Circulating angiopoietin-like proteins in metabolic-associated fatty liver disease: a systematic review and meta-analysis

Abstract

Background: Angiopoietin-like proteins (ANGPTLs) are closely related to insulin resistance and lipid metabolism, and may be a key in metabolic syndrome. Non-alcoholic fatty liver disease (NAFLD) (newly named metabolic-associated fatty liver disease (MAFLD)) is based on metabolic dysfunction. There may be some correlation between ANGPTLs and MAFLD, but the specific correlation is unclear. This study aims to explore the predictive role of ANGPTLs in MAFLD and its progression.

Methods: Seven databases (PubMed, EMBASE, Cochrane Library, CNKI, WANFANG, CBM and Clinicaltrials.gov ) were searched with free terms and MeSH terms. The random-effects model was used to pool the data, and Standardized Mean Difference (SMD) and 95% confidence intervals (CI) were taken as the overall outcome. No language restrictions existed in the article selection. RevMan 5.3, Stata 16 and MetaXL software were applied to analyse the data and the GRADE system was utilized to assess the certainty of evidence.

Results: After reviewing 823 related articles, 13 studies (854 cases and 610 controls) met the inclusion criteria, and contributed to this meta-analysis. The results showed that circulating ANGPTL8 level was significantly elevated in the MAFLD group than in the healthy control group (SMD = 0.97 pg/mL, 95%CI: 0.77, 1.18). Conversely, there was no significant difference in the ANGPTL4 (SMD = 0.11 ng/mL, 95%CI: - 0.32, 0.54) and ANGPTL3 (SMD = - 0.95 ng/mL, 95%CI: - 4.38, 2.48) between the two groups. Subgroup analysis showed that: 1) the MAFLD group had significantly higher ANGPTL8 levels than the healthy control group in Asian and other races; 2) the ANGPTL8 levels in Body Mass Index (BMI) > 25 kg/m² patients with MAFLD were higher than those in the healthy control group; 3) the higher ANGPTL8 levels were observed in moderate to severe MAFLD group than the healthy control group. Meta-regression demonstrated that BMI might effectively explain the high heterogeneity. No significant publication bias existed (P > 0.05). The certainty of evidence was assessed as very low by the GRADE system.

Conclusions: The ANGPTLs may be related to MAFLD. The increased ANGPTL8 level may be positively correlated with different situations of MAFLD, which may act as a potential indicator to monitor the development trends.

Keywords: Angiopoietin-like protein 8; Angiopoietin-like proteins; Meta-analysis; Metabolic-associated fatty liver disease; Non-alcoholic fatty liver disease; Non-alcoholic steatohepatitis.

Fig. 1

Flowchart of study inclusions and exclusions

Fig. 2

Forest plot of circulating ANGPTLs levels between NAFLD and the healthy control group (Random-Effects Model, SMD)

Fig. 3

Forest plot of circulating ANGPTL8 levels between NAFLD and the healthy control group (Quality-Effects Model, SMD)

Fig. 4

Galbraith Test result of circulating ANGPTL8 levels between NAFLD and the healthy control group

Fig. 5

Forest plot of circulating ANGPTL8 levels between NAFLD and the healthy control group by race (Random-Effects Model, SMD)

Fig. 6

Forest plot of circulating ANGPTL8 levels between NAFLD and the healthy control group by severity (Random-Effects Model, SMD)

Fig. 7

Forest plot of circulating ANGPTL8 levels between NAFLD and the healthy control group by BMI (Random-Effects Model, SMD)

Fig. 8

Omission of single study figure

Fig. 9

Forest plot of circulating ANGPTL8 levels between NAFLD and the healthy control group (Fixed-Effects Model, SMD)

Fig. 10

Forest plot of circulating ANGPTL8 levels between NAFLD and the healthy control group (Random-Effects Model, MD)

Fig. 11

Egger’s publication bias plot

Fig. 12

Funnel figure

Fig. 13

Doi plot