Why Women Face Higher Liver Fibrosis Risk: The Role of Cardiometabolic Factors

Liver fibrosis is a growing health concern globally, with increasing rates of advanced liver disease and cirrhosis. While men generally show a higher overall prevalence of liver disease, recent evidence suggests that women may experience faster progression of liver fibrosis and its complications. Emerging research highlights the importance of cardiometabolic risk factors, such as obesity, glucose intolerance, and hypertension, in driving liver disease. Interestingly, these risk factors do not affect men and women equally. A recent cross-sectional study using US population data provides new insights into how sex-specific differences influence liver fibrosis risk.

What Are Cardiometabolic Risk Factors?

Cardiometabolic risk factors (CMRFs) are conditions that increase the likelihood of developing cardiovascular and metabolic diseases, and they also play a critical role in liver health. Common CMRFs include:

• Obesity (body mass index ≥30, or ≥27.5 for Asian adults)
• Central adiposity (high waist circumference)
• Glucose intolerance or diabetes
• Hypertension (high blood pressure)
• Hypertriglyceridemia (elevated triglycerides)
• Low HDL cholesterol levels

The accumulation of two or more of these risk factors is associated with a greater likelihood of liver damage, particularly metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease.

Study Overview: Examining Sex Differences

Researchers analyzed data from 5,981 adults in the US National Health and Nutrition Examination Survey (NHANES) conducted between 2017 and 2020. Participants were adults aged 20 years or older with valid transient elastography measurements to assess liver stiffness, a reliable noninvasive marker of fibrosis. Individuals with viral hepatitis or incomplete data were excluded.

The primary goal was to examine whether women and men differ in their risk of significant liver fibrosis based on the presence of CMRFs.

Key Findings on Sex-Specific Risk

Higher Central Adiposity in Women

Although overall obesity rates were similar between women (41.9%) and men (42.3%), women had a much higher prevalence of central adiposity, measured as high waist circumference (69% in women versus 48.6% in men).

Glucose Intolerance and Cardiometabolic Burden

Men had higher rates of glucose intolerance (41.7% vs 31.1%) and hypertension (44.9% vs 41%). Hypertriglyceridemia was also more common in men (48.8% vs 36.6%). However, women with multiple CMRFs had a markedly higher risk of significant liver fibrosis than men with similar profiles.

Multiple CMRFs Compound Risk in Women

The presence of two or more CMRFs dramatically increased the odds of liver fibrosis in women compared to men. Women with two or more CMRFs had an adjusted odds ratio (aOR) of 10.22 for significant fibrosis, while the corresponding risk for men was 2.87. This suggests that women are more vulnerable to liver damage when facing multiple metabolic stressors.

Waist Circumference and Glucose Intolerance: Critical Indicators

Central adiposity and glucose intolerance were particularly important predictors of liver fibrosis in women. Women with high waist circumference had more than triple the odds of significant fibrosis compared to men with the same condition. Glucose intolerance was also more strongly associated with liver fibrosis in women, indicating that even modest impairments in glucose metabolism may have more severe consequences for female liver health.

Biological Explanations for Sex Differences

Several mechanisms may explain why women with CMRFs face higher risks of liver fibrosis:

1. Visceral Fat Distribution – Women generally store more subcutaneous fat, which is less metabolically harmful. However, after menopause, visceral fat accumulation increases, raising the risk of metabolic stress on the liver.
2. Hormonal Influence – Estrogen has protective effects on liver metabolism, inflammation, and fibrogenesis. Declining estrogen levels with age or menopause can increase vulnerability to fibrosis.
3. Insulin Sensitivity and Lipid Metabolism – Women are typically more insulin sensitive than men. When glucose intolerance develops, the relative loss of this advantage can result in more severe liver injury, including increased fat accumulation and inflammation.
4. Proinflammatory Response – Central adiposity in women is associated with heightened secretion of inflammatory cytokines and oxidative stress, contributing to hepatic fibrogenesis.

These factors collectively create a scenario in which women with multiple CMRFs or high central adiposity experience a disproportionate burden of liver fibrosis risk.

Clinical Implications

Rethinking Obesity Metrics

Traditional reliance on body mass index (BMI) may not adequately capture liver fibrosis risk, especially in women. Metrics that assess body fat distribution, such as waist circumference or the body roundness index (BRI), may provide more meaningful insights into liver health.

Early Screening and Prevention

Given the heightened risk for women with central adiposity, glucose intolerance, or multiple CMRFs, healthcare providers may consider sex-specific screening strategies. Early detection of liver fibrosis through noninvasive tools such as transient elastography could enable timely interventions, including lifestyle modifications, weight management, and glucose control.

Personalized Risk Stratification

Sex-specific differences highlight the need for tailored risk assessment models. Women with metabolic risk factors may benefit from earlier and more frequent monitoring, even in the absence of overt obesity or other traditional markers. This approach could reduce missed opportunities for early intervention and improve long-term liver health outcomes.

Sensitivity Analyses Support Findings

The study performed multiple sensitivity analyses, including:

• Assessing participants with severe steatosis
• Excluding individuals with excessive alcohol intake
• Focusing on those with MASLD
• Using BRI to evaluate central adiposity

Across these analyses, the pattern remained consistent: women with multiple cardiometabolic risk factors or high central adiposity had higher odds of significant liver fibrosis than men.

Limitations to Consider

While this study provides valuable insights, certain limitations should be acknowledged:

1. Cross-Sectional Design – Causality cannot be established; longitudinal studies are needed to confirm progression trends.
2. Noninvasive Measurement – Fibrosis was assessed via transient elastography rather than liver biopsy, which may lead to misclassification.
3. Hormonal Status Not Stratified – Menopausal status and hormone therapy use were not analyzed, though these factors likely influence liver risk in women.
4. Other Risk Factors – Dietary patterns, environmental toxins, and medications were not evaluated.
5. Multiple Comparisons – Some associations with marginal statistical significance should be interpreted as exploratory.

Despite these limitations, the study uses nationally representative data and standardized methods, making the findings relevant for public health strategies.

Recommendations for Women’s Liver Health

• Monitor Waist Circumference – Central adiposity may be a stronger indicator of liver fibrosis risk than BMI.
• Address Glucose Intolerance – Early management of prediabetes or diabetes is critical to reduce liver damage.
• Assess Multiple Risk Factors – The combination of CMRFs significantly increases fibrosis risk, especially in women.
• Engage in Lifestyle Interventions – Balanced diet, regular physical activity, and weight management can mitigate metabolic and hepatic risk.
• Regular Screening – Noninvasive assessments such as transient elastography or imaging-based measures may help identify early fibrosis.

Future Directions

Research should focus on prospective studies to:

• Understand how menopause and hormone therapy influence liver fibrosis risk
• Develop sex-specific risk stratification models for liver disease
• Explore interventions targeting visceral fat reduction in women
• Evaluate the impact of early detection strategies on long-term liver outcomes

By integrating sex-specific insights into clinical practice, healthcare providers can better address the growing burden of advanced liver disease, particularly among women with metabolic risk factors.

Conclusion

This study underscores important sex-specific differences in liver fibrosis risk related to cardiometabolic health. Women with central adiposity, glucose intolerance, or multiple CMRFs face disproportionately higher odds of significant liver fibrosis compared with men. Recognizing these differences can guide more precise screening, prevention, and treatment strategies, potentially improving liver health outcomes for women.

Healthcare professionals should consider central adiposity, glucose intolerance, and cumulative metabolic risk when assessing liver disease in women, rather than relying solely on traditional obesity metrics. This approach may help detect liver fibrosis earlier and reduce the progression of chronic liver disease among high-risk female populations.

Sources:

1. Albhaisi S, Kim S, Terrault N, et al. Sex-Specific Cardiometabolic Profiles and Severity of Liver Fibrosis. JAMA Netw Open. 2026;9(3):e260863. doi:10.1001/jamanetworkopen.2026.0863
2. Younossi ZM, et al. Global epidemiology of nonalcoholic fatty liver disease. Hepatology. 2021;73:1-16
3. EASL Clinical Practice Guidelines on Non-Alcoholic Fatty Liver Disease. J Hepatol. 2016;64:1388-1402

Disclaimer: This article is for educational purposes and general health awareness. It does not substitute for professional medical advice. Individuals concerned about liver disease should consult a qualified healthcare provider for personalized evaluation and treatment.