Current trends and future directions in liver transplantation

Transforming liver transplantation (LT): trends, challenges, and future directions

LT in the United States has undergone substantial transformation over the past decade, driven by shifting disease epidemiology, therapeutic advancements, and innovations in organ preservation (Table 1). Historically, hepatitis C virus (HCV)-related cirrhosis was the leading indication for LT. However, with the widespread use of direct-acting antiviral agents, the primary drivers have shifted to metabolic associated fatty liver disease (MAFLD), alcohol-related liver disease (ALD), and hepatocellular carcinoma (HCC), now the three most common indications for LT (1,2). In parallel, novel therapies for hepatic malignancies—including HCC, intrahepatic cholangiocarcinoma (iCCA), and colorectal liver metastases (CRLM)—are expanding the boundaries of LT to include selected patients with unresectable primary and secondary liver cancers (3-5). Technological innovations, such as normothermic machine perfusion (NMP) and experimental approaches like xenotransplantation, are further reshaping the field by improving graft preservation and expanding the donor pool (6). This editorial synthesizes recent developments and explores their implications for clinical practice, current challenges, and future directions.

The changing landscape of LT indications

The increasing prominence of MAFLD and ALD as leading causes of LT reflects significant public health challenges. MAFLD, driven by the obesity epidemic and associated metabolic conditions such as type 2 diabetes and dyslipidemia, has become a major contributor to liver-related morbidity (7). LT remains the definitive treatment for end-stage MAFLD-related cirrhosis, highlighting the critical importance of early interventions (8,9). The rising prevalence of ALD, exacerbated by increased alcohol consumption during the coronavirus disease 2019 (COVID-19) pandemic, underscores the dynamic nature of transplant epidemiology (10). Advances in addiction management, including pharmacological therapies like naltrexone and integrated behavioral health programs, are critical for reducing relapse rates and improving outcomes for ALD patients (11).

Emerging pharmacotherapies offer hope for addressing MAFLD before it progresses to cirrhosis. Agents such as glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and fibroblast growth factor 21 (FGF21) analogs have shown promise in reducing liver fat, inflammation, and fibrosis (12,13). If these therapies are effective in preventing or slowing disease progression, they could significantly reduce the demand for LT. This shift toward earlier disease intervention highlights the intersection of metabolic health and liver disease.

Innovations in liver cancer management

HCC remains one of the most common indications for LT, but advancements in systemic and locoregional therapies are altering its management. Immune checkpoint inhibitors, including nivolumab and pembrolizumab, in combination with targeted therapies such as lenvatinib and bevacizumab, have improved survival for patients with advanced disease (14,15). Locoregional treatments like transarterial chemoembolization (TACE), selective internal radiation therapy (SIRT), and hepatic arterial infusion (HAI), serve as bridges to transplantation, controlling tumor growth while patients await suitable grafts (16). Expanded transplantation criteria, such as the Milan and University of California San Francisco (UCSF) guidelines, have increased access for patients with early-stage HCC, demonstrating the adaptability of transplantation practices (17).

LT for CRLM and iCCA, historically considered high-risk indications, is gaining acceptance due to advances in systemic therapy and improved patient selection. For CRLM, tools like the Oslo score stratify candidates based on tumor biology and chemotherapy response, resulting in outcomes comparable to traditional indications (18). Similarly, iCCA outcomes have improved with the use of neoadjuvant therapies and targeted agents such as isocitrate dehydrogenase (IDH) and fibroblast growth factor receptor (FGFR) inhibitors (19,20). These developments are challenging conventional paradigms and expanding the role of transplantation in oncologic care.

Technological advances in organ preservation and utilization

NMP represents a transformative approach to organ preservation, enabling reconditioning and functional assessment of marginal donor livers. By restoring blood flow and allowing ex vivo evaluation, NMP reduces organ discard rates and expands the donor pool. This technology is particularly promising in with limited deceased donor availability (6). Despite these advancements, living donor liver transplantation (LDLT) remains critical, providing immediate access to high-quality grafts and bypassing allocation systems. In areas with long waiting lists or constrained deceased donor resources, LDLT remains a life-saving solution. However, as organ preservation technologies evolve, the necessity of LDLT may diminish, especially in high-resource settings.

Xenotransplantation represents a frontier in addressing organ shortages. Advances in genetic editing, particularly with clustered regularly interspaced short palindromic repeats (CRISPR) technology, have reduced the risks of hyperacute rejection, bringing xenotransplantation closer to clinical reality. However, challenges such as zoonotic disease risks, long-term graft viability, and ethical considerations must be addressed (20). If successful, xenotransplantation could provide a sustainable solution to organ shortages, potentially revolutionizing transplantation practices and improving equity in access (21).

Challenges and opportunities with an aging population

The aging U.S. population presents unique challenges for LT. Older candidates often have comorbidities such as cardiovascular disease and frailty, complicating surgery and recovery. Similarly, older donor livers may have reduced regenerative capacity and higher susceptibility to ischemic injury. Implementing frailty assessments and focusing on biological rather than chronological age in patient selection could improve the fairness and precision. Ethical considerations regarding organ allocation for older patients further complicate these decisions, emphasizing the need for nuanced approaches that balance equity and efficacy (22,23).

Emergence of organ rehabilitation as a subspecialty

The emergence of organ rehabilitation as a potential subspecialty underscores the transformative impact of advanced preservation technologies, particularly NMP. The ability to salvage and recondition high-risk or marginal grafts represents a significant opportunity to expand the donor pool while improving post-transplant outcomes. This evolving field fosters interdisciplinary collaboration, with transplant surgeons and hepatologists uniquely positioned to jointly assess the viability of rehabilitated organs. Formalizing organ rehabilitation as a dedicated subspecialty could standardize best practices, accelerate innovation, and address persistent challenges related to organ shortages.

Critical reflections and future directions

While progress in LT is undeniable, several challenges remain. Data on portal venous flow modulation, evolving immunological markers, and the management of marginal grafts are still incomplete (24). Furthermore, disparities in access to advanced technologies—including NMP and LDLT—highlight the need for more equitable distribution of resources across transplant centers.

Future research should prioritize the refinement of donor-recipient matching algorithms, improved utilization of marginal grafts, and the removal of systemic barriers that continue to limit access to LT for socioeconomically disadvantaged populations. Ethical and practical considerations related to the implementation of new technologies—such as xenotransplantation and organ rehabilitation—must also be addressed through robust regulatory oversight, long-term safety studies, and sustained interdisciplinary collaboration. The full integration of these innovations will require not only technological readiness but also a steadfast commitment to ethical integrity and health equity.

Conclusions

LT in the U.S. is undergoing a period of significant transformation, driven by shifting disease epidemiology, emerging therapeutic indications, and technological innovation. The increasing prevalence of MAFLD and ALD, along with the expanding role of LT in select cases of CRLM and iCCA, reflect this evolving landscape (25). Simultaneously, advances in organ preservation technologies—such as NMP—and the exploration of xenotransplantation are redefining the boundaries of graft viability and availability. These developments underscore the necessity of a multidisciplinary approach that integrates clinical expertise, cutting-edge technology, and ethical stewardship. By addressing ongoing challenges and embracing emerging opportunities, the field is well-positioned to sustain life-saving outcomes while advancing the science and practice of transplantation.

Acknowledgments

The authors would like to thank the clinical and administrative teams involved in liver transplantation at the University of Pittsburgh Medical Center for their dedication and contributions to the field. We are also grateful to our colleagues for their valuable discussions and insights during the development of this work.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Surgical Journal. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://asj.amegroups.com/article/view/10.21037/asj-25-18/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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