Gai-Ya Gao, Jing-Dong Xue

1. Shaanxi university of traditional Chinese medicine,xianyang 712046,China

2. Shaanxi provincial hospital of traditional Chinese medicine,xi 'an 710004,China

Keywords:Non-alcoholic fatty liver TCM constitution Correlation System evaluation Meta analysis

ABSTRACT Objective: Through literature research,the distribution of TCM constitution of nonalcoholic fatty liver (NAFLD) was discussed, the common constitution types of the disease were determined, and medical evidence was provided for the prevention and treatment of NAFLD by traditional Chinese medicine. Methods: The literatures on the correlation between NAFLD and TCM constitution published in domestic journals from the database establishment to April 2020 were searched with "non-alcoholic fatty liver disease and TCM constitution" as the search term, and screening, quality evaluation and data extraction were conducted according to the na exclusion criteria. Statistical software stata16.0 was used for meta analysis of the included literature. Results: Sixteen studies were included. The results showed that the proportions of TCM constitution types and 95%CI of NAFLD patients were phlegmdampness0.28(0.24,0.31), moisture-heat0.16(0.13,0.20),qi-asthenia0.13(0.10,0.16),qistagnation0.11(0.06,0.17),qi-stagnation0.08(0.06,0.10),yi-stagnation0.08(0.06,0.10),yi--stagnation0.08(0.06,0.10), blood stasis0.07(0.04, 0.08), yang-asthenia0.06(0.04,0.08),and special report 0.02(0.01,0.02). Conclusion: The common constitution types of patients with nonalcoholic fatty liver are phlegm-dam-pness, damp-heat, q-asthenia and mild, especially phlegm-dampness, which are most closely related to nonalcoholic fatty liver.

1. Introduction

In recent years, with the continuous development of social economy and the change of people's lifestyle, obesity, diabetes and metabolic syndrome have shown a global trend, and non-alcoholic fatty liver (NAFLD) has become the main cause of chronic liver disease in many countries in the world, including China [1].Previous studies have shown that the prevalence of NAFLD in ordinary adults is 6.3% to 45%[2].At present, the etiology and pathogenesis of NAFLD have not been clear, and the western medicine treatment is still in the clinical trial stage, so there is currently a shortage of ideal targeted specific drugs, while the theory of traditional Chinese medicine has certain advantages in the field of NAFLD prevention and treatment.Currently, researches on TCM constitution types based on NAFLD population are increasing year by year, providing a large amount of data for TCM constitution distribution of NAFLD patients.However, there is no systematic analysis and summary of the existing research literature.Therefore, it is necessary to conduct a meta-analysis of the clinical literature on TCM constitution of NAFLD patients, so as to obtain a larger sample size of TCM constitution distribution data of NAFLD patients, determine the type of constitution prone to the disease, and provide evidence-based medical evidence for clinical and scientific research.

2. Materials and methods

2.1 Literature retrieval

The research literature on the correlation between NAFLD and TCM constitution type published by zhiwang, wanfang and weipu was searched by computer.The search term "non-alcoholic fatty liver, traditional Chinese medicine constitution" was used.The retrieval period is from database construction to April 2020.

2.2 Inclusion and exclusion criteria

Inclusion criteria: (1) case-control study and cross-sectional study on the correlation between NAFLD and TCM constitution type;(2)Patients with NAFLD have clear diagnostic criteria;(3)Constitution identification according to the classification and judgment standards of TCM constitution proposed by Chinese medical association [3];(4)The Research index was the proportion of various TCM constitutions in NAFLD patients.Exclusion criteria: (1) inconsistent with the research subject;(2) the included research objects are combined with other organic diseases that may affect the type of TCM constitution;(3)Repeated publication and incomplete result data;(4)Reviews, editorials, letters, reviews, etc.

2.3 Data screening and extraction

Independent literature screening, data extraction and crosschecking were conducted by two researchers according to the exclusion criteria. If there is any doubt or disagreement, it shall be resolved through discussion or negotiation with a third party.Data extraction included: author information, publication date, study area, survey subjects, study type, time, sample size, mean age, sex ratio, diagnostic criteria, constitution type, quality score.

2.4 Quality evaluation

The quality of case-control study methodology was evaluated using the newcastle-ottawa scale (NOS) [4], with a full score of 9 and a score higher than 6 as high quality.The standard recommended by the American institute of health care quality and research (AHRQ) [4] was selected for the cross-sectional study, with a full score of 11, 0 to 3 being low quality, 4 to 7 being medium quality, and 8 to 11 being high quality.

2.5 Statistical analysis

Stata16.0 software was used for meta analysis of single group rate, the rate of each included study and its standard error were calculated, the heterogeneity was determined qualitatively by p-value and quantitatively by I2, and the meta-analysis model was selected to obtain the combined "incidence" and 95%CI.

3. Results

3.1 Retrieval process and results a total of 118 articles were retrieved from major databases.After screening, 16 studies were finally included [5-20].The literature selection process and results are shown in figure 1.

Figure. 1 Flow chart of literature selection

3.2 Research status included

Of the 16 included studies, 2 [19-20] were case-control studies and 14 [5-18] were cross-sectional studies.Published between 2013 and 2019, the total sample size of the included study was 10,982, including 8734 patients with NAFLD and 2248 patientsin the control group.The study covered nine provinces and cities, including guangdong, hunan, jiangsu, guizhou, Shanghai, Beijing, fujian, zhejiang and xinjiang.Sources of cases included outpatient, inpatient, physical examination center, B - ultrasound room and community investigation.In diagnostic criteria, 11 [5, 8, 10, 13, 16] using liver diseases of Chinese medical association of fatty liver and alcoholic liver disease group. The nonalcoholic fatty liver disease diagnosis and guide (2010 edition), 4 study [7, 9, 11, 12] by 2006 the nonalcoholic fatty liver disease diagnosis and treatment guidelines, 1 study [6] the 2002 "nonalcoholic fatty liver disease diagnosis and treatment guidelines".Eight items [5-7, 10-13, 17] are journal papers, and eight items [8, 9, 14-16, 18-20] are dissertations.In terms of quality evaluation, the 2 included case-control studies were evaluated according to NOS scale, and the response rate was not mentioned in either of them. 1 [15] study was not adequately controlled for confounding factors, and 1 [16] study was not sufficiently determined for exposure. The remaining items were all consistent, so the score was 7, suggesting that the study quality was high and the risk of bias was low.According to AHRQ to evaluate 14 into the crosssectional study, all research has been clear about the source, lists the exposure group and non exposed group of discharge standards, and identifies patients are given the time period, and 1 study [6] described in order to ensure the quality and to evaluate, 2 study [8, 9] describes the analysis of patients with any reason, 1 study [9] describes the analysis of how to deal with missing data, 8 study [6, 8, 9, 12, 13, 16 and 18] describes the measures to control confounding factors,None of the studies addressed whether the subjects were continuous, followup, evaluators' subjective factors, patient response rates, and data collection integrity.It is suggested that there is a certain publication bias. See table 1.

Table 1 included the basic characteristics of the study

3.3 Meta analysis of the distribution of TCM constitution types

The results of meta-analysis indicated that there was significant heterogeneity among the studies, and the combined "incidence" and its 95%CI were obtained by using the random effect model, in which the results with the incidence ≥10% were shown in the forest map, and the results with the incidence <10% were shown in the table.

3.3.1 The proportion of qi-asmodic in NAFLD patients (793 cases) was reported in all the 16 studies included, and the random-effect model was selected, suggesting that the proportion of qi-asmodic in NAFLD patients was 0.13[95%CI (0.10,0.16),P<0.0001].As shown in figure 2.

Figure. 2 meta analysis of proportion of qi-deficient mass in NAFLD patients

3.3.2 The proportion of placidity in NAFLD patients (1426 cases) was mentioned in 15 studies, and the random-effect model was used, suggesting that the proportion of placidity in NAFLD patients was 0.11[95%CI(0.06,0.17),P<0.0001] .As shown in figure 3.

Figure 3 meta analysis of the proportion of patients with NAFLD with moderate quality

3.3.3 The proportion of hyg in NAFLD patients (1454 cases) was mentioned in all the 16 studies, and the random effect model was selected, suggesting that the proportion of hyg in NAFLD patients was 0.16[95%CI(0.13,0.20),P< 0.0001]. As shown in figure 4.

Figure 4 meta analysis of the proportion of patients with NAFLD with moderate quality

3.3.4 Sputum and dampness the proportion of sputum and dampness in NAFLD patients (2,586 cases) was mentioned in 16 studies, and the random-effect model was selected, suggesting that the proportion of sputum and dampness in NAFLD patients was 0.28[95%CI (0.24,0.31),P<0.0001].As shown in figure 5.

Figure. 5 meta analysis of the proportion of phlegm and dampness in patients with NAFLD

3.3.5Other constitution types the distribution ratio of 5 TCM constitution types in NAFLD population is less than 10%, and from low to high, they are in the order of special report quality, Yang deficiency quality, blood stasis quality, Yin deficiency quality, and qi stagnation quality, as shown in table 2.

Table 2 meta analysis results of 5 rare TCM constitution types in NAFLD patients

3.4 Subgroup analysis

The 16 included studies covered six regions in north, east, central, south, northwest and southwest China.According to the study area, 7 studies in east China, 2 in north China and 4 in south China were included in the subgroup analysis.

Results the proportion of TCM constitution type of NAFLD patients in eastern China from low to high was 2% [95%CI (0.01, 0.03), p < 0.001], 4% [95%CI (0.03, 0.06), p < 0.001], 6% [95%CI (0.04, 0.09), p < 0.001], 8% [95%CI (0.02, 0.14), p < 0.001], and 9% [95%CI (0.06, 0.12), p < 0.001].Yin quality 10% [95% CI (0.07, 0.13), p < 0.001], hot and humid mass 12% [95% CI (0.09, 0.15), p < 0.001], the deficiency of qualitative 17% [95% CI (0.09, 0.24), p < 0.001], phlegmy wet mass 29% [95% CI (0.28, 0.31), p = 0.48).

The proportion of TCM constitution type in NAFLD patients in south China was 2% [95%CI (0.01, 0.04), p = 0.071], 3% [95%CI (0.01, 0.05), p < 0.001], 4% [95%CI (0.02, 0.06), p = 0.088], and 4% [95%CI (0.03, 0.05).10%, p = 0.745), the deficiency of qualitative [95% CI (0.04, 0.15), p < 0.001] peace and 11% [95% CI (0.05, 0.18), p < 0.001), blood stasis quality 13% [95% CI (0.07, 0.06), p < 0.019], hot and humid mass 26% [95% CI (0.17, 0.36), p < 0.001], phlegmy wet mass 29% [95% CI (0.23, 0.35), p < 0.001).

The proportion of TCM constitution type of NAFLD patients in north China from low to high was 2% [95%CI (0.00, 0.04), p = 0.0217], 4% [95%CI (0.00, 0.08), p = 0.052], 8% [95%CI (0.05, 0.11), p = 0.842], 8% [95%CI (0.00, 0.16), p = 0.027], 12% [95%CI (0.09, 0.16), p = 0.454],Hot and humid mass 13% [95% CI (0.10, 0.17), p = 0.407), qi depression mass 14% [95% CI (0.10, 0.17), p = 0.916), the deficiency of qualitative 16% [95% CI (0.12, 0.20), p = 0.528), phlegmy wet mass 23% [95% CI (0.15, 0.31), p = 0.124).

4. Discussion

4.1 Analysis of the reasons for the high distribution ratio of phlegm and dampness

The distribution of TCM constitution types in NAFLD patients was significantly different from that in non-nafld patients.Professor wang qi [21] conducted a large sample survey on the distribution of TCM constitution types, covering 21,948 people in 9 provinces and cities. The results showed that the proportion of mild quality in the general population was the largest (32.14%), followed by qi-deficiency quality, dam-heat quality and yang-deficiency quality, which were 13.42%, 9.08% and 9.04% respectively.In this NAFLD study, 11% of the patients were mild, and the largest proportion was phlegm and dampness, up to 28%.The reason may be related to the particularity of phlegm-dampness constitution itself, which is a common and relatively stable pathological constitution of individuals, and forms the dual effects of the preexisting and acquired environmental factors [22].Wang in the yuan dynasty has stated in "phlegm syndrome" as early as "parents have phlegm disease, I report this disease, then with born born also", "lu shi chunqiu." "form does not move is fine flow, fine flow is qi yu" and "miscellaneous disease source flow rhinoceron" "eat too much, good eating fat, so bad temper, obstructed into phlegm".

4.2 Methodological problems in the research

The quality control, into the study of various literature information report of law is not comprehensive, most of the research is simply describes the data sources, standards and to identify patients with time, the research object is the continuous, follow-up, confounding factors control, quality control and eliminate any patients with reason analysis, loss of data processing, the response rate and the integrity of the data collected are not report, increase the risk of the conclusion of bias and heterogeneity.As for the detailed design of the study, first of all, the original literature included in the study provided insufficient information, so the relationship between gender, age and other factors and the constitution type of NAFLD could not be studied and analyzed.All these factors may bias the research results and bring some difficulties for future research.

5. Conclusion

Through a meta-analysis of clinical literature on TCM constitution of NAFLD patients, it was found that phlegm and dampness, heat and humidity, qi deficiency and calmness were the main constitution types and risk factors of NAFLD patients, and the most common predisposition type was phlegm and dampness.Traditional Chinese medicine has always attached great importance to "preventing disease before disease and preventing disease from changing". In addition, the constitution of traditional Chinese medicine is adjustable and NAFLD has the disease transmutation trend of simple fatty liver, fatty hepatitis, fatty liver fibrosis, cirrhosis and even liver cancer.Therefore, it is suggested that the future research should pay attention to the early intervention of TCM constitution, distinguish the body and recuperate, correct the transformation of the constitution of diseases prone to disease, prevent the disease first, so as to reduce the incidence of diseases.