Same risk factors, different impact: diabetes and waist size hit women's livers harder than men's

Why do women with type 2 diabetes develop liver scarring faster than men with the same condition? That question drives a new study published in JAMA Network Open that examines how common cardiometabolic risk factors affect liver fibrosis differently depending on sex. The answer is not that women are at higher baseline risk. They are not. It is that when the risk factors are present, women's livers appear to be more vulnerable to the damage.

The data behind the disparity

Researchers from the Keck School of Medicine of USC analyzed data from 5,981 U.S. adults in the National Health and Nutrition Examination Survey (NHANES), collected between 2017 and 2020. The dataset includes lab tests, clinical exams, ultrasound imaging of the liver, and lifestyle information, making it more objective than studies that rely on self-reports or medical records alone.

The team examined six cardiometabolic risk factors: waist circumference, high blood pressure, type 2 diabetes or pre-diabetes, high triglycerides, low HDL cholesterol, and the presence of two or more of these factors. They controlled for age, race, ethnicity, smoking, and alcohol intake.

The numbers that stand out

Overall, women had similar or lower baseline rates of liver fibrosis compared with men. But when cardiometabolic risk factors entered the picture, the increases in women were disproportionately large.

High waist circumference was associated with an increase in fibrosis rates from 0.8% to 9.2% in women, roughly an 11-fold jump. In men, the same risk factor pushed rates from 4.4% to 17.0%, a fourfold increase. The absolute numbers were still higher in men, but the relative impact of the risk factor was nearly three times greater in women.

Type 2 diabetes or pre-diabetes was linked to a 2.8-fold increase in fibrosis rates among women, versus 1.4-fold in men. Having two or more cardiometabolic risk factors was associated with an 8.4-fold increase in women, compared to 2.6-fold in men.

The pattern was consistent: women start from a lower floor but climb more steeply.

Estrogen, menopause, and the protective threshold

Jennifer Dodge, the study's corresponding author and an associate professor at the Keck School of Medicine, points to a potential biological explanation. Estrogen is thought to protect against liver disease, but that protection may decline as estrogen levels fall during menopause. If the protective effect of estrogen is masking underlying vulnerability in premenopausal women, then the loss of that protection could accelerate disease progression.

The current study did not have sufficient sample size to examine the relationship between liver fibrosis and menopausal status directly. Dodge and her team plan to investigate this in a future study, including whether hormone replacement therapy has any impact on liver outcomes.

Clinical implications beyond the liver

The findings carry a message that extends beyond hepatology. The same risk factors that drive heart disease also drive liver disease, and they appear to do so through sex-specific pathways that standard clinical assessments may not account for. A woman whose blood pressure, waist circumference, and glucose levels are within the same range as a man's may face a substantially different liver risk profile.

Dodge emphasizes that these findings are a reminder that managing cardiometabolic risk factors is not just about preventing heart disease. It is about protecting the liver as well.

Limitations and next steps

The study is cross-sectional, capturing a single point in time rather than tracking disease progression. It cannot determine whether the sex differences in risk factor impact directly cause faster fibrosis development or reflect confounding variables not captured in the data. The researchers plan to address this with prospective studies that follow participants over time.

They also intend to examine how sex and cardiometabolic risk factors interact in metabolic dysfunction-associated steatotic liver disease (MASLD), the increasingly prevalent form of liver disease not driven by heavy alcohol use. With both liver fibrosis and MASLD on the rise globally, understanding who is most vulnerable and why is becoming increasingly urgent.