TREATMENT AND PREVENTION OF LIVER FIBROSIS
Liver fibrosis is one of the processes that occurs when the liver is damaged. Such damage may be the result of:
Fibrosis is both a sign of liver damage and a potential contributor to liver failure via progressive cirrhosis of the liver. In China, liver fibrosis due to viral hepatitis is the major concern because the level of hepatitis B (and, to a lesser extent, C) viral infection is very high. Detection of the underlying liver disease is often delayed and effective medical treatment for viral hepatitis (e.g. interferon, which has a limited success rate) may not be readily available; thus, many people in China have moderate to advanced cirrhosis when they first seek treatment.
In a recent issue (June 2002, English language version) of the Chinese Journal of Integrated Traditional and Western Medicine, 10 articles were devoted to the subject of liver diseases, with 5 original research articles (1-5) plus one review (6) about liver fibrosis specifically. The current article summarizes what was presented about liver fibrosis therapy in that issue of the journal and adds commentaries to aid in interpreting the results. In addition, another review article about liver fibrosis (7) appeared a year earlier in the Journal of Traditional Chinese Medicine (June 2001); it provided few details of the treatments, mainly focusing on possible mechanisms of action for herbal therapies. The introduction to that article, written by Du Bin of the Nanjing University of TCM and Pharmacy, succinctly describes the process of liver fibrosis and is reproduced here:
Liver fibrosis is a gradual process of increased secretion and decreased degradation of extracellular materials. Most authors hold that the process is initiated by the damage of hepatic cells, which leads to activation and secretion of multiple cellular factors from Kupffer cells [macrophages which line the liver sinusoids]. These factors-along with the cellular factors secreted by damaged hepatic cells, thrombocytes, and endothelial cells of the hepatic sinusoid, and some chemical mediators-are activators of hepatic stellate cells. Being activated, the hepatic stellate cells differentiate into myofibroblasts, and, via self-secretion and parasecretion, proliferate and synthesize a massive amount of extracellular materials, which gradually accumulate and lead to formation of liver fibrosis. Since fibrosis is a common development in a variety of chronic liver diseases, prevention against its formation is of great importance.
Essentially, damaged liver cells activate stellate cells that dump materials (e.g., collagens) into the matrix outside the cells; the materials accumulate and form fibrous masses.
Chinese research publications frequently display flaws in research design and reporting that make it difficult to interpret the results. In his review article on liver fibrosis (6), Nie Guang commented: "It is worth pointing out that the level of recent studies is low, with many concrete tasks waiting to be done." Almost all published reports from China about traditional Chinese medicine therapies are positive ones. In the following outlines of the journal articles, the basic nature of the study is presented, but the details of the results are left out. Instead, a quotation from the study author(s) reflecting on their interpretation is provided, edited as necessary for clarity.
In traditional Chinese medical therapy, attempts are often made to address several aspects of a disease rather than only one of its manifestations. The Qinggan Capsule is an example of a broad formulation to treat hepatitis symptoms with a focus on the accompanying hepatic fibrosis in patients with chronic hepatitis B. In this study, 63 out-patients were treated with a preparation of B vitamins with glucurone as the control substance, while some patients additionally received Qinggan Capsules, containing 16 herbs: astragalus, salvia, white peony, capillaris, polygonatum, licorice, codonopsis, rehmannia, shen-chu, tang-kuei, curcuma, crataegus, alisma, dioscorea, isatis root, and chin-chiu. The dosing of the herbs was three capsules each time (made from 2.75 grams of crude herbs), three times daily. A therapeutic course was 6 months.
The authors stated:
So far, there is no proof that Qinggan Capsule has an inhibitory effect on the hepatitis B virus itself; therefore, the effects of Qinggan Capsule in improving pathological changes in the liver, particularly the antifibrosis effect, may be through mechanisms other than antiviral action....Liver fibrosis is the pathological process of fibrous connective tissue development secondary to inflammatory necrosis of liver cells. Once it happens, fibrosis could further accelerate the inflammatory necrosis process by way of cytokines or by affecting the intrahepatic microcirculation. Hans Popper [a famous hepatologist in the U.S. during the 20th century] has pointed out that "anyone who can stop or delay liver fibrosis would be able to cure most chronic liver diseases." Hence, in treating chronic hepatitis B, attention should be paid to both stopping liver fibrosis and killing the virus. Qinggan Capsule consists of 16 Chinese herbal drugs. Some components, such as salvia, tang-kuei, and astragalus, have been proven to have antifibrosis action.
Gingko leaf (see: Ginkgo) is a blood vitalizing herb that has flavonoids and glycosides as active components. In this study, 86 out-patients with chronic hepatitis B were treated either with ginkgo tablets that each contained 2.4 mg ginkgolide and 9.6 mg flavones or with Yiganling Tablet (for which the main active component was silymarin, extract of milk thistle, 35 mg/tablet). The dosing was 10 tablets each time of the ginkgo and 3 tablets each time of the silymarin (silybin), three times daily. In addition, all patients received appropriate medical care that did not include other agents known to have anti-fibrosis activity or immune effects. Treatment time was three months. To determine effect on liver fibrosis, measurements were made of blood content of hyaluronic acid, collagen type IV, laminin, pro-collagen peptide type III, and platelet activating factor (PAF). In addition, some patients underwent liver biopsy.
The authors commented:
It was found in this study that the serum level of PAF was elevated in patients with chronic hepatic cirrhosis, and in those after anti-fibrosis treatment [the gingko tablets], it could be lowered along with improving of the liver fibrosis in a positively correlated manner, suggesting that PAF participates in the genesis and development of liver fibrosis in chronic hepatitis.
Ginkgo glycoside ß, one of the chief components of ginkgo leaf, is a strong PAF receptor antagonist....It was reported that good effect was obtained by using composite ginkgo leaf granule, containing ginkgo leaf and 9 other Chinese herbs to treat early stage liver fibrosis, with evident improvement in blood level of superoxide dismutase [SOD, a well known antioxidant] and malondialdehyde [MDA, an indicator of lipid peroxidation activity]. It illustrated that the ginkgo preparation has anti-lipid peroxidation effects and can reduce the injury by oxygen free radicals on liver cells. Similar therapeutic effect has also been obtained by the authors by applying the ginkgo preparation in treating acute hepatitis with severe jaundice.
Results in this study showed that, after treatment for three months, the clinical effect of ginkgo preparation was markedly superior to that of Yiganling Tablet (silybin)....These results indicate that ginkgo leaf has obvious effects of liver protection, anti-inflammation, and anti-fibrosis, and may even reverse liver fibrosis.
Preparations of astragalus and salvia are frequently used to vitalize blood circulation and treat chronic diseases involving blood stasis. In this study 120, out-patients with chronic hepatitis B were treated with either Ruangan Granules, consisting of several herbs including astragalus, salvia, prunella, turtle shell, red peony, bupleurum, atractylodes, zedoaria, notoginseng, and cordyceps, or Biejia Ruangan Tablets (undefined contents). The Ruangan Granules contained the extract of 2.63 grams of crude herb materials in each gram of granules, and was administered 20 grams each time, three times daily (hence, the equivalent of about 158 grams of crude herbs per day). In addition, some patients in each of the groups received an IV drip of glycyrrhizin (the main active component of licorice, shown to have antiviral action), along with cysteine and glycine (the combination of these two amino acids is said to prevent some of the sodium/potassium imbalance that can arise with high dose licorice treatments). To monitor liver fibrosis, the researchers measured serum levels of fibronectin, laminin, and hyaluronic acid. Ultrasound tests were conducted to monitor the morphology of the liver. Treatment time was three months.
The authors commented:
We consider that liver fibrosis is caused by evil damp-heat left behind by chronic hepatitis, and by the combination of liver stagnancy, spleen deficiency, and blood stasis resulting from the long-term course of the disease. In the early stage of liver disease, a TCM syndrome of pathogenic excess, such as qi stagnation and dampness accumulation, is manifested along with spleen qi deficiency. The syndrome of insufficient essence [yin deficiency] would occur with the further development of the disease. Therefore, for patients with liver fibrosis, qi deficiency with yin deficiency is the root syndrome and blood stasis impeding the collaterals is the branch. The appropriate therapy involves nourishing yin, supplementing qi, activating blood circulation, and softening the hard mass to dissolve accumulation.
Studies in recent years showed that the pathogenesis of liver fibrosis is directly related to the activation and metabolism of the extra-cellular matrix of the liver, liver stellate cells, and cytokines; the non-collagen glycoproteins also play a key role in liver fibrosis formation. Fibronectin and laminin have an effect on the extra-cellular matrix, and they also regulate the cellular function. Large amounts of hyaluronic acid deposited in the liver blood sinus is the key basis of liver fibrosis and portal hypertension formation. This study showed that beside the effect of improving liver function, Ruanguan Granules could regulate the serum levels of fibronectin, laminin, and hyaluronic acid and reduce the size of the spleen and width of the portal vein, indicating that it has definite effects in reverting the formation of liver fibrosis in the course of chronic hepatitis.
The Benefit Liver Granules (Yigan Tang or Yigan Chongji) is a formulation based on the use of astragalus and salvia as a treatment for chronic liver diseases. Its ingredients, for a one day dose in clinical application, are derived from: 45 grams salvia, 30 grams isatis root, 12 grams each of white atractylodes and white peony, 10 grams each of tang-kuei tails and curcuma, 8 grams each of astragalus, gallus (chicken gizzard lining), and magnolia bark, and 6 grams each of hoelen and citrus. The researchers tested this formulation, as well as the decoction of just salvia and astragalus, in rats which were induced to have liver fibrosis via treatment with liver toxic chemicals, namely carbon tetrachloride initial treatment followed by alcohol regular treatment.
The authors stated:
TCM holds that hepatic fibrosis is mainly caused by blood stasis, which manifests chiefly by symptoms such as hepatomegaly, splenomegaly, expanded venation on the abdominal wall, blood nevi [skin patches of red color, also called spider moles, similar to congenital moles], liver palm [palmar erythema; palms redden and feel hot], and wiry, unsmooth pulse. Medicines which promote blood circulation to remove blood stasis are effective in treating these disorders and have been applied widely. Studies have illustrated that Chinese herbal medicines for promoting blood circulation, removing blood stasis, dredging the channels, and nourishing the liver have the effect of anti-liver fibrosis. For example, research conducted by Wang Baoen, et al., proved that the Composite 861, consisting of salvia, astragalus, spatholobus [jixueteng], etc., could prevent liver fibrosis formation and block its development, even reversing the pathological progress.
Benefit Liver Granules is an effective drug for treatment of chronic hepatopathy prepared by professor Yao Xixian and his colleagues, consisting of high doses of Chinese herbal medicines for promoting blood circulation to remove stasis, such as salvia and tang-kuei. It possesses the effects of improving symptoms of chronic hepatopathy, lowering transaminase, subsiding jaundice, softening the liver, and shrinking the spleen. The essential elements of Benefit Liver Granules, such as salvia and tang-kuei, could lower the portal venous pressure in dogs with liver cirrhosis. Salvia has a good effect of anti-hepatic fibrosis, raises the superoxide dismutase activity [SOD, a well known antioxidant] in the liver, and reduces the content of liver malondialdehyde [MDA, an indicator of lipid peroxidation activity] significantly. It was demonstrated that anti-lipid peroxidation action may be an important mechanism of its anti-hepatic fibrosis effect. In another article of the study, the concentrated decoction of Benefit Liver Granules showed significant effect in abating hepatic fibrosis and pathological ultrastructural changes of the liver in rats, and in reducing the deposition of collagens in liver tissue. Further, the effects could be enhanced by prolonging the therapeutic course.
Salvia (see: Salvia and the history of microcirculation research in China) is one of the most commonly used agents for treating fibrosis. One of the proposed mechanisms is to inhibit the hepatic stellate cells that proliferate and contribute substances to the hepatic extracellular matrix, forming the fibrotic mass. An active fraction of salvia, labeled IH764-3, was applied to cultured hepatic stellate cells. The authors stated:
Recent studies showed that to inhibit hepatic stellate cell (HSC) proliferation and promote HSC apoptosis would be helpful in reverting liver fibrosis. The effect of IH764-3 in different concentrations on HSC proliferation was observed in this study....The results showed that IH764-3 is effective in obviously inhibiting HSC proliferation....The apoptotic rate of HSC as revealed with brown staining in the IH764-3 group was significantly higher than that in the blank control group....It is held in TCM that the chief function of salvia is activating blood circulation and removing blood stasis. By modern pharmaco-chemical studies, the active fraction was found to consist chiefly of tanshinone, salviol, and tanshiol, etc....The mechanism of salvia in treating liver fibrosis may be multisided and very complex, and the mechanism of salvia in inducing HSC apoptosis remains for further study.
Some further study has been conducted, indicating that a particular protein (caspase-3) is expressed in HSC exposed to this salvia component, which may contribute to apoptosis of the cells (8).
The review article in the Journal of Integrated Traditional and Western Medicine relays information from articles published from 1992-2001. It concisely mentions test methods and results with some complex formulas, single herbs, and active components. Here are the therapies reported:
The reports mentioned here include laboratory studies (both cell cultures and animal tests) and clinical trials. The principle of vitalizing blood circulation is the dominant therapy claimed to be of some benefit, and key herbs are salvia, tang-kuei, persica, notoginseng, curcuma, and red peony. A few other herbs commonly used to treat liver diseases are sometimes used as well, including bupleurum and white peony. Tonic herbs are mentioned in some cases, the main ones being astragalus and atractylodes. Licorice, which is classed with the qi tonics, is the only herb included in these studies for which a possible viral inhibitory action has been proposed; all the other herbs are thought to primarily impact the process by which a virus (or chemical assault) induces fibrosis.
There are several mechanisms by which the herbs can inhibit liver fibrosis, including: inhibition of hepatic stellate cells; reduced production and deposition of fibrotic materials (e.g., collagen); regulation of cytokines; reduction in oxidation reactions; and possible degradation and reabsorption of fibrotic materials. These, and other possible mechanisms, may be triggered by a single herb with multiple actions (as proposed, for example, with salvia). Alternatively, several mechanisms that ultimately serve to reduce fibrosis may be stimulated by properly combining herbs, each of which impacts one or two of the mechanisms.
The laboratory studies described here are especially relevant to acute processes of liver damage, but don't readily address the problem of chronic liver disease. The clinical studies involved patients with advanced hepatitis B disease, the most common chronic hepatovirus infection that occurs in the Chinese population. There is no reason to believe that the effects would be any different with hepatitis C.
Treatment times for clinical evaluations ranged from a minimum of three months up to a maximum of three years. Unless the underlying cause of liver fibrosis is removed, the treatment may need to be continued indefinitely, or, at the least, repeated from time to time. Some herbal materials have been proposed as viral inhibitors, such as oxymatrine (from sophora root) and glycyrrhizin (from licorice root). However, it is unclear whether these herbs or isolated active components can completely remove the virus, as opposed to only reducing its activity while the substances are administered.
Imperfections in the research methodology and reporting limit the interest that can be generated among researchers outside China to pursue the Chinese herb treatment of liver fibrosis in greater detail. However, Chinese researchers have already provided adequate data on the effects of salvia to justify further expenditure on research in this area. Salvia has the advantages of being non-toxic, inexpensive, readily available, well-defined chemically, and already subjected to numerous pharmacology studies revealing mechanism of action (5, 8, 9, 10, 11, 12, 13) and clinical trials suggesting positive effects (1, 3, 14, 15). It is possible that results superior to using salvia alone might be attained by utilizing a small herb formula in which salvia is a key ingredient, but further confirmation of salvia's effects-or that of its active components-would be essential in order to form the basis for future study of a more complex therapy.