Frailty as a determinant of liver transplant outcomes: A call for integrative strategies

Abstract

Frailty has emerged as a pivotal determinant of post-liver transplant (LT) outcomes, yet its integration into clinical practice remains inconsistent. Defined by functional impairments and reduced physiologic reserve, frailty transcends traditional metrics like the model for end-stage liver disease (MELD) score, demonstrating increasing predictive value for mortality beyond the immediate post-operative period. Recent findings suggest that frail recipients experience significantly higher mortality within the first 12 months following transplantation—a period when traditional monitoring often wanes. This raises critical questions about the adequacy of current assessment and follow-up protocols. The observed dissociation between MELD scores and long-term survival underscores the limitations of existing selection criteria. Frailty, as a dynamic and modifiable condition, represents an opportunity for targeted intervention. Prehabilitation programs focusing on nutritional optimization, physical rehabilitation, and psychosocial support could enhance resilience in transplant candidates, reducing their risk profile and improving post-transplant outcomes. Furthermore, these findings call for an expanded approach to post-transplant monitoring. Extending surveillance for frail recipients beyond standard timelines may facilitate early detection of complications, mitigating their impact on survival. Incorporating frailty into both pre- and post-transplant protocols could redefine how transplant centers evaluate and manage risk. This editorial advocates for a paradigm shift: Frailty must no longer be viewed as a secondary consideration but as a core element in LT care. By addressing frailty comprehensively, we can move toward more personalized, effective strategies that improve survival and quality of life for LT recipients.

Key Words: Frailty; Liver transplant; Outcomes; Sarcopenia; Index; Hand grip; Score; Strategies

Core Tip: Frailty has emerged as a pivotal determinant of post-liver transplant (LT) outcomes, yet its integration into clinical practice remains inconsistent. Recent findings suggest that frail recipients experience significantly higher mortality within the first 12 months following transplantation—a period when traditional monitoring often wanes. Frailty, as a dynamic and modifiable condition, represents an opportunity for targeted intervention. Prehabilitation programs focusing on nutritional optimization, physical rehabilitation, and psychosocial support could enhance resilience in transplant candidates, reducing their risk profile and improving post-transplant outcomes. By addressing frailty comprehensively, we can move toward more personalized, effective strategies that improve survival and quality of life for LT recipients.

INTRODUCTION

In the intricate web of liver transplantation (LT), metrics like the model for end-stage liver disease (MELD) score have long been the cornerstone of discussions about candidacy and prognosis. This focus on biochemical parameters provides precision but also fosters a false sense of completeness. Yet, beyond these numbers, a silent yet transformative predictor—frailty—has emerged as a critical factor, reshaping our understanding of outcomes in LT. Frailty, characterized by diminished physiological reserve, reduced resilience, and increased vulnerability to stressors, transcends the physical domain; it reflects deeper, systemic gaps in how we assess, treat, and support transplant candidates. Far from being a mere patient descriptor, frailty is a mirror reflecting the limitations of our current healthcare frameworks—frameworks designed to prioritize survival but often ill-equipped to ensure recovery, resilience, and quality of life. It challenges the efficacy of traditional metrics like MELD, demanding a broader lens through which we evaluate risk and potential. As LT medicine advances with cutting-edge surgical techniques and immunosuppressive regimens, the critical question looms: Are we prepared to confront the complexities frailty brings to the table? Or will frailty persist as the Achilles' heel of our success—a vulnerability undermining the transformative potential of transplantation? This moment calls for introspection and action. Frailty is not a roadblock but an opportunity to redefine priorities, ensuring that advancements in transplantation align with the holistic needs of patients. The future of LT depends not just on how well we manage organs but on how thoughtfully we address the human condition.

Frailty assessment has become a critical component in evaluating LT candidates, offering insights into both short-term surgical risks and long-term patient outcomes. Various assessment tools have been developed to quantify frailty, with some focusing on physical function and others incorporating cognitive, nutritional, and psychosocial factors. While these tools provide valuable information, their effectiveness, limitations, and applicability in different patient populations remain subjects of ongoing investigation. Furthermore, frailty’s impact extends beyond survival, influencing a patient's ability to engage in daily activities, maintain social relationships, and experience psychological well-being. A more comprehensive exploration of frailty’s long-term consequences is crucial in guiding transplant decision-making and post-transplant care.

The liver frailty index (LFI) is one of the most commonly used tools in LT, specifically designed for cirrhotic patients. It incorporates grip strength, chair stands, and balance assessments, providing an objective measure of physical frailty. Studies have validated LFI as an independent predictor of waitlist mortality, post-transplant complications, and length of hospital stay[1,2]. However, its primary limitation is its focus on physical attributes, which may underestimate frailty’s broader effects on cognitive function and psychosocial resilience. Additionally, while LFI is widely applicable across different patient populations, it may be less effective in severely deconditioned patients or those with mobility impairments, where assessments like chair stands are not feasible[3]. The Fried Frailty Phenotype (FFP) is another widely used tool, evaluating five core criteria: Weight loss, exhaustion, low physical activity, slow walking speed, and weak grip strength. Unlike LFI, FFP is not liver disease-specific but has been extensively studied across different chronic illnesses[4]. Its strength lies in its ability to capture broader aspects of frailty, including energy levels and nutritional decline, both of which are highly relevant in liver disease. However, FFP’s subjective components—such as self-reported exhaustion and physical activity—can introduce variability in patient responses, making it less reliable in standardized transplant evaluations[5].

Another promising tool is the Clinical Frailty Scale (CFS), a global frailty assessment that includes physical, cognitive, and functional parameters. It is simple to administer and provides a holistic view of a patient's overall condition. However, it lacks specificity for liver disease, making it less predictive of transplant-related outcomes compared to LFI or FFP[6]. In practice, a combination of frailty tools may provide the most accurate representation of a patient’s condition, ensuring that both physical and psychosocial factors are considered. Beyond its impact on surgical outcomes, frailty significantly affects long-term quality of life in transplant recipients. Physically frail patients often experience prolonged functional impairment, struggling with mobility limitations, persistent fatigue, and difficulty performing activities of daily living even months after transplantation[7]. Many frail patients require extended rehabilitation, and in some cases, they never regain full pre-illness functional capacity, leading to a reduced ability to live independently[8]. The mental health consequences of frailty are equally concerning. Studies indicate that frail LT recipients have higher rates of depression, anxiety, and cognitive decline, which may be exacerbated by the psychological distress of long-term illness, social isolation, and post-transplant medication side effects[9]. Hepatic encephalopathy, which often precedes transplantation, can contribute to persistent cognitive deficits, further limiting post-transplant recovery[10]. Psychological resilience, therefore, becomes a key determinant of successful reintegration into daily life.

Frailty also has profound implications for social functioning and quality of relationships. Many frail patients lose their ability to work, face financial instability, or become increasingly dependent on caregivers, which can strain familial relationships and reduce overall well-being[11]. Social reintegration remains a challenge, as patients may struggle with a loss of autonomy, role changes within the family, or feelings of guilt over their dependency. For younger transplant recipients, frailty can disrupt career trajectories and personal aspirations, leading to long-term socioeconomic consequences[12]. Given these far-reaching effects, frailty assessment must be more than a perioperative risk stratification tool—it should be a comprehensive predictor of long-term quality of life. Transplant programs should integrate frailty-focused rehabilitation strategies, including nutritional support, physical therapy, and mental health interventions, not only to improve survival rates but to enhance patients’ post-transplant quality of life[13]. The goal should not merely be prolonging life but ensuring that life after transplantation is meaningful, independent, and fulfilling.

For decades, the MELD score has reigned as the gold standard for prioritizing LT candidates. It is precise, quantifiable, and seemingly objective—a reassuring tool in the complex calculus of organ allocation. But is it sufficient? Emerging evidence suggests that while MELD excels at predicting short-term mortality, it falls short in capturing the nuanced, long-term risks that frailty embodies. This gap in predictive accuracy becomes particularly stark when frailty is brought into the equation. Consider this: Patients with high frailty scores but modest MELD numbers often fare worse post-transplant than their non-frail counterparts with higher MELD scores[1]. This paradox challenges the very ethos of transplantation—saving lives and ensuring a meaningful recovery. The MELD-centric framework, while invaluable, inadvertently creates a blind spot, focusing narrowly on biochemical parameters while overlooking the broader, functional vulnerabilities that frailty represents. This disconnect underscores an uncomfortable truth: Our reliance on traditional metrics may inadvertently undermine the goals of LT. By prioritizing candidates based solely on MELD, we risk sidelining patients whose frailty places them at higher risk for complications and mortality, even if their lab results suggest otherwise. The limitations of MELD are not a critique of its utility but a call to expand our perspective. To truly fulfill the promise of LT, we must integrate frailty assessments into the framework, acknowledging that survival alone is not enough—what matters is the quality and durability of life post-transplant. This shift is not just necessary; it is overdue. The metrics we trust implicitly are incomplete without a human context. Frailty is not a static number; it is a dynamic condition encompassing sarcopenia, malnutrition, and psychosocial vulnerability. By failing to address frailty explicitly, we risk perpetuating a system that prioritizes survival over recovery and quality of life.

WHY DOES FRAILTY REMAIN ON THE PERIPHERY OF TRANSPLANT EVALUATION?

Perhaps because acknowledging frailty forces a confrontation with the deeply entrenched efficiency-driven ethos of modern medicine. In an era where metrics dominate decision-making and efficiency often eclipses nuance, frailty disrupts the narrative. It demands more than numerical scores and quick solutions—it requires time, resources, and a steadfast commitment to holistic care. These are not conveniences in high-pressure, resource-limited transplant settings; they are challenges that test the flexibility of institutions. Yet, the cost of sidelining frailty is far greater: Higher post-operative complications, prolonged hospitalizations, and ultimately, poorer survival rates[2]. Frailty's invisibility is not due to a lack of significance but rather to its complexity. It resists simplification, requiring a multidimensional approach that incorporates physical fitness, nutritional status, and psychosocial resilience. For some, addressing frailty feels like adding layers of complexity to an already intricate field. But what is at stake is not merely institutional efficiency—it is patient lives. When frailty is ignored, we are not simply deferring care; we are undermining outcomes, placing patients and caregivers at a disadvantage. Acknowledging frailty compels a shift from reactive to proactive care. It urges transplant teams to view the perioperative journey not as an isolated event but as a continuum that begins with prehabilitation and extends into long-term recovery. This broader perspective is not an inconvenience—it is an ethical imperative that prioritizes patient-centered care over operational expediency. Frailty is not an obstacle; it is an opportunity to redefine success in LT. What if we reframed frailty not as an obstacle but as an opportunity? Frailty is modifiable. Prehabilitation—targeted interventions focusing on strength, nutrition, and mental health—has shown promise in reversing aspects of frailty in LT candidates[3]. By integrating such measures into routine care, we could transform frailty from a prognostic warning sign to a treatable risk factor.

Frailty is not a fixed state but a modifiable risk factor that can be addressed through structured prehabilitation programs targeting nutrition, physical rehabilitation, and psychosocial support. Prehabilitation, a proactive approach aimed at optimizing transplant candidates before surgery, has demonstrated significant benefits in improving post-transplant survival and reducing complications[12]. Given the growing recognition of frailty’s impact on outcomes, transplant programs must incorporate evidence-based interventions that enhance resilience and functional recovery. Malnutrition and sarcopenia are key drivers of frailty in LT candidates, with over 60% of cirrhotic patients suffering from muscle wasting, contributing to poor post-transplant recovery and increased mortality risk. Nutritional interventions should focus on high-protein, calorie-dense diets to support muscle preservation, branched-chain amino acids to improve hepatic encephalopathy and muscle mass retention, and micronutrient supplementation, including vitamin D, zinc, and omega-3 fatty acids, to enhance immune function and reduce inflammation. Personalized dietary interventions led by a multidisciplinary transplant nutrition team should be implemented for all frail candidates to optimize preoperative metabolic reserves and improve surgical outcomes.

Transplant care has historically been episodic, with an intense focus on immediate post-operative outcomes, often tapering into less rigorous monitoring as time progresses. While this approach is effective for many, it falls significantly short for frail patients, whose vulnerabilities are not confined to the surgical recovery period but often manifest and intensify months after transplantation. Frailty is not a transient condition; it reflects a deeper physiological fragility that amplifies the risks of complications, delayed recovery, and mortality over time. Studies have shown that the association between frailty and mortality becomes increasingly pronounced during the first 12 months post-transplant, a period when clinical surveillance traditionally diminishes[13]. This reveals a critical oversight in the existing model of transplant care. Shouldn’t the reality of frailty compel us to rethink this timeline? Extending and individualizing monitoring protocols for frail recipients could bridge the gap between short-term survival and sustained recovery. This might involve frequent clinical assessments, early detection of complications, and interventions tailored to the specific needs of frail patients. Such an approach could prevent small setbacks from escalating into life-threatening conditions. However, this is not merely a logistical adjustment; it is a cultural shift. Frailty demands that we reframe our priorities in transplantation care, placing equal value on resilience and recovery as we do on survival. Resilience, in this context, means empowering patients not only to live longer but to live better—stronger, more independent, and more integrated into their lives post-transplant. This change requires that we move beyond viewing transplantation as the culmination of care and instead embrace it as a transition point in a continuum where post-operative vigilance is as critical as pre-transplant preparation. Ultimately, extending the continuum of care for frail recipients underscores a broader principle: That success in transplantation is not defined solely by immediate survival but by the sustained well-being and quality of life of our patients. It is an approach that reimagines what we owe to those whose second chances depend on our care.

Table 1[14-29] summarizes the findings which highlight the significant impact of frailty on LT outcomes, encompassing survival prediction, hospitalization risk, postoperative complications, and quality of life. The LFI, a widely validated tool, was shown to be a strong predictor of mortality and hospital stays, with a 12% increased hazard of death per 0.1-unit increase in LFI. The Fried Frailty Index, while useful, exhibited reduced predictive accuracy in patients with hepatic encephalopathy, underscoring the need for refined assessments in this subgroup. The CFS was also validated as a mortality predictor, with patients scoring ≥ 5 experiencing a 2.5-fold increased mortality risk. Studies further demonstrated that frailty extends beyond mortality risk to quality of life and healthcare utilization. Lower health-related quality of life scores and low health literacy were linked to increased frailty and a higher likelihood of hospitalization and transplant ineligibility. Post-transplant, frail patients had longer hospital stays, higher complication rates, and lower survival rates, particularly among those with low MELD scores. Importantly, prehabilitation-driven improvements in frailty were associated with better post-transplant outcomes, highlighting the role of structured interventions in modifying frailty. Additionally, frailty was associated with higher self-reported symptom burdens, including fatigue, pain, and depression, indicating its profound impact on both physical and mental health. Some studies found that frailty did not significantly affect caregiver burden, suggesting other factors might be at play. Overall, these findings reinforce the importance of integrating frailty assessments and targeted interventions into LT programs to optimize outcomes.

Table 1 Key findings of recent studies on frailty in liver transplant.

Ref.	Study design	Age (years)	Male (%)	Frailty evaluation tool	Sample (frail/non-frail)	Key findings
Lai et al[1]	PCS	58	59%	LFI	536 (142/394)	Developed the LFI. A 0.1-unit increase in LFI was associated with a 12% increased hazard of mortality
Tapper et al[14]	PCS	54.5	60%	FFI	685 (279/406)	Patients with hepatic encephalopathy had a 25-fold higher hazard of mortality compared to others
Bhanji et al[15]	PCS	50.1	48.6%	CFS	105 (51/54)	Sarcopenia is more common in alcoholic disease and frailty in nonalcoholic steatohepatitis
DeMaria et al[16]	PCS	60	55%	FFS	50 (15/35)	Standardized frailty measures predicted hospital stays after liver transplantation
Bittermann et al[17]	PCS	54.1	56%	FFI	350 (120/230)	Low health literacy was associated with increased frailty and a 40% lower likelihood of liver transplantation
Kok et al[18]	PCS	56.4	40%	FFC	409 (146/263)	A 10-point reduction in quality of life score increased hospitalization by 20%
Kremer et al[19]	PCS	56.7	48%	CFS	299 (63/236)	Patients with a frailty score (Clinical Frailty Scale) ≥ 5 had a 25-fold higher mortality risk
Raveh et al[20]	RCS	54	52%	FSI	143 (76/67)	Developed a Comprehensive Frailty Severity Index, which predicts early outcomes after liver transplantation
Aby et al[21]	PCS	61	57%	LFI	233 (43/190)	Frailty in cirrhotic patients did not significantly impact caregiver burden, suggesting other factors may play a more prominent role
Deng et al[22]	PCS	57	58%	LFI	75 (11/64)	Frailty was associated with higher symptom burdens in cirrhotic patients, like fatigue, pain, and depression
Johnston et al[23]	PCS	53	57%	LFI	517 (125/392)	Dietetic assessments of frailty and sarcopenia in liver transplant candidates were highly reliable and feasible
Klein et al[24]	PCS	59.1	43%	LFI	114 (29/85)	Frailty was a significant predictor of survival after liver transplantation, especially in patients with MELD ≤ 15
Lin et al[25]	PCS	64	52.4%	LFI	881 (349–1277)	Prehabilitation-driven improvements in frailty metrics predicted reduced mortality in advanced liver disease patients
Skladany et al[26]	RCS	58	64%	FFI	385 (184/201)	Compared frailty in nonalcoholic fatty liver cirrhosis to alcoholic cirrhosis. Frailty was more prevalent in nonalcoholic cases and associated with worse survival
Soto et al[27]	PCS	64	56%	FFP	126 (84/42)	Frailty and reduced gait speed were independently related to long-term mortality in cirrhotic patients
Choi et al[28]	PCS	69.2	54%	mFI-5	155 (22/133)	Validated the Modified Charlson Comorbidity Index as a survival prediction tool for older liver transplant recipients
Williams et al[29]	RCS	54	57%	LFI	307 (47/260)	Both the Duke Activity Status Index and Liver Frailty Index effectively predicted mortality in ambulatory patients with advanced chronic liver disease

CFS: Clinical frailty scale; FFC: Fried frailty criteria; FFI: Fried frailty index; FFP: Fried frailty phenotype; FFS: Fried frailty score; FSI: Frailty severity index; LFI: Liver frailty index; mFI: Modified frailty index; NA: Not available; PCS: Prospective cohort study; RCS: Retrospective cohort study; CFS: CSHA Clinical frailty scale; MELD: Model for end-stage liver disease.

WHO BEARS THE BURDEN?

Frailty is more than a clinical descriptor; it is a socioeconomic phenomenon deeply intertwined with inequality. Frailty disproportionately affects vulnerable populations—older adults, those with lower socioeconomic status, and individuals with limited access to healthcare and preventive measures. These groups often have compounded disadvantages, including higher rates of malnutrition, poorer access to rehabilitation services, and increased exposure to chronic stress. This reality raises a pressing ethical question: Are we perpetuating healthcare inequities by failing to address frailty in LT? Current frameworks privilege quantifiable metrics such as the MELD score, which offers precision but lacks the nuance to account for the lived realities of frail patients. A frail individual with a borderline MELD score may fall through the cracks of a system designed to prioritize the "sickest first," despite evidence showing that frailty places them at significantly greater risk of post-transplant complications and mortality. By continuing to overlook frailty, we risk creating a transplant paradigm that inadvertently prioritizes efficiency over equity. Integrating frailty into decision-making could act as an equalizer, offering a more comprehensive and fair assessment of transplant candidacy. Frailty-aware practices would acknowledge the compounded vulnerabilities of these patients, ensuring that decisions are guided by a holistic understanding of risk. Addressing frailty is not only an ethical necessity but also a practical one; patients who are better prepared to withstand the rigors of transplantation are more likely to achieve favorable outcomes. Extending the focus on frailty beyond candidacy to include post-operative care is equally critical. Frailty often manifests as a continuum, with its effects lingering well into the recovery phase. Tailored follow-up protocols that emphasize nutritional support, rehabilitation, and frequent monitoring for frail recipients could bridge the gap between short-term survival and long-term well-being. This shift requires more than logistical adjustments—it necessitates a cultural change that redefines success as resilience and quality of life, not merely survival. By recognizing frailty as a central consideration in transplantation, we not only confront inequities but also honor our ethical responsibility to provide care that is just, compassionate, and comprehensive. Frailty is not a peripheral issue; it is a lens through which we can view and address the broader disparities inherent in healthcare.

Integrating traditional practices into LT prehabilitation may enhance patient resilience; however, their efficacy and safety require further research. Silymarin (milk thistle) has demonstrated hepatoprotective properties by reducing oxidative stress, yet its interactions with immunosuppressants in transplant patients remain uncertain[30]. Tai Chi and Qigong, emphasizing controlled movements and deep breathing, have been associated with improved physical performance and reduced fall risk in frail older adults. Incorporating these low-impact exercises into prehabilitation programs could benefit patients unable to engage in high-intensity activities[31]. Nevertheless, rigorous clinical trials are essential to validate the safety and effectiveness of these traditional interventions in the context of LT.

Specific steps a transplant program might take to address frailty are recommended as follows:

Early identification and assessment

Screening: Implement systematic screening for frailty in LT candidates, using validated tools like the LFI.

Assessment: Conduct comprehensive assessments that include physical function, sarcopenia (muscle loss), and nutritional status.

Reassessment: Regularly reassess frailty status, especially on the waitlist, as it can fluctuate.

Prehabilitation

Multidisciplinary approach: Involve specialists like dietitians, physical therapists, and rehabilitation teams to address frailty.

Nutritional support: Ensure adequate protein and calorie intake to combat malnutrition and sarcopenia.

Physical activity: Encourage and prescribe exercise programs tailored to the individual's needs and abilities.

Home-based programs: Utilize fitness trackers, smartphone applications, and home-based exercise programs to facilitate adherence.

Prehabilitation programs: Implement prehabilitation programs to enhance physical strength and nutritional status before surgery.

Post-transplant management

Continued monitoring: Continue to monitor for frailty and its complications after transplantation.

Rehabilitation: Provide access to physical therapy and rehabilitation services to help patients regain function and independence.

Addressing comorbidities: Manage any non-cirrhosis-related comorbidities that may contribute to frailty.

Immunosuppression: Optimize immunosuppression to minimize the risk of post-transplant complications that can worsen frailty.

Education: Educate patients and families about the importance of physical activity, nutrition, and adherence to medical recommendations.

Psychosocial support: Address the psychosocial aspects of frailty and LT, as these can significantly impact quality of life.

CONCLUSION

In the era of frailty, how do we define success?

Transplant medicine has always been about more than survival—it is about giving patients a second chance at life and the opportunity to thrive. Success can no longer be measured solely by graft function or patient survival rates. Instead, it must be reframed to include metrics like functional recovery, independence, resilience, and quality of life. Frailty forces us to confront the limitations of our current approach and realign our goals to reflect the lived experiences of our patients. This is not a call for incremental change—it is a demand for a paradigm shift. Table 1 summarizes the statistics and findings from recent researches which studied frailty in LT patients. Transplant centers must move beyond traditional evaluation metrics to incorporate frailty as a central component of preoperative assessment, surgical planning, and postoperative care. Functional status and vulnerability should inform not only patient selection but also the intensity and duration of follow-up care. A frailty-informed approach could guide personalized interventions, ensuring that each patient’s unique needs are addressed comprehensively. Policymakers play a pivotal role in this transition. The integration of frailty into transplant protocols requires robust support for prehabilitation programs, which include targeted physical therapy, nutritional optimization, and cognitive support. These programs have the potential to transform frailty from a risk factor into a modifiable condition, thereby improving outcomes and reducing healthcare costs. Furthermore, increased funding for research into frailty-focused interventions will provide evidence-based solutions for the challenges faced by transplant recipients and their caregivers. As a community, we must shift our perspective. Patients are more than MELD scores or surgical challenges; they are individuals with complex vulnerabilities and aspirations for recovery. Recognizing this complexity demands a broader, more compassionate view of care—one that prioritizes holistic well-being over survival alone. By redefining success, we acknowledge the intricate interplay of medical, functional, and psychosocial factors that shape each patient’s journey. This vision of transplant care, informed by the realities of frailty, has the potential to set a new standard—one that ensures survival is not the endpoint but the foundation for a meaningful and fulfilling life.