In the course of long-term practice, the Chinese people have accumulated rich experience in using herbal medicines to treat various diseases, and natural medicines have become the main means of Chinese medicine to treat diseases. While attention is paid to the efficacy of drugs, the observation of possible adverse reactions has always been emphasized. What is natural is not necessarily safe and harmless. Like other drugs, herbal medicines can have toxic side effects and adverse reactions. There are more than 350 plants worldwide that contain hepatotoxic alkaloids, and Europe and the United States have also learned the hard lesson of hepatotoxicity caused by wild stonewort for weight loss and cordyceps for health care and alcohol withdrawal. The incidence of liver damage caused by Chinese herbal medicines accounts for 32.6% of pharmacogenic liver diseases. According to the comprehensive domestic literature, from 1986 to 2002, more than 800 cases of liver damage caused by Chinese herbal medicines were published in domestic journals, and the trend is increasing year by year. Recently, some people have included adverse reactions to Chinese medicine as one of the “three scourges” of adverse drug reactions. In recent years, the composition of liver damage caused by various types of drugs: 33,7% of anti-TB drugs, 23,7% of Chinese herbal medicines, 10,8% of antipyretic and analgesic drugs for the first three. The classification of the primary diseases treated on herbal medicines causing liver damage: 33,4% for bone and joint, 25,9% for kidney diseases, 20,3% for dermatology, and 7,3% for thyroid diseases are the top four.
How can we look at the adverse effects of natural medicines? First of all, we must distinguish the difference between Chinese herbal medicine and herbal medicine: Chinese herbal medicine is a safer medicine, which is formulated and used under the guidance of Chinese medicine theory, and is entered into the national pharmacopoeia after thousands of years of medical practice, strict processing and preparation, and theoretical contraindications, while herbal medicine is a natural plant used by folk according to their experience to treat or relieve a certain disease.
In ancient times, there were different concepts of the “toxicity” of drugs.
1. In early times, the term “poison” referred to all medicines that could cure diseases.
2, drug “toxicity” also refers to the odor bias.
3, specifically refers to the toxic side effects harmful to the human body, such as “Shen Nong Ben Cao” contains 365 kinds of drugs. According to the efficacy and toxicity of the upper grade – non-toxic; middle grade – non-toxic toxic, discretionary; lower grade – multi-toxic can not be taken for a long time.
The “18 anti” and “19 fears” in Chinese medical literature indicate that the ancients have paid attention to the toxic side effects that can occur when combining certain drugs. The herbal medicine is used by the folk with the same thing different names, the same name different things are more common, adverse reactions are difficult to track and observe, not to mention the pharmacological toxicology experiments.
The classification of side effects of natural drugs common.
1, side effects.
2, toxic effects.
3, allergic reactions.
4, idiosyncratic reactions.
5. dependence.
6, carcinogenicity and teratogenicity.
7, mutagenic.
However, the liver damage caused by not only the incidence of significantly increased, but also the high mortality rate, is well worth the attention of clinical workers. In particular, the abuse, misuse, long-term overdose, nutrition and fitness health care drinking, and bright room prescriptions and other poisoning occur more opportunities. Therefore, it is important to recognize the characteristics and mechanisms of the pathogenesis of pharmacogenic liver damage, to strictly apply the principles of medication, to pay attention to the contraindications of compounding, and to ensure the safe use of medication to reduce the occurrence of pharmacogenic liver disease.
The main causes of adverse reactions
I. Problems in the use of both doctors and patients.
1. Overdose: misleading traditional concepts and advertising. Chinese medicine is non-toxic, no side effects, no harm in overdose. Huang Yao Zi causes drug liver, ginseng 60g causes blindness, etc.
2, the drug is not the right medicine: set aside the essence of the clinical use of Chinese medicine, the identification and treatment of the cold in the hot …… and other principles of drug use.
3, misuse of drugs, influenced by the misconception that Chinese medicine can have a disease cure, no disease tonic body.
4, the duration of the drug is too long, so that the accumulation of poisoning. Such as licorice for a long period of time to pseudo-aldosteronism.
5, improper drug combination: improper combination of Chinese medicine is not yet rare. The combination of Chinese and Western medicines cause adverse reactions increasingly attract attention. Such as ephedra and eugenol, gypsum and cardiac glycosides.
In short for both doctors and patients lack of awareness of the potential hepatotoxicity of certain herbal medicines and their preparations.
Second, the problem of the drug itself.
1, the pharmacological effects and chemical composition of the herbs. Glycyrrhiza glabra water sodium retention, potassium excretion, etc.
2. Confusion of herbal species and misuse of misuse. Mouton Tongcao mixed, wide Fangji (Aristolochiaceae) instead of powder Fangji, used in Europe for diet pills, causing more than ten cases of kidney failure, etc.
3, the quality of herbs: the environment, harvesting season, medicinal parts, storage and transportation, etc. can affect the quality. Such as environmental pollution to drug heavy metal content exceeds the standard, improper storage and transportation of drug mold, etc..
4, improper preparation decoction, itself in order to reduce its toxic side effects, not according to the protocol counterproductive.
Third, the organism factors.
1, gender: the incidence of female than male.
2, age: the elderly, young children are higher than young adults.
3, special physiological and pathological conditions: pregnancy, lactation, liver and kidney dysfunction.
4, individual differences. We have seen some clinical cases of menstrual disorders or spermatorrhea caused by the use of angelica.
Classification according to the type of damage to the liver manifestations.
1, drugs that can cause hepatocyte-type damage
The main types of drugs that can cause hepatocellular damage include Huang Yao Zi, Cang Er Zi, Castor Root, Tu San Qi, Crow’s Gall Bladder, Wu Bei Zi, Chuan Neem, Lei Gong Vine, Qian Li Guang, Ai Ye, Bletilla, Fang Ji, Qing Dai, Da Huang, Ze Di Di, Jiang Han Xia, Sang Sang Sang, Di Yu, Mitra Sinensis, Hu Zong, Pomegranate Bark, Sour Date Root Bark, Smallpox Powder, Xiong Huang, Arsenicum, Compound Qing Dai Zi, Nong Jili (Wild Lily), Fish Gall Bladder, Pu Huang, etc.
2. Drugs that can cause cholestasis or mixed type
Chinese herbs that can cause cholestatic or mixed liver damage include Cang Er Zi, Guan Zong, Red Fennel, Copper Green, Compound Dan Shen Injection, Strong Bone Joint Pill, Jin Guo Lan, etc.
According to the main toxic components and chemical properties of herbal medicines
Alkaloids, alkaloids are a class of heterocyclic compounds with complex structure containing nitrogen, and their toxicity, in addition to damage to the nervous system, in recent years it was found that the alkaloids that can damage the liver are not uncommon, and can be divided into the following species.
1, containing hydroxybipyrrolidine alkaloids
Chinese herbal medicines containing hydroxybipyrrolizidine alkaloids include wild lily, thousand-lipped light, earth panax notoginseng, big white top grass, cat’s tail and so on. These alkaloids are converted into pyrrole derivatives by the action of cytochrome P450 after ingestion, and this unstable metabolite can cause tumorigenesis in experimental animals, in addition to causing measurement-related liver damage. Acute intoxication resembles the manifestation of hepatitis, while chronic intoxication resembles the manifestation of cirrhosis.
2. Containing Yianhuosuo
Chinese herbal medicines containing yanhuosuo include yuan hu and jin buxue, which are often used as analgesics without paying attention to their hepatotoxicity. It is found that acute hepatitis occurs in healthy people after 20 weeks of taking such drugs, so these alkaloids have direct toxicity to liver cell metabolism.
3. Ephedrine
Ephedrine contained in the Chinese medicine ephedra, the central nervous system, cardiovascular and respiratory system have excitatory effects, in addition to headache, dizziness, tremor, arrhythmia and hypertension, but also found toxic hepatitis reports.
4. Other herbs containing alkaloids
Other herbs containing alkaloids include Radix Rehmanniae, Aconite, and Changshan, etc., which have been reported to cause toxic hepatitis or chronic liver damage.
Glycosides
Glycosides are composed of sugar and non-sugar parts, and the non-sugar parts are called glycosides, which can be divided into saponins, flavonoid glycosides, cardiac glycosides, cyanogenic glycosides, etc. according to the structure of glycosides. Chinese herbal medicines containing saponins and flavonoid glycosides such as huang yao zi, chai hu, guan dou roots, wu hua, baicalin, etc. can cause liver damage. Huang Yao Zi can both damage liver cells and affect bile secretion, the severity of liver damage is related to the measurement, most of the total amount of 500 ~ 1500g into the disease, the onset of severe symptoms. It is related to its toxic components Diosgenin, Diosgenin, Huang Duxin, Huang Toxin Terpene A, B, C, etc. The manifestations of scutellaria, chai hu, atractylodes, and senna damaging the liver are all related to their related glycosides and manifest as toxic hepatitis or hepatic necrosis. Huang Yao Zi damaged the liver in the second place among single drugs, with 46 cases reported in the domestic literature.
Terpene-containing and lactones
Terpene- and lactone-containing drugs have complex structures, including chemicals with acids and phenols. The representative drugs are Radix et Rhizoma, Neem, Aesculus, Cassia, and Guanzhong. The diterpenoids, triterpenoids, and sesquiterpenoids in Radix et Rhizoma have damaging effects on the heart, liver, and kidneys, and can cause toxic hepatitis and chronic liver damage. 91 cases of liver damage due to Radix et Rhizoma have been reported in the domestic literature, ranking first among single herbs that damage the liver.
Neem is toxic to the whole plant, and its toxic components contain neemin and neem terpene lactone, which can stimulate and damage the gastrointestinal mucosa and act on the liver after absorption, manifesting as poor appetite, nausea, vomiting, abdominal pain, diarrhea, hepatomegaly and jaundice. Mugwort mainly contains volatile oil and bitter mugwort, which can cause toxic hepatitis in addition to stimulating the intestinal tract when taken internally.
Toxic plant proteins
These plant proteins, mostly present in the seeds, with the role of cytoplasmic toxicity, such as celery seeds, castor seeds, oleander seeds, Wang Jiangnan seeds, toxic effects not only damage the liver, but also damage the gastrointestinal mucosa and kidneys.
Animals and minerals
Animal herbs such as red maidenhair, fish bile, pig bile, toadflax, pangolin, centipede, as well as mineral herbs such as strophanthus and mitragynine can cause toxic liver damage.
Chinese herbal medicines with liver damage in animal experiments
According to the National Compendium of Chinese Herbs and the Dictionary of Traditional Chinese Medicine, herbs with hepatotoxicity (mostly tested on animals) include white flower, salvia, five-colored plum, clove, staunton, eucommia, dafengzi, big white top grass (containing alkaloids of silybin), silybin, smallpox powder, wintergreen leaf, nutmeg, helianthus bark, wheat horn, rue, musk, seven-leaved one flower, wintergreen grass, hippophae, etc., in which toxic ingredients have been proposed. The above herbs with hepatotoxicity should not be used in combination with western drugs with liver damage, and the combination can aggravate the hepatotoxic reaction. There are also compound herbal medicines with positive drug lymphocyte stimulation test, while single drugs are negative, such as Ge Gen Tang, which may be the result of interaction.
Drugs containing hydrolyzed tannins
Five times, chebul, pomegranate bark, sour date root bark, tiger scepter, tiger puff leaf, Huang Cang leaf, oak bowl, etc. all contain hydrolyzed tannins, which have serious toxic effects on the liver, and these drugs can also be absorbed when used in topical burns, causing severe central hepatic lobular necrosis.
Chinese medicine damage to the liver, Chinese medicine is a compound preparation, due to the convenience of taking and carrying, in recent years the application is very widespread, causing adverse reactions are also gradually increasing reports. The most prominent ones that cause liver damage are: Strong Bone and Joint Pill, Noma Jie San, Compound Qing Dai Pill, Ke Yin Pill, Xiao Jin Dan (Tablet), Shou Wu Tablet, Zeng Sheng Ping, Ruminative Pill, Kunming Shan Hai Tang, Yin Qi San, Liushen Pill, and Shou Bone Powder, etc. The other ones can be seen as Damp Poison Qing, Shou Bone and Tendon Capsule, Yang Bao Xuan Tendon Capsule, Bone and Immortality Tablet, Women’s Health Tablet, Hualu Pill, Shuang Huang Lian Oral Liquid, Yin Qiao Tablet, Chuan Xun Ning Injection, Ginseng and Bai Zhu Pill, Niu Huang detoxification tablets, etc. Several proprietary Chinese medicines that cause more liver damage are the following.
1.Strong Bone and Joint Pills
The drugs that damage the liver in Strong Bone and Joint Pills are mainly Doklam and Epimedium. The active ingredients bergamot lactone, parsleyol methyl ether, parsley genus B, and pepper toxin in Doklam are directly damaging to liver cells. The pathological changes are swelling of hepatocytes, steatosis, etc. Epimedium has androgen-like effects that interfere with the metabolism of liver cells and interfere with the excretion of bile, which can cause cholestasis.
2.Chanjisan
It is a very good idea to use it for the first time.
3. Qing Dai Pill
Compound Qing Dai Wan (capsule) contains Fu Ling, Dan Shen, Atractylodes and Jian Qu. It is used for the treatment of psoriasis, which causes liver damage manifested as hepatitis type, and the pathology is dominated by hepatocyte necrosis.
4.Legongteng Tablets
Leigongteng tablets are mostly used for the treatment of rheumatoid arthritis and nephropathy, manifesting as single liver function abnormalities, such as elevated transaminases, and jaundice occurring in a few cases.
5.He Shou Wu Tablet
He Shou Wu Tablet is used for anti-aging, skin care and fitness. Its main component is anthraquinone derivative, which has toxic effects on the liver. Causes liver damage manifested mainly by mild or moderate jaundice.
6.Lix Shen Wan
The Ming Xiong Huang in Liushen Pill contains toxic arsenicals, which can cause arsenic poisoning after long-term or large consumption. The drug can accumulate in the body and act as a protoplasmic poison, causing liver, kidney and multi-organ damage. The toadstool in the formula contains toadstool poison, which has digitalis-like effects.
7.Xiao Chai Hu Tang
Xiao Chai Hu Tang is composed of seven herbs: Chai Hu, Radix Panax, Ginger, Scutellaria, Jujube, Ginseng (or Dang Shen) and Licorice. Chai Hu can change the surface of cell protoplasm and is therefore a protoplasmic poison. New research suggests that liver damage is more likely to be related to the protoplasmic toxicity of Scutellaria baicalensis.
8.Other
Other Chinese patent medicines with liver damage that have been reported in the literature less frequently include Shu Feng Ding Pain Pill, Fang Feng Tong Sheng Pill, Dragon Snake Chasing Wind Capsules, De-Feng Pill, Blood Poison Pill, Jiu Li San, Chasing Wind and Bone Pill, Compound Dan Shen Injection, Ge Gen Injection, Ma Ren Shi Gan Tang, Ning Hong Weight Loss Tea, Anti-thirst Pill, Neem Tablet (Deworming), Qian Li Guang Injection, Clove Oil, Nasal Kang Tablet, Piglet Polysaccharide, Ginseng and Mai Injection, etc.
Diagnosis and treatment of liver damage by natural drugs
I. Diagnosis of liver damage from natural drugs.
1, liver function damage generally appears 1 to 4 weeks after taking the drug, and may also appear several months or even longer after taking the drug.
2, clinical symptoms may include fever, joint pain, rash, scratching, jaundice, etc.
3.There are clinical or pathological signs of intrahepatic cholestasis or damage to hepatic parenchymal cells.
4, Positive leukocyte movement inhibition test or lymphocyte transformation test.
5, Hepatitis virus markers are all negative.
6, Occasionally, if the drug is given again, liver damage can occur again.
Differential diagnosis
Pharmacogenic liver damage should be distinguished from viral hepatitis, alcoholic hepatitis and autoimmune hepatitis. In addition, in some systemic diseases that can be accompanied by liver damage, liver damage occurs when taking drugs, attention should be paid to distinguish whether the original disease is accompanied by liver damage, or pharmacogenic liver damage.
1, and viral hepatitis points of differentiation
①Acute pharmacogenic liver damage must be distinguished from hepatitis A and E. The latter two have a history of hepatitis exposure. The latter two have a history of exposure to hepatitis and often dine out or travel history. Hepatitis A and E may have fever at the beginning of the disease, and the body temperature usually returns to normal in 3-5 days, but the gastrointestinal symptoms increase and jaundice appears; pharmacogenic liver damage usually appears first with gastrointestinal symptoms, fever at the same time as liver damage, and is accompanied by rash, itching, joint pain and other allergic manifestations.
Chronic pharmacogenic liver damage must be differentiated from hepatitis B and C. Hepatitis B and C are mostly insidious and have a family history of liver disease or blood transfusion.
③No history of drug use and drug allergy
④Hepatitis virology test is positive.
2.The main points of differentiation with alcoholic hepatitis
①Patients with alcoholic hepatitis have a history of long-term heavy alcohol consumption; patients with pharmacogenic liver damage have a history of taking medication.
②Patients with alcoholic hepatitis mostly have alcoholic peripheral neuropathy damage; patients with pharmacogenic liver damage may have rash, pruritus and other allergic manifestations.
③Serum γ-GT is significantly elevated and AST/ALT is elevated in patients with alcoholic hepatitis.
④After quitting alcohol, alcohol withdrawal reaction is obvious in patients with alcoholic hepatitis, and liver disease improves after quitting alcohol; liver function improves after stopping drugs for pharmacogenic liver damage.
3. Points of differentiation from autoimmune liver disease.
(1) Autoimmune hepatitis is mostly seen in women.
(2) Often accompanied by extrahepatic systemic manifestations.
(3) Accelerated blood sedimentation and markedly elevated serum globulin.
(4) Autoantibody test is positive, and lupus cells can be detected in 30% of patients.
(4) Identify whether the liver damage is associated with the original disease or caused by the treatment drugs.
(1) If there is no liver damage or liver damage is not obvious before treatment, and if the primary disease improves after treatment and liver damage appears, it should be mostly considered as pharmacogenic liver damage; if there is aggravation of the primary disease, it should be mostly considered as liver damage associated with the original disease.
(2) After the occurrence of liver damage, change the original treatment plan and pay attention to the use of drugs with less liver damage. If the liver damage is reduced after the original drug is discontinued, drug-derived liver damage is mostly considered; if the liver damage does not improve after the drug is discontinued, attention should be paid to the liver damage that may be associated with the original disease.
Prevention and treatment
In view of the current causes and status of liver damage caused by natural drugs, our future clinical work should pay attention to the following aspects.
1, the correct understanding of the toxicity of herbal medicines, strict dose, regimen, dosing, route of administration and other aspects to prevent the occurrence of poisoning.
2.Particular attention should be paid to those who have a history of allergy, old and frail, and those with unsound liver and kidney functions.
3. Monitor toxic side effects during drug administration and regularly measure blood, urine and liver function tests.
4.Once rash, jaundice and abnormal liver function are found, the drug should be discontinued immediately.
5.Discontinue the use of disease-causing herbs.
6.Supportive therapy: bed rest, application of vitamin B and vitamin C. In addition to symptomatic treatment for severe gastrointestinal symptoms, intravenous infusion of hypertonic glucose solution. Maintain water-electrolyte balance.
7, obvious biliary siltation can be treated with adenosine nitrate and ursodeoxycholic acid.
8.For fulminant hepatic failure, treat according to the principles of fulminant hepatitis treatment.
9.Reduced glutathione (GSH) has better efficacy for certain drugs liver disease, can be injected intravenously 600mg/d for 2-4 weeks as a course of treatment.
10, accelerate the excretion of drugs, such as acute poisoning can be given gastric lavage, diarrhea, activated carbon adsorption, etc., but also through osmotic diuresis, hemodialysis, etc.