Commentary Open Access
Copyright ©The Author(s) 1996. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 25, 1996; 2(2): 65-68
Published online Jun 25, 1996. doi: 10.3748/wjg.v2.i2.65
Update on the recent progress in chronic hepatitis B therapy in China
Xie-Ning Wu, Gastroenterology Department, Shanghai First People′s Hospital, Shanghai 200080, China
Author contributions: Wu XN solely contributed to this work.
Correspondence to: Dr. Xie-Ning Wu, Professor, Chief Doctor, Department of Gastroenterology, Shanghai First People′s Hospital, Shanghai 200080, China
Telephone: +86-21-63240090
Received: December 15, 1995
Revised: May 6, 1996
Accepted: May 28, 1996
Published online: June 25, 1996

Abstract
Key Words: Hepatitis B/therapy, Chinese herbal



INTRODUCTION

Chronic hepatitis B is prevalent in China and certain South-Eastern Asian countries, and great efforts have been made to search for an effective therapeutic regimen. More experimental and clinical studies have emerged recently, providing insightful and useful results based on Chinese populations; the most important of these studies are presented here.

Chronic hepatitis B is primarily caused by interaction of the replication of the hepatitis B virus (HBV), the impaired immuno-modulating function of the host, the release of host-derived cytokines, inflammatory mediators, free radicals, and the microcirculatory impairment of the host-target organ, the liver. The end results are hepatic inflammation, degeneration and fibrosis, and necrosis of hepatocytes. In treatment, elimination of serum HBV DNA is of primary importance. In a study of 1016 serum specimens from patients with chronic hepatitis B and a few cases of hepatic cirrhosis, serum HBV DNA was detected by PCR in all kinds of combinations of HBV markers, among which positive serum HBV DNA was most common in the samples showing positivity for hepatitis B surface antigen (HBsAg), anti-HBs and hepatitis B e antigen (HBeAg) (86%, 259/301) and was not infrequent in the samples showing positivity for HBsAg, anti-HB core protein (c), anti-HBe (13.2%, 421/311), although the latter still indicated the presence of viral replication. Anti-HBs was positive in one case and negative in one case, with all other five classified as HBVM, but still having positivity for serum HBV DNA. The cases of recrudescence of obscure origin are most probably due to reactivation of viral replication.

ELIMINATION OF SERUM HBV DNA AND HBeAg

Besides interferon-α, there are several Chinese herbal polysaccharides that are effective in eliminating serum HBV DNA and HBeAg. These include Cordeceps, Grifola umbellata and Mocre, and their elimination rates are reported as 60%-68% and 53%-68% for HBV DNA and HBeAg respectively. The related adverse effects are insignificant.

Cordeceps sinensis polysaccharide coated with liposome[1]

This herbal polysaccharide was administered at a dosage of 400 mg b.i.d. orally for 3 mo. After one course of treatment, CD4 increased, CD8 decreased, CD4/CD8 ratio increased, and natural killer cell (NK) activity was enhanced (P < 0.001). Rates of negative seroconversion were as follows: HBV DNA: 68.4%; HBeAg: 53.2%; Pre-S2: 85%; HBsAg: 19.2%. Anti-HBe became positive in 20%. Follow-up for 1 year showed that the rate of negative seroconversion of HBV DNA increased to 73.6%, and that of HBeAg to 66.6%. Serum albumin and prothrombin times reverted to normal, gamma-glutamyltransferase (GGT) levels improved, and bilirubin and alanine aminotransferase (ALT) levels returned to normal or reduced in 73% and 90%, respectively. The mechanisms of action are many. First, Cordeceps has an immuno-modulating effect, as shown by changes in T-cell subsets and enhanced NK activity, and liposome itself has an immune-enhancing adjunct effect. Second, liposome is hepatophilic and can serve as a carrier for targeting and can be phagocytized by monocytes/macrophages. Third, the herbal polysaccharide is released intermittently with prolonged effect and produces no observable immunogenic effect or toxicity. In comparison, Cordeceps coated with liposome is more effective than Cordeceps without the liposome coating.

Grifola umbellata polysaccharide combined with hepatitis B vaccine[2]

A randomized controlled study was conducted with groups of 100 patients of similar age, sex, course of illness and hepatic functional status. All HBV-infected participants showed positivity for serum HBV DNA, HBeAg and anti-HBc-IgG. Liver biopsy was performed in 28 patients of the treated group, and 10 of those patients underwent a second biopsy; only 18 individuals in the control group underwent liver biopsy. Grifola umbellata polysaccharide was given at 40 mg im daily for 20 d, then discontinued for 10 d and repeated again over a total period of 3 mo. Concomitantly, hepatitis B vaccine was given at a dosage of 30 μg sconce every 2 wk, also for 3 mo. The rates of negative seroconversion of HBV DNA and HBeAg were 67.5% and 60%, (vs control group, P < 0.005 and 0.01 respectively), the rate of positive seroconversion of anti-HBe was 10% (vs 3% in control group, P < 0.05). Ten of the 28 patients in the treated group showed varied improvement in hepatic pathology. Normalization of serum ALT was found in 95.9%. Follow-up was made for an average of 9 mo (ranging from 6 mo to 6 years). The rate of negative seroconversion of HBV DNA remained at 56% and that of HBeAg increased further to 66%. Transient low grade fever occurred in 5 cases, minimal axillary lymph node enlargement occurred in 15 cases, and slight skin rash occurred in 4 cases with no need to discontinue the treatment. Another study showed that better effect was achieved with a combined treatment than with Grifola umbellata alone, the reason for this difference remains unknown at present (Figure 1).

Figure 1
Figure 1 Not available
Mocrea

Two capsules of Mocrea were given twice daily for 3 mo, and 5 out of total 38 patients received 3 capsules twice daily beginning at the third month, in a randomized control study. After completion of the treatment course, rates of negative seroconversion of HBV DNA and HBeAg were both 63.2%, with those of HBsAg and anti-HBc at 18.2% and 10.5% respectively; the rates of positive seroconversion of HBV DNA and HBeAg remained at 57%, that of HBsAg elevated to 25.7%, and those of anti-HBe and anti-HBs increased to 45.7% and 8.6% (vs control group, P < 0.01)[3]. In addition, after completion of the treatment course, patients′ appetite increased, weakness and hepatic pain disappeared, the enlarged liver regressed, the slight jaundice disappeared, serum ALT fell to normal level in 80%-95% of the patients; in general, the results were much better than in the controls. Immunologically, CD4 increased, CD8 decreased, CD4/CD8 ratio increased and NK activity increased.

Transfusion of autologous and heterologous lymphokine-activated killer (LAK) cells[4,5]

Around ten papers have reported on transfusion of LAK cells. One paper reported the LAK cells were incubated with 10000 U or 20000 U of IL-2, with or without Ara-AMP, and then all were compared with controls; the limitation of this study was small sample size. The rates of negative seroconversion of HBV DNA were 58% (16/27) and 58% (21/36) respectively in both treated groups, and those of HBeAg were 29% and 42% respectively (vs control groups, P < 0.01); duration of the reversion of serum ALT to normal level was shortened in the treated group. LAK cell activity was increased by the presence of IL-2, in a dose-dependent manner, and was much lower in patients with chronic hepatitis B. Ara-AMP, when given as the sole treatment, was also effective. In another article using heterologous LAK cells, the rates of negative seroconversion of HBV DNA were 73.7% (19 cases) and 26.6% (15 cases) compared with the effect of autologous LAK cells; the rates of HBeAg were 63% and 46.6% respectively and positive seroconversion of anti-HBe were 47% and 40% respectively. Both groups were given LAK cells once per week, altogether six times, and the response in all was elevated temperature after transfusion, with increased CD4 and CD4/CD8 ratio. Thus, IL-2 appears to increase the activities of both Tc and NK cells.

Dane particles, when incubated with monocytes, can cause degenerative and necrotic changes, resulting in eventual disruption of these cells; in this experiment, HBcAg and HBeAg were detected by immune-electron microscopy with suppression of erythrocytes in vitro, demonstrating that HBV could infect and replicate within the blood cells. It was proposed that cell membrane fluidity was involved first and followed by loss of normal cellular function with alteration of surface receptor function. Many patients relapsed after completion of interferon-α therapy, which may have resulted from the release of HBV DNA from the peripheral blood mononuclei, supporting the idea that elimination of serum HBV DNA (as a therapeutic approach) is of great importance[6].

ALLEVIATION OF INFLAMMATION AND IMPROVEMENT OF HEPATIC MICROCIRCULATION

Monocytes/macrophages and neutrophils can all produce TNF after being infected with HBV. TXB2 has been found to be expressed at higher than normal levels in patients with chronic hepatitis B who present with moderate or severe disease activity; the level of 6-keto-PGF1a, on the contrary, was lower than normal, and the TXB2/6-keto-PGF1a ratio was elevated and platelet aggregation remained high. In cases of chronic hepatitis presenting as mild disease activity, the reverse was true except that the platelet aggregation was slightly higher than normal. It is believed in more severe cases, that the serum levels of IL-1, IL-6 and TNF can all increase, thereby causing impairment of hepatic microcirculation and leading to hepatocyte damage. Besides, liberated oxygen free radicals can further promote liver damage through their lipid peroxidation effects on the hepatocyte membrane, resulting in hepatic dysfunction. A number of effective drugs have been found to ameliorate the above changes and these will be presented below.

Glycerrhyzin mimics the action of glucocorticoid in ameliorating inflammation but does not have the latter′s side effects. It can reduce the serum levels of IL-6 and TNF, and it is capable of inhibiting the mRNA of procollagen I and III.

Tetramethylpyrazine can inhibit TXB2 synthetase and increase PGI2 production, so as to maintain the balance of TXB2/PGI2; in addition, it is also an antioxidant.

Dan Shen (Salvia miltiorrhiza) is a useful drug, exerting not only antioxidant effects but also causing increases in hepatic blood flow, improvements in hepatic microcirculation and inhibition of platelet aggregation. It can protect hepatocytes from toxic injury induced by CCl4 and its long-term administration can promote synthesis of RNA of hepatocytes, increase glycogen content in hepatocytes and lower the hepatic lipids.

Sedum sarmentosum can significantly inhibit the disease-related decrease of glutathione and increase production of malondialdehyde (MDA) in experimental liver injury[7]. It protects liver cells by inhibiting lipid peroxidation and has long been used clinically as an adjuvant therapy for chronic hepatitis B.

Astragalus is also an immune-modulating agent, as well as antioxidant.

Mocrea can ameliorate the disease-related features of ballooning, vacuolation, eosinophilic degeneration and spotty necrosis involving hepatocytes. It can also help to maintain the integrity of the mitochondrial and endoplasmic membrane system[8], lower the serum ALT level, and increase the serum albumin level and the total protein level in rat liver damaged by CCl4.

Hepatocyte stimulating substance (HSS) can promote the synthetic functions of hepatic cells and suppress replication of HBV DNA. In patients with chronic hepatitis B in the active stage, the IL-2 activity and IL-2R cell number was found to be increased profoundly after HSS treatment, and as a result the production of IL-2 and expression of IL-2R returned to normal levels; hence, HSS is believed to have a cellular immuno-enhancing effect[9].

ANTI-HEPATIC FIBROSIS THERAPY

Animal models of hepatic fibrosis are useful for screening therapeutic drugs. The models can be induced by bovine serum albumin, human serum albumin, D-galactosamine, CCl4, alcohol and schistosoma infestation. Both bovine and human serum albumin are well recognized for their abilities to cause liver fibrosis through formation of immune-complexes (i.e. the type III immunologic reaction), which are sufficiently reflective of the mechanism of hepatic fibrosis in human viral hepatitis.

There are several elaborated herbal products that produce a definite effect on the alleviation of hepatic fibrosis, and these include Cordeceps, semen persicae and tetrandrine.

Cordeceps mycelium has been shown to increase the collagenase activity in both experimental animals and humans with schistosomal hepatic fibrosis. The deposition of total and subsets of collagen I and II in the rat liver was much less after treatment with Cordeceps than in the untreated controls, and these effects were comparable to those obtained with colchicine treatment (P > 0.05). The microscopy-based study revealed that Cordeceps could decrease the infiltration of inflammatory cells and increase the phagocytic function of Kupffer cells of the fibrotic liver. The human serum albumin animal model showed that the deposition of intrahepatic IgG-immune complexes along the hepatic sinusoids diminished significantly. The underlying mechanism likely involves the following: an increase in phagocytic function of phagocytes and Kupffer cells, as well as of scavenging of the IgG-immune complexes; inhibition of cell necrosis and inflammation, as well as release of the relevant cytokines; stimulation of collagenase activity, and promotion of lysis and resorption of collagen. In another study, Cordeceps and colchicine were both found to markedly reduce the serum procollagen level and collagen I, III and IV deposition in liver tissues, as well as the number of desmin-positive cells, which were much less than those in controls; finally, the pathologic changes were identical to those obtained with Cordeceps and colchicine respective treatments. In the condition of hepatic fibrosis, collagen III appeared early and collagen I appeared late. Both Cordeceps and colochicine treatments led to inhibition of the proliferation and transformation of Ito cells, thereby inhibiting the synthesis and perisinusoidal deposition of collagen. Such effects caused by Cordeceps have been confirmed clinically. Furthermore, Cordeceps produced no adverse effect, unlike colchicine which produced side effects, suggesting Cordeceps as having better future prospects[10,11].

When extract of semen persicae was given to rats with experimental fibrosis induced by CCl4, the number of Ito cells that secreted collagen I and laminin changed, which led to capilarization of the sinusoids, interfering with exchange of nutrients and waste products between hepatocytes and the sinusoids. Desmin is an immunohistochemistry marker used to differentiate Ito cells from other cell types. Apparently, extract of semen persicae inhibits the activation and proliferation of Ito cells, and it can increase hepatic blood flow and enhance collagenase activity, which is the main mechanism of its actions in ameliorating hepatic fibrosis[12,13]. Combined therapy using extract of semen persicae and Cordeceps mycelium was applied in one study of 6 patients with hepatic cirrhosis due to viral hepatitis B. The semen persicae was given at a dose of 1.5 g in 500 mL of 5% glucose infusion every other day and the oral Cordeceps was given at a dose of 1.5 g twice daily, both for a course of 3 mo. Repeat peritoneoscopy evaluation after treatments showed that the hepatic consistency and coloration had improved, edema of falciform ligament and ascitic fluid had disappeared, and varices had diminished in caliber. Liver biopsy at the same sites, performed prior to and after the treatments, showed diminished perisinusoidal collagen I and III by immunohistochemistry in 3 of the patients; in addition, the collagen bundles had become thinner, and the perisinusoidal and intercellular fibronectin had decreased in amount in 2 of the patients, with the other 4 patients showing no change. These findings indicated that this therapy reduced portal venous hypertension accompanied by an increase in hepatic blood flow, which occurred primarily through increased collagenase activity and degradation of collagen metabolism, leading to eventual improvement in the hepatic microcirculation. In most of the patients, the degenerative changes and inflammatory cellular infiltration rate were diminished, resulting in improvement of hepatic consistency and coloration. The decrease of variceal caliber and subsidence of edema agreed with the ultrasonic findings. These experimental and clinical data indicate inactivation of the Ito cell, inhibition of collagen synthesis, promotion of collagenase activity and the immune-modulating effect of the two drugs[14].

Tetrandrine, like semen persicae, had been used as one constituent of decoction in treatment of liver cirrhosis in China for 2000 years. In the animal model of hepatic fibrosis induced by CCl4, the serum markers PIIIP and hyaluronic acid (HA) were measured, immunohistochemical staining of collage I, III and IV and electromicroscopy of hepatic cells were performed as well. The number of Ito cells and the changes in their ultrastructural organelles were used as the parameters for evaluation. Tetrandrine was given to 22 rats of the CCl4 model group and to 115 patients with chronic hepatitis B. The patients received 50 mg twice daily for 6 mo as one course, for a total of 2-5 courses, and were followed-up for 6, 12, 24 and 36 mo. Glucoronic acid tablets were used as control.

A comparative analysis of tetrandrine and verapamil was performed in rats. Both treatments demonstrated only modest collagenous proliferation and inflammatory cellular infiltration, with none of the rats developing cirrhosis. Electromicroscopy revealed that the treatments diminished number of Ito cells and the mean surface area of rough endoplasmic reticulum and mitochondria. In a group of patients, tetrandrine treatment led to remarkably reduced serum levels of PIIIP and HA (vs control group, P < 0.01); moreover, the longer the observation period, the more marked the decrease of the two markers, with the order following as 6 mo < 12 mo < 24 mo < 36 mo. A follow-up study was done with 93 of the patients, and it was found that the fibrotic lesions at 36 mo and at 24 mo after the treatment were much less extensive than those measured prior to treatment. The hepatic fibrosis resolved completely in 14 patients (15.4%), collagen deposition attenuated in 54 (58.1%), inflammation improved in general, and 26.5% of the study population remained unchanged[15,16]. Possible mechanism of actions for these effects are various. First, tetrandrine is also a calcium channel blocker, and it may have produced the effects by modulating the intracellular Ca levels, thereby ameliorating the inflammation. Second, this herbal medicine has antioxidant action. Third, this herbal medicine inhibits LTB4, TXB2 and cytokines such as IL-1, TGF-B and TNF, which may induce production of fibronectin, laminin proteoglycan and collagen, all of which are known to interact and lead to fibrosis.

In conclusion, Chinese herbal medicines have multi-actions on multi-systems and tissues, but rarely induce significant adverse effects. Therefore, they are preferred for use in treatment by many of the Chinese doctors who were trained in Western medicine. In the author′s viewpoint, these medicines can be used in combination or in succession with Western medicine, in order to achieve an optimum effect, in particular, at the earlier stage of the disease.

Footnotes

Disclaimer: Presented at the 3rd International Conference of Gastroenterology, Hong Kong/Shanghai, November 10-16, 1995.

Original title: China National Journal of New Gastroenterology (1995-1997) renamed World Journal of Gastroenterology (1998-).

S- Editor: Filipodia L- Editor: Jennifer E- Editor: Zhang FF

References
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