Crosstalk between Irisin Levels, Liver Fibrogenesis and Liver Damage in Non-Obese, Non-Diabetic Individuals with Non-Alcoholic Fatty Liver Disease

Armandi A, Rosso C, Nicolosi A, Caviglia GP; Abate ML, Olivero A, D’Amato D, Verbero M, Gaggini M, Saracco GM, Ribaldone DG, Leeming DJ, Gastaldelli A, Bugianesi E.      

J Clin Med. 2022 Jan 27;11(3):635. doi: 10.3390/jcm11030635. PMID: 35160087 PMCID: PMC8837035

Abstract

Background: Insulin resistance plays a relevant role in the onset of non-alcoholic fatty liver disease (NAFLD) and its progression to non-alcoholic steatohepatitis (NASH) and fibrosis. Irisin is an exercise-induced myokine involved in the regulation of energy homeostasis and glucose metabolism. Additionally, pre-clinical models have shown a potential role of irisin in the pathogenesis of NAFLD. The aim of this study is to explore the association between irisin, histological features and biomarkers of liver fibrogenesis in non-diabetic, non-obese, biopsy-proven NAFLD individuals.

Methods: Forty-one patients with histological evidence of NAFLD were included. Circulating irisin and direct markers of fibrogenesis N-terminal type III collagen propeptide (PRO-C3) and type VI collagen cleavage product (PRO-C6) were measured by ELISA.

Results: Median age of the cohort was 45 years (41-51) and 80.4% were male. Significant fibrosis (stage ≥ 2) was present in 36.6% of cases. Circulating irisin, PRO-C3 and PRO-C6 levels were significantly higher in subjects with fibrosis stage ≥ 2 when compared to those with fibrosis stage < 2 (5.96 ng/mL (95% CI = 4.42-9.19) vs. 2.42 ng/mL (95% CI = 1.73-5.95), p = 0.033; 9.5 ng/mL (95% CI = 7.7-13.6) vs. 6.2 ng/mL (95% CI = 4.9-8.9), p = 0.016; 6.6 ng/mL (95% CI = 5.6-7.9) vs. 5.1 ng/mL (95% CI = 4.2-5.4), p = 0.013, respectively). Irisin levels were similarly distributed between the features of NASH. Circulating irisin positively correlated with both PRO-C3 and PRO-C6 levels (r = 0.47, p = 0.008 and r = 0.46, p = 0.002).

Conclusions: Increased circulating irisin levels may identify a more aggressive phenotype of liver disease with increased fibrogenesis and more severe liver damage.

Keywords: NAFLD; PRO-C3; PRO-C6; insulin resistance; irisin; liver fibrogenesis; liver fibrosis; non-invasive biomarkers.

Long-term outcomes and predictive ability of non-invasive scoring systems in patients with non-alcoholic fatty liver disease.

Younes R, Caviglia GP, Govaere O, Rosso C, Armandi A, Sanavia T, Pennisi G, Liguori A, Francione P, Gallego-Durán R, Ampuero J, Garcia Blanco MJ, Aller R, Tiniakos D, Burt A, David E, Vecchio FM, Maggioni M, Cabibi D, Pareja MJ, Zaki MYW, Grieco A, Fracanzani AL, Valenti L, Miele L, Fariselli P, Petta S, Romero-Gomez M, Anstee QM, Bugianesi E.

J Hepatol. 2021 Oct;75(4):786-794. doi: 10.1016/j.jhep.2021.05.008. Epub 2021 Jun 4.

Abstract

Background & aims: Non-invasive scoring systems (NSS) are used to identify patients with non-alcoholic fatty liver disease (NAFLD) who are at risk of advanced fibrosis, but their reliability in predicting long-term outcomes for hepatic/extrahepatic complications or death and their concordance in cross-sectional and longitudinal risk stratification remain uncertain.

Methods: The most common NSS (NFS, FIB-4, BARD, APRI) and the Hepamet fibrosis score (HFS) were assessed in 1,173 European patients with NAFLD from tertiary centres. Performance for fibrosis risk stratification and for the prediction of long-term hepatic/extrahepatic events, hepatocarcinoma (HCC) and overall mortality were evaluated in terms of AUC and Harrell's c-index. For longitudinal data, NSS-based Cox proportional hazard models were trained on the whole cohort with repeated 5-fold cross-validation, sampling for testing from the 607 patients with all NSS available.

Results: Cross-sectional analysis revealed HFS as the best performer for the identification of significant (F0-1 vs. F2-4, AUC = 0.758) and advanced (F0-2 vs. F3-4, AUC = 0.805) fibrosis, while NFS and FIB-4 showed the best performance for detecting histological cirrhosis (range AUCs 0.85-0.88). Considering longitudinal data (follow-up between 62 and 110 months), NFS and FIB-4 were the best at predicting liver-related events (c-indices>0.7), NFS for HCC (c-index = 0.9 on average), and FIB-4 and HFS for overall mortality (c-indices >0.8). All NSS showed limited performance (c-indices <0.7) for extrahepatic events.

Conclusions: Overall, NFS, HFS and FIB-4 outperformed APRI and BARD for both cross-sectional identification of fibrosis and prediction of long-term outcomes, confirming that they are useful tools for the clinical management of patients with NAFLD at increased risk of fibrosis and liver-related complications or death.

Lay summary: Non-invasive scoring systems are increasingly being used in patients with non-alcoholic fatty liver disease to identify those at risk of advanced fibrosis and hence clinical complications. Herein, we compared various non-invasive scoring systems and identified those that were best at identifying risk, as well as those that were best for the prediction of long-term outcomes, such as liver-related events, liver cancer and death.

Keywords: APRI; BARD; FIB-4; HFS; NASH; NFS; NSS.