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Review

New Definition, New Point of View: Sex and Gender Interpretation of MASLD—Interpretation of Guidelines and Review of the Literature

by
Massimo De Luca
1,†,
Rita Verdoliva
2,†,
Anna Lombardi
2,* and
Antonio Giorgio
3
1
Liver Unit, Cardarelli Hospital, 80131 Naples, Italy
2
Department of Translational Medical Sciences, Federico II University Hospital, 80131 Naples, Italy
3
Liver Unit, Athena Clinical Center, 81016 Caserta, Italy
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Gastroenterol. Insights 2026, 17(1), 7; https://doi.org/10.3390/gastroent17010007
Submission received: 18 November 2025 / Revised: 22 December 2025 / Accepted: 3 January 2026 / Published: 23 January 2026
(This article belongs to the Section Gastrointestinal Disease)
Versions Notes

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses a spectrum from simple steatosis to steatohepatitis (MASH), including liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The 2023 EASL–EASD–EASO guidelines provide updated definitions and emphasize personalized management, yet do not explicitly address sex- and gender-related differences. This review highlights the impact of biological sex and gender on MASLD epidemiology, pathogenesis, clinical presentation, and therapeutic response. Men show earlier peak prevalence, greater visceral obesity, higher insulin resistance, and increased risk of fibrosis, HCC, and cardiovascular mortality. Women of childbearing age benefit from estrogen-mediated protection, which diminishes after menopause, leading to disease risk similar to men. Genetic variants (PNPLA3, TM6SF2), hormonal factors, platelet parameters, liver biomarkers, and environmental exposures contribute to sex-specific susceptibility and disease progression. Lifestyle interventions and pharmacological therapies exhibit differential efficacy across sexes, influenced by hormonal status. Integrating biological sex, gender identity, and sociocultural factors into diagnostic and therapeutic strategies is essential to optimize MASLD management and reduce its global burden.

1. Introduction

The most recent guidelines published by EASL and AASLD [1] have reformulated the concept of non-alcoholic fatty liver disease (NAFLD). This revision broadens the framework of chronic liver disease by emphasizing the pathophysiological complexity of metabolic dysfunction related to obesity, cardiometabolic risk, cardiovascular risk and proinflammatory state. In doing so, it overcomes the centrality of the correlation or non-correlation with alcohol consumption intrinsic to the definition of NAFLD, and replaces it with the term MASLD (Metabolic Dysfunction-Associated Steatotic Liver Disease). This change in nomenclature aims to reduce the stigma “non-alcoholic” and to emphasize the central metabolic component in pathogenesis, partially modifying the diagnostic and therapeutic framework [1,2].
One of the aims of joint guidelines EASL–EASD–EASO [1] is to define the different metabolic involvements of the liver, offering the opportunity to better understand the underlying mechanisms and disparities and facilitating the development of personalized therapeutic strategies. However, these guidelines do not sufficiently address sex- and gender-related differences in diagnosis, clinical manifestations, and therapeutic outcomes.
The purpose of this document is to emphasize how sex and gender differences in MASLD are relevant to optimizing diagnosis, treatment, and prevention. In addition to differences related to biological sex—defined as biological and physiological characteristics such as chromosomes, hormones, and reproductive organs—we refer to gender according to the World Health Organization definition. Gender encompasses the socially constructed characteristics of women, men, girls, and boys, including norms, behaviors, roles, and social relationships [3].
Throughout this paper, we will use the term MASLD, although some of the cited studies refer to NAFLD.

2. Definition

MASLD is a disease characterized by hepatic steatosis in the presence of one or more cardiometabolic risk factors and in the absence of harmful alcohol consumption. The spectrum of MASLD includes simple steatosis, metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis, and MASH-related hepatocellular carcinoma [1].
According to the guidelines [1], the diagnosis of MASLD is based on two main elements: hepatic steatosis and cardiometabolic factors. Hepatic steatosis is an accumulation of fat in the liver visible on tests such as ultrasound or MRI, not associated with other causes (such as alcohol abuse or viral infections). Moreover, the presence of at least one of the following metabolic factors is needed: BMI ≥ 25 kg/m2, type 2 diabetes (T2D) or elevated fasting blood glucose, hypertension, elevated triglycerides, low HDL cholesterol levels. Furthermore, the guidelines recognize liver biopsy as the gold standard for identifying steatohepatitis and staging liver fibrosis. However, due to its invasiveness and practical limitations, the guidelines recommend the use of noninvasive tests. In particular, a multiphase approach is suggested, which involves the initial use of blood test scores, followed by imaging techniques such as liver elastography (e.g., transient elastography) to confirm or exclude advanced fibrosis, while liver biopsy is reserved for selected cases where the results of noninvasive tests are inconclusive or there is a specific clinical need [1].
FIB-4 is a noninvasive score derived from age, AST, ALT and platelet count, explicitly recommended as the first step in the noninvasive diagnostic pathway to identify patients with possible advanced liver fibrosis who should be referred for in-depth diagnostic investigations. FIB-4 has a particularly high sensitivity and a very high negative predictive value (almost 99.2%) [4].
Data from recent studies highlight the role of various clinical parameters, including platelet count, liver biomarkers, and the influence of sex hormones, in both adults and children, which may be useful and should be evaluated for greater diagnostic accuracy.
An observational cross-sectional study [5] stratified 829 patients with MASLD according to BMI, hepatic steatosis assessed by Controlled Attenuation Parameter (CAP), liver stiffness measured by transient elastography (LSM), ALT levels, and platelet parameters, including platelet count (PC), mean platelet volume (MPV), and platelet distribution width (PDW). Significant sex-related differences were observed. Platelet count decreased with age in both sexes, more markedly in women, whereas MPV increased with age only in women. PDW was significantly higher in women aged 30–59 years, indicating greater platelet size heterogeneity. In addition, higher BMI and more severe hepatic steatosis were associated with lower platelet count. Notably, MPV increased with CAP in men, whereas in women it was primarily age-related, suggesting that sex-specific hormonal or metabolic factors may modulate platelet physiology. Overall, these findings support the potential role of platelet count as a noninvasive biomarker of liver fibrosis severity.
It would therefore be useful if FIB-4 also took into account sex in relation to age concerning the platelet count parameter.
Moreover, a large analysis of over 14,000 subjects (NAGALA 12 cohort) [6] compared the predictive value of the liver biomarkers ALT, AST, and GGT for the diagnosis of MASLD, highlighting significant sex differences. ALT was the biomarker with the highest association with MASLD in both men and women. The diagnostic accuracy (area under the ROC curve, AUC) of ALT was slightly higher in men (0.79) than in women (0.77). The combination of ALT and GGT further improved AUC 0.79 in men, 0.77 in women. In the context of diagnosis, it should be considered that men show more sensitive liver biomarkers (e.g., ALT) for diagnosis, while in women, normal ALT levels may mask disease progression. These data highlight the importance of a sex- and gender-based approach in the interpretation of liver biomarkers for the diagnosis and management of MASLD [6,7].

3. Epidemiological Data

MASLD affects approximately 25–30% of the global population, with significant sex differences depending on age, geographic location, and hormonal status. Studies analyzing the global impact of MASLD/MASH and its complications using data from the Global Burden of Disease (GBD) 2017, observed that from 1990 to 2017 the global number of disability-adjusted life years (DALYs) associated with complications more than doubled [8].
Indeed, analyses reveal that the global prevalence of liver cancer from MASH peaks between the ages of 60 and 64 in men and between the ages of 65 and 69 in women. Men are more affected than women, with a positive male-to-female ratio in regions with high sociodemographic indices (SDI). Geographically, Australia recorded the largest increase in the age-standardized DALY rate (+143.54%), while lower rates were observed in regions with higher SDI, indicating a possible inverse relationship between socioeconomic status and the impact of MASH [9].
These studies provide new insights into the biological mechanisms of and demographic differences in MASLD/MASH, highlighting the importance of a targeted therapeutic approach that takes into account sex, gender and socioeconomic background.
In men, the highest prevalence of MASLD/MASH is found in the 40–60 age group, due to greater visceral obesity and metabolic dysfunction (27.9% for men compared to 6.8% for women of childbearing age; data from European and Asian cohorts, p < 0.001). In women of childbearing age, the prevalence is significantly lower than in men, due to the protective effects of estrogens. After menopause, the prevalence increases rapidly, becoming similar to or higher than that of men, with a peak between the ages of 65 and 69. Furthermore, the risk increases for both sexes in regions with SDI, where metabolic risk factors control is less effective [8].

4. Sex- and Gender-Specific Causes and Predisposing Factors

The liver is a sexually dimorphic organ in which the interaction between sex hormones and nuclear receptors (NRs), rather than intrinsic genetic differences, largely determines sex-specific features. In mice, male and female livers express distinct sets of proteins and enzymes that vary across the lifespan and in response to physiological demands. During pregnancy, for example, the liver undergoes adaptations to support maternal metabolism and preparation for lactation [9,10].
Accordingly, sex-related differences exist in the transcriptional regulation of genes involved in lipid, carbohydrate, cholesterol metabolism, immune responses, detoxification pathways, and enzymatic regulation [10,11]. In lipid metabolism, NRs such as PPARα (Peroxisome Proliferator-Activated Receptor alpha), LXR (Liver X Receptor), and FXR (Farnesoid X Receptor) play central roles in controlling fatty acid oxidation, lipogenesis, and lipoprotein secretion. PPARα activity is particularly prominent in males, promoting mitochondrial and peroxisomal β-oxidation, whereas in females, estrogens enhance metabolic flexibility and limit lipid accumulation. Carbohydrate metabolism is also sex-dependent, with differences in gluconeogenesis, glycogen synthesis, and insulin sensitivity. Estrogen receptors improve glycemic control in the female liver by repressing gluconeogenic gene expression and enhancing insulin responsiveness. Cholesterol metabolism likewise exhibits marked sex-specific regulation, as the interplay among ERs, LXRs, and FXR influences cholesterol synthesis, bile acid production, and hepatic excretion, contributing to sex-related differences in lipid profiles and susceptibility to steatosis and dyslipidemia [10].
Consistently, evidence from both human and animal studies indicates that hormonal imbalances increase susceptibility to metabolic diseases [9,11].
Metabolic dysfunction differs between men and women due to biological, genetic, and environmental factors. In this regard, visceral obesity, insulin resistance (IR), and hormonal differences should be considered.
Men and women differ in body composition and lipid metabolism. Hormonal profiles and the distribution of hormone receptors between the sexes determine distinct patterns of fat deposition. While women generally exhibit a higher percentage of total body fat, and a preferential deposit of subcutaneous fat, men tend to accumulate a greater proportion of visceral abdominal fat, which is a well-established risk factor for metabolic and cardiovascular diseases. Furthermore, basal metabolic rate differs between sexes: men display a higher capacity to metabolize lipids for energy production, whereas women’s metabolism tends to respond more slowly to hypocaloric dietary interventions [12,13,14].
As also underlined by the study “Korean Genome and Epidemiology Study” [15] evaluating the correlation between different patterns of abdominal obesity (AO) and the risk of developing fatty liver disease, in men the greatest risk is associated with the predominance of visceral obesity due to the potential lipotoxicity of visceral fat compared to subcutaneous fat, and for the inflammatory potential mediated by the action of pro-inflammatory cytokines, such as IL-6 and TNF-α, which promote steatosis and liver fibrosis [15,16].
Among the hormonal factors, estrogens exert direct and indirect effects by modulating lipid metabolism and insulin sensitivity, reducing hepatic lipotoxicity and visceral fat accumulation. In studies of Formyl Peptide Receptor 2 (FPR2) [17], a modulator of inflammatory responses more highly expressed in female hepatocytes, it has been shown to be a key player in the progression of MASLD to MASH. Indeed, in animal models subjected to a high-fat diet, males showed more severe liver damage than females. This effect correlates with higher levels of FPR2 expression in female hepatocytes, thanks to the protective power of estradiol, which increases the receptor expression. Suppression of the FPR2 gene worsened liver damage in females, suggesting that FPR2 could be a promising therapeutic target for personalized treatments against MASLD/MASH, taking into account sex differences.
Men also have higher levels of insulin resistance (IR) than women, resulting in increased de novo hepatic lipogenesis and the risk of steatosis, with the exception of postmenopausal women, as the decline in estrogen leads to a rapid increase in insulin resistance, hepatic lipogenesis, and the risk of advanced fibrosis [17]. Furthermore, a review conducted by the Italian Association for the Study of the Liver (AISF) highlighted that sex differences significantly influence the presentation and progression of MASLD/MASH. For example, premenopausal women appear to be protected from disease progression thanks to the anti-inflammatory effect of estrogen, while men and postmenopausal women show greater vulnerability to advanced liver fibrosis [18].
In addition to the indirect effects already presented, estrogens also exert direct hormonal effects by activating the AMPK-SREBP pathway, a mechanism that regulates lipid metabolism in the liver. AMPK (5′ adenosine monophosphate-activated protein kinase) is a protein that acts as a cellular energy sensor: when energy is low, such as during fasting or exercise, AMPK is activated to reduce energy-consuming processes, such as lipid synthesis. SREBP (sterol regulatory element binding protein), on the other hand, is a protein that stimulates the synthesis of lipids, including fatty acids and cholesterol. Normally, AMPK inhibits SREBP to prevent fat accumulation in the liver. When AMPK functions properly, it reduces lipid synthesis, preventing liver damage. However, in situations of insulin resistance and metabolic syndrome, AMPK can be dysfunctional, promoting excessive lipid production and increasing the risk of MASLD and MASH. This pathway limits the accumulation of hepatic triglycerides, while their absence favors the progression to MASH [19].
Evidence of hormonal involvement in metabolic disorders is also demonstrated by the fact that hyperandrogenism associated with polycystic ovary syndrome (PCOS) is a risk factor for MASLD in women, due to the interaction between insulin resistance, obesity, hormonal imbalance, and inflammation. Insulin resistance and hyperinsulinemia promote fat accumulation in the liver, while visceral adipose tissue produces pro-inflammatory cytokines that contribute to disease progression to MASH. Furthermore, reduced estrogen levels can reduce hepatic protection against inflammation and fibrosis, as occurs in postmenopausal women [18]. Dyslipidemia and increased free fatty acids intensify hepatic oxidative stress, while an altered gut microbiota can aggravate the disease through increased intestinal permeability and worsening systemic inflammation and thus consequent metabolic dysfunction [20].
The prevalence of MASLD increases with age in both sexes, but an earlier peak is observed in boys (11 years) than in girls. Estradiol levels are positively associated with MASLD in boys, while they show an inverse relationship in girls. Testosterone decreases with increasing prevalence of MASLD in boys, while hormones such as prolactin and luteinizing hormone (LH) show an inverse influence in girls and boys, respectively [21,22].
Among genetic factors, the PNPLA3 (patatin-like phospholipase domain-containing protein 3) gene encodes a protein involved in lipid metabolism in the liver. The I148M variant is a mutation in which the amino acid isoleucine (I) is replaced with methionine (M) at position 148. This mutation alters the protein’s function, promoting fat accumulation in the liver and increasing the risk of inflammation and fibrosis, and therefore the risk of fatty liver disease, including MASLD. The I148M variant of the PNPLA3 gene, strongly associated with MASLD, shows more pronounced effects in men, increasing the risk of advanced fibrosis [23]. Another implicated genetic variant is the E167K mutation in the TM6SF2 (transmembrane 6 superfamily member 2) gene, which encodes a protein involved in lipid metabolism, particularly the accumulation and transport of lipids in the liver. This mutation, in which glutamate (E) at position 167 is replaced by lysine (K), has been associated with an increased risk of developing liver diseases such as MASLD and MASH [23]. This genetic variant leads to a malfunction of the TM6SF2 protein, reducing its ability to export lipids from the liver, thus promoting the accumulation of fat within liver cells, triggering inflammatory processes, fibrosis, and other metabolic complications. This mutation, associated with severe hepatic steatosis, shows a greater phenotypic expression in men [23].
Another area of growing interest in MASDL is the intestinal microbiome. It is well established that the gut microbiota exhibits sex-specific characteristics that vary with age. Influenced by sex hormones, and in turn influencing them, the microbiota participates in multiple host metabolic pathways. Likewise, alterations in sex hormone levels are often associated with dysbiosis [24,25]. In humans, certain bacterial species appear to be particularly associated with serum lipid concentrations. For example, Odoribacter, Anaerostipes, and Parabacteroides have been linked to elevated lipid levels, whereas Massilistercora timonensis seems to be more abundant in individuals with lower cholesterol concentrations [26]. Variations in gut microbiota diversity and composition between sexes and intestinal regions may contribute to elucidating the mechanisms involved in MASLD-related biological pathways. Studies in MASLD rat models further confirm sex-specific differences in microbiota composition within the upper small intestine and colon, suggesting that this dimorphism may influence lipid synthesis, bile acid profiles, and inflammatory signaling pathways [24,27].
No less important are environmental factors. Indeed, exposure to chemicals and environmental substances can lead to different outcomes between men and women, influencing the pathophysiology, progression, and severity of disease. Biological differences in cellular and molecular processes, driven by sexual dimorphism of organs such as the liver and by gene–environment interactions, can result in different responses to the same environmental factors between men and women. The association between environmental and occupational chemical exposures and MASLD is well documented by human epidemiological studies and supported by experimental models [28]. However, studies on sex differences in liver toxicology are still limited and do not allow definitive conclusions to be drawn regarding chemical toxicity by sex. Biological sex influences the risk of fatty liver disease due to the interference of toxicants with growth hormone and estrogen receptor signaling. Men and women differ in their ability to metabolize and eliminate toxic substances; women are often exposed to greater toxin accumulation due to enzymatic and body composition differences, such as a higher percentage of fat mass than men, which can influence the bioaccumulation of some pollutants. These interactions may affect liver and metabolic functions, with potential implications for liver disease progression and changes in vulnerability to liver injury [8,28].
Finally, despite biological differences and environmental factors, lifestyle factors remain the primary determinants of individual health or, conversely, of metabolic disorders, particularly dietary habits and physical activity. In this case, gender-related behavioral patterns are involved. Men and women differ also in their food preferences and eating behaviours. In general, women tend to choose healthier foods, whereas men are more likely to consume alcohol, high-calorie, and salty foods. Males often experience greater hunger in the late afternoon and before dinner, particularly in cases of overweight or obesity, also suggesting that obesity is associated with disruptions in circadian rhythms. Conversely, women tend to report greater hunger in the morning and they reach satiety more easily than men [13,29]. Overall, there is a clear sexual dimorphism not only in body composition and hormonal state, but also in nutritional behaviours. Gender-related behavioural patterns significantly influence lifestyle choices, yet economic factors also play an important role. Food prices can limit access to nutrient-rich options, often driving individuals toward cheaper, energy-dense, and nutrient-poor foods [30].
A summary of the main sex- and gender-specific causes and predisposing factors for MASLD is presented in Table 1.

5. Clinical Manifestation and Evolution

Among patients with MASLD, clear sex-related differences emerge in disease progression and clinical outcomes. Men exhibit a higher risk of disease progression, cardiovascular (CV)-related mortality, advanced liver fibrosis (stages F3–F4), and hepatocellular carcinoma (HCC), largely driven by dyslipidemia, metabolic syndrome, and chronic systemic inflammation. Women, in contrast, show a higher predisposition to intrahepatic cholestasis and related complications. Cardiovascular disease remains a major cause of mortality in both sexes; however, women of childbearing age are relatively protected, displaying lower CV risk and reduced progression to advanced fibrosis due to estrogen-mediated modulation of inflammatory pathways. This protective effect is lost after menopause, when women experience a marked increase in CV events and liver disease progression, reaching risk profiles more comparable to those observed in men [5,31]. Conversely, a 2024 study [20] explored the implications of sex differences in bile acid profiles in patients with MASLD, also highlighting the role of sex hormones and the gut microbiota. Differences in bile acid profiles between men and women may explain the disparities in disease prevalence and severity, demonstrated as higher levels of total and primary bile acids suggest a greater tendency for intrahepatic cholestasis in women than in men.
The prevalence of different Steatotic Liver Disease (SLD) phenotypes, is significantly higher in men than in women. However, the implications for mortality vary by sex: while the MASLD phenotype shows no significant associations, the MetALD phenotype (metabolic dysfunction and moderate to heavy alcohol consumption) is associated with an increased risk of mortality only in women, and ALD (alcohol-related liver disease) is associated with an increased risk in both sexes, with a potentially more pronounced impact on women. These findings highlight the importance of considering sex differences in the assessment and management of SLD. Therefore, the new nomenclature offers the opportunity to delve deeper into the mechanisms underlying these disparities, fostering the development of personalized therapeutic strategies. In particular, the greater vulnerability of women with MetALD and ALD may require differentiated clinical attention to improve health outcomes. The approach to SLD must take into account not only the presence of hepatic steatosis, but also etiological factors and sex and gender differences, to guide more targeted and effective preventive and therapeutic interventions [8].
At least, one of MASLD complication is HCC, which can appear earlier than liver cirrhosis develops. HCC is the most common form of liver cancer, usually developing secondary to chronic liver diseases, and placing fifth among cancers in men and ninth in women. Men tend to develop gastrointestinal cancers more than women, and notably, HCC has a more severe manifestation and prognosis in men [32,33,34,35].
Table 2 summarizes the principal differences in clinical manifestation and evolution between men and women.

6. Personalized Therapy

Management of MASLD requires interventions tailored to the patient’s hormonal status and metabolic profile (Table 3). Lifestyle modifications are among the first approaches. According to EASL–EASD–EASO recommendations [1] it is important to emphasize that weight loss and physical activity are essential for the management of MASLD. A 7–10% reduction in body weight improves steatosis in 90% of patients and reduces fibrosis in 30–50% [23]. In a study of a very-low-carbohydrate ketogenic diet (VLCKD) in subjects with severe obesity [36], with particular attention to sex-related differences where various parameters were measured (anthropometric, bioimpedance, degree of hepatic steatosis by ultrasound, liver function tests and blood glucose control) before and after treatment, it was demonstrated that men achieved greater body weight loss (Excess Body Weight Loss, EBWL) significantly greater than in women, with a more marked reduction in γ-glutamyl transferase (γGT) that was also more marked in men. When analyzing women according to menopausal status, it was observed that premenopausal women showed lower results than men in terms of EBWL and reduction in γGT, less significant however with respect to the degree of hepatic steatosis. The efficacy of VLCKD in subjects with severe obesity is influenced by sex differences and, in women, by menopausal status; men appear to benefit more in terms of weight loss and improvement of MASLD than premenopausal women [36]. However, there are significant differences between the sexes: men show a more rapid response to weight loss, thanks to a greater reduction in visceral fat; women, especially postmenopausal women, require intensive approaches to achieve comparable metabolic improvements. After menopause, these differences diminish, likely due to changes in hormonal profile and body composition. Sex and menopausal status may modulate the benefits of nutritional treatment aimed at obesity and related liver complications [37].
Exercise can be beneficial, with 150 min per week of aerobic and resistance activity being associated with a significant reduction in liver fat. Women of childbearing age respond less to exercise than men, due to differences in body composition [38].
In addition to lifestyle modifications, pharmacological therapies are currently suggested. Pioglitazone is recommended for patients with MASH and fibrosis ≥ F2, effective in both men and women, reducing insulin resistance and improving liver inflammation [39]. In a recent Chinese study of 185 participants, concomitant use of berberine, a plant alkaloid active in reducing cholestyramine, was shown to be more effective than Lifestyle intervention (LSI) alone, combined treatment with pioglitazone and LSI. A further reduction in liver fat content was observed in women (−15.24% ± 14.54% vs. −8.76% ± 13.49%, p = 0.025), while in men the reduction was smaller (−9.95% ± 15.18% vs. −12.64% ± 17.78%, p = 0.046). A significant interaction between sex and pioglitazone efficacy was observed, even after controlling for age, smoking, alcohol consumption, baseline BMI, change in BMI, treatment adherence, baseline liver fat content, and glucose metabolism. The study concludes by recommending the use of pioglitazone in combination with lifestyle interventions for Chinese female patients with MASLD with impaired glucose metabolism [40]. Women respond better to pioglitazone therapy for hormonal reasons, insulin resistance, and a higher expression of genes related to liver metabolism. Some studies indicate that women express more PPARγ receptors, the target of pioglitazone, making them more sensitive to the drug’s action; they also have greater activity of liver enzymes involved in fat metabolism. Furthermore, in women, a body fat distribution with less visceral fat may favor a greater response to drugs and a reduced inflammatory effect. The inflammatory response in the liver also appears to be less aggressive in women than in men; levels of pro-inflammatory cytokines (such as TNF-α and IL-6) are often higher in men with MASH, contributing to a more rapid progression of the disease and a poorer response to treatments [40,41]. While studies on various lifestyle responses have shown a better response in men, other studies show that during pioglitazone therapy, women, in general, tend to follow changes in diet and physical activity more carefully, increasing the effectiveness of the treatment and amplifying its effect [41].
Women may also benefit from postmenopausal hormone replacement therapy (HRT), as HRT has been shown to improve lipid metabolism and reduce the progression of fibrosis, improving metabolic parameters and reducing fat accumulation in the liver. However, further research is needed to determine the long-term efficacy and safety of these therapies [18].
Examining the use of the Metabolic Syndrome Severity Score (MetS-Z) as a predictor of treatment success and as an indicator of response in patients with MASH, Vitamin E is also effective in non-diabetic patients with MASH, but data suggest greater efficacy in men. However, the researchers analyzed data from the PIVENS study [42], in which individuals with biopsy-confirmed MASH were randomized to receive pioglitazone, vitamin E, or placebo for 96 weeks. MetS-Z score is calculated using a statistical model that combines these parameters to provide a continuous measure of the severity of metabolic syndrome based on blood glucose, HDL, triglyceride, blood pressure, and BMI values. They found that a high baseline value is associated with a lower likelihood of MASH resolution. The reduction in MetS-Z in the first 48 weeks was more significant in the pioglitazone-treated group. In general, a reduction in MetS-Z correlates with MASH resolution, although aminotransferases were more consistent indicators of treatment success. The study suggests that greater severity of metabolic syndrome may reduce the likelihood of therapeutic success in MASH. Studies suggest that women may benefit more from some treatments for NASH/MASH and metabolic syndrome than men, but more research is needed to better understand these mechanisms [42].
Latest molecules involved in the management of MASLD/MASH are glucagon-like peptide-1 receptor agonists (GLP-1RAs). Several evidences support the use of GLP-1RAs in the management of MASLD and type 2 diabetes, demonstrating safety, tolerability, and significant improvements in liver fat fraction, glycemic control, insulin resistance, and lipid profile, suggesting a potential therapeutic effect on overall metabolic syndrome beyond the simple weight loss [43]. GLP-1RAs not only improve the metabolic profile but also prevent the progression to liver cirrhosis. A retrospective study of patients with MASLD and T2D compared the effects of GLP-1RAs with those of DPP-4 (dipeptidyl peptidase-4) inhibitors, demonstrating that the use of GLP-1RAs was associated with a significant reduction in the risk of developing cirrhosis (HR 0.86; 95% CI 0.75–0.98) and mortality (HR 0.89; 95% CI 0.81–0.98) in patients without cirrhosis at baseline, while no significant differences were observed in individuals with pre-existing cirrhosis, suggesting their prophylactic role in the potential progression of advanced liver damage [44].
Moreover, always a larger number of studies demonstrate GLP-1RAs efficacy in treatment of MASLD/MASH, beyond the presence of T2D. Semaglutide has been shown to improve hepatic steatosis and to promote weight loss, showing similar benefits in both sexes, but the efficacy in women could be influenced by the postmenopausal status [45].
The ESSENCE study indicates that semaglutide, compared to placebo, can significantly improve MASH and reduce hepatic fibrosis in patients with moderate to advanced disease. Among 1200 adults with MASH and moderate to advanced hepatic fibrosis, after 72 weeks of treatment 62.9% of patients receiving semaglutide achieved resolution of MASH without worsening of hepatic fibrosis and 32.7% of patients treated with semaglutide demonstrated both MASH resolution and fibrosis improvement [46].
Furthermore, tirzepatide, a dual GLP-1RAs and glucose-dependent insulinotropic polypeptide (GIP) agonist, in a post hoc analysis of the SYNERGY-NASH study, showed consistent improvements in liver histology in different patient subgroups, including those with T2D and obesity, confirming the cross-sectional efficacy of the treatment thanks to its ability to reduce liver fat content, improve fibrosis and modulate liver inflammation. Tirzepatide improves both metabolic parameters and liver fibrosis in patients with advanced MASLD, suggesting its role as a novel therapeutic approach in MASH [47,48]. These results suggest that tirzepatide not only improves glycemic control and body weight but may also represent a prophylactic intervention against progression to advanced fibrosis and cirrhosis, offering a new perspective in the integrated management of MASLD/MASH.
Although there are few studies, often with partial results, that have explored whether the response to GLP-1RAs (and, more recently, to tirzepatide) differs between men and women in terms of clinical outcome and especially weight loss, but with no regard to the therapeutic response in terms of reduction in hepatic steatosis.
Observational studies indicate that, although women tend to achieve greater weight loss than men during treatment with GLP-1RAs, this does not necessarily translate into significant differences in reduction of hepatic steatosis or liver biomarkers. For example, in a retrospective analysis of patients with T2D and MASLD, sex was not a significant predictor of reduction in the fatty liver index after treatment with tirzepatide [49]. Similarly, trials of semaglutide in patients with MASLD showed significant improvements in hepatic steatosis with no differences in response stratified by sex [50]. Regarding weight loss, meta-analyses and real-world studies confirm greater efficacy in female subjects treated with GLP-1RAs [51]. But there is no evidence that these differences translate into a differential impact on liver disease. The SYNERGY-NASH trial, evaluating tirzepatide in patients with NASH, has not yet reported specific data on response by sex [47]. In conclusion, although sex differences in the pathophysiology of MASLD are known, their clinical relevance in the response to GLP-1RAs drugs and tirzepatide remains to be explored.
Lastly, the only drug specifically approved for MASH is resmetirom, an oral agonist of the hepatic thyroid hormone receptor beta (THR-β). Resmetirom has been shown to reduce liver fat content and fibrosis, thereby improving liver histology. Activation of THR-β stimulates hepatic metabolic pathways through RXR-α (retinoid X receptor alpha) and other co-activators, leading to reduced lipotoxicity and enhanced mitochondrial function, ultimately decreasing intrahepatic triglyceride accumulation and circulating atherogenic lipids. Through these mechanisms, resmetirom may also contribute to a reduction in cardiovascular risk [52,53,54,55,56]. In 2024, resmetirom was approved in the United States for adult patients with MASH and significant hepatic fibrosis (F2–F3), in combination with diet and lifestyle interventions [54,57,58,59]. Despite its favorable safety profile, however, rates of MASH resolution and fibrosis improvement remain modest, and the therapeutic response varies across patients. Furthermore, sex-stratified data are still lacking in this context [52,60].
Table 3. Management of MASLD: Treatment Options and Sex Differences.
Table 3. Management of MASLD: Treatment Options and Sex Differences.
Treatment OptionsMechanism/ObjectiveSex-Based DifferencesKey Studies/Evidence
Lifestyle Modifications
(Diet & Exercise)		≥7–10% weight loss reduces steatosis (90%) and fibrosis (30–50%);
≥150 min/week reduces liver fat		♂ faster weight loss, greater reduction in visceral fat
♀ premenopausal less responsive; ♀ postmenopausal similar to men		EASL–EASD–EASO Guidelines [1], VLCKD Study [36], Exercise [38]
Very-Low-Carb Ketogenic Diet
(VLCKD)		Reduces liver fat,
improves GGT, steatosis and anthropometric measures		♂ greater weight and GGT reduction
♀ premenopausal lower response; ♀ postmenopausal more similar to ♂		VLCKD Study [36]
PioglitazoneIncreases insulin sensitivity, reduces liver inflammation and fibrosis (F ≥ 2)♀ better response (more PPARγ receptors), better adherence to therapyPIVENS Study [42]
Vitamin EAntioxidant♂ possibly more effective
♀ mixed evidence		PIVENS Study [42]
Hormone Replacement Therapy (HRT)Improves lipid metabolism, reduces fibrosis progression ♀ postmenopausal potential benefit, more research needed Emerging Evidence [18]
GLP-1RAs
(e.g., Semaglutide)		Reduces steatosis, body weight and fibrosis risk, improves insulin sensitivity and lipid profile♀ greater weight loss, no clear difference in liver fat response,
♀ post-menopause may reduce efficacy		ESSENCE Study [46], Retrospective Analyses [49]
Tirzepatide (dual agonist GLP-1 + GIP)Improves glycemic control, reduces body weight, liver fat, inflammation and fibrosis♀ greater weight loss
♀♂ similar steatosis response		SYNERGY-NASH [47,48]
Resmetirom (THR-β agonist)Reduces intrahepatic fat and liver fibrosis Sex-stratified data not yet availableFDA Approval 2024, Clinical Trials [52,53,54,55,56,57,58,59,60]

7. Discussion

The most recent guidelines have redefined the definition of MASLD with the aim of optimizing diagnostic criteria and eliminating the stigma implied by the term “non-alcoholic.” Nevertheless, another stigma remains to be overcome: the insufficient consideration of sex- and gender-related differences. Evidence from several studies suggests that tools currently used in clinical practice, such as FIB-4, may need to be reconsidered, as certain analytes show significant sex-related variability, also influenced by metabolic factors. Metabolic diseases, and consequently MASLD, are increasing rapidly worldwide. with men appearing to be more frequently affected even when different disease phenotypes are taken into account. Hormones are well known to play a major role, and men and women differ in body composition and fat distribution and metabolism. These differences translate into distinct risks of insulin resistance and diabetes, as well as divergent inflammatory profiles. Sex-related differences are also evident in the gut microbiome, which contributes to MASLD through complex microbiota–host interactions that further influence hormonal pathways. In addition, the differential ability to metabolize toxicants and to respond to environmental factors further impacts hepatic inflammatory responses and the susceptibility to steatosis, fibrosis, and other liver diseases.
Consequently, significant sex-related differences are observed in the clinical manifestations of MASLD and in its progression, with a generally more unfavorable prognosis reported in men.
Despite numerous unsuccessful attempts in the past to identify an effective therapy for MASLD/MASH, the first truly promising pharmacological options are now emerging. However, robust sex-disaggregated data are still largely lacking for these novel treatments.
The educational aspect also warrants further exploration, as lifestyle and dietary habits remain the cornerstone of MASLD management. In this context, it is important to recognize that gender-related disparities in access to healthcare may persist, particularly in settings where healthcare coverage is limited. In disadvantaged settings, women are often disproportionately affected, as they may have reduced access to education and to stable employment that ensures financial independence.
Furthermore, the cost of healthy food represents an additional barrier. In an era dominated by inexpensive ultra-processed food, financial limitations play a crucial role in determining one’s ability to adhere to a balanced and health-promoting diet.

8. Conclusions

The 2023 Joint EASL–EASD–EASO Clinical Guidelines on MASLD provide a comprehensive framework for the diagnosis, prevention, and treatment. However, they do not significantly highlight sex- and gender-related differences in their overall recommendations. Although the guidelines promote a personalized approach that takes into account individual cardiometabolic risk factors and patient characteristics, they do not specify to include adjustments based specifically on sex or gender.
A deeper understanding of the role of sex hormones, sex-specific genetics, and metabolic pathways may enable more effective and targeted interventions, ultimately contributing to a reduction in the global burden of MASLD. In addition, gender-related factors, such as dietary habits, physical activity, and lifestyle, play a crucial role in MASLD development. Future research should therefore also address gender-related aspects of the disease, while acknowledging that biological sex assigned at birth and gender identity may not always align.
Finally, social determinants of health may lead to discrepancies in access to prevention and treatment options, highlighting the need for educational interventions and social support within the population that, in some circumstances, may require a different approach between men and women.
In conclusion, we believe that future guidelines should strongly focus on sex- and gender-related differences in MASLD genesis, clinical manifestation, and treatment to provide a further significant contribution to reducing the burden of MASLD.

Author Contributions

Conceptualization, A.L. and R.V.; methodology, A.L.; investigation, R.V.; resources, A.L. and R.V.; data curation, M.D.L. and R.V.; writing—original draft preparation, R.V.; writing—review and editing, A.L. and A.G.; visualization, A.L.; supervision, M.D.L.; project administration, A.G. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflict of interest.

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Table 1. Main sex- and gender-specific causes and predisposing factors in MASLD.
Table 1. Main sex- and gender-specific causes and predisposing factors in MASLD.
MenWomenImplications for MASLD/MASH
AgeMASLD increases steadily;
early peak		MASLD increases steadily;
delayed peak		Different risk according to the age-related hormonal changes
Visceral obesityHigher prevalence;
lipotoxic fat		Lower prevalence;
more subcutaneous fat 		♂ have higher risk of hepatic steatosis and fibrosis due to visceral fat and its pro-inflammatory properties
Insulin resistanceHigher levels; increases hepatic fat accumulationLower in premenopause; increases after menopause♂ and postmenopausal ♀ have higher risk of fat accumulation and advanced steatosis
EstrogensEstradiol levels positively associated with MASLD in boysReduce hepatic fat accumulation and fibrosis progression in premenopauseFPR2 induction and AMPK-SREBP pathway activation in ♀ modulates inflammation, protecting against progression to MASH
Hyperandrogenism (i.e., PCOS)Not applicableReduces hepatic protection; increases IR and hepatic fat accumulationIncreased MASLD/MASH risk in ♀
Genetic predisponents
(PNPLA3/TM6SF2 variants)		Greater expressionLower expression and phenotypic impactMajor presence of steatosis and fibrosis progression in ♂
Metabolic and behavioral factorsHigher capacity of lipids metabolization; higher alcohol consumption and high-calorie and salty foodsGreater toxin accumulation; lower response to hypocaloric dietary; healthier dietary habits♂ and ♀ respond differently to environmental exposures and exhibit distinct dietary and lifestyle habits
Table 2. Clinical manifestation and evolution of MASLD in men and women.
Table 2. Clinical manifestation and evolution of MASLD in men and women.
MenWomenImplications
SLD phenotypesMASLD, MetALD and ALD more commonLower prevalence overallMASLD: no sex-specific mortality differences; MetALD: increased mortality in ♀;
ALD: increased mortality in both sexes, potentially more severe in ♀
Cardiovascular riskHigher;
main cause of death in MASLD ♂		Lower in ♀ of childbearing age; increases in post-menopause♂ have higher CV mortality;
♀ protected pre-menopause by estrogens; risk rises after menopause
Liver fibrosis progressionGreater tendencyLower risk in pre-menopause♂ have higher risk of fibrosis;
♀ protected by estrogens; risk rises after menopause
Intrahepatic cholestasisLower tendencyHigher tendencySex hormones and gut microbiota promote intrahepatic cholestasis in ♀
Hepatocellular carcinoma (HCC)Higher incidenceLower incidence in pre-menopause♂ have higher risk of HCC; risk in ♂ linked to dyslipidemia, metabolic syndrome, chronic inflammation
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De Luca, M.; Verdoliva, R.; Lombardi, A.; Giorgio, A. New Definition, New Point of View: Sex and Gender Interpretation of MASLD—Interpretation of Guidelines and Review of the Literature. Gastroenterol. Insights 2026, 17, 7. https://doi.org/10.3390/gastroent17010007

AMA Style

De Luca M, Verdoliva R, Lombardi A, Giorgio A. New Definition, New Point of View: Sex and Gender Interpretation of MASLD—Interpretation of Guidelines and Review of the Literature. Gastroenterology Insights. 2026; 17(1):7. https://doi.org/10.3390/gastroent17010007

Chicago/Turabian Style

De Luca, Massimo, Rita Verdoliva, Anna Lombardi, and Antonio Giorgio. 2026. "New Definition, New Point of View: Sex and Gender Interpretation of MASLD—Interpretation of Guidelines and Review of the Literature" Gastroenterology Insights 17, no. 1: 7. https://doi.org/10.3390/gastroent17010007

APA Style

De Luca, M., Verdoliva, R., Lombardi, A., & Giorgio, A. (2026). New Definition, New Point of View: Sex and Gender Interpretation of MASLD—Interpretation of Guidelines and Review of the Literature. Gastroenterology Insights, 17(1), 7. https://doi.org/10.3390/gastroent17010007

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