Liver fibrosis is associated with carotid atherosclerosis in patients with liver biopsy-proven nonalcoholic fatty liver disease

Masanori Atsukawa,Yūji Yoshida ,Naoya Emoto,Fujio Izumi ,Ai Nakagawa‐Iwashita ,Tomohide Tanabe,Norio Itokawa,Chisa Kondo,Korenobu Hayama,Taeang Arai,Mototsugu Nagao,Katsuhiko Iwakiri,Kyoko Inagaki,Hitoshi Sugihara,Hirotaka Ono,Keiko Kaneko,Akihito Tsubota,Hiroshi Abe,Tomomi Okubo,Tadamichi Kawano,Kazúo Kato

doi:10.1038/s41598-021-95581-8

Abstract

Nonalcoholic fatty liver disease (NAFLD) is related to subclinical atherosclerosis. However, whether the severity of the disease (or which histopathological component) is associated with subclinical atherosclerosis remains controversial. This study aimed to investigate the association between the histopathological severity of NAFLD and carotid intima-media thickness (CIMT) in Japanese patients with liver biopsy-proven NAFLD. Maximum-CIMT (max-CIMT) was measured as an index of carotid atherosclerosis in 195 biopsy-proven NAFLD patients. A significant association was observed between the severity of fibrosis (but not steatosis, inflammation, and ballooning) and max-CIMT. Older age, male gender, hypertension, and advanced fibrosis were independently linked to max-CIMT ≥ 1.2 mm. The prevalence of max-CIMT ≥ 1.2 mm was significantly higher in the advanced fibrosis group than in the non-advanced fibrosis group (75.4% versus 44.0%; p < 0.01). Non-invasive liver fibrosis markers and scoring systems, including fibrosis-4 index, NAFLD fibrosis score, hyaluronic acid, and Wisteria floribunda agglutinin positive Mac-2-binding protein, demonstrated that the diagnostic performance for max-CIMT ≥ 1.2 mm was similar to that of biopsy-based fibrosis staging. In conclusion, advanced fibrosis is significantly and independently associated with high-risk CIMT. Non-invasive fibrosis markers and scoring systems could help estimate the risk of atherosclerosis progression in patients with NAFLD.

Highlights

Nonalcoholic fatty liver disease (NAFLD) is related to subclinical atherosclerosis
Hyaluronic acid[18] and Wisteria floribunda agglutinin positive Mac-2-binding protein ( WFA+-M2BP)[19,20,21], which have been reported as useful liver fibrosis markers in NAFLD, have recently attracted attention as indicators of early atherosclerosis[22,23,24], albeit they remain to be investigated in association with carotid atherosclerosis in NAFLD
This study demonstrated that advanced liver fibrosis, in addition to conventional risk factors for cardiovascular events, was significantly and independently associated with a high-risk level of carotid intima-media thickness (CIMT) in 195 Japanese patients with NAFLD

Summary

Introduction

Nonalcoholic fatty liver disease (NAFLD) is related to subclinical atherosclerosis. whether the severity of the disease (or which histopathological component) is associated with subclinical atherosclerosis remains controversial. This study aimed to investigate the association between the histopathological severity of NAFLD and carotid intima-media thickness (CIMT) in Japanese patients with liver biopsy-proven NAFLD. It has been recently suggested that NAFLD is a key driver of multi-organ syndrome, including cardiovascular disease (CVD), atherosclerosis, chronic kidney disease, type 2 diabetes mellitus, and o steoporosis[4,5] From this viewpoint, hepatic involvement is just one aspect of NAFLD, and attention should be paid to other organ disorders in addition to the liver. We have recently reported that advanced fibrosis is associated with brachial-ankle pulse wave velocity independent of conventional risk factors in 153 Japanese patients with liver biopsy-proven NAFLD26.

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