Menopause and Increased Risk of Metabolic Dysfunction–Associated Steatotic Liver Disease

Is menopause associated with an increased risk of metabolic dysfunction–associated steatotic liver disease (MASLD)?

Menopause is associated with a 2.19 times higher risk of MASLD, previously known as nonalcoholic fatty liver disease. (Strength of Recommendation: B, sensitivity analysis of six cross-sectional studies in a systematic review and meta-analysis of 12 studies.) In a nested case-control study, patients with menopause due to oophorectomy had a 1.41 times higher risk for MASLD than patients who experienced natural menopause. Physicians should consider a diagnosis of MASLD in postmenopausal patients with elevated transaminase levels, heterogeneous liver findings on ultrasonography, or hepatomegaly.

A 2023 systematic review and meta-analysis of 12 cross-sectional studies (N = 19,917) examined the relationship between menopause and MASLD. The authors searched EMBASE, Medline, and Web of Science databases for eligible studies from inception through December 2021. Included studies were required to contain one group each of pre- and postmenopausal women and to report the association between menopause and MASLD.¹

The meta-analysis found menopause is associated with an approximately 2.4 times higher likelihood of MASLD (pooled odds ratio [OR] = 2.37; 95% CI, 1.99–2.82; I² = 73%). The association remained statistically significant in a sensitivity analysis of six of the studies that adjusted for age, body mass index, and waist circumference (pooled OR = 2.19; 95% CI, 1.73–2.78; I² = 74%).¹

A 2021 nested case-control study (N = 19,525) investigated the associations of menstrual and hormone-related factors with MASLD risk. Patients with MASLD were identified using Medicare claims data. Control patients without liver disease were selected and individually matched to patients with MASLD by birth year, ethnicity (determination was not defined or reported), and length of Medicare enrollment.²

The study showed that patients with surgically induced menopause via bilateral oophorectomy had an increased risk of developing MASLD (OR = 1.41; 95% CI, 1.18–1.68) compared with patients who experienced natural menopause. Patients with surgically induced menopause via hysterectomy also had an increased risk of MASLD (OR = 1.33; 95% CI, 1.11–1.60).²

The findings of this study were supported by a 2016 retrospective study that examined risk factors for developing MASLD among patients with endometrial cancer who underwent surgical staging and hysterectomy-based treatment. The study included 712 oophorectomy cases and 163 non-oophorectomy cases. It controlled for age, ethnicity (self-reported), body mass index, medical comorbidities, tumor type, hormonal treatment pattern, and oophorectomy status. The study found that bilateral oophorectomy was an independent predictor for increased risk of MASLD (hazard ratio = 1.70; 95% CI, 1.01–2.86; P = .047).³

There is some consensus that menopause and estrogen-deficient states are broadly associated with increased risk of MASLD. However, a 2023 retrospective cohort study (N = 368) from South Korea found that oral hormone replacement therapy was associated with an increase in MASLD prevalence from 25.3% to 29.4%, whereas transdermal hormone therapy was associated with a decrease from 24.0% to 17.3% after 1 year, showing an apparent route-specific effect on MASLD risk. The overall difference between groups after treatment was statistically significant (P = .036).⁴