Low HDL cholesterol levels in women and hypertriglyceridemia in men: predictors of MASLD onset in individuals without steatosis

Tsubasa Tsutsumi; Takumi Kawaguchi; Hideki Fujii; Yoshihiro Kamada; Yuichiro Suzuki; Koji Sawada; Miwa Tatsuta; Tatsuji Maeshiro; Hiroshi Tobita; Takemi Akahane; Chitomi Hasebe; Miwa Kawanaka; Takaomi Kessoku; Yuichiro Eguchi; Hayashi Syokita; Atsushi Nakajima; Tomoari Kamada; Hitoshi Yoshiji; Hiroshi Sakugawa; Asahiro Morishita; Tsutomu Masaki; Takumi Ohmura; Toshio Watanabe; Yoshioki Yoda; Nobuyuki Enomoto; Masafumi Ono; Kanako Fuyama; Kazufumi Okada; Naoki Nishimoto; Yoichi M Ito; Hirokazu Takahashi; Michael R Charlton; Mary E Rinella; Yoshio Sumida

doi:10.1007/s00535-025-02242-y

Low HDL cholesterol levels in women and hypertriglyceridemia in men: predictors of MASLD onset in individuals without steatosis

J Gastroenterol. 2025 Mar 18. doi: 10.1007/s00535-025-02242-y. Online ahead of print.

Authors

Tsubasa Tsutsumi^{1

2}, Takumi Kawaguchi³, Hideki Fujii⁴, Yoshihiro Kamada⁵, Yuichiro Suzuki⁶, Koji Sawada⁷, Miwa Tatsuta⁸, Tatsuji Maeshiro⁹, Hiroshi Tobita¹⁰, Takemi Akahane¹¹, Chitomi Hasebe¹², Miwa Kawanaka¹³, Takaomi Kessoku^{14

15

16}, Yuichiro Eguchi¹⁷, Hayashi Syokita¹⁸, Atsushi Nakajima¹⁶, Tomoari Kamada¹³, Hitoshi Yoshiji¹¹, Hiroshi Sakugawa¹⁹, Asahiro Morishita²⁰, Tsutomu Masaki²⁰, Takumi Ohmura²¹, Toshio Watanabe⁵, Yoshioki Yoda²², Nobuyuki Enomoto⁶, Masafumi Ono²⁰, Kanako Fuyama²³, Kazufumi Okada²³, Naoki Nishimoto²³, Yoichi M Ito²³, Hirokazu Takahashi²⁴, Michael R Charlton²⁵, Mary E Rinella²⁵, Yoshio Sumida²⁶

Affiliations

¹ Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago, 5841 South Maryland Ave., Chicago, IL, 60637, USA. tsubasa@uchicagomedicine.org.
² Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-Machi, Kurume, 830-0011, Japan. tsubasa@uchicagomedicine.org.
³ Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-Machi, Kurume, 830-0011, Japan.
⁴ Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, 1-4-3, Asahimachi, Abeno, Osaka, 545-8585, Japan.
⁵ Department of Advanced Metabolic Hepatology, Osaka University Graduate School of Medicine, 1-7, Yamadaoka, Suita, Osaka, 565-0871, Japan.
⁶ First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, 1110, Shimokato, Chuo-Shi, Yamanashi, 409-3898, Japan.
⁷ Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1-1-1, Midorigaoka Higashi, Asahikawa-City, Hokkaido, 078-8510, Japan.
⁸ Department of Gastroenterology, KKR Takamatsu Hospital, 4-18 Tenjinmae, Takamatsu, Kagawa, 760-0018, Japan.
⁹ First Department of Internal Medicine, University of the Ryukyus Hospital, 207 Uehara, Nishihara, Nakagami, Okinawa, 903-0215, Japan.
¹⁰ Department of Hepatology, Shimane University Hospital, 89-1 Enya-Cho, Izumo, Shimane, 693-8501, Japan.
¹¹ Department of Gastroenterology, Uda City Hospital, 815 Haibarahagihara, Uda, Nara, 633-0253, Japan.
¹² Department of Gastroenterology, Japanese Red Cross Asahikawa Hospital, Akebono-1Jo 1Chome 1-1, Asahikawa-City, Hokkaido, 070-0061, Japan.
¹³ Department of General Internal Medicine 2, Kawasaki Medical School, Kawasaki Medical Center, 2-6-1, Nakayamashimo, Kita, Okayama, 700-8505, Japan.
¹⁴ Kanagawa Dental University Yokohama Clinic, Yokohama, Kanagawa, Japan.
¹⁵ Department of Palliative Medicine and Gastroenterology, International University Health and Welfare Narita Hospital, 4-3, Kimizunomori 4-Chome, Narita-Shi, Chiba, 286-8686, Japan.
¹⁶ Division of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9, Fukuura, Kanazawa-Ku, Yokohama, 236-0004, Japan.
¹⁷ Loco Medical General Institute, Mikatsukicho Kanada, Ogi-Shi, Saga, 845-0032, Japan.
¹⁸ Department of Gastroenterology, Northern OKINAWA Medical Center, 1712-3 Umusa, Nago, Okinawa, 905-0006, Japan.
¹⁹ Department of Gastroenterology, Heartlife Hospital, 208, Iju, Nakagusuku, Nakagami, Okinawa, 901-2492, Japan.
²⁰ Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Oaza Ikenobe Miki-Cho, Kita-Gun, Kagawa, 761-0793, Japan.
²¹ Department of Health Care, Asahikawa-Kosei General Hospital, 24-111, 1 Jo-Dori, Asahikawa-City, Hokkaido, 078-8211, Japan.
²² JA Yamanashi Koseiren Health Care Center, 1-26, Iida 1, Kofu, Yamanashi, 400-0035, Japan.
²³ Data Science Center, Promotion Unit, Institute of Health Science Innovation for Medical Care, Hokkaido University Hospital, Sapporo, 060-8648, Japan.
²⁴ Liver Center, Saga University Hospital, 5-1-1 Nabeshima, Saga, 849-8501, Japan.
²⁵ Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago, 5841 South Maryland Ave., Chicago, IL, 60637, USA.
²⁶ Graduate School of Healthcare Management, International University of Healthcare and Welfare, 4-1-26, Akasaka, Minato-Ku, Tokyo, Japan.

PMID: 40097845
DOI: 10.1007/s00535-025-02242-y

Abstract

Background: Individuals with metabolic-associated steatotic liver disease (MASLD) have a worse prognosis compared to patients without steatosis, and its prevalence is increasing. However, detailed risk factors based on obesity and sex remain unclear. We aimed to investigate the impact of cardiometabolic risk factors (CMRFs) on the risk of MASLD in individuals without pre-existing SLD.

Methods: SLD was diagnosed by ultrasonography. Non-SLD individuals were followed 65,657 person-years. Incidence rates of MASLD were assessed by Kaplan-Meier analysis. Furthermore, independent factors associated with the development of MASLD were identified using Cox regression analysis, stratified by four groups: obese men, non-obese men, obese women, and non-obese women.

Results: The overall incidence rate of MASLD was 39.3/1,000 person-years. The cumulative incidence was highest in obese men, followed by obese women, non-obese men, and non-obese women. Two or more CMRFs increased the risk of MASLD in all groups. Low HDL cholesterol level was the strongest independent risk factor in both obese and non-obese women and hypertriglyceridemia for both obese and non-obese men. The impact of these CMRFs was stronger in non-obese individuals. (HR [95% CI]: women non-obese 1.9 [1.5-2.4], obese 1.4 [1.1-1.8]; men non-obese 2.3 [1.9-2.9], obese 1.5 [1.2-2.0]).

Conclusions: Multiple CMRFs are important to MASLD development, regardless of sex and obesity. In this Japanese cohort, low HDL cholesterol in women and hypertriglyceridemia in men were the most significant risk factors, especially among the non-obese group. These findings suggest that sex-specific CMRFs may play a role in the development of MASLD.

Keywords: Cardiometabolic risk factors; Hypertriglyceridemia; Low HDL cholesterol levels; Metabolic dysfunction-associated steatotic liver disease (MASLD); Steatotic liver disease.

Grants and funding

Startup Award for Researchers with Life Events/Kurume University