Prognostic non-invasive biomarkers for all-cause mortality in non-alcoholic fatty liver disease: A systematic review and meta-analysis

Table 1 Characteristics of studies included in the meta-analysis

Study characteristics	Le et al[18]	Kim et al[29]	Hagstrom et al[30]	Angulo et al[31]
Year	2019	2013	2019	2013
Country (setting)	United States (community care)	United States (community care)	Sweden (secondary care)	United States, United Kingdom, Australia, Thailand, Italy, Iceland (secondary care)
Study design	Retrospective cohort study	Retrospective cohort study	Retrospective cohort study	Retrospective cohort study
NAFLD diagnostic method	USFLI1	Ultrasound2	Liver biopsy3	Liver biopsy3
Number of NAFLD participants	4680	4079	646	320
Average length of follow-up (yr)	Not specified, however follow-up period was 1999-2016	14.5 (median)	19.9 (mean)	8.7 (median)
Proportion of males (%)	56.3	50.9	62	43
Mean age (yr)	52.6	46.2	50	52
Caucasians (%)	74.8	75.8	Not specified	92
Mean BMI (kg/m2)	34.3	29.05	28	33
Cardiovascular disease (%)	13.3	7.1	Not specified	Not specified
Hypertension (%)	52.3	32.4	30	47.5
Diabetes (%)	24.4	9.5	14	36.2
Smoking (%)	45	55.2	Not specified	Not specified
Deaths (n)	683	778	214	22
Low NFS4 (%)	32.4	67.5	76.2	39.1
Intermediate NFS4 (%)	51.7	28.2	5.1	37.5
High NFS4 (%)	17.3	4.2	2.3	23.4

¹USFLI ≥ 30 and exclusion of liver disease of other aetiology.

²Ultrasound hepatic steatosis and exclusion of liver disease of other aetiology.

³Liver biopsy confirmed non-alcoholic fatty liver disease (NAFLD) and exclusion of liver disease of other aetiology.

⁴The same NAFLD fibrosis score (NFS) cut-offs have been used in all studies: High NFS (> 0.676), intermediate NFS (-1.455-0.676), low NFS (<-1.455).

NAFLD: Non-alcoholic fatty liver disease; BMI: Body mass index; NFS: NAFLD fibrosis score.

Table 2 Meta-analysis of non-invasive scoring systems and all-cause mortality and cardiovascular-related mortality

Comparison categories1	No. studies	Studies included	Heterogeneity: I2 (P value for Q)2	Pooled HR (95%CI)	P value for overall effect (pHR)
All-cause mortality
NFS high vs low	4	Le et al[18], 2019; Kim et al[29], 2013; Hagstrom et al[30], 2019; Angulo et al[31], 2013	75.7%(0.006)	3.07 (1.62 – 5.83)	0.001
NFS Int. vs low	4	Le et al[18], 2019; Kim et al[29], 2013; Hagstrom et al[30], 2019; Angulo et al[31], 2013	81.5%(0.001)	1.91 (1.18 – 3.09)	0.008
FIB-4 high vs low	3	Kim et al[29], 2013; Hagstrom et al[30], 2019; Angulo et al[31], 2013	73.0%(0.025)	3.06 (1.54 – 6.07)	0.001
FIB-4 Int. vs low	3	Kim et al[29], 2013; Hagstrom et al[30], 2019; Angulo et al[31], 2013	0.0%(0.396)	1.60 (1.33 – 1.91)	< 0.001
APRI high vs low	3	Kim et al[29], 2013; Hagstrom et al[30], 2019; Angulo et al[31], 2013	0.0%(0.589)	1.90 (1.32 – 2.73)	0.001
APRI Int. vs low	3	Kim et al[29], 2013; Hagstrom et al[30], 2019; Angulo et al[31], 2013	0.0%(0.411)	0.98 (0.76 – 1.26)	0.887
BARD high vs low	2	Hagstrom et al[30], 2019; Angulo et al[31], 2013	45.1%(0.177)3	2.87 (1.27 – 6.46)	0.011
BARD Int. vs low	2	Hagstrom et al[30], 2019; Angulo et al[31], 2013	0.0%(0.862)	1.64 (1.21 – 2.23)	0.001
Cardiovascular mortality
NFS high vs low	2	Le et al[18], 2019; Kim et al[29], 2013	0.0%(0.317)	3.09 (1.78 – 5.34)	< 0.001
NFS Int. vs low	2	Le et al[18], 2019; Kim et al[29], 2013	0.0%(0.759)	2.12 (1.41 – 3.17)	< 0.001

¹For Non-alcoholic fatty liver disease fibrosis score, cut-off values were “low” < -1.455 (reference group), “intermediate” -1.455 – 0.676, and “high” > 0.676. For fibrosis-4 index, cut-off values were “low” < 1.30 (reference group), “intermediate” 1.30-2.67, and “high” > 2.67. For AST to platelet ratio index, “low” < 0.5 (reference group), “intermediate” 0.5-1.5, and “high” > 1.5. For BARD, “low” 0-1 (reference group), “intermediate” 2-3, and “high” 4.

²Where the heterogeneity is statistically significant the results of the random effects analysis (DerSimonian-Laird method) are shown. Where heterogeneity is not a concern the results of the fixed effects analysis (inverse variance method) are shown. The P value is for the Cochran’s Q statistic.

³For the analysis of BARD high vs low the results of the random effects analysis are shown as the I² value suggests moderate heterogeneity is present, however note the low number (n = 2) of studies included.

NAFLD: Non-alcoholic fatty liver disease; NFS: NAFLD fibrosis score; FIB-4: Fibrosis-4 index; APRI: AST to platelet ratio index; BARD score: BMI ≥ 28 kg/m² (1 point), AST/ALT ratio ≥ 0.8 (2 points), and diabetes mellitus (1 point).