Women face higher liver fibrosis risk from cardiometabolic factors than men

Women with certain cardiometabolic risk factors, including type 2 diabetes and high waist circumference, face a greater increase in risk for liver fibrosis than men with the same risk factors. The study, just published in JAMA Network Open, is one of the first to explore sex differences in cardiometabolic risk factors for liver fibrosis, a condition on the rise globally.

Liver fibrosis is the buildup of scar tissue in the liver due to chronic inflammation. Over time, it can lead to serious complications, including cirrhosis, liver failure and liver cancer. While men face higher rates of liver fibrosis, severe cases are increasing among women, prompting researchers from the Keck School of Medicine of USC to explore potential sex differences.

We're seeing that women are progressing more quickly than men to liver fibrosis once liver disease is established-and our findings suggest that cardiometabolic risks may be part of the story. These findings are a reminder for both clinicians and the public that managing these cardiometabolic risk factors are not just important for heart disease, but also for liver disease."

Jennifer Dodge, MPH, associate professor of research medicine and population and public health sciences, Keck School of Medicine and study's corresponding author

A rich liver health dataset

By including lab tests and imaging data, the study captured objective health measures left out of many national surveys, which are often based on self-reports or medical records.

Data came from the U.S. Centers for Disease Control and Prevention's National Health and Nutrition Examination Survey, which includes details on participant lifestyle, including alcohol intake, exercise and diet; cholesterol and glucose levels detected in blood samples; body mass index and waist circumference measured in clinical exams; and details on liver fibrosis and steatosis (an abnormal buildup of fat inside liver cells) from ultrasound imaging tests.

The researchers included data from 5,981 U.S. adults, representative of the U.S. population with an average age of 47, collected between 2017 and 2020. They analyzed whether the link between liver fibrosis and key cardiometabolic risk factors differed by sex, including waist circumference, high blood pressure, diabetes or pre-diabetes, high triglycerides, low high-density lipoprotein (HDL) cholesterol and the presence of two or more of these factors.

In their statistical analysis, the researchers controlled for age, race, ethnicity, smoking and alcohol intake to rule out the influence of those factors.

Sex differences in fibrosis risk

Overall, women faced similar or lower baseline rates of liver fibrosis compared with men. However, when certain risk factors were present, women's fibrosis rates tended to increase more sharply than men.

For example, high waist circumference was associated with an increase in fibrosis rates from 0.8% to 9.2% in women (about 11-fold), compared with an increase from 4.4% to 17.0% in men (about fourfold). Type 2 diabetes or pre-diabetes was linked to a 2.8-fold increase in fibrosis rates among women, versus a 1.4-fold increase among men. Having two or more cardiometabolic risk factors was associated with an 8.4-fold increase in women, compared to a 2.6-fold increase in men.

"Women start with lower risk levels, but once these factors are present, their risk is greater," Dodge said.

Next steps in research

The findings underscore that maintaining good heart and metabolic health has implications well beyond heart disease prevention, Dodge said. They also point to potential sex differences in the biological processes that underlie liver disease. For example, estrogen is thought to help protect women against liver disease, but that protection may decline as estrogen levels fall during menopause.

"Our sample size was not large enough to explore this link, but we plan to investigate liver fibrosis and menopause in a future study, including whether hormone replacement therapy may have an impact," Dodge said.

The researchers also plan to repeat the study using prospective data, meaning they will follow participants over time, to better understand whether these sex differences directly contribute to the development of liver fibrosis. They will also examine how sex and cardiometabolic risk factors interact in metabolic dysfunction–associated steatotic liver disease, a form of liver disease not driven by heavy alcohol use, which is also on the rise.

About this research

In addition to Dodge, the study's other authors are Somaya Albhaisi and Norah Terrault from the Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine of USC, University of Southern California; and Steve Kim from the Department of Population and Public Health Sciences, Keck School of Medicine of USC, University of Southern California.

This work was supported by the National Institutes of Health T32 Translational Research Training in Hepatology grant [T32DK127977].