Interleukin-34 as a fibroblast-derived marker of liver fibrosis in patients with non-alcoholic fatty liver disease.

Hirotaka Shoji,Tatsuya Kanto,Yuichi Nozaki,Akinobu Taketomi,Masashi Mizokami,Kiyoaki Ito,Moto Fukai,Norio Itokawa,Hiroshi Aikata,Takuji Torimura,Sachiyo Yoshio,Erina Kumagai,Takumi Kawaguchi,Masaya Sugiyama,Kazuaki Chayama,Taeang Arai,Masashi Yoneda,Yoichi Hiasa,Masanori Atsukawa,Masaaki Korenaga,Yohei Mano,Hideyuki Hyogo,Masanori Abe,Toshiya Kamiyama,Tomohiko Ohashi

doi:10.1038/srep28814

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic non-viral liver disease. Activation of macrophages and hepatic stellate cells is a critical step that promotes liver fibrosis. We aimed to explore the feasibility of interleukin-34 (IL-34), a key regulator of macrophages, as a fibrosis marker in patients with NAFLD. We enrolled 197 liver biopsy-proven NAFLD patients. We evaluated the serum levels of IL-34, macrophage-colony stimulating factor (M-CSF), soluble CD163 (sCD163), 40 cytokines/chemokines, hyaluronic acid, type IV collagen 7s, and clinically-approved fibrosis scores. IL-34 increased with the progression of fibrosis and was an independent marker for liver fibrosis. Immunostaining experiments, using resected liver specimens from NAFLD patients, revealed that IL-34 was mainly expressed on liver fibroblasts. IL-34 based fibrosis score (0.0387*IL-34 (pg/ml) + 0.3623*type IV collagen 7s (ng/ml) + 0.0184*age (year)–1.1850) was a practical predictive model of liver fibrosis. Using receiver-operating characteristic analyses, the area under the curve, sensitivity, and specificity of IL-34 based fibrosis score were superior or comparable to the other fibrosis biomarkers and scores. In conclusion, the IL-34 based fibrosis score, including serum IL-34, type IV collagen 7s and age, is a feasible diagnostic marker of liver fibrosis in NAFLD patients.

Highlights

Kazankov et al reported that soluble CD163 levels increased in association with the fibrosis stage in patients with chronic hepatitis C, suggesting that sCD163 can be useful as a marker of liver fibrosis[21]
Because we hypothesized that macrophage-related factors could serve as biomarkers of fibrosis, we examined serum levels of IL-34, macrophage colony-stimulating factor (M-CSF), and sCD163 as well as hyaluronic acid, type IV collagen 7s, and aspartate transaminase (AST)to-platelet ratio index (APRI), FIB-4 index, and Non-alcoholic fatty liver disease (NAFLD) fibrosis score (NFS), in 197 liver biopsy-proven NAFLD patients and 20 healthy volunteers (HVs)
We aimed to investigate the possibility of IL-34, M-CSF, sCD163, MIP-3α/CCL20, hyaluronic acid, type IV collagen 7s, APRI, FIB-4 index, and NFS as a marker of liver fibrosis in NAFLD patients

Summary

Introduction

Liver biopsy still remains the gold standard for evaluating the degree of hepatic necro-inflammation and fibrosis in patients with chronic liver disease[10]. Preisser et al recently reported that IL-34 and M-CSF increased in the sera of hepatitis C virus (HCV) infected patients with advanced liver fibrosis and that they were capable of inducing pro-fibrotic macrophages in vitro[20]. Kazankov et al reported that soluble CD163 (sCD163) levels increased in association with the fibrosis stage in patients with chronic hepatitis C, suggesting that sCD163 can be useful as a marker of liver fibrosis[21]. We evaluated the possibility of using the above-mentioned macrophage-related factors as a marker of liver fibrosis in patients with NAFLD.

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