Commentary: Of women, liver, and heart

Definitions and burden

While playing a major role in different physiological processes, at variance with the adipose tissue, the liver is not involved in the storage of fatty substrates under normal conditions^[1]. Intrahepatic accumulation of even minimal amounts of fat is indeed associated with insulin resistance, hepatic metaflammation, and the ensuing risk of fibrosis progression in a subset of individuals^[1,2]. These notions explain why steatosis (i.e., intrahepatic accumulation of fat which occurs in the absence of alcohol, drugs, viral infections, autoimmunity, or specific genetic disorders of metabolism (hence “nonalcoholic”) is a true disease [namely “nonalcoholic fatty liver disease” (NAFLD)] rather than an irrelevant variation from normality^[3,4]. Although displaying a mutual and bi-directional relationship with the metabolic syndrome (MetS), NAFLD is not comprised in the definition of the MetS, which embraces a cluster of factors including expanded visceral adiposity, impaired glucose metabolism, arterial hypertension, and dyslipidemia^[5,6]. However, studies have shown that adding NAFLD to the definition of MetS allows the identification of more severe oxidative stress and endothelial dysfunction and also helps in identifying a larger fraction of the population at metabolic risk^[7,8].

Affecting 38% of the population globally, NAFLD is the leading cause of chronic liver disease worldwide, and its prevalence is also projected to increase in the future^[9]. As a systemic disorder, the spectrum of manifestations of NAFLD is not limited to hepatic manifestations and complications but also includes metabolic disorders, extra-hepatic cancers, and cardiovascular disease (CVD)^[1,10]. Of concern, cardiovascular mortality is the first cause of death among NAFLD patients^[9,10]. The long-term risk of fatal or non-fatal CVD events is strongly associated with more advanced NAFLD forms that exhibit higher fibrosis stages, supporting the notion that NAFLD is probably an independent risk factor for morbidity and mortality owing to CVD^[11].

In 2020, in an attempt to overcome the critiques regarding the limitations and potentially stigmatizing consequences of using the term “NAFLD”, a panel of experts from 22 countries proposed the novel metabolic dysfunction-associated fatty liver disease (MAFLD) nomenclature (reviewed in^[12]). The MAFLD definition, which has met universal consensus in Latin America, North Africa and the Middle East, indicates that the motivations to abandon the old nosography prevail on the reasons for keeping it^[12]. MAFLD is defined by liver steatosis among patients who have either type 2 diabetes or obesity. Interestingly, the presence of at least two, among the criteria belonging to the MetS domain (expanded abdominal adiposity; arterial hypertension; hypertriglyceridemia; low HDL-cholesterol; pre-diabetes; insulin resistance; and subclinical systemic inflammatory state), is considered to be equivalent to either obesity or diabetes^[12]. As discussed in this commentary, the above-listed dysmetabolic traits are deeply implicated in the determination of the risk of CVD.

In 2023, a new nomenclature was proposed by a panel of 236 experts from 56 countries to replace MAFLD with metabolic dysfunction-associated steatotic liver disease (MASLD)^[13]. Furthermore, consensus was reached regarding changing the definition to include the presence of at least one of five cardiometabolic risk factors in addition to hepatic steatosis, while those with no metabolic parameters were classified as cryptogenic steatotic liver disease. The new nomenclature highlights the close link between MASLD and cardiovascular (CV) risk factors.

Sex differences

Over the last 10 years, in various fields of medical research, there has been an increasing interest in sex differences that principally result from sex chromosomes and sex hormones, as opposed to gender differences that are influenced by socio-cultural factors^[14]. Given that sex and gender differences bolster variability in disease pathobiology from development to progression, consideration of sex, age, and reproductive status (e.g., menarche and menopause) is presently deemed key in determining precision medicine approaches in NAFLD arena^[15]. Like NAFLD, and before sexual dimorphism became apparent in NAFLD arena, a robust line of research has highlighted sexual dimorphism in cardiometabolic disorders^[14,16,17].

Aim

In the previously described context, our Commentary is devoted to a recent study by Ren and Zheng^[16]. This study aimed at analyzing sex-stratified long-term outcomes relevant to all-cause and CV field outcomes among 2627 NAFLD adult patients (65.4% were men), identified with United States Fatty Liver Index (US FLI) score of ≥ 30, enrolled in the 2000-2014 National Health and Nutrition Examination Surveys. Data have shown that, compared to women, men were exposed to a significantly higher all-cause mortality (crude or unadjusted mortality rate 12.4% vs. 7.7%; P = 0.005) and the maximal risk was seen among those who had obesity (body mass index > 30 kg/m²) and diabetes. However, women aged ≤ 60 years had a higher risk of death owing to CVD (compared to women, adjusted HR for men: 0.214, 95%CI: 0.053 - 0.869, P = 0.031). On the other hand, no significantly increased risk of death from CVD was observed among women older than 60 years compared to men in the same age category. The authors conclude that mortality owing to CVD is affected by age and sex, with young and middle-aged women being at a higher risk of dying due to CVD^[18].

Sex differences in NAFLD natural course

As for other metabolic diseases, women are seemingly protected from the development of disease. However, once diseases occur, their course tends to be more aggressive. This can result from a variety of explanations, including delayed diagnosis and immunological pathomechanisms. Regarding NAFLD, this point is strongly corroborated by recent data. Balakrishnan et al. have published a milestone meta-analytic review of 54 studies totaling 62,239 cases with NAFLD, 5,428 with NASH, and 6,444 with advanced fibrosis^[19]. Data have shown that, compared to men, women in the general population were protected from NAFLD [having a 19% lower risk of NAFLD (pooled risk ratio [RR], 0.81; 95%CI: 0.68-0.97; I² = 97.5%)] while the odds of NASH were similar to men (RR, 1.00; 95%CI: 0.88-1.14; I² = 85.1%), and the risk of advanced fibrosis was 37% higher (RR, 1.37; 95%CI: 1.12-1.68; I² = 74.0%). Age of 50, a surrogate index of menopausal status, was a modifier of the effect of sex on disease severity, odds of NASH and advanced fibrosis being substantially higher in women ≥ 50 years (RR, 1.17; 95%CI: 1.01-1.36; and RR, 1.56; 95%CI: 1.36-1.80, respectively) while sex differences in NASH and advanced fibrosis were attenuated, among younger cohorts.

Sex differences in NAFLD pathobiology as related to cardiovascular risk

Physiopathological explanations underlying the findings reported above include sex differences in the supply and utilization of energetic substrates, storage of excess lipids, and mobilization of accumulated lipids in metabolic organs^[20,21].

For any given BMI, compared to men, women of fertile age have a more abundant mass of adipose tissue, which is typically located at subcutaneous sites, predominantly in the gluteo-femoral area^[22]. Therefore, sexual dimorphism in adipose tissue, skeletal muscle, and liver substrate metabolism accounts for sex differences in tissue-specific insulin sensitivity and lays the foundations for variable risks of target tissue damage and different profiles of cardiometabolic risk^[21]. Women of fertile age are protected from cardiometabolic diseases compared to BMI and age-matched men, although this protective effect wanes post-menopausally: one explanation could be owing to post-menopausal impaired glucose metabolism^[21].

However, it is apparent from the study by Ren and Zheng that NAFLD abrogates the natural protection women have from CVD. Results from Ren and Zheng are consistent with an earlier longitudinal study, which also found that the protective effect of female sex on CVD in the general population diminished or no longer existed among women with NAFLD^[23]. A recent meta-analysis of over 108,000 people with NAFLD (44% were women) also reported that the female sex was associated with more than doubled risk of cardiovascular events and mortality (odds ratio = 2.12, 95%CI: 1.65-2.73)^[24]. However, both prior studies did not find a stronger association (or higher risk) in young and middle-aged women compared to older women as seen in Ren and Zhang’s study. Young-onset arterial hypertension could be one of the mechanisms underlying NAFLD’s negative influx on cardiovascular health in women. Kim et al. investigated the hypothesis that sex might modulate the association between NAFLD and incident hypertension in young adults < 40 years^[25]. To this end, a study population of 85,789 women and 67,553 men aged < 40 years who were hypertension-free at the baseline were followed for a median follow-up of 4.5 years to ascertain whether incident hypertension was in relationship with the NAFLD status. Data have shown stronger associations between NAFLD and incident hypertension in women, regardless of obesity/central obesity (all P-values for interaction by sex < 0.001), supporting the notion that NAFLD, as a potential risk factor for young-onset hypertension, exerts a proportionally superior impact in women and among those with more severe NAFLD. Alternatively, women who developed NAFLD at a younger age (e.g., during pre-menopausal) may lose the protection from sex-related or hormonal factors while having to bear the metabolic burden of more severe insulin resistance and low-grade chronic inflammation at a younger age, thus rendering them more susceptible to CVD.