1Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul National University College of Medicine , Seoul, Korea
*Corresponding author: Won Kim,
Division of Gastroenterology and Hepatology, Department of Internal Medicine,
Seoul Metropolitan Government Boramae Medical Center, Seoul National University
College of Medicine, 20, Boramae-ro 5 gil, Dongjakgu, Seoul 07061, Korea,
E-mail: drwon1@snu.ac.kr
• Received: March 20, 2024 • Revised: April 22, 2024 • Accepted: April 22, 2024
This is an Open-Access article distributed under the terms of the
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Understanding the effects of sex and sex differences on liver health and disease
is crucial for individualized healthcare and informed decision-making for
patients with liver disease. The impact of sex on liver disease varies according
to its etiology. Women have a lower prevalence of metabolic
dysfunction-associated steatotic liver disease (MASLD) than men. However,
postmenopausal women face a higher risk of advanced liver fibrosis due to
hormonal influences. Sex differences affect the pathogenesis of MASLD, which
involves a complex process involving several factors such as hormones, obesity,
and the gut microbiome. Furthermore, sex-related differences in the development
of MASLDrelated hepatocellular carcinoma have been observed. The sex-specific
characteristics of MASLD necessitate an individualized management approach based
on scientific evidence. However, research in this area has been lacking. This
article reviews the current understanding of sex differences in MASLD.
There has been growing interest in sex differences in medical conditions both in
Korea and around the world [1,2]. Additionally, Korea has established its
first institute focusing on sex differences in medicine, mirroring a global
trend towards increased awareness of these differences.
Sex-specific medicine strives to deliver optimal personalized care for both men
and women, grounded in scientific evidence. Physiological differences between
the sexes, including hormone levels and fat distribution, along with variations
in social and cultural factors such as dietary habits and physical activity, can
affect the onset and progression of liver disease. Consequently, it is crucial
for systematic research to concentrate on exploring the sex-specific differences
in disease development.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a significant
health concern, affecting roughly one-third of the global population. Its
prevalence differs by sex and reproductive status [3–5]. The
nature of MASLD as a sex-differentiated disease necessitates an individualized
management approach based on scientific evidence. However, research on this
topic has been limited.
Objectives
This article aimed to review sex differences in the epidemiology and
pathophysiology of MASLD.
Methods
Ethics statement
Neither approval by the institutional review board nor obtainment of informed
consent was required, since this was a literature-based study.
Identifying the literature
A comprehensive literature search was conducted in March 2024 using the PubMed
databases to identify relevant studies. The search keywords included "sex
differences," "sex characteristics,"
"estrogen," "postmenopause,"
"gastrointestinal microbiome," "gut-liver axis,"
"hepatocellular carcinoma," "liver cirrhosis,"
"nonalcoholic fatty liver disease," "metabolic
dysfunction-associated steatotic disease," "nonalcoholic
steatohepatitis," and "metabolic dysfunction-associated
steatohepatitis." These keywords were used individually or in
combination. The initial search yielded published reports from 2012 to August
2023. From this extensive list of search results, studies that met the following
criteria were included in this review: published after 2015, review articles,
and articles on MASLD or MASLD-related epidemiology and pathophysiology.
Initially, the type of study was reviewed, followed by a screening of abstracts
to identify suitable studies. Ultimately, ten studies were included in this
review and subjected to a comprehensive evaluation in terms of the epidemiology
and pathophysiology of MASLD (Supplement 1).
Epidemiology
MASLD is caused by the excessive accumulation of fat in the liver. Differences in
the distribution of adipose tissue and various associated mechanisms between
sexes are linked to variations in MASLD, which subsequently influence its
epidemiology, risk factors, complications, and treatment [6]. The prevalence of MASLD varies among studies [4]. Studies have shown that MASLD is more
prevalent in men than in women during the premenopausal stage; however, its
prevalence is higher in postmenopausal women [7–11]. A recent
meta-analysis revealed a lower prevalence of MASLD among women; however, no
significant sex differences were observed in metabolic dysfunction-associated
steatohepatitis (MASH) [12]. Advanced
liver fibrosis is more prevalent in women, particularly those in the
postmenopausal stage [6,13,14]. The lower incidence of MASLD in postmenopausal women has been
associated with the use of hormone replacement therapy [15]. Furthermore, a multinational study of histologically
confirmed MASLD and advanced liver fibrosis reported poorer survival and a
higher incidence of hepatocellular carcinoma (HCC) among older individuals and
men, suggesting that estrogen may have a protective effect against MASLD
progression.
Pathophysiology, adiposity, and estrogen
Obesity manifests differently in men and women. Men generally accumulate more
visceral fat within the abdominal cavity, leading to upper body or apple-shaped
obesity. Visceral fat is known for its high lipolysis rate and an inflammatory
adipokine profile. Anatomically, this type of fat drains directly into the
hepatic portal vein, which results in the liver being exposed to elevated levels
of lipids and inflammatory adipokines. In contrast, premenopausal women tend to
accumulate more subcutaneous fat around the lower body and hips, resulting in
lower body or pear-shaped obesity [6].
This subcutaneous fat is characterized by a lower rate of lipolysis, a higher
capacity for fat storage, and increased potential for fat browning, and it is
associated with the release of adiponectin, which protects against metabolic
syndrome and MASLD [16]. However, the
redistribution of fat following menopause heightens the risk of MASLD [7,17]. Moreover, metabolic syndrome is more common among both men and
women in the postmenopausal stage than in premenopausal women [18].
Estrogen influences the interactions between the liver and adipose tissue;
consequently, women generally have a higher percentage of body fat than men.
However, women tend to accumulate a lower ratio of visceral fat to subcutaneous
fat. Research indicates that the expandability and browning capacity of adipose
tissue are more pronounced in women than in men, which helps to reduce the
metabolic load on the liver. Women exhibit higher blood levels of adiponectin
and leptin, along with increased expression and activation of downstream
adiponectin signaling elements such as AMP-activated protein kinase, peroxisome
proliferator-activated receptor-α, and peroxisome proliferator-activated
receptor-γ coactivator-1α. Additionally, women are shielded from
intrahepatic fat accumulation due to enhanced mitochondrial biosynthesis and
heightened fatty acid oxidation. Moreover, women have higher expression of
antioxidant enzymes compared to men, leading to reduced oxidative stress and
preventing the continuous activation of c-Jun N-terminal kinase in response to
various stimuli, including fatty acids and pro-inflammatory cytokines. In
contrast, men are more prone to sustained activation of c-Jun N-terminal kinase,
which can lead to insulin resistance and liver damage through apoptotic
necrosis. Although the expression of fibroblast growth factor 21 is stimulated
by peroxisome proliferator-activated receptor-γ, no differences in blood
levels have been noted between sexes in humans. Fibroblast growth factor 21
primarily affects adipose tissue, promoting glucose uptake, fat browning, and
adiponectin expression. Levels of intrahepatic cytokines, such as
retinol-binding protein 4 and certain angiopoietin-like isoforms, are elevated
in men [16].
Additionally, estrogen plays a role in the development of MASLD in premenopausal
women by suppressing the expression of adipogenesis-related genes in
hepatocytes, inhibiting the release of inflammatory cytokines from Kupffer
cells, and reducing the expression of fibrosis-related genes in hepatic stellate
cells [19]. Summarizing these findings,
the epidemiology and pathophysiology of MASLD are influenced by age and hormonal
changes during the premenopausal and postmenopausal stages [20]. For example, early menarche may
heighten the risk of MASLD in adulthood, a risk partially mediated by excessive
obesity. Ovarian aging, due to estrogen deficiency, eventually leads to the
progression of hepatic steatosis and liver fibrosis through metabolic
dysregulation. This metabolic dysregulation also leads to type 2 diabetes,
hypertriglyceridemia, and visceral obesity, which are commonly observed
post-menopause. Thus, sex-based differences in adiposity and other metabolic
risk factors contribute to variations in disease progression based on sex.
Microbiome and bile acids
It is well established that alterations in gut microbiota and bile acids
contribute to the development of MASLD, MASH, and HCC [21,22]. In a healthy
gut, the microbiome provides nutrients and energy, protects against cancer,
inhibits pathogens, and supports normal gastrointestinal immune functions and
bowel movements [23]. However, when the
gut microbiota is disrupted, bacterial metabolites and commensal components
compromise intestinal epithelial integrity and facilitate access to the liver
via the portal vein [24]. These
byproducts of the microbiome contribute to inflammation, intrahepatic steatosis,
liver injury, and, ultimately, MASLD and MASH [25].
The gut microbiota regulates the gut-liver axis via farnesoid X receptor
signaling. This signaling pathway releases fibroblast growth factor 15 and
fibroblast growth factor 19, which modulate bile acid synthesis, lipid
metabolism, and glucose metabolism. Bile acids, products of cholesterol
metabolism, are secreted into the intestine through the biliary tree and
regulate energy homeostasis through hepatic and extrahepatic metabolism [26].
Scientific evidence indicates that various factors, including age, hormones,
ethnicity, diet, antibiotics, stress, and physical activity, influence the
diversity and composition of the gut microbiota [27]. The gut microbiome evolves in response to age-related changes
in sex hormones. Clinical studies have shown body mass index-specific sex
differences and dimorphism in the gut microbiota associated with the menopausal
stage, highlighting a strong connection between the gut microbiota and sex
hormones [28–30]. However, further research is needed to explore the
effects of the gut microbiome and bile acids on MASLD related to sex
differences.
Metabolic dysfunction-associated steatotic liver disease with hepatocellular
carcinoma
HCC is more prevalent in men than in women, regardless of its etiology [31]. A large study of patients with MASH
and cirrhosis revealed that the incidence of HCC in men was two to seven times
higher than in women [32,33]. Women have a higher survival rate
associated with HCC until the age of 55 years; after this age, the trend
reverses [34]. Chronic injury and
inflammation are well-known precursors to HCC. Additionally, the incidence of
HCC in patients with MASH increases alongside the incidence of liver fibrosis. A
cross-sectional study involving 87 patients with MASH indicated that men are
more likely to develop HCC at earlier stages of liver fibrosis compared to women
[35]. Therefore, this study suggests
that there are sex differences in the development of MASH-related HCC.
Suggestions for future research
Sex and sex hormones play crucial roles in biological differences in MASLD.
Despite evident sex differences in the mechanisms of MASLD, the development of
tailored treatments is hindered by a lack of sufficient evidence. Therefore, it
is vital to consider potential sex or hormonal influences in population-level
analyses. Additional research, encompassing preclinical studies, epidemiological
surveys, and clinical trials, is necessary to investigate how sex differences
and reproductive status influence disease risk in women with MASLD.
Conclusion
The prevalence of MASLD is rapidly increasing worldwide. Furthermore, MASLD can
progress to MASH and cirrhosis, with a rising incidence of MASLD-associated HCC.
MASLD has clinical significance due to its association with cardiovascular disease
and the development of malignant neoplasms. The complex and multifactorial
mechanisms underlying MASLD involve factors such as female hormones, adipose tissue
distribution, gut microbiota, and bile acids. However, the development of tailored
treatments is contingent upon the availability of sufficient evidence. Consequently,
studies that take into account variables such as sex, age, and hormonal status could
pave the way for evidence-based and personalized clinical treatments that alleviate
the burden of MASLD.
Authors' contributions
Project administration: Kim W
Conceptualization: Kim W
Methodology & data curation: Joo SK
Funding acquisition: not applicable
Writing – original draft: Joo SK
Writing – review & editing: Joo SK, Kim W
Conflict of interest
No potential conflict of interest relevant to this article was reported.
Supplement 1. List of studies finally included in this review for a comprehensive
evaluation in terms of the epidemiology and pathophysiology of metabolic
dysfunction-associated steatotic liver disease (MASLD).
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