Lower prevalence, higher severity: why sex differences in MASLD demand a different approach

(…) Women remain underrepresented in liver disease research, and sex-disaggregated analyses are inconsistently reported.

– President, Canadian Association for the Study of the Liver

Women are often perceived as being at lower risk of advanced chronic liver disease, yet they are frequently diagnosed later and with more severe disease. This apparent paradox reflects more than biology. It reflects a mismatch between how MASLD develops in women and how healthcare systems identify, assess, and refer patients at risk; many pathways remain calibrated around male-typical patterns of presentation and progression.

Sex differences in MASLD begin long before diagnosis. Premenopausal women appear relatively protected against MASLD and fibrosis progression, largely because of the beneficial effects of estrogen on metabolism, inflammation, and fat distribution. However, this biological shield is temporary. Menopause represents a critical turning point in liver health.

As estrogen levels decline, women experience a sharp increase in metabolic dysfunction, accompanied by higher rates of cardiovascular disease, type 2 diabetes, hepatic steatosis, and liver fibrosis. This post-menopausal catch-up results in women approaching, and in some cases even exceeding, the risk profiles observed in men. Indeed, in the United States, MASLD has become the leading indication for liver transplantation among women.

Women also face a unique constellation of life-course risk factors, including polyendocrine metabolic ovarian syndrome (PMOS), gestational diabetes, hypertensive disorders of pregnancy, that predict future liver disease. Moreover, women may be disproportionately impacted by social determinants of health, including caregiving responsibilities, material deprivation, and barriers to preventive healthcare. Yet these biological, reproductive, and social factors remain largely absent from risk assessment strategies, clinical guidelines, and public health initiatives. In many respects, current approaches to MASLD remain sex-blind.

What’s Happening Behind The Scenes

The evidence base remains incomplete. Women remain underrepresented in liver disease research, and sex-disaggregated analyses are inconsistently reported. Consequently, the tools used to identify and risk-stratify MASLD have been often developed and validated in populations that may not have fully reflected patterns of disease in women. Emerging data suggest that non-invasive fibrosis tests may perform differently across sexes and metabolic profiles, particularly in the presence of indicator conditions such as type 2 diabetes and obesity. This raises concerns that women may be disproportionately affected by delayed recognition of clinically significant disease.

Diagnostic overshadowing represents another important barrier. Women who raise concerns about liver health may be redirected toward weight management rather than being evaluated for underlying liver disease. Screening triggers, risk stratification tools, and referral pathways may therefore underestimate risk in women, particularly before and during the menopausal transition. The repercussion is a pattern of later diagnoses and greater severity at presentation.

These gaps matter because MASLD is entering a new era. Effective pharmacotherapies are becoming available, and health systems are increasingly adopting strategies for early detection and risk stratification. If sex differences are not explicitly considered, existing inequities may widen. Women diagnosed later may gain access to specialist care and treatment later, thereby reducing the potential benefits of timely intervention.

The challenge is not awareness alone. It is how pathways are calibrated: how we define high risk,how we interpret borderline test results, and when we escalate care. Addressing this challenge requires ensuring that sex is systematically considered across the continuum of care:from research and guideline development to screening, diagnosis, referral, and treatment.

From Words to Action: Practical Tips

A minimum sex-aware MASLD pathway should include:

  • Earlier triggers for assessment. Women living with obesity, T2D, PMOS, a history of gestational diabetes or hypertensive disorders of pregnancy, premature menopause, or post-menopausal metabolic dysfunction should be recognised as priority populations for fibrosis risk assessment.
  • Menopause as a reassessment point. The menopausal transition should be treated as a clinical opportunity to reassess metabolic and liver risk, particularly in women with new or worsening cardiometabolic risk factors.
  • Standardised referral and follow-up pathways. Clear escalation criteria and reassessment intervals should ensure that liver health is assessed at the first point of contact with primary care, diabetology and obesity medicine, and liver services, whenever risk factors are present, enabling timely referral to liver services and reducing delayed diagnosis.
  • Sex-disaggregated evaluation. Non-invasive diagnostics, screening outcomes, referrals, treatment access, and clinical outcomes should be routinely monitored by sex to identify and address inequities.

Precision medicine means delivering the right intervention to the right patient at the right time. Achieving that goal in MASLD will require acknowledging a fundamental reality: sex matters. A meaningful measure of success over the next 12 months would be the adoption of sex-aware screening triggers, referral thresholds, and follow-up standards within at least one routine MASLD care pathway.

Additional reading

**This expert commentary was reviewed by Dr. Nicola Pugliese and Dr. Priya Jaisinghani,**