Addressing gender-based disparities in liver transplantation: A global analysis of surgical access and donor organ allocation

Abstract

BACKGROUND

Sex- and gender-based inequities remain a persistent challenge in liver transplantation (LT), influencing referral pathways, waitlist outcomes, donor organ allocation, and post-transplant survival. Differences in body size, model for end-stage liver disease (MELD)-based prioritization, disease etiology, and structural healthcare factors have contributed to disparities in surgical access and organ distribution worldwide. Recent policy modifications, including MELD 3.0 implementation, aim to mitigate longstanding inequities.

AIM

To synthesize global evidence from 2000-2026 evaluating gender disparities in LT access, waitlist mortality, donor allocation practices, and surgical outcomes, and to highlight emerging strategies designed to improve equity in transplantation systems.

METHODS

A narrative global analysis was conducted using recent registry analysis, multicenter cohort studies, systematic reviews, and policy evaluations published between 2000 and 2026. Key endpoints included listing probability, waitlist duration and mortality, access to deceased and living donor transplantation, allocation algorithms, donor-recipient size matching, and post-transplant outcomes.

RESULTS

Across studies, women consistently demonstrated reduced access to transplantation and increased waitlist mortality compared with men. Pooled analyses involving > 377000 candidates reported lower transplant access for women (hazard ratio = 0.88) and increased waitlist mortality risk (hazard ratio = 1.16). Allocation systems incorporating serum creatinine and body-size metrics contributed to lower prioritization scores, with women showing higher adjusted waitlist mortality risk and increased disadvantage associated with estimated liver volume and body surface area. Disease-specific cohorts revealed longer waitlist duration and lower transplant probability among female candidates with hepatocellular carcinoma and metabolic liver disease. Policy reforms such as MELD 3.0 were associated with increased female transplant representation and reduced disparities in transplant opportunity and waitlist mortality, although improvements diminished over time, and body-size differences remained influential. Living donor LT and split-liver strategies emerged as potential mechanisms to mitigate sex-based inequities by addressing donor-recipient size mismatch and expanding organ access. Post-transplant outcomes showed complex patterns, with some data suggesting higher early mortality but improved long-term survival in women compared with men.

CONCLUSION

Gender disparities in LT arise from multifactorial interactions among biological differences, allocation algorithms, surgical considerations, and systemic healthcare inequities. Although policy innovation such as MELD 3.0 have improved equity, persistent gaps in surgical access and donor allocation remain globally. Future strategies should include sex-adjusted allocation metrics, expansion of living donor programs, improved referral pathways, and prospective evaluation of equitable transplant policies to ensure fair access and optimal outcomes in LT worldwide. Future strategies should directly target the cause of disparity. Renal function-informed or sex-adjusted scoring to reduce creatinine-related underprioritization, along with size-aware allocation and greater use of split or living-donor transplantation, may improve access for smaller candidates. Reducing procedural variation can be achieved by standardizing, monitoring and reevaluating organ acceptance processes specifically for sex- and gender-associated inequities. The above-mentioned changes should be evaluated in studies that can produce sex- and body size-stratified transplant rates, waiting time, waitlist death or delisting and post-transplant graft and patient outcomes.

Key Words: Liver transplantation; Model for end-stage liver disease; Transplantation; Gender disparities; Model for end-stage liver disease 3.0

Core Tip: Sex- and gender-based disparities remain a significant challenge in liver transplantation despite advances in allocation systems. Female patients continue to experience lower transplant access, longer waiting times, and higher waitlist mortality due to multifactorial factors, including model for end-stage liver disease-related creatinine bias, donor-recipient size mismatch, reduced access to exception points, and barriers in referral and evaluation pathways. Recent innovations, such as model for end-stage liver disease 3.0, sex-adjusted allocation models, living donor liver transplantation, and size-aware allocation strategies, have improved equity but have not fully eliminated disparities. This review summarizes contemporary global evidence and highlights emerging approaches aimed at achieving fairer organ allocation and improved outcomes for female liver transplant candidates.

INTRODUCTION

Liver transplantation (LT) remains the definitive treatment for patients with end-stage liver disease (ESLD), acute liver failure, selected hepatic malignancies, and several inherited metabolic disorders. Since the introduction of the model for ESLD (MELD)-based allocation system in 2002, organ distribution has increasingly relied on objective laboratory measures intended to prioritize candidate according to urgency and predicted short-term mortality[1,2]. Although MELD substantially improved transparency and reduced subjectivity in organ allocation, growing evidence indicated that important inequities persist within transplantation systems worldwide, particularly regarding sex and gender[1-3].

Over the past two decades, women have consistently experienced lower rates of deceased-donor liver transplantation (DDLT), prolonged waiting times, and higher waitlist mortality compared with men. These disparities arise from a complex interaction of biological, anatomical, clinical, and healthcare-system factors[1-3]. One of the most extensively studied contributors is the reliance of MELD-based scoring systems on serum creatinine, a marker that systematically underestimates renal dysfunction in women because of lower average muscle mass and reduced creatinine production[4,5]. Women often receive lower priority scores despite comparable disease severity. Additional mechanisms include donor-recipient size mismatch, lower access to MELD exception points, differences in disease etiology and progression, referral and evaluation barriers, and broader structural inequities within healthcare systems[4-6].

Recent changes in liver allocation policy, including the implementation of MELD 3.0 and the development of sex-adjusted prognostic models, have sought to address longstanding inequities[3-6]. Growing evidence from North American, European and international registries has highlighted the importance of body-size considerations, living-donor liver transplantation (LDLT), split-liver allocation strategies, and disease-specific pathways in shaping transplant access[7]. Despite these advances, substantial disparities remain evident across multiple stages of the transplantation continuum, from referral to waitlisting to transplantation and long-term outcomes[6-8]. The aim of this review is to provide a comprehensive overview of contemporary evidence regarding sex- and gender-based disparities in LT. We summarize recent findings on allocation systems, waitlist outcomes, disease-specific patterns, referral pathways, donor-recipient matching, and post-transplant outcomes, while examining emerging strategies designed to improve equity in LT worldwide.

MATERIALS AND METHODS

This study was conducted to synthesize contemporary evidence regarding sex- and gender-based disparities in LT. Relevant literature published between January 2000 and May 2026 was reviewed, with inclusion of selected landmark studies published before 2010 when necessary to provide historical context regarding MELD implementation and the evolution of allocation systems. Additional references were identified through the manual review of bibliographies from key articles, systematic reviews and policy reports. Search terms included combinations of keywords and Medical Subject Headings related to LT and sex disparities, including “liver transplantation”, “sex differences”, “gender disparities”, “waitlist mortality”, “organ allocation”, “MELD”, “MELD 3.0”, “transplant access”, “living donor liver transplantation” and “transplant outcomes”. Studies were eligible for inclusion if they examined sex- or gender-related differences in access to transplantation, waitlist outcomes, allocation policies, donor-recipient matching, transplant rated, or post-transplant outcomes among adult liver transplant candidate or recipients. Registry analyses, multicenter cohort studies, population-based investigations, policy evaluations, observational studies and relevant systematic reviews were included. Studies focusing exclusively on pediatric populations, lacking sex-specific analyses, or consisting solely of case reports, conference abstracts, editorials or expert opinions without original data were excluded (Figure 1).

Figure 1 PRISMA 2020 standard guidelines. ¹Records identified from PubMed, Scopus/MEDLINE, Google Scholar and National and International Liver Transplantation Registries; ²If automation tools were used, indicate how many records were excluded by a human and how many were excluded by automation tools.

This article incorporated evidence from national and international transplant registries, multicenter cohort studies, population-based analyses, systematic reviews, policy evaluations and observational studies examining access to LT and transplant outcome. Major data sources included analyses from the Organ Procurement and Transplantation Network (OPTN), Scientific Registry of Transplant Recipients, United Network for Organ Sharing (UNOS), Eurotransplant, European Liver Transplant Registry and national transplantation databases from North America and Europe. Studies were evaluated for information regarding sex differences in referral patterns, transplant evaluation, waitlist outcomes, MELD-based prioritization, exception-point allocation, donor-recipient size matching, deceased and living donor transplantation, disease-specific transplant access and post-transplant survival. Particular emphasis was placed on recent investigations evaluating the effects of MELD 3.0, body-size-adjusted allocation approaches and novel sex-adjusted prognostic models. Given the heterogeneity of study design, patient populations and outcome measures, a quantitative meta-analysis was not performed. Instead, findings were synthesized narratively, focusing on recurrent themes, consistent observations across datasets and emerging policy implications relevant to transplant equity.

RESULTS

MELD score structural bias

The MELD score, adopted in 2002 for LT prioritization, relies on the formula MELD = 9.57 × ln(creatinine) + 3.75 × ln (bilirubin) + 11.20 × ln (international normalized ratio) + 6.43 (with subsequent incorporation of sodium in MELD-Na variants)[9]. This laboratory-based system was designed to provide objective ranking of disease severity. However, it creates exclusive structural bias against female candidates[10], as women exhibit lower muscle mass, and consequently, lower endogenous creatinine production at any given level of glomerular filtration rate (GFR). The result is lower MELD scores for women compared with men who have equivalent degrees of renal impairment and overall disease severity. This under-prioritization directly translates into prolonged waiting times, elevated risk of decompensation and reduced probability of receiving a deceased-donor graft[11].

Early evidence quantifies this disparity with precision. In a large competing-risk analysis of 43322 registrants, women demonstrated a significantly higher 3-year cumulative incidence of waitlist death (19% vs 17% in men), with the widest gap observed among non-dialysis patients who had moderate renal dysfunction [estimated glomerular filtration rate (eGFR) 15- < 30 mL/minute/1.73 m²]. The disparity was driven by a 32% lower transplantation rate among women. When creatinine was substituted by estimated GFR in multivariable models, the excess female mortality vanished entirely, confirming the creatinine component as the dominant modifiable driver. Similar findings emerged from pre- and post-MELD natural experiments: After implementation, sex replaced race as the primary inequity, with women 30% more likely to die or become too sick for transplantation and 30% less likely to receive an organ[12]. Within individual MELD strata, women had lower creatinine but higher bilirubin and international normalized ratio (INR) levels, underscoring that the score failed to capture their true disease burden[11]. Even substitution of the four-variable modification of diet in renal disease-derived eGFR did not improve mortality discrimination[11,12].

Subsequent studies dissected the relative contributions of laboratory, anthropometric and allocation factors. Inverse-odds ratio (OR) weighting more than 81000 candidates attributed approximately 50% of excess female waitlist mortality and 10% of the transplantation deficit to the MELD score itself[13]. Height and estimated liver volume explained additional variance, but laboratory MELD remained the single largest correctable element. Delisting practices further amplified the problem: Women were removed from the list for being “too sick” at higher rates than men, and once delisted, they exhibited poorer functional status and lower rates of private insurance coverage[14]. Living-donor pathways offered a partial counterbalance. The presence of a potential living donor eliminated the sex-based survival disadvantages, with women deriving disproportionately greater instantaneous transplant-rate benefit[15].

International data have confirmed that these inequities are not confined to high-volume North American systems. In Germany, where MELD-based allocation was introduced in 2006, women, already underrepresented on the waiting list (33.3%) and among transplant recipients (31.1%) relative to their proportion of patients with severe liver disease (35.1%), experienced a further widening of the transplantation gap after MELD implementation, with the adjusted hazard ratio (HR) for transplantation declining from 0.86 before MELD to 0.77 after its introduction. Three interrelated mechanisms were identified: (1) Lower creatinine values despite comparable or worse renal function (median deficit 1-3 MELD points); (2) Lower receipt of exceptional MELD points (men benefited with HR = 1.61); and (3) The dominant effect of shorter stature (adjusted HR = 0.85 for non-transplantation). These findings demonstrate that MELD-driven inequity persists even in settings with different organ-donation rates and regulatory frameworks[7,8,15,16].

Size mismatch and exception-point allocation compound the laboratory bias. Female candidates, who on average have a smaller body habitus, are less likely to receive organs from larger male donors because of graft-to-recipient weight ratio constraints. Small or split grafts are frequently allocated to pediatric recipients instead. In the hepatocellular carcinoma (HCC) exception cohort (n = 31725), women had an 8% lower incidence of DDLT and a 6% higher incidence of death or delisting within 1 year than men[16]. Multivariable adjustment for height and weight largely eliminated the sex difference, except among the shortest women (< 1.66 m), in whom a persistent 7% transplantation deficit remained. These findings suggest that height functions as both a mediator and an independent effect modifier[16]. Women also receive MELD exception points less frequently for conditions such as HCC, in which transplant priority is based on tumor burden rather than laboratory measures of disease severity. The net effect is that women undergo transplantation with more advanced hepatic decompensation despite having ostensibly comparable or lower MELD scores[16,17].

The clinical consequences of this persistent bias are profound. Women have a 20%-30% higher risk of waitlist mortality or delisting because of clinical deterioration, experience longer waiting times, and undergo transplantation at more advanced stages of liver disease[14,17]. In some cohorts, MELD-Na exacerbated rather than mitigated these disparities because the sodium component interacted unfavorably with the already underestimated creatinine values in women[17]. Even after statistical adjustment for body size or estimated liver volume, residual disparities persist, indicating that creatinine-based scoring cannot be rendered sex neutral through simple linear corrections. Within the female population, shorter stature and lower muscle mass identify the most vulnerable subgroups. Women with acute-on-chronic liver failure, severe alcohol-associated hepatitis, or cholestatic liver disease often present with disproportionately preserved serum creatinine and are therefore disadvantaged because MELD and MELD-Na underestimate their mortality risk[18]. Consequently, these patients accrue fewer MELD points than their true clinical urgency warrants and are less likely to qualify for exception points, increasing their risk of delisting or death[18].

Policy-level responses have attempted to address these shortcomings. The OPTN implemented MELD 3.0 in 2023, adding an explicit +1.33-point female coefficient, incorporating albumin with interaction terms, lowering the creatinine ceiling to 3.0 mg/dL and refining bilirubin-sodium relationships[19]. Early post-implementation analyses documented encouraging gains: Women experienced greater relative increases in top-five organ offer rates and the probability of transplantation during the first 3 months, with OR favoring women up to 1.60[20]. However, these advantages attenuated over time, and mediation analyses confirmed that body-size differences continued to drive residual inequity. Height adjustment fully eliminated the sex difference in transplantation rates, while shorter women derived the largest initial benefit[19]. Simulation modeling of a sex-adjusted MELD-Na variant predicted higher female transplantation rates and lower overall waitlist mortality, suggesting that further refinement along these lines remains feasible[20].

More comprehensive solutions replace creatinine entirely. The gender-equity model for liver allocation (GEMA) and its sodium-extended version (GEMA-Na) employ the royal free GFR, which inherently accounts for sex, age and body weight, thereby eliminating the creatinine artifact[6,8,19,20]. In a nationwide Spanish cohort of 6071 registrants, both GEMA-Na and MELD 3.0 corrected the independent female risk of non-transplantation observed with conventional scores. GEMA-Na provided superior calibration and discrimination for waitlist outcomes[20,21]. Extension to a nonlinear explainable artificial-neural-network architecture further improved performance by removing arbitrary caps and capturing complex interactions without pre-specification[22]. Head-to-head comparisons across European and multinational cohorts rank GEMA variants highest in reclassification benefit for women, the subgroup historically most penalized[21,22]. These structural inequities translate into tangible clinical harm for specific patient populations. Shorter female candidates and those with smaller body size remain disproportionately affected because donor-recipient size mismatch further limits organ offers and access to transplantation. Women presenting with acute-on-chronic liver failure, alcohol-associated hepatitis, or conditions ineligible for MELD exception points also remain particularly vulnerable, as conventional scoring systems continue to underestimate disease severity in these subgroups, compounding the risks of waitlist mortality and delisting[17,18]. Future allocation policy must therefore transition beyond incremental linear adjustments to fully sex-neutral GFR-based and physiologically informed systems if the equity intended by the original MELD framework is to be realized while protecting the most vulnerable female candidates[17,18,22].

Body size, graft matching and sex-based inequities

Female patients experience persistently lower access to DDLT, with subsequent higher pretransplant mortality. A relevant portion of this inequity is explained by size: Shorter and smaller body habitus candidates are primarily women, and current allocation mechanics, while prioritizing urgency, do not explicitly guarantee access to size-compatible grafts[23]. In the most recent United States registry reporting, the sex gap narrowed after the implementation of MELD 3.0, yet adult female candidates still had lower deceased-donor transplant rates and higher pretransplant mortality than males, with the report explicitly noting that height/body size-based effects likely persist[7,8,23]. In 2023, MELD 3.0 replaced MELD-Na in July and the transplant-rate gap by sex began to narrow. Nevertheless, adult male candidates still had a higher DDLT rate than females (96.6 vs 91.4 transplants per 1000 patient/years), and adult female candidates still had higher pretransplant mortality (13.9 vs 12.2 deaths per 100 patients/years), with the report attributing residual disparity to “height- or body size-based” mechanisms that MELD 3.0 does not fully eliminate[16,23].

Evidence interrogating size mismatch has demonstrated that graft-recipient size compatibility is not merely a logistical consideration. It has measurable clinical consequences, including an increased risk of vascular complications and reduced early graft survival at the extremes of donor-recipient size mismatch, as demonstrated in the United Kingdom National Health Service Blood and Transplant registry[24]. These findings provide both a biological rationale and outcome-based justification for size-aware allocation strategies[24].

Although current organ allocation systems are largely gender-neutral, organ acceptance decisions may still be influenced by biological and anthropometric factors, including donor-recipient sex matching. The potential contribution of these factors to geographic and center-level differences in acceptance patterns warrants further discussion. In a United States cohort of 28313 adult patients who underwent liver transplant for a primary or secondary HCC diagnosis were identified. A total of 14685 were excluded due to non-compliance. The remaining 13628 patients with LT showed that the female-recipient/male-donor constellation was independently associated with reduced all-cause mortality [adjusted HR = 0.84, 95% confidence interval (CI): 0.71-0.99], while the male-recipient/female-donor combination conferred the highest cumulative incidence of HCC recurrence-related death [sub-distribution HR (SHR) = 1.41, 95%CI: 1.08-1.83][25].

The clinical legitimacy of size-aware allocation is strengthened by transplant-outcome studies demonstrating harm at size extremes. In a large United States cohort of deceased-donor adult liver recipients (UNS 2013-2022), donor-recipient size mismatch defined by a donor-to-recipient body surface area (BSA) index (BSAi) showed time-dependent risk: Small-for-size grafts (low BSAi) were linked to inferior 90-day graft survival and were associated with vascular complications early after transplant, while large-for-size grafts (high BSAi) were associated with inferior 1-year graft survival among early survivors; beyond 1 year, graft size was not a dominant determinant[25]. The same study connects deceased-donor size mismatch metrics (BSA, standard total liver volume surrogates) to living-donor conventions, such as graft-to-recipient weight ratio, underscoring that size thresholds are clinically meaningful and routinely operationalized when volumetry is feasible[26].

Evidence from simulation studies and observational registries converges on a set of pragmatic solutions, including preferential allocation of smaller donor livers to candidates with a smaller body habitus, expanded use of split-LT, and size-focused allocation policies that extend beyond revision of the MELD score alone[25,26]. Two complementary lines of evidence clarify why size functions as an allocation barrier rather than merely a demographic correlate. First, OPTN date (2013-2020) shows that the smallest body habitus candidates by BSA face longer waiting times and lower transplant probabilities and smaller body habitus patients are disproportionately women (more that 80% of female patients in the smallest decile)[26]. A simulated solution that directed the smallest 10% of donors to the smallest 15% of candidates or expanded split-liver use, eliminated the size-based allocation deficit and improved female allocation share[27]. Observational registry of HCC-exception candidates between 2010-2023 shows that women had lower 1-year cumulative incidences of deceased-donor transplant and higher 1-year death/delisting than men; simulated adjustment for height and weight rendered the “female sex” association non-significant, but a residual disadvantage persisted for “short women” compared with “short men”, implying that simple height/weight proxies may capture the operative size constraints, such as those related to the intraabdominal domain itself and graft fit, and/or non-size mediators[16].

Findings in the aforementioned United Kingdom registry[24] (adult first, deceased-donor whole-graft, liver-only transplants from 2000-2020) show that donor-recipient BSAi extremes correlate with early technical complications and graft outcomes: Oversizing (BSAi > 1.3) was associated with a higher risk of portal vein thrombosis within 3 months, whereas both undersizing (BSAi < 0.85) and marked oversizing (BSAi > 1.4) were associated with poorer overall graft survival compared with intermediate BSAi values. No statistically significant differences in recipient survival were observed[24]. In the Eurotransplant setting, a multinational European organ allocation network, a large analysis of transplant candidates from 2007-2019[7] suggested that the primary inequity is not necessarily that MELD underestimates mortality in women. Rather, women experience lower transplantation rates, a disparity that is largely explained after candidate body size and MELD are modeled as mediators, implying that size-related access to appropriately matched grafts is a key pathway underlying the observed sex disparity[7]. Another Italian retrospective study of 7563 transplant candidates (73.7% men) listed between 2017 and 2021 found that men were more likely to undergo LT within 1-2 years and had lower waitlist mortality than women (7.0% vs 8.5%), whereas post-LT survival was comparable between the sexes[28]. Furthermore, a 2018 systematic review and meta-analysis found that female-to-male donor-recipient mismatch was associated with the poorest outcomes and should therefore be considered during pretransplant donor-recipient matching[29]. A single-center study of 2144 patients attributed the favorable outcomes observed in male donor - female-recipient transplants to differences in donor-quality and recipient characteristics rather than to donor-recipient sex mismatch itself[30]. To reconcile these discrepancies, we suggest that decisions regarding donor-recipient sex matching should remain at the discretion of individual transplant centers, guided by graft quality and clinical urgency. However, allocation policy developers should also acknowledge that organ acceptance is not entirely sex-neutral and consider its potential impact when evaluating equity and transplant outcomes[29,30].

MELD exception policies and disease phenotypes

Although the MELD score was developed as a needs-based organ allocation system, its reliance on biochemical parameters limits its ability to fully reflect disease severity across diverse etiologies of chronic liver disease[5,6,31]. MELD exception policies were introduced to address clinical scenarios captured by standard MELD scoring. Despite these modifications, substantial gender-based inequities persist, with women continuing to experience systematic disadvantages in both access to and allocation for LT. In an analysis of the UNOS registry involving 64995 waitlisted patients, exception points were granted more frequently to men and women were less likely to be ranked first on the waiting list (OR = 0.93, 95%CI: 0.88-0.99)[31]. Through simulations and subsequent validation, there have been suggestions to modify the allocation formulas in order to narrow the female access gap. A simulation of a sex-adjusted MELD-Na yielded higher projected female transplant volumes and reduced 1-year waitlist mortality compared with the standard MELD-Na score[18]. Implementation of the GEMA rationale demonstrated that MELD rollout was associated with a substantial increase in death odds on the United States waiting list for women[18]. Outside the United States, MELD introduction has widened the transplantation gap for women. Therefore, future allocation system design should adopt a hybrid reform package: (1) Replacement of creatinine levels with sex-neutral renal-function metrics such as cystatin-c based eGFR; (2) Integration of height- and body surface area-aware matching thresholds; (3) Incorporation of transplant benefit as a tiebreaker for candidates of comparable urgency; and (4) Expansion of split-liver and LDLT pathways[32].

Acute liver failure: A study evaluating 8408 patients listed as status 1 for LT due to acute liver failure demonstrated a marked female predominance, with women accounting for 63.9% of the cohort. Women exhibited higher INR values, a greater prevalence of grade 3 to 4 hepatic encephalopathy and district etiological patterns compared with men[33]. Univariable analysis revealed that women were less likely to undergo LT (SHR = 0.90, 95%CI: 0.84-0.97) and more likely to die or be removed from the waiting list because of clinical deterioration (SHR = 1.14, 95%CI: 1.002-1.30)[29]. However, these differences did not retain statistical significance following multivariable adjustment, suggesting that disease-related and clinical confounders may partially account for the observed disparities[33].

HCC: HCC constitutes the largest and most significant MELD exception category within LT allocation systems. In a large multicenter study involving 5327 patients with HCC, pronounced gender-based differences were observed (P < 0.0001). Women demonstrated a higher prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) (23% vs 12%) and a lower prevalence of alanine aminotransferase (ALT) (5% vs 15%) compared with men[34]. In addition, non-cirrhotic HCC occurred more frequently in women (17% vs 10%, P < 0.0001). Female patients also presented with less advanced disease according to tumor-node-metastasis staging (P < 0.0001) and were more frequently within Milan criteria at presentation (39% vs 35%, P = 0.002). Overall survival was higher among women[34]. Despite these favorable oncological characteristics, disparities in transplant access persisted. A separate United States transplant registry analysis including 31725 patients with HCC who received MELD exception points reported that women had a lower 1-year cumulative incidence of DDLT than men (50.8% vs 54.0%, P < 0.001), alongside a higher 1-year cumulative incidence of death or delisting due to clinical deterioration (16.2% vs 15.0%, 95%CI: 0.89-0.95) and a higher incidence of death or delisting due to clinical deterioration (16.2% vs 15.0% P = 0.002)[16]. In unadjusted analyses, women exhibited a lower incidence of DDLT (SHR = 0.92, 95%CI: 0.89-0.95) and a higher incidence of death or delisting (SHR = 1.06, 95%CI: 1.00-1.13). These associations lost significance after adjustment for candidate height and weight, underscoring the influence of body size on organ allocation. Among shorter candidates (< 1.66 m), women remained less likely than men to undergo transplantation (SHR = 0.93, 95%CI: 0.88-0.99)[34]. Comparable findings were reported in a French cohort study involving 384 transplant recipients for HCC[35]. Female patients were diagnosed earlier and experienced a shorter interval between diagnosis and transplantation compared with men. However, the duration between listing and transplantation remained similar between groups. Women were more likely to fulfill Milan criteria, while only a small proportion of patients in either group demonstrated an α-fetoprotein score > 2[35].

MASLD/metabolic dysfunction associated steatohepatitis: Among 20045 patients with cirrhosis, women demonstrated higher rates of cholestatic liver disease and non-alcoholic steatohepatitis compared with men[36]. Female patients were less likely to develop portal hypertensive complications and exhibited lower peak MELD-Na scores during follow-up. Female sex was associated with a reduced hazard of all-cause mortality. Despite this apparent survival advantage, women had significantly lower rates of waitlisting (7.5% vs 9.8%, P < 0.001) and transplantation (3.5% vs 5.2%, P < 0.001)[36], highlighting a discordance between disease severity metrics and access to transplantation[36].

In another UNOS-based study that included 51721 individuals with HCC between 2000 and 2022, comprising 39765 men and 12256 women, metabolic dysfunction associated steatohepatitis (MASH) emerged as the fastest-growing etiology among female transplant candidates with HCC (P < 0.01), followed by ALT[37]. MASH surpassed chronic hepatitis C as the leading indication for transplantation in waitlisted women by 2020 and in men by 2022. Women with HCC experienced longer waitlisting times for transplantation than men[37]. In addition, female patients with ALT-related HCC were less likely to receive a transplant. Importantly, among recipients transplanted for MASH-related HCC, female sex was associated with lower post-transplant mortality compared with male sex[37].

Primary biliary cholangitis: In another study among 940 patients with primary biliary cholangitis, women comprised the majority of the cohort (81.8%) and were older than men [61.5 years (53.4-70.9) vs 57.5 years (interquartile range: 37.7-69.7), P < 0.001][38]. Women also had lower rates of chronic kidney disease (8.7% vs 14.6%, P = 0.023)[33]. In contrast, male patients demonstrated higher median ALT, aspartate aminotransferase, alkaline phosphatase, γ-glutamyl transferase, INR and bilirubin levels at admission, accompanied by higher MELD and MELD-Na scores. Men experienced a greater burden of complications, including bacterial peritonitis and portal vein thrombosis[38]. Men had also increased odds of the composite outcome of inpatient death or transplantation (OR = 4.28, 95%CI: 2.52-7.23, P < 0.001)[38].

Primary sclerosing cholangitis: Primary sclerosing cholangitis (PSC) is an autoimmune cholestatic disorder characterized by marked male predominance with an approximate male-to-female ratio of 2:1. Data from European Liver Transplant Registry demonstrated PSC as an indication for transplantation among women increased from 1.8% to 4.3% over the past three decades[39]. Female recipients more frequently received grafts from female donors (59.2% vs 40.7%), whereas donation after brain death grafts were less commonly utilized in women than in men (90.2% vs 94.4%)[39]. Despite these allocation differences, no statistically significant disparity in post-transplant survival was observed between sexes[39]. Survival among men at 1 year, 5 years, 10 years, 15 years, and 20 years was 91%, 81.2%, 71.8%, 57.6% and 41%, respectively, whereas corresponding survival rates among women were 91.6%, 83.9%, 74%, 59.5%, and 47.1%, respectively[39].

Alcohol-associated liver disease: The RESOLVE-ALD study, which evaluated 617 patients referred for LT, identified substantial gender disparities in both listing and waitlist outcomes. Women were less likely to be listed for transplantation than men (51.9% vs 60.9%, P = 0.03), with the disparity being pronounced among patients with MELD-Na scores < 25 (44.2% vs 57.7%, P = 0.04), despite women demonstrating similar or greater rates of hepatic decompensation compared with age-matched men[40]. After adjustment for relevant covariates, female sex remained associated with 36% lower odds listing for transplantation (OR = 0.64, 95%CI: 0.42-0.91, P = 0.01)[40]. Moreover, listed women were more likely to be removed from the waitlist than listed men. Reasons for delisting included clinical deterioration, clinical improvement, substance use, miscellaneous causes and psychosocial concerns[40]. The disparity in delisting persisted even after excluding patients removed because of clinical improvement. After adjustment for MELD-Na score, abstinence duration and serum albumin, female sex remained associated with nearly threefold higher odds of waitlist removal (OR = 2.68, 95%CI: 1.52-4.71, P < 0.001)[40,41].

Health access and referral patterns

Upon meeting the clinical criteria for LT, receiving a transplant is a multistep process from referring providers to completion of psychosocial evaluation and health insurance amenities. It is well-established that racial, socioeconomic and geographic factors are substantial determinants of the transplantation process[42,43]. However, little is known about the early parts of the process and patients’ navigation through referral systems and evaluation procedures. Yet, studies focusing on sex disparities in referral timing to actual waitlisting and transplantation completion are limited and derive from multi-regression analysis of associations between various demographic characteristics[41,42].

International studies confirm sex-based inequities in access to LT for waitlisted patients with ESLD with high disease severity and equally high MELD scores. A large national data registry study showed that women spent more time on the waiting list before reaching MELD 40, and the acceptance rate was lower in women than men (P < 0.001)[43]. After adjusting for confounding donor and factors, women had a lower rate of LT (HR = 0.86, 95%CI: 0.82-0.91, P < 0.001) and higher cumulative incidence of death or waitlist removal (HR = 1.14, 95%CI: 1.02-1.27, P < 0.021)[43]. By eliminating the direct contribution of MELD score with a cohort of patients with similar MELD score, this and other studies have confirmed the suspicion that MELD score alone cannot fully explain the lower proportion of women who undergo LT once listed. Referral practice patterns remain an elusive area of investigation as those of community physicians to liver transplant centers are not yet standardized and may depend on variable preferences and attitudes towards patient referral, evaluation and eligibility for LT[16,43].

The need to quantify the disparities on the first barrier to liver transplant, the referral stage, was encountered by large national databases of LT, such as that of Moylan et al[12], which used data from the OPTN. Women were less likely to receive a liver transplant within 3 years, both pre-MELD and post-MELD stratification (OR = 0.80, 95%CI: 0.70-0.92, and OR = 0.70, 95%CI: 0.62-0.79, P < 0.001)[12]. Diagnosis was a modifying factor of waitlisting outcomes, as such differences were not observed upon HCC diagnosis. This fact remains controversial, as the use of exception points on MELD score improves the likelihood of transplantation for patients with HCC. This dynamic co-variate complicates the investigation of allocation plans for HCC and the detection of sex disparities in the process[12]. Complementary data derived from an updated cohort study evaluating sex disparities in the allocation system for patients with HCC after adjustments for MELD score and donor size mismatch[16]. Female sex was associated with lower incidence of DDLT (HR = 0.92, 95%CI: 0.89-0.95, P < 0.001). However, when adjusting for weight and height, this difference was obscured[16]. This reveals the confounding effect of size mismatch, as women were more likely to be shorter than men, and shorter women were less likely to receive a transplant. What is now recognized is that sex disparities in transplant allocation reflect size disparities and vice versa[16]. This is the predominant, but not sole factor responsible for differences in access to DDLT. Thus, intrinsic variations are extended to referral systems beyond body size measurements. This is contradictory because women experience a higher incidence of post-transplant mortality compared with men (HR = 0.52, 95%CI: 0.75-0.89, P < 0.01) due to lower recurrence of HCC post-transplantation (HR = 22.8 vs 29.2, P < 0.01)[44]. This raises the conclusion that women should be prioritized for transplantation because of a greater survival benefit[43].

Beyond the large volume American systems, Ross-Driscoll et al[44] sought to map the distribution of demographic factors, including sex, hypothesized to be associated with access to three defined stages of LT in patients with HCC: Transplantation referral, evaluation initiation and evaluation completion. Multivariate analysis revealed that sex was not a statistically significant determinant for the referral process and evaluation. Thus, a tendency for lower rates of male patients to continue through the evaluation steps was observed[45]. Data from Eurotransplant reveal the same tendency, with a calculated waitlist mortality HR of 1.03, 95%CI: 0.88-1.20[46]. Multiregression analysis showed that interactions of body size with candidate sex were insignificant and small body size confers similar disadvantages in both sexes[7]. A clinical inference is that transplantation centers should consider the potential disadvantages faced by small-statures candidates during offer acceptance decisions. In the modern era of allocation scores, adding extra points for short candidates could potentially result in more equalized outcomes between the two sexes[7,45]. The Spanish Model in Organ Donation and Transplantation showed that the overall probability of women undergoing LT was lower after adjusting for age, height, blood group and MELD score with longer waitlists and higher mortality waiting time, with observed sex-related inequities after 2011[45]. This is related to the fact that overall waiting times have drastically decreased during the last decade, which likely contributes to the observation that women, particularly those with intermediate MELD scores, do not face higher drop-out rates from death or worsening conditions, even with longer waiting periods than men[44].

Unanimous results derived from studies in the field of non-cancerous liver disease, where data have grown rapidly due to the increasing incidence of alcoholic liver disease (ALD) and time-changing modalities in selection criteria for this patient group. This is a historically proven entity where women have been disadvantaged in the allocation system and referral criteria[45-47]. As for health access, women are more often considered either too clinically well to meet transplant eligibility criteria or too severely ill to derive benefit. They are also perceived to have inadequate psychosocial support and an increased risk of substance relapse[47,48]. Updated data on listing decisions between the two sexes derive from a multicenter study investigating sex and psychosocial patterns in LT waitlisting[40]. Women with similar MELD-Na score as men were less likely to be listed for LT, a fact that was more prominent in younger women with MELD-Na score < 25[17,40]. After adjusting for significant co-factors, including MELD-Na, abstinence period and serum albumin, employment status and mood disorders, the OR for delisting remained nearly three-fold higher (OR = 2.46, 95%CI: 1.37-4.41)[17,40]. The distinguishable clinical profiles of liver-related history between men and women reveal higher listing rates for men in all liver-disease categories[40]. Women continue to be disadvantaged at all stages of transplantation, highlighting an ongoing sex-based disparity from pre- to post-transplant care[48]. The factors contributing to this disparity not only include an imperfect organ allocation system based on MELD score and donor-recipient liver size mismatch, but also systematic biases in health access and referral systems[49]. Those areas require continued research to promote education of the transplantation community to create a culture of organ donation and to initiate policies and legal reform to increase organ donors in all populations (Figure 2)[48,49].

Figure 2 Model for end-stage liver disease score structural bias. (Figure created through Adobe Photoshop). Conceptual illustration showing how biological, disease-related, and healthcare-system factors can influence model for end-stage liver disease (MELD) scores and transplant priority, potentially leading to disparities in waitlist mortality and access to liver transplantation among different patient populations. eGFR: Estimated glomerular filtration rate; HCC: Hepatocellular carcinoma; INR: International normalized ratio.

Post-transplant outcomes and survival patterns

A growing body of literature has highlighted significant sex-specific outcomes in patients undergoing solid organ transplantation, driven by biological variations such as differential immune activation pathways, hormone levels, and sex-determined minor histocompatibility antigens[50]. In 2022, a comprehensive systematic review and meta-analysis highlighted sex-based inequalities across all solid organ transplant modalities. Within LT subgroup analysis, the authors found that overall mortality was significantly lower among female recipients. Paradoxically, female sex was associated with a higher risk of 30- and 90-day hospital readmission rates, allograft loss and post-operative infections[50]. These findings indicate that female patients frequently experience a superior long-term prognosis following LT, a phenomenon that may be justified by several distinct clinical and biological mechanisms[51]. Higher estrogen levels in females have been shown to promote biliary epithelial cell proliferation and bile duct growth during the critical early post-transplant period. Furthermore, the primary indications for transplantation often differ by sex. Females more frequently undergo transplantation for autoimmune cholestatic conditions, such as primary biliary cholangitis and PSC, which carry a more favorable long-term post-transplant prognosis compared with viral or metabolic etiologies. Female recipients typically exhibit lower rates of pre-transplant cardiovascular morbidity[51]. Because severe cardiovascular disease is more prevalent in the male population and represents a major driver of adverse post-operative events, this baseline health disparity further shields female recipients from early cardiovascular mortality[51]. On the other hand, ALD stands out as a critical exception. It represents the primary condition associated with higher post-transplant mortality in females compared with males, an effect that is particularly pronounced among young female recipients under 40 years of age[51].

This female survival advantage was further corroborated by a retrospective cohort study from Israel, which demonstrated significantly superior survival curves for women. The study reported 1-, 3- and 5-year survival rates of 83.3%, 83.4% and 78.3% in female recipients compared with 72.8%, 69.0% and 64.9% in male recipients, respectively (P = 0.004)[52]. Analysis of transplant indications within this cohort revealed that when HCC was the primary indication for LT, sex-specific survival curves were significantly lower[52]. When HCC was excluded and ESLD served as the direct indication, post-transplant survival was considerably and statistically significantly superior in women. The female’s survival advantages remained robust independent of the baseline MELD score, persisting in both the low-risk (< 20) and high-risk (> 20) MELD strata[52].

A large-scale registry evaluated a nationwide Italian cohort with specific focus on the allocation framework. Their findings revealed disadvantages for female candidates on the waiting list; women demonstrated a lower probability of undergoing transplantation, faced prolonged waiting times when listed for HCC, and experienced higher rates of waitlist dropouts or death[28]. Nonetheless, post-transplant survival rates for women who ultimately achieved transplantation were statistically similar or superior to those of their male counterparts[53], aligning with the survival trends observed in the above cited international studies.

DISCUSSION

This review demonstrated that sex-based disparities remain a persistent and clinically meaningful challenge in LT despite substantial advances in allocation systems and transplant policy. Across diverse healthcare systems and geographical regions, women consistently experience lower access to transplantation, longer waiting times, and higher risks of waitlist mortality or delisting compared with men. It is important to mention that these disparities are multifactorial and cannot be solely attributed to a single component of the allocation process.

The most prominent mechanism remains the structural bias embedded within traditional MELD-based allocation. Because serum creatinine is strongly influenced by muscle mass, women frequently receive lower MELD scores despite similar degrees of renal dysfunction and overall disease severity. Multiple studies reviewed herein demonstrate that replacing creatinine with more accurate estimations of renal function substantially reduced or eliminated the excess mortality observed among female candidate. The persistence of sex disparities across different healthcare systems further suggests that the creatinine-related limitations of MELD represent a universal challenge rather than a region-specific phenomenon.

However, contemporary evidence increasingly indicated that body size may explain a substantial proportion of the observed inequity. Women are disproportionately represented among smaller transplant candidates and therefore face reduced access to appropriately sized donor organs. Recent studies from the United States, Eurotransplant and the United Kingdom consistently demonstrate that donor-recipient size mismatch significantly contributes to reduced transplantation rates among women. Simulation studies suggest that preferential allocation of smaller donor grafts to candidates with smaller body habitues and increased utilization of split-LT could substantially mitigate these disparities. These findings highlight that future allocation reforms must simultaneously address both urgency and anatomical compatibility. Disease-specific analyses reveal additional complexity. Women with HCC, MASLD, ALD and cholestatic liver disorders experience unique disadvantages. Particularly concerning are lower access to MELD exception points, reduced listing despite comparable disease severity, and higher rates of waitlist removal among women with alcohol-related liver disease. These observations suggest that psychosocial assessment processes, referral practices, and transplant candidacy evaluation may contribute to disparities beyond those explained by allocation algorithms alone. Referral and healthcare access patterns represent another critical but less studied source of inequity. Existing evidence suggests that women encounter barriers throughout the transplant pathway, including delayed referral, lower listing rates, reduced access to specialized transplant evaluation, and increased likelihood of delisting. These findings emphasize that equity cannot be achieved solely through modification of allocation scores. Broader interventions targeting provider awareness, referral standardization, psychosocial assessment practices, and healthcare accessibility are equally necessary.

The introduction of MELD 3.0 represents a major step toward improving fairness in liver allocation. Early post-implementation analyses demonstrate increased transplantation opportunities for women and reductions in waitlist mortality disparities. Nevertheless, residual differences persist, particularly among shorter candidates and those with similar body size. Emerging models such as GEMA, GEMA-Na, and machine-learning-based allocation frameworks may offer additional improvements by incorporating sex-specific physiological parameters and more accurate assessments of renal function. Whether these approaches can translate into meaningful long-term improvements in clinical outcomes requires prospective studies, designed according to sex and body-size stratified score calibrations on top of the traditional organ offer and acceptance rates, transplant probability, waiting time, and waitlist death or delisting.

Despite disadvantages in transplantation access, women often achieve comparable or superior long-term post-transplant outcomes. Several studies report lower rates of HCC recurrence and improved long-term survival among female recipients. This paradox raises important questions regarding the optimal balance between urgency-based allocation and expected post-transplant benefit. A future allocation system may benefit from incorporating measures that capture both pro-transplant mortality risk and anticipated post-transplant outcomes. The evidence suggests that sex disparities in LT arise from a convergence of biological differences, body-size considerations, disease-specific factors, psychosocial evaluation processes, and structural healthcare inequities. Addressing only one component is unlikely to completely eliminate the problem. Instead, a comprehensive and multidisciplinary approach is required to achieve true equity in transplantation access.

To develop proper and clear targets, it is important to define the term “equity” in the context of LT, as different operational meanings have been related to this term and they are not always aligned. The concept of health equity has been introduced as the fair ability of all individuals to attain their full health potential with no disparities between groups. In the troublesome context of transplantation, where medical efficiency conflicts with the principle of equity, the definition of fair scarce-resource allocation comprises three distinct allocation criteria that are mutually incompatible. First, justice demands that all candidates in equivalent medical circumstances should be treated identically through uniform allocation rules, irrespective of the outcomes; second, those in medical urgency should be prioritized; and finally, sufficient efforts should be made to maximize the aggregate benefit of transplantation as a whole. These criteria do not necessarily align and are filtered by allocation systems that must make explicit choices about how they are weighted and compromised. Applied to sex- and gender-based disparities in LT, a horizontal approach of equal probability of receiving an organ transplant requires that male and female candidates matched for disease severity, transplantation urgency, etiology, body size, and blood group should have equivalent probabilities across the outcome measures considered in this article, including waitlist time, waitlist mortality, likelihood of receiving a transplant, and post-transplant survival. The evidence summarized in our article demonstrates that this condition is frequently not met, and women who are clinically comparable to men by objective measures of disease severity experience worse outcomes across several of these domains, pointing to structural and allocation-related sources of inequity rather than real differences in medical indications.

CONCLUSION

Sex- and gender-based disparities remain deeply embedded within the LT system worldwide. Women continue to experience lower transplantation rates, longer waiting times, and increased risks of waitlist mortality despite ongoing efforts to improve allocation fairness. The underlying causes are multifactorial and include MELD-related structural bias, donor-recipient size mismatch, unequal access to exception points, disease-specific differences, referral barriers, and broader healthcare system inequities. Recent innovations, particularly the implementation of MELD 3.0, have produced measurable improvements and narrowed some longstanding gaps. Nevertheless, residual disparities persist, especially among smaller-bodied female candidates and patients with disease phenotypes that are inadequately represented by current allocation metrics. Emerging allocation models that incorporate sex-adjusted physiological parameters, improved renal function assessment, and body-size considerations may further enhance equity. Those models need to be supported by prospective studies that will measure their efficacy regarding resolving the disparities.

Future efforts should focus on the development of sex-neutral allocation systems, expansion of living donor and split-LT programs, standardization of referral and evaluation pathways, and prospective assessment of equity-focused policy interventions. Achieving fair access to LT requires recognition that biological sex, body size, and social determinants of health interact through the transplant continuum. Addressing these factors comprehensively will be essential for ensuring equitable access and optimal outcomes for all transplant candidates.