Research progress of external therapies of traditional Chinese medicine in the treatment of non-alcoholic fatty liver disease

Chong-JieYao,Ling-Jun Kong,2, Qing-Guang Zhu,2, Yan-Bin Cheng,2, Zhi-Zhen Lv,Cheng Tang,MinFang,2,3✉

1. Yueyang Hospital of Integrated Chinese and Western Medicine, Shanghai University of TCM, Shanghai 200437, China

2. Tuina Research Institute, Shanghai Academy of Traditional Chinese Medicine, Shanghai 200437, China

3. College of Acupuncture-moxibustion and Tuina, Shanghai University of TCM, Shanghai 201203, China

ABSTRACT

Keywords:External therapies of traditional Chinese medicine Acupuncture Massage Non-alcoholic fatty liver disease(NAFLD)

Non-alcoholic fatty liver disease (NAFLD) is a clinical syndrome characterized by steatosis and increased lipid deposition in liver cells, which is caused by alcohol and other liver damaging factors [1].At present, NAFLD affects about 30% of the global population, and the prevalence rate is increasing year by year [2]. With the progress of the disease, about one third of NAFLD patients can develop from simple fatty liver disease to nonalcoholic steatosis hepatitis (NASH),and even further worsen to cirrhosis and liver cancer [3]. However,there is no specific drug for the treatment of NAFLD, mainly through changing the bad lifestyle and symptomatic treatment for related metabolic syndrome and liver injury, which helps to improve NAFLD to a certain extent, but how to balance the benefits and risks brought by long-term use of therapeutic drugs is still a problem [4].At present, the pathogenesis of NAFLD is not fully understood, but heterotopic fat accumulation in hepatocytes is the main pathological basis of its occurrence and development, which can be completed by a variety of mechanisms, including lipid metabolism, oxidative stress, and inflammatory reaction [5]. As the initial initiating factor of NAFLD, abnormal lipid metabolism of hepatocytes can promote the production of reactive oxygen species (ROS) and cell peroxidation,leading to a series of pathological changes such as the release of pro-inflammatory factors and inflammatory cell infiltration, thus further aggravating tissue damage [6, 7]. These complex mechanisms make there is no recognized standardized treatment scheme in the world, which brings challenges to the clinical treatment of NAFLD[8].

There is no disease name related to NAFLD in traditional Chinese medicine, but in clinical practice, it mostly belongs to “hypochondriac pain”, “fullness” and other categories for syndrome differentiation and treatment. Based on the overall concept of traditional Chinese medicine theory, it fully considers the relationship between viscera, Qi, blood, yin and Yang, and plays its unique advantages in clinical treatment [9]. Clinical studies have shown that [10-12], including acupuncture, moxibustion, massage and other external treatment of traditional Chinese medicine in NAFLD has obvious curative effect, can significantly reduce the blood lipid level of patients, improve liver function, so as to effectively alleviate clinical symptoms, but its mechanism has not been systematically explained. This paper aims to summarize the relevant research on NAFLD treated by TCM External Therapy at home and abroad in recent years, and analyze its possible mechanism of action, so as to provide scientific theoretical basis for future basic experiments and clinical research.

1. The regulating effects of external therapies of traditional Chinese medicine on abnormal lipid metabolism

Liver lipid deposition caused by lipid metabolism disorder is the direct cause of NAFLD. When the number of fatty acids entering the liver is greater than the amount of fatty acid oxidation and secretion, lipid will accumulate in the liver [13]. Acupuncture at specific acupoints can effectively regulate and promote the body's lipid metabolism. Acupuncture at Guanyuan can promote the accumulation of lipid in liver of mice, and thus inhibit the accumulation of lipid in liver of mice [14]. As an important point for resolving phlegm, electroacupuncture at Fenglong point can effectively improve hyperlipidemia; combined with Zusanli,Sanyinjiao and Taichong, it can down regulate the levels of total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL)and free fatty acids in NAFLD rats, FFA) and up-regulated high density lipoprotein (HDL). In addition, abdominal massage with the method of "harmonizing the liver and spleen" has also been proved to be effective in clinical practice [15]. Massage in Zhongwan,Guanyuan, Shuishui and Tianshu of NAFLD patients with pingbu pingxie technique can effectively improve TC, TG and alanine aminotransferase. In another study [16], by rubbing the whole abdomen with palm, pressing Tianshu, Daheng, Qimen, Guanyuan and Fenglong, and rubbing lumbosacral, the idea of treatment from liver and spleen was better reflected, and better curative effect was achieved.

In this series of processes, intervention in insulin resistance (IR) or regulation of lipid metabolism is the key. According to the classic“second strike” hypothesis of NAFLD pathogenesis [17], the “first strike” is initiated by IR, through the increase of fatty acid influx, the decrease of fatty acid oxidation and other ways, the accumulation of TG in the liver leads to the accumulation of liver lipid, which leads to NAFLD; while the “second strike” is the further oxidative stress and inflammatory damage on the basis of Pathology, which promotes the development of NAFLD. The development of NAFLD will aggravate IR by interfering with related signaling pathways,making IR interact with abnormal lipid metabolism, and jointly promote the progress of NAFLD [18]. Therefore, the regulatory effect of acupuncture and massage on lipid metabolism may be related to the improvement of IR. At present, a large number of clinical studies [19] have observed the curative effect of acupuncture in the intervention of IR, and confirmed that acupuncture can improve IR to a certain extent, significantly reduce fasting blood glucose and 2-hour postprandial blood glucose. Studies [20] have shown that electroacupuncture at Guanyuan, Zusanli, Zhongwan and other acupoints can effectively interfere with the metabolic mode of the body, inhibit appetite and increase insulin sensitivity, so as to reduce blood glucose and regulate lipid metabolism. Massage of abdominal acupoints can have a similar effect. It can improve the insulin sensitivity by increasing the fasting insulin content, reducing the IR index, fasting blood glucose, and serum ALT, TG, TC levels in patients with NAFLD [21].

2. The protective effects of external therapies of traditional Chinese medicine on oxidative stress injury

Under normal physiological conditions, the body has a perfect antioxidant system, free radicals and antioxidant factors maintain a dynamic balance, protect the body from oxidative stress damage.As an important link in the development of NAFLD, "second strike" can make its level exceed the scavenging capacity of antioxidant factors through excessive ROS production, leading to lipid peroxidation (LPO), which leads to the occurrence of NASH. Therefore, the antioxidant level in hepatocytes determines the development of the disease [22]. Among them, superoxide dismutase (SOD) is an important antioxidant factor, along with glutathione (GSH); and malondialdehyde (MDA) is the product of oxidative stress metabolic damage [23]. Studies [24] have shown that electroacupuncture at bilateral Housanli, Sanyinjiao, Pishu and Weiwanxiashu can reduce ROS and MDA in serum, increase SOD activity, protect mitochondrial structure and improve IR; in NAFLD rat model, electroacupuncture at bilateral Pishu, Shenshu and Geshu can increase SOD activity in liver tissue, reduce MDA expression and FFA content, and alleviate LPO damage [25]. In addition, the mechanism of acupuncture improving liver lipid metabolism may also be related to the inhibition of oxidative stress.Electroacupuncture at bilateral Dai Mai acupoints of NAFLD rats can significantly reduce the content of MDA in liver tissue, increase the activities of SOD and GSH; at the same time, electroacupuncture can also reduce the levels of alt, TC and TG in serum, reduce visceral fat, liver wet weight, and abdominal visceral fat accumulation.

Massage has a similar mechanism in repairing tissue damage,which can reduce tissue oxidative stress damage by increasing serum SOD and reducing MDA content [26]. In the traditional massage technique of "bundle regret therapy", by selecting the route of the great blood vessels or the great nerve trunk of the limbs as the operation site, and promoting the movement of Qi and blood through"slow press and rapid release" and "fast press and slow release",the content of SOD in the sciatic nerve can be increased and the expression of MDA can be reduced in the peripheral neuropathy model, which indicates that massage therapy has the protective effect on oxidative stress injury [27]. However, there is no direct evidence that massage directly interferes with NAFLD and regulates oxidative stress, but it may participate in the relevant mechanism through the "brain gut" axis. Studies have shown that [28, 29], improper diet,obesity and other factors can cause excessive accumulation of lipopolysaccharide (LPS) in the intestine, increase the permeability of the intestine, make a large number of LPS enter the portal vein,affect the liver, induce oxidative stress reaction, and cause steatosis of hepatocytes. Abdominal massage based on kneading method can reduce the intestinal permeability of NAFLD model rats, improve the structural changes of intestinal mucosa caused by modeling,restore the normal structure of intestinal cells and mitochondrial state, block the invasion of LPS to the liver, so as to prevent and treat NAFLD [12, 30]. Similar mechanism is also reflected in moxibustion.Moxibustion at zhangmen, Qimen, Xuehai and Fenglong points of NAFLD patients combined with western medicine can significantly relieve their clinical symptoms, protect liver function and reduce blood lipid level, which may be related to the down-regulation of serum LPS level [11].

3. The regulatory effects of external treatment of traditional Chinese medicine on inflammatory cytokines

Inflammatory response is an important pathological basis of hepatocyte injury and plays an important role in the progression of NAFLD. Injured hepatocytes can induce the production of proinflammatory cytokines such as tumor necrosis factor (TNF)-α,interleukin (IL)-1β and IL-6 by promoting the activation of nuclear factor (NF)-κB pathway, which is the key step in the transformation of hepatocytes from pure steatosis to Nash [31]. These inflammatory factors may accelerate the development of Nash by inducing the activation of stellate cells and remodeling of cell matrix; at the same time, they may aggravate hepatic steatosis by promoting IR.Relevant studies have also found that anti-inflammatory drugs can reduce liver fat deposition and fibrosis in NAFLD rats, and improve insulin signal transduction, but the relevant clinical efficacy has yet to be evaluated [32].

The role of acupuncture in regulating inflammatory response has been reported in a large number of studies, but there are some differences in the role of different acupoints in different models.The study found that [33] acupuncture at Sanyinjiao of muscle inflammation model rats can increase the level of anti-inflammatory factor IL-10, while bilateral Yanglingquan and Quchi of stroke model rats can reduce the expression of NF - κ B and IL-6 in brain tissue [34]. In NAFLD model mice, proinflammatory signal factors were significantly up-regulated in liver tissue, while acupuncture at Zusanli, Yongquan and Guanyuan could reduce the expression of TNF -α and IL-1 β in liver tissue and inhibit the inflammatory reaction [14]. In another study [35], acupuncture at Fenglong and Zusanli points of NAFLD rats can improve inflammatory response,regulate lipid metabolism and improve endoplasmic reticulum stress by down regulating the expression levels of TNF - α and IL-6;however, the study also found that the effect of Fenglong is better than that of Zusanli point, and the effect of electroacupuncture is better than that of hand acupuncture. In addition, there are also experimental studies based on apolipoprotein gene knockout mice[36]. It is found that acupuncture at Fenglong and Neiguan Points can reduce the expression of IL-6 and IL-17 in serum of model mice,significantly reduce the steatosis of liver cells and normalize the tissue.

In recent years, clinical studies have shown that [37,38], abdominal massage is effective in the treatment of NAFLD, which may also be achieved by reducing inflammation related factors. By selecting Zhongwan, Guanyuan, Shuishui and Tianshu points for massage,the serum levels of TNF - α and IL-8 in patients with NAFLD can be significantly reduced, so as to reduce liver inflammation[39]. Compared with simple warm acupuncture, massage combined with warm acupuncture has more advantages in regulating the level of inflammatory factors, which can significantly reduce the levels of TNF -α, IL-1 β and IL-6 in patients' serum, suggesting that massage may have different targets in regulating the inflammatory reaction of liver tissue from acupuncture, and the combined use can achieve better curative effect [11]. In addition, pricking collaterals and purging blood derived from acupuncture can also be used in the treatment of NAFLD. Pricking collaterals and purging blood at Fenglong and Taichong points of hyperlipidemia rats can significantly reduce the contents of TNF - α, IL-6 and IL-18 in serum of rats [40].

4. Thoughts and prospects

To sum up, the curative effect of TCM external treatment including acupuncture, moxibustion and massage in NAFLD is obvious, which has been confirmed by a large number of experimental and clinical studies at home and abroad. However, it is still unclear how these methods regulate the metabolism of the whole body by stimulating the viscera on the body surface. Whether different treatment methods and acupoints will have different effects on the body is also the focus of future research.

Based on the above, we should further carry out in-depth experimental research and large sample randomized controlled trials,scientifically explain and evaluate the mechanism and efficacy of external treatment of traditional Chinese medicine in the treatment of NAFLD, and closely integrate modern medicine with the application of traditional Chinese medicine theory, so as to form a set of standardized clinical diagnosis and treatment scheme with traditional Chinese medicine characteristics in the future.