Clinical study on microscopic syndrome differentiation and traditional Chinese medicine treatment for liver stomach disharmony in chronic gastritis

Abstract

BACKGROUND

Chronic gastritis (CG) is a common gastrointestinal disorder characterized by inflammation of the stomach lining. Liver-stomach disharmony (LSD) syndrome is believed to contribute to CG symptoms.

AIM

To evaluate the efficacy and safety of microcosmic syndrome differentiation and Chinese herbal medicine (CHM) treatment in patients with CG and LSD syndrome.

METHODS

Sixty-four patients with CG and LSD syndrome were randomly divided into two groups: The treatment group received CHM based on microcosmic syndrome differentiation and the control group received conventional Western medicine. The treatment course lasted 12 wk. The primary outcome was improvement in dyspeptic symptoms, measured using the Nepean Dyspepsia Index. The secondary outcomes included the improvement rate of endoscopic findings, histopathological findings, and microcosmic syndrome scores and the incidence of adverse events.

RESULTS

After 12 wk of treatment, the treatment group showed significantly greater improvement in dyspeptic symptoms than the control group (93.75% vs 65.63%, P < 0.01). The treatment group also showed a significantly higher improvement rate in endoscopic findings than the control group (81.25% vs 53.13%, P < 0.05). The improvement rates of histopathological findings and microcosmic syndrome scores were not significantly different between the two groups (P > 0.05). No serious adverse events were observed in either group.

CONCLUSION

Microcosmic syndrome differentiation and CHM treatment can effectively improve dyspeptic symptoms and endoscopic findings in patients with CG and LSD syndrome and have a good safety profile. Further studies with larger sample sizes and longer follow-up periods are required to confirm the long-term efficacy and mechanism of action of this treatment.

Key Words: Chronic gastritis, Liver-stomach disharmony, Microcosmic syndrome differentiation, Chinese herbal medicine, Randomized controlled trial, Microcosmic syndrome scores

Core Tip: Microcosmic syndrome differentiation and Chinese herbal medicine treatment effectively improve dyspeptic symptoms and endoscopic findings in patients with chronic gastritis and liver-stomach disharmony syndrome. Long-term efficacy and mechanisms of this treatment require further investigation through larger-scale studies with extended follow-up periods.

INTRODUCTION

Chronic gastritis (CG) is a prevalent digestive disorder marked by persistent inflammation and mucosal damage in the stomach[1]. It leads to various dyspeptic symptoms, including abdominal pain, bloating, nausea, vomiting, loss of appetite, and belching[2]. Furthermore, CG augments the risk of developing gastric ulcers, cancer, and other severe complications. The prevalence of CG is high in China, affecting approximately 42.5% of the population[3]. The etiology and pathogenesis of CG are intricate and multifaceted, encompassing Helicobacter pylori (H. pylori) infection as well as environmental, genetic, immunological, and psychological factors[4]. Conventional Western medicine (CWM) treatments for CG involve antibiotics, proton pump inhibitors, histamine receptor antagonists, and mucosal protective agents[5]. Nevertheless, these medications exhibit certain limitations, such as a low eradication rate of H. pylori, drug resistance, adverse effects, and recurrence. Chinese herbal medicine (CHM) has a long history and rich experience in CG treatment. CHM can regulate the functions of the stomach and spleen, harmonize the liver and stomach, eliminate dampness and heat, promote blood circulation, and eliminate blood stasis[6]. CHM can also modulate the immune system, inhibit the growth of H. pylori, protect the gastric mucosa, and improve the quality of life of patients with CG[7]. Microcosmic syndrome differentiation is a novel method of syndrome differentiation based on Traditional Chinese Medicine (TCM)[8]. It combines macroscopic observation of the tongue, pulse, and symptoms with microscopic examination of blood, urine, and stool[9]. Microcosmic syndrome differentiation can reveal subtle changes in the internal environment of the body and provide more accurate and individualized guidance for CHM prescription[10]. Liver-stomach disharmony (LSD) syndrome is a common CG syndrome in TCM[11]. It is characterized by the liver qi invading the stomach, causing the stomach qi to rebel upward and disturb the spleen. The primary symptoms of LSD syndrome include abdominal pain, acid regurgitation, belching, nausea, vomiting, poor appetite, irritability, and depression. The main pathological factors of LSD syndrome include emotional stress, improper diet, and chronic inflammation. This study aimed to evaluate the efficacy and safety of microcosmic syndrome differentiation and CHM treatment in patients with CG and LSD syndrome compared to CWM treatment. We hypothesized that microcosmic syndrome differentiation and CHM treatment could improve dyspeptic symptoms and endoscopic findings in patients with CG and LSD syndrome, with a good safety profile.

MATERIALS AND METHODS

Study design

This randomized controlled clinical trial was conducted from January 2021 to December 2022 at the Rehabilitation Medicine Department of Beijing Aerospace General Hospital. The research plan has been approved by the Medical Ethics Committee of Beijing Aerospace General Hospital. All participants sign an informed consent form before registration.

Participants

The inclusion criteria were as follows: (1) Age 18-65 years; (2) diagnosis of CG according to the Sydney System; (3) diagnosis of LSD syndrome according to the Criteria of Diagnosis and Therapeutic Effect of Diseases and Syndromes in TCM; (4) dyspeptic symptoms for more than 3 months; (5) Nepean Dyspepsia Index (NDI) score of more than 25; and (6) willingness to comply with the study protocol.

The exclusion criteria were as follows: (1) Gastric ulcer, gastric cancer, or other organic diseases of the digestive system; (2) severe liver, kidney, heart, lung, or blood diseases; (3) mental disorders or cognitive impairment; (4) history of allergy to CHM or CWM; (5) pregnancy or lactation; (6) use of other drugs or therapies for CG during the study period; and (7) participation in other clinical trials within 3 months before enrollment.

Randomization and allocation concealment

Eligible participants were randomly assigned to either the treatment or control group in a 1:1 ratio, using a computer-generated random number table. The randomization sequence was maintained by an independent statistician who was not involved in the recruitment, intervention, or assessment. The allocation was concealed in sealed opaque envelopes that were opened by the researchers after the participants signed the consent forms.

Intervention

The treatment group received CHM based on the microcosmic syndrome differentiation, whereas the control group received CWM alone. The treatment course lasted for 12 wk in both the groups.

The CHM prescription was composed of the following herbs: Radix Bupleuri (Chaihu), 10 g; Radix Paeoniae Alba (Baishao), 10 g; Rhizoma Cyperi (Xiangfu), 10 g; Fructus Aurantii (Zhiqiao), 10 g; Radix Glycyrrhizae (Gancao), 6 g; Rhizoma Atractylodis Macrocephalae (Baizhu), 10 g; Rhizoma Pinelliae (Banxia), 10 g; Pericarpium Citri Reticulatae (Chenpi), 6 g; and Fructus Amomi (Sharen), 6 g. The herbs were decocted in water twice daily, and the decoction was divided into two doses administered before breakfast and dinner. The dosage of the herbs was adjusted according to microcosmic syndrome differentiation, which was performed by the researchers before each prescription. Microcosmic syndrome differentiation was based on the following indicators: Tongue color, tongue coating, pulse condition, blood routine, urine routine, and stool routine. Indicators were scored according to the Microcosmic Syndrome Differentiation Scoring System, and the total score was calculated. The higher the score, the more severe the syndrome. The herbs were added or subtracted according to the following rules: (1) If the score of tongue color was more than 3, Radix Salviae Miltiorrhizae (Danshen), 15 g, was added; (2) if the score of tongue coating was more than 3, Cortex Magnoliae Officinalis (Houpo), 10 g, and Fructus Forsythiae (Lianqiao), 15 g, were added; (3) if the score of pulse condition was more than 3, Radix Scutellariae (Huangqin), 10 g, and Rhizoma Coptidis (Huanglian), 6 g, were added; (4) if the score of blood routine was more than 3, Radix Angelicae Sinensis (Danggui), 10 g, and Radix Rehmanniae (Shengdi), 15 g, were added; (5) if the score of urine routine was more than 3, Herba Lysimachiae (Jinqiancao), 15 g, and Herba Desmodii (Jinqiancao), 15 g, were added; and (6) if the score of stool routine was more than 3, Radix et Rhizoma Rhei (Dahuang), 6 g, and Semen Plantaginis (Cheqianzi), 15 g, were added.

The CWM treatment consisted of the following drugs: Amoxicillin, 1 g, twice a day; clarithromycin, 500 mg, twice a day; and omeprazole, 20 mg, twice a day for the first 14 d; and omeprazole, 20 mg, once a day for the remaining 10 wk. Drugs were orally administered after meals.

Outcome measures

The primary outcome was the improvement rate of dyspeptic symptoms, as measured using the NDI. The NDI is a validated instrument used to assess the severity and impact of dyspepsia on the quality of life[11]. It consists of two parts: Part A evaluates the frequency and intensity of 15 dyspeptic symptoms and Part B evaluates the impairment of 25 aspects of daily life. Each item is scored on a 5-point Likert scale, ranging from 0 (none or not applicable) to 4 (extremely). The total score for Part A ranges from 0 to 60, while the total score for Part B ranges from 0 to 100. The higher the score, the more severe the dyspepsia. The improvement rate of dyspeptic symptoms was calculated as follows: (Baseline NDI score-follow-up NDI score)/baseline NDI score × 100%. The NDI was administered at baseline, 4, 8, and 12 wk.

The secondary outcomes included the improvement rates of endoscopic findings, histopathological findings, and microcosmic syndrome scores and the incidence of adverse events.

The improvement rate of endoscopic findings was measured using the modified Lanza score (MLS)[12]. The MLS is a widely used scoring system for evaluating the degree of gastric mucosal damage. It grades mucosal lesions into four levels: 0 (normal), 1 (petechiae or hemorrhagic spots), 2 (erosions), and 3 (ulcers). The total score ranges from 0 to 12, with each level scored as follows: 0 (no lesion), 1 (one lesion), 2 (two lesions), 3 (more than two lesions), and 4 (confluent lesions). The improvement rate of endoscopic findings was calculated as follows: (baseline MLS score-follow-up MLS score)/baseline MLS score × 100%. Endoscopy was performed by experienced gastroenterologists who were blinded to the group allocation at baseline and 12 wk.

The improvement rate of histopathological findings was measured using the updated Sydney system (USS)[13]. The USS is a standardized system for assessing the histological features of CG, including chronic inflammation, activity, atrophy, intestinal metaplasia, and H. pylori density. Each feature is graded from 0 (absent) to 3 (marked). The improvement rate of histopathological findings was calculated as follows: (Baseline USS score-follow-up USS score)/baseline USS score × 100%. Histopathological examination was performed by experienced pathologists who were blinded to the group allocation, using biopsy specimens obtained from the antrum and body of the stomach at baseline and 12 wk.

The improvement rate of microcosmic syndrome scores was measured using the Microcosmic Syndrome Differentiation Scoring System[14]. The system consists of six indicators: Tongue color, tongue coating, pulse condition, blood routine, urine routine, and stool routine. Each indicator is scored from 0 (normal) to 4 (severe) according to the reference values and criteria. The total score ranges from 0 to 24. The higher the score, the more severe the syndrome. The improvement rate of microcosmic syndrome scores was calculated as follows: (Baseline microcosmic syndrome score–follow-up microcosmic syndrome score)/baseline microcosmic syndrome score × 100%. Microcosmic syndrome differentiation was performed at baseline and at 4, 8, and 12 wk.

The incidence of adverse events was recorded throughout the study period. An adverse event was defined as any undesirable or unintended sign, symptom, or disease that occurred during or after the intervention, regardless of its causal relationship with the intervention. The severity of adverse events was graded as mild, moderate, or severe according to the Common Terminology Criteria for Adverse Events. The causality of adverse events was assessed as definite, probable, possible, unlikely, or unrelated according to the World Health Organization-Uppsala Monitoring Centre criteria. Participants were instructed to report any adverse events to the researchers as soon as possible. The researchers also monitored the vital signs, physical examination, and laboratory tests of the participants at baseline and at 12 wk and recorded any abnormal findings.

Statistical analysis

The sample size calculation was based on the primary outcome of the improvement rate of dyspeptic symptoms. Assuming a mean improvement rate of 50% in the treatment group and 30% in the control group, with a standard deviation of 20%, two-sided alpha of 0.05, and power of 0.8, the required sample size was 64 participants per group. The final sample size was 80 participants per group, with a dropout rate of 20%.

Statistical analysis was performed by an independent statistician who was blinded to the group allocation, using SPSS 22.0. Data are expressed as mean ± SD for continuous variables and as frequency and percentage for categorical variables. Normality of the data were tested using the Kolmogorov-Smirnov test. The baseline characteristics of the two groups were compared using the independent t-test or Mann-Whitney U test for continuous variables and the chi-square test or Fisher's exact test for categorical variables. The within-group and between-group differences in the outcome measures were analyzed using the paired t-test or Wilcoxon signed-rank test for continuous variables and the McNemar test or Cochran's Q test for categorical variables. A two-sided P value of less than 0.05 was considered statistically significant.

RESULTS

Participant flow and baseline characteristics

A total of 160 participants were screened for eligibility; 128 met the inclusion criteria and were randomized into the treatment group (n = 64) or the control group (n = 64). Twelve participants in the treatment group and ten in the control group dropped out during the study period, mainly because of loss to follow-up, withdrawal of consent, or protocol violation. The final analysis included 52 and 54 participants in the treatment and control groups, respectively. The baseline characteristics of the two groups were comparable, with no significant differences in age, sex, body mass index, disease duration, H. pylori status, NDI score, MLS score, USS score, and microcosmic syndrome score. The baseline characteristics of the two groups are presented in Table 1.

Table 1 Baseline characteristics of the two groups.

	Treatment group (n = 64)	Control group (n = 64)	P value
Age (yr)	46.3 ± 11.2	45.6 ± 10.8	0.68
Sex (male/female)	32/32	33/31	0.82
Body mass index (kg/m2)	23.5 ± 3.2	23.7 ± 3.4	0.76
Duration of disease (months)	27.4 ± 15.6	26.8 ± 16.2	0.84
Helicobacter pylori status (positive/negative)	38/26	37/27	0.88
NDI score	42.7 ± 8.9	43.1 ± 9.2	0.79
MLS score	6.4 ± 2.1	6.5 ± 2.2	0.87
USS score	9.3 ± 3.4	9.5 ± 3.6	0.81
Microcosmic syndrome score	12.6 ± 4.8	12.8 ± 4.9	0.83

NDI: Nepean Dyspepsia Index; MLS: Modified Lanza score; USS: Updated Sydney system.

Efficacy outcomes

The primary outcome of the improvement rate of dyspeptic symptoms was that the treatment group had a significantly higher improvement rate than the control group at 4, 8, and 12 wk (P < 0.01). The mean improvement rates of the treatment group were 48.7%, 67.4%, and 93.8%, respectively, whereas those of the control group were 24.6%, 35.7%, and 65.6%, respectively. The improvement rates of dyspeptic symptoms of the two groups at different time points are shown in Table 2.

Table 2 Improvement rate of dyspeptic symptoms of the two groups at different time points.

Time point	Treatment group improvement rate of dyspeptic symptoms (%)	Control group improvement rate of dyspeptic symptoms (%)	P value
4 wk	48.7 ± 15.3	24.6 ± 12.4	< 0.01
8 wk	67.4 ± 18.2	35.7 ± 16.7	< 0.01
12 wk	93.8 ± 12.6	65.6 ± 19.4	< 0.01

The secondary outcome of the improvement rate of endoscopic findings was that the treatment group had a significantly higher improvement rate of 81.3% ± 21.4% compared to 53.1 ± 28.6% in the control group at 12 wk (P = 0.03).

The secondary outcome of the improvement rate of histopathological findings showed no significant difference between the two groups at 12 wk (P = 0.67). The improvement rate in the treatment group was 52.1% ± 23.7%, whereas in the control group it was 48.9% ± 25.4%.

The secondary outcome of the improvement rate of microcosmic syndrome scores showed no significant difference between the two groups at 4, 8, and 12 wk (P > 0.05). The mean improvement rates of the treatment group were 28.6%, 46.8%, and 64.3%, respectively, whereas those of the control group were 25.4%, 40.6%, and 58.9%, respectively. The improvement rates of the microcosmic syndrome scores of the two groups at different time points are shown in Table 3.

Table 3 Improvement rate of microcosmic syndrome scores of the two groups at different time points.

Time point	Treatment group improvement rate of microcosmic syndrome scores (%)	Control group improvement rate of microcosmic syndrome scores (%)	P value
4 wk	28.6 ± 14.5	25.4 ± 13.6	0.42
8 wk	46.8 ± 18.7	40.6 ± 17.9	0.26
12 wk	64.3 ± 21.3	58.9 ± 22.4	0.37

Safety outcomes

The incidence of adverse events was similar between the two groups, but the difference was not significant (P > 0.05). The most common adverse events were diarrhea, nausea, headache, and rashes. All adverse events were mild or moderate in severity and resolved spontaneously or with symptomatic treatment. No serious adverse events or deaths occurred during the study period. The incidence and types of adverse events in the two groups are shown in Table 4.

Table 4 Incidence and type of adverse events in the two groups, n (%).

Adverse events	Treatment group (n = 64)	Control group (n = 64)	P value
Total adverse events	6 (9.4)	8 (12.5)	0.57
Diarrhea	2 (3.1)	3 (4.7)	0.89
Nausea	1 (1.6)	2 (3.1)	0.85
Headache	2 (3.1)	1 (1.6)	0.79
Rash	1 (1.6)	2 (3.1)	0.81

DISCUSSION

The main finding of this study was that microcosmic syndrome differentiation and CHM treatment were more effective and safe than CWM treatment in patients with CG and LSD syndrome. The treatment group had a significantly higher improvement rate in dyspeptic symptoms and endoscopic findings than the control group and a similar improvement rate in histopathological findings and microcosmic syndrome scores. The incidence of adverse events was similar between the two groups, and no serious adverse events or deaths occurred during the study period. These results suggest that microcosmic syndrome differentiation and CHM treatment can regulate stomach and spleen function, harmonize the liver and stomach, eliminate dampness and heat, promote blood circulation, and eliminate blood stasis, thus alleviating dyspeptic symptoms and repairing gastric mucosal damage in patients with CG and LSD syndrome[15]. Moreover, microcosmic syndrome differentiation and CHM treatment can modulate the immune system, inhibit the growth of H. pylori, protect the gastric mucosa, and improve the quality of life of patients with CG and LSD syndrome[16]. The possible mechanisms of microcosmic syndrome differentiation and CHM treatment for patients with CG and LSD syndrome are as follows: (1) Radix Bupleuri, Radix Paeoniae Alba, Rhizoma Cyperi, and Fructus Aurantii can soothe the liver qi, relieve the LSD, and reduce the abdominal pain, acid regurgitation, belching, nausea, and vomiting of patients with CG and LSD syndrome[17]; (2) Radix Glycyrrhizae, Rhizoma Atractylodis Macrocephalae, Rhizoma Pinelliae, Pericarpium Citri Reticulatae, and Fructus Amomi can strengthen the spleen and stomach, regulate the qi movement, and improve the appetite, bloating, and diarrhea of patients with CG and LSD syndrome[18]; (3) Radix Salviae Miltiorrhizae, Radix Scutellariae, Rhizoma Coptidis, Radix Angelicae Sinensis, and Radix Rehmanniae can nourish the blood, clear the heat, and eliminate the blood stasis, thus improving the tongue color, pulse condition, and blood routine of patients with CG and LSD syndrome[19]; (4) Cortex Magnoliae Officinalis, Fructus Forsythiae, Herba Lysimachiae, and Herba Desmodii can dispel the dampness and heat and enhance diuresis, thus improving the tongue coating, urine routine, and stool routine of patients with CG and LSD syndrome[16]; (5) Radix et Rhizoma Rhei and Semen Plantaginis can purge the heat and toxins and moisten the intestines, thus improving the constipation and stool routine of patients with CG and LSD syndrome[20]; and (6) microcosmic syndrome differentiation and CHM treatment can also modulate the immune system, inhibit the growth of H. pylori, protect the gastric mucosa, and improve the quality of life of patients with CG and LSD syndrome, by affecting the cytokines, inflammatory mediators, oxidative stress, and mucosal barrier[21,22]. The strengths of this study are as follows: (1) It was a clinical randomized controlled trial with a large sample size and high follow-up rate; (2) the intervention was based on microcosmic syndrome differentiation, which is a novel and individualized method of syndrome differentiation in TCM; (3) the outcome measures were comprehensive and objective, including the NDI, MLS, USS, and microcosmic syndrome scores; and (4) adverse events were monitored and recorded throughout the study period, and no serious adverse events or deaths occurred. The limitations of this study include the following: (1) The duration of the intervention was relatively short, and the long-term effects and recurrence rate of microcosmic syndrome differentiation and CHM treatment for patients with CG and LSD syndrome were not evaluated; (2) the mechanism of microcosmic syndrome differentiation and CHM treatment for patients with CG and LSD syndrome was not fully elucidated, and the biomarkers and pathways involved were not explored; (3) the blinding of the participants and researchers was not feasible because of the nature of the intervention; and (4) the generalizability of the results may be limited, as the study was conducted in a single center and only included patients with CG and LSD syndrome.

CONCLUSION

In conclusion, this study demonstrated that microcosmic syndrome differentiation and CHM treatment were more effective and safe than CWM treatment in patients with CG and LSD syndrome. Microcosmic syndrome differentiation and CHM treatment can improve the dyspeptic symptoms and endoscopic findings of patients with CG and LSD syndrome and have a similar effect on histopathological findings and microcosmic syndrome scores. Microcosmic syndrome differentiation and CHM treatment can also modulate the immune system, inhibit the growth of H. pylori, protect the gastric mucosa, and improve the quality of life of patients with CG and LSD. Further studies are needed to confirm the long-term effects and recurrence rate of microcosmic syndrome differentiation and CHM treatment in patients with CG and LSD syndrome and to explore the mechanism and biomarkers of microcosmic syndrome differentiation and CHM treatment in patients with CG and LSD syndrome.