Study on Herbs-induced Liver Damages

Drugs, either Western or Oriental, all can cause liver damages if used inappropriately or misused. The causes of liver damages resulted from the use of Chinese herbs  are mostly due to overdose, use not according to traditional indications, arbitrary use of poisonous or unprocessed herbs, long-term use of therapeutically potent herbal formulas, improper application to the patient's individual conformation, and mistaken use of incorrect or bad-quality herbs. The most positive preventive action is to emphasize the education and understanding of TCM knowledge, and enact strict control on the quality of the TCM manufacturing industry.

Introduction

The liver is an organ of our body, which is chiefly responsible for metabolizing foreign substances and plays an important role in the metabolism of drugs. Most drugs are subject to biological transformation in the liver and then excreted out of the body. Liver damages caused by the toxic side effects or overdoses of drugs during the process of drug metabolism are called "drug-induced liver diseases" According to statistics, at present there are over 600 drugs that can cause liver damages and the incidences of drug-induced diseases are only less than the drug-induced skin and mucous membrane diseases and drug fever[1,2].In the past, studies on drug-induced liver diseases are limited to Western drugs, i.e. the chemically synthesized drugs, and studies on liver damages caused by Chinese herbal medicines and nature drugs are not extensive enough. Currently the condition has changed somewhat. With the propagation of Chinese herbal medicines and nature drugs throughout the world, the side effects of liver damages induced by herbal drugs have gradually caught people's attention. Cases of liver damages caused by herbal drugs are reported from time to time all over the world. In Asian regions where herbal drugs are popularly used, clinical statistics shows that individual cases of herbal drugs-induced liver damages occupy even as high as 30% of all drug-induced liver disease cases[3].Moreover, drug interaction resulted from combined use of herbal drugs with Western drugs further increases the incidence of drug-induced liver diseases. Clinical studies have revealed that some herbal drugs not only can affect the normal physiological functions of the liver, but also can change liver structure, causing damages ranging from mild elevation in GPT to acute and chronic hepatitis, hepatic fat degeneration, bile stagnation, venous obstruction, teniform or disseminative liver necrosis, liver fibrosis, liver cirrhosis, acute liver failure, etc. The present study makes a full literature review regarding herbal drugs-induced liver damages, and discusses the etiology, clinical manifestation, pathological changes, pathogenesis and prophylaxis in order to call for physician and patient's attention, and to reduce and avoid unnecessary herbal drugs-induced liver damages.

Biotransformation of drugs in the liver

The liver is the primary site for drug metabolism in our body. Drug metabolism in our body usually takes place in two processes. The first is the redox (reduction- oxidation) and hydrolysis process and the second, the combination process. The first process for most drugs occurs in the smooth-surfaced endoplasmic reticulum of the liver cell's mitochondria, which is an oxidation reaction in various forms catalyzed by the oxidative enzyme system with mixed functions. The most important in this process is cytochrome P450. On the smooth-surfaced endoplasmic reticulum, drugs combine with the oxidative cytochrome P450, forming a complex, which under the action of NADPH (reductive coenzyme II) cytochrome P450 reductive enzyme is then reduced by the electron from NADPH to form a reductive complex. The reductive complex then reacts with an oxygen molecule to form an oxygen-containing complex as shown in the following formula.

where NADP=    nicotinamide-adenine dinucleotide phosphate (coenzyme II),

         NADPH= the reduced form of NADP (reduced form of coenzyme II)

After the oxidation reaction in the first process, drugs are turned into highly water soluble metabolites, which after combination reaction to combine with glucuronic acid, sulfuric acid, methyl group, acetyl group, mercapto group, glutathione, glycine, glutamine, etc will further increase their water solubility, thereby facilitating their excretion from the body through bile or urine. Owing to genetic variation of the organic body, human drug-enzyme functions appear in a multiply distributed pattern, and different bodies have different metabolizing capabilities. For example, deficiency in the cytochrome P450 complex isozyme may lead to increased drug action and prolonged retention in the body, which easily cause drug-induced hepatic damages[2].

Clinical manifestation and diagnosis of drug-induced hepatic damages[2]

The clinical manifestation of drug-induced hepatic damages is multifarious, varying greatly in terms of disease development, clinical characteristics and severity of disease. Moreover, chronic drug-induced hepatic diseases are clinically easily ignored and usually misdiagnosed as chronic viral hepatitis[4].

1.     Clinical manifestation of acute drug-induced liver diseases

a.     Acute hepatitis type

The drug-induced damage and necrosis of liver parenchymal cells is clinically manifested similar to those of acute hepatitis. Mild liver cell damages are usually clinically asymptomatic or only mild in symptoms. There are only slight elevations in ALT (alanine transferase) and AST (aspartate transferase). Moderate liver damages manifest nausea, vomiting, inappetence, dread of oil, jaundice, pain at liver area, hepatomegaly, marked elevation in ALT and AST, and prolonged prothrombin time. Severe cases may have hepatic failure, hepatic coma and even death. Pathological changes chiefly involve liver cell necrosis and inflammatory cell infiltration, bile stagnation and proliferation of Kupffer's cells. The Chinese herbs Zhu Shi Dou (Crotalaria pallida Ait.) and fish file can cause liver damages[5].

b.     Acute cholestasis type

Drugs may cause disturbances in the process of bile secretion, making it difficult for the bile to get discharged into the duodenum, and as a consequence the bile flows back into the blood stream. Clinically the patient may have severer jaundice, often accompanied by fever, skin rash and arthralgia; while the alimentary symptoms are comparatively milder. Clinical examination can find that the extent of elevation of ALT and prolongation in prothrombin time are relatively mild. Pathological changes are chiefly in capillary cholangiectasis, reduction in microvilli, formation of microbiliary thrombosis, liver cell degeneration and necrosis, and bile pigment sedimentation. The Chinese herb Guan Zhong (Blechni Rhizoma) can cause this type of liver diseases[5].

c.     Fatty liver type

Drugs interfere with the protein synthesis in the liver, causing reduction in low density protein, hindering hepatic secretion of triglycerides and leading to lipid sedimentation in liver cells. Clinical manifestation is similar to that of acute hepatitis, or there are no marked symptoms but only elevated ALT and AST. However, it may also manifest progressive hepatic failure until death. Pathological changes are chiefly sedimentation in the liver cells of fatty droplets (microvesicles) or mega fatty drops (marcovesicles).

d.     Mixed type

Drug induced liver damages are compound in character. Pathological changes are chiefly liver cell necroses, which are nevertheless sometimes accompanied by different degrees of bile stagnation and meantime a lot of extrahepatic damages such as skin rashes, lymphaden pathological changes, changes in bone marrow and blood pattern, myocarditis, parenchymal nephritis, and arthritis. The Chinese herb Huang Yao Zi (Dioscoreae Bulbiferae Rhizoma) can cause mixed type liver damages[5].

2.     Clinical manifestation of chronic drug-induced liver damages

a.     Chronic hepatitis

The patient usually has a long medication history, a clinically slow rise of disease, and in addition to the symptoms of adynamia, anorexia, pain at the liver area and jaundice, the patient also has hepatomegaly, liver palm, spider moles and extrahepatic manifestations such as arthralgia, arthritis, mucocutaneous pathological change, amenorrhea, hirsutism, acne, etc. Also seen are elevated serum ALT, prolonged prothrombin time, elevated bilirubin and increased -globulin, IgG and IgM. Pathohistological manifestations include peripheral chipping necrosis of hepatic lobule, intralobule necrosis, acidocytic changes, formation of basocytes, presence of plasmocytic, lymphocytic and monocytic infiltration at the portal area and presence of pseudocholangiolar proliferation and fibrosis.

b.     Chronic cholestasis type

Clinical manifestations are jaundice, yellow wart on the skin, hepatosplenomegaly, elevated serum ALP, ALT, cholesterol and combined hemoglobin, and prolonged prothrombin time. Pathohistological finding shows bile thrombus in capillary bile tubules, bile pigment sedimentation in liver cells and Kupffer's cell, proliferation of cholangioles and formation of pseudocholangioles.

c.     Fatty liver

Clinical findings are hepatomegaly, elevated ALT, mild to middle elevation in bilirubin, prolonged prothrombin time; and histological finding shows disseminated fatty degeneration of liver cells.

d.     Others

Chronic drug-induced liver damages also include pathological changes of liver vessels, liver cirrhosis and liver tumors.

3.     Clinical diagnosis of herb drug-induced liver damages

Because the herb drug-induced liver damages are not clinically specific in manifestation against laboratory examinations, they have really brought some troubles to clinical diagnosis and are often mishandled, or even misdiagnosed for other liver diseases such as viral hepatitis. Therefore, the patient's medication history plays an important role in the clinical diagnosis of herb drug-induced liver damages, and evidences regarding the species and dosage of prescription or non-prescription herb drugs, and the names and doses of health foods taken by the patient currently or in the past are helpful to the diagnosis. The presence of clinical symptoms bears a close relation with the herb drugs taken. The betterment or worsening in clinical manifestation that is related to the interruption or reuse of herb drugs is also helpful to the diagnosis of herb drug-induced liver damages. Besides medication history, excluding diagnosis is a key process in clinical diagnosis of herb drug-induced liver damages. Under the circumstances of hepatopathic symptoms and abnormal liver functions, the exclusion of commonly seen hepatocholic diseases and chemical-induced liver damages may be a prerequisite for the diagnosis of herb drug-induced liver damages. The commonly seen liver diseases include hepatitis A, B and C, alcoholic hepatopathy, gall system infection, gall stone, benignant tumor of the liver and bile duct, primary or secondary liver cancer, etc. In spite the trend of increasing cases of herb drug-induced liver damages, cases of chemical-induced liver damages far surpass the former, and the exclusion of chemical-induced liver damages is extremely necessary, especially under the condition of combined medication. Besides, some liver damages that are not commonly seen should be considered to be induced by herb drugs. For example, the teniform liver cell necrosis, liver cell necrosis accompanied by fatty degeneration or cholangiolar and vascular damages, especially the veno-occlusive disease (VOD)[6]. The pathological change of VOD is chiefly due to the liver venular (including the lobular central venular and sublobular venular) intimitis and fibrosis that finally lead to stenosis or even occlusion of venular lumen, causing obstruction of blood backflow, marked dilation of liver sinus, blood stasis, and liver cell compression, atrophy, degeneration and necrosis. It must be stressed that the manifestation of herb drug-induced liver damages is seldom histologically specific and is very similar to that of other types of liver disease[6].

Pathogenesis of herb drug-induced liver damages[2,3,5,8]

The pathogenesis of herb drug-induced liver damages is usually divided into two categories: toxic hepatic damages and allergic hepatic damages.

The toxic hepatic damages are caused directly by drugs per se or their metabolites. Some drugs are acted upon by cytochrome P450 in the live and converted through metabolism into toxic substances. For example, the electrophilic groups, free radicals and oxygen groups that combine with high molecules such as proteins, nucleic acids and fats to interfere with cell metabolism, and break up membrane intactness and membrane Ca++-ATP enzyme system, thereby disturbing the stable environment in the cell and finally leading to death of liver cells. Some other drugs undergo selective interference with cell metabolism to induce liver damages. The human bile comprises chiefly two combined forms of cholic acid, which are primary combined cholic acid and secondary combined cholic acid. The combined cholic acid combines with sodium ion Na+ to form a salt that is then secreted by the liver cells into the bile tubules. If a drug metabolite interferes with any of the processes of bile combination or secretion, it may cause bile stagnation and thus cause liver damages. Still some other drugs possess proteins which are hepatotoxic and can deactivate the activities of liver enzyme system to cause disturbances in liver cell functions and metabolism. The herb drug-induced liver damages have the same characteristics as ordinary toxic hepatitis, which are accompanied or not accompanied with marked bile stagnation and in severe cases may have acute or subacute liver necrosis with manifestation of progressive hepatic failure. Herb drugs such as Sang Ji Sheng (Loranthi Ramulus), Jiang Ban Xia (Pinelliae Tuber cum Gingeris), Pu Huang (Typhae Pollen), Tian Hua Fen (Trichosanthis Radix), Wu Bei Zi (Galla Rhois), Da Huang (Rhei Rhizoma), Ze Xie (Alismatis Rhizoma), Su Ji Qing (Ilicis Folium), Ca Mu (Sassafras tzumu), O Ya Bo He (European and Asian Menthae Herba), Qing Dai (Indigo Pulverata Levis) and Huang Yao Zi (Dioscoreae Bulbiferae Rhizoma) belong the category of herb drugs that cause toxic liver damages that have something to do with the one-time dose and cumulated dose of the herbs.

The allergic hepatic damages are caused by the antigen formed from the combination of the hapten (semiantigen) of an herb drug with the liver specific protein. The liver specific protein could be the component of part of the liver cell membrane, the mitochondria component of the liver cell membrane or some soluble substance containing liver specific antigen. The drug-combined antigen is then processed by the macrophage and identified by immunoactive cells to trigger the allergic reaction to cause immunity hepatic damages. Such reaction involves humoral immunity and cell immunity. Generally speaking, the drug-induced allergic hepatic damages have nothing to do with drug dose. The allergic hepatic damages have the clinical characteristics of acute onset in the form of most other allergic reactions such as skin rashes, GI upset followed by liver functional anomaly, jaundice, and hepatomegaly. Herb drugs that cause allergic hepatic damages include Mang Cao (Illicium lanceolatum A.C. Smith), Zi Jin Niu (Ardisiae Herba), Lei Gong Teng (Polygoni Perfoliate Herba), Si Ji Qing (Ilicis Folium) and the compound herb formula Fu Fang Dan Shen Zhu She Ye (Salvia Formula Injection).

Western herbs that can cause liver damages

1.     Plants containing pyrrolizidine alkaloids (PAs)

Pyrrolizidine alkaloids (PAs) refer generally to those alkaloids that have a pyrrolizidine nucleus. They are found in several ten genera with several thousand species of plants. It has been reported that one third of flowering plants in this world contain such alkaloids. The Boraginacea, Compositae (Asteraceae) and Leguminosae (Fabaceae) families are the three families where the toxic PAs are concentrated. So far some 600 kinds of such alkaloids have been isolated from over six thousand species of plants, and about half of the alkaloids are toxic[9-12]. PAs are the most broadly studied hepatotoxic constituents, of which people have understood the toxicities for over 80 years. In 1920 in South Africa massive food poisoning occurred, which was caused by a poisonous plant, Senecio, that contains PAs[13]. Later, there were reports that in 1950 in South Africa, 1970s in India and Afghanistan and in 1992 in Tajikistan severe PAs poisoning occurred[11]. These cases were all caused by admixture of food grains with PAs-containing seeds[9].

In the current 20 years, herbal drugs sales have been increasing rapidly in Europe, North America and Australia, and some herbal drugs are even sold as food supplements, causing sporadic poisoning cases from time to time. So far there have been some ten reports on poisoning, involving about 20 people of whom most were due to ingestion of overdoses or inappropriate use of herbal drugs[9,10]. Plants involved in the poisoning were Symphytum officinale (comfrey of Symphytum family, 4 cases), S. longilobus (Senecio, 4 cases), Heliotropium eichwaldii and H. lasiocarpum (Heliotropium family, 4 cases), substitute of Tussilago fargara (2 cases) and plants of unknown origins (5 cases). Among these cases, 3 occurred in China, which were probably associated with the use of Chinese herbal medicine. The other cases occurred in Europe, America and South Africa. The plants causing such poisoning are indigenous to the local regions and are outside the scope of Chinese herbal medicine (For details, see Appendix I).

No all PAs are toxic. Only those containing 1,2-unsaturated necine, such as ¤U¦V¤d¨½¥ú¦¸ÆP¡B¤d¨½¥úµõÆPand¤ÑªãµæÔr are toxic to human beings and animals[14]. After ingestion into the body, the toxic PAs are converted by cytochrome P450 into pyrol derivatives which are unstable metabolites and can cause dose-dependent liver damages[3]. PAs can cause lowering in liver cell RNA enzyme activity, reduced RNA and DNA syntheses, incomplete cell mitosis to result in the formation of polynucleic, liver cell necrosis, reduced DNA synthesis and transverse breakage of DNA[15].

Clinical reports point out that people of different ages are subject to the toxic effect of PAs, but children seem to be most venerable[10]. Clinically the PAs poisoning manifests acute onset, displaying epigastric upset, abdomenache, ascites, increase abdominal periphery, and there may be accompaniment by oliguria, foot edema, hepatomegaly and serum transferase elevation, which are caused by the so-called veno-occlusive disease (VOD). As the venules are obstructed, blood backflow to the heart is also obstructed, leading to a series of pathological changes. The disease progresses rapidly and in severe condition may cause hematemesis, hepatic failure and a higher fatality rate reaching 20~40%, but most cases are reversible. In chronic cases, some patients only have uncertain symptoms with the only positive body sign being hepatomegaly, but some may develop into liver cirrhosis[10,3,6].

Human and animal pathological examinations have found that the liver lobule central hemorrhagic necrosis is the chief pathological manifestation of acute PAs poisoning. Chronic poisoning manifests non-thrombotic lobule central venous occlusion, liver cell fat degeneration, cell nucleus enlargement, increase nuclear chromosome, inhibited mitosis, proliferation in cholangiolar epithelia, liver cirrhosis, proliferation in liver nodules, liver adenoma and liver cancer. Besides liver pathological changes, the lungs, brain, kidneys, bone marrow and blood vessels may also undergo pathological changes such as erythrocytic enlargement (macroerythrocytosis), intra-pulmonary veno-occlusion, nervous cell degeneration, etc.[11,3].

Current studies show that PAs are also genotoxic and carcinogenic. The genotoxicity is developed through the formation 6,7-dihydro-7-hydroxy-1-hydroxy- methyl-5H-prrolizine (DHP) whose derivative addition product leads to the genotoxic mechanism[11]. Data from animal experiment with the fruit fly show that16 PAs have mutagenicity ranking in order of strength as follows:

Senkirkine > monocrotaline >seneciphylline > senecionine > 7-acetylintermedine > heliotrine > retrosine > 7-acetyllycopsamine > symphytine > jacoline > symlandine > intermedine > indicine > lycopsamine > indicine N-oxid > supinine[16]

The acute toxicity of PAs varies with different alkaloids, the rat's LD50 ranges between 34~300mg/kg[10].

2.     Germander

Germander (Teucrium chamaedrys) is a commonly seen wild plant containing iridoid glycosides, clerodane, neoclerodane diterpenes, phenylpropanoids and essential oils capable of cholagogue, diaphoresis, antirheumatism and antibacteria effects[17]. This herb drug was used as an antiobesity drug in France in 1986. Later, owing to 30 episodes of hepatitis that occurred during the use of the herb drug, the drug was prohibited from sales in 1992[6]. Hepatitis occurs two months after administration, which in addition to manifesting mild and moderate typical cytolytic hepatitis may also display the pathological changes of fulminant hepatitis, chronic hepatitis, and liver cirrhosis. The pathological changes disappear completely 2~6 months after suspension of medication. Later in Canada, Spain and other places, there were also reports of liver poisoning by germander[18,19]. Regarding the mechanism of liver damages by germander, there are different opinions, of which one is that the metabolites directly act, damaging the liver cells by the mechanism that the diterpenoids contained in germander are converted by cytochrome P450 into electrophilic metabolites that can inhibit the mercapto group, increase Ca++, activate Ca++-dependent glutamine transferase and finally cause cell death. The second opinion is that of autoimmunity theory which suggests that in the serum of patients suffering from germander-caused hepatitis, an autoantibody of the liver cell mitochondria epoxide hydrolyzing enzyme can be found, which supports the autoimmunity pathogenesis[20,21]. Another plant Tenucrium plum belongs to the same family as germander, which is used as an antimicrobial and antiphlogistic herb in the Mediterranean area. There was a case, a 37-year-old female, who took the herb drug for 10 days and developed acute liver failure requiring liver transplant[6].

3.     Kava Kava (Piper methysticum)

Kava Kava is an African plant containing kava pyrones, kavaine alkaloids and other constituents in its tuber. In Europe and the U.S. the herb has been widely used for treating anxiety, nervousness and psychosis due to heavy life or work stress. In the first 8 months in 1999 in the U.S. the herb had a sale of US$11,590,000[22~24]. So far, there have been over 20 cases reported to have acute liver damages from the use of the herb. Except the two cases requiring liver transplant, the other cases recovered 8 weeks after cessation of Kava Kava intake. Liver damages induced by Kava Kava are pathological changes of broad liver cell necrosis, which may be accompanied by cholestasis. The mechanism of Kava Kava-caused liver damages is still not clear. Cytochrome P2D6 catalytic activity test has found that in some cases suffering from Kava Kava-induced liver damages, there is functional deficiency in metabolizing debrisoquine, which indicates that lower activity in cytochrome P2D6 is prone to Kava Kava-induced liver damages[6,25].

4.     Callilepsis laureola and Atractylis qummifera

The generic name for Callilepsis laureola is impila, which is an African herb drug indicated for gastric ailments, parasites, impotency and cough. Since the 70s, many cases of liver damage and renal damages resulted from the use of the herb. The onset is prompt with clinical symptoms and signs of abdomen ache, vomit, diarrhea, loss of consciousness, convulsions and other acute hepatic and renal failure signs, and in grave cases severe hypoglycemia is also very commonly found. 63% of the patients died within 24 hours with a 5-day total fatality rate reaching as high as 91%. Autopsy reveals liver atrophy and central teniform necrosis of the liver lobule[6,26]. Atractyloside and carboxyatractylosde are the two chief toxic constituents of Callilepsis laureola. The exact mechanism for liver damages caused by Callilepsis llaureola is not clear. Given that atractyloside has been known to competitively inhibit ADP and ATP transportation and thereby further inhibit oxidative phosphorylation, atracyloside still can act through affecting the membrane permeability of the mitochondria to effect the release of cytochrome C and caspase-activated proteiase to induce cell death. However, to date no direct evidence supports atractyloside to be able to cause liver lobule central necrosis -- the characteristic pathological change of Callilepsis laureola-induced liver damages[6,27].

Another plant, Atractylis gummifera, also contains atracyloside. In Europe there are also reports of poisoning by this herb. The patient's clinical symptoms are similar to those of poisoning by Callilepsis laureola, all being manifested as acute hepatorenal necrosis[6,26].

5.     Chaparral (Larrea tridentate, L. divaricata, L. mexicana, L. glutinosa)

The Chaparral leaf is a traditional herb drug used by the natives of the U.S. It contains quercetin, nordihydroguaiaretic acid, lignin and essential oil and is used for treating respiratory infections, rheumatalgia, gastralgia, chickenpox, antiobesity, tumors, pulmonary tuberculosis, venereal disease, snake bite, etc.6.28 So far there have been some 20 cases of poisoning from using the herb. American FDA analyzed 18 poisoning cases that happened in the U.S. Among the cases, 13 cases were of the liver damage type. Similar cases were also reported in Canada and Australia[6,28~31]. Clinical symptoms appeared 3~52 weeks after administration of the herb drug, which were chiefly manifested as jaundice and severe liver function anomaly. The chief liver damage type was chlolestatic hepatitis, which in cases that used the herb drug for more than one year might develop into liver cirrhosis and hepatic failure. The mechanism by which Chaparral induces liver damages is still unknown. The lignin contained in the herb possesses some estrogenic activity, and it is known that estrogenic compounds can induce cholestasis that is manifested in the same way as that manifested by the liver damages caused by the herb. Moreover, the pathways of direct inhibition of cyclooxygenase and immunity reaction cannot be ruled out also[6,29].

Single Chinese herb drugs that can induce liver damages

1.     PAs-containing Chinese herb drugs

In the process of screening Chinese herb drugs, 49 plants are found to have contained PAs, of which 4 plants are included in the People's Republic of China Pharmacopoeia (2000 ed.), namely, Lithospermum erythrorhizon[32], Eupatorium fortunei[33], Tussilago fargara[34]and Arnebia euchroma[32]. The other 45 plants are regional folk medicines used in limited fields. They are not commonly used herb drugs and a large portion of them are not used medicinally. The families and species of these plants are listed in Appendix 2. Despite the many herb drugs containing PAs, poisoning cases are rarely seen and there are only two relevant case reports. In one case report in 1980, two cases took large doses of Gynura segetum to result in liver damages and deaths. The doses of Gynura segetum taken were 45g and 36g respectively, which were taken for 10 strong and 50 strong days. Autopsy confirmed veno-occlusive disease (VOD), which is a typical pathological change of PAs-induced liver damages[7]. Another case report in 1993 gave two cases which took 500g of a decoction of Gynura segetum and one week later symptoms of liver damages such as abdomen ache, nausea, vomiting, jaundice, ascites and hepatosplenomegaly appeared[15].The four reported cases of poisoning were all induced by Glynura segetumn (non-commonly used folk medicines). While many commonly used Chinese herbal drugs that contain such alkaloids have not seen any poisoning cases reported. This is probably something connected with the contents of the alkaloids in the herb drugs and the administered doses of the herb drugs. For example, Lithospermum erythrorhizon has a total PAs content of only 0.02%, which is chiefly of intermedine and myoscopine. Arnebia euchroma has a total PAs content of 0.0006%, chiefly of angeloylretronecine. PAs content in Tussilago fargara ranges from negligible to 0.0015%. These contents are all very minute[9]. Besides, most Chinese herbal drugs are used in specified doses and people consume Chinese herbal products under the instructions of medical professionals well versed in Chinese herbal medicines. That is why in the Asian area where Chinese herbal medicines are popularly used, but PAs poisoning cases are rarely seen.

2. Lycopodii Serrati Herba (Lycopodium serratum Thunb.)

Lycopodium serratum belongs to the Lycopodium family and Lycopodium genus. Its orthodox name is Qian Cen Ta (Thousan-story Pagoda). The commonly used name Jin Bu Huan is just its alias. The whole herb is used medicinally. It has a bitter and slightly sweet taste, a bland nature and a little toxicity. It possesses the functions of subsiding extravasation, resolving swelling, detoxification and allaying pain and is thus indicated for wounds from beating, falling, contusion, extravasation, swelling pain, internal injuries with hematemesis. It is also applied externally for treating snake bite, burns and scalds[35].In 1993 in Colorado in the U.S., there was a report on poisoning in three children who erroneously ingested large amounts of Lycopodium serratum and fell into unconscious sleep for several hours. Later, there was also a report on three adults who took an analgesic tablet made from Lycopodium serratum for a long period of time to result in liver damages[36,37]. In 1994, an American hospital in Los Angeles observed 7 cases poisoned by Lycopodium serratum analgesic tablets. After taking the herb drug for an average period of 20 weeks (from 7 to 52 weeks) the patients appeared to have fever, adynamia, nausea, vomit, abdomenache, pruritus, jaundice and hepatomegaly which are symptoms and signs of acute hepatitis, which disappeared in an average period of 8 weeks (from 2 to 30 weeks) after suspension of the drug. Among 4 of the cases, two cases took the drug for 2 months, one case appeared to have liver cell focal necrosis accompanied by acidocyte infiltration at the portal area, and cholestasis, one case had moderate fibrosis; and the other two cases which took the drug for 1 to 2.5 years have moderate abutting fibrosis in addition to liver cell focal necrosis and micro fat drop degeneration. Clinical observation found that one case had improvement in liver functions after suspension of the Lycopodium serrtum analgesic tablets. Another two cases suspended the drug and then took the drug again, and as a result hepatitis relapsed. Drug analyses show that the herbal product contains as high as 36% of l-tetrahydropalmatine(THP)[38,39,3,6]. The liver damaging mechanism of this compound is unknown. Clinical cases exhibit pyrexia and increased acidocytes in peripheral blood, and acute relapse of hepatitis, which all suggest the pathogenetic mechanism of drug-induced allergic reaction or anaphylaxis. Besides, the molecular structure of l-tetrahydropalmatine is similar to that of PAs, hence its direct toxic effect on the liver also cannot be ruled out[38,6].

3.     Ephedrae Herba (Ephedra sinica Stapf)

This item is derived from the dried herbaceous stems of Ephedra sinica Stapf, E. intermedia Schrenk et C.A. Mey and E. equisetina Bge. The herb has an acrid and slightly bitter taste and a warming nature. It functions to render diaphoresis, disperse chills, vent the lungs, arrest asthma, induce diuresis to resolve edema, and is thus indicated for wind or cold-inflicted common cold, chest depression, coughing, wind and water-inflicted edema, and bronchial asthma[40]. Its chief constituent l-ephedrine occupies 40~90% of its total alkaloids content and the next high-content constituent is d-pseudoephedrine. In addition to the effects of expectoration and bronchodilation, Ephedra sinica can also stimulate the respiratory center and vasomotor center[41]. Currently, in some Western countries, this herb drug has been used askew from the regular track of traditional Chinese medicine in that it is not used for treating common cold, cough, asthma and other respiratory diseases, but broadly used as an antiobesity agent or an excitant, and the products contain this herb in amounts far higher than that prescribed for traditional use. What's more, some products even use separated or artificially synthesized ephedrine in place of the herb and has thus caused many toxic side effects. According to a 2000 investigation commissioned by the FDA of the U.S., the population using ephedra (or ephedrine)-containing products in 1999 numbered 12,000,000. In the 5-year period from 1994 to 1999, there were 1,000 reports associated with the adverse effects of ephedrine such as headache, vertigo, insomnia, anxiety, tremor, cardiac arrhythmia, hypertension, convulsion, coma and even death[42]. In comparison with the nervous system and cardiovascular system adverse effects, cases of ephedra-induced liver damages are extremely rare. In 1996, there were 4 cases reported to have connection with the use of ephedra, of which one case was fulminant liver failure manifesting severe jaundice, coagulation disturbance and hepatic cerebropathy. The case survived after liver transplant. The dissected liver showed marked liver atrophy with the slide showing disseminative lobule central necrosis, cholangiolar proliferation at the portal area and inflammatory reaction[43,3]. Borum reported on a 58-year-old female who developed fulminant hepatitis after taking ephedra-containing preparation for 4 months. The patient manifested the clinical sings of autoimmunity disease[44].

4.     Tripterigii Causlis (Tripterygium wilfordii)

This item refers to the dried root, leaf and flower of the Celastraceous plant Tripterygium wilfordii, which has an acrid taste and is highly toxic. It contains wilforgine and several ten other alkaloids, and triptolide and 1,8-dihydroxy-4- hydroxymethyl anthraquinone. The herb has the functions of expelling winds, eliminating dampness, enlivening branch meridians, stopping pains, killing worms and detoxifying. Clinically it is applied to the treatment of rheumatic arthritis, lupus erythematosus, chronic nephritis, nephrotic syndrome, psoriasis, etc.[45] Owing to its toxicity, this herb has comparatively more liver damage cases. In China in a period of 15 years from 1983 through 1998, statistics on liver damages caused by traditional Chinese medicines shows that among single Chinese herb drugs, it is Tripterygium wilfordii that has caused the most cases of liver damages, which occupy 91 among 427 liver damages cases[46,4]. The poisoning symptoms include nausea, vomit, abdomenache, diarrhea, inappetence, hepatomegaly, percussion pain at the liver and kidney area, etc. The liver's pathological changes are fat sedimentation in liver cells, lobular central necrosis, inflammatory cell infiltration at the portal area, proliferation of fiber tissue and cholestasis, which indicates Tripterygium wilfordii has direct harm to liver cells[47,15].

5.     Dioscoreae Bulbiferae Rhizoma (Dioscorea bulbifera)

This item is the dried tuber of the Dioscoreous plant, Dioscorea bulbifera, which has a bitter taste and a cold nature. The herb contains diosbulbins and diosgenin and possesses the functions of disintegrating masses, resolving goiter, clears heat, detoxifying poisoning, cooling blood and arresting bleeding. It is commonly used in treating goiters, throat swelling pain and alimentary tumors[48,49]. Dioscorea bulbifera is one of the single Chinese herb drugs that causes comparatively more cases of liver damages[50,51]. A statistic data shows that in a total of 427 cases of Chinese herb drug-induced liver damages, 46 cases were caused by Dioscorea bulbifera[4]. Another literature source of quantitative analysis shows that the liver damages cases caused by Dioscorea bulbifera occupy 23.16% (16/69) of all Chinese herb drug-induced liver damages cases[52]. The chief poisoning symptoms in its liver damages are inappetence, adynamia, nausea, jaundice, hepatosplenomegaly, and maybe the presence of high fever, skin red patchy maculation as well as hepatic dysfunction marked by elevated ALT and AST. The daily dose to induce liver damages is 15~36g or a total dose of 90~3,500g. Sources indicate that at a daily dose of 30 g or a total dose of 600~1,000g, the incidence of liver damages is 53%[53,54]. Toxicological test on animals fed with Dioscorea bulbifera found that the mice's liver cells displayed fat degeneration small focal necrosis and lymphocytic and acidocytic infiltration at the portal area. The severity of liver damages is closely related to the dose and length of time of administration[54,55]. The toxic constituents of this herb drug are dioscin, diostoxin and diosgenins[15,56]. The poisoning mechanism could be the direct action of these toxic constituents on the liver cells.

6.     Meliae Fructus (Melia toosendan)

This item is the dried fruit of the Meliaceous plant Melia toosendan, which has a bitter and acrid taste, a cold nature and a little toxicity. It contains triterpenes such as toosendanin and isotoosendanin, and possesses the functions of relieving the liver, moving chi (qi), stopping pain, and expelling worms. Clinically it is used for peptic ulcer, gastritis, mastitis, pelvitis, appendicitis, ascariasis, cholangitis, etc.[57,58] The whole plant of Melia toosendan is toxic with the toxicity of the fruit being stronger than that of the root. The toxic constituents are toosendanin and toxoprotein. The poisoning dose of the herb is close to the effective dose. Eating just 6~8 fruits will readily induce severe poisoning. The toxic effect is chiefly in central inhibition and liver damages. Liver damages are manifested in the symptoms and body signs of acute toxicotic hepatitis, with which the patient has mental weariness, adynamia, inappetence, abdomen ache, hepatomegaly, jaundice, and elevated transferase and serum total bilirubin. Histological changes are liver congestion and liver cell fat degeneration. Animal experiment can find liver cell swelling and degeneration, shrunk cell nucleus, chromosomes fused into patches and stenosis of liver sinus. The toxicity may increase with increase of single dose[5,10,57,59]. Deaths from poisoning by Melia toosendan are not due to liver damages but chiefly due to respiratory paralysis and acute circulatory failure[57].

7.     Other single Chinese herb drugs liable to induce liver damages

According to reports, the following single Chinese herb drugs are also liable to induce liver damages: Xanthii Fructus, Galla Rhois, Granati Pericarpium, Artemisiae Argyi Folium, Polygoni Multiflori Radix, Duchesneae Herba, Cassiae Occidentalis Semen, Ardisiae Herba, Loranthi Ramulus, Typhae Pollen, Trichosanthes Radix, Rhei Rhizoma, Ilicis Folium, Indigo Pulverata Levis, Ricini Semen, Litharge, Ginkgo Semen, Blechni Rhizoma, etc.[4,8,52,54]

Chinese herbal formulas liable to induce liver damages

Chinese herbal formulas are the traditionally accepted form of Chinese herb drugs for treating diseases and are the essences of traditional Chinese medicines. According to the guidelines of the Five Elements theory, different types of herbs are put together in a formula for the purposes of enhancing therapeutic effects and reducing adverse effects. In Asian areas, herbal formulas are used more popularly than single herb drugs. Chinese herbal formulas are further divided into two categories: One is the traditional Chinese herbal formulas which have been used and clinically validated for several hundred years or even several thousand years. They have positive therapeutic effects and less toxic side effects. Even if they have toxic effects, such effects have been recorded in the literature that records also the preparation, dosage and clinical contraindications. Among herbal formulas of this category, very few can induce liver damages. The more noticed are the adverse effects of Hsiao Chai Hu Tang (Minor Bupleurum Combination) and similar formulas, which have more reports in Japan. The reported occasions are 5 cases with Hsiao Chai Hu Tang (Minor Bupleurum Combination) and one case each with Chai Pu Tang (Bupleurum and P.M. Combination) and Hsiao Chai Hu Chia Chie Keng Shih Kao Tang (Bupleurum, Platycodon and Gypsum Combination)[54,60]. In China, analyses of herb drugs-induced liver damage cases indicate that cases associated with Hsiao Chai Hu Tang occupy 2.89% (2/69)[52]. In addition, other traditional Chinese herbal formulas that have caused liver damages also include Ta Huang Mu Tan Pi Tang (Rhubarb and Moutan Combination), Fang Feng Tung Sheng San (Siler and Platycodon Formula) and Shih Wei Pai Tu Tang (Bupleurum and Schizonepeta Combination)[54,60]. Liver damages induced by traditional Chinese herbal formulas usually appear in patients suffering from chronic liver diseases or in mid-aged and old aged individuals who have been under medication for a long time. For example, Hsiao Chai Hu Tang itself is a commonly used formula for treating liver diseases, and it is therefore not a clever practice to administer this formula under the circumstances of long-term medication to patients with impaired liver functions. The other category of Chinese herbal formulas is the newly developed formulas such as Zhuang Gu Guan Jie Wan[61], Gan Ji San[62], Xiao Yin Pian[63], etc. Such new formulas are very therapy specific and yet lack support for their safety by large scale and long-term clinical verification. Some toxic side effects of these formulas gradually appeared only during their applications. Among a few major issues of large scale liver damages induced by Chinese herb drugs, these formulas are usually statiscally listed atop others For example, among 427 cases of Chinese herb drug-induced hepatic damages, 111 (26.00%) and 14 (3.28%) were induced respectively by Zhuang Gu Guan Jie Wan and Gan Ji San[46]. In another source, the two formulas caused 30.45% and 15.94% of liver damages respectively[52].

Factors associated with the episodes of herb drug-induced liver damages

The liver takes upon itself a very important role in drug metabolism. Under normal condition, an absolute majority of drugs are transformed and excreted by the liver. If the liver is in a diseased state, the administration of highly hepatotoxic drugs and long-term medication to result in accumulation or overdose may cause poisoning, and as a consequence adverse effects and liver damages ensue. Statistic figures show that acute liver damages (93%) number the most among liver damages induced by Chinese herb drugs. The causes are attributable to the use of peculiar prescr