat chronic liver diseases. Fuzheng Huayu (FZHY), a preparation containing herbs such as Radix Salvia Miltiorrhizae, Cordyceps, Semen Persicae, was formulated on the basis of Chinese medicine theory in treating liver fibrosis and was approved. Pharmacological studies and clinical trials demonstrate that FZHY has a significant effect against liver fibrosis and that many of the pharmacological actions are attributable to the effect. This article reviews the effects and actions of FZHY, in particular the effects observed from clinical trials in treating liver fibrosis caused by chronic hepatitis B and the actions on inhibition of hepatic stellate cell activation, protection of hepatocytes and inhibition of hepatic sinusoidal capillarization. This article also reviews the coordinated effects of the constituent herbs of FZHY and the actions of their active compounds such as salvianonic acid B (SA-B) on liver fibrosis.
Liver fibrosis is characterized by overproduction and irregular deposition of extracellular matrix (ECM) in liver tissues , leading to the distortion of hepatic microstructure and liver dysfunction. The structural changes include hepatic sinusoid capillarization, portal area and liver lobule fibrosis and alterations in microvascular structure. The dysfunction is manifested by the deficiency of liver function and portal hypertension. The main causes of liver fibrosis include hepatitis viruses, alcohol, drugs, toxins, schistosome, nonalcoholic steatohepatitis (NASH), cholestasis and autoimmune liver disease. Their persistent insults on the liver activate hepatic stellate cells (HSCs) in the sinusoid, resulting in the imbalance of ECM metabolism. For example, ECM overproduction may cause over deposition in liver and hepatic structure remodeling. Liver fibrosis can progress into liver cirrhosis which causes further hepatocellular dysfunction and increases intrahepatic resistance to blood flow, leading to hepatic insufficiency and portal hypertension. Liver cirrhosis is the seventh leading cause of disease-related death in the United States .
Liver fibrosis was considered to be a passive and irreversible process due to the collapse of the hepatic parenchyma and its substitution with ECM components . However, the reversibility of liver fibrosis has now been demonstrated both in patients and animal models .
Antifibrotic strategies against liver fibrosis include early intervention or control of etiologies, hepatic inflammation prevention and regulation of hepatic ECM metabolism and stellate cell activation. Viral hepatitis is the most important antecedent factor for liver fibrosis. Tremendous progress has been made in targeted antiviral treatment in recent years. Recent evidence showed that liver fibrosis could regress with effective antiviral treatment. However, even removal of initial fibrotic stimulus such as viruses may slow fibrosis progression but does not stop the progression entirely . Treatment to improve ECM metabolism is still needed for antiviral treatment. Animal experiments suggest that some fibrosis may persist for very long periods after liver injuries, particularly if the remaining collagen is cross-linked by tissue transglutaminase and thus more resistant to metalloproteinase. Efficacy of antiviral treatment is limited in fibrotic patients suffering from viral infection, in particular hepatitis B patients. Patients with lowered viral replication may have hepatic inflammation which can still develop into cirrhosis through fibrosis. In patients with hepatitis C virus, the severity of liver fibrosis is not necessarily correlated with viral loads or viral genotypes affecting the response of antiviral treatment.
From the studies on liver fibrosis in recent decades , we understand that the activation of HSC is a crucial cellular change in liver fibrosis . The regulation of the activation of HSCs has been partially elucidated . The fibrogenetic factors including free radicals, ECM environment and cytokines, in particular transforming growth factor beta one (TGF-β1) were only found in recent years. While effective treatment which targets these specific factors is still not ready. Chinese medicine has significantly contributed to antifibrotic treatment.
Antifibrotic treatment with Chinese medicinal herbs
Although Chinese medicine does not have the concept of liver fibrosis, its does treat chronic liver diseases effectively. Research on liver fibrosis in Chinese medicine has gone through three stages: (1) Clinical exploration (1950s to 1970s). Chinese medicine considers liver fibrosis as Xietong (Hypochondriac pain), Zhengjia (mass in the abdomen) and Guzhang (Tympanites). The basic pathogenesis of liver fibrosis is regarded as deficiency of healthy energy and stagnation of blood and treatment of liver fibrosis is to activate blood stasis and invigorate spleen according to Chinese medicine syndrome differentiation. Some frequently used formulas include Taohong decoction consisting of Semen Persicae (Taoren), Flos Carthami (Honghua), Rhizoma Ligustici Chuanxiong (Chuanxiong), Radix Angelicae Sinensis (Danggui) and Radix Clematidis (Weilingxian), and Xiayuxue decoction consisting of Radix et Rhizoma Rhei (Dahuang), Semen Persicae and Eupolyphaga seu Opisthoplatia (Zhechong) . (2) Experimental investigation (late 1970s to early 1990s). The efficacy of Chinese medicine against liver fibrosis was investigated with animal experiments. Effective Chinese medicine formulae and herbs include Qianggan Ruanjian decoction  consisting of Radix Angelicae Sinensis, Radix Paeoniae Alba (Baishao), Radix Salviae Miltiorrhizae (Danshen), Radix Curcumae (Yujin), Herba Patriniae (Baijiangcao), Fructus Gardeniae (Zhizi), Radix Rehmanniae Recens (Shengdi), Rhizoma Atractylodis Macrocephalae (Baizhu), Radix Astragali (Huangqi), Fructus Crataegi (Shanzha) and Herba Artemisiae Scopariae (Yinchen). In particular, the effects of Radix Salviae Miltiorrhizae (Danshen) and Semen Persicae and their extracts, cucurbitacin B, oleanolic acid, glycyrrhizic acid and hanfangchin A against liver fibrosis were investigated extensively. (3) Clinical trials and molecular studies (1990s onwards).
In 2006, the first national guideline on the diagnosis and treatment of liver fibrosis with integrative medicine was published . The efficacy of Chinese medicine formulae against liver fibrosis is being evaluated in multicenter, randomized controlled clinical trials and the molecular actions are also being studied. In particular, Fuzheng Huayu (FZHY) formula has been shown to have efficacy on liver fibrosis, post-hepatic cirrhosis and the prevention of hepatic encephalopathy [11–14].
Effects of FZHY on liver fibrosis
Composition of Fuzheng Huayu (FZHY)
Daily dose (g/60 kg adult)
Radix Salviae Miltiorrhizae
Fermentation Mycelium Powder
Fructus Schisandrae Chinensis
The effects of FZHY on the decompensated cirrhosis caused by hepatitis B were investigated in clinical studies . Eighty patients were enrolled and randomly assigned to the control and treatment groups (40 patients per group), and received FZHY plus Vitamins B and C, and Vitamins B and C respectively. The results showed that FZHY improved liver function parameters, albumin (Alb) level in particular, while it decreased γ-globin content, enhanced the plasma ratio of branched chain amino acid (BCAA)/aromatic amino acid (AAA), increased urine Hyp excretion, decreased serum laminin (LM) and haluronic acid (HA) level. FZHY also modulated the immune system, for example, it improved CD3+ and CD4+ counts, natural killer cell activity and complement 3 (C3) content.
The effects of FZHY on liver fibrosis caused by chronic hepatitis B were studied in a clinical trial [11, 13], in which 95 patients with chronic hepatitis B were randomly assigned to the treatment (63 patients) and control (32 patients) groups, and received FZHY and Dahuang Zhechong Wan respcetively. The liver function and serological fibrotic markers were tested before and after treatment and 12 patients in the treated group were examined with liver biopsy. The results showed that FZHY markedly decreased serum alanine aminotransferase (ALT) activities and total bilirubin. FZHY also significantly improved serum albumin and A/G ratio, lowered serum monamine oxidase activities, tissue inhibitor of metalloproteinase-1 (TIMP-1), type III procollagen (P-III-P) and LM and increased urine Hyp content. The improvement of these markers except TIMP-1 in treatment group was better than those in the control. Liver biopsy of seven out of 12 patients showed significantly decreased fibrosis. The results suggest that FZHY is effective in treating liver fibrosis and inflammation caused by chronic hepatitis B.
Recently, we conducted a phase III trial  and collectively analyzed the effects of FZHY, on liver fibrosis caused by chronic hepatitis B. The results show that FZHY is effective to treat liver fibrosis caused by chronic hepatitis B, including fibrotic stage S3 with hepatic inflammation, hypochondriac pain and dry mouth. The dynamic pathological changes in liver, the contents of serum Alb, HA and P-III-P, GGT activities, prothrombin time (PT), and blackish complexion, except the serum LN and IV-C, were all found significantly improved after treatment .
Actions of FZHY against liver fibrosis
Inhibition of HSC activation
Activation of HSC is a key cellular process of liver fibrosis . Under normal conditions, quiescent HSCs are located in the hepatic perisinusoidal spaces with vitamin A storage in their cytoplsamic lipid droplets. Paracrine activation of HSCs is stimulated by oxidative stress, inflammatory cytokines and endothelial matrix alternation. The activated HSCs release cytokines such as TGF-β and perpetuate the autocrine activation of HSCs. All activated HSCs increase the capabilities of cell proliferation, fibrogenesis and contraction, contributing to the overproduction and accumulation of ECM in liver .
Protection of hepatocytes from oxidative stress and apoptosis
Liver injuries, such as hepatocytic inflammatory necrosis and apoptosis, are the precursors of liver fibrosis . Free radicals and oxidative products such as malondialdehyde (MDA) stimulate HSC activation. Liver peroxidation also increases matrix metalloproteinases-2/9 (MMP-2/9), thereby degrading membrane matrix and disrupting hepatic micro-structure and finally activating HSCs. Therefore, liver injury is a bridge between liver inflammation and fibrosis and protecting hepatocytes from oxidative and apoptosis is important in preventing liver fibrosis.
Actions on sinusoidal endothelial cell and hepatic sinusoidal capillarization
Hepatic sinusoidal capillarization in endothelial space of Disse is a key event in liver fibrogenesis. Normally this space contains the components of a basement membrane that is low-dense matrix mainly consisting of type IV collagen and laminin and forms a discontinuous endothelial basement membrane. Sinusoidal endothelial cell (SEC), which lines inner sinusoid, has a lot of fenestrate. The structure of hepatic sinusoid serves as a sieve to facilitate the rapid interchange of material between the blood and hepatocytes. In early fibrogenesis, the accumulation of subendothelial matrix, in particular replacement of normally low-density matrix with high-density ones, and loss of fenestrate in SEC, would lead to transformation of continuous subendothelial basement membrane from discontinuous one and transition of closed circulation to an open one, i.e. a process known as "capillarization" . Such capillarization causes hepatocytic dysfunction and high portal pressure, leading to advanced fibrosis or cirrhosis.
In our studies [29–32], the DMN-induced rats had high portal pressure and low interstitial collagenases 13 (MMP-13). The SEC damage was manifested by increased Factor VIII related antigen (vWF) expression and serum HA level. FZHY significantly improved twisting and occlusions of hepatic sinusoids, and alleviated loss of fenestrate in SEC and formation of continuous subendothelial basement membrane. FZHY decreased high portal pressure and liver fibrosis, and reduced the expression of Factor VIII related antigen and α-SMA in hepatic sinusoidal wall significantly. FZHY improved MMP-13 activity in liver tissue, through decreasing plasminogen activator inhibitor-1 (PAI-1) and TIMP-1 which are inhibitors of stromelysin and MMP-13. The results show that FZHY can inhibit and improve the reversal of hepatic sinusoidal capillarization and that FZHY's actions are associated with protection of SEC and inhibition of HSC activation.
Coordinated effects of FZHY and its actions against liver fibrosis
Orthogonal design of FZHY pharmacological experiments L16(215)
The fibrotic models were induced by hypodermic injection of CCl4 plus oral administration of high fat and low protein food and DMN. The fibrotic rats were randomly divided into subgroups according to the experiment design and orally fed with different composition of herbs from start of CCl4 intoxication or after DMN models were established. In prophylaxis experiment with CCl4 model, Semen Persicae was a key factor to decrease hepatic hydroxyproline, Radix Salvia Miltiorrhizae had prominent effect on improving serum Alb and decreasing total bilirubin level, while Cordyceps and Gynostemma Pentaphyllammak had a remarkable effect on decreasing serum ALT activity. These four herbs have coordinated effects for prevention of liver fibrosis, while Semen Persicae and Radix Salvia Miltiorrhizae are the main herbs of FZHY in preventing liver fibrosis .
In the experiments with the DMN model of liver fibrosis, Cordyceps and Gynostemma Pentaphyllammak had strong effects on reducing hepatic hydroxyproline contents and attenuating collagen deposition, while Radix Salvia Miltiorrhizae and Cordyceps Extract piece had significant effects on improving liver function such as reducing serum ALT activity. These findings indicate that Cordyceps plays an important role in reversing liver fibrosis, as a main ingredient of FZHY.
While the active ingredients of FZHY have not been elucidated, we found several effective compounds from the constituent herbs of FZHY, such as amygdalin from Semen Persicae, salvianolic acid B (SA-B) from Radix Salvia Miltiorrhizae. In particular, SA-B against liver fibrosis was found effective.
Radix Salviae Miltiorrhizae and its active ingredients
Action of Radix Salviae Miltiorrhizae and salvianolic acid B against liver fibrosis
In the early 1950s, there were reports on the decoctions containing Radix Salviae Miltiorrhizae (Sm) in treating splenomegaly due to schistosomiasis at advanced stage . In recent years, this formula has been widely used to treat chronic hepatitis B and posthepatitic cirrhosis at its early stage. The extract from Sm is now used clinically as injection formulation for treating chronic hepatitis B. The liver biopsy tests before and after treatment with Sm injection revealed that liver fibrosis was improved . The dynamic ultrasound Doppler examination of the patients with post-hepatitic cirrhosis revealed that Sm root injection effectively increased the portal blood flow .
SA-B, a major water soluble component in Sm, relieves the CCl4-induced fibrosis and reverses DMN-induced liver fibrosis in rats. It prevents liver cell injury, inhibits proliferation of HSCs and collagen production in vitro [38–42]. Therefore, SA-B is one of the active components of Sm against liver fibrosis.
Actions of salvianolic acid B on TGF-β1 in hepatic stellate cell and fibrotic liver
Our in vitro studies [44–46] showed that 0.1 μmol/L-10 μmol/L SA-B had no toxic effect on primary cultured HSCs, but inhibited serum stimulated HSC proliferation in a dosage dependent manner as indicated by [3H] thymine incorporation. SA-B (1 μmol/L-10 μmol/L) had significant effects against the biological responses of TGF-β1 stimulated HSCs, including collagen gene expression, α-SMA and PAI-1 expression. Furthermore, SA-B (1 μmol/L-10 μmol/L) inhibited the plasmic and nuclear protein expression of Small Mothers against decapentaplegic deleted 2/3 (Smad2/3) and significantly inhibited intracellular phosphorylation of Smad2, decreased type I receptor expression and TβR binding. These results suggest that the main actions of SA-B against liver fibrosis are to antagonize TGF-β1-dependent activation of HSCs by inhibiting intracellular signal transduction of TGF-β1/Smads in HSCs.
FZHY has been developed and tested in the past 20 years as a new Chinese medicine product to treat liver fibrosis. Although only some of the action mechanisms and active components of FZHY were discovered and much effort should be made to improve our scientific understanding, a high potential of developing new drug products such as FZHY from Chinese medicine for treating liver fibrosis has been demonstrated.
aromatic amino acid
- Act D:
aspartate aminotransferase aminotransferase
branched chain amino acid
cell conditional medium
type I collagen
drug serum treated hepatic stellate cell's conditioned medium
extracellular signal-regulated protein kinase
focal adhesion kinase
hepatitis C virus
hepatic stellate cell
International Classification of Diseases, 10th edition
Kuppfer cell conditional medium
plasminogen activator inhibitor 1
platelet-derived growth factor-BB
type III procollagen
Salvianolic acid B
sinusoidal endothelial cell
Radix Salviae Miltiorrhizae
Small Mothers against Decapentaplegic Deleted 2/3
tissue inhibitor of metalloproteinase 1
tumor necrosis factor α
terminal deoxynucleotidyl-transferase-mediated nick end-labeling
TGF-β type II receptor
α-smooth muscle actin.
The work was supported by the grants from the Major State Basic Research Development Program of China (973 Program) (2006CB504801), National Natural Science Foundation of China (39570889, 39700192, 30772869), Shanghai Leading Academic Discipline Project (Y0302) and E-Institutes of the Shanghai Municipal Education Commission (E-03008).
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