Advances in Studies on Treatment of Hepatic Fibrosis with Dai and Western Medicine

Yuanmei BAI, Lijie ZHENG, Haimei WU, Peixin GUO*

1. Yunnan University of Traditional Chinese Medicine, Kunming 650500, China; 2. The Second Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou 510000, China

Abstract Hepatic fibrosis is a necessary stage in the development of chronic liver disease to cirrhosis. Western medicine drug treatment takes etiological treatment, symptomatic treatment and anti-fibrosis treatment as the main means and aims to protect the liver and improve hepatic function while there are many adverse reactions after long-term administration. However, Dai medicine mainly focuses on balancing the four towers and five aggregates, and regulating the "three plates". Hence it has slight side effects and is safe and effective. Therefore, this paper reviewed the current status of Dai and Western medicine in the treatment of hepatic fibrosis, in order to provide reference for clinical medication.

Key words Hepatic fibrosis, Dai medicine, Western medicine, Research progress

1 Introduction

In modern medicine, it is believed that hepatic fibrosis is a joint result of factors such as viruses, autoimmune diseases, drug-induced,etc., resulting in the proliferation of hepatic stellate cells, the main effector molecules in hepatocytes. Hence it stimulates the deposition of a large amount of extracellular matrix (ECM) mainly composed of collagen, and thus induces the development of hepatic fibrosis[1]. Liver cirrhosis is the end-stage of progressive liver fibrosis. According to statistics, hepatic fibrosis affects 1%-2% of the global population and leads to more than 1 million deaths worldwide every year, seriously affecting people’s quality of life and increasing family economic burden[2].

2 Advances in western medical treatment research

2.1 Etiology and pathogenesis

2.1.1Autoimmune hepatic fibrosis. Immune complexes formed by autoimmune diseases bind to FC receptors (the Fc receptor) on the surface of hepatocytes and are deposited in hepatocytes, causing abnormalities in their metabolism, which leads to the development of autoimmune hepatic fibrosis through the release of pro-fibrotic factors and thus the activation of HSC[3]. Abnormal autoimmune reactions are the common pathogenetic basis of hepatic fibrosis, including autoimmune hepatitis, primary biliary cholangitis and primary sclerosing cholangitis[4-5].

2.1.2Viral hepatitis. Viral hepatitis is mainly caused by chronic hepatitis B and C. Hepatitis B accounts for the majority of cases in China, about 10%-20% of which develop cirrhosis[6]. The mechanisms of HSC activation induced by hepatitis virus are as follows: (i) after acting on human hepatic stellate cells and activating the paracrine pathway, hepatitis B X protein (BHx) activates the paracrine pathway, regulates the transforming growth factor-β (TGF-β) signaling pathway, and induces interleukin-11 (IL-11) expression, thereby promoting the proliferation of HSC leading to the development of hepatic fibrosis[7]; (ii) hepatitis C virus (HCV) infection promotes mitochondrial damage, and increases oxidative stress; and iron overload is also closely associated with the degree of histological damage and increased number of HSC in HCV-infected patients, promoting the development of hepatic fibrosis[8]; (iii) human immunodeficiency virus (HIV) infection leads to increased oxidative stress, apoptosis of hepatocytes, direct viral effects, dysregulation of immune factors and intestinal failure of HIV-associated CD4 cells, resulting in the activation of HSC that will lead to the development of hepatic fibrosis[9-10].

2.1.3Fatty hepatic fibrosis. Obesity, insulin resistance, diabetes mellitus, and metabolic syndrome caused by nonalcoholic fatty liver disease (NAFLD) are closely associated with the degree of fibrosis in NAFLD[11]. In the process of nonalcoholic hepatitis, pro-fibrotic factors, platelet-derived growth factors can activate various signaling pathways (e.g., Wnt/β-catenin signaling pathway, Notch signaling pathway, and Hedgehog signaling pathway) to promote HSC proliferation, leading to hepatic fibrosis[12].

2.1.4Alcoholic hepatic fibrosis. The alcohol metabolite acetaldehyde inhibits killer cell-mediated γ-interferon, which induces activated HSC death-mediated hepatocyte injury and induces degradation that inhibits fibrosis[13]. Alcohol stimulation can affect viral replication and cytotoxicity, and produce oxidative stress affecting immune regulation, thereby accelerating the development of hepatic fibrosis[14].

2.2 Western medical treatmentCurrently, no chemical or biological agents with definite efficacy have been found for the western medical treatment of hepatic fibrosis. Its therapeutic measures mainly include: (i) treatment for the cause: in antiviral therapy for viral hepatitis, alcoholic hepatitis should be abstained from alcohol, fatty hepatic should adjust dietary habits and appropriately exercise, and autoimmune hepatitis should apply hormones combined with immunosuppressants; (ii) targeted therapy: therapeutic drugs such as sorafenib induce autophagy and apoptosis of HSC mainly through JNK and Akt signaling pathways, thus inhibiting the progression of hepatic fibrosis[15]; (iii) anti-fibrotic therapy: colchicine can inhibit the secretion of pro-collagen molecules to reach anti-fibrosis; interferon, adrenocorticotropic hormone, and malotilate can inhibit and reduce collagen synthesis or accumulation[16]; rilpivirine can selectively induce HSC apoptosis by activating STAT1 and promote hepatocyte proliferation by activating STAT3, showing significant anti-inflammatory and anti-fibrotic effects[17].

However, there are greater side effects or adverse reactions of the above drugs, for instance, colchicine can lead to renal damage seen as hematuria and oliguria[18], and rilpivirine can lead to cholecystitis and cholelithiasis in patients[19]. Therefore, it has become a research hotspot to find solutions from traditional medical treatments and prescriptions. Dai medicine antidotes (detoxification prescriptions) have obvious therapeutic advantages because they have good therapeutic effects on hepatic diseases in clinical applications with the characteristics of multi-component, multi-pathway and multi-target.

3 Advances in Dai medical treatment research

3.1 Etiology and pathogenesis of Dai medicineIn Dai medicine, the four towers (earth, water, fire, and wind) and the five aggregates (color, consciousness, receptivity, thought, and action) are taken as the theoretical core. And they interact with each other to jointly maintain human life and health activities[20]. In Dai medicine, it is believed that the main physiological function of the Dai (liver) is to regulate the blood movement of the human body to nourish the human body and metabolize and excrete poisons. The bile produced by Dai (liver) is a component of Tatan (water and blood), which can promote food digestion[21]. This disease is mainly caused by the dysfunction of the four towers and the five aggregates with the Talong (wind and fire) being in abundance, the Tanan (water and blood) and Tafei (fire) being insufficient, and the Taling (earth) being congested, coupled with the external "Payalonghuang, Payalongga"(wind-heat, wind, and cold evil) or the simultaneous disease of the three pagodas, and the inability to transport and excrete water and dampness, the abnormal gallbladder, the stagnation of the liver and spleen, resulting in head and face thick and greasy, poor diet, weakness and shortness of breath, belching and vomiting, thin and weak body. Secondly, the patient may suffer from uncontrolled diet, overeating, excessive alcoholism, obesity, diabetes mellitus, or misuse of food that is not clear, or suffering from other diseases, mismanagement, improper treatment, the combination of internal and external, damage to the four towers, resulting in the swelling and pain of the ribs, the white and greasy fur, the poor diet, the lack of energy and shortness of breath, the nausea and vomiting of belching, and the thin body. Also it is due to improper diet, overeating, excessive drinking, obesity, diabetes, and eating unclear food by mistake. Or suffering from other diseases, losing treatment and mistaking treatment, improper treatment, internal and external consistency, damaging the four towers, resulting in the dysfunction of the four towers in the body. The wind and fire are insufficient to warm the whole body, the soil is insufficient to transport water moisture, and the water is insufficient to make fire. Therefore, the skin and the whole body are overflowed and the disease occurs[22].

3.2 Dialectical treatmentAccording to Dai medicine, in the process of living and treating diseases, various internal and external pathogenic factors can lead to the imbalance and physiological disorder of the four towers and five aggregates, and the disharmony of the four towers produces various toxins, leading to the development and deterioration of diseases[23]. In clinical practice, it is usually guided by the "elegant solution" theory of "detoxification before illness and treatment after detoxification". The main point of treatment is to detoxify the toxin and relieve the bile, ventilate and relieve pain[24]. The solution and antidote are used to remove the accumulated toxins in the body and adjust the balance of the functions of the four towers and five aggregates. The key points of treatment are detoxification, cholagogic, ventilation and pain relief[24]. According to the clinical symptoms of hepatic fibrosis, it can be classified under the category of Dai medicine Andale (viral infectious hepatitis A), Andahao (viral infectious hepatitis B), Bandagaijie (swelling and pain in the hepatic and spleen), Daman (fatty hepatic), and Dabingdongfeisang (liver cancer), which are treated with antidotes respectively.

3.2.1Andale (viral infectious hepatitis A). (i) Andalehuang (febrile viral infectious hepatitis A). The treatment is to clear the fire and detoxify the toxin, benefit the bile, and reduce the yellow. The commonly used prescription of Dai medicine is Yajieshaba (Baijie capsule)[25]. The whole prescription consists of Jieyuan Mengla (Naiziteng) 90 g, Wenshanghai (bamboo leaf orchid) 70 g, Heitaohan (rhubarb vine) 35 g, Denghehan (Dingxin vine) 30 g, Yajie Xianda (Dabaijie) 25 g, Hebie (Puerarialobata) 25 g, and Sha Ying (licorice) 100 g. It is taken orally, 4-8 capsules each time, 3 times a day. In addition, the commonly used Dai medicine includes Xianlelong (treeCoptischinensis), Maishanhan (golden green bamboo), Xianfei (fragrant root), Heihan (rootless vine),etc.

(ii) Andalega (cold viral infectious hepatitis A). The treatment is to dissolve dampness with warm water, benefit the bile, and reduce yellow. The common prescription of Dai medicine is Buleixiaohuang powder. It is composed of Bulei (wild ginger) 15 g, Shagan (green vine) 10 g, Heha (red cardamom root) 15 g, pepper 5 g, small ginger 5 g, and black seeds 1 g. The powder is ground to 3-5 g each time, led by lemon juice and salt, and taken with boiled water.

3.2.2Andahao (viral infectious hepatitis B). (i) Andahao Talongruan (viral infectious hepatitis B deficient in wind and qi). The treatment is to clear the fire and detoxify the toxin, stimulate the bile, and reduce yellow. The commonly used prescription of Dai medicine is Yajiao Hadun (Wubao capsule)[26], which is composed of 15 g of inner tube bottom (Manjingzi), 15 g of Maxin Habu (Malian saddle), 15 g of Mabamenhong (bitter wax gourd), 15 g of Jilonglei (Diantiandong) and 15 g of Nahan (Yangerju). It is taken orally, 3-6 g each time, 3 times a day, and mixed with honey water.

(ii) Andahaotananruan (water-blood deficiency type viral hepatitis B). The treatment is to regulate the water-blood, and detoxify and bile. The commonly used prescription in Dai medicine is Yaxieshaba (Baixie capsule) (the composition and usage of the formula have been discussed previously)[25].

3.2.3Bandagaijie (swelling and pain in the hepatic and spleen). (i) Banda Gaijie Talongxiang (swelling and pain of the hepatic and spleen caused by excessive wind and qi). The treatment is to move along the qi and relieve pain through ventilation. The commonly used prescription in Dai medicine is Yaji Hutton (Five Treasure Capsules) (the composition and usage of the prescription are as discussed above)[27]. For those with hard stool, take honey. For those with insufficient earth pagodas, take rice soup.

(ii) Banda Gaijie Talongxiang (wind and qi deficiency type hepatic and spleen swelling and pain)[22]. The treatment is to regulate and supplement the four towers, ventilate qi and relieve pain. The commonly used prescription in Dai medicine is Biliang Lebeng Sanyu Xiaozhong decoction. The whole recipe consists of 5 g of bibilang (safflower pill) and 15 g of halebun (banyan root). It is taken with water and honey internally. In addition, commonly used Dai drugs include Habenliang (root of red flower and stinky peony), Haluomai Lianglong (root ofHibiscus), Gujima (fern of lotus root), Quhanhaonan (calamus),etc.

(iii) Banda Gaijie Talong Mangshang (water and blood does not run smoothly type hepatic and spleen swelling pain)[22]. The treatment is to regulate and supplement the four towers, ventilate qi and relieve pain. Dai medicine commonly used prescription for Mahe Huoxue Zhitong decoction. The whole recipe consists of 30 g of Hamahe (dishwashing leaf root), ground and washed with boiling water. In addition, for patients with hepatosplenomegaly and pain, take Dai medicine bibilang (safflower) and Hahangban (Phyllanthusemblicaroot) and grind them into wine for oral use.

3.2.4Daman (fatty hepatic). (i)Daman Tafenanxiang (fatty hepatic with excessive damp heat)[22]. The treatment is to clear the fire and detoxify the toxins, ventilate the blood, and protect the hepatic and bile. Commonly used prescriptions in Dai medicine are: (a) Yajie tablets[27]composed of Yaxiexianda (Dabaixie), Hebielong (Gegen), Nahan (Yangerju) and Sha Ying (licorice), and it is taken orally, 4-8 tablets each time, 3 times a day for 3 d; (b) Yaxiedali (Baogan Jiedu Decoction) composed of 20 g of Wenshanghai (Baiyangjie), 20 g of Neiguosong (hawthorn), 20 g of Danshen and 15 g of Xianle (ten Mahonia), and it is taken with water decoction.

(ii) Damantalongruan (wind and qi deficiency type fatty hepatic)[22]. The treatment is to tonify the four towers, ventilate the qi and eliminate swelling, activate the blood and relieve pain. Commonly used prescriptions in Dai medicine are: (a) Yalongganduanbingnei(swelling and pain elimination) composed of Liluohan (purple Manjusri orchid), Nanduanliang (acanthus bark) and Pendulum (reed leaf), pounded and fried with honey and wrapped externally; (b) Yabandajiegaibeng (Tonic ligament prescription) composed of 25 g of Bulei (wild ginger), 30 g of Hanhaonan (water calamus). Mash it and add water. Burn the pig iron red and immerse it in the medicine juice, and then take it orally or decoct it in water.

3.2.5DaBingdongfeisang (hepatic cancer)[22]. The treatment is to regulate and supplement the four pagodas, promote blood circulation and remove blood stasis, and relieve pain through ventilation. The commonly used prescriptions in Dai medicine are: (a) Yajieshaba (Baijie capsule) (the composition and usage of the prescriptions are as discussed above)[26]; (b) 10 g of Hanhaonan (Calamuscalamus), mashed, fried with rice washing water and lard, and then outsourced. In addition, take 5 g of bibilang (safflower) and 15 g of haleban (banyan root). Decoct in water and take orally with honey.

4 Discussion

Hepatic fibrosis is closely related to the proliferation of hepatic stellate cells and to the deposition of collagen-based extracellular matrix, but the specific pathogenesis has not been clarified. The treatment is based on etiological treatment, symptomatic treatment and anti-fibrotic treatment and aims to protect the hepatic and improve hepatic function. The lack of specific therapeutic drugs and the adverse effects of drugs commonly used in the treatment of hepatic fibrosis have made the western medical treatment of hepatic fibrosis face many difficulties[27]. According to Dai medicine, hepatic fibrosis is characterized by an imbalance of the four towers of Talong (wind and qi), fire (Tafei), and earth (Taling), or an overabundance of Tafei (fire). In clinical practice, the theory of "Yaxie" is usually applied, and the method of detoxification is used to release the accumulated toxins in the body and regulate the balance of the four towers and five aggregates[28].

In modern studies, it has been shown that the treatment of hepatic fibrosis by Dai medicine can slow down or reverse the process of hepatic fibrosis and restore hepatic function by reducing the four items of hepatic fibrosis, antioxidant free radicals, and anti-lipid peroxidation[29-31]. However, the current research on hepatic fibrosis in Dai medicine is based on pharmacodynamic experiments while the study of its mechanism is still not perfect. It is still in a single target and a single animal experiment, and can not systematically explain the mechanism and treatment of liver fibrosis. In view of the above mentioned problems, in the next stage of research, the specific mechanism of action of Dai medicine for the treatment of hepatic fibrosis should be elaborated more from proteomics, genomics, metabolomics,etc.for some Dai medicines and Dai prescriptions with definite efficacy in the prevention and treatment of hepatic fibrosis to promote the further development of the mechanism principles related to the treatment of hepatic fibrosis and the anti-hepatic fibrosis of Dai medicine.