Background: Non-alcoholic fatty liver disease (NAFLD) is a common liver disease that may progress into, in the absence of proper treatment, severe liver damage. While the optimal pharmacotherapy for NAFLD remains uncertain and the adherence to lifestyle interventions is challenging, the use of herbal medicines such as traditional Chinese medicines (TCMs) to manage the condition is common. The evidence about TCMs in the management of NAFLD is continuously developing through randomized controlled trials (RCTs). This study aims to identify and evaluate the emerging evidence about the efficacy and safety of TCMs for NAFLD. Methods: A systematic literature search was conducted to identify RCTs which investigated TCMs in the management of NAFLD published in 6 electronic databases including PubMed, the Cochrane Library, EMBASE, Web of Science, Scopus and China National Knowledge Infrastructure since inception to September 2020. RCTs comparing TCMs with no treatment, placebo, non-pharmacological and/or pharmacological interventions were included irrespective of language or blinding. The quality of reporting was evaluated using the Consolidated Standards of Reporting Trials Statement extensions for Chinese herbal medicine Formulas (CONSORT-CHM). Risk-of-bias for each study was assessed using the Cochrane risk of bias tool. Results: A total of 53 RCTs involving 5997 participants with NAFLD were included in this review. Each included RCT tested a different TCMs giving a total of 53 TCMs identified in this study. Based on the evaluation of the RCT results, TCMs might have various beneficial effects such as improving TCM syndrome score, liver function, and body lipid profile. A range of non-serious, reversible adverse effects associated with the use of TCMs were also reported. However, no conclusion about the efficacy and safety of TCMs in NAFLD can be made. The quality of reporting was generally poor and the risks of bias was mostly uncertain in all trials. Conclusions: There is some evidence from RCTs that supported the effectiveness and safety of TCMs for NAFLD. However, no conclusive recommendations can be made due to the questionable quality of the RCTs. Improvement in the RCT protocol, the use of a larger sample size, a setting of multicenter, and a more focused approach in selecting TCMs are recommended for developing high quality evidence about the use of TCMs in managing NAFLD.
Keywords: Non-alcoholic fatty liver disease; Traditional Chinese medicine; Randomized clinical trial; RCT; CONSORT-CHM; Risk of bias
Zuanji Liang and Xianwen Chen share co-first authorship
Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease that refers to liver steatosis in the absence of significant alcohol consumption, use of susceptible medication, or other pre-existing liver condition or infections that result in fat accumulation [[
In light of limited treatment options for NAFLD, herbal medicines, with traditional Chinese medicines (TCMs) in particular, have become an increasingly common healthcare choice for patients to manage or even treat the disease [[
In recent years, increasing number of RCTs have been conducted to investigate the benefits and risks of TCMs in treating NAFLD. A systematic review conducted in 2013 assessed the benefits and risks of herbal medicines (including TCMs) for people with NAFLD and reported that some of the herbal preparations investigated seemed to have positive efforts on selected clinical indicators without inducing increased risks of adverse effects compared to the control groups [[
This systematic review was conducted in compliance with the Preferred Reporting Items for Systematic Reviews and Meta analyses (PRISMA-P guidelines) [[
Randomized, double or triple-blinded, controlled trials which investigated the use of TCMs in NAFLD irrespective of blinding, publication status or date of publication, published in English or Chinese were considered for inclusion in this study. Quasi-randomized and observational studies were excluded. In this review, TCMs encompassed preparations which might include the use of the plant, animal materials, and mineral substances in preparations administered as capsules, tablets, teas, decoctions, granules and powders according to the unique principles and comprehensive theory of Traditional Chinese Medicine. In additional, TCM preparations which contained TCMs listed in TCM related standards such as the Chinese Pharmacopoeia [[
Participants of any age, gender or ethnic origin with a clear diagnosis of NAFLD irrespective of the diagnostic method, diabetic status or the presence of non-alcoholic steatohepatitis (NASH) were eligible for the studies. We excluded RCTs in which participants recorded had viral hepatitis, liver function decompensation, other liver diseases or undergone liver transplantation previously.
For inclusions, RCTs which compared TCMs alone or TCMs in combination with behavioral interventions against placebo, no treatment, pharmacological therapy and/or other behavioral interventions were considered. Behavioral interventions referred to lifestyle interventions such as dietary modification and/or exercise regime. Pharmacological therapies referred to any other medicinal herbs not considered TCMs or conventional medicines such as prescription medicines regardless of the mechanisms of actions.
In order to address the objectives of this study, both efficacy and safety of the TCMs investigated in the RCTs included in this review were to be analyzed. As such, the primary and the secondary outcomes of managing NAFLD with the use of TCMs included the following:
The primary outcome measures considered included changes in TCM syndrome score and experiences in adverse reactions. According to the Chinese Medicine Clinical Research of New Drugs Guiding Principles [[
On the other hand, adverse reactions experienced during or immediately after the intervention duration would be considered. Depending on the availability of data, adverse events would be classified as serious or non-serious. A serious adverse reaction was defined as any effects that could increase mortality; was life-threatening; required hospitalization; resulted in persistent or significant disability; caused a congenital anomaly or birth defect, or any important medical event that might have jeopardized the health of the patients. Non-serious adverse events, on the other hand, referred to any untoward medical occurrence not necessarily having a causal relationship with the treatment, but resulting in a dose reduction or discontinuation of treatment (at any time after commencement of treatment) [[
The secondary outcome measures were considered as the followings [[
- Radiological response which indicated the degree of fatty liver infiltration assessed by B-ultrasound, computed tomography, magnetic resonance spectroscopy (MRS), or other imaging techniques).
- Liver function as reflected by the serum activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatases (ALP), gamma-glutamyl-transpeptidase (GGT), total bilirubin (TB), direct bilirubin (DB), total serum protein (TP), albumin (ALB), or albumin/globulin ratio (A/G).
- Indicators of body weight which might include the body mass(BM), body mass index (BMI), and waist hip ratio (WHR).
- Blood sugar which referred to the fasting blood glucose (FBG), fasting plasma insulins (FINs), and homeostasis model assessment-estimated insulin resistance (HOMA-IR).
- Blood lipids such as serum activities of triglyceride (TG), total cholesterol (TC), high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), and cholesterol (CHOL).
- Other secondary outcome might include diamine oxidase (DAO), lipopolysaccharide, D-lactic acid, Claudin-1, Claudin-4, high sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-α and so on.
This systematic review was performed according to the PRISMA-P guidelines [[
Table 1 Search term identifiers
Category Entry search terms in English Entry search terms in Chinese RCT Clinical 隨機AND對照AND臨床試驗 Triala 隨機AND對照AND臨床研究 隨機AND對照AND臨床觀察 NAFLD "Nonalcoholic fatty" 非酒精性脂肪肝 "Non-alcoholic fatty" 非酒精性脂肪性肝病 "Non-alcoholic fatty liver disease" [mesh] 非酒精性脂肪性肝炎 Nonalcoholic AND "fatty liver" [mesh] Non-alcoholic AND "fatty liver" [mesh] NAFLD "Nonalcoholic steatohepatitis" TCM Phytotherapy 中醫 Herbal medicinea 中藥 Plant preparationa 草藥 Chinese medicinea Complementary medicinea "Drugs, Chinese herbal" [Mesh] "Medicine, Chinese traditional" [Mesh] "Medicine, traditional" [Mesh] "Plant preparations" [Mesh] Medicinal planta Plant medicinal producta Herba
AND retrieves results that include all the search terms
The title, abstract and full text of each study were screened for meeting the inclusion criteria. The process of screening for inclusion consisted of 2 rounds of assessment. In Round 1, the title and the abstract were studied to exclude non-TCMs related RCTs. The following studies were also excluded from the first round of screening (
The title and abstract was separately screened by 2 of the authors (ZL, XC) according to the inclusion criteria outlined above. Full texts of potentially relevant articles were retrieved for detailed assessment. The Cochrane evaluations and CONSORT-CHM statement evaluation were independently performed by two of the authors (ZL, XC) following the guidelines, and the disagreements were discussed and resolved by discussion or consultation with two other authors (JS, COLU).
Endnote X9 was used to categorize and file all the references. Excel 2013 was used to extract data and record. A standard extraction form was used to extract relevant data from the eligible trials, which contained the basic information of study, methods, intervention, participants, outcomes, overall findings, etc. The main information extracted from each included studies for further analysis is listed in the following:
- Basic information of study
- First author and publication year; and
- Language.
• Methods
- Trial design;
- Date of trial;
- Setting of trial;
- Inclusion and exclusion of patients; and
- Diagnosed criteria (integration medicine or western medicine).
- Intervention
- Treatment drugs;
- Using does;
- Interment duration;
- lifestyle intervention; and
- Follow-up period.
- Participants
- The number of participants randomized;
- The number of participants analyzed;
- Sex ratio, history of NFALD, mean age; and
- Dropouts.
- Outcomes
- Primary outcomes;
- Secondary outcomes;
- Overall findings
- Efficacy rate;
- Statistical difference in the efficacy;
- Safety information.
Two of the authors (ZL, XC) evaluated the risk of bias of each trial independently in accordance with the Cochrane Handbook for Systematic Reviews of Interventions [[
- Sequence generation
- Low risk of bias: clearly indicate the method used (e.g., table of random numbers, random block or computer random number generation);
- Unclear risk of bias: no specified information about the methods; and
- High risk of bias: no mentioned about the methods.
- Allocation concealment
- Low risk of bias: the participants were allocated table of random numbers, random block or computer random number generation;
- Unclear risk of bias: no specified information about the allocation methods (e.g. only reported the ratio of different groups); and
- High risk of bias: no mentioned about the allocation methods.
- Blinding
- Low risk of bias: the study authors described the trial as blinding and mentioned the methods of blinding;
- Unclear risk of bias: the study authors mentioned used blinding methods without any descriptions of blinding; and
- High risk of bias: no mentioned about the blinding and the methods.
- Incomplete outcome data
- Low risk of bias: the study authors reported the number of dropouts and withdrawals, and described the reason or reported there was no dropouts or withdrawals;
- Unclear risk of bias: the study author reported there was dropout or withdrawals without any specified information; and
- High risk of bias: no mentioned about dropout or withdrawals.
- Selective outcome reporting
- Low risk of bias: the study authors reported predefined, or clinically relevant and reasonably expected outcomes;
- Unclear risk of bias: the study authors did not report all predefined, or clinically relevant and reasonably expected outcomes, or the data reported did not match the methods; and
- High risk of bias: no mentioned about the predefined, or clinically relevant and reasonably expected outcomes.
- Other bias
- Low risk of bias: the trial appeared no other components that may cause the risk of bias;
- Unclear risk of bias: the trial may or may not have other components that may cause the risk of bias. and
- High risk of bias: there were other factors in the trial that could put it at risk of bias (e.g. the differences of baseline, for-profit involvement, and inappropriate intervention design).
Each article included was independently assessed by two of the authors (ZL, XW). Disagreements were settled through discussion or consultation with the other two authors (JS, COLU). The 25-item version of the CONSORT CHM statement was used to assess for the quality of the trials included. The checklist provides a set of guidelines that may be used to identify the strengths and weaknesses of clinical trials for the treatments of TCM intervention. To measure compliance, a grading system was devised for each criterion, where the reviewer gave a score of "0" if the item was not present at all, a "1" if the feature was partially present, for instance, some aspects of the CONSORT item were missing or being described unclearly, and a "2" if the item was present and clear. By applying the CONSORT criteria for all relevant sections of each study, an overall summary of the reporting quality of the included RCTs was produced. The evaluation method and results were independently checked for validity and consistency by all 6 authors.
The screening process conducted in accordance with the PRISMA guidelines is summarized in the flow diagram as shown in Fig. 1. A total of 954 citations were identified in the initial searches from the selected electronic databases and related sources. After the removal of duplications, 817 potentially relevant articles were retained for further assessment. Due to a range of reasons, 761 records were further excluded after Round 1 of the screening process (reading titles and abstracts): not randomized trials, review or meta-analysis or protocol articles, pharmacodynamics or pharmacology studies, acupuncture studies, other disease studies, or combined other diseases studies, or herbal ingredients not listed in the TCMs-related standards [[
Graph: Fig. 1 PRISMA flow-chart of study selection
Among the 53 publications included in this review, 48 were published in Chinese and only 5 were published in English [[
Table 2 Basic descriptions of the studies included in this review
No Authors, year TCM name in the test group TCM component Diagnosis criteria of NAFLD History of NAFLD Number of participants in total (test group, control group) Number of male, female Participants' mean age (years old) 1 Wu et al., 2020 [ Jianpi Qingzhi prescription Atractylodis Macrocephalae Rhizoma, Alismatis Rhizoma, Crataegi Fructus, Curcumae Radix, Poria, Cassiae Semen, etc. IM T: 3.05 ± 0.61 years C: 2.96 ± 0.67 years 60 (30, 30) 35, 25 T: 49.22 ± 5.65 C: 48.96 ± 5.71 2 Lyv et al., 2020 [ Shenge formula Codonopsis Radix, Puerariae Lobatae Radix, Atractylodis Rhizoma, Atractylodis Macrocephalae Rhizoma, Salviae Miltiorrhizae Radix Et Rhizoma, etc. WM N/A 65 (34, 31) 37, 28 T: 42.03 ± 13.91 C: 44.94 ± 13.09 3 Yang et al., 2019 [ Yanggan Jieyu granule Moutan Cortex, Gardeniae Fructus, Angelicae Sinensis Radix, Paeoniae Radix Alba, Radix Bupleuri, Poria, etc. IM N/A 65 (30, 30) 37, 28 T: 42.03 ± 13.91 C: 44.94 ± 13.09 4 Yang et al., 2019 [ Qinjiang Baoling decoction Radix Bupleur, Paeoniae Radix Alba, Gynostemmatis Herba, Schisandrae Chinensis Fructus, Curcumae Rhizoma, Poria, etc. IM T: 21.3 ± 13.4 months C: 20.9 ± 12.7 months 100 (50, 50) 59, 41 T: 57.3 ± 12.2 C: 51.7 ± 10.3 5 Li et al., 2018 [ Qutan Huoxue decoction Atractylodis Macrocephalae Rhizoma, Gynostemmatis Herba, Curcumae Longae Rhizoma, Rhodiolae Crenulatae Radix Et Rhizoma, etc. IM N/A 140 (63, 62) 113, 27 T: 42.01 ± 9.60 C: 41.43 ± 9.31 6 Chen et al., 2017 [ Shuangqing granule Gynostemmae Herba, Salviae Miltiorrhizae Radix Et Rhizoma, Polygonum Cuspidati Rhizoma Et Radix, Artemisia Scopariae Herba, and Nelumbinis Folium IM T: 0.5–8 years C: 0.6–7 years 103 (78, 25) 49, 53 Range: 18–65 7 Hu et al., 2017 [ Jianpishugan and Huoxuehuatan formulae Astragali Radix, Radix Bupleuri, Atractylodis Macrocephalae Rhizoma, Alismatis Rhizoma, Cassiae Semen, Angelicae Sinensis Radix, etc. IM T: 1–12 years C: 1–13 year 140 (70, 70) 83, 57 T: 42.9 ± 5.3 C: 43.2 ± 5.7 8 Jiang et al., 2017 [ Dahuang Lidan capsule Rhei Radix Et Rhizoma, Phyllanthi Fructus and Radix Gymnadeniae IM N/A 144 (72, 72) 104, 40 T: 43.0 ± 0.03 C: 43.4 ± 7.60 9 Yang et al., 2017 [ Cigu Xiaozhi capsule Cremastrae Pseudobulbus, Alismatis Rhizoma, Crataegi Fructus, Salviae Miltiorrhizae Radix Et Rhizoma, Radix Bupleuri, Pinelliae Rhizoma Praeparatum, Cassiae Semen, etc. WM N/A 87 (43, 44) 50, 37 T: 49.02 ± 11.19 C: 50.63 ± 10.97 10 Jeong et al., 2017 [ HL tablet Extract of WM N/A 72 (22, 23, 23)* 54, 18 H: 39.1 ± 9.5 L: 45.5 ± 11.5 C: 42.7 ± 11.2 11 Sun et al., 2017 [ Jianpi Qushi prescription Codonopsis Radix, Poria, Microctis Folium, Microctis Folium, Crataegi Fructus, Cassiae Semen, Pogostemonis Herba, etc. IM T: 3.41 ± 2.56 years C: 4.02 ± 2.73 years 120 (60, 60) 67, 53 T: 34.61 ± 12.47 C: 36.37 ± 10.25 12 Niu, 2016 [ Shugan Jianpi Huatan decoction Codonopsis Radix, Atractylodis Macrocephalae Rhizoma, Poria, Alismatis Rhizoma, Coicis Semen, Artemisia Scopariae Herba, Radix Bupleuri, Curcumae Radix, Salviae Miltiorrhizae Radix Et Rhizoma, etc. IM T: 3.3 ± 0.4 years C: 3.5 ± 0.8 years 120 (60, 60) 72, 48 T: 47.2 ± 2.7 C: 46.4 ± 2.4 13 Zhang et al., 2016 [ Yiqi Qizhu decoction Atractylodis Macrocephalae Rhizoma, Astragali Radix, Poria, Citri Pericarpium Reticulatae, Radix Bupleuri, Curcumae Radix, Coicis Semen, Pogostemonis Herba, etc. IM N/A 104 (52, 52) 67, 37 T: 24–60 C: 25–58 14 Zhang et al., 2016 [ Jiang Zhi granules Gynostemmatis Herba, Polygonum Cuspidati Rhizoma Et Radix, Artemisia Scopariae Herba, Salviae Miltiorrhizae Radix Et Rhizoma and Nelumbinis Folium IM N/A 144 (73, 71) 110, 34 T: 42.4 ± 11.6 C: 44.8 ± 11.4 15 Qi et al., 2016 [ Jiangpi Shugan Huoxue Huatan decoction Radix Bupleuri, Curcumae Radix, Atractylodis Macrocephalae Rhizoma, Pinelliae Rhizoma Praeparatum, Artemisia Scopariae Herba, Alismatis Rhizoma, Cassiae Semen, Salviae Miltiorrhizae Radix Et Rhizoma, Angelicae Sinensis Radix, Crataegi Fructus, etc. IM N/A 90 (45, 45) 53, 37 T: 49.49 ± 9.91 C: 48.87 ± 9.06 16 Tan et al., 2016 [ Shugan Jianpi decoction Radix Bupleuri, Aurantii Fructus, Atractylodis Macrocephalae Rhizoma, Poria, Crataegi Fructus, Cyperi Rhizoma, Alismatis Rhizoma, Salviae Miltiorrhizae Radix Et Rhizoma, Citri Pericarpium Reticulatae, etc. WM T: 5.75 ± 2.41 years C: 5.43 ± 2.85 years 92 (45, 47) 50, 42 T: 40.25 ± 4.78 C: 43.02 ± 5.48 17 Yu et al., 2016 [ Qinggan Jiangzhi decoction Poria, Atractylodis Macrocephalae Rhizoma, Salviae Miltiorrhizae Radix Et Rhizoma, Curcumae Longae Rhizoma, Cassiae Semen, Alismatis Rhizoma, etc. IM T: mean = 7.5 years C: mean = 8.2 years 125 (62, 63) 71, 54 T: 48.28 C: 49.81 18 Yin et al., 2016 [ Danxia Zhifang decoction; Simulated Zhiganxiao capsule Salviae Miltiorrhizae Radix Et Rhizoma, Pinelliae Rhizoma Praeparatum, Radix Bupleuri, Poria, Citri Pericarpium Reticulatae, Raphani Semen, Crataegi Fructus, etc. IM N/A 202 (98, 104) 149, 53 T: 43.38 ± 9.75 C: 44.49 ± 9.80 19 Zhu, 2015 [ Qingdan Jiangzhi decoction Artemisia Scopariae Herba, Poria, Atractylodis Macrocephalae Rhizoma, Citri Pericarpium Reticulatae, Nelumbinis Folium, Crataegi Fructus, Curcumae Radix, Alismatis Rhizoma, Radix Bupleuri, etc. IM T: 5.1 ± 1.2 years C:4.9 ± 1.3 years 80 (40, 40) 43, 37 T: 44.6 ± 9.6 C: 42.8 ± 8.4 20 Li, 2015 [ Huatan Lishi Huoxue granule combined granule decoction Alismatis Rhizoma, Salviae Miltiorrhizae Radix Et Rhizoma, Crataegi Fructus, Cassiae Semen and Radix Bupleuri N/A T: 3.5 ± 2.2 years C: 3.9 ± 2.3 years 104 (52, 52) 78, 26 T: 42.3 ± 8.4 C: 41.7 ± 7.8 21 Chen et al., 2015 [ Zaozhu Yinchen decoction Gleditsiae Spina, Atractylodis Macrocephalae Rhizoma, Artemisia Scopariae Herba, Rhei Radix Et Rhizoma and Gardeniae Fructus IM T: 30.32 ± 6.98 months C: 31.14 ± 7.21 months 78 (40, 38) 41, 37 T: 38.28 ± 4.82 C: 39.53 ± 4.62 22 Yu et al., 2015 [ Tiaogan Lipi recipe Astragali Radix, Atractylodis Macrocephalae Rhizoma, Coicis Semen, Salviae Miltiorrhizae Radix Et Rhizoma, Cyperi Rhizoma, Radix Bupleuri, Artemisia Scopariae Herba, Polygonum Cuspidati Rhizoma Et Radix, Cassiae Semen, Crataegi Fructus, etc. IM T: 3.38 ± 4.17 years C: 3.61 ± 4.93 years 99 (66, 33) 52, 47 T: 49.22 ± 11.08 C: 49.34 ± 10.77 23 Li et al., 2015 [ Qinghua decoction Nelumbinis Folium, Gynostemmatis Herba, Coicis Semen, Poria, Citri Pericarpium Reticulatae, Alismatis Rhizoma, Salviae Miltiorrhizae Radix Et Rhizoma, Atractylodis Macrocephalae Rhizoma, etc. WM T: 3.15 ± 1.52 years C: 3.82 ± 1.3 years 119 (60, 59) 74, 45 T: 51.1 ± 9.8 C: 48.8 ± 11.2 24 Liu et al., 2014 [ Heze lipid-lowering oral liquid Gynostemmatis Herba, Atractylodis Macrocephalae Rhizoma, Salviae Miltiorrhizae Radix Et Rhizoma, Alismatis Rhizoma, Nelumbinis Folium, Citri Pericarpium Reticulatae, Crataegi Fructus, etc. IM Range: 0.5–10 years 120 (60, 60) 55, 65 T: 50 ± 12.27 C: 50.88 ± 13.17 25 Liu et al., 2014 [ Ruangan Jiangzhi capsule Radix Bupleuri, Rhei Radix Et Rhizoma, Prunus Semen, Paeoniae Radix Alba, Nelumbinis Folium, Salviae Miltiorrhizae Radix Et Rhizoma, Crataegi Fructus, Atractylodis Macrocephalae Rhizoma, Astragali Radix, Schisandrae Chinensis Fructus, etc. IM T: mean = 2.9 years C: mean = 2.8 years 120 (60, 60) 87, 33 T: 45.7 C: 44.3 26 Li et al., 2014 [ Jianpi Shugan recipe Gynostemmae Herba, Curcumae Radix, Atractylodis Macrocephalae Rhizoma, Poria, Alismatis Rhizoma, Salviae Miltiorrhizae Radix Et Rhizoma, Crataegi Fructus, etc. IM N/A 201 (100, 101) 143, 58 T: 43.41 ± 10.80 C: 39.81 ± 11.79 27 Zhu et al., 2014 [ Zhigan pill Alismatis Rhizoma, Salviae Miltiorrhizae Radix Et Rhizoma, Cassiae Semen, Crataegi Fructus, Curcumae Radix, Polygonum Cuspidati Rhizoma Et Radix, etc. IM T: 3.72 ± 2.53 years C: 3.00 ± 2.35 years 158 (120, 38) 122, 36 T: 46.15 ± 7.37 C: 45.70 ± 9.41 28 Wen et al., 2014 [ Jiangan Xiaozhi granule Curcumae Rhizoma, Curcumae Longae Rhizoma, Notoginseng Radix Et Rhizoma, Salviae Miltiorrhizae Radix Et Rhizoma, Astragali Radix, etc. IM T: 29.97 ± 10.96 months C: 30.14 ± 10.60 months 73 (37, 36) 35, 38 T: 43.10 ± 9.14 C: 43.08 ± 8.65 29 Deng, 2013 [ Jiangan Sanqing decoction Lycii Fructus, Astragali Radix, Atractylodis Macrocephalae Rhizoma, Crataegi Fructus, Nelumbinis Folium, Citri Pericarpium Reticulatae, Pinelliae Rhizoma Praeparatum, Radix Bupleuri, Salviae Miltiorrhizae Radix Et Rhizoma, etc. WM T: 3.3 ± 1.2 years C: 3.1 ± 1.3 years 60 (30, 30) 40, 20 T: 44.1 ± 6.2 C: 43.3 ± 5.9 30 Li et al., 2013 [ Jianpi Huatan Zhuyu prescription Artemisia Scopariae Herba, Crataegi Fructus, Curcumae Longae Rhizoma, Prunus Semen, Atractylodis Macrocephalae Rhizoma, Cassiae Semen, Raphani Semen, etc. IM T: 23.3 ± 11.1 months C: 21.4 ± 13.2 months 118 (60, 58) 59, 59 T: 43.2 ± 14.2 C: 42.7 ± 13.0 31 Song et al., 2013 [ Modified Linggui Zhugan decoction Poria, Atractylodis Macrocephalae Rhizoma, Cinnamomi Ramulus, Glycyrrhizae Radix Et Rhizoma, Caulis Nelumbonis and Alismatis Rhizoma IM T: 4.24 ± 2.10 years C: 4.20 ± 2.12 years 90 (48, 42) 72, 18 T: 44.8 ± 4.2 C: 42.2 ± 4.9 32 Li et al., 2013 [ Qushi Huayu decoction Artemisia Scopariae Herba, Polygonum Cuspidati Rhizoma Et Radix, Herba Hyperici Japonici, Curcumae Longae Rhizoma, and Gardeniae Fructus IM N/A 164 (72, 73) 82, 82 T: 44.6 ± 10.9 C: 45.6 ± 11.2 33 Wong et al., 2013 [ N/A N/A 60 (40, 20) 33, 27 T: 52 ± 10 C: 48 ± 11 34 Pan et al., 2013 [ Jiang Zhi granule Gynostemmatis Herba, Salviae Miltiorrhizae Radix Et Rhizoma, Polygonum Cuspidati Rhizoma Et Radix, Artemisia Scopariae Herba, Nelumbinis Folium WM T: 26.61 ± 29.29 m C: 30.02 ± 34.59 m 221 (111, 110) 177, 44 T: 42.39 ± 11.55 C: 44.82 ± 11.41 35 Chen et al., 2012 [ Jindanwang mixture lysimachiae Herba, Sargassum, Plantaginis Semen, Salviae Miltiorrhizae Radix Et Rhizoma, Curcumae Radix, Artemisia Scopariae Herba, etc. IM Mean = 1.25 years 124 (62, 62) 79, 45 Range: 28–65 36 Zhao et al., 2012 [ Huatan Xiezhuo recipe Alismatis Rhizoma, Cassiae Semen, Salviae Miltiorrhizae Radix Et Rhizoma, Crataegi Fructus, Radix Bupleuri, etc. IM N/A 194 (96, 98) N/A N/A 37 Wang et al., 2012 [ Yigan Jiedu decoction Sargassum, Curcumae Radix, Cassiae Semen, Curcumae Longae Rhizoma, Sedi Herba, Ginseng Folium, Radix Bupleuri, etc. IM T: 4.8 ± 3.6 years C: 4.1 ± 4.3 years 90 (45, 45) 49, 41 T: 49.64 ± 14.29 C: 47.82 ± 15.08 38 Pei et al., 2012 [ Qinggan Huatan Huoxue recipe Cassiae Semen, Radix Bupleuri, Citri Pericarpium Reticulatae, Pinelliae Rhizoma, Curcumae Radix, Crataegi Fructus, Rhei Radix Et Rhizoma, Artemisia Scopariae Herba, etc. IM T: 17.83 ± 19.55 months C: 20.05 ± 28.11 months 150 (78, 72) 101, 49 T: 43.44 ± 12.76 C: 44.56 ± 12.30 39 Wu, 2012 [ Jianpi Huatan Fang Atractylodis Rhizoma, Atractylodis Macrocephalae Rhizoma, Poria, Alismatis Rhizoma, Curcumae Radix, Crataegi Fructus, Salviae Miltiorrhizae Radix Et Rhizoma, etc. WM T: 1.8 ± 1.2 years C: 2.1 ± 1.4 years 60 (30, 30) 53, 7 T: 9.3 ± 2.1 C: 8.9 ± 2.5 40 Tong et al., 2011 [ Jiedu Jianpi Tongluo decoction Semen Hoveniae, Curcumae Longae Rhizoma, and Salviae Miltiorrhizae Radix Et Rhizoma WM Range: 1–8 years 100 (45, 46) 58, 42 36.9 41 Zhang et al., 2011 [ Kangzhi decoction Astragali Radix, Crataegi Fructus, Chrysanthemi Flos, Atractylodis Macrocephalae Rhizoma, Cassiae Semen, Alismatis Rhizoma, Nelumbinis Folium, Atractylodis Rhizoma, Sedi Herba, etc. IM T: 0.3–12.5 years C: 0.3–11.5 years 182 (92, 90) 79, 103 T: 38.6 ± 12.65 C: 39.3 ± 13.47 42 Gu et al., 2011 [ Zhigan capsule Alismatis Rhizoma, Poria, Artemisia Scopariae Herba, Nelumbinis Folium, Crataegi Fructus, Radix Bupleuri, Puerariae Lobatae Radix, Salviae Miltiorrhizae Radix Et Rhizoma, etc. IM T: 1–10 years C: 1–11 years 100 (50, 50) 70, 30 T: 41.2 ± 10.7 C: 41.6 ± 11.1 43 Zhao et al., 2010 [ Qiyin tea Astragali Radix, Artemisia Scopariae Herba, Crataegi Fructus, Psoraleae Fructus, Alismatis Rhizoma, Cassiae Semen, Notoginseng Radix Et Rhizoma, Rhei Radix Et Rhizoma, etc. IM N/A 112 (56, 56) 46, 66 N/A 44 Ding et al., 2010 [ Pingganjian decoction Astragali Radix, Typhae Pollen, Curcumae Longae Rhizoma,Coptidis Rhizomacoptidis Rhizoma, Alismatis Rhizoma, Poria, Artemisia Scopariae Herba, Crataegi Fructus, etc. IM N/A 105 (54, 51) 60, 45 T: 45.8 ± 13.5 C: 47.2 ± 15.6 45 Pan et al., 2010 [ Tiaozhiji granules Curcumae Rhizoma, Curcumae Radix, Raphani Semen, Crataegi Fructus, Aurantii Fructus, Alismatis Rhizoma, etc. IM T: 24.1 ± 10.4 years C: 22.3 ± 12.1 years 70 (35, 35) 49, 21 T: 46.0 ± 13.7 C: 50.9 ± 16.4 46 Liu et al., 2008 [ Qiyin granules Astragali Radix, Artemisia Scopariae Herba, Crataegi Fructus, Psoraleae Fructus, Alismatis Rhizoma, Cassiae Semen, etc. IM N/A 70 (35, 35) N/A N/A 47 Ji et al., 2008 [ Danning tablet Radix Et Rhizoma Rhei, Giant Knotweed Rhizome, Pericarpium Citri Reticulatae Viride, Aurantii Nobilis Pericarpium, Radix Curcu Mae, Fructus Crataegi and Imperatae Rhizoma IM N/A 135 (102, 33) 102, 33 T: 48.37 ± 9.60 C: 44.43 ± 10.40 48 Chen et al., 2008 [ Xiaoyao San decoction and Danggui Shaoyao San decoction Radix Bupleuri, Angelicae Sinensis Radix, Paeoniae Radix Alba, Atractylodis Macrocephalae Rhizoma, Poria, Alismatis Rhizoma, Glycyrrhizae Radix Et Rhizoma, etc. IM Range: 0.5–5 years 120 (60, 60) 58, 62 49.56 ± 5.67 49 Lou et al., 2008 [ Yiqi Sanju formula Astragali Radix, Coptidis Rhizoma, etc. WM N/A 67 (39, 28) 44, 23 T: 52.6 ± 12.8 C: 54.8 ± 11.0 50 Li et al., 2007 [ Jianpi Bushen decoction Astragali Radix, Codonopsis Radix, Atractylodis Macrocephalae Rhizoma, Corni Fructus, Rehmanniae Radix Praeparata, Dioscoreae Rhizoma, etc. WM Range: 1–6 years 100 (47, 45) 78, 22 38.5 51 Yang et al., 2007 [ Yigan Jiangzhi capsule Polygoni Multiflori Radix, Curcumae Radix, Ginkgo Folium, Nelumbinis Folium, Salviae Miltiorrhizae Radix Et Rhizoma, Artemisia Scopariae Herba, etc. WM T: 2.0 ± 0.5 C: 1.5 ± 0.6 128 (68, 60) 68, 60 T: 45 ± 2 C: 47 ± 4 52 Gu et al., 2007 [ Tiaozhi Yanggan decoction Thorowax Root, Turmeric Root, Red Peony Root, Hawthorn Fruit, Water-Plantain Tuber, Cassia Seed, Giant Knotweed Rhizome, Prepared Rhubarb, Peach Kernel, Red Sage Root, Radish Seed and Tangerine Peel IM T: mean = 3 months and 8 years C: mean = 2 months and 6 years 130 (101, 29) 98, 32 T: 47.38 ± 9.50 years C: 43.34 ± 10.54 years 53 Chen et al., 2006 [ Qianggan capsule Astragali Radix, Salviae Miltiorrhizae Radix Et Rhizoma, Angelicae Sinensis Radix, Paeoniae Radix Alba, Curcumae Radix, Codonopsis Radix, Alismatis Rhizoma, Dioscoreae Rhizoma, Crataegi Fructus, Artemisia Scopariae Herba, Glycyrrhizae Radix Et Rhizoma, etc. IM N/A 122 (64, 58) 77, 45 T: 42.5 C: 45.8
T test group, C control group, H high dose group, L low dose group, IM integrative medicine, WM Western medicine 74(
A total of 5997 participants with NAFLD were recruited in the RCTs included in this review. Two trials did not report the number of males and females [[
Chinese expert consensus and treatment guidelines were the preferred reference for diagnosis standards among the included trials. Fifty-one trials specified the diagnostic criteria including 39 trials selected the relevant standards of Chinese and Western medicine diagnostic, and 12 trials used the Western medicine diagnostic criteria. Detailed information is shown in Table 1. The most common diagnosis criteria reported in the studies were: Guidelines for management of NAFLD (2007 [[
A total of 53 different TCMs preparations were tested in the included trials. The combination of multiple herbs was the main intervention method. All the Chinese medicinal materials from each TCM preparation were summarized as shown in Table 2. The TCMs preparation tested in the included studies might be given in the form of tablets, capsules, decoctions, pills or granules. Most of the TCMs preparations tested were hospitalized-based preparations and no quality standards or quality control of the TCMs being tested was mentioned in any of the RCTs.
At least 86 herbs were used in the included trials for treating NAFLD. The 20 most common Chinese medicinal materials found in the 53 TCMs preparations analyzed in this review included: Crataegi Fructus, Alismatis Rhizoma, Atractylodis Macrocephalae Rhizoma, Salviae Miltiorrhizae Radix Et Rhizoma, Radix Bupleuri, Artemisia Scopariae Herba, Poria, Cassiae Semen, Curcumae Radix, Astragali Radix, Nelumbinis Folium, Citri Pericarpium Reticulatae, Curcumae Longae Rhizoma, Gynostemmatis Herba, Angelicae Sinensis Radix, Codonopsis Radix, Paeoniae Radix Alba, Coicis Semen, Pinelliae Rhizoma Praeparatum, Polygonum Cuspidati Rhizoma Et Radix. Over 20 trials tested TCMs preparations which consisted of the following 4 Chinese medicinal materials: Crataegi Fructus, Alismatis Rhizoma, Atractylodis Macrocephalae Rhizoma, Salviae Miltiorrhizae Radix Et Rhizoma.
The control interventions included placebo, conventional medicine, lifestyle intervention, or lifestyle intervention plus conventional drug(s). Thirty-nine trials set a conventional medicine control group, such as polyene phosphatidylcholine capsules (n = 17), silibinin capsules or tablets (n = 4), ursodeoxycholic acid capsules or tablets (n = 3). Four trials used Chinese patent medicine as the intervention in the comparison group. Six trials designed a placebo control group and 32 trials designed a lifestyle intervention, diet or exercise as the comparison group. Detailed information is shown in Table 3.
Table 3 Major findings of the RCTs included in the review
No. Authors, year Test group Control group Duration Primary outcome Secondary outcome TCMs Behavioral interventions Pharmacological interventions Behavioral interventions TCM syndrome score Adverse reactions Radiological response Liver function Body weight Blood sugar Blood lipid Others 1 Wu et al., 2020 [ Jianpi Qingzhi prescription Diet and exercise Polyene Phosphatidylcholine capsules Diet and exercise 12 weeks Yes N/A BU, CT ALT, AST, GGT N/A FBG, FINs, HOMA-IR, TG, TC DAO, LPS, 2 Lyv et al., 2020 [ Shenge formula Diet and exercise N/A Diet and exercise 6 months Yes N/A N/A ALT, AST N/A N/A TG, TC N/A 3 Yang et al., 2019 [ Yanggan Jieyu granule Diet and exercise Polyene phosphatidylcholine capsules Diet and exercise 24 weeks Yes N/A CT ALT, AST, GGT N/A N/A TG, TC, LDL-C N/A 4 Yang et al., 2019 [ Qinjiang Baoling decoction Diet and exercise N/A Diet and exercise 3 months Yes N/A BU, CT ALT, GGT BMI HOMA-IR TC, HDL-C N/A 5 Li et al., 2018 [ Qutan Huoxue decoction N/A Silibinin capsules N/A 24 weeks Yes Yes CT ALT, AST, GGT N/A N/A TG, TC N/A 6 Chen et al., 2017 [ Shuangqing granule Diet and exercise Xuezhikang capsules Diet and exercise 12 weeks Yes N/A BU AST, ALT N/A N/A TG, TC, HDL-C, LDL-C N/A 7 Hu et al., 2017 [ Jianpishugan and Huoxuehuatan formula Diet and exercise Polyene Phosphatidylcholine capsules Diet and exercise 3 months Yes Yes BU ALT, AST, GGT BMI N/A TG, TC, HDL-C, LDL-C N/A 8 Jiang et al., 2017 [ Dahuang Lidan capsule Diet and exercise Polyene Phosphatidylcholine capsules Diet and exercise 12 weeks Yes Yes BU ALT, AST, GGT N/A N/A TG, TC, HDL-C, LDL-C N/A 9 Yang et al.,2017 [ Cigu Xiaozhi capsule Diet and exercise Polyene Phosphatidylcholine capsules Diet and exercise 8 weeks Yes N/A BU ALT, AST, ALP, GGT BMI N/A TG, TC, HDL-C, LDL-C N/A 10 Jeong et al., 2017 [ Test group 1—HL tablet—high dose N/A Placebo N/A 12 weeks N/A Yes N/A ALT, AST BMI HOMA-IR TG, TC, HDL-C, LDL-C MRS, free fatty acid Test group 2—HL tablet—low dose N/A Placebo N/A 12 weeks N/A 11 Sun et al., 2017 [ Jianpi Qushi prescription Diet and exercise N/A Diet and exercise 3 months Yes N/A BU ALT, AST N/A FPG, FINs TG, TC N/A 12 Niu 2016 [ Shugan Jianpi Huatan decoction Diet and exercise Atorvastatin calcium tablets Diet and exercise 3 months Yes N/A N/A ALT, AST N/A FBG, FNIs, HOMA-IR TG, TC N/A 13 Zhang et al., 2016 [ Yiqi Qizhu decoction Diet and exercise Polyene phosphatidylcholine capsules Diet and exercise 3 months Yes Yes BU ALT, AST, GGT N/A N/A TG, TC N/A 14 Zhang et al., 2016 [ Jiang Zhi granules N/A Ursodeoxycholic acid capsules N/A 24 weeks Yes N/A BU N/A N/A N/A N/A N/A 15 Qi et al., 2016 [ Jiangpi Shugan Huoxue Huatan decoction Diet and exercise Silibinin capsules N/A 3 months Yes N/A BU ALT, AST, GGT N/A N/A TG, TC, HDL-C, LDL-C N/A 16 Tan et al., 2016 [ Shugan Jianpi decoction Diet and exercise Pioglitazone N/A 3 months Yes Yes BU ALT, AST BMI, WHR FBG, FNIs, HOMA-IR TG, TC N/A 17 Yu et al., 2016 [ Qinggan Jiangzhi decoction Diet and exercise Polyene phosphatidylcholine tablet and Dangfei Liganning capsule Diet and exercise 24 weeks Yes N/A BU ALT, AST, GGT BMI, BM N/A TG, TC N/A 18 Yin et al., 2016 [ Danxia Zhifang decoction; simulated Zhiganxiao capsule N/A Qianggan capsule N/A 3 months Yes N/A BU, CT ALT, AST, GGT,TB, DB, TP, ALB, A/G, N/A N/A TG, TC N/A 19 Zhu 2015 [ Qingdan Jiangzhi decoction Diet and exercise Tiopronin enteric-coated tablets Diet and exercise 12 weeks Yes N/A BU N/A N/A N/A N/A N/A 20 Li 2015 [ Huatan Lishi Huoxue granule combined granule decoction Diet and exercise Polyene phosphatidylcholine capsules Diet and exercise 3 months Yes Yes CT ALT N/A N/A TG N/A 21 Chen et al., 2015 [ Zaozhu Yinchen decoction N/A Silymarin meglumine tablet N/A 2 months Yes Yes BU ALT, AST N/A N/A TG, TC N/A 22 Yu et al., 2015 [ Tiaogan Lipi recipe Diet and exercise Placebo Diet and exercise 12 weeks Yes Yes CT ALT, AST, GGT N/A N/A TG, TC N/A 23 Li et al., 2015 [ Qinghua decoction Diet and exercise N/A Diet and exercise 6 months Yes N/A BU ALT, AST, GGT, TB BMI, WHR N/A TG, TC N/A 24 Liu et al., 2014 [ Heze lipid-lowering oral liquid N/A Polyene phosphatidylcholine capsules N/A 4 months Yes N/A CT ALP, AST, GGT, GLP, ALB BMI N/A TG, TC, HDL-C, LDL-C N/A 25 Liu et al., 2014 [ Ruangan Jiangzhi capsule Diet and exercise Polyene phosphatidylcholine capsules Diet and exercise 12 weeks Yes Yes BU ALT, GGT N/A N/A TG, TC N/A 26 Li et al., 2014 [ Jianpi Shugan recipe Diet and exercise Polyene phosphatidylcholine capsules Diet and exercise 3 months Yes Yes CT ALT N/A N/A N/A N/A 27 Zhu et al., 2014 [ Zhigan pill N/A Placebo N/A 3 months Yes N/A BU N/A N/A N/A N/A N/A 28 Wen et al., 2014 [ Jiangan Xiaozhi granule Diet and exercise Hedan tablet Diet and exercise 3 months Yes Yes CT ALT, AST, GGT N/A N/A TG, TC, HDL-C, LDL-C N/A 29 Deng, 2013 [ Jiangan Sanqing decoction N/A Polyene Phosphatidylcholine capsules N/A 3 months Yes N/A BU ALT, AST N/A N/A TG, TC N/A 30 Li et al., 2013 [ Jianpi Huatan Zhuyu prescription N/A Qianggan capsule N/A 3 months Yes Yes BU ALT, AST, GGT N/A N/A TG, TC N/A 31 Song et al., 2013 [ Modified Linggui Zhugan decoction N/A Polyene phosphatidylcholine capsules N/A 3 months Yes N/A CT ALT, AST N/A N/A TG, TC N/A 32 Li et al., 2013 [ Qushi Huayu decoction N/A Polyene phosphatidylcholine capsules N/A 24 weeks Yes Yes BU ALT, AST N/A N/A TG, TC, HDL-C, LDL-C N/A 33 Wong et al., 2013 [ Diet and exercise Placebo Diet and exercise 24 weeks N/A Yes N/A ALT, AST N/A HbA1 HDL-C, LDL-C N/A 34 Pan et al., 2013 [ Jiang Zhi granule Diet and exercise Placebo Diet and exercise 24 weeks N/A Yes CT N/A BMI N/A TG, TC N/A 35 Chen et al., 2012 [ Jindanwang mixture Diet Ursodeoxycholic acid capsules Diet 24 weeks Yes N/A BU, CT ALT, AST N/A N/A TG, TC N/A 36 Zhao et al., 2012 [ Huatan Xiezhuo recipe Diet and exercise Polyene phosphatidylcholine capsules Diet and exercise 3 months Yes Yes N/A ALT BMI N/A TG N/A 37 Wang et al., 2012 [ Yigan Jiedu decoction Diet and exercise Silymarin Diet and exercise 2 months Yes N/A N/A ALT, AST, GGT N/A N/A TG, TC N/A 38 Pei et al., 2012 [ Qinggan Huatan Huoxue recipe Diet and exercise Danning tablet Diet and exercise 3 months Yes Yes BU ALT, AST, GGT BMI FBG, FNIs, HOMA-IR TG, TC, HDL-C, LDL-C N/A 39 Wu 2012 [ Jianpi Huatan formula N/A Vitamin E N/A 3 months N/A Yes BU ALT, AST N/A FBG, FNIs, HOMA-IR TG, TC, HDL-C, LDL-C N/A 40 Tong et al., 2011 [ Jiedu Jianpi Tongluo decoction N/A Silibinin capsules N/A 12 weeks Yes Yes BU ALT, AST, GGT, TB N/A N/A TG, TC, HDL-C, LDL-C N/A 41 Zhang et al., 2011 [ Kangzhi decoction N/A Tiopronin enteric-coated tablets N/A 6 months Yes Yes BU, CT ALT, AST, GGT N/A N/A TG, TC N/A 42 Gu et al., 2011 [ Zhigan capsule Diet and exercise Polyene phosphatidylcholine capsules Diet and exercise 3 months Yes Yes BU ALT, AST, GGT BMI FBG TG, TC, LDL-C N/A 43 Zhao et al., 2010 [ Qiyin tea N/A Polyene phosphatidylcholine capsules N/A 2 months Yes N/A BU AST, ALP, AST, GGT N/A N/A TG, TC N/A 44 Ding et al., 2010 [ Pingganjian decoction Diet and exercise Silymarin, Ultivarietas Oryzae Saltlicae Et Monasci Diet and exercise 3 months Yes Yes CT ALT, AST BMI,WHR FBG, FNIs, HOMA-IR TG, TC N/A 45 Pan et al., 2010 [ Tiaozhiji granules N/A Hedan tablet N/A 3 months Yes Yes BU, CT ALT, AST, GGT N/A N/A TG, TC N/A 46 Liu et al., 2008 [ Qiyin granules Diet and exercise Polyene phosphatidylcholine capsules Diet and exercise 2 months Yes N/A BU ALT, AST N/A N/A TG, TC N/A 47 Ji et al., 2008 [ Danning tablet Diet and exercise Ursodeoxycholic acid tablet Diet and exercise 24 weeks Yes Yes CT ALT, AST, GGT BMI N/A TG, TC N/A 48 Chen et al., 2008 [ Xiaoyao San decoction and Danggui Shaoyao San decoction Diet Anethol trithione Diet 3 months Yes N/A BU ALT, AST N/A N/A TG, TC N/A 49 Lou et al., 2008 [ Yiqi Sanju formula N/A Placebo N/A 3 months Yes Yes CT ALT, AST BMI FBG, FNIs, HOMA-IR TG, TC, HDL-C, LDL-C hs-CRP, TNF-α 50 Li et al., 2007 [ Jianpi Bushen decoction N/A Silibinin N/A 8 weeks Yes Yes BU ALT, AST, GGT,TB N/A N/A TG, TC, HDL-C, LDL-C N/A 51 Yang et al., 2007 [ Yigan Jiangzhi capsule N/A Dongbao Gantai tablet N/A 3 months N/A N/A BU, CT ALT, AST, GGT N/A N/A TG, TC, HDL-C, LDL-C N/A 52 Gu et al., 2007 [ Tiaozhi Yanggan decoction Diet and exercise Thiola tablet Diet and exercise 12 weeks Yes Yes N/A ALT, AST, GGT N/A N/A TG, TC, HDL-C, LDL-C N/A 53 Chen et al., 2006 [ Qianggan capsule Diet and exercise Tiopronin Diet and exercise 3 months N/A N/A BU ALT, GGT N/A N/A TG N/A
Table 3 Major findings of the RCTs included in the review
No. Authors, year Overall findings Efficacy Safety Overall efficacy rate of test group Overall efficacy rate of control group Difference between the 2 groups Non-serious Serious 1 Wu et al., 2020 [ 93.33% 80.00% Test group (P < 0.05) N/A N/A 2 Lyv et al., 2020 [ 100.00% 48.39% Test group (P < 0.05) N/A N/A 3 Yang et al., 2019 [ 86.67% 73.33% Test group (P < 0.01) N/A N/A 4 Yang et al., 2019 [ 64.00% 52.00% Test group (P < 0.05) N/A N/A 5 Li et al., 2018 [ 84.13% 56.45% Test group (P < 0.01) None None 6 Chen et al., 2017 [ 89.7% 84.0% Test group (P < 0.05) N/A N/A 7 Hu et al., 2017 [ 94.28% 77.14% Test group (P < 0.01) None None 8 Jiang et al., 2017 [ Specific outcome readings Specific outcome readings Test group (P < 0.01) ADR1 None 9 Yang et al., 2017 [ 93.02% 68.18% Test group (P < 0.01) N/A N/A 10 Jeong et al., 2017 [ Specific outcome readings Specific outcome readings High dose group (P = 0.033) ADR2 None Specific outcome readings Specific outcome readings Low dose group (P = 0.386) 11 Sun et al., 2017 [ 93.33% 61.67% Test group (P < 0.01) N/A N/A 12 Niu 2016 [ 95.00% 76.60% Test group (P < 0.05) N/A N/A 13 Zhang et al., 2016 [ 92.31% 78.85% Test group (P < 0.05) None None 14 Zhang et al., 2016 [ 33.80% 23.39% Test group (P < 0.05) N/A N/A 15 Qi et al., 2016 [ 93.30% 62.20% Test group (P < 0.05) N/A N/A 16 Tan et al., 2016 [ 87.23% 71.11% Test group (P < 0.05) ADR3 None 17 Yu et al., 2016 [ Specific outcome readings Specific outcome readings Test group (P < 0.01) N/A N/A 18 Yin et al., 2016 [ 81.63% 62.5% Test group (P < 0.05) N/A N/A 19 Zhu, 2015 [ Specific outcome readings Specific outcome readings Test group (P < 0.05) N/A N/A 20 Li, 2015 [ 98.10% 80.80% Test group (P < 0.05) None None 21 Chen et al., 2015 [ 87.50% 73.68% Test group (P < 0.05) None None 22 Yu et al., 2015[ Specific outcome readings Specific outcome readings Test group (P < 0.05) None None 23 Li et al., 2015 [ 58.33% 30.51% Test group (P < 0.01) N/A N/A 24 Liu et al., 2014 [ 52.94% 29.09% Test group (P < 0.05) N/A N/A 25 Liu et al., 2014 [ 91.67% 56.67% Test group (P < 0.05) ADR4 None 26 Li et al., 2014 [ 84.09% 75.00% Test group (P < 0.05) ADR5 None 27 Zhu et al., 2014 [ 85.83% 63.16% Test group (P < 0.05) N/A N/A 28 Wen et al., 2014 [ 78.40% 55.60% Test group (P < 0.05) None None 29 Deng, 2013 [ 90.00% 70.00% Test group (P < 0.05) N/A N/A 30 Li et al., 2013 [ 86.60% 66.60% Test group (P < 0.05) None None 31 Song et al., 2013 [ 91.70% 69.00% Test group (P < 0.01) N/A N/A 32 Li et al., 2013 [ specific outcome readings specific outcome readings Test group (P < 0.01) ADR6 None 33 Wong et al., 2013 [ Specific outcome readings Specific outcome readings Not siginificant ADR7 ADR8 34 Pan et al., 2013 [ Specific outcome readings Specific outcome readings Test group (P < 0.05) ADR9 None 35 Chen et al., 2012 [ 94.00% 92.00% No siginificant differences (P > 0.05) N/A N/A 36 Zhao et al., 2012 [ Specific outcome readings Specific outcome readings Test group (P < 0.01) None None 37 Wang et al., 2012 [ 75.56% 51.11% Test group (P < 0.01) N/A N/A 38 Pei et al., 2012 [ 87.20% 73.60% Test group (P < 0.05) ADR10 None 39 Wu 2012 [ 83.30% 46.67% Test group (P < 0.05) None None 40 Tong et al., 2011 [ 86.67% 76.09% Test group (P < 0.05) None None 41 Zhang et al., 2011 [ 86.90% 67.70% Test group (P < 0.05) None None 42 Gu et al., 2011 [ 90.00% 72.00% Test group (P < 0.05) ADR11 None 43 Zhao et al., 2010 [ 87.60% 83.90% No siginificant differences (p = 0.873) N/A N/A 44 Ding et al., 2010 [ 83.33% 45.10% Test group (P < 0.05) ADR12 None 45 Pan et al., 2010 [ Specific outcome readings Specific outcome readings Test group (P < 0.05) None None 46 Liu et al., 2008 [ Specific outcome readings Specific outcome readings Test group (P < 0.05) N/A N/A 47 Ji et al., 2008 [ Specific outcome readings Specific outcome readings Test group (P < 0.05) ADR13 None 48 Chen et al., 2008 [ 96.77% 83.87% Test group (P < 0.05) N/A N/A 49 Lou et al., 2008 [ 94.87% 32.14% Test group (P < 0.01) ADR14 None 50 Li et al., 2007 [ 87.23% 71.11% Test group (P < 0.05) None None 51 Yang et al., 2007 [ 88.20% 71.70% Test group (P < 0.05) N/A N/A 52 Gu et al., 2007 [ 81.19% 68.97% Test group (P < 0.05) ADR15 None 53 Chen et al., 2006 [ 79.69% 62.07% Test group (P < 0.05) N/A N/A
ALB albumin, ALP alkaline phosphatases, ALT aminotransferase, AST aspartate aminotransferase, A/G albumin/globulin ratio, BU B-ultrasound, CT computed tomography, DAO diamine oxidase, DB direct bilirubin, FBG fasting blood glucose, FINS fasting plasma insulin, GGT gamma-glutamyl-transpeptidase, GLB globulin, HDL high density lipoprotein-cholesterol, HFC hepatic fat content, HOMA-IR homeostasis model assessment-estimated insulin resistance, hs-CRP high sensitivity C-reactive protein, L/S ratio liver to spleen ratio, LDL low density lipoprotein-cholesterol, MRS magnetic resonance spectroscopy, TB total bilirubin, TC total cholesterol, TG triglyceride, TP total serum protein, TNF-α tumor necrosis factor-α, VLDL very low density lipoprotein, WHR waist/hip ratio ADR1: one patient in the control group had a mild prothrombin time ADR2: high dose group: abdominal pain upper(1 patient); low dose group: dizziness(1 patient); Palcebo group: nausea (1 patient) ADR3: one case in the control group had mild edema of both lower limbs ADR4: 4 patients in the test group had different degrees of diarrhea ADR5: 1 case in test group; 3 cases in control group(not specified) ADR6: in the test group, 3 cases developed nausea and 2 cases of gastric cavity discomfort; in the control group, 2 cases of gastric cavity discomfort ADR7: dyspepsia, diarrhea, per-rectal bleeding, chest pain, cough, headache, blurred vision, toothache, gum bleeding, flu-like symptoms ADR8: hospitalization occurred in two patients in the Phyllanthus group (back pain, stroke) and one patient in the placebo group (acute appendicitis) ADR9: 16 patients with 19 cases of adverse events were reported in the test group, and 14 patients with 19 cases were reported tn the control group (no mention of the mild adverse name). 1 case exhaustion/dizziness and 1 case sloppy stool were related the study ADR10: 3 cases in the test group had loose stools; In the control group, 2 cases had nausea and 5 cases had loose stools ADR11: 5 patients in the test group had different degrees of diarrhea symptoms ADR12: in the test group, 3 patients had mild diarrhea, gastrointestinal discomfort and reduced appetite, 1 case of hypertension; In the control group 2 cases of hypertension ADR13: in test group, most of pat ients showed diarrhea. There was one patient with skin rash and three patients with nausea ADR14: in the test group, 3 patients developed mild diarrhea, recovered and decreased appetite ADR15: 21 cases of diarrhea, 22 of gastric discomfort or light pain, 15 of abdominal discomfort or dull pain, and 11 cases of nausea
All the comparisons were:
- TCMs versus placebo (2 trials);
- TCMs plus lifestyle intervention versus placebo plus lifestyle intervention (4 trials);
- TCMs plus lifestyle intervention versus lifestyle intervention (4 trials);
- TCMs versus conventional medicine (19 trials);
- TCMs plus lifestyle intervention versus conventional drug plus lifestyle intervention (18 trials);
- TCMs plus lifestyle intervention (only diet) versus conventional drug plus lifestyle intervention (only diet) (2 trials);
- TCMs versus TCMs (1 trial);
- TCMs plus lifestyle intervention versus TCMs plus lifestyle intervention (3 trials).
The duration of the intervention among the included trials ranged between 8 weeks and 6 months. In 34 trials, 12 weeks or 3 months was set as intervention duration; in 12 trials, 24 weeks or 6 months was set as the intervention duration; in 6 trials, 8 weeks or 2 months were the intervention duration; and 1 trial set 4 months as intervention duration.
As shown in Table 3, the reported outcomes of the 53 trials included changes in the TCM syndrome score and any reports of adverse reactions, along with B-ultrasound findings, computed tomography (CT) scan findings, body weight (BMI, BM), related biochemical response measures of 1iver function (ALT, AST, ALP, GGT, TB, TP, ALB, A/G, GLB, DB), related biochemical response measures of blood sugar (FBG, FNIs, HOMA-IR, Hb1A, MRS), related biochemical response measures of blood lipids (TG, TC,HDL-C, LDL-C, CHOL), and others (DAO, lipopolysaccharide, d-lactic acid, Claudin-1, Claudin-4, hs-CRP, TNF-α).
All trials measured the outcomes at the end of the intervention duration, and no RCTs reported any follow-up data of the outcomes after the interventions ended. The most commonly measured outcomes included related biochemical response measures of 1iver function (n = 49), blood lipids (n = 49), TCM syndrome score (n = 47) and B-ultrasound findings and computed tomography (CT) scan findings (n = 46). Blood sugar levels (n = 12) and body weight (n = 15) were less frequently used as part of the outcome measurements. Most of the RCTs (n = 41) compared the overall efficacy of interventions in the test groups and the control/comparison groups whereas 12 RCTs compared the 2 groups in terms of the each of the specific outcome measures in each study. All but 3 RCTs showed positive effects of TCMs on the outcomes measured in the test groups compared to the control/comparison groups with statistical differences.
All the 28 RCTs set out to measure the safety of the TCMs were the only RCTs which reported the data of adverse events experienced by the participants. Fourteen of these 28 RCTs did not identify any adverse events associated with the interventions used in the studies. Among the remaining 14 RCTs which reported adverse events, 13 RCTs reported only non-serious adverse events and 1 RCT reported both serious and non-serious adverse events in which hospitalization occurred in two participants from the test group receiving phyllanthus due to back pain and stroke and one participant in the placebo group had acute appendicitis [[
All the comparisons were:
- TCMs versus placebo (2 trials);
Further information about the reporting of each outcome measurements is provided in the following:
- Radiological response (BU, CT)
- Seven trials conducted the B-ultrasound and CT to evaluate the efficacy of treatment on NFALD. 12 trials only conducted the CT results before and after treatment, and 27 trials only conducted B-ultrasound results.
- Liver function
- Out of the 47 trials which tested the related biochemical response measures of liver function, 19 trials reported the changes in AST, ALT, GGT, 17 trials reported ALT and AST change, 4 trials reported ALT, AST, ALP and GGT change, and 4 trials also reported TB. One trial also reported the MRS and free fatty acid to assess of hepatic fat content [[
28 ]]. - Blood sugar
- Out of the 12 trials that reported the results of the related biochemical response measures of blood sugar, 7 trials reported FBG, FNIs, HOMA-IR results, and 1 trial [[
42 ]] reported the Hb1A results. - Blood lipids
- Among the 49 trials that reported the results of blood lipids. 43 trials reported the TG and TC results, of which 16 trials reported the TG, TC, HDL-C and LDL-C results.
- Others (DAO, lipopolysaccharide, d-lactic acid, Claudin-1, Claudin-4, hs-CRP, TNF-α).
- One trial [[
43 ]] reported the results of DAO, lipopolysaccharide, d-lactic acid, Claudin-1, Claudin-4, and one trial [[44 ]] reported the hs-CRP, TNF-α to test the liver inflammation.
The final result of 50 trials reported that the test group was more effective than the control group, of which 37 trials showed statistical difference at a two-sided P-value of less than 0.05, while 13 trials showed statistical differences taken p < 0.01. A total of 41 trials reported the overall efficacy rates, the effective rate of the test groups ranged from 33.80 to 100%, of which 16 trials reported the overall effective over 90%, and only 1 [[
Compared with Ursodeoxycholic Acid Capsules, one trial found that the Jindanwang Mixture was equally effective in treating NAFLD, with the overall efficacy rate 94% vs. 92% in (p > 0.05) [[
The summary of the CONSORT-CHM quality assessment results of the 53 RCTs included in this review is shown in Table 4. None of the RCTs fully met all the CONSORT-CHM criteria. The most common reasons for non-compliance in descending order were: a lack of "Other information" (which included information about funding sources, where the full trial protocol could be assessed, and the registration number and the name of trial registry); a lack of discussion about trial limitations; incomplete results due to a lack of information about all the important harms and unintended effects in each group and a lack of ancillary analyses; and incomplete information about the trial methods (which included description about participant flow, blinding, allocation methods and implementation).
Table 4 Evaluation of included trial studies using the CONSORT-CHM statement
Number Authors, year Title/abstract Background Objectives Trial design Participants Interventions Outcomes Sample size Randomization Allocation Implementation Blinding Statistical methods 1 Wu et al., 2020 △ ◯ ◯ △ ◯ ◯ ◯ △ △ △ × × ◯ 2 Lyv et al., 2020 △ ◯ ◯ △ ◯ ◯ ◯ △ △ △ × × ◯ 3 Yang et al., 2019 △ △ × △ △ △ ◯ △ △ △ × × ◯ 4 Yang et al., 2019 △ △ × △ ◯ ◯ ◯ △ △ × × × ◯ 5 Li et al., 2018 △ △ ◯ △ ◯ △ ◯ △ △ △ × × ◯ 6 Chen 2017 △ △ × △ △ △ △ △ △ × △ × ◯ 7 Hu et al., 2017 △ × △ △ ◯ △ △ △ △ × △ × ◯ 8 Jiang et al., 2017 △ △ × △ ◯ △ △ △ △ × △ × ◯ 9 Yang et al., 2017 △ △ △ △ △ △ ◯ △ △ △ × × ◯ 10 Jeong et al., 2017 ◯ ◯ ◯ ◯ △ △ ◯ △ △ △ × × ◯ 11 Sun et al., 2017 △ × × △ ◯ △ △ △ △ × △ × ◯ 12 Niu 2016 △ ◯ △ △ ◯ △ ◯ △ △ × × × △ 13 Zhang et al., 2016 △ ◯ ◯ △ ◯ ◯ ◯ △ △ △ △ × ◯ 14 Zhang et al., 2016 △ × × △ ◯ △ △ △ △ × △ × △ 15 Qi et al., 2016 △ △ ◯ △ ◯ ◯ ◯ △ △ × × × ◯ 16 Tan et al., 2016 △ △ × △ ◯ ◯ ◯ △ △ × × × ◯ 17 Yu et al., 2016 △ △ × ◯ ◯ △ △ △ △ × △ × ◯ 18 Yin et al., 2016 △ △ △ ◯ ◯ △ ◯ △ △ × × △ ◯ 19 Zhu 2015 △ △ × △ ◯ ◯ ◯ △ △ △ × × ◯ 20 Li 2015 △ △ × × △ △ ◯ △ △ × × × ◯ 21 Chen et al., 2015 △ △ △ △ ◯ ◯ ◯ △ △ △ × △ ◯ 22 Yu et al.,2015 ◯ ◯ ◯ △ ◯ ◯ ◯ △ △ × × × △ 23 Li 2015 △ △ △ △ ◯ △ ◯ △ △ △ × × ◯ 24 Liu et al., 2014 △ ◯ ◯ ◯ ◯ ◯ ◯ △ △ × × × ◯ 25 Liu et al., 2014 △ × △ △ △ △ ◯ △ △ × × × ◯ 26 Li et al., 2014 ◯ ◯ ◯ ◯ ◯ ◯ ◯ △ △ △ ◯ △ ◯ 27 Zhu et al., 2014 △ △ ◯ ◯ ◯ △ ◯ △ △ × △ × ◯ 28 Wen et al., 2014 △ △ × △ △ ◯ ◯ △ △ × × × ◯ 29 Deng, 2013 △ △ ◯ ◯ ◯ ◯ ◯ △ △ × × × ◯ 30 Li et al., 2013 △ △ △ △ △ △ △ △ △ × × × ◯ 31 Song et al., 2013 △ △ × △ ◯ ◯ ◯ △ △ × × × ◯ 32 Li et al., 2013 △ △ ◯ △ ◯ △ △ △ △ × △ × ◯ 33 Wong et al., 2013 ◯ ◯ △ ◯ ◯ △ ◯ △ △ △ ◯ △ ◯ 34 Pan et al., 2013 ◯ ◯ ◯ ◯ ◯ ◯ ◯ △ △ △ × × ◯ 35 Chen et al., 2012 △ △ × △ ◯ △ △ △ △ × △ × ◯ 36 Zhao et al., 2012 △ △ △ ◯ △ △ △ △ ◯ △ ◯ △ △ 37 Wang et al., 2012 △ △ × △ ◯ △ △ △ △ × △ × ◯ 38 Pei et al.,2012 △ ◯ × ◯ ◯ ◯ ◯ △ ◯ ◯ × × ◯ 39 Wu et al., 2012 △ × × △ △ △ △ △ △ × × × ◯ 40 Tong et al., 2011 △ △ ◯ △ ◯ △ △ △ △ × △ × ◯ 41 Zhang et al., 2011 △ △ × △ △ △ △ △ △ × △ × ◯ 42 Gu et al., 2011 △ △ ◯ △ △ △ △ △ △ × △ × ◯ 43 Zhao et al., 2010 △ △ × △ ◯ △ ◯ △ △ × △ × ◯ 44 Ding et al., 2010 △ △ ◯ △ ◯ △ △ △ △ × △ × ◯ 45 Pan et al., 2010 △ △ △ △ △ △ △ △ △ × △ × ◯ 46 Liu et al.,2008 △ △ △ △ ◯ △ ◯ △ ◯ △ △ △ ◯ 47 Ji et al., 2008 ◯ △ ◯ ◯ ◯ △ △ △ ◯ × △ × ◯ 48 Chen et al., 2008 △ △ ◯ △ ◯ △ ◯ △ △ × △ × △ 49 Lou et al., 2008 △ ◯ △ ◯ ◯ △ △ △ ◯ △ △ △ △ 50 Li et al., 2007 △ ◯ ◯ △ △ △ ◯ △ △ × △ × ◯ 51 Yang et al., 2007 △ × × △ △ △ △ △ △ × △ × ◯ 52 Gu et al., 2007 △ ◯ △ ◯ ◯ △ △ △ ◯ △ × × △ 53 Chen et al., 2006 △ △ △ △ △ △ △ △ △ × △ × △
Table 4 Evaluation of included trial studies using the CONSORT-CHM statement
Number Authors, year Participant flow Recruitment Baseline data Numbers analysed Outcomes Ancillary analysis Harms Limitations Generalizability Interpretation Registration Protocol Funding 1 Wu et al., 2020 × △ ◯ ◯ △ × × × ◯ ◯ × × ◯ 2 Lyv et al., 2020 × △ △ ◯ △ × × × ◯ ◯ × × ◯ 3 Yang et al., 2019 × △ ◯ ◯ △ × × ◯ △ △ × × ◯ 4 Yang et al., 2019 × △ ◯ ◯ △ × × × ◯ ◯ × × ◯ 5 Li et al., 2018 × △ △ ◯ △ × ◯ ◯ △ △ × × ◯ 6 Chen 2017 × △ ◯ △ △ × × × △ ◯ × × ◯ 7 Hu et al., 2017 × ◯ ◯ ◯ △ × ◯ × ◯ ◯ × × ◯ 8 Jiang et al., 2017 × ◯ ◯ ◯ △ × ◯ × △ ◯ × × ◯ 9 Yang et al., 2017 × △ △ △ △ × × × △ △ × × × 10 Jeong et al., 2017 ◯ × ◯ ◯ △ × ◯ △ △ △ ◯ ◯ × 11 Sun et al., 2017 × ◯ ◯ △ △ × × × △ ◯ × × ◯ 12 Niu 2016 × △ ◯ ◯ △ × × × △ △ △ × × 13 Zhang et al., 2016 × △ × ◯ △ × ◯ × △ △ × × ◯ 14 Zhang et al., 2016 × × ◯ ◯ △ × × × △ △ × × ◯ 15 Qi et al., 2016 × △ ◯ ◯ △ × × × △ △ × × × 16 Tan et al., 2016 × △ ◯ ◯ △ × ◯ × △ △ × × × 17 Yu et al., 2016 × △ ◯ ◯ △ × × × △ △ × × ◯ 18 Yin et al., 2016 × △ ◯ △ △ × × × △ △ × × ◯ 19 Zhu 2015 × △ ◯ ◯ △ × × × △ △ × × × 20 Li 2015 × ◯ ◯ ◯ △ × ◯ × △ △ ◯ × × 21 Chen et al., 2015 × △ ◯ ◯ △ × ◯ × △ △ × × ◯ 22 Yu et al.,2015 × △ ◯ △ ◯ × ◯ × △ △ × × ◯ 23 Li 2015 × △ △ ◯ △ × × × △ △ × × ◯ 24 Liu et al., 2014 × △ × ◯ △ × × × △ △ × × × 25 Liu et al., 2014 × △ △ ◯ △ × △ × △ △ × × ◯ 26 Li et al., 2014 × △ ◯ ◯ △ × ◯ × △ △ ◯ × × 27 Zhu et al., 2014 × ◯ △ ◯ △ × × × △ △ × × × 28 Wen et al., 2014 × △ △ ◯ △ × ◯ × △ △ × × × 29 Deng, 2013 × △ × ◯ △ × × × △ △ × × × 30 Li et al., 2013 × △ △ ◯ △ × ◯ × △ △ × × × 31 Song et al., 2013 × △ ◯ ◯ △ × × × △ △ × × × 32 Li et al., 2013 △ △ △ ◯ △ × ◯ × ◯ △ × × × 33 Wong et al., 2013 ◯ △ ◯ ◯ ◯ × ◯ ◯ △ △ ◯ ◯ × 34 Pan et al., 2013 ◯ △ ◯ ◯ ◯ △ ◯ ◯ △ △ ◯ × × 35 Chen et al., 2012 × △ △ ◯ △ × × × ◯ △ × × ◯ 36 Zhao et al., 2012 × △ △ ◯ △ △ ◯ × △ △ △ × ◯ 37 Wang et al., 2012 × △ △ ◯ △ × × × ◯ ◯ × × × 38 Pei et al.,2012 × △ ◯ ◯ ◯ × ◯ × △ △ × × ◯ 39 Wu et al., 2012 ◯ ◯ △ △ △ × ◯ × ◯ △ × × ◯ 40 Tong et al., 2011 × △ △ ◯ △ × ◯ × ◯ △ × × × 41 Zhang et al., 2011 × ◯ ◯ ◯ △ × ◯ × ◯ △ × × × 42 Gu et al., 2011 × ◯ ◯ ◯ △ × ◯ × ◯ △ × × × 43 Zhao et al., 2010 × △ × ◯ △ × × × ◯ ◯ × × × 44 Ding et al., 2010 × × ◯ ◯ △ × ◯ × ◯ △ × × × 45 Pan et al., 2010 × △ × ◯ △ × ◯ × ◯ △ × × × 46 Liu et al.,2008 × ◯ △ ◯ △ × × × ◯ ◯ × × × 47 Ji et al., 2008 × △ ◯ ◯ △ × △ × ◯ ◯ × × ◯ 48 Chen et al., 2008 × ◯ ◯ ◯ △ × × × ◯ ◯ × × × 49 Lou et al., 2008 × ◯ ◯ ◯ △ △ ◯ × △ △ △ × × 50 Li et al., 2007 × ◯ × ◯ △ × ◯ × △ ◯ × × × 51 Yang et al., 2007 × ◯ △ ◯ △ × × × △ △ × × × 52 Gu et al., 2007 △ △ × ◯ △ × ◯ × △ ◯ ◯ × × 53 Chen et al., 2006 × △ △ ◯ △ △ × × △ △ △ × ×
All 53 trials reported randomization, but only 6 of them fully reported the method of generating random sequences, including 4 trials used random number tables and 2 RCTs used the central randomized method. Only 3 trials specified the implementation of clinical trials, including random methods, recruitment of participants, and intervention process. None of the studies fully described how to conduct blinding. Seven trials mentioned that blinding method was used, but there was a lack of detailed descriptions of blinding personnel and implementation methods. Forty-six trials did not mention the blinding procedures at all. Only 4 trials fully reported the primary outcome, the secondary outcome, and the outcome of the relevant indicators stated in the method. The remaining 46 trials did not report all the outcomes that the study design had set to measure. Among the 14 trials reported the adverse reaction, 2 trials did not specify information of the cases number of test group or control group. A total of 25 trials did not include adverse effects as one of the outcome measurements.
Most of the trials provided limited information about study design and methodology. Five multicentre randomized clinical trials were identified [[
Graph: Fig. 2 Risk of bias graph: the judgements of the review authors about each domain of the risk of bias presented as percentages across all included studies
Graph: Fig. 3 Risk of bias summary: the judgements of the review authors about each risk of bias item presented for each included trial
Further information about the judgement of the 6 domains of the risks of bias is provided in the following:
- Randomization
- We assessed 18 trials at low of bias due to adequate reporting and application of random sequence generation, the remainder were assessed at unclear risk of bias.
- Allocation (sequence generation and allocation concealment)
- Two trials reported detailed information on allocation concealment methods and were regarded as adequate [[
26 ]], and 51 trials were assessed at unclear risk of bias due to not providing the specific methods of allocation concealment. - Blinding
- Two trials claimed that they respectively used single-blinding or double-blinding but they did not report who was blinded [[
28 ], [58 ]]. Two trial reported that it used blindness-method evaluation [[51 ]]. One trial reported specifically who were blinded to the treatment assignment [[26 ]]. The remaining trials did not mention blinding. - Incomplete outcome data
- Three trials specified the numbers and reasons of withdrawal and loss to follow-up and were assessed as trials with a low risk of bias [[
26 ], [47 ], [52 ]]. One trial gave unclear information on withdrawals and loss to follow-up [[58 ]]. 18 trials reported participants lost to follow-up without providing the reasons for the loss and were assessed as trials with unclear risk of bias [[28 ], [30 ]–[32 ], [43 ]–[45 ], [50 ], [55 ], [62 ]–[70 ]]. The remaining trials reported that no participants were lost to follow-up during the trial. - Selective reporting
- Only 2 trials specified outcome measures were not reported [[
60 ]] and the remaining trials were assessed as having high risk of reporting bias. All 53 trials were considered to have unclear risks of bias due to lack of adequate information. - Other potential sources of bias
- All the trials did not report the sample size calculations and were assessed as not free of other potential sources of bias.
This systematic review identified RCTs and evaluate clinical evidence for the use of TCMs on treating NAFLD. Fifty-three RCTs involving 5997 participants were included. The mean sample size was 113 participants (range 60 to 221 participants) per trial. Each included RCT tested different TCMs giving a total of 53 TCMs identified in this study. The most common Chinese medicinal materials found in the investigated TCMs were Crataegi Fructus (山楂), Alismatis Rhizoma (澤瀉), Atractylodis Macrocephalae Rhizoma (白術) and Salviae Miltiorrhizae Radix Et Rhizoma (丹參). TCMs (with or without behavioral interventions) have been shown to be more effective statistically than the control, placebo, pharmacological interventions (with or without behavioral interventions) (P < 0.05 or P < 0.01) as reported in 50 RCTs. The present systematic review also suggests that TCMs such as Shenge formula, Shugan Jianpi Huatan decoction and Heze lipid lowing oral liquid decoction might have positive effects on NAFLD by improving TCM syndrome scores, liver function, and body lipid profile. A range of non-serious, reversible adverse effects associated with the use of TCMs was also reported.
Nevertheless, the evidence reported in the included RCTs is not sufficient to recommend any of the investigated TCMs for the treatment of NAFLD due to the questionable quality of RCTs, the risk of bias and the lack of homogeneous data. None of the included RCTs was in full compliance with the CONSORT-CHM guideline. The risks of bias were either identified or could not be ruled out due to incomplete information. The heterogeneity in the methodology across all the trials meant that a meta-analysis was not possible, and thus further recommendation about a common or predominant medicine for NAFLD could not be made. Improvement in the RCT protocol, the use of a larger sample size, a setting of multicenter and a more focused approach in selecting TCMs for testing in the future might allow more reliable evidence to be developed effectively to support the role of TCMs in NAFLD treatment. Further analysis of the RCTs included in this review identified common limitations and provided an insight about priority areas of improvement for RCTs testing TCMs as discussed in the following.
Firstly, the reporting quality of the 53 RCTs was generally poor. None of the trials completely fulfilled the criteria of the CONSORT-CHM statement. The evaluation results of the Cochrane risk-of-bias tool were also concerning in light of the multiple risks of bias associated with the randomization sequence generation and blinding. Although all the trials reported the study protocol was designed according to recommended standards, only 3 RCTs fully reported the randomization sequence generation in detail, and none of the 53 trials conducted a blinding process in full compliance. Blinding is important in minimizing bias and maximizing the validity of the study results. As a review of 3159 RCTs previously reported, compared with the RCTs using blinding, the RCTs not using blinding yielded 17% larger estimates of treatment effects and in trials with subjective outcomes, the effect estimates could be exaggerated by 25% [[
Secondly, most of the RCTs included in this review measured the TCM syndrome score to estimate the efficacy of the investigated TCMs. The score system is determined based on the assessment of TCM symptoms and signs, and is one of the most important indexes for evaluating the effectiveness of a TCM in the treatment of a disease [[
Thirdly, the limited sample size as reported in some of the included RCTs was another cause of concern. While most of the included RCTs recruited nearly 100 participants and some having over 200 participants, 19 trials (35.19%) reported less than 100 participants in the clinical studies. Insufficient participant's number may result in the inability to detect a precise effect and affect the statistic bias and the quality of trial, possibly leading to a lack of statistical ability to properly estimate the effect of treatment and overestimating the risk of intervention benefit. A sample size calculation involves determining the minimum number of participants needed to detect a treatment effect that is clinically relevant [[
The age and sex of participants in the included trials were representative factors of people with NAFLD. Nearly all the included RCTs recruited participants in China and only 1 RCT was conducted abroad [[
Many crude extracts from medicinal plants have significant anti-NAFLD effects. For instance, berberine, which was isolated from the Chinese medicinal material Coptidis Rhizoma and widely used to treat diarrhea and other inflammatory diseases in China [[
Apart from efficacy, evaluation of the safety of TCMs in the management of NAFLD was another primary goal of this review. However, no clear conclusions can be made about the safety of TCMs due to inadequate reporting on adverse reactions in the included trials. If the studies were to be assessed for causality, it would clearly show that adverse events caused by TCMs are relatively infrequent [[
There were several limitations in our study. Although only RCTs were included in our study, the quality of the RCT design was not high. Together with the vastly different TCMs investigated and the lack of homogeneity in the study design across the included RCTs, it was difficult to draw a clear conclusion about the efficacy and safety of TCMs for NAFLD. Moreover, the evaluation of the TCMs efficacy and safety was based on the quality assessment in this study which was in turn based on how the original study was reported. The judgment about the TCMs efficacy and safety, therefore, may be subject to the influence of the quality of reporting. The CONSORT-CHM extensions adopted as the evaluation framework in this review were designed to improve the completeness and transparency of reporting of interventions in controlled trials of Chinese herbal medicines. However, few researchers had adopted the recommendations fully. By employing the CONSORT-CHM guidelines as an assessment tool and revealing the shortfalls in the current RCT design and reporting, it is anticipated that the quality of TCMs RCT research would be improved through improved awareness, recognition and adoption of the CONSORT-CHM guidelines.
Based on this review, the efficacy of TCMs in NAFLD management appears to be promising and the risks associated with the investigated TCMs were reportedly minimal. However, no conclusion can be made so far due to the concerns over the quality of RCTs and the possible risks of bias. Improvement in the RCT protocol, the use of a larger sample size, a setting of a multicenter, a more focused approach in selecting TCMs and measures that allow the investigation of long term safety of TCMs are recommended for achieving a high-level quality of TCMs evidence for NAFLD to be used to inform clinical practice.
We are also grateful to Chair Prof. Yi-Tao Wang for his technical guidance and support.
COLU, ZL and JS conceived and designed the study. ZL and XC were responsible for data management and analysis. COLU, ZL, JS, and YX contributed to interpretation of study results. ZL, XC and YX drafted the manuscript. COLU, HH and JS critically reviewed and revised the manuscript. All authors read and approved the final manuscript.
This work was financially supported by the Research Fund of University of Macau (MYRG2019-00038-ICMS).
All data are fully available without restriction.
Not applicable.
All of authors consent to publication of this work in Chinese Medicine.
The authors declare that they have no competing interests.
• NAFLD
- Nonalcoholic fatty liver disease
• TCMs
- Traditional Chinese medicines
• RCTs
- Randomized controlled trial
• ALB
• Albumin
• ALP
- Alkaline phosphatases
• ALT
- Aminotransferase
• AST
- Aspartate aminotransferase
• BMI
- Body mass index
• BU
- B-ultrasound
• CT
- Computed tomography
• DAO
- Diamine oxidase
• FBG
- Fasting blood glucose
• FINS
- Fasting plasma insulin
• GGT
- Gamma-glutamyl-transpeptidase
• GLB
- Globulin
• GTP
- Glutamyl transpeptidase
• HDL
- High density lipoprotein-cholesterol
• HFC
- Hepatic fat content
• HOMA-IR
- Homeostasis model assessment-estimated insulin resistance
• hs-CRP
- High sensitivity C-reactive protein
• IM
- Integrative medicine
• IRI
- Insulin resistance index
- L/S ratio
- Liver to spleen ratio
• LDL
- Low density lipoprotein-cholesterol
• MRS
- Magnetic resonance spectroscopy
• TB
- Total bilirubin
• TC
- Total cholesterol
• TG
- Triglyceride
- TNF-α
- Tumor necrosis factor-α
• VLDL
- Very low density lipoprotein
• WHR
- Waist/hip ratio
• WM
- Western medicine
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By Zuanji Liang; Xianwen Chen; Junnan Shi; Hao Hu; Yan Xue and Carolina Oi Lam Ung
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