A groundbreaking new study published in JAMA Network Open reveals that women harbor a markedly heightened risk for liver fibrosis associated with certain cardiometabolic factors compared to men possessing the same risks. This pivotal research conducted by scientists at the Keck School of Medicine at the University of Southern California sheds critical light on sex-specific disparities in the progression and severity of liver fibrosis, a disease increasingly burdening populations worldwide.
Liver fibrosis, a pathological process characterized by excessive scarring within the liver due to persistent inflammation, remains a major clinical challenge. If unchecked, this fibrotic accumulation can escalate to cirrhosis, liver failure, or hepatocellular carcinoma. Although men generally exhibit a higher overall prevalence of liver fibrosis, the severity and rapid progression in women with underlying cardiometabolic comorbidities have become a focal concern. This study directly addresses this paradox, interrogating sex-specific biological and epidemiological differences underpinning liver fibrogenesis.
Lead author Jennifer Dodge, MPH, associate professor and researcher in medicine and population health sciences, emphasizes the clinical implications. “Our analysis confirms that women with high waist circumference and type 2 diabetes are at a disproportionately elevated risk for severe liver fibrosis compared to their male counterparts,” Dodge explains. “These findings underscore the urgent need for sex-tailored approaches in monitoring and managing cardiometabolic health to mitigate liver disease progression.”
Unlike many earlier investigations reliant on self-reported data or diagnostic coding, this study harnessed a robust dataset integrating laboratory biomarkers, anthropometric measurements, and advanced imaging techniques. The data were extracted from the CDC’s National Health and Nutrition Examination Survey (NHANES) spanning 2017 to 2020. This comprehensive dataset encompasses blood-based assays for cholesterol and glucose, clinical measurements of body mass index and waist circumference, and ultrasound-based evaluation of liver fibrosis and steatosis, enabling objective and precise phenotyping.
The cohort comprised nearly 6,000 adults representative of the U.S. population’s age, sex, race, and ethnicity. Researchers meticulously modeled the associations between liver fibrosis severity and key cardiometabolic factors: elevated waist circumference, hypertension, diabetes or prediabetes status, hypertriglyceridemia, and low HDL cholesterol levels. Importantly, analyses adjusted for confounders including age, smoking status, alcohol consumption, and demographic variables, thereby isolating sex-specific effects.
One of the study’s most striking revelations was the differential magnitude of fibrosis risk linked to elevated waist circumference. Women exhibited an 11-fold increase in liver fibrosis prevalence—from 0.8% in those with normal waist circumference to 9.2% among women with high waist circumference. Meanwhile, men experienced a comparatively smaller fourfold increase, rising from 4.4% to 17.0%. Similarly, the presence of type 2 diabetes or prediabetes resulted in a 2.8-fold surge in fibrosis risk in women, nearly double the relative risk observed in men (1.4-fold).
Even more compelling, the cumulative burden of multiple cardiometabolic derangements demonstrated an exponential relationship with fibrosis severity in women. Women harboring two or more cardiometabolic risk factors showed an 8.4-fold elevation in fibrosis prevalence, in stark contrast to a 2.6-fold increase in men. These findings collectively illuminate a critical vulnerability in women’s liver pathophysiology that may otherwise remain obscured by aggregate population statistics.
Experts hypothesize that hormonal influences, particularly estrogen, modulate hepatic fibrogenesis and contribute to sex-specific disease trajectories. Estrogen’s protective effects against liver injury and fibrosis are well documented; however, menopause-associated declines in estrogen may precipitate accelerated fibrosis progression in women. While this study did not directly examine menopausal status, it lays fertile groundwork for future investigations into the intersection of hormonal changes, cardiometabolic health, and liver disease outcomes.
Further research plans include longitudinal, prospective cohort studies to delineate causal pathways that underlie the observed sex disparities. Tracking individuals over time will allow for a more nuanced understanding of how cardiometabolic risk factors interact dynamically with liver fibrosis progression across the lifespan and between sexes. Additionally, the team aims to explore the impact of hormone replacement therapy on mitigating fibrosis risk among postmenopausal women.
Another priority is probing the relationship between sex, cardiometabolic dysfunction, and metabolic dysfunction–associated steatotic liver disease (MASLD), a non-alcoholic form of liver injury gaining global prevalence due to increasing obesity rates. Deciphering how sex and metabolic health interface in MASLD pathogenesis could revolutionize personalized medicine strategies to prevent liver-related morbidity and mortality.
This seminal study amplifies the call for clinicians to adopt a holistic mindset when managing cardiometabolic risk, recognizing that interventions to optimize glycemic control, lipid profiles, blood pressure, and body composition yield benefits extending beyond cardiovascular protection to encompass hepatic health. Tailored screening protocols attentive to sex-specific risk profiles could be key to early detection and improved outcomes in liver disease.
Liver fibrosis, long relegated as a secondary concern in metabolic syndrome management, now emerges as a central player intricately entwined with cardiometabolic pathways in a sex-dependent manner. This research not only advances our mechanistic understanding of fibrotic liver disease but also challenges existing paradigms, fostering a new era of precision hepatology rooted in gender medicine.
The collective expertise driving this study includes Somaya Albhaisi and Norah Terrault from the Gastrointestinal and Liver Diseases Division and Steve Kim from the Department of Population and Public Health Sciences, all affiliated with USC’s Keck School of Medicine. Supported by NIH funding, their collaborative endeavor underscores the critical intersection between epidemiology, clinical medicine, and basic science needed to tackle complex liver diseases confronting modern healthcare.
As liver fibrosis continues its stealthy climb as a public health menace, especially among women with diabetes and central obesity, these data call for urgent action. Holistic, informed strategies that leverage sex-specific insights harbor the promise of curbing the escalating global burden of liver disease—potentially saving countless lives through targeted prevention and therapeutic innovation.
Subject of Research: People
Article Title: Sex-Specific Cardiometabolic Profiles and Severity of Liver Fibrosis
News Publication Date: 9-Mar-2026
Web References: https://doi.org/10.1001/jamanetworkopen.2026.0863
Keywords: Liver, Liver damage, Fibrosis, Cardiovascular disorders, Metabolic disorders, Liver cancer, Cardiovascular disease, Type 2 diabetes
Tags: cardiometabolic risk factors and liver diseasecirrhosis risk factors in womengender disparities in liver disease outcomeshepatocellular carcinoma and metabolic risksliver fibrosis clinical implicationsliver fibrosis epidemiology by genderliver fibrosis in womenmetabolic syndrome and liver scarringsex differences in liver fibrosissex-specific liver disease progressiontype 2 diabetes impact on liver fibrosiswaist circumference and liver health
