Influence of Sex in the Development of Liver Diseases

• Epidemiological Studies
• Drug-Induced Liver Injury
• Alcohol-Associated Liver Disease
• Metabolic Dysfunction-Associated Fatty Liver Disease
• Autoimmune Liver Diseases
• Liver Fibrosis
• Hepatocellular Carcinoma
• Hepatic Ischemia/Reperfusion Injury
• Liver Repair and Regeneration
• Other Liver Diseases
• Sex Hormones/Sex Hormone Receptors
• Drug-Induced Liver Injury
• Alcohol-Associated Liver Disease
• Metabolic Dysfunction-Associated Fatty Liver Disease
• Autoimmune Liver Diseases
• Liver Fibrosis
• Hepatocellular Carcinoma
• Hepatic Ischemia/Reperfusion Injury
• Liver Repair and Regeneration
• X or Y Chromosome-Related Genes
• Drug-Induced Liver Injury
• Alcohol-Associated Liver Disease
• Metabolic Dysfunction-Associated Fatty Liver Disease
• Autoimmune Liver Diseases
• Liver Fibrosis
• Hepatocellular Carcinoma
• Hepatic Ischemia/Reperfusion Injury
• Liver Repair and Regeneration
• Other Potential Mechanisms
• Drug-Induced Liver Injury
• Autoimmune Liver Diseases
• Hepatocellular Carcinoma
• Hepatic Ischemia/Reperfusion Injury
• Liver Repair and Regeneration
• Clinical Research and Guidelines
• Conclusion
• References

Abstract

The liver is a sexually dimorphic organ. Sex differences in prevalence, progression, prognosis, and treatment prevail in most liver diseases, and the mechanism of how liver diseases act differently among male versus female patients has not been fully elucidated. Biological sex differences in normal physiology and disease arise principally from sex hormones and/or sex chromosomes. Sex hormones contribute to the development and progression of most liver diseases, with estrogen- and androgen-mediated signaling pathways mechanistically involved. In addition, genetic factors in sex chromosomes have recently been found to contribute to the sex disparity of many liver diseases, which might explain, to some extent, the difference in gene expression pattern, immune response, and xenobiotic metabolism between men and women. Although increasing evidence suggests that sex is one of the most important modulators of disease prevalence and outcomes, at present, basic and clinical studies have long been sex unbalanced, with female subjects underestimated. As such, this review focuses on sex disparities of liver diseases and summarizes the current understanding of sex-specific mechanisms, including sex hormones, sex chromosomes, etc. We anticipate that understanding sex-specific pathogenesis will aid in promoting personalized therapies for liver disease among male versus female patients.

Liver disease, accounting for 2 million deaths annually, remains a leading cause of disability and mortality and has developed into a global public health problem.[1] According to epidemiological data, chronic liver disease is the tenth leading cause of death for men, but not for women.[2] Sex is a strong determinant of prevalence and outcomes in many diseases. However, essential biological differences between male and female individuals are rarely considered during clinical studies.[3] The consequences of overlooking sex are often deleterious for both sexes and can cause delayed diagnosis and inappropriate treatment.[4] For these reasons, a better understanding of sex-specific pathogenesis may help to personalize therapies for both men and women through the development of novel therapeutic approaches.

The liver is a sexually dimorphic organ. It plays a central role in many physiological processes, such as metabolism, energy and lipid storage, and xenobiotic detoxification, and accounts for at least 72% of sexually differentiated genes.[5] [6] In addition, most liver diseases predominantly affect one sex over the other. For example, men are two-fold more likely to develop and die from viral- or non-viral-related liver fibrosis, and five to six times more often in developing hepatocellular carcinoma (HCC) than women.[7] [8] [9] [10] [11] In contrast, females are more susceptible to drug- and alcohol-induced liver disease, as well as autoimmune hepatitis (AIH) than males.[12] [13] [14] [15] As such, sex difference has been recommended to be included in practice guidelines of liver disease.[10] In fact, biological sex differences in normal physiology and disease arise principally from sex chromosomes and/or sex hormones.[10] Sex hormones, notably estrogens and androgens, were found to regulate a variety of pathophysiological processes in the liver, including lipid metabolism, inflammation, and fibrogenesis.[16] [17] [18] [19] However, sex hormone supplements have failed in the treatment of most liver diseases.[20] [21]

As such, increasing studies have focused on the genetic alterations of sex chromosomes, and reported that several X- or Y-chromosome-related genes may contribute to sex disparity in liver diseases. For example, we and others have initially demonstrated that Y-chromosome-encoded genes, including the sex-determining region Y gene (SRY), promoted hepatocarcinogenesis, which might account for the male predominance of HCC.[22] [23] [24] [25] [26] In addition, we have further found that SRY, as the male determinant, exacerbated hepatic I/R injury and liver fibrosis.[27] [28]

Extensive studies have been conducted on exploring mechanisms involved in the sex disparity of liver diseases. As such, this review aims to illustrate the current knowledge on sex-based differences in several liver diseases, including sex-associated epidemiological characteristics, as well as underlying mechanisms and clinical implications of sex disparity in liver diseases ([Table 1]).

Epidemiological Studies

Drug-Induced Liver Injury

Drug-induced liver injury (DILI) is an adverse reaction to a wide spectrum of medications, and it is the most common cause of acute liver failure and drug withdrawal from the market.[29] [30] [31] DILI is increasingly appreciated to be one of the most challenging diseases for clinicians. Some clinical trials demonstrated that women generally have a greater risk of adverse drug reactions,[32] [33] but other studies did not support this gender disparity in DILI cases.[34] [35] [36] Moreover, many potential confounding factors that can influence sex-dependent differences in drug toxicity, such as concomitant alcohol use, concurrent medications, and underlying fatty liver disease, need to be considered in human studies. While whether gender is a risk factor for susceptibility to DILI is still controversial, it is clear that female patients experience more severe clinical manifestations, have a higher frequency of jaundice, and are more likely to progress to acute liver failure than men.[34] [36] [37] [38] Acetaminophen (APAP) overdose is a leading cause of DILI; however, in contrast to clinical studies, a greater susceptibility of male mice to APAP hepatotoxicity has been well-documented.[39] [40] [41] The possible reason may be that female patients account for most cases of APAP overdose and have a higher prevalence of co-ingestions with sedating agents.[42] [43] [44] However, the reason for the disparity of phenotype in humans and mice needs to be further explored.

Alcohol-Associated Liver Disease

Alcohol-associated liver disease (ALD) is a spectrum of clinical disorders caused by excessive and chronic alcohol consumption that comprises alcohol-associated hepatitis (AH), alcohol-associated steatohepatitis, fibrosis/cirrhosis, and HCC.[45] Recently, there has been increasing evidence that the risk factors, incidence, severity, and clinical outcomes of ALD are influenced by sex. Alcohol consumption differs in males and females. In general, men drink more, drink more frequently, and are more likely to be diagnosed with an alcohol use disorder than women.[46] [47] [48] However, epidemiologic data suggest that by consuming equal doses of alcohol, women are more likely to develop ALD with faster progression and worse prognosis.[13] [49]

Metabolic Dysfunction-Associated Fatty Liver Disease

Metabolic dysfunction-associated fatty liver disease (MAFLD) is considered a complex metabolic disease characterized by an excessive fat accumulation in hepatocytes, and refers to a wide spectrum of liver damages ranging from metabolic dysfunction-associated fatty liver to metabolic dysfunction-associated steatohepatitis (MASH), advanced fibrosis, cirrhosis, and HCC.[50] Studies to date have supported that there are substantial sex differences in the prevalence, progression, and risk factors of MAFLD. Men are reported to have a higher prevalence of MAFLD than women.[51] [52] Moreover, it has been observed that postmenopausal women are at increased risk of MAFLD compared with premenopausal, and have a comparable prevalence of MAFLD as men.[53] [54] Intriguingly, it was shown that the prevalence of MAFLD in women steadily increased with age, whereas men had a similar prevalence in all age groups.[55]

Of note, risk factors associated with MAFLD are increasingly proven to be sex dimorphic. For example, obese men have lower insulin sensitivity versus obese women,[56] and the mechanism of which is strongly associated with sex-specific risk factors, that is, fasting insulin and leptin levels in men versus the body mass index and transaminase levels in women.[57]

Autoimmune Liver Diseases

Autoimmune liver diseases (AILDs) are rare chronic immune-mediated hepatobiliary disorders, including primary biliary cholangitis (PBC), AIH, and primary sclerosing cholangitis (PSC). Strikingly, PBC and AIH are characterized by a strong female preponderance, in-line with trends reported for autoimmune diseases that affect more women than men.[58] It has been reported that women are 10 times more likely to have PBC and 4 times more likely to have AIH, compared with men.[59] [60] However, it is not the case in PSC, which presented a male predominance, and men with PSC tended to have worse survival outcomes than women.[61] [62] [63]

Liver Fibrosis

Liver fibrosis is a sustained injury-healing process characterized by progressive deposition of extracellular matrix (ECM), resulting from chronic liver injury of any etiology, and resulting in fibrotic scarring and tissue dysfunction.[64] [65] Males have significantly stronger progression and worse outcomes than females. Of note, the death rate among males was estimated to be 1.5 times higher than that among females globally.[28]

Hepatocellular Carcinoma

Primary liver cancer ranks fifth in incidence and third in mortality among all cancers.[66] HCC, accounting for 85 to 90% of primary liver cancer, is the most common type of liver cancer.[67] [68] Of note, men had three to four times higher incidence of HCC than women.[67] [69] In addition, men had an age-standardized mortality rate of 2.8 versus women at the global level.[70]

Hepatic Ischemia/Reperfusion Injury

Hepatic ischemia/reperfusion (I/R) injury is a common occurrence in liver transplant, hepatic resection (HR), and hypovolemic shock, with its clinical manifestations ranging from asymptomatic elevation of liver enzymes to liver dysfunction, multiple organ failure, and even death.[71] I/R injury could enhance the risk of morbidity and mortality after liver transplantation or HR and lead to donor organ shortage as well as poor early graft function and primary non-function.[18] [71] Notably, it has been increasingly appreciated that sex-based differences exist in the response to I/R injury in many organs, including heart, brain, kidney, intestines, and the liver.[72] [73] [74] [75] [76] Males are more susceptible to hepatic I/R injury than females.[27]

Liver Repair and Regeneration

Liver repair and regeneration is a complex process following hepatic injuries, including acute liver injury, chronic liver injury, and hepatectomy.[77] Studies have demonstrated that females and males have different regenerative capacities. It has been found that, after acute poisoning with CCl₄, male mice showed a slower recovery capacity than females.[78] Regarding regression of liver fibrosis, female mice showed lower collagen content and α-smooth muscle actin protein levels than males, indicating a better regeneration ability.[79] Additionally, clinical studies have demonstrated that female patients recover better from HR compared with males.[27] [80] However, conflicting results on sex disparities in initiation and speed of hepatic regeneration were reported. Female patients and mice regenerated faster than males after liver partition and portal vein ligation,[80] whereas male zebrafish began liver regeneration earlier than females after partial hepatectomy (PH).[81] To confirm sex differences in liver regeneration, further clinical studies are required. Although studies conducted in zebrafish and rodents can provide valuable references for humans, the differences between species need to be considered.

Other Liver Diseases

Several benign liver tumors, including cavernous hemangioma, focal nodular hyperplasia, and hepatic adenoma, predominantly occur in women.[82] Hereditary hemochromatosis (HH) is a disease caused by the toxic effects of excess iron deposition in parenchymal organs due to partial or total loss of hepcidin activity,[83] and it has been found that male patients with HH tend to have higher levels of ferritin, experience more iron accumulation, and have a higher incidence of liver injury and progression to fibrosis compared with women.[84] [85] In addition, some vascular liver diseases show sex differences in prevalence. Budd–Chiari syndrome, a rare disorder featuring venous flow obstruction at the suprahepatic level, is more common in males than females (1.5:1).[86] Hereditary hemorrhagic telangiectasia (HHT), a rare genetic condition that affects the liver by the development of venous malformations, shows a strong and significant predominance of hepatic venous malformations in females who have HHT, with a male:female ratio varying from 1:2 to 1:4.5.[87]

Sex Hormones/Sex Hormone Receptors

Drug-Induced Liver Injury

Previous studies have reported that sex hormones play a role in the regulation of drug reactions, hepatic inflammation, as well as the immune response following drug exposure, contributing to sex disparity in DILI.[88] It has been found that estrogen could inhibit gastric emptying, which directly influences the bioavailability of drugs taken orally.[89] Moreover, sex-specific disparity in drug-metabolizing enzymes was demonstrated. There is evidence that females have higher activity of CYP3A4, CYP2B6, and CTP2A6, and lower activity of CYP1A2 and CYP2E1.[90] [91] Sex hormones can regulate the expression and activity of cytochrome P450 protein (CYP) enzymes.[92] For example, estrogen inhibits the expression of CYP1A2.[93] In addition, estrogen exerts a protective role in DILI by reducing inflammation and apoptosis, whereas androgen exacerbates DILI.[94] [95] Furthermore, the drug-induced immune response was found to be sex dimorphic, characterized by higher recruitment of proinflammatory immature monocytes to the male liver through the androgen receptor (AR) signaling pathway.[78]

Alcohol-Associated Liver Disease

There are multiple mechanisms accounting for sex differences in the development of ALDs ([Fig. 1]). Orally ingested alcohol is metabolized in the stomach with the enzyme gastric alcohol dehydrogenase (ADH), the activity and level of which is demonstrated to decrease in females compared with males, leading to higher blood alcohol levels in females.[96] Excessive alcohol consumption is known to disrupt the gastrointestinal barrier and increase gut-derived endotoxin, subsequently inducing Kupffer cell (KC) activation, which proved crucial for the development of ALD.[14] [97] Estrogen could exacerbate ethanol-associated liver injury by enhancing intestinal permeability and portal endotoxin levels, upregulating the expression of the endotoxin receptor CD14 and proinflammatory cytokine TNF-a, and enhancing KC sensitivity to endotoxin.[98] [99] [100] [101] Hepatic ADH activity is higher in female rats and mice than their male counterparts.[102] Increased rates of the resulting production of toxic acetaldehyde in females compared with males may be responsible for the known increased susceptibility to alcohol-induced liver injury by females. In fact, steady expression of group hormones, resembling that in females, could increase hepatic ADH activity, which may accordingly contribute to sex disparity in ALD that females are more likely to progress from AH to cirrhosis even if they abstain.[103] In addition, hepatic CYP2E1, an important resource of reactive oxygen species (ROS) during ethanol metabolism, could be activated by estrogen-related receptor γ (ERRγ) and aggravate oxidative liver injury, which may account for severe alcohol-induced injury in females.[104] Additionally, the antagonist of estrogen or CYP2E1 has been demonstrated to alleviate experimental alcoholic liver injury, suggesting their potential therapeutic role in ALD.[105] [106] [107]

Metabolic Dysfunction-Associated Fatty Liver Disease

Numerous studies have demonstrated the protective role of estrogen in the development of hepatic steatosis ([Fig. 2]).[20] [51] [53] [108] In mice without estrogen receptor α (ERα), higher levels of obesity, especially visceral fat accumulation were observed, suggesting the crucial role of ERα in preventing pathologic lipid synthesis and deposition.[109] Moreover, ERα exerts a prominent role in ROS detoxification and mitigating oxidative damage in the liver through hepatic peroxisome proliferator-activated receptor-γ coactivator 1α.[17] [110] In addition, M1 macrophage activation is inhibited by ERα.[111] It has recently been demonstrated that estrogen-related receptor α (ERRα) mediates the secretion of hepatic triglyceride-rich very low-density lipoprotein and halts fat accumulation in the liver.[112] Moreover, the G-protein-coupled estrogen receptor (GPER) has proven to increase high-density lipoprotein levels in females, reducing female hepatic lipid accumulation.[113] [114] [115] In addition, estrogen may ameliorate hepatic steatosis in female mice through upregulating miRNA-125b and miRNA-29.[116] [117] Formyl peptide receptor 2, regulated by estrogen, can also play a key role in protecting female mice from MAFLD/MASH development.[118]

Testosterone appears to have opposite effects on hepatic steatosis in males and females ([Fig. 2]). High levels of testosterone in females were reported to increase the risk of MAFLD,[119] while high serum testosterone level was associated with decreased risk of MAFLD in men.[120] [121] Furthermore, it has been demonstrated that androgen signaling could suppress lipid deposits and play a protective role in hepatic steatosis.[122] [123]

Moreover, a phase 2 clinical trial (NCT04134091) has reported that LPCN 1144, an oral testosterone prodrug, can improve MASH activity in adult men, indicating the therapeutic potential of LPCN 1144.

Autoimmune Liver Diseases

Although sex disparity is increasingly indicated in AILDs, the exact mechanisms underlying this difference in general are unknown. Recent studies have discovered that several sex-related factors, such as environmental factors, sex hormones, and X and Y chromosomes, may influence sex differences in AILDs.[124] Moreover, in patients with PBC, female individuals are observed to have increased levels of CD4+ T cells and antibody production with respect to males, implying the role of sex hormones in autoimmune response.[125]

Liver Fibrosis

Previous studies have suggested the protective role of estrogen in liver fibrosis ([Fig. 3]). It was widely reported that high estrogen could counteract hepatic fibrogenesis by reducing ECM deposition and inhibiting the transformation of quiescent hepatic stellate cells (HSCs) to myofibroblast-like HSCs.[126] [127] [128] [129] [130] [131] [132] Given that HSCs typically express only estrogen receptor β (ERβ), it has been suggested that the antifibrotic effect of estrogen may be mediated by ERβ through inhibiting HSCs activation and proliferation.[133] [134] Furthermore, studies have demonstrated that ERβ alleviates liver fibrosis by negatively regulating the ROS/NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome and blocking the transforming growth factor β (TGF-β)/Smad signaling pathway.[135] [136] [137] [138] ERβ selective agonists may be a potential therapeutic target for liver fibrosis. In addition, ERα could inhibit liver inflammation and protect against hepatic fibrogenesis.[139]

In contrast, few studies have investigated the role of androgen in hepatic fibrosis. Ma et al reported that androgen exacerbates hepatic fibrosis by modulating the activation of NLRP3 inflammatory vesicles ([Fig. 3]).[140]

Hepatocellular Carcinoma

Increased androgen levels, overexpression of ARs, and more active androgen response elements have been identified in HCC ([Fig. 4]).[16] [141] [142] Mechanically, androgen enhances the replication and transcription of hepatitis B virus (HBV) genes and HBV-induced hepatocarcinogenesis by binding to the ARE in the enhancer I (Enh I) of the HBV genome.[141] In addition, hepatitis B virus X protein (HBx) can induce AR transactivation through c-Src and glycogen synthase kinase-3 kinase, which could improve the N-terminal domain of AR activity.[143] [144] [145] [146] Meanwhile, AR promotes HCC development by upregulation of miR-216a and downregulation of the tumor suppressor in lung cancer-1 (TSLC1) gene.[147] It was found that AR, cell cycle-related kinase (CCRK), and β-catenin form a vicious cycle in HCC. Androgen enhances the CCRK transcription, subsequently activating the Wnt/β-catenin signaling pathway, and enhancing the expression and function of AR in HCC.[148] As such, some have proposed that HCC was an androgen-response tumor like prostate cancer. However, targeting androgen or receptor signaling has little impact on the survival outcome of patients with HCC.[149] [150] [151]

Numerous studies have demonstrated the protective role of estrogen in hepatocarcinogenesis ([Fig. 4]). It was found that estrogen may act as an inhibitor of HCC cell metastasis via downregulating IL-6 production from KCs in the diethylnitrosamine-treated male mice.[152] Moreover, ERα inhibits the hepatocarcinogenic effects of IL-6 by inhibiting nuclear factor kappa-B activation regulated by the Toll-like receptor articulating protein myeloid differentiation primary response protein 88.[146] Similarly, ERα can transcriptionally upregulate the O-type protein tyrosine phosphatase receptor (PTPRO), then inactivating signal transducer and activator of transcription 3 by downregulating phospho-Janus kinase 2 levels to promote HCC apoptosis.[153] The estrogen-ERα pathway can also promote p53 activation in SNU-387 cells, subsequently activating caspase3 and HCC apoptosis.[154] Furthermore, it has also been proved that p53 may facilitate miR-18a processing to decrease the expression level of ERα in female patients with HCC.[155] Interestingly, studies revealed that ERβ activated by E2 could inhibit the malignant behavior of HCC in three HCC cell lines, BEL7402, SMMC7721, and HepG2, through mitogen-activated protein kinase/extracellular regulated protein kinases pathway-mediated upregulation of the NLRP3 inflammasome.[156] Herein, some researchers advocate that HCC is an estrogen-responsive tumor like breast cancer. However, several randomized controlled trials showed no survival advantage of anti-estrogen treatments of HCC.[157] [158] [159] [160] As such, there is no robust evidence to consider HCC as a hormone-responsive tumor.

Hepatic Ischemia/Reperfusion Injury

Estrogen could significantly reduce injury after I/R to the liver ([Fig. 5]).[161] [162] Mechanistically, it was reported that ERα could enhance the activity of hepatic endothelial nitric oxide synthase (eNOS) and alleviate I/R-induced liver injury.[163] In addition, estrogens and ERs are involved in the regulation of mitochondrial permeability transitions (MPTs), which are associated with Ca²⁺ dysregulation and subsequent cell death in I/R injury, suggesting sex differences in MPTs may contribute to disparities in I/R injury between men and women.[164] In contrast, male-related hormones, such as testosterone, aggravate I/R injury through its proinflammatory and proapoptotic effects ([Fig. 5]).[165] [166]

Liver Repair and Regeneration

The correlation between estrogen and liver regeneration has been reported for decades.[167] [168] [169] [170] It has been found that ER is activated following PH and can accelerate hepatocyte proliferation.[167] [168] A recent study demonstrated that ERs orchestrate hepatic regeneration. ERα promotes hepatocyte proliferation by upregulating Ssxb6, Crygc, and Cst1, while ERβ mediates differentiation and metabolic function of hepatocytes through upregulating Ifna5.[171] Moreover, GPER1 is also responsible for cellular proliferation and cell cycle progression.[172] On the contrary, another study showed that activated ERs were associated with the later onset of hepatocyte proliferation in female zebrafish.[81]

Unlike estrogen, the specific functions of androgen in hepatic regeneration are poorly investigated. A study of rats showed that the regenerating liver takes up testosterone following PH, indicating the involvement of AR in liver regeneration.[173] Furthermore, it has been reported that AR regulates sex-biased liver regeneration through interacting with Hippo-Yap1 signaling, accounting for earlier initiation of hepatocyte proliferation and recovery in male zebrafish.[81]

X or Y Chromosome-Related Genes

Drug-Induced Liver Injury

Few types of research focus on sex chromosomes and drug toxicity. A study by Du et al showed that XX or XY contributes to sex-specific response to toxicity in neurons and splenocytes.[174] However, whether the sex chromosomes exert a similar role in hepatocytes or cholangiocytes requires further investigation.

Alcohol-Associated Liver Disease

There is little evidence investigating sex chromosomes and ALD. A study by Barker et al proposed that sex chromosome complement influences alcohol habit formation, independent of gonadal phenotype and hormone circulation, suggesting its potential role in the pathogenesis of ALD.[175]

Metabolic Dysfunction-Associated Fatty Liver Disease

Apart from hormonal factors, present studies have suggested the sex chromosome may account for sex differences seen in MAFLD ([Fig. 2]). Chen et al found that XX mice showed greater adiposity than XY mice, even after gonadectomy was carried out.[176] Furthermore, it was suggested that the increased adiposity was attributable to the presence of an extra X chromosome, rather than the absence of a Y chromosome.[176] Notch signaling is implicated to have metabolic effects, such as increasing intrahepatic triglyceride synthesis, thus being considered to be involved in MAFLD pathogenesis and progression.[177] A study by Zhu et al demonstrated that Notch activation could enhance SRY-Box transcription factor 9 (SOX9)-dependent osteopontin (OPN) expression and secretion from hepatocytes, which activates resident HSCs, thus inducing MASH-associated fibrosis.[178]

Autoimmune Liver Diseases

The involvement of sex chromosomes in the development of PBC has been suggested by findings of decreased DNA methylation of X chromosome-related genes, sex chromosome instability, and escape from X chromosome inactivation in patients with PBC.[124] [125]

Liver Fibrosis

Recently, we have identified that among all Y chromosome-encoded genes, SRY was the most upregulated gene in toxin- or cholestasis-induced liver fibrosis of mouse model, and SRY in hepatocytes can transcriptionally regulate platelet-derived growth factor receptor alpha (PDGFRα) expression, and promote high mobility group box 1 (HMGB1) release and subsequent HSCs activation ([Fig. 3]).[28] As a target gene of SRY, SOX9 is ectopically expressed during activation of HSCs and is responsible for the production of type 1 collagen, a major component of the fibrotic ECM, which leads to scarring in liver fibrosis.[179] It was shown that SOX9 could modulate OPN expression and promote liver fibrosis through Hedgehog (Hh) signaling.[180] In addition, it was suggested that SOX9 could be used to detect the severity of hepatic fibrosis in patients.[181] Moreover, several long non-coding RNAs (lncRNAs) and miRNAs, such as miR-15a, lncRNA H19, have been found to regulate SOX9-induced liver fibrosis.[182] [183]

Hepatocellular Carcinoma

Genes in the X chromosome may similarly have a role in this sex difference ([Fig. 4]). It was found that the dosage-sensitive sex-reversal adrenal insufficiency X chromosome congenital critical region, gene 1 (DAX1), was downregulated in HCC tissues and cell lines, and could interact with β-catenin and downregulates Wnt/β-catenin pathway.[184] Additionally, glypican-3 (GPC3) rs2267531, located in the Xq26 region, has been reported to be associated with the risk of HCC, the mutation of which may contribute to X-linked recessive inheritance, contributing to a male predominance in HCC.[185]

For Y chromosome-specific genes, we and others have demonstrated that the male-specific gene SRY is an oncogene, and promotes male-specific hepatocarcinogenesis ([Fig. 4]).[23] [24] [52] SRY-related genes, such as SOX9, SOX4, are also associated with HCC progression.[186] [187] [188] Liu et al proposed that activation of SOX9 and PDGFRa/phosphatidylin-ositol-3-kinase/protein kinase B pathways are commonly involved in male hepatocarcinogenesis.[22] Moreover, Tsai et al found that SOX4 could regulate chemokine C-X-C motif ligand 12 in HCC and promote distant metastasis of tumors.[189] In addition, some other Y chromosome-encoded genes, such as the RNA-binding motif gene on the Y chromosome (RBMY) and testis-specific protein Y-encoded (TSPY), have been considered new candidate oncogenes specific for male liver cancer.[26] [190] [191] [192]

Hepatic Ischemia/Reperfusion Injury

Recent study from our group has demonstrated that SRY was significantly upregulated in male mice throughout the entire process of hepatic I/R injury ([Fig. 5]).[27] SRY exacerbates hepatic I/R injury by promoting β-linker phosphorylation and subsequent degradation, which leads to inhibition of Wnt/β-catenin signaling, suppression of FOXOs, and activation of NF-kB and TLR4 signaling, resulting in increased oxidative stress, inflammation, and cell death.[27] In addition, SOX9, a direct target gene of SRY, has also been found to promote hepatic I/R injury via enhancing inflammation and apoptosis by activating TGF-β1.[193] Thus, suppressing SOX9-TGF-β1 may be an effective therapeutic strategy to prevent hepatic ischemia/reperfusion injury.

Liver Repair and Regeneration

Few studies concentrate on the role of sex chromosome-related genes in liver repair and regeneration. However, recent studies have reported that SOX9 is involved in liver regeneration. After chronic liver damage, SOX9+ hepatocytes expand from the original periportal area to all liver zones and contribute to hepatocyte regeneration.[194] During chronic biliary injury, SOX9 in periportal hepatocytes can be upregulated and promote hepatocyte-to-biliary epithelial cell differentiation.[195] Similarly, after PH, the conversion of mature hepatocytes into SOX9+ hepatocytes increased via an lipopolysaccharide/B-cell lymphoma 3/yes-associated protein1 signaling pathway, suggesting an important role of SOX9+ hepatocytes in liver regeneration.[196]

Other Potential Mechanisms

Drug-Induced Liver Injury

The sexually dimorphic gut bacteria may also account for sex differences in drug exposure by modulating the pharmacokinetic properties of drugs.[92] Similarly, Gong et al found that the gut microbiota metabolite deguelin is responsible for the resistance to APAP-induced hepatotoxicity in female mice.[197]

Autoimmune Liver Diseases

In the case of PBC, it has been demonstrated that there are no specific male-related risk factors for the development of PBC, while many risk factors, including hair dye use, recurrent urinary tract infections, smoking, and estrogen deficiency have been identified in females and at least in part responsible for increased disease in females.[125] [198] [199] [200]

In addition, a study by Karlsen et al suggested that AILDs carry a significant association with HLA haplotypes, while only in AIH, a relationship between HLA expression and sex is described.[201] Furthermore, in AIH patients, males showed an enhanced expression of HLA-DR3, whereas an increased prevalence of HLA-DR4 was observed in females.[124]

Hepatocellular Carcinoma

Several studies identified that CYP39A1, a liver-specific autosomal gene with a female-preferential expression, could inhibit hepatocarcinogenesis by blocking the transcriptional activation activity of c-Myc through its c-terminal region.[151] Additionally, adiponectin, which was shown to block IL-6 production in macrophages, thus providing potential crosstalk between adiponectin and sex steroid studies in HCC, could protect against cancer development by activating AMP-activated protein kinase and p38α.[202] [203] Notably, research on zebrafish demonstrated that higher serotonin synthesis and accumulation in male models could result in enhanced activation of HSCs and TGF-β1 expression, which accelerated the progression of HCC in males.[204]

Hepatic Ischemia/Reperfusion Injury

There are sex differences in the production of cytokines/chemokines (e.g., IL-6, macrophage inflammatory protein-2, and KC), all of which are observed to be more significantly elevated in I/R-treated males versus females.[73] Potassium voltage-gated channel subfamily E member 4 (KCNE4) is also an important sex-specific modulator of hepatic I/R injury, and its deletion may produce sex-dependent inhibition of the “reperfusion injury salvage kinase (RISK)” pathway in mice and exacerbate hepatic I/R injury.[205] In addition, autophagy, one of the mechanisms of hepatic I/R injury, could be modulated through the X chromosome, androgen and estrogen receptors, which may also contribute to the sex differences in hepatic I/R injury.[206] As such, the sex differences in the development and prognosis of hepatic I/R injury should be considered in the perioperative management of patients who underwent liver resection or transplantation.

Liver Repair and Regeneration

It is well-known that the recruitment of monocyte-derived macrophages (MoMFs) correlates with liver regeneration.[207] During fibrosis regression, a larger number of Ly6C^low MoMFs were observed in female mice, facilitating restoration of liver fibrosis through promoting ECM degradation and apoptosis of activated HSCs.[79]

Clinical Research and Guidelines

As major causes of illness and death worldwide, liver diseases have an important influence on human health. The fact that sex disparities exist in liver diseases cannot be disregarded. At the moment, the advocacy for sex-inclusive research and reporting has been proposed.[208] [209] [210] There are several sex-specific clinical studies in the management of liver diseases ([Table 2]).

Abstinence from alcohol is the cornerstone of therapy for ALD. An open-label trial showed that the necessary maximal daily dose of baclofen in females was significantly lower than that in men to achieve craving control, indicating better treatment response in women.[211] Practice guidance of ALD from American Association for the Study of Liver Diseases has suggested that particular attention should be paid to sex in patients with alcoholic hepatitis.[212] Currently, there are no clinically approved drugs for MAFLD, and the mainstay of treatment is lifestyle modifications, including diet, exercise, and weight loss.[213] D'Abbondanza et al have reported that in patients with severe obesity receiving a very low-carbohydrate ketogenic diet (VLCKD), males experienced a significantly larger excess body weight loss and a better MAFLD improvement compared with females. Apart from lifestyle intervention, clinical trials on effective pharmacological treatments have also been conducted. Quercetin was found to reduce intrahepatic lipid contents effectively and perform more outstanding effects in women.[214] It was also reported that females with MAFLD profited more than males from pioglitazone based on lifestyle intervention treatment.[215] At the moment, ursodeoxycholic acid (UDCA) is one of the licensed therapies of PBC, and it was found that males were significantly less likely to respond to UDCA than females.[216] [217] The British Society of Gastroenterology PBC treatment and management guidelines have recommended that male sex should be included in risk assessment at baseline and on treatment.[218] Regarding AIH, prednisolone alone or in combination with azathioprine is an effective treatment.[219] However, in terms of sex-related responses to the therapy, studies to date have reported controversial results. For example, Czaja and Donaldson did not identify sex-related responses to steroids,[220] while Al-Chalabi et al found a higher relapse rate among reduction or withdrawal of treatment in male versus female patients.[221] Moreover, given the significant sex disparity in the development and prognosis of liver fibrosis, guidelines of hepatic fibrosis have proposed that patient sex needs to be considered when interpreting vibration-controlled transient elastography measurements and selecting patients in clinical trials of anti-liver fibrosis drugs.[222] [223] Additionally, gender dimorphism in the efficacy and toxicity of oncology treatments has been reported. A recent data analysis article showed that females have better outcomes and treatment responses, while males underwent fewer side effects, in the majority of oncology clinical trials.[224]

Although the sex differences have been widely reported, few sex-specific clinical studies have been conducted. Current evidence in liver diseases may be insufficient to propose sex-specific recommendations. As such, guidelines highlight the importance of sex and call on the research community to provide the evidence required.

Conclusion

Despite increasing evidence indicating that many diseases manifest differently in men and women, female individuals have long been underestimated in basic and clinical research. Exploring sex disparities in diseases is essential for getting the science right for the benefit of all. However, at present, sex-specific studies in liver diseases are still limited. Some controversial results are reported on sex-associated epidemiological characteristics in liver diseases. The underlying mechanisms of sex differences are not elucidated. Clinical trials rarely focus on disparities between males and females. Therefore, large-scale clinical and basic studies on sex differences are required to further explore sex differences and reveal underlying mechanisms. Clinical trials should incorporate women to observe the effects on the efficacy and safety of treatment. All these approaches can contribute to developing personalized therapies for liver diseases in both sexes.

Conflict of Interest

None declared.

Acknowledgments

All the figures in the manuscript were drawn in Figdraw.

Authors' Contributions

X-F.Z. and Y.L. conceived and mentored this study. J-W.Z. and N.Z. acquired and analyzed data, and wrote the draft of the manuscript. X-F.Z. and Y.L. wrote and revised the manuscript.

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Accepted Manuscript online:
14 January 2025

Article published online:
11 February 2025

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