The regularity of nourishing-yin prescription for treating ascites due to hepatitis B cirrhosis based on data mining technology

Introduction

Hepatitis B cirrhosis, caused by the hepatitis B virus (HBV), is a chronic progressive liver disease. Hepatitis B cirrhosis results in diffuse liver disease due to the effect of prolonged or repeated action of one or multiple etiologies (1). It is estimated that 240 million people worldwide experience chronic HBV, and approximately 2% to 4% of patients develop compensated cirrhosis without effective treatment each year (2). Microscopically, cirrhosis shows absolute attenuation of the normal hepatocytes, massive fibrous hyperplasia, and nodule formation (3). Macroscopically, cirrhosis shows decreased volume atrophy in the liver (4). Cirrhosis is theoretically described as a “tympanite” disease in traditional Chinese medicine (TCM). In Suwen·Yinyang Yingxiang Dalun, cirrhosis was described as “yang transforming qi and yin transforming shape”. Therefore, cirrhosis is the embodiment of yin deficiency. The etiology and pathogenesis of cirrhosis can mostly be attributed to deficiency in the origin and excess in superficiality. Tonifying deficiency is the common treatment principle in treatment for cirrhosis in TCM (5).

Ascites is one of the most common complications of cirrhosis. Refractory ascites is present in 15–20% of all patients with ascites. Refractory ascites brings repeated hospitalizations, severe reduction in quality of life, and even death for patients (6). Therefore, it is particularly important to actively prevent the occurrence and development of cirrhotic ascites at an early stage.

TCM classifies patients with post-hepatitis B cirrhosis into “liver-kidney yin deficiency”, “dampness-heat internal smoldering”, “stasis-heat internal smoldering”, “liver depression and spleen deficiency”, and “spleen-kidney qi deficiency” (7). “Yin deficiency” is defined as a pathophysiological state with yin-related dysfunction (8). In the early stages of ascites due to hepatitis B cirrhosis, most of the symptoms of yin deficiency are not obvious, so yin deficiency is easily ignored in the process of treatment. However, in the late stage of hepatitis B cirrhosis-related ascites, yin deficiency is aggravated. Nourishing yin can easily invigorate the spleen for diuresis, while invigorating the spleen for diuresis can damage yin at this time (9). The treatment of late-stage hepatitis B cirrhosis-related ascites is difficult, as the disease is prone to variation and a threat to the life of patients. It has been proposed in TCM that Shaoyang-Taiyin syndrome is the basic pathogenesis of ascites from hepatitis B cirrhosis. Congestion and water stagnation are the symptoms of the occurrence of Shaoyang-Taiyin disease. Yin deficiency is an important pathological factor of ascites due to hepatitis B cirrhosis. In the treatment of ascites due to hepatitis B cirrhosis, the “reconciliation and Shaoyang” method and “warming Taiyin” are radical therapies, and promoting blood circulation and disinhibiting water are symptomatic treatments (10). In recent years, a large number of studies have proved that Chinese medicine has significant clinical effects and fewer side effects in the treatment of ascites due to hepatitis B cirrhosis, but the clinical ideas and medication habits of various scholars and physicians vary, and there are many experiences in the treatment of ascites due to hepatitis B cirrhosis, which are inconvenient to learn and pass on better (11,12). In order to optimize the treatment of ascites due to hepatitis B cirrhosis, we used the Auxiliary Platform for Traditional Chinese Medicine Inheritance (Institute of Traditional Chinese Medicine, Chinese Academy of Traditional Chinese Medicine, China) to analyze the composition of nourishing-yin prescription in the literature of hepatitis B cirrhosis-related ascites in the past 20 years. In this way, a reference basis for the clinical treatment of ascites due to hepatitis B cirrhosis was created.

Methods

Source and screening of prescriptions

Articles published from the year 2000 to 2020 related to ascites due to hepatitis B cirrhosis were searched in the Chinese National Knowledge Infrastructure (CNKI 2.0) and the Chinese Science and Technology Journal Database (CSTJ). The search terms for the first search were as follows: “ascites”, “peritoneal effusion”, and “tympanites”. The search terms for the second search were as follows: “yin”, “jing”, “blood”, “liquid”, and “jin”. The subject headings, keywords, and abstracts of each paper were combined to conduct a cross search. Tracing and querying were subsequently performed for the references of the target literature and review literature. This yielded 174 articles related to the treatment of ascites due to hepatitis B cirrhosis with the method of nourishing yin, which were then manually screened. This resulted in 198 complete prescriptions from the screened articles. The search terms for the second search were changed to “experience”, which yielded 25 articles about the treatment of ascites due to hepatitis B cirrhosis as summarized by prominent TCM doctors. After the articles were read one by one, 3 prescriptions about the treatment of ascites due to hepatitis B cirrhosis with the method of nourishing yin were selected. Finally, through combing 199 articles, a total of 201 target prescriptions were obtained. Inclusion and exclusion criteria were as follows. Inclusion criteria: (I) the disease diagnosis in the literature was clearly ascites from hepatitis B cirrhosis; the TCM certificate type included Yin deficiency. (II) The type of literature was clinical observation with effective treatment results, medical cases or experience summary of TCM experts. (III) There were clear prescriptions, flavors and dosages of herbal medicines in the literature. Exclusion criteria: (I) the prescription, flavor and dosage of Chinese medicine in the literature were incomplete; (II) duplicate literature and the same prescriptions in different literature.

Database establishment

First, a database was established with Microsoft Excel. Downloaded the medical case entry template provided by the TCM inheritance computing platform, entered the prescription data that met the inclusion criteria according to the template requirements, and standardized the terms involved in the prescriptions: deleted the method of concoction from the Chinese medicine drug names. For example, “processed rhizoma pinelliae” and “rhizoma pinellinae praeparata” were uniformly entered as “pinellia ternata” and modified according to the platform requirements with reference to the Pharmacopoeia of the People’s Republic of China (2015 edition) (13). The data was individually reviewed by two team members and timely proofread for incorrect information to ensure data authenticity and accuracy and reduce bias. After the entry was completed, the excel file was uploaded to the TCM inheritance computing platform to establish the database.

Data entry and analysis methods

The screened prescriptions were then entered with the help of the Auxiliary Platform for Traditional Chinese Medicine Inheritance. The specific steps for data entry were as follows: (I) the established database was uploaded in the “Data Upload” module of the software. (II) After “Statistical Analysis” in the “Data Analysis” module was run, “Four Properties (cold, hot, warm, and cool) (14)”, “Five Flavors (sour, sweet, bitter, pungent, and salty) (15)”, “Channel Tropism”, and “Efficiency” were analyzed, and the results of analysis were exported. (III) The “Herb Frequency”, “Association Rule”, and “Cluster Analysis” in the “Analysis of Prescription” modules were each entered. In “Association Rule”, Set the “Number of Support” (the numbers of occurrences of the same herbs at the same time among all herbs), and “Confidence Level”, and export results. In “Cluster Analysis”, cluster analysis [the core algorithm, including the improved mutual information method and complex system entropy cluster (2,5)] was conducted. Before cluster analysis, the number of clusters was selected. The “Extraction and Combination” command was then executed to perform network display [the basic algorithm was unsupervised entropy hierarchical clustering (16-18)]. Finally, the related results were exported one by one.

Results

Property, flavor, channel tropism, and efficacy statistics of the medicines in prescriptions

A total of 201 prescriptions were included. Property, flavor, channel tropism, and efficacy statistics of all medicines were recorded. According to the results, most of the medicines in prescriptions were cold, with a sweet flavor, placing them in the liver channel (Table 1). Most of the cold herbs belonged to tonifying herbs (36.3%) (Figure 1), suggesting TCM treatment of ascites due to hepatitis B cirrhosis was mainly based on tonifying deficiency.

Figure 1 Classification frequency diagram of herb efficacy.

Frequency statistics of herb used in prescriptions

The frequency of the herbs used in 201 prescriptions were further determined. The frequency of herbs appearing ≥26 times is shown in Table 2. Poria cocos, rhizoma atractylodis macrocephalae, and radix astragali were applied frequently. Poria cocos could clear damp-heat, which had spleen-fortifying effects; rhizoma atractylodis macrocephalae focused on percolating water and resolving dampness; and radix astragali could invigorate qi for strengthening superficies. The results above indicated that TCM treatment of ascites due to hepatitis B cirrhosis consisted primarily of tonifying deficiency and invigorating the spleen for diuresis.

Prescription regularities analysis based on association rules

A total of 99 common herb combinations were obtained according to association rules. The associated herb groups that appeared ≥34 times are shown in Table 3. The combination of poria cocos-rhizoma atractylodis macrocephalae and poria cocos oriental water plantain rhizome occurred with a high frequency. The association of herb combinations (confidence level ≥0.76) in prescriptions was further examined. It was found that the confidence level of oriental water plantain rhizome-radix rehmanniae recens-poria cocos, radix astragali oriental water plantain rhizome-radix salviae miltiorrhizae-poria cocos, and cassia twig-poria cocos was close to 1 (Table 4). The confidence level of the above herb combinations indicated that the prescriptions mainly contained the herbs for tonifying deficiency and invigorating spleen for diuresis. These results suggested that poria cocos, radix astragali, and rhizoma atractylodis macrocephalae were the most common compatible herbs.

Prescription regularities analysis based on an unsupervised clustering algorithm (k means) and regression analysis

According to the unsupervised clustering algorithm (k means), the prescriptions underwent cluster analysis. After further regression analysis, 5 core herb combinations were found (Figure 2). All 5 core herb combinations contained 6 herbs (Table 5), with the efficacy related to nourishing yin, soothing liver, and invigorating spleen for diuresis.

Figure 2 Regression analysis simulation diagram for prescription frequency. (A) Cluster analysis diagram for the prescriptions. (B) Simulation diagram for k means and regression analysis. 1= combination 1, Rhizoma dioscoreae-poria cocos-oriental water plantain rhizome-fructus corni-cortex moutan-radix rehmanniae preparata; 2= combination 2, Rhizoma atractylodis macrocephalae-radix astragali-poria cocos-pericarpium arecae-carapax trionycis-radix salviae miltiorrhizae; 3= combination 3, Rhizoma atractylodis macrocephalae-poria cocos-radix astragali-pericarpium arecae-grifola-oriental water plantain rhizome; 4= combination 4, Rhizoma atractylodis macrocephalae-cocos-radix astragali-carapax trionycis-radix salviae miltiorrhizae-oriental water plantain rhizome; 5= combination 5, Radix ophiopogonis-radix rehmanniae recens-adenophora stricta miq-poria cocos-grifola-fructus lycii.

Discussion

HBV is a hepatotropic virus, and within TCM, it is a type of damp-heat epidemic virus. After invading the human body, HVB directly enters the liver and remains there for a long time, causing liver damage. Zheng et al. showed that HBV damaged and consumed body liquid, causing hepatic yin injury (19). The kidney is a water viscus, with the function of storing essence. However, the liver and kidney are present together in the lower energizer, exchanging essence and blood between each other. The liver and kidney share a common source, so when liver damage occurs, there is often concomitant kidney damage. Che et al. (20) thought that liver and kidney yin deficiency were the core pathogenesis in deficiency in origin and excess in superficiality and “coexistence of blood stasis and deficiency” for post hepatitis cirrhosis. In TCM, it is thought that ascites due to hepatitis B cirrhosis is a deficiency in origin and excess in superficiality; specifically, the deficiency of the liver, spleen, and kidney is the origin, while qi stagnation, blood stasis, and retained fluid is the superficiality (21,22). Ascites, one of the common complications of hepatitis B cirrhosis, is difficult to treat and characterized by frequent recurrence and high mortality (23). At present, the treatment of Western medicine for ascites consists mainly of diuretics, with poor efficacy and considerable side effects. Patients with ascites due to hepatitis B cirrhosis accompanied by deficiency in the liver, spleen, and kidney, are also prone to a deficiency in systemic yin fluid. A related study has revealed that, compared with Western medicine, the treatment of TCM for ascites due to hepatitis B cirrhosis has clear advantages (24).

Deficiency of the liver, spleen, and kidney is the predominant etiology in patients with ascites due to hepatitis B cirrhosis. Clinically, patients with severe ascites and abdominal distension are prone to experiencing complicating hydrothorax, especially right pleural effusion. Based on systemic qi and blood, the heart stores the spirit. Deficiency of qi and blood can result in loss of mind. Moreover, pathogenic factors like phlegm-heat syndrome, damp-heat, and others can blind the mind and heart, causing obnubilation and hepatic coma. Based on the theory of the liver governing free coursing, the liver can help the stomach digest food. In this study, we found that the frequencies of cold herbs were higher than those of warm herbs in clinical prescriptions. Sweet, bitter, and pungent were the main flavors of the herbs. Herbs with a sweet flavor can tonify deficiency and so are applied at high frequencies. Herbs with a bitter flavor can nourish yin and clear heat. Herbs with pungent flavor can promote qi and activate blood as well as eliminate stagnation and activate meridians. The combination of herbs of different natures and flavors can strengthen healthy qi and eliminate pathogenic factors. The efficacy of herbs examined in this study was mainly related to toxification deficiency, and the combination of herbs included diuretics for eliminating dampness, medicines for promoting blood circulation and removing blood stasis, and supplements for clearing heat and regulating qi. The efficacy of the above herbs was consistent with the treatment method of ascites due to hepatitis B cirrhosis.

Zan et al. (25) suggested that the disease position of ascites due to cirrhosis in the spleen, liver, kidney, and the spleen was the major position. Therefore, the treatment of ascites due to cirrhosis relies mainly on strengthening the spleen. Chen et al. (26) posited that in the lesion process of ascites due to cirrhosis, the key to the lesion is the spleen, with the main etiology being the insufficiency of the spleen. In this study, the 2 herbs with the highest frequencies were poria cocos and rhizoma atractylodis macrocephalae. Poria cocos and rhizoma atractylodis macrocephalae are the major components of Lishui formulas like Wuling powder, Lingguizhugan decoction, and other medicines. The herbs above are the common herbs in the treatment of ascites due to hepatitis B cirrhosis for invigorating spleen for diuresis. Li et al. (27) believe that the deficiency of vital energy, blood stasis, and fluid retention throughout each period of tympanites is the major etiology. Deficiency of vital energy is the initiating and aggravating factor of tympanites. Fan et al. (28) proposed that promoting blood circulation for removing blood stasis plays a key part in Lishui and should be continued throughout the whole process of treatment for ascites due to hepatitis B cirrhosis. Zhao et al. pointed out that the symptom of ascites due to hepatitis B cirrhosis was ascites while the disease sources were located in the blood. The stagnation of blood stasis is the basic contradiction of ascites due to hepatitis B cirrhosis (29). Ma et al. (30) reported that Jianpi Huoxue Lishui decoction could treat ascites due to hepatitis B cirrhosis and could improve the liver function of patients. In the present study, the associated herb groups of poria cocos-rhizoma atractylodis macrocephalae-grifola-oriental water plantain rhizome and poria cocos-rhizoma atractylodis macrocephalae-radix astragali could invigorate the spleen for diuresis and nourish and tonify blood, which was consistent with previous studies.

(I) Rhizoma dioscoreae-poria cocos-oriental water plantain rhizome-fructus corni-cortex moutan-radix rehmanniae preparata (combination 1) is the core combination of the prescription of Liuwei Dihuang pills with the function of nourishing-kidney yin. The above core combination of herbs can be applied for the treatment of deficiency of kidney-yin characterized by soreness and weakness of waist and knees as well as hot flashes and night sweat. (II) Rhizoma atractylodis macrocephalae-radix astragali-poria cocos-pericarpium arecae-carapax trionycis-radix salviae miltiorrhizae (combination 2) is the combination that can invigorate spleen for diuresis, nourish yin, and soften hard mass as well as nourish blood and promote blood circulation. Pericarpium arecae can lower qi and eliminate turgor, which is more valuable for the treatment of ascites due to hepatitis B cirrhosis with the symptom of abdominal distension. (III) Rhizoma atractylodis macrocephalae-poria cocos-radix astragali-pericarpium arecae-grifola-oriental water plantain rhizome (combination 3) is a herb combination that can tonify qi and invigorate the spleen for diuresis. Poria cocos, grifola, and oriental water plantain rhizome can promote urination, which can treat patients with severe ascites due to hepatitis B cirrhosis. (IV) Rhizoma atractylodis macrocephalae-cocos-radix astragali-carapax trionycis-radix salviae miltiorrhizae-oriental water plantain rhizome (combination 4) has a high cluster frequency. Compared with core combination 2, combination 4 replaces pericarpium arecae with oriental water plantain rhizome. Oriental water plantain rhizome can promote urination, clear damp-heat, and eliminate kidney zang turbidity, which are described in New Compilation of Materia Medica. Oriental water plantain rhizome can be applied for the treatment of patients with ascites due to hepatitis B cirrhosis. (V) Radix ophiopogonis-radix rehmanniae recens-adenophora stricta miq-poria cocos-grifola-fructus lycii (combination 5). The core combination above belongs to the prescription of Yiguanjian decoction, which can nourish hepatic yin and invigorate spleen for diuresis. Combination 5 is consistent the treatment principles of ascites due to hepatitis B cirrhosis.

Conclusions

Deficiency of yin is an important pathological factor for ascites due to hepatitis B cirrhosis. Dispersion, elimination, and invigoration should be all applied in the treatment process of deficiency of yin. Healthy energy is supported mainly by the combination with upper, middle, and lower energizers (triple energizers). Based on qi-blood-water, multiple visceral functions can be fully used to adjust qi movement and smooth the blood and body liquid. Overall, the results of this study aim to provide a theoretical basis for the clinical treatment of ascites due to hepatitis B cirrhosis.

Acknowledgments

Funding: This study was supported by the National Natural Science Foundation of China (No. 81173183) and the clinical effect and mechanism of TCM formula therapy on cirrhosis ascites (No. 2021M217).

Footnote

Peer Review File: Available at https://atm.amegroups.com/article/view/10.21037/atm-23-883/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-23-883/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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