Therapeutic Advantages of Traditional Chinese Medicine in Non-erosive Reflux Disease

Che Hui, Xie Jingyi, Ma Xiangxue, Tang Xudong , Wang Fengyun

ABSTRACT The incidence of gastroesophageal reflux disease (GERD) is increasing year by year. Non-erosive reflux disease (NERD)is not only the most common subtype of GERD, but also has the highest proportion of refractory GERD. The pathogenesis may be closely related to mixed reflux, non-acid reflux, esophageal hypersensitivity, psychology and so forth. On the one hand,the treatment with acid suppression drugs alone has a high recurrence rate, and the maintenance treatment continues to be controversial. On the other hand, the comprehensive treatment with the traditional Chinese medicine (TCM), which is based on a number of hybrid mechanisms, is more prominent in individualization with more advantages in long-term efficacy and improvement of quality of life for the patient. The authors conduct a comprehensive analysis on characteristics of NERD and advantages of TCM in treatment, in order to provide more ideas for clinical treatment.

KEY WORDS: Gastroesophageal reflux disease; non-erosive reflux disease; TCM; advantage

Gastroesophageal reflux disease (GERD), also known as acid reflux, is a long-term condition where stomach contents come back up into the esophagus resulting in either symptoms or complications[1]. It includes three subtypes: reflux esophagitis (RE),Barrett's esophagus (BE), and non-erosive reflux disease(NERD). Epidemiology shows that the prevalence of the disease in our country is 5-10% and there is a trend of rising year by year in the incidence[2]. Among the three subtypes, RE accounts for 3.4%-16.3%, BE 0.22%-8.3%, and NERD is the most common, accounting for 50%-85%[3]. The main clinical manifestation is discomfort, No esophageal mucosal damage is found. At present, about 30% of patients with refractory GERD are less effective in the conventional treatment using acid suppression drugs[4], of which NERD accounts for the highest proportion[5]. In addition to the acid reflux, the pathogenesis may be closely related with mixed reflux,non-acid reflux, esophageal hypersensitivity, psychology and etc. Currently, no specific drug can completely relieve the symptoms. TCM treatment of the disease, in addition to reducing gastric acid reflux, has an integrated conditioning effect in mixed / non-acid reflux, esophageal hypersensitivity, depression and etc. Therefore, to explore ideas and methods of TCM treatment of NERD for improving the clinical diagnosis and treatment of NERD is of great significance.

THE PATHOGENESIS OF NERD

As a common subtype of GERD, NERD has has typical symptoms of heartburn and acid reflux as well as atypical symptoms. For example, reflux-related chest pain, cough, asthma, and pharynx foreign body sensation etc. Its symptoms are not specific, from which physicians cannot determine whether it is NERD or RE, therefore, gastroscopy is a preferred method in the diagnosis of NERD. The pathogenesis of GERD is the result of the unbalance between reflux on esophageal mucosa and anti-reflux barrier defense[6], and is related to the following factors: esophageal-gastric motility abnormality, attack of gastric contents, reduced esophageal clearance ability and so forth[7]. Except the common mechanism, NERD pathogenesis has its own characteristics below:

Weak acid / non-acid reflux as a major cause of NERD

Gastric contents include gastric acid, gastric pepsin,bile, pancreatin and so on. In the long-term treatment with acid suppression drugs, the gastric acid secretion is inhibited, the corresponding number of acid reflux decreased, and the number of weak acid and non-acid reflux increased significantly. Studies have shown that 50% of symptoms in patients with NERD are associated with weak acid reflux, and 40% associated with acid reflux[8], indicating that weak acid is more prominent in causing symptoms. According to study reports, non-acid reflux is closely related with heartburn and can increase the detection rate of GERD, a phenomenon that has a higher proportion in the NERD patients[9].

Esophageal hypersensitivity as the key to cause NERD

Visceral hypersensitivity refers to visceral discomfort, irritation or reduced threshold of abnormal pain. The phenomena (in which the physiological stimuli may cause discomfort and there is a strong reaction to noxious stimuli) is one of the important pathogenesis of NERD. 24-hour esophageal PH monitoring shows that 33%-50% of acid exposure time in patients with NERD is normal, and the physiological reflux can lead to increased esophageal sensitivity that results in discomfort and so forth[10]. It may be due to increased sensitivity to acid. These discomfort symptoms are mediated by the peripheral mechanism (sensitization of the end of the esophageal sensory nerve fiber) and the central mechanism(sensitization of spinal cord and central nervous system with the brain as a part of it)[11]. The esophageal nerve fiber sensitized by repeated stimulation can release cytokines (interleukin, bradykinin, etc.) and neuropeptide substances (SP, CGRP, etc.) and promote the high expression of nerve endings receptors (TRPV1 etc.). It further amplifies the signal to cause central sensitization,resulting in neuroinflammation or neuropathic pain and resulting in hypersensitivity to the visceral organ[12]. This kind of visceral hypersensitivity status increases the incidence of NERD.

Mental disorder as an important factor in induction of NERD

For most patients with NERD, their anxiety or depression is significantly higher than normal people.On the one hand, discomfort symptoms continue to plague the patient, leaving the body in a chronic state of stress. On the other hand, mental disorders can make plasma corticotropin to generate higher hormone levels when compared with normal people, activating the hypothalamus-pituitary-adrenal axis, acting on the gastrointestinal tract nerves, increasing the visceral perception, and aggravating symptoms of discomfort[13].

PROTON PUMP INHIBITORS (PPIS):DRUG RESISTANCE ANALYSIS

NERD treatment methods include changing lifestyle, medication, surgery, endoscopic treatment,psychological intervention and etc. Acid suppression drug treatment is preferred, and it can also combine with the gastrointestinal motility drug and mucosal protector to increase the pressure of the lower esophageal sphincter (LES), improve esophageal peristalsis and promote gastric emptying, so as to achieve the purpose of enhancing efficacy. The PPI as a kind of acid suppression drug is the most commonly used in initial treatment and long-term maintenance treatment, whose efficacy has been af firmed by the medical community. However, there are serious problems in the long-term application of PPI:for example, weakening of digestion, abdominal bloating,abdominal pain, and constipation so forth. The increase of gastrin secretion leads to the mucosal problem and the polyps formation. The weakening of barrier function of natural host leads to imbalance of flora, increased risks of infection and gastrointestinal tumor incidence.Absorption of nutrients can cause the following problems:hypomagnesemia, iron absorption disorders, osteoporosis,and vitamin C, B12 levels decline etc. In addition, the combined use of PPI and certain anticoagulant drugs such as clopidogrel may result in some interactions. For the pros and cons of the long-term use, there is a need for further study[14-15].

BASIC UNDERSTANDING OF TCM TOWARDS NERD

The disease name of gastroesophageal reflux does not exist in ancient books of traditional Chineses medicine(TCM). Instead, this disease belongs to swallowing acid, acid regurgitation, gastric discomfort,and globus hysteriocus so forth in TCM. There is an connotation in Huang di Nei Jing, "All syndromes characterized by vomiting and acid regurgitation are associated with heat." In a large number of studies reported, it is believed that the deficiency of spleen and stomach is the main pathogenesis and that functional activity of QI being not smooth is the pathological basis[16]. With the development of statistics and data analysis system, the pathogenesis of this disease is analyzed with the following finding that the ascending and descending of spleen and stomach are important in the pathogenesis. Academician Tong Jianhua's theory of Dredging-Descending holds that[17]the physiological disorder of the stomach obeying the principle of harmony by descending (this disorder being due to various reasons)may lead to the descending or adverse rising of stomach qi, failing to send up essential substances so forth, further causing or aggravating phlegm turbidity, pathogenic dampness, blood stasis and so forth and aggravating blockade of qi movement. According to Bu Yuru a famous veteran TCM doctor[18], the lung governs qi of the body.If lung qi fails in dispersing, then qi movement of spleen and stomach may be affected, leading to the stagnation of stomach qi. Professor Tian Delu believes that liver qi stagnation causes heat in gallbladder, which, together with stomach qi, adversely rises because of the failure to send down the essential substance, thereby resulting in this disease[19]. Professor Zhu Shengliang[20]thinks that liver qi stagnation should be as an entry point and that the treatment method of Relieving Qi Stagnancy in Liver ,harmonizing stomach for descending adverse qi should be adopted with the emphasis on concurrent conditioning of liver and spleen. Li Zhi, et al[21]think that GERD accompanied by emotional disorders is closely related with syndrome of heat stagnation in liver and stomach,syndrome of stomach -liver disharmony, and syndrome of qi stagnation and phlegm blockade. The dysfunction of liver controlling dispersion plays an important role in the NERD. In the clinical treatment, special attention should be paid to dispersing stagnated liver qi for relieving qi stagnation , and normalizing the functional activities of qi. Attention is also paid to the patient's physical and mental therapy.

In a word, it is believed in the majority of literature that this disease is in the stomach with the poor smoothness of qi movement in middle-jiao as a basis. The long-term poor smoothness of qi movement results in phlegm, dampness and stasis, and the gastrointestinal descending & dredging function is weakened. Moreover, stomach qi does not descend but ascend, and turbid qi adversely rises. Thus, it is closely related with liver, spleen, gallbladder, and lung. In the treatment, the key is to regulate qi movement and restore the function of dredging and descending in stomach qi.

SYNDROME DIFFERENTIATION AND TREATMENT OF TCM

The treatment based on syndrome differentiation takes into account clinical manifestations. It plays an important role in the treatment of TCM compound preparations, and also a representative treatment means of TCM clinical practices. This disease is caused a variety of etiological factors and has different symptoms, so its syndrome differentiation is still controversial. Some experts put forward their dialectical view based on clinical experience. For example, famous TCM doctor Xu Jingfan divides this disease into qi stagnation type, phlegm and qi obstructing each other type, liver depression and stomach heat type, qi stagnation and blood stasis type in treatment[22]. Li Zhi[21]thinks that this disease is divided into liver and stomach disharmony type, stagnated heat of liver and stomach type, phlegm and qi obstructing each other type, deficiency of middle-warmer energy and adverse rising of qi type, stomach heat and adverse rising of qi type. Pan Wanxiong[23]divides this disease into the following nine types: stagnated heat in stomach, stomach disorder due to liver qi, stagnated heat of liver and stomach,stagnated qi and phlegm obstruction syndrome, excessive heat and phlegm obstruction syndrome, lung-stomach disharmony syndrome, stomach-yin deficiency syndrome,internal stagnation of phlegm and blood stasis syndrome,syndrome of deficient cold of spleen and stomach. Tang Xudong[24]thinks that the pathogenesis of this disease is the failure of descending of stomach qi, namely, adverse rising of it. Clinically, syndrome of disharmony between liver and stomach, cold-heat complicated syndrome, syndrome of spleen deficiency and qi stagnation are commonly seen.Summing up the above views, we think that the common syndromes are as follows:

Syndrome of disharmony between liver and stomach

The disharmony of liver and stomach is mainly due to: (1) emotional depression that leads to dysfunction of conveyance and dispersion in liver, stomach being attacked, and adverse rising of stomach qi; (2) improper diet that lead to damage & deficiency of spleen and stomach, and Wood overwhelming Earth. The main clinical manifestations include gastric discomfort with acid regurgitation, rib-side distention and fullness occurring concurrently, depression, impatience etc. The treatment method is to disperse stagnated liver-qi and harmonize stomach by depressing the adverse rising of qi.Commonly used prescriptions: Chaihu Shugansan, Sini San, Cyperus and Perilla Beverage and etc.

Syndrome of stagnated heat in liver and stomach

Syndrome of stagnated heat in liver and stomach is due to liver qi stagnation or heat accumulation in stomach. Liver qi stagnation leads to failure of descending of stomach qi, namely, adverse rising of it.Heat accumulation in stomach leads to liver wood being subjugated with the adverse rising of turbid qi together with liver qi. The main clinical manifestations include burning pain in stomach, impatience, irritability, acid regurgitation, gastric discomfort, dry mouth and bitter taste in mouth and so on. The treatment method is to remove heat from the liver and harmonize stomach by depressing the adverse rising of qi. Commonly used prescriptions: Ease Powder of Moutan Bark and Cape Jasmine Fruit, Liver-Comforting Decoction, Zuo Jin Wan,Yi Gan Jian and etc.

Syndrome of dampness-heat due to spleen deficiency

This syndrome is due to the improper diet. In it,food stagnation is in stomach with the failure of stomach qi to descend, leading to an impact on transportation and transformation of the spleen; or the spleen is always deficient and dysfunctional in transportation and transformation, leading to the stagnation in stomach(long-time stagnation generates heat and dampness). The main clinical manifestations are abdominal distension and fullness, acid regurgitation, gastric discomfort,poor appetite, dry mouth, loss of desire to drink, and sticky stool etc. The treatment method is to clear away heat, eliminate dampness, strengthen spleen, harmonize stomach by depressing the adverse rising of qi.Commonly used prescriptions: Pinelliae Decoction for Purging Stomach-Fire, Seutellaria and Talc Decoction,Three-seeds Decoction and etc.

Syndrome of deficiency of reversed flow of qi

This syndrome is due to the deficiency of constitution and long-time deficiency of spleen and stomach, or cold diet resulting in dysfunction of spleen-qi ascending and stomach-qi descending. or stomach caused by dysfunction. The main clinical manifestations include belching, spitting clear water, stomach distention and fullness, dull pain in abdomen relieved by pressing and warmth, and dilute stool etc. The treatment method is to strengthen spleen, replenish qi, and harmonize stomach by depressing the adverse rising of qi. Commonly used prescriptions: Decoction of Four Mild Drugs, Decoction of Cyperus and Amomum with Six Noble Ingredients,Small Jianzhong Decoction , Huangqi Jianzhong Decoction and so forth.

Syndrome of phlegm qi obstructing each other

This syndrome is due to improper diet that results in abnormal transportation and transformation of spleen and stomach as well as the transformation of the poorly transported and distributed fluid into phlegm. The adverse rising of stomach qi also affects the adverse rising of lung qi. The main clinical manifestations include cough with sputum, discomfort and pharynx foreign body sensation,asthma and so on. The treatment method is to depurate the lung and transform phlegm , and harmonize stomach by depressing the adverse rising of qi. Commonly used prescriptions: Pinelliae and Magnoliae Officinalis Decoction, Er Chen Decoction, Xuanfu Daizhe Decoction and etc.

Stomach Yin deficiency

This syndrome is due to the long-term heat disease(that consumes and damages stomach Yin) or spicy preference that damages stomach Yin (leading to internal generation of deficiency heat and adverse rising of stomach qi). The main clinical manifestations include discomfort and hidden pain in stomach or burning pain behind chest bone, nausea, retching, feeling hungry but having no desire to eat etc. The treatment method is to supplement qi and promote the production of body fluid,and harmonize stomach by depressing the adverse rising of qi. Commonly used prescriptions: Yi Wei Decoction,Maimendong Decoction, Decoction of Glehnia and Ophiopogon and so forth.

Syndrome of qi stagnation and blood stasis

This syndrome is due to the long-term retardation of qi-movement. In it, the bloods circulation is weakly promoted, namely, slow or poor, leading to the formation of blood stasis. If stagnant blood does not circulate in the vessels for a long time, then such retardation may be aggravated. The main clinical manifestations are a fixed stabbing pain behind sternum or in stomach, abdominal distension, poor appetite, depression or irritability and so on. The treatment method is to promote qi to activate blood, and harmonize stomach by depressing the adverse rising of qi. Commonly used prescriptions: Xuefu Zhuyu Decoction, Dansen Decoction, Powder for Dissipating Blood Stasis and etc.

ADVANTAGES OF TCM TREATMENT OF NERD

The TCM treatment of NERD takes into account its complex and diverse symptoms, adopts the mode of combined disease differentiation and syndrome differentiation, and is carried out according to the patient's individual differences and overall characteristics.Therefore, as an individualized regimen, such TCM treatment is more advantageous in significantly improving clinical symptoms, improving patient quality of life and long-term prognosis.

Remarkable comprehensive effect

In the NERD pathogenesis, weak acid reflux and non-acid reflux occupy a higher proportion.Esophageal hypersensitivity and gastrointestinal motility problems are also commonly seen. These mechanisms may be associated with increased neuropeptides and gastrointestinal neural regulation imbalance. The treatment of NERD with acid-suppressing drugs alone is dif ficult to obtain a comprehensive effect. The treatment of this disease when taken as an overall treatment model,is consistent with Montreal Consensus and Integrated Medical Model advocated by modern. The traditional Chinese medicine and theoretical system emphasize that man is an organic whole, and emphasize the unity of man and nature and the unity of human and social environment. Modern TCM diagnosis and treatment is a combination of holistic view of traditional Chinese medicine and the mode of modern medical diagnosis and treatment. Prescriptions are made according to the pathological diagnosis of modern medicine. In the mental health, the indicators and quality of life of patients are comprehensively assessed. Thus, it can treat the typical symptoms of NERD, comprehensively treat concurrent diseases. Moreover, it is an individualized regimen.

Improve long-term efficacy and effectively reduce recurrence

Currently, acid-suppressing drug PPI is the most commonly used for the treatment of NERD. In the early stages of treatment, PPI can rapidly produce an effect that is powerful, but the biggest problem is the long-term maintenance treatment and easy recurrence after drug withdrawal. It has been reported that the recurrence rate of reflux symptoms is as high as 90% half a year after antacid drug withdrawal[25], and its causes are related with pathogenesis, individual differences, lifestyle changes,mental burden and other factors. In the long-term maintenance treatment, Multi-target TCM compounds have advantages including flexible prescriptions,increased or decreased doses according to symptoms,good tolerance in long-term use, thereby not only being suitable for long-term maintenance treatment, but also to some extent being able to reduce the Western medicine dose. According to Zhou Bin et al[26], the TCM treatment of GERD (syndrome of liver and stomach disharmony)is obviously advantageous in the short term or long-term recurrence. Li Xiujuan et al[27]conducted a systematic review on the randomized controlled clinical trials of TCM treatment of GERD in recent years, confirming that TCM treatment can effectively reduce the recurrence rate of GERD.

Improve quality of life of patients

In addition to the typical symptoms, NERD patients often have other concurrent symptoms, such as refluxrelated cough, post-sternal pain, asthma, nighttime cough,and pharynx foreign body sensation. Furthermore, its symptoms may overlap with functional gastrointestinal disease symptoms, for example, early satiety, abdominal distension, gastric blockade and other symptoms of functional dyspepsia, abdominal pain, diarrhea and other symptoms of irritable bowel syndrome. These symptoms occur repeatedly and interact with the brain-gut axis,further aggravating visceral sensitivity and forming a vicious circle, seriously affecting the patient's work and life. TCM thinks that the disharmony of stomach results in disturbed sleep. In the course of TCM treatment,the comprehensive analysis is based on the theory of dredging and descending in stomach and gut, involving the pathogenesis, asthenia and sthenia, cold and heat, qi and blood, and pathological characteristics; yin- yang,and zang-fu organs are taken into account; treatment methods are adopted, for example, harmonizing qi and blood, reinforcing insufficiency and reducing excess, concurrent use of cold and warm drugs, in order to achieve the purpose of dredging and the overall improvement of life for the patient[28].

Improve mental and psychological state

Mental and psychological problems are v ery important in the pathogenesis of NERD. On the one hand, the discomfort caused by reflux results in the psychological burden. On the other hand, the chaotic rhythm of social life and the increased psychological pressure may cause the enhanced information of brain-intestinal axis interaction, leading to repeated discomfort in the patient. TCM recognizes the emotional factors, matches the emotions into theories of five internal organs, five elements, and yin and yang, and adjust them using these theories. Special attention is paid to the relationship between liver dysfunction and emotion and this disease. The methods of dispersing stagnant liver-qi,strengthen spleen, harmonizing stomach, and calming the nerves so forth, in addition to treating typical symptoms,can improve sleep and regulate bad mood in patients.This produces the direct or indirect effect on the cerebral limbic system and the brainstem reticular structure and restores the gastrointestinal function in NERD patients.The brain-gut axis can promote gastrointestinal motility,reduce acid reflux and lower esophageal acid sensitivity.Moreover, Qigong, Daoyin, Taijiquan , and five-elementmusic therapy can be auxiliary means to produce an effect of empathy, thereby being more conducive to the regulation of emotions.

SUMMARY

The pathogenesis of NERD has not been fully elucidated so far. It has been found that psychiatric factors and brain-gut axis have an important impact on gastrointestinal nerves of NERD. The long-term use of acid suppression drugs alone may cause drug resistance and side effects that bring difficulties for clinical treatment. In particular, the long-term application of PPIs cause a change in the gastrointestinal environment,resulting in dysbacteriosis of the digestive tract, decreased immunity, nutrient absorption disorders and other issues that have gradually attracted the attention from the medical community. The TCM multi-target and holistic treatment model can intervene in the pathogenesis of NERD from many ways. It not only can improve the typical clinical symptoms of NERD patients, but also can significantly improve symptoms outside esophagus and mental state and better improve patients' quality of life, thereby having greater advantages. However, most of TCM treatment of NERD recently reported emphasize on personal experience and subjective effects, while the dialectical method is not adopted. For the objective indicators of efficacy mechanism, the further in-depth study is needed.