UPDATE ON HEPATITIS C TREATMENTS
Since publication of the September 1998 START Group manuscript Hepatitis C: recent treatment strategies ( revision and update of a 1996 report), calls for newer information have been one of the dominant themes of practitioner contacts with ITM. This comes about for several reasons:
Virtually all the experience of using Chinese herbs for hepatitis C is in China, where the situation surrounding hepatitis C has the following characteristics that are different from those encountered here:
When a patient arrives at your office with no significant symptoms of liver disease and with limited elevation of liver enzymes, they are presenting a case that, for all practical purposes, has not been previously subjected to treatment by Chinese herbs. Similarly, when a patient asks you to provide an herbal treatment to reduce viral load or to eliminate the virus, they are asking you to attain a treatment objective that has not been the subject of much clinical evaluation. Further, when a patient asks your advice whether to pursue Chinese herbs or the current standard therapy, or to pursue both, or to do them consecutively, the patient is asking you about a clinical situation that has not been the subject of either extensive prior experience or carefully designed clinical trials. This is a new area that must be considered carefully before proceeding.
Following is a summary of new information that has been made available to ITM that may help practitioners better understand the situation. Refer to the original article, Hepatitis C: recent treatment strategies, for further background information on the disease and its treatment in China.
Several herbal formulas were described in Hepatitis C: recent treatment strategies based on an extensive review of Chinese literature. Since that time, only a few additional articles have come to light, but they do not go any further towards answering the question: are there any herbs specific for inhibiting the hepatitis C virus? Instead, the possibility is raised that herb formulas primarily function to help restore and maintain the liver cells without affecting the virus.
ITM received a translation of an article on hepatitis C by Chen Liping and colleagues (working in Guangdong) that had been published in 1995 (1). The focus of the article was the role of blood stasis in the progression of hepatitis C. The symptoms of blood stasis in hepatitis C patients were listed as including:
If the disease has one of the chief symptoms of pain or mass below the axilla and one or more of the confirming signs of discoloration and/or venous distention, then the blood-stasis type is deemed present. One can readily see that this indicates an advanced form of the disease. In the discussion section of the article, the authors state: "Internal retention of blood stasis is the basic pathological change in chronic hepatitis and is also an important mark for the unfavorable turn in the condition of the disease." The formula they recommended was Huoluo Xiaoling Dan (Efficacious Powder for Vitalizing the Luo Vessels; luo vessels correspond to veins). The chief ingredients reported were cinnamon twig, red peony, persica, hoelen, and moutan. This is the traditional Cinnamon and Hoelen Formula (Guizhi Fuling Wan) presented in the Jingui Yaolue that is used for blood-stasis syndromes, especially when there is abdominal pain or mass. Some modifications suggested were oldenlandia and sedum (chuipencao) for damp-heat; buffalo horn and rubia for blood heat; malt and gallus for spleen deficiency (for more information on sedum, see: Tibetan herbal medicine; sedum is a relative of rhodiola and described in that article).
Another report received by ITM was a translation from a study conducted during 1995 in Zhejiang at an infectious diseases hospital (2). The typical symptoms reported were fatigue, lack of appetite, yellow urine, pain in the portal area, dull complexion, dull red tongue, and yellow, sticky, tongue coating. The formula used for treatment was called Jiedu Huoxue Tang (Decoction to Clear Toxins and Vitalize Blood), comprised of 40 grams sedum, 30 grams each of lobelia, oldenlandia, red peony, and salvia, plus 15 grams each of turtle shell, pangolin scale, and hoelen. In addition, herbs could be added for specific symptoms, such as magnolia bark and chih-ko for abdominal distention. Of 18 patients so treated for four months, it was reported that all but 4 cases responded obviously; there were 3 cases (17%) in which it was said that the viral test turned negative (no details of test method given). The authors stated that, in the long run, patients with hepatitis C suffer from "damp-heat accumulating in the spleen, stomach, liver, and gallbladder, blocking the smooth flow of qi and blood; stasis shows up when the chronic illness gets into the luo vessels." The formula ingredients were selected to clear heat and toxin, move blood and break stasis, and soften hardness and disperse accumulation. The authors recommended using high doses for all herbs.
In the September 1998 issue of the English language Journal of Traditional Chinese Medicine, an article appeared on treatment of hepatitis C with a self-designed formula (3). According to the authors, their analysis of TCM theory and their experience of patients led to a conclusion that the disease should be interpreted as "stagnation of toxic heat and injuries in the liver and spleen." They paid particular attention to tongue and pulse diagnosis and found that the majority of patients had a dark purple tongue or other signs of blood stasis, a yellowish and greasy tongue coating or other signs of damp-heat, and a thready and taut pulse, characteristic of liver stagnation. The following formula was used as the basis for treatment: buffalo horn, hu-chang, red peony, astragalus, lycium, bupleurum, citrus, hoelen, and abrus (jigucao); the proportions were not stated. The mixture was made as a syrup given in two doses of 60 ml each. The authors reported that 15 of 60 patients (25%) had their viral load dropped to below detection for three consecutive readings as a result of this therapy. Also, another 19 patients (32%) had a negative PCR (Polymerase Chain Reaction) reading after treatment, but some evidence of persistence of the liver disease.
At first, this sounds very encouraging, because the results appear to be somewhat similar-in terms of PCR effects-to what is obtained with modern medical therapies, minus the severe side effects. Unfortunately, on closer examination, the reported results of the PCR test are suspect. There is not a single detail of how the PCR test was conducted in order to give one any sense of whether the testing was done properly. There were no statements of the lowest viral load able to be detected. As important, there were no statements of duration of therapy or duration of follow-up with the PCR tests.
Another report from China that described PCR tests, with results turning negative after treatment, that described the use of oxymatrine (major alkaloid component of sophora root), had already been relayed in the ITM article (see also: Sophora). In that case, the rate of effectiveness for getting the viral load to decline below detection was about 40% (comparable to the modern drug therapies). Unfortunately, that initial report (which was published a second time in English in the Journal of Integrated Chinese and Western Medicine) has not been followed up with reports of any larger study with this substance (only 17 patients had completed the original trial). The item used, injectable oxymatrine, is not available for use in the West, but ITM was able to acquire oral oxymatrine and make it available to practitioners since 1998. At this time, ITM has received no reports of hepatitis C viral load dropping below detection in patients taking this oral form. It is possible that the injectable form, by yielding a higher blood level, is more effective than the oral form, but it is also possible that the tests for PCR used in the published Chinese report were not reliable ones. In the article, this is the total information about the PCR test methods presented: "Serum HCV-RNA were determined by reverse transcription polymerase chain reaction." Therefore, at this time, the question of whether the Chinese have succeeded in reducing or eliminating (temporarily or permanently) the hepatitis C virus remains unresolved.
The herbal therapies for hepatitis C used in China have been devised on the basis of traditional considerations: certain herbs are used if the syndrome involves damp-heat, others for blood stasis, yet others for spleen-qi deficiency, etc. Of all the herbs available for treating each of these syndromes, only a few are mentioned frequently. These herbs are chosen on the basis of prior experience treating hepatitis (mostly hepatitis A and hepatitis B) as well as some influence of modern research studies (finding active constituents that reduce liver enzymes in laboratory animal experiments in which the animals are subjected to toxic chemicals as an inducer of liver damage). Among the most frequently-used herbs (considering all the reports) are those included in a prescription designed at ITM called Bupleurum-Gardenia Tablets, which contains bupleurum, red peony, astragalus, oldenlandia, gardenia, and forsythia. No studies have come to the ITM office that would suggest that an individual herb or active constituent is a specific or general inhibitor of hepatitis C viral replication. Red peony and oldenlandia appear to be the herbs that are more commonly used for hepatitis C than for other hepatitis types.
A traditional-style diagnosis followed by the corresponding herbal therapy remains the standard method of treatment in China. When differential diagnosis and treatment is not practical, complex formulas based on addressing the most commonly-manifest symptoms and signs may be used. Patients with no symptoms and only a diagnosis of having a virus infecting their liver do not have a clear recourse at this time. There is no viable evidence that formulas designed for highly-symptomatic patients will have an impact on those without symptoms.
In Japan, glycyrrhizin (from licorice) and ursodeoxycholic acid (from bile) have been tested individually, together, and in combination with interferon therapy for hepatitis C (see Appendix 1). These active ingredients derived from traditional medicines were able to lower liver enzymes, but not viral load.
In addition to the clinical reports from China indicating reduction of symptoms and reduction of liver enzymes, ITM has received a number of informal case reports, either verbally or in writing, from American practitioners who have given Chinese herbs to their hepatitis C patients. In general, patients who have significantly elevated liver enzymes prior to the Chinese herb treatment are reported to show a decline of liver enzymes over a period of several weeks.
As an example, ITM was recently sent the following data (5) on a patient who was taking Salvia-Ligustrum Tablets (Seven Forests; made with salvia, ligustrum, licorice, hu-chang, curcuma, atractylodes, and schizandra) at the recommended therapeutic dosage used in a Chinese clinical evaluation (9 tablets, three times daily):
|
Date of Test |
AST |
ALT |
|
1/12/00 |
379 |
538 |
|
2/03/00 |
159 |
279 |
|
2/29/00 |
138 |
167 |
The patient had begun taking herbs just a few days after the first test (1/12/00), and one can see significant improvements in the values after about 2 weeks, with further improvement over the next 4 weeks. In this case, the patient has significant liver inflammation. According to reports received at ITM, it is common for the laboratory test results to indicate marked improvement in liver enzymes over a similar time course when the patient is regularly using the Chinese herbs. Among the reports are cases of liver enzymes returning to the normal range (for the above test lab, the normal range is less than 32), usually after a few months of therapy.
A practitioner who has consulted frequently with ITM regarding hepatitis C treatment published two cases from her practice in 1997 (6). The liver enzyme results were reported as follows:
|
Patient 1 |
Patient 2 |
|||||
|
Date of Test |
AST |
ALT |
Date of Test |
AST |
ALT |
|
|
8/95 |
50 |
81 |
12/94 |
223 |
185 |
|
|
12/95 |
39 |
65 |
9/95 |
132 |
86 |
|
|
4/96 |
34 |
52 |
5/96 |
98 |
89 |
|
|
9/96 |
33 |
56 |
- |
- |
- |
|
The first test reports in each of the two cases are from before treatment and the following ones are during treatment; the duration of the treatment here (13-18 months) is longer than reported above (6 weeks). The very dramatic effects seen with the higher initial levels of liver enzymes have been relayed to ITM by several other practitioners.
Some patients are said to have a dramatic improvement of liver-enzyme levels even if their viral load goes up rather than down. Reports of dramatic decline in viral load have been rare. In the START report: Two case histories of hepatitis C treatment (based on treatments at the ITM clinics), one example was given of a patient who had an extremely-high viral load (13 million) that reduced markedly (below 2 million) during a few months of treatment. According to the clinician making that report, the patient has continued to maintain the relatively lower viral load ever since, even without substantial herbal therapy (a course of low-dosage constitutional herb therapy is all that is said to be used). The initial viral load was much higher than typical for patients being seen in Chinese medical practices.
Dr. Qingcai Zhang, working in New York City, has been providing herbal formulas for patients with hepatitis C for several years. The materials administered include herbal formulas in capsules (containing dried extracts), glycyrrhizin tablets, and oleanolic acid tablets. Zhang has distributed background information (received by ITM in a fax message of 1998), including four successful case studies. Among the reported effects of treatment were decline of liver enzymes, reduction of symptoms, and reduction of fibrosis (compared to earlier biopsy). In one case in which viral load was said to be reduced, he reported that the initial viral load was 14 million, and that this was reduced to 500,000 after treatment. As with the other case of viral-load decline mentioned above, the initial level is extremely high; the reduced viral load after treatment in both those cases was still quite high compared to typical patients, despite the marked change. Dr. Zhang claims that "Using this protocol, above 80% of the patients will see their liver enzyme levels normalized within about two to three months. If there was jaundice, the yellow color can be cleared within three weeks. Subjective symptoms, such as fatigue, nausea, and poor appetite, can be improved within three to four weeks. The dull pain in the liver area will be relieved within a few weeks. After two to three months taking the herbs, biopsy will show reduction of inflammation. In many patients, the viral load will be reduced." Although the effects are noted within a few weeks or months, he recommends that treatment proceed for at least two years in an attempt to clear the liver of the virus via the normal turnover of liver cells (with lifespan of about 18 months).
A small double-blind clinical trial of a Chinese herb formula for hepatitis C was carried out in Australia and published as a preliminary report (7). Forty patients were divided equally into two groups: one receiving herb tablets (5 tablets three times daily) and the other receiving placebo. It was found that those taking the herbs had a significant reduction in ALT (the enzyme most commonly used as a reference for hepatitis C since it is the one most significantly affected by the disease), but not in viral load. The author concluded that "Chinese herbal medication was associated with a significant reduction in alanine aminotransferase (ALT) levels over the 6 month study period. No patient cleared the virus, but four normalized their ALT on treatment. Appropriately prescribed Chinese herbal medicine may have a role in the management of chronic hepatitis C and further controlled studies are indicated." The formula used included salvia, red peony, and tien-chi ginseng (sanqi).
In Japan, the use of injectable glycyrrhizin for treatment of chronic hepatitis C reportedly reduces the progression of this liver disease to hepatocellular carcinoma (see Appendix 1). A study was conducted in the Netherlands (8) to evaluate the effect of glycyrrhizin on ALT and hepatitis C viral load. Fifty-seven patients with chronic hepatitis C, non-responders or unlikely to respond to interferon therapy, were randomized to one of the four dose groups of glycyrrhizin: 240, 160, 80 mg, or 0 mg (placebo). The herbal drug was given intravenously 3 days per week for 4 weeks; follow up also lasted for 4 weeks. It was reported that within 2 days of start of therapy, serum ALT had dropped 15% in the three non-placebo dosage groups. The mean ALT decrease at the end of active treatment was 26%, significantly higher than the placebo group (6%). A dose-response effect was not observed, however, indicating that the low-dosage treatment worked about the same as the higher-dosage treatments. Normalization of ALT at the end of treatment occurred in 10% (4 of 41) of patients receiving glycyrrhizin. The effect on ALT disappeared after cessation of therapy. The duration of therapy was relatively short compared to most standard hepatitis C treatments of 3-6 months, and the frequency of treatment was half that usually used in Japan, where the drug is given 6 times per week. During treatment, viral clearance was not observed; there was a slight but non-significant decline in the active treatment group. No major side effects were noted. None of the patients withdrew from the study because of intolerance.
In the U.S., a small trial was conducted in California in which patients received a complex herbal mixture for six months. The formula was designed on the basis of a prescription being used by a Chinese doctor in California who claimed success in treating the disease, as well as on the basis of formulas described in the Chinese literature. ITM acquired the herbal extracts and prepared the tablets for the study; patient treatment began in September 1999, with continued enrollment for some months afterward. Although the clinical trial results have not yet been fully tabulated and reported, the lead investigator (E. Stern, who published the two case studies in reference 6) relayed the fact that liver enzyme improvements were noted but that the PCR tests did not show an improvement. This is consistent with all other reports ITM has received from practitioners using a variety of herbal combinations for hepatitis C.
Another trial of Chinese herbal therapies for hepatitis C is being carried out in Minnesota, with the help of an acupuncturist who had previously observed the treatment of hepatitis C patients in Guangdong, China (9). The double-blind, placebo-controlled evaluation of an herbal extract formula (ingredients list to be released when the trial is completed) is funded by the National Institutes of Health (NIH), as part of their evolving alternative medicines program. Thus far, only 2 patients (out of a total of at least 40 to be enrolled) have completed treatment and another 8 are taking the herbs (or placebo) at the time of this writing. Enrollment has been slow, partly because the protocol requires patients to delete use of potentially confounding substances, such as milk thistle extract (silymarin; see Appendix 2). Use of such substances is common among those who are interested in taking herbal formulas for the disease. Treatment time in this study is just 3 months and the researchers hope to complete the treatments and report results by the end of 2001.
The ability of herbal therapies to reduce liver enzymes while having the viral load remain essentially the same, as appears to occur in most instances, may seem contradictory. Viral load is a measure of hepatitis C virus that has been released into the blood stream. In order to be released, the virus must reproduce (usually many millions of copies within a single cell) and then burst the liver cell, destroying it and releasing its enzymes into the blood along with the virus. One might expect that the liver-enzyme level would remain somewhat proportional to the viral load.
However, it is possible that in the untreated patient the viral reproduction is resulting in what might be termed collateral damage: destroying liver cells that are not currently yielding the virus. For example, the enzyme nitric oxide (NO) synthetase is stimulated in persons with hepatitis C, and the increased output of NO may be causing the collateral damage. If the herbs protect these other cells from the secondary damage by squelching the NO effect, then the marker liver enzymes will be reduced, even cells with active virus continue to pour out their enzymes when they break down to release the viral particles.
Patients who experience a lowering of liver-enzyme levels are usually encouraged by the fact that the improved levels are close to, or within, the laboratory "normal" range. However, at close examination, it is realized that the test results in these patients are usually near the upper part of the range. (e.g., in the patient depicted above who had AST decline to 33, the laboratory normal range was 0-37; at the same time, the ALT remained just above the upper normal level of 40, being last reported at 56). Thus, while the enzyme levels after treatment may be deemed normal or near normal, the figures are usually consistent with there being a certain level of liver inflammation or damage still occurring. A hepatitis C viral load of many thousands might involve destruction of a small enough number of cells that the liver enzyme levels will be near the top of the "normal" range. These cells are dumping huge amounts of virus into the blood stream, just as they were before.
Consistently, it is found in laboratory animals that Chinese herbs that are clinically useful for treating viral hepatitis protect liver cells from damage due to chemicals. This kind of testing was done, for example, with the previously-mentioned hepatitis C treatment in syrup form (3). There is no evidence, as yet, that these herbs halt the virus from reproducing.
Chinese reports, from laboratory animal experiments and limited work with humans, suggest that some herbs, such as salvia (used for vitalizing blood) can limit liver fibrosis, a condition that leads to permanent damage. At this time, it cannot be confirmed whether or not this takes place; most patients in the U.S. who come to acupuncturists for treatment have early-stage hepatitis C and do not have before and after biopsies to prove the condition of their livers. However, interferon-alpha therapy is reported to reduce liver fibrosis, even in patients who do not have clearance of the virus as a result of the treatment, so reduction of fibrosis is a reasonable objective of therapies that are not able to clear the virus or reduce viral load.
According to liver biopsy specialists, liver enzyme levels in hepatitis C patients have relatively little correlation with the extent of liver damage. Thus, whether the ALT levels are high or low does not inform a patient about the condition of their liver. This does not mean that lowering the liver enzymes by use of herbs or drugs is not protective, but only that the enzyme level cannot be counted on to accurately reflect the changes that may occur in the liver.
Chinese clinical reports frequently describe marked therapeutic outcomes from treatments that utilize high doses of herbs. More-limited clinical effects may result from a similar herbal formula given at the lower dosages commonly applied in the West. If the Chinese reports of the viral load falling below detection reflects a true result rather than poor methodology, then the apparent failure of most Western patients to attain the same results might be due to inadequate dosing.
In the case of oxymatrine, the Chinese method of therapy involves injections of the herb alkaloid. This method of application is not available here, and would not be used due to the unknown level of risk. The dosage of oral oxymatrine that ITM recommends is the same as that used in the injection form (total daily dose: 600 mg). Higher oral doses, as might be needed to attain the same blood levels as with the injection, are not recommended due to concerns about potential side effects or toxicity. Although the Chinese reports of the injection treatment do not include serious adverse effects, the number of patients is small, and infrequent problems are easily missed. Alkaloids have the potential for serious reactions if the dosage is high enough. No evident adverse responses have been reported to ITM for use of oral oxymatrine in the dose of 3-4 tablets daily, taken one tablet at a time (as recommended), and the beneficial effects on liver enzymes appear to be attainable.
In the case of the glycyrrhizin treatment, Japanese clinicians reported a persisting effect of the treatment, but the Netherlands study did not find that (8); the liver enzymes rebounded shortly after discontinuing the herb drug injections. However, the Japanese doctors applied the treatment twice as often as the European doctors who conducted the study, which may explain the discrepancy. Glycyrrhizin can accumulate with frequent administration to yield a higher blood level.
A formula described in the earlier ITM publications is Qing Tui Fang, one of the first herbal prescriptions reported in the Chinese literature to successfully treat hepatitis C patients. This formula has been made available by ITM as granules (dried decoctions that are reconstituted to an instant tea preparation) and recommended at a dosage of 18-27 grams/day. This is the highest dosage level recommended by ITM for this form of herb preparation. Typical dosing of such dried decoctions in Japan and Taiwan where they are commonly used is 6-9 grams, which is a low dosage form. ITM recommends up to a maximum of 3 times this amount for treatment of some diseases, if the Chinese literature indicates that application of the high dosage yields desired effects but few or no side effects.
The Chinese report on which this treatment method is based indicated the following dosages for the formula ingredients:
|
Qing Tui Fang |
|
|
salvia |
30 g |
|
red peony |
30 g |
|
astragalus |
30 g |
|
forsythia |
30 g |
|
gardenia |
15 g |
|
crataegus |
15 g |
|
moutan |
15 g |
|
dandelion |
15 g |
|
ho-shou-wu |
15 g |
|
bupleurum |
10 g |
The total dosage is 205 grams, a relatively high amount, though not inconsistent with other preparations recommended in China. According to suppliers of the dried extracts, the typical herb extract is a 5:1 concentration, which means that 5 grams of crude herbs yields 1 gram of the dried extract. The amount of extract corresponding to 205 grams would then be 41 grams, or about 50% more than the highest dose recommended for the granule preparation by ITM (27 grams). At 41 grams, the cost and inconvenience would probably render the treatment unusable.
Although adverse reactions were not reported in the Chinese medical journal article on Qing Tui Fang, Americans frequently report discomforts or adverse reactions to the high dosage decoctions, regardless of formula composition. ITM has received a small number of reports of adverse reactions from taking the Qing Tui Fang at the dosage of 18-27 grams per day in patients with "spleen deficiency". For example (10), one patient reported feeling "wiped out" (fatigued) from taking the formula; she was then switched to a formula that treats spleen-qi deficiency and accumulation of dampness (the formula was not aimed at treating hepatitis C, but only at her constitutional syndrome), which gave the opposite effect: she felt energized. While this experience emphasizes the importance of checking the patient's total syndrome before prescribing a set formula, it also points to the fact that adverse responses may be experienced and caution must be used in administering large amounts of herbs.
Patients with hepatitis C usually approach practitioners of Chinese herbal medicine with the hope of finding an alternative to the standard medical treatments. In addition, they usually hope to cure the disease.
The standard medical treatment currently recommended is particularly unattractive to many people. Both drugs in use at the time of this report produce side effects in many patients, including some potentially serious long-term effects for a few patients. The chances of removing the virus entirely or putting it into remission for many months or years is limited. Therefore, the medical treatment might be regarded as a resort for those who cannot easily put the disease into at least a partial remission by other means.
Many new drugs are in development for treatment of hepatitis C, including new varieties of interferon that yield better results and fewer side effects. A curative method (or one that puts the disease into remission for many years) with an acceptable level of side effects may become available within the next few years. For example, enzymes involved in the production of the hepatitis C virus are being identified and there may be a means of blocking their action without producing significant side effects. Therefore, except in those patients with evident progressive liver disease uncontrollable by other means, it may be best to wait for the next generation of medical therapies.
In order to wait for the potentially curative drug therapy, one must feel confident that adequate liver protection is being attained. While freedom from symptoms and low liver-enzyme levels cannot guarantee absence of slowly progressing liver damage, at present, these indicators are the only means of evaluating success short of getting regular liver biopsies (which virtually all patients will decline, despite physician recommendations).
Patients who have little or no symptoms and who already have relatively low liver enzymes might undertake a conservative treatment of using antioxidants (these are liver protective in almost all cases) and being careful to minimize use of substances that can potentially accelerate liver damage (e.g., alcohol and acetominophen). Good diet, moderate exercise, and other healthy living patterns may help keep the liver in the best possible condition while affording a minimum of chance for the virus to become more active and damaging. Coactivation of the hepatitic virus by other viruses, such as herpes, may occur. Therefore, efforts should be made to avoid viral infections and such infections should be treated promptly and effectively (whether with herbs or drugs) to minimize coactivation.
Patients who have symptoms and/or elevated liver enzymes can be additionally treated with herbal formulas that are similar to those evaluated in Chinese clinical studies. There appears to be no need to match any one of the study formulas exactly, as there is no evidence to suggest that one formula is superior to another; but it is reasonable to gain guidance from the tested formulas: the selection of ingredients for those formulas was based on considerable efforts by experienced physicians.
Those with some obvious degree of liver disease may need to use a combination of the standard medical therapy and the approaches outlined above. It is recommended that during the six-month course (sometimes longer) of standard medical therapy, the Chinese herb formulas should not be used (to avoid any concerns about interactions; see below). However, most antioxidant and nutritional strategies will prove compatible with the drug therapies, based on experience with treatment of other diseases. The herbal formulas (usually given in high dosage) can be utilized before and after the standard medical treatment.
In 1999, several informal Chinese medicine publications in the U.S. relayed a report from Japan claiming adverse reactions, even deaths, from combining a traditional Chinese herb formula with interferon therapy for hepatitis C. A sample newsletter report ITM received from a practitioner read as follows:
The CAAOM has recently heard from several different Japanese sources that over sixteen people have died in Japan from taking the herbal formula Xiao Chai Hu Tang (Minor Bupleurum) with interferon for the treatment of hepatitis. According to Dr. Hirohisa Oda, a licensed pharmacist with a doctorate of Medical Science from Japan and president of the Meiji College of Oriental Medicine [California], all product containers of Xiao Chai Hu Tang are labeled [in Japan] with a warning that this formula should not be taken with interferon. Japanese researchers suspect the culprit may be a saiko-saponin chemical found in Chai Hu (bupleurum). Please don't give your patients this formula when they are taking interferon.
The Oriental Healing Arts Institute (Long Beach, California) was requested by ITM to try and find an original Japanese article and provide a partial translation to English. In addition, an extensive MedLine (National Library of Medicine) search was performed that yielded most of the information provided below, and a Japanese web site was accessed (www.nihs.go.jp/dig/infodrug) thanks to a notice from an acupuncturist (9). The adverse effect attributed to the herb formula was interstitial pneumonia, also called pneumonitis; it manifests as an acute disorder impairing breathing and oxygenation of the blood, sometimes with high fever.
The traditional formula in question is Minor Bupleurum Combination (Xiao Chaihu Tang; in Japanese: sho-saiko-to; SST), comprised of bupleurum, scute, pinellia, ginger, ginseng, jujube, and licorice. This formula is perhaps the most commonly-used herbal prescription in Japan (and extensively used in China). It is frequently employed in the treatment of liver disorders, including both the traditional patterns of liver disharmony and the specific liver diseases as described in modern medical terminology, including viral hepatitis. Numerous reports from Japan during the 1970's and 1980's mentioned use of this prescription for hepatitis, used mainly for hepatitis B, the most common form of the disease. It was then adopted for use in treating hepatitis C.
In 1989, the first case report of interstitial pneumonitis attributed to use of SST was published (11). The patient, a 71-year-old woman, agreed to a challenge test, that is, repeating exposure to the formula. On two trials with just 2.5 grams of the extract granules (usual daily dosage for this preparation is 7.5 grams, taken in three divided doses of 2.5 grams each), she developed the clear signs of pneumonitis (high fever, dyspnea, X-ray evidence of infiltrative shadows in the lungs). The reaction to the formula was described as pulmonary hypersensitivity, which seems appropriate given the dramatic response to such a low dosage.
Additional case reports appeared in the literature in subsequent years, such as a report of pneumonitis in a 66-year-old man who had been taking SST for just 20 days (12). The doctors found an elevated level of lymphocytes and eosinophils in the lung fluid, indicating an immunological type of response. The authors stated that 13 cases of Chinese-herb-induced pneumonitis had appeared in the literature up to that time (1993).
Interstitial pneumonia is also a side effect of interferon therapy (13). Interferon is known to cause a number of pulmonary disorders in susceptible patients, including sarcoidosis, an immune-based disorder (14). In 1995, the Department of Respiratory Medicine at Tokyo General Hospital reported five cases of pneumonitis that was attributed to "sho-saiko-to or interferon-alpha or both" during treatment of hepatitis C (15). One of the patients took interferon-alpha alone (no SST), two patients took SST alone (no interferon), and one patient took both. Lymphocyte stimulation tests were conducted to reveal that there was sensitivity to both SST and interferon. According to an analysis done by the authors, the incidence of pneumonitis in patients with chronic hepatitis or liver cirrhosis was 0.5% for alpha interferon and 0.7% for sho-saiko-to, thus indicating a nearly identical risk of this side effect; however, they reported that the risk rose to 4.0% in those given both, suggesting that there might be a synergistic action.
A possible explanation for the problem with the herb formula and interferon was proposed by members of the Kumamoto University Medical School (16). They stated that it is well known that activated neutrophils are important mediators of pulmonary fibrosis, and that these neutrophils damage lung tissue when activated by cytokines such as tumor necrosis factor (TNF) or interleukin-1 (IL-1). The mechanism by which a synergistic action could be produced by SST and interferon was revealed by their laboratory test results: interferon causes neutrophils to accumulate in the lungs and SST increases the production of TNF. In general practice SST may not cause any lung damage, but it increases the effect of either interferon treatment or the immunological consequences of a predisposing disease condition in relation to neutrophilic damage of the lungs. The cascade of events may be triggered if some antigen is present.
A treatment for the pneumonitis was described in a report from the Fukui Medical School (17). They described four cases of acute pneumonitis with symptoms of fever, dry cough, dyspnea, hypoxemia, and diffuse infiltrates in chest scans. The patients with the disorder had taken either interferon, SST, or both. A lymphocyte stimulation test in two patients showed one responded to interferon and the other to SST. Oral prednisolone therapy was successful in all four cases, and there were no recurrences during a follow-up of 1-3 years. The authors concluded that the mechanism of action by which interferon and SST induced pneumonitis was an allergic-immunological mechanism and not a toxicity problem. The level of the cytokine interleukin-2 (IL-2) in peripheral blood was reported to be a marker of the pneumonitis severity. One of the reported antiviral actions of glycyrrhizin in licorice, which is used as a single active ingredient in the treatment of viral hepatitis and which is an ingredient of SST, is stimulation of IL-2 production.
Based on the accumulating evidence, a formal warning about the association between use of SST and pneumonitis in patients with chronic hepatitis was issued in Japan by the Ministry of Health in March 1996. A death associated with interstitial pneumonia attributed to SST was first described in 1996 (18). The patient had taken the herb formula for about 50 days and then reported symptoms of fever, diarrhea, progressive dyspnea. After six weeks of follow-up treatments, he died from a combination of respiratory distress and gastro-intestinal bleeding (the latter probably due to high-dose steroids aimed at alleviating the pneumonia). The government warning about use of SST in patients with liver cirrhosis was issued again, in revised form in December of 1997.
An evaluation of reported cases of SST reactions was undertaken at the Hamamatsu University School of Medicine (19). They concluded that of 94 cases of pneumonitis reported to the manufacturer of the herb formula, 72 appeared to be actually related to the herb use (average age of patient: 64 years). Most of the cases were patients having chronic hepatitis C. The mean duration of taking the herbs before the pneumonitis symptoms arose was 50 days. Typical symptoms were coughing, dyspnea, and fever with acute onset. X-rays showed diffuse "ground-glass" shadows and infiltration. Abnormally high levels of C-reactive protein and lactate dehydrogenase were common. The bronchoalveolar fluid revealed abnormally high percentages of lymphocytes and neutrophils and a low CD4/CD8 ratio. Of the 72 cases, 64 survived after discontinuing SST, with some patients receiving high-dose steroid therapy; 8 patients, including the one described above, died. The patients that died were said to have had an underlying lung disorder, had taken the herbs for a longer time, and had more severe hypoxemia.
In a case of pneumonitis attributed to sho-saiko-to that occurred recently (20), it was reported that the patient, a 71-year-old women, had been treated with SST for 14 days until the symptoms arose. Her bronchial fluid was tested for sensitivity to both the entire formula and to two of its ingredients, scute and pinellia, and was found to be sensitive to all of them. The authors also suggested that her liver had developed autoimmune hepatitis in reaction to the herbs. In another report (21), a 62-year-old man with pneumonitis attributed to herbs was taking both SST and Coptis and Scute Combination (Huanglian Jiedu Tang; Japanese: oren-gedoku-to) for two months. Challenge tests with both formulas applied separately were positive. The authors suggested that scute, the ingredient common to both formulas, might be of concern; this ingredient was also reactive in the previously described case.
Nearly all the cases of the pneomonitis induced by interferon alpha or SST were in patients with advanced liver disease associated with hepatitis C. It is possible that the virus might yield immunological stimulation and dysfunction that makes these treatments more likely to cause a reaction. Hepatitis C has numerous secondary effects including (22): glomerulonephritis, thyroiditis, and possibly Sjogren's syndrome, IgA deficiency, Mooren's corneal ulcers, Behcet's syndrome, polyarthritis, Guillain-Barre syndrome, and ITP (Idiopathic Thrombocytopenic Purpura). Hepatitis C, without treatment by interferon or SST, may cause idiopathic pulmonary fibrosis.
In the Japanese government warnings (24), the main concern expressed is for patients with advanced liver cirrhosis or advanced liver cancer and especially those who have low platelet counts (ITP). In these patients, various autoimmune processes may be stimulated, and the use of interferon or the immunologically-active SST in such circumstances may lead to a further immunological development that causes a severe reaction even after a few days. In response to interferon therapy, one patient was reported (24) to develop not only interstitial pneumonia, but also hemolytic anemia, implying an immunological sensitization. Hemolytic anemia is similar to ITP in nature and mechanism; a different blood cell line, red blood cells rather than platelets, is the target of the autoimmune response.
Despite several investigations of sensitivity to ingredients within SST as relayed above, it is not known which herbal components might be yielding an adverse effect. The pneumonitis may not be the result of reaction to any individual herb, but to the immunological effects of the entire formula. The two main therapeutic compounds in Minor Bupleurum Combination are triterpene saponins, referred to as "saiko-saponin chemical" in the newsletter warning about the formula (see: Platycodon and other herbs with triterpene glycosides), and flavonoids. Generally, these compounds appear harmless in the dosage used and may require some rare combination of predisposing factors to produce the adverse effects.
One of the primary product manufacturers (Tsumura Juntendo) recently investigated the mechanism by which SST might be causing pneumonitis; it was shown that the formula stimulates interleukin-6 (IL-6, a pro-inflammatory cytokine) in laboratory mouse models of lung injury (25). When active fractions of SST were analyzed, it was found that multiple ingredients had the IL-6 stimulating capability, and the authors cited liquiritin, a component of licorice, as an example. Liquiritin is a flavonoid; the active constituents of scute, suggested to be implicated in a prior evaluation, are flavonoids. However, both bupleurum and pinellia have been potentially implicated as well, and these have triterpene saponins and alkaloids, respectively, for their main active ingredients.
SST is used for treatment of many inflammatory disorders, lung diseases, and viral infections. One would expect from such uses that it has the capability to promote antiinflammatory cytokines and reduce pro-inflammatory cytokines (such as IL-1 and IL-6). However, the hepatitis C virus, interferon, and/or other things influencing the patients who develop pneumonitis, may alter the immune system in such a way that it responds adversely to the otherwise beneficial action of the herb formula. SST is extensively used in the treatment of hepatitis and, as a result, there have been opportunities for rare adverse reactions. It is possible that other herb formulas would also produce this result, but their less frequent use has either led to no cases or to not enough reproducible results to raise a concern about the specific formulation.
Particular caution should be used in patients who are taking multiple drug therapies. The Japanese government has released (via a web site) three sample cases of deaths attributed to sho-saiko-to, which may help illustrate ways to avoid problems:
Case 1: the 61-year-old female patient had experienced interstitial pneumonia from interferon therapy for chronic hepatitis C; therefore, she was withdrawn from the drug therapy and placed, instead, on SST. She took the formula for nearly three years, and then developed interstitial pneumonia again. She had also been taking glycyrrhizin, as well as drugs, such as troxipide.
Case 2: a 68-year-old female with Alzheimer's disease and hepatitis C was treated with SST for just 5 days before developing interstitial pneumonia. The patient was taking numerous drugs, including aniracetam, famotidin, indeloxazine, sparfloxacine, cefotiam, and teprenone.
Case 3: a 68-year-old female with chronic hepatitis, gastritis, post-stroke syndrome, and insomnia, took SST for more than three months and developed interstitial pneumonia. She was taking glycyrrhizin and several drugs, including cisapride, ticlopidine, and rilmazafone.
These patients were all elderly and were taking either numerous drugs or glycyrrhizin or both. They had advanced liver disease in which the metabolism of herbs and drugs is impaired. It has been found that patients with liver cirrhosis have higher levels of glycyrrhizin in their blood than others receiving the same glycyrrhizin treatment (26). If glycyrrhizin can contribute to the development of pneumonitis, then the presence of liver cirrhosis would increase the risk. Practitioners in the U.S. are advised that patients with advanced liver disease, and especially those manifesting secondary immunological disorders (such as ITP), as well as those taking multiple drug therapies, should probably avoid all herbal therapies during treatment with interferon until more is known.
In fact, because of the severity of the reactions to interferon and/or SST, it is best to not take chances with mixing interferon with Chinese herbs until a better understanding of the situation arises. Later, it may be possible to identify specific circumstances where the combination could be recommended and others where it must be avoided. Since Minor Bupleurum Combination (SST) alone had some potential for causing interstitial pneumonia in some of the patients described in the literature, herbal formulas, particularly SST, should be used cautiously in elderly patients who have both hepatitis C and any signs of autoimmune disorders or who are relying on multiple drug therapies. If a patient reports symptoms of acute onset fever, dyspnea, or coughing, they should immediately discontinue use of the herbs in case it is a rare instance of herb-induced pneumonitis. In Japan, doctors are cautioned to monitor the platelet levels of patients with advanced hepatic cirrhosis and to discontinue use of Minor Bupleurum Combination if the platelets are dropping.
Licorice has been found to have potent antiviral action and it is especially suited to inhibiting retroviruses. In Japan, a special glycyrrhizin preparation for treating viral infections has been available for more than 20 years and has been tried for HIV, hepatitis B, and hepatitis C. The product is called stronger neominophagen (SNMC), and is mainly comprised of glycyrrhizin with cysteine (an amino acid used to protect against the undesired effects of glycyrrhizin on the sodium-potassium balance). It is often given by injection, but is also available as a pill and a syrup. Bile products (whole gallbladders or isolated bile) have long been used in traditional medicine to treat liver and gallbladder diseases. For example, the patent formula Li Gan Pian (Liver Normalizing Tablets) indicated for chronic hepatitis, is comprised of lysimachia (jinqiancao) and ox bile (niudan); Jigucao Wan (Abrus Pills), also indicated for chronic hepatitis, contains abrus, tang-kuei, lycium, salvia, and ox bile (listed as ox gallstone) as the main ingredients. Cholic acid is the base compound in bile salt (cholic = bile-derived), and a variant, deoxycholic acid, is the most common form. Ursodeoxycholic acid, a specific bile salt, has been adopted into modern drug therapy and is used in treatment of hepatitis. This bile salt is the main one found in bear bile (urso = bear), but it is also found in other bile products and can now be produced synthetically, making it a practical source for drug therapy.
Both of these substances have been reported helpful in lowering liver enzymes in patients with hepatitis C. Recently, a large clinical study (170 patients) compared use of glycyrrhizin alone or with ursodeoxycholic acid (27). It was found that glycyrrhizin alone could markedly lower AST and ALT levels, but only by adding ursodeoxycholic acid (600 mg/day), could the GGT level also be markedly reduced. The level of hepatitis C virus was not affected by the treatment. The authors of the study concluded that: "The combined therapy with ursodeoxycholic acid and glycyrrhizin is safe and effective in improving liver-specific enzyme abnormalities, and may be an alternative to interferon in chronic hepatitis C virus infection, especially for interferon-resistant or unstable patients." The possibility of using such liver-stabilizing therapies in place of interferon was suggested for non-responders to interferon therapy in a review article on the subject (28). The authors stated that "For the many patients who still do not respond with viral clearance despite these new approaches [using interferon in differing dosages and with ribavirin], the goal of therapy might be shifted towards persistent ALT normalization in order to reduce the progression of liver disease."
In a small study (28 patients), SNMC was combined with interferon for 15 patients and the 13 others were given interferon alone (29). It was reported that the serum viral clearance was higher (but not with statistical significance) in the group receiving the combined therapy, and that there was a higher rate of improvement in liver condition as observed by biopsy in the combined therapy group. This study was too small to reveal whether there might be side effects, such as pneumonitis, from the combination therapy that otherwise appears quite favorable.
Another small study (41 patients), compared treatment of interferon alone (20 patients) with interferon plus ursodeoxycholic acid (21 patients). It was reported (30) that decline in liver enzymes was faster in the combined therapy group than in the interferon-only group; further, there were greater improvements in the liver condition as revealed by biopsy in the combination therapy group. A second study for long-term response compared use of either ursodeoxycholic acid or interferon alone and in combination (31). The ursodeoxycholic acid alone was said to be ineffective; the combination increased the interferon response rates, but the difference was not deemed significant nor sustained. In another study comparing use of interferon alone or with ursodeoxycholic acid (31), it was reported that the combination was not significantly more effective than interferon alone except that the response to interferon (e.g., lowering liver enzyme levels) was prolonged in some patients receiving the combination. A situation where ursodeoxycholic acid appears to be effective, even if given alone, is autoimmune-associated chronic hepatitis C (32). This is a liver disease in which hepatitis C induces a secondary autoimmune process (interferon therapy may also induce this process). According to the report, patients with the autoimmune component responded to a one year treatment with ursodeoxycholic acid by having significantly lowered liver enzyme levels.
Silymarin, the active fraction from milk thistle (Silybum marianum) has become a well-known agent for treatment of liver disease. In a review of its application and efficacy (33), doctors at the Division of Gastroenterology at the Oregon Health Sciences University stated that:
In a recent poll of patients attending our hepatology clinic, we found that 31% were using over-the-counter alternative agents for the therapy of their liver diseases. The most commonly-used nontraditional therapy was milk thistle (silymarin)....Most of the clinical trials designed to assess the efficacy of silymarin are difficult to interpret, as they are flawed by the small numbers of subjects, variability in etiologies, and severity of the liver diseases studied, as well as inconsistencies in alcohol usage by patients, heterogeneous dosing, inconsistent use of control groups, and inadequately defined endpoints.
Clinical trials with silymarin and hepatitis C have not been reported up to now. During acute viral hepatitis A or B, silymarin has been reported to hasten recovery and shorten hospital stays, consistent with an anti-inflammatory activity that is supported by laboratory animal studies with chemical-induced hepatitis.
A report on three patients with advanced liver disease associated with hepatitis C treated by the antioxidant approach was presented by a doctor at the Integrative Medical Center of New Mexico (34). Patients received a combination of silymarin, alpha-lipoic acid, and selenium and were said to have a quick alleviation of major symptoms and an improvement in liver enzyme levels.
In Spain, liver biopsies of hepatitis C patients were conducted to evaluate the extent to which inflammatory nitrogen compounds influence liver damage (35). It was reported that the severity of liver disease seen in the tissue samples was correlated with the content of the damaging nitrogen compounds, nitric oxide and nitrotyrosine. The possibility that silymarin and other antioxidants, such as green tea extract and quercetin, might help protect against these effects is raised by preliminary work reported at the College of Pharmacy at Florida A and M University (36). Using in vitro assays, they noted that silymarin, green tea, quercetin, curcumin and a variety of flavonoid compounds could inhibit nitric oxide by stimulated cells.
Nitric oxide production is stimulated by interferon alpha in patients with hepatitis C according to researchers at the Duke University Medical Centers in North Carolina (37). These researchers proposed that nitric oxide stimulated by interferon may contribute to the anti-viral action, though it is also possible that such stimulus is merely a reflection of enhanced antiviral action from other components of immune cells. The use of antioxidants during interferon therapy for hepatitis C might be questioned, if it reduces a nitric oxide mediated attack against the virus. At this time, there is no evidence to support use of silymarin during the time of interferon treatment. As with the recommendation above for other herbal therapies, the best use of silymarin and other antioxidant therapies (as supplements taken in larger than normal dietary levels) might be before or after interferon therapy. In Appendix 1, examples of natural products that have been tested along with interferon are described.
The usual dose of silymarin used in clinical trials is reported to be 140 mg each time, three times daily. However, this amount usually refers to the crude preparation that is 70% silymarin, which means the actual dose of the compound is about 100 mg each time, for a total daily dose of 300 mg.