Introduction to Sex Dimorphism in Liver and Heart Health

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a cornerstone of modern cardiometabolic medicine, particularly in regions like India where metabolic syndrome is prevalent. Recent clinical evidence highlights a striking sex dimorphism in how this condition impacts the heart. Researchers now recognize that MASLD related atherosclerosis does not manifest identically in men and women. While the liver remains the primary site of metabolic dysfunction, the resulting systemic inflammation and lipid imbalances lead to divergent vascular outcomes. For clinicians, understanding these nuances is no longer optional; it is essential for accurate risk stratification. Traditionally, cardiovascular risk models have relied on male-centric data, potentially overlooking the unique physiological trajectories of female patients. As the global burden of MASLD continues to rise, especially among postmenopausal women, the medical community must pivot toward a sex-aware paradigm. This transition involves recognizing that the absence of obstructive calcification does not equate to the absence of cardiovascular risk. Consequently, a deeper dive into the mechanisms behind these differences reveals a complex interplay of hormones, genetics, and inflammatory pathways that dictate how plaque forms and progresses in different biological environments.

The Masculine Phenotype: Calcified Plaque and Obstruction

In the context of MASLD related atherosclerosis, men typically present with a phenotype characterized by advanced coronary artery calcification and obstructive lesions. Metabolic dysfunction in men often correlates strongly with higher coronary artery calcium (CAC) scores. This calcified burden usually reflects a longer duration of metabolic stress and a higher prevalence of traditional risk factors such as smoking or visceral adiposity. Men tend to develop larger, more stable calcified plaques that are easily detectable on standard computed tomography scans. Furthermore, the association between hepatic steatosis and obstructive coronary disease is particularly robust in male cohorts. This trend suggests that for men, the presence of MASLD serves as a powerful accelerator of traditional atherosclerotic pathways. Consequently, standard diagnostic tools that focus on luminal narrowing and calcium deposition are highly effective in identifying high-risk male patients. However, the reliance on these markers creates a diagnostic bias. Because men show more "visible" disease through calcification, the clinical algorithms calibrated on these findings may not translate effectively to women, whose vascular damage often follows a more subtle, non-obstructive path that nevertheless carries a high risk of adverse events.

The Feminine Phenotype: Functional Dysfunction and Non-Calcified Plaque

Conversely, women with MASLD frequently exhibit a distinct vascular profile that prioritizes functional abnormalities over structural calcification. Rather than the obstructive, calcified plaques seen in men, women are more likely to harbor non-calcified atherosclerotic phenotypes. These plaques are often lipid-rich and more prone to erosion or rupture, despite causing less luminal narrowing. Beyond plaque morphology, women with MASLD demonstrate significant functional vascular impairment, including endothelial dysfunction and increased arterial stiffness. Notably, coronary microvascular dysfunction is a hallmark of the female MASLD phenotype, which can lead to myocardial ischemia even in the absence of major artery obstruction. This functional decline is often driven by a heightened state of systemic inflammation and immune-metabolic signaling unique to the female biological environment. Therefore, focusing solely on the coronary artery calcium burden might lead to a dangerous underestimation of risk. Women may experience severe cardiovascular events due to these functional deficits, even when their CAC scores remain deceptively low. This emphasizes the need for clinicians to look beyond the "pipes" and consider the overall health of the vascular endothelium and microcirculation when managing MASLD in female patients.

The Coronary Artery Calcium Paradox and Underdiagnosis

A critical challenge in managing MASLD related atherosclerosis is the "CAC paradox" observed in women. Clinical data suggest that women with MASLD experience a disproportionately greater risk of adverse cardiovascular events despite having lower average CAC scores than their male counterparts. This discrepancy implies that calcification-centered assessments fail to capture the true risk profile of the female vasculature. By failing to identify non-calcified plaque and microvascular issues, traditional screening tools may provide a false sense of security. Consequently, many women are diagnosed with cardiovascular disease only after a major event has occurred. This diagnostic gap is particularly concerning given the rising prevalence of MASLD in aging populations. To bridge this gap, some experts suggest the use of multimodality imaging, such as coronary CT angiography, which can visualize non-calcified plaque and measure perivascular fat. Additionally, functional tests that assess endothelial health could offer a more comprehensive view of risk. Moving away from a one-size-fits-all screening approach allows for earlier intervention. For the Indian clinician, where early-onset metabolic disease is common, recognizing this paradox is vital for preventing premature cardiovascular mortality in female patients who do not fit the traditional high-calcium risk profile.

Biological and Socio-Cultural Drivers of Sex Differences

The divergent pathways of MASLD related atherosclerosis are mediated by a complex web of pathobiological and socio-cultural factors. Sex hormones play a central role, with estrogen providing a protective effect on both liver metabolism and vascular health during the premenopausal years. However, the menopausal transition marks a period of rapid metabolic decline, characterized by a shift in adipose tissue distribution from subcutaneous to visceral depots. This transition significantly elevates the risk of both MASLD and subsequent atherosclerosis. Moreover, genetic susceptibility often shows sex-specific patterns, with certain variants impacting lipid metabolism more severely in one sex than the other. Beyond biology, gender-related influences, such as dietary patterns, physical activity levels, and healthcare-seeking behaviors, further shape the clinical landscape. In many societies, women may face delays in diagnosis due to atypical symptom presentation or socio-cultural barriers to care. Understanding that these differences are both biological and environmental is crucial for developing personalized treatment plans. Addressing the immune-metabolic and inflammatory profiles that differ between sexes can lead to more targeted pharmacological interventions. Ultimately, a sex-aware approach considers the patient's entire biological history, including reproductive milestones, to provide truly holistic care in the management of MASLD.

Strategic Screening and Future Clinical Directions

Addressing the risks of MASLD related atherosclerosis requires a paradigm shift toward sex-and-menopause-aware cardiovascular evaluation. For selected high-risk women, clinicians should consider complementary diagnostic strategies that go beyond the basic CAC score. This might include advanced imaging techniques or the use of specific biomarkers that reflect systemic inflammation and liver-heart crosstalk. Furthermore, lifestyle interventions should be tailored to the specific metabolic needs of the patient, acknowledging that women may respond differently to certain dietary or exercise regimens compared to men. Early detection remains the gold standard, and this is only possible if the screening tools used are sensitive to the female phenotype of vascular disease. Future research must continue to explore the molecular mechanisms behind sex-specific plaque stability and microvascular health. As precision medicine becomes the new standard, the integration of sex-specific risk calculators into clinical practice will be essential. This evolution in care will ensure that both men and women receive the most accurate assessments and effective interventions possible. By recognizing the unique cardiovascular trajectories associated with MASLD, the medical community can significantly reduce the global burden of heart disease and improve long-term outcomes for all patients, regardless of biological sex.

Frequently Asked Questions

Why is the CAC score sometimes unreliable for women with MASLD?

The coronary artery calcium (CAC) score primarily measures calcified plaque, which is more common in men. Women with MASLD are more likely to develop non-calcified plaque and functional issues like endothelial dysfunction or microvascular disease. Because these conditions do not always involve significant calcium deposits, a low CAC score may falsely suggest low risk in women. Clinicians should consider broader imaging and functional assessments for high-risk female patients to ensure accurate diagnosis.

How does menopause influence the risk of MASLD-related cardiovascular disease?

Menopause triggers a significant decline in estrogen, a hormone that normally protects liver metabolism and maintains vascular elasticity. This loss leads to increased visceral fat, higher systemic inflammation, and worsening lipid profiles, all of which accelerate MASLD progression and atherosclerosis. Consequently, postmenopausal women often see a sharp rise in cardiovascular risk, making the menopausal transition a critical window for metabolic screening and aggressive lifestyle or pharmacological intervention to prevent future heart events.

What are the primary differences in plaque morphology between men and women with MASLD?

Men with MASLD typically exhibit more calcified, obstructive atherosclerotic plaques, which are highly visible on standard CT scans. In contrast, women more frequently develop non-calcified, lipid-rich plaques that may not cause significant narrowing of the arteries but are highly prone to erosion. Additionally, women show more functional vascular abnormalities, such as arterial stiffness and coronary microvascular dysfunction, which contribute to cardiovascular risk independently of the total plaque burden seen in major vessels.

Disclaimer: This content is for informational and educational purposes only. It is not intended to provide specific medical advice or to be a substitute for professional medical expertise. Diagnosis and treatment should always be conducted by a qualified healthcare professional. Refer to the latest local and national guidelines for clinical practice.

References

Jamalinia M et al. Sex differences in MASLD-related atherosclerosis: plaque phenotype, vascular dysfunction, and cardiovascular outcomes. Biol Sex Differ. 2026 Jul 07. doi: 10.1186/s13293-026-00952-3. PMID: 42415214.

Yan T et al. Sex Differences in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): Epidemiology, Pathophysiology, and Clinical Implications. PubMed. 2026. DOI: 10.1016/j.jceh.2026.103533.

Ciba-Stemplewska A et al. Sex-related differences in the prevalence, clinical characteristics, and comorbidities of metabolic dysfunction-associated steatotic liver disease. Med Res J. 2025; 10(3): 240–246.