Role of sex in liver tumor occurrence and clinical outcomes: A comprehensive review.

Clinical research on sex-based differences in the manifestations, pathophysiology, and prevalence of several diseases, including those affecting the liver, has expanded considerably in recent years. Increasing evidence suggests that liver diseases develop, progress, and respond to treatment differently depending on the sex. These observations support the concept that the liver is a sexually dimorphic organ in which estrogen and androgen receptors are present, which results in disparities between men and women in liver gene expression patterns, immune responses, and the progression of liver damage, including the propensity to develop liver malignancies. Sex hormones play protective or deleterious roles depending on the patient's sex, the severity of the underlying disease, and the nature of precipitating factors. Moreover, obesity, alcohol consumption, and active smoking, as well as social determinants of liver diseases leading to sex-related inequalities, may interact strongly with hormone-related mechanisms of liver damage. Drug-induced liver injury, viral hepatitis, and metabolic liver diseases are influenced by the status of sex hormones. Available data on the roles of sex hormones and gender differences in liver tumor occurrence and clinical outcomes are conflicting. Here, we critically review the main gender-based differences in the molecular mechanisms associated with liver carcinogenesis and the prevalence, prognosis, and treatment of primary and metastatic liver tumors.

Role of nonneoplastic PVT in the natural history of patients with cirrhosis and first diagnosis of HCC.

BACKGROUND AND AIMS: HCC can increase the risk of nonneoplastic PVT in cirrhosis. However, the natural history of PVT and its prognostic role in HCC patients are unknown. APPROACH AND RESULTS: Consecutive HCC patients with cirrhosis undergoing laparoscopic ablation were retrospectively evaluated and followed up to 36 months. HCC and PVT characteristics and evolution were reviewed. PVT was categorized according to lumen occupancy (≤50%, >50% <100%, and = 100%) and extension to other veins. The evolution of thrombosis was considered at 1 year from diagnosis. Variables associated with the presence of PVT and evolution patterns were analyzed, as well as their impact on survival. In all, 750 patients were included, 88 of whom had PVT. On multivariate analysis, the occurrence of PVT at HCC diagnosis was associated with pretreatment total tumor volume ( p < 0.001) and clinically significant portal hypertension ( p = 0.005). During the follow-up, 46 de novo PVT occurred, 27/46 (58.7%) in the presence of a viable tumor. Among 115 PVT diagnosed in the presence of HCC, 83 had available radiological follow-up, and 22 were anticoagulated. The "complete/progressive" evolution pattern was associated with nonresponse to HCC treatment in non-anticoagulated patients. The presence of PVT was independently associated with lower overall survival, particularly when progressive or occlusive ( p < 0.001). A higher competing risk of death emerged for "complete and progressive" PVT, both for HCC-related ( p < 0.001) and non-HCC-related ( p = 0.002) death. CONCLUSIONS: HCC represents an independent risk factor for the occurrence and progression of PVT in cirrhosis. Since progressive and occlusive PVT seems to be an independent factor associated with mortality, screening and prompt treatment of this complication should be considered.

Profiling plasma alterations of extracellular vesicles in patients with acutely decompensated cirrhosis and bacterial infection.

BACKGROUND: Extracellular vesicles (EVs) modulate inflammation, coagulation and vascular homeostasis in decompensated cirrhosis. AIM: To characterize the profile of plasmatic EVs in patients with decompensated cirrhosis and bacterial infections and evaluate the association between EVs and the development of hemostatic complications. METHODS: We measured the levels of EVs using high-sensitivity flow cytometry and phospholipid-dependent clotting time (PPL) in a prospective cohort of hospitalized patients with acutely decompensated cirrhosis with versus without bacterial infections. A separate cohort of patients with bacterial infections without cirrhosis was also enrolled. We measured endothelium-, tissue factor (TF)-bearing, platelet- and leukocyte-derived EVs. In patients with infections, EVs were reassessed upon resolution of infection. Bleeding and thrombotic complications were recorded during 1-year follow-up. RESULTS: Eighty patients with decompensated cirrhosis were recruited (40 each with and without bacterial infections). Electron microscopy confirmed the presence of plasma EVs. Despite no difference in total EVs and PPL, patients with cirrhosis and infection had significantly higher TF+ EVs, P-Selectin+ EVs (activated platelet-derived), CD14+ EVs (monocyte/macrophages derived) and CD14+ TF+ EVs versus those with cirrhosis without infection. Upon infection resolution, levels of these EVs returned to those without infection. Patients with infections showed a significant association between reduced P-Selectin+ EVs and bleeding complications (HR 8.0 [95%CI 1.3-48.1]), whereas high levels of leukocyte-derived EVs (CD45+) and CD14+ EVs were significantly associated with thrombotic complications (HR 16.4 [95%CI 1.7-160] and 10.9 [95%CI 1.13-106], respectively). Results were confirmed in a validation cohort. CONCLUSION: Bacterial infections are associated with particular alterations of plasma EVs profile in decompensated cirrhosis. Bacterial infections trigger the release of EVs originating from various cell types, which may tip the precarious hemostatic balance of patients with acutely decompensated cirrhosis towards hyper- or hypocoagulability.

The genetics of portal hypertension: Recent developments and the road ahead.

Portal hypertension (PH), defined as a pathological increase in the portal vein pressure, has different aetiologies and causes. Intrahepatic PH is mostly secondary to the presence of underlying liver disease leading to cirrhosis, characterized by parenchymal changes with deregulated accumulation of extracellular matrix and vascular abnormalities; liver sinusoidal endothelial cells and hepatic stellate cells are key players in PH progression, able to influence each other. However, PH may also develop independently of parenchymal damage, as occur in portosinusoidal vascular disorder (PSVD), a group of clinical and histological entities characterized by portal vasculature dysfunctions. In this particular group of disorders, the pathophysiology of PH is still poorly understood. In the last years, several genetic studies, based on genome-wide association studies or whole-exome sequencing analysis, have highlighted the importance of genetic heritability in PH pathogenesis, both in cirrhotic and non-cirrhotic cases. The common PNPLA3 p.I148M variant, one of the main determinants of the susceptibility to steatotic liver disease, has also been associated with decompensation in patients with PH. Genetic variations at loci influencing coagulation, mainly the ABO locus, may directly contribute to the pathogenesis of PH. Rare genetic variants have been associated with familiar cases of progressive PSVD. In this review, we summarize the recent knowledges on genetic variants predisposing to PH development, contributing to better understand the role of genetic factors in PH pathogenesis.

Hepatocellular carcinoma recurrence after direct-acting antiviral therapy: an individual patient data meta-analysis.

OBJECTIVE: The benefit of direct-acting antivirals (DAAs) against HCV following successful treatment of hepatocellular carcinoma (HCC) remains controversial. This meta-analysis of individual patient data assessed HCC recurrence risk following DAA administration. DESIGN: We pooled the data of 977 consecutive patients from 21 studies of HCV-related cirrhosis and HCC, who achieved complete radiological response after surgical/locoregional treatments and received DAAs (DAA group). Recurrence or death risk was expressed as HCC recurrence or death per 100 person-years (100PY). Propensity score-matched patients from the ITA.LI.CA. cohort (n=328) served as DAA-unexposed controls (no-DAA group). Risk factors for HCC recurrence were identified using random-effects Poisson. RESULTS: Recurrence rate and death risk per 100PY in DAA-treated patients were 20 (95% CI 13.9 to 29.8, I2=74.6%) and 5.7 (2.5 to 15.3, I2=54.3), respectively. Predictive factors for recurrence were alpha-fetoprotein logarithm (relative risk (RR)=1.11, 95% CI 1.03 to 1.19; p=0.01, per 1 log of ng/mL), HCC recurrence history pre-DAA initiation (RR=1.11, 95% CI 1.07 to 1.16; p<0.001), performance status (2 vs 0, RR=4.35, 95% CI 1.54 to 11.11; 2 vs 1, RR=3.7, 95% CI 1.3 to 11.11; p=0.01) and tumour burden pre-HCC treatment (multifocal vs solitary nodule, RR=1.75, 95% CI 1.25 to 2.43; p<0.001). No significant difference was observed in RR between the DAA-exposed and DAA-unexposed groups in propensity score-matched patients (RR=0.64, 95% CI 0.37 to 1.1; p=0.1). CONCLUSION: Effects of DAA exposure on HCC recurrence risk remain inconclusive. Active clinical and radiological follow-up of patients with HCC after HCV eradication with DAA is justified.

Clinical impact of sexual dimorphism in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

NAFLD/NASH is a sex-dimorphic disease, with a general higher prevalence in men. Women are at reduced risk of NAFLD compared to men in fertile age, whereas after menopause women have a comparable prevalence of NAFLD as men. Indeed, sexual category, sex hormones and gender habits interact with numerous NAFLD factors including cytokines, stress and environmental factors and alter the risk profiles and phenotypes of NAFLD. In the present review, we summarized the last findings about the influence of sex on epidemiology, pathogenesis, progression in cirrhosis, indication for liver transplantation and alternative therapies, including lifestyle modification and pharmacological strategies. We are confident that an appropriate consideration of sex, age, hormonal status and sociocultural gender differences will lead to a better understanding of sex differences in NAFLD risk, therapeutic targets and treatment responses and will aid in achieving sex-specific personalized therapies.

Hepatocellular carcinoma and the risk of de novo malignancies after liver transplantation - a multicenter cohort study.

Patients with hepatocellular carcinoma (HCC) are at high risk of second primary malignancies. As HCC has become the leading indication of liver transplant (LT), the aim of this study was to investigate whether the presence of HCC before LT could influence the onset of de novo malignancies (DNM). A cohort study was conducted on 2653 LT recipients. Hazard ratios (HR) of DNM development for patients transplanted for HCC (HCC patients) were compared with those of patients without any previous malignancy (non-HCC patients). All models were adjusted for sex, age, calendar year at transplant, and liver disease etiology. Throughout 17 903 person-years, 6.6% of HCC patients and 7.4% of non-HCC patients developed DNM (202 cases). The median time from LT to first DNM diagnosis was shorter for solid tumors in HCC patients (2.7 vs 4.5 years for HCC and non-HCC patients, respectively, P < 0.01). HCC patients were at a higher risk of bladder cancer and skin melanoma. There were no differences in cumulative DNM-specific mortality by HCC status. This study suggests that primary HCC could be a risk factor for DNM in LT recipients, allowing for risk stratification and screening individualization.

Changes in plasma circulating microvesicles in patients with HCV-related cirrhosis after treatment with direct-acting antivirals.

BACKGROUND & AIMS: The eradication of Hepatitis C (HCV) infection by direct-acting antiviral (DAAs) agents has been linked to an amelioration of liver synthesis and regression of fibrosis. Although changes in number and type of circulating microvesicles (MVs) have been reported in cirrhosis, conclusive data on the effect of DAAs treatment on MVs profile in HCV cirrhotic patients remain scarce. METHODS: We measured the levels of endothelial, platelet and hepatocyte MVs, as well as MVs-expressing versican core protein (VCAN+) in patients with HCV-related cirrhosis at baseline, end of treatment (EOT), at 12, 24 and 48 weeks (W) after EOT by new generation flow cytometry. RESULTS: Fifty-eight patients were enrolled (86% Child's A). MVs were increased at EOT vs baseline, though only platelet MVs revealed a statistically significant difference (P < .01). MV levels did not change significantly after EOT notwithstanding a steady downward trend towards baseline levels. Conversely, VCAN + MVs dropped significantly at EOT (P < .001) and remained low throughout the follow-up. Hepatocyte MVs significantly correlated with liver stiffness (r = .40, P = .0021). Eight composite outcomes occurred during the 1-year follow-up: three portal vein thromboses (PVTs), two hepatocellular carcinomas (HCCs) and three liver decompensation. Child's B, the presence of F2 oesophageal varices (OR for interaction 19.2 [95% CI 1.45-253.7], P = .023) and platelet MVs (OR 1.026 [95% CI 1.00-1.05, P = .023) correlated significantly with clinical outcomes. CONCLUSIONS: VCAN + MVs appear to mirror the profibrotic status of the cirrhotic disease; hepatocyte MVs correlate with liver stiffness and increased platelet MV levels could be associated with a worse clinical outcome.

Survival after the diagnosis of de novo malignancy in liver transplant recipients.

In the setting of liver transplant (LT), the survival after the diagnosis of de novo malignancies (DNMs) has been poorly investigated. In this study, we assessed the impact of DNMs on survival of LT recipients as compared to corresponding LT recipients without DNM. A nested case-control study was conducted in a cohort of 2,818 LT recipients enrolled in nine Italian centres between 1985 and 2014. Cases were 244 LT recipients who developed DNMs after LT. For each case, two controls matched for gender, age, and year at transplant were selected by incidence density sampling among cohort members without DNM. The survival probabilities were estimated using the Kaplan-Meier method. Hazard ratios (HRs) of death and 95% confidence intervals (CIs) were estimated using Cox proportional hazard models. The all-cancer 10-year survival was 43% in cases versus 70% in controls (HR = 4.66; 95% CI: 3.17-6.85). Survival was impaired in cases for all the most frequent cancer types, including lung (HR = 37.13; 95% CI: 4.98-276.74), non-Hodgkin lymphoma (HR = 6.57; 95% CI: 2.15-20.01), head and neck (HR = 4.65; 95% CI: 1.81-11.95), and colon-rectum (HR = 3.61; 95% CI: 1.08-12.07). The survival gap was observed for both early and late mortality, although the effect was more pronounced in the first year after cancer diagnosis. No significant differences in survival emerged for Kaposi's sarcoma and nonmelanoma skin cancers. The survival gap herein quantified included a broad range of malignancies following LT and prompts close monitoring during the post-transplant follow-up to ensure early cancer diagnosis and to improve survival.

Risk of virus and non-virus related malignancies following immunosuppression in a cohort of liver transplant recipients. Italy, 1985-2014.

This cohort study assessed, in Italy, the overall pattern of risk of de novo malignancies following liver transplantation (LT). The study group included 2,832 individuals who underwent LT between 1985 and 2014 in nine centers all over Italy. Person-years (PYs) at cancer risk were computed from 30 days after LT to the date of cancer diagnosis, to the date of death or to the end of follow-up. Excess cancer risk, as compared to the general population, was estimated using standardized incidence ratios (SIRs) and 95% confidence intervals (CIs). During 18,642 PYs, 246 LT recipients developed 266 de novo malignancies, corresponding to a 1.8-fold higher cancer risk (95% CI: 1.6-2.0). SIRs were particularly elevated for virus-related malignancies, including Kaposi's sarcoma (SIR = 53.6, 95% CI: 30.0-88.5), non-Hodgkin lymphomas (SIR = 7.1, 95% CI: 4.8-10.1) and cervix uteri (SIR = 5.4, 95% CI: 1.1-15.8). Among virus-unrelated malignancies, elevated risks emerged for head and neck (SIR = 4.4, 95% CI: 3.1-6.2), esophagus (SIR = 6.7, 95% CI: 2.9-13.3) and adrenal gland (SIR = 22.9, 95% CI: 2.8-82.7). Borderline statistically significant elevated risks were found for lung cancer (SIR = 1.4, 95% CI: 1.0-2.1) and skin melanoma (SIR = 2.6, 95% CI: 1.0-5.3). A reduced risk emerged for prostate cancer (SIR = 0.1, 95% CI: 0.0-0.5). These findings underline the need of preventive interventions and early detection of malignancies, specifically tailored to LT recipients.

Reversal of hypercoagulability in patients with HCV-related cirrhosis after treatment with direct-acting antivirals.

BACKGROUND & AIMS: The long-term impact of sustained virological response (SVR) after direct-acting antivirals (DAAs) on the hypercoagulability associated with HCV cirrhosis is unknown. We longitudinally evaluated the effect of DAAs treatment on cirrhotic coagulopathy. METHODS: Pro- and anticoagulant factor levels and thrombin generation were assessed in patients with HCV-related cirrhosis at baseline, end of therapy (EOT), at 12, 24 and 48 weeks (W) after EOT. RESULTS: Fifty-eight patients were enrolled (86% Child's A). SVR was 100%. Median factor VIII activity significantly decreased at EOT, 12 weeks and 24 weeks compared with baseline, whereas protein C significantly increased at 24 weeks and 48 weeks. Cirrhotic patients showed a slight but sustained increase in endogenous thrombin potential (ETP) with a statistically significant difference at EOT, 12 weeks, 24 weeks and 48 weeks compared with baseline. Conversely, thrombomodulin-modified ETP was elevated before treatment and decreased over time to normal levels at 24 weeks and 48 weeks. The ETP ratio decreased slowly at EOT and 12 weeks, and was significantly decreased at 24 weeks and 48 weeks compared with baseline (P < .001 for both comparisons), being not statistically different from ETP ratio measured in healthy controls. Child's B patients showed a significantly higher ETP ratio compared to Child's A at baseline and did not show any significant improvement in ETP ratio through 12 weeks. Two Child's B patients developed PVT with an incidence rate of 1.1% p-yrs (95%CI, 0.18 to 3.58). CONCLUSIONS: DAAs therapy in HCV-related cirrhotic patients is associated with significant changes in thrombin generation suggesting a reversal of hypercoagulability particularly in Child's A patients.

Long-term care of transplant recipients: de novo neoplasms after liver transplantation.

PURPOSE OF REVIEW: Since the first liver transplantation in the early 1960s, there have been significant improvements in the recipients' long-term outcome. Patients who have undergone transplantation are exposed to a high risk of developing neoplastic disease, not only because of their chronic immunosuppression, but also related to physiological aging, lifestyle, chronic viral infections, liver disease cause, and carcinogenic immunosuppressants. The present review covers the latest and most relevant data on de novo neoplasms after liver transplantation, and discusses their implications for clinical practice. RECENT FINDINGS: Given the impact of de novo neoplasms, in terms of morbidity and mortality, transplant teams must be prepared to diagnose and treat these conditions promptly. Dedicated cancer screening protocols are warranted. Although surveillance strategies are based on data concerning the general population, they should be customized in the light of each transplant recipient's risk factors. The resulting risk stratification is crucially important to the design of early intervention programs, and for addressing the modulation of individualized immunosuppressive regimens. SUMMARY: De novo malignancies are a significant issue for the liver transplant population, but targeted screening programs have shown that survival rates similar to those of nonimmunosuppressed patients can be achieved. New oncological surveillance strategies covering the prophylaxis, monitoring, and treatment of de novo neoplasms should take high priority in clinical research.

Dropout rate from the liver transplant waiting list because of hepatocellular carcinoma progression in hepatitis C virus-infected patients treated with direct-acting antivirals.

Concerns about an increased hepatocellular carcinoma (HCC) recurrence rate following direct-acting antiviral (DAA) therapy in patients with cirrhosis with a prior complete oncological response have been raised. Data regarding the impact of HCV treatment with DAAs on wait-list dropout rates in patients with active HCC and HCV-related cirrhosis awaiting liver transplantation (LT) are lacking. HCV-HCC patients listed for LT between January 2015 and May 2016 at Padua Liver Transplant Center were considered eligible for the study. After enrollment, patients were divided into 2 groups, depending on whether they underwent DAA treatment while awaiting LT or not. For each patient clinical, serological, and virological data were collected. HCC characteristics were radiologically evaluated at baseline and during follow-up (FU). For transplanted patients, pathological assessment of the explants was performed and recurrence rates were calculated. A total of 23 patients treated with DAAs and 23 controls were enrolled. HCC characteristics at time of LT listing were comparable between the 2 groups. Median FU was 10 and 7 months, respectively, during which 2/23 (8.7%) and 1/23 (4.3%) dropout events due to HCC progression were registered (P = 0.90). No significant differences in terms of radiological progression were highlighted (P = 0.16). A total of 9 out of 23 (39%) patients and 14 out of 23 (61%) controls underwent LT, and histopathological analysis showed no differences in terms of median number and total tumor volume of HCC nodules, tumor differentiation, or microvascular invasion. During post-LT FU, 1/8 (12.5%) DAA-treated patient and 1/12 (8.3%) control patient experienced HCC recurrence (P = 0.60). In conclusion, viral eradication does not seem to be associated with an increased risk of dropout due to neoplastic progression in HCV-HCC patients awaiting LT. Liver Transplantation 23 1103-1112 2017 AASLD.

Transjugular Intrahepatic Portosystemic Shunt in Nonmalignant Noncirrhotic Portal Vein Thrombosis and Portosinusoidal Vascular Disorder.

Transjugular intrahepatic portosystemic shunt (TIPS) emerges as a key treatment for portal hypertension (PH) complications. While international guidelines provide clear indications for its use in cirrhosis, empirical knowledge is notably scarcer in non-cirrhotic PH, particularly in nonmalignant noncirrhotic portal vein thrombosis (NNPVT) and in patients with portosinusoidal vascular disorder (PSVD). Patients afflicted by these rare diseases exhibit distinct clinical profiles compared to their cirrhotic counterparts, often characterized by a younger age, predominantly preserved hepatic functionality even in cases of severe PH, and a higher propensity for extensive splanchnic thrombosis, which intricately complicates TIPS placement, posing unique challenges for its creation. The objective of this review is to synthesize existing literature on the effectiveness, safety, specific indications, and clinical outcomes of TIPS in adult patients with NNPVT or PSVD, focusing also on the technical challenges of TIPS insertion in the presence of portal cavernoma.

The evolution of the TIPS placement technique and its applications over four decades.

Transjugular intrahepatic portosystemic shunt (TIPS), a highly effective procedure reducing portal hypertension, has been in use for over seven decades and is now a cornerstone in managing portal hypertension-related complications such as variceal bleeding and ascites. Historically, TIPS has dealt with two main challenges: ensuring stent patency and preventing post-TIPS hepatic encephalopathy. The introduction of PTFE-coated stents markedly reduced the risk of TIPS dysfunction and stent patency is no longer a major concern. However, despite improved patient selection criteria, hepatic encephalopathy continues to be a significant and persistent issue. In addition, the broader application of TIPS in recent decades has brought to light additional, albeit less common, complications, such as post-TIPS heart failure. This review offers a comprehensive overview of TIPS historical evolution, advancements in technique, and its application in the treatment of portal hypertension.

Porto-sinusoidal vascular disorder in chronic HBV: A significant coexistence not to be overlooked.

Background & Aims: Porto-sinusoidal vascular disorder (PSVD) encompasses a group of liver diseases with vascular abnormalities that can cause portal hypertension in the absence of cirrhosis. The new diagnostic criteria allow for coexistence with other liver diseases, however its relationship with chronic hepatitis B (CHB) remains unclear. This study aimed to assess HBV prevalence in a PSVD cohort and evaluate its clinical impact. Methods: This retrospective study was conducted on patients with PSVD at Hospital Clínic Barcelona. HBV serology was evaluated, and patients were categorized into HBV chronic infection, past infection, or no HBV exposure. Clinical characteristics and outcomes were compared. Results: We included 155 patients with PSVD. Prevalence of CHB and past HBV infection in patients with PSVD was higher than in the general population (5.8% vs. 0.5%, p <0.0001 and 20% vs. 9.1%, p <0.0001, respectively). Patients with CHB had a significant delay in PSVD diagnosis compared to those without CHB (11 [5-25] vs. 1 [0-3] years, p = 0.002) and had a more advanced disease (MELD score 12 [9-17] vs. 9 [7-11], p = 0.012) at the time of PSVD diagnosis. The clinical evolution of PSVD in patients with CHB was marked by a significantly higher transplantation rate at the last follow-up (33% vs. 4.1%, p = 0.001). Conclusions: Recognizing the coexistence of PSVD and CHB is important for timely diagnosis and optimal management, highlighting the potential benefits of specialized care for potentially improved outcomes. Impact and implications: The new diagnostic criteria for porto-sinusoidal vascular disorder (PSVD) allow for coexistence with other liver diseases. The results of the present study highlight, for the first time, a non-negligible prevalence of chronic hepatitis B in the PSVD population that was previously unknown. Coexistence may challenge and delay the PSVD diagnosis and is associated with a more unfavorable clinical course. Our findings will increase awareness of this coexistence and improve PSVD diagnosis and management. Furthermore, the data will encourage new studies to determine the prevalence and clinical behavior of other chronic liver diseases that coexist with PSVD.

Changings and Challenges in Liver Transplantation for Nonalcoholic Fatty Liver Disease/Steatohepatitis.

Liver transplantation for nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) is increasing rapidly worldwide. Compared with alcohol and viral-related liver disease, NAFLD/NASH is more frequently associated with a systemic metabolic syndrome, which significantly affects other organs, requiring multidisciplinary management, in all phases of liver transplant.

Vascular liver diseases: A sex-oriented analysis of the literature.

Vascular liver diseases are an heterogenous group of diseases that collectively represent an important health issue in the field of liver diseases. This narrative review was elaborated by the Special Interest Group (SIG) "Gender in Hepatology" of the Italian Association for the Study of the Liver (AISF). We aimed to review the current knowledge regarding the potential role of biological sex in patients with vascular liver diseases such as splanchnic vein thrombosis, hepatic vein thrombosis, porto-sinusoidal vascular disorder, and hereditary hemorrhagic telangiectasia. As vascular liver diseases commonly affect young individuals, including women in childbearing age, we also included a specific section on the management of pregnancy in these challenging patients.