Chinese medicine formulas for nonalcoholic fatty liver disease: Overview of systematic reviews

Table 1 General characteristics of included systematic reviews

Ref.	Included study design, n	Total sample size	Intervention	Comparator	Evaluation of methodological quality	Outcomes
Cai et al[9], 2019	RCT, 13	1429	TCM formulas based on HuoXueHuaYu principle	Conventional medications	Cochrane Risk of Bias Tool	Ultrasound improvement rate, blood lipid profiles (TC, TG), hepatic function (ALT, AST), global improvement rate
Shi et al[8], 2012	RCT, 62	5904	TCM formulas, alone or in combination with conventional medications	Placebo or conventional medications	Not mentioned	ALT normalization rate, blood lipids normalization rate, hepatic steatosis disappearance rate
He et al[16], 2010	RCT, 11	1078	TCM formulas, alone	Conventional medications	Jadad Scale	Hepatic function (ALT, AST, GGT), blood lipid profiles (TC, TG, HDL-C)
Li et al[17], 2011	RCT, 22	2442	TCM formulas, alone	Conventional medications	Schulz and Jadad Criteria	Cure rate, global improvement rate, hepatic function (ALT, AST, GGT), blood lipid profiles (TC, TG, HDL-C, LDL-C)
Li et al[18], 2014	RCT, 17	1552	TCM formulas, alone or in combination with polyene phosphatidyl choline	Polyene phosphatidyl choline	Not mentioned	Global improvement rate
Yang et al[19], 2019	RCT, 19	1490	TCM formulas based on JianPiHuaTan principle, alone or in combination with conventional medications	Conventional medications	Jadad Scale	Global improvement rate, hepatic function (ALT, AST), blood lipid profiles (TC, TG), adverse events
Zhang et al[20], 2014	RCT, 10	1395	TCM formulas alone	Placebo or conventional medications	Jadad Scale	Global improvement rate, adverse events

ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: Gamma-glutamyl transpeptidase; HDL-C: High-density lipoprotein cholesterol; LDL-C: Low-density lipoprotein cholesterol; RCTs: Randomized controlled trials; TC: Total cholesterol; TCM: Traditional Chinese medicine; TG: Triglyceride.

Table 2 Methodological quality of included systematic reviews using a measure tool to assess systematic reviews 2

Ref.	Cai et al[9], 2019	Shi et al[8], 2012	He et al[16], 2010	Li et al[17], 2011	Li et al[18], 2014	Yang et al[19], 2019	Zhang et al[20], 2014
Item 1	Yes	Yes	Yes	Yes	No	Yes	Yes
Item 2	No	No	No	No	No	No	No
Item 3	No	Yes	No	No	No	No	No
Item 4	Partial Yes	Partial Yes	No	No	Partial Yes	Partial Yes	Partial Yes
Item 5	No	Yes	Yes	Yes	No	No	No
Item 6	Yes	Yes	No	Yes	No	No	Yes
Item 7	No	No	No	No	No	No	No
Item 8	No	Partial Yes	No	No	No	No	No
Item 9	Yes	No	Partial Yes	Partial Yes	No	Partial Yes	Partial Yes
Item 10	No	No	No	No	No	No	No
Item 11	Yes	Yes	No	No	Yes	Yes	Yes
Item 12	No	No	No	No	No	Yes	No
Item 13	No	No	No	No	No	Yes	No
Item 14	Yes	No	Yes	No	No	Yes	Yes
Item 15	Yes	Yes	No	No	Yes	Yes	Yes
Item 16	Yes	Yes	No	No	No	No	No
Overall quality	Low	Extremely low	Extremely low	Extremely low	Extremely low	Moderate	Low

Table 3 Risk of bias of the included systematic reviews evaluated by risk of bias in the systematic review

Ref.	Phase 1	Phase 2				Phase 3
	Relevance	Study eligibility criteria	Identification and selection of studies	Data collection and study appraisal	Synthesis and findings	Risk of bias in the review
Cai et al[9], 2019	Yes	Low risk	High risk	Low risk	Low risk	High risk
Shi et al[8], 2012	Yes	Low risk	High risk	High risk	High risk	High risk
He et al[16], 2010	Yes	Low risk	High risk	High risk	High risk	High risk
Li et al[17], 2011	Yes	High risk	High risk	High risk	High risk	High risk
Li et al[18], 2014	Yes	High risk	High risk	High risk	Not clear	High risk
Yang et al[19], 2019	Yes	Low risk	High risk	High risk	Low risk	High risk
Zhang et al[20], 2014	Yes	Low risk	High risk	High risk	High risk	High risk

Table 4 Quality of evidence in the included systematic reviews based on grading of recommendations assessment, development and evaluation system

Ref.	Intervention vs comparator	Outcomes	Study numbers and sample size	A	B	C	D	E	Quality of evidence
Cai et al[9], 2019	TCM formulas based on HuoXueHuaYu principle vs conventional medications	Ultrasound improvement rate: OR = 2.33; 95%CI: 1.60, 3.40; P < 0.001	7 (590)	0	0	0	0	0	High
		TC: MD = -0.38; 95%CI: -0.48, -0.29; P < 0.001	5 (358)	0	-21	0	-12	0	Very low
		TG: MD = -0.31; 95%CI: -0.37, -0.24; P < 0.001	6 (418)	0	-21	0	0	0	Low
		ALT: SMD = -1.69; 95%CI: -2.24, -1.14; P < 0.001	6 (418)	0	-21	0	0	0	Low
		AST: MD = -22.53; 95%CI: -33.16, -11.90; P < 0.001	5 (354)	0	-21	0	-12	0	Very low
		Global improvement rate: OR = 3.55; 95%CI: 2.65, 4.76; P < 0.001	12 (1389)	-13	0	0	0	0	Moderate
Shi et al[8], 2012	TCM formulas vs placebo	ALT normalization rate: OR = 1.73, 95%CI: 1.34, 2.23; P < 0.001	8 (902)	0	0	0	-14	-15	Low
		Blood lipids normalization rate: OR = 1.74, 95%CI: 1.34, 2.26; P < 0.001	8 (922)	0	0	0	0	-15	Moderate
		Hepatic steatosis disappearance rate: OR = 2.43, 95%CI: 1.48, 3.97; P < 0.001	9 (933)	0	-16	0	-14	-15	Very low
	TCM formulas vs UDCA	ALT normalization rate: OR = 1.45, 95%CI: 1.05, 1.98; P = 0.023	7 (702)	0	0	0	-14	0	Moderate
		Blood lipids normalization rate: OR = 1.57, 95%CI: 0.88, 2.80; P = 0.124	3 (350)	0	0	0	-14	0	Moderate
		Hepatic steatosis disappearance rate: OR = 1.92, 95%CI: 1.20, 3.07; P = 0.006	5 (519)	0	0	0	-14	-15	Low
	TCM formulas + UDCA vs UDCA	ALT normalization rate: OR = 1.55, 95%CI: 1.08, 2.23; P = 0.019	4 (341)	0	0	0	-14	-15	Low
		Blood lipids normalization rate: OR = 1.65, 95%CI: 0.71, 3.87; P = 0.247	1 (60)	-17,8	0	0	-14	0	Low
		Hepatic steatosis disappearance rate: OR = 1.94, 95%CI: 1.28, 2.96; P = 0.002	4 (341)	0	0	0	-14	-15	Low
	TCM formulas vs insulin sensitizers	ALT normalization rate: OR = 1.67, 95%CI: 0.53, 5.28; P = 0.385	1 (80)	-17,8	0	0	-14	0	Low
		Blood lipids normalization rate: OR = 1.67, 95%CI: 0.53, 5.28; P = 0.385	1 (80)	-17,8	0	0	-14	0	Low
		Hepatic steatosis disappearance rate: OR = 1.67, 95%CI: 0.53, 5.28; P = 0.385	1 (80)	-17,8	0	0	-14	0	Low
	TCM formulas + insulin sensitizers vs insulin sensitizers	ALT normalization rate: OR = 3.31, 95%CI: 0.82, 13.42; P = 0.094	1 (61)	0	0	0	-14	0	Moderate
		Blood lipids normalization rate: OR = 5.51, 95%CI: 0.25, 119.50; P = 0.277	1 (61)	0	0	0	-14	0	Moderate
		Hepatic steatosis disappearance rate: OR = 5.51, 95%CI: 0.25, 119.50; P = 0.277	1 (61)	0	0	0	-14	0	Moderate
	TCM formulas vs fibrates	ALT normalization rate: OR = 2.36, 95%CI: 1.55, 3.60; P < 0.001	5 (681)	0	0	0	-14	-15	Low
		Blood lipids normalization rate: OR = 2.13, 95%CI: 1.34, 3.39; P = 0.001	4 (463)	0	0	0	-14	-15	Low
		Hepatic steatosis disappearance rate: OR = 2.35, 95%CI: 1.61, 3.41; P < 0.001	7 (781)	0	0	0	-14	0	Moderate
	TCM formulas + fibrates vs fibrates	ALT normalization rate: OR = 1.47, 95%CI: 0.84, 2.56; P = 0.180	2 (132)	0	0	0	-14	0	Moderate
		Blood lipids normalization rate: OR = 1.83, 95%CI: 0.89, 3.75; P = 0.102	2 (132)	0	0	0	-14	0	Moderate
		Hepatic steatosis disappearance rate: OR = 1.80, 95%CI: 0.76, 4.29; P = 0.183	1 (70)	-17,8	0	0	-14	0	Low
	TCM formulas vs statins	ALT normalization rate: OR = 1.43, 95%CI: 1.03, 2.00; P = 0.035	5 (456)	0	0	0	-14	0	Moderate
		Blood lipids normalization rate: OR = 1.26, 95%CI: 0.85, 1.87; P = 0.249	4 (364)	0	0	0	-14	-15	Low
		Hepatic steatosis disappearance rate: OR = 1.76, 95%CI: 1.30, 2.37; P < 0.001	8 (764)	0	0	0	-14	-15	Low
	TCM formulas + statins vs statins	ALT normalization rate: OR = 1.51, 95%CI: 1.11, 2.05; P = 0.009	6 (571)	0	0	0	-14	0	Moderate
		Blood lipids normalization rate: OR = 1.32, 95%CI: 0.91, 1.93; P = 0.148	5 (504)	0	0	0	-14	0	Moderate
		Hepatic steatosis disappearance rate: OR = 2.13, 95CI: 1.42, 3.19; P < 0.001	6 (601)	0	0	0	-14	0	Moderate
	TCM formulas vs antioxidants	ALT normalization rate: OR = 1.48, 95%CI: 1.15, 1.92; P = 0.003	8 (652)	0	0	0	0	0	High
		Blood lipids normalization rate: OR = 1.53, 95%CI: 0.94, 2.51; P = 0.087	3 (257)	0	0	0	-14	-15	Low
		Hepatic steatosis disappearance rate: OR = 1.81, 95%CI: 1.27, 2.58; P < 0.001	7 (585)	0	0	0	-14	0	Moderate
	TCM formulas + antioxidants vs antioxidants	ALT normalization rate: OR = 1.62, 95%CI: 1.06, 2.46; P = 0.025	4 (267)	0	0	0	-14	0	Moderate
		Blood lipids normalization rate: OR = 1.26, 95%CI: 0.95, 2.94; P = 0.075	2 (143)	0	0	0	-14	0	Moderate
		Hepatic steatosis disappearance rate: OR = 1.77, 95%CI: 1.10, 2.84; P = 0.018	4 (257)	0	0	0	-14	0	Moderate
He et al[16], 2010	TCM formulas vs conventional medications	ALT: MD = -9.55; 95%CI: -12.45, -6.65; P < 0.001	11 (1078)	0	-21	0	0	-19	Very low
		AST: MD = -9.40; 95%CI: -12.96, -5.85; P < 0.001	11 (1078)	0	-21	0	0	-19	Very low
		GGT: MD = -18.31; 95%CI: -27.06, -9.56; P < 0.001	11 (1078)	0	-21	0	0	-19	Very low
		TC: MD = -1.12; 95%CI: -1.80, -0.44; P < 0.001	11 (1078)	0	-21	0	0	-19	Very low
		TG: MD = -0.39; 95%CI: -0.64, -0.15; P = 0.002	11 (1078)	0	-21	0	0	-19	Very low
		HDL-C: MD = 0.21; 95%CI: 0.14, 0.28; P < 0.001	11 (1078)	0	-21	0	0	-19	Very low
Li et al[17], 2011	TCM formulas vs conventional medications	Cure rate: RR = 1.48, 95%CI: 1.12, 1.94; P = 0.005	16 (1644)	0	-16	0	0	-19	Low
		Global improvement rate: RR = 1.29, 95%CI: 1.16, 1.43; P < 0.001	20 (2118)	-13	-21	0	0	-19	Very low
		ALT: MD = -18.90; 95%CI: -26.34, -11.46; P < 0.001	18 (1935)	0	-21	0	0	-19	Very low
		AST: MD = -10.59; 95%CI: -15.61, -5.58; P < 0.001	14 (1480)	0	-21	0	0	-19	Very low
		GGT cannot be evaluated due to data mistake	\	\	\	\	\	\	\
		TC: MD = -0.68; 95%CI: -1.14, -0.21; P = 0.004	17 (1885)	0	-21	0	0	-19	Very low
		TG: MD = -0.48; 95%CI: -0.92, -0.03; P = 0.036	17 (1885)	0	-21	0	0	-19	Very low
		HDL-C: MD = 0.07; 95%CI: -0.17, 0.37; P = 0.561	8 (731)	0	-21	0	0	-19	Very low
		LDL-C: MD = -0.59; 95%CI: -0.80, -0.37; P < 0.001	7 (776)	0	-21	0	0	-19	Very low
Li et al[18], 2014	TCM formulas vs PPC	Global improvement rate: RR = 1.20, 95%CI: 1.12, 1.28; P value not reported	11 (982)	-13	0	0	0	-19	Low
	TCM formulas + PPC vs PPC	Global improvement rate: RR = 1.31, 95%CI: 1.20, 1.43; P value not reported	7 (600)	-13	0	0	0	-19	Low
Yang et al[19], 2019	TCM formulas based on JianPiHuaTan principle vs conventional medications	Global improvement rate: RR = 1.30, 95%CI: 1.16, 1.46; P < 0.001	17 (1344)	-13	-21	0	0	-15	Very low
		ALT: MD = -8.55; 95%CI: -12.76, -4.34; P < 0.001	15 (1151)	0	-21	0	0	-19	Very low
		AST: MD = -3.60; 95%CI: -5.83, -1.37; P = 0.002	13 (979)	0	-16	0	0	-19	Low
		TC: MD = -0.88; 95%CI: -1.15, -0.61; P < 0.001	13 (1008)	0	0	0	0	-19	Moderate
		TG: MD = -0.47; 95%CI: -0.65, -0.30; P < 0.001	14 (1088)	0	-21	0	0	-19	Very low
		Adverse events: OR = 5.62, 95%CI: 2.02, 15.59; P < 0.001	4 (292)	-13	-16	0	-14	-19	Very low
	TCM formulas based on JianPiHuaTan principle + conventional medications vs conventional medications	Global improvement rate: RR = 1.33, 95%CI: 1.14, 1.55; P < 0.001	2 (146)	-13	0	0	0	0	Moderate
Zhang et al[20], 2014	TCM formulas vs conventional medications	Global improvement rate: RR = 1.51, 95%CI: 1.41, 1.62; P < 0.01	10 (1395)	-13	0	0	0	0	Moderate
		Adverse events: No meta-analysis conducted	5 (618)	\	\	\	\	\	\

¹I² > 75%.

²Total cases < 400.

³Serious limitations exist, and the outcomes contained subjective assessments.

⁴The optimal information size was not satisfied.

⁵Asymmetric funnel plot.

⁶I² > 50%.

⁷Unclear information on allocation concealment.

⁸Unclear information on blinding.

⁹Small sample studies accounted for the majority. ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: Gamma-glutamyl transpeptidase; HDL-C: High-density lipoprotein cholesterol; LDL-C: Low-density lipoprotein cholesterol; MD: Mean difference; OR: Odds ratio; PPC: Polyene phosphatidyl choline; RR: Risk ratio; SMD: Standardized mean difference; TC: Total cholesterol; TCM: Traditional Chinese medicine; TG: Triglyceride; UDCA: Ursodeoxycholic acid.