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Development of a novel frailty index to predict mortality in patients with end‐stage liver disease
Open accessAbstract
Cirrhosis is characterized by muscle wasting, malnutrition, and functional decline that confer excess mortality not well quantified by the Model for End-Stage Liver Disease (MELD) Sodium (MELDNa) score. We aimed to develop a frailty index to capture these extrahepatic complications of cirrhosis and enhance mortality prediction in patients with cirrhosis. Consecutive outpatients listed for liver transplantation at a single transplant center without MELD exceptions were assessed with candidate frailty measures. Best subset selection analyses with Cox regression identified subsets of frailty measures that predicted waitlist mortality (=death or delisting because of sickness). We selected the frailty index by balancing statistical accuracy with clinical utility. The net reclassification index (NRI) evaluated the %patients correctly reclassified by adding the frailty index to MELDNa. Included were 536 patients with cirrhosis with median MELDNa of 18. One hundred seven (20%) died/were delisted. The final frailty index consisted of: grip strength, chair stands, and balance. The ability of MELDNa and the frailty index to correctly rank patients according to their 3-month waitlist mortality risk (i.e., concordance-statistic) was 0.80 and 0.76, respectively, but 0.82 for MELDNa+frailty index together. Compared with MELDNa alone, MELDNa+frailty index correctly reclassified 16% of deaths/delistings (P = 0.005) and 3% of nondeaths/delistings (P = 0.17) with a total NRI of 19% (P < 0.001). Compared to those with robust frailty index scores (<20th percentile), cirrhotics with poor frailty index scores (>80th percentile) were more impaired by gait speed, difficulty with Instrumental Activities of Daily Living, exhaustion, and low physical activity (P < 0.001 for each). CONCLUSION: Our frailty index for patients with cirrhosis, comprised of three performance-based metrics, has construct validity for the concept of frailty and improves risk prediction of waitlist mortality over MELDNa alone. (Hepatology 2017;66:564-574).
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“Finally, malnutrition [105], frailty [106, 107] and especially sarcopenia [108, 109, 110, 111] have become increasingly important in patients with advanced chronic liver disease and should be evaluated and treated in each patient.”
From Current treatment of non‐alcoholic fatty liver disease (2022) · cites this paper as [106]
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“(1), good (2), fair (3), poor (4), or very poor (5).”
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“Given the inherent sex differences in grip strength((8)) and walk speed((9)) norms, we converted grip strength and walk speed into sexspecific z-scores for use in the prediction modeling:”
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Internal validation of predictive models
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Items 301–400 of 554
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“The results from the dominant hand grip strength, sit- to-stand and balance tests were combined to calculate the gender-normalised LFI using the following formula: ( − 0.330 × gender—mean grip strength) + ( − 2.529 × number of chair stands per second) + ( − 0.040 × balance time) + 6 [10].”
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BackgroundThe Impact of Metabolic Health and Obesity on Liver Transplant Candidates and Recipients
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The gastrointestinal system in the critically ill cirrhotic patient
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“[43] is derived using three easily obtained clinical variables, sexadjusted grip strength, number of chair stands per second, and balance time.”
MethodPHYSICAL FRAILTY IN LIVER TRANSPLANTATION
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“F IGURE 2 Predicted probabilities of survival for 4 patients with cirrhosis on liver transplantation waitlist by the combination of MELDNa and frailty index scores.[5] Abbreviation: MELDNa, model for end-stage liver disease sodium.”
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“The diagnosis of frailty in patients with liver cirrhosis primarily relies on tools that assess impaired muscle contraction function (Lai et al., 2017).”
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“The idea behind the LFI was to improve risk stratification and risk prediction of waitlist mortality [32].”
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Liver Transplant Is Associated with Sustained Improvement in Tandem Gait and Risk of Falls
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“The LFI is an objective, performance-based calculation that uses a continuous scale to provide a frailty score.(19) It uses a combination of grip strength (sex adjusted), unassisted chair stand time, and time able to maintain three different balance positions.”
Mao, L., Li, C., Wang, X., Sun, M., Li, Y., Yu, Z., Cui, B., Guo, G., Yang, W., Hui, Y., et al. (2022) · Journal of Clinical and Translational Hepatology · doi:10.14218/jcth.2022.00027 · Cited by 5
“The following exclusion criteria were adopted: (1) primary hepatocellular carcinoma or extrahepatic malignancies; (2) acute-on-chronic liver failure during hospitalization; (3) severe hepatic encephalopathy precluding finishing Frailty Index questionnaire; (4) liver transplantation, and (5) denial of regular follow-up.”
MethodLow back pain in patients hospitalised with liver cirrhosis- a retrospective study
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Self-citationCirrhosis and frailty assessment in elderly patients
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Implementation of the frailty assessment to improve liver transplant outcomes
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“[10] focusing on the physical domain of the individual, by capturing the frailty phenotype proposed by Fried et al.”
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“Liver transplantation is the best treatment option for patients with end-stage liver disease [4].”
BackgroundSarcopenia is Closely Associated With Frailty in Decompensated Cirrhosis
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“[42] We will also assess Activities of Daily Living (ADLs).”
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“18,19 Frailty is identified in nearly half of patients with advanced liver disease.”
InfluentialImpact of age on frailty in liver cirrhosis: a prospective cohort study
Alhaddad, O., Elsabaawy, M., Abedelhai, A., Badra, G., & Elfayoumy, M. (2025) · Clinical and Experimental Medicine · doi:10.1007/s10238-025-01747-3 · Cited by 3
“This discrepancy mirrors the findings from prior research who reported a frailty prevalence exceeding 50% by sixties in cirrhosis cohorts, highlighting the synergistic impact of chronic liver disease on age-related vulnerability [15].”
Nationwide Analysis of Failure to Rescue After Liver Transplantation
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“The Liver Frailty Index was developed specifically to measure the construct of physical frailty in liver transplant candidates [16].”
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“Sit- to-stand and balance tests were performed according to the validated LFI protocol [29].”
“Too Female” for Liver Transplantation
Oloruntoba, O., & Moylan, C. A. (2018) · Hepatology · doi:10.1002/hep.30053 · Cited by 3
“The frailty index, based on metrics easily measured in an outpatient setting, is more accurate at predicting deaths after listing and delisting than the MELD-Na score.(7) It could serve as an objective and reproducible measurement not only to identify individuals who should be delisted, but also those who can be relis…”
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“48,49 Grip strength was measured in kilograms using a handheld dynamometer in the dominant hand; the average of three trials was calculated for analysis.”
MethodFrailty and Sarcopenia in Cirrhosis: Current Knowledge and Future Directions
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“LFI is composed by three performance objective-based tests already in use in geriatric literature showing good results in term of reproducibility [28, 30, 31].”
Cullaro, G., Allegretti, A. S., Patidar, K. R., Verna, E. C., & Lai, J. C. (2025) · Digestive Diseases and Sciences · doi:10.1007/s10620-025-09223-4 · Cited by 3
“The FrAILT study is a prospective evaluation of ambulatory patients listed for liver transplantation at the University of California, San Francisco (UCSF) [16].”
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Sarcopenia in high acuity liver transplantation: Does it predict outcomes?
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“Frailty in patients with cirrhosis is common but often under-diagnosed, and therefore the functional status of cirrhotic patients may not have been accurately categorised by the WHO performance status [27].”
BackgroundPashayee-Khamene, F., Hatami, B., Cheraghpour, M., & Yari, Z. (2023) · Clinical Nutrition ESPEN · doi:10.1016/j.clnesp.2023.09.927 · Cited by 3
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Frailty as a determinant of liver transplant outcomes: A call for integrative strategies
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Rifaximin Improves Frailty in Patients with Decompensated Cirrhosis: A Randomized Trial
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“Patients were defined as frail if LFI score was > 4.5, pre-frail when LFI ranged between 3.2 and 4.5, and robust when LFI < 3.2 [9, 10, 18].”
InfluentialOrman, E. S., Desai, A. P., Kuchana, S. K., Campbell, N. L., Fowler, N. R., McCarty, J., Pike, F., Mosesso, K. M., Hotchkiss, T., Chalasani, N., et al. (2026) · Clinical and Translational Gastroenterology · doi:10.14309/ctg.0000000000001013 · Cited by 2
“…using the Medical Outcome Study Short Form (SF-36) (22), physical performance using the short physical performance battery (23) and the liver frailty index (24), and depression and anxiety measured using the Patient Health Questionnaire (PHQ-9) (25) and the Generalized Anxiety Disorder Scale (26).”
Suzuki, T., Yamada, K., Anoushiravani, A., Pham, P. T., Grossberg, A. J., Naugler, W. E., & Farsad, K. (2026) · CardioVascular and Interventional Radiology · doi:10.1007/s00270-026-04405-7 · Cited by 2
“The 6-month observation period represents a potentially critical window for pre-transplant physical optimization and postoperative recovery [8, 12, 24, 33, 34].”
InfluentialSierra, L., Prakash, S., Esfeh, J. M., Sims, O. T., & Chiang, D. J. (2026) · Annals of Hepatology · doi:10.1016/j.aohep.2026.102201 · Cited by 2
Development and validation of an administrative frailty index for patients with cirrhosis (CAFI)
Calthorpe, L. M., Lee, C., Fenton, C. L., Barry, F., Roll, G. R., Feng, S., & Lai, J. C. (2026) · Liver Transplantation · doi:10.1097/lvt.0000000000000856 · Cited by 2
Self-citationMajumdar, A., Holmes, J., Roberts, S. K., Bhat, P., Mitchell, T., Ramachandran, J., O’Beirne, J. P., Walker, S., Sawhney, R., Jagarlamudi, N., et al. (2026) · Hepatology Communications · doi:10.1097/hc9.0000000000000934 · Cited by 2
“[97] Other methods of frailty and sarcopenia measurement are summarized in Supplemental Table S5, http://links.lww.com/HC9/C284.”
Skow, R. J., Haykowsky, M. J., McMurtry, T. J., Cruz, C., Tomczak, C. R., & Tandon, P. (2026) · Liver Transplantation · doi:10.1097/lvt.0000000000000906 · Cited by 2
Kim, D. G., Hwang, S., Lee, K., Choi, G., You, Y. K., Ryu, J. H., Kim, B., Nah, Y. W., Kim, D., Cho, J. Y., et al. (2023) · Transplantation · doi:10.1097/tp.0000000000004517 · Cited by 2
Geng, N., Kong, M., Chen, H., Zhang, J., Xu, M., Song, W., Chen, Y., & Duan, Z. (2023) · Nutrition · doi:10.1016/j.nut.2023.112290 · Cited by 2
Chen, H., Lu, H., Zhou, H., Wu, B., Dong, Z., Zhang, S., Gu, Y., Zhou, G., Xiang, J., & Yang, J. (2024) · BMJ Open · doi:10.1136/bmjopen-2023-083228 · Cited by 2
“12 21 The implementation of dietary and exercise interventions is considered a fundamental approach in the management of sarcopenia and frailty.”
BackgroundLiu, G., Yi, Y., Wang, Y., Feng, Y., Lin, M., Yan, X., Wang, J., Ning, X., & Ma, N. (2024) · International Journal of General Medicine · doi:10.2147/ijgm.s448154 · Cited by 2
“10 Despite these developments, the evaluation of nutritional status and frailty in liver transplant recipients is hindered by a lack of universally accepted and clinically practical assessment tools.”
BackgroundPredictors of Frailty in Patients With Liver Cirrhosis
Panezai, M. Q., Yaseen, R. T., Khan, S. A., Abrar, G., Khalid, M. A., Haque, M. M. U., Lail, G., Kumar, D., Laeeq, S. M., & Luck, N. H. (2024) · Cureus · doi:10.7759/cureus.61626 · Cited by 2
“Studies have shown that LFI is correlated to MELD-Na and it not only improves the efficiency of MELD-Na while predicting short-term mortality in cirrhosis but also enhances subjective analysis of patient overall health status [9,15].”
BackgroundGeng, N., Kong, M., Zhang, J., Xu, M., Chen, H., Song, W., Chen, Y., & Duan, Z. (2025) · Frontiers in Nutrition · doi:10.3389/fnut.2025.1446265 · Cited by 2
Home-based LIver FrailTy Intervention (LIFT) in Transplant Candidates: A Feasibility Study
Thuluvath, A. J., Polineni, P., Morrissey, S., Belfanti, K., Nizamuddin, M., Siddiqui, O., Daud, A., Simpson, D. C., Levitsky, J., Flores, A. M., et al. (2024) · Transplantation · doi:10.1097/tp.0000000000005263 · Cited by 2
Hu, M. D., Chiou, S. H., Delk, M., Fenton, C. L., Lai, J. C., & Li, M. (2025) · Clinical and Translational Gastroenterology · doi:10.14309/ctg.0000000000000854 · Cited by 2
Self-citationPérez‐Sáez, M. J., Melilli, E., Arias‐Guillén, M., Franco, A., Martínez, R., Sancho, A., Molina, M., Facundo, C., Polanco, N., López, V., et al. (2025) · Transplant International · doi:10.3389/ti.2025.14098 · Cited by 2
“Reasons to choose one frailty tool over the rest are broad, and KT candidates lack of a speci fi c frailty tool (in contrast to liver transplant candidates) [38].”
Li, M., Zhao, Y., Liu, X., Dang, Z., Wang, X., Jiang, Y., & Yang, Z. (2018) · Oncology Letters · doi:10.3892/ol.2018.9590 · Cited by 2
CON: Patients of Advanced Age Should Not Routinely Undergo Liver Transplantation
Kalra, A., Kriss, M. S., Francis, P., & Norvell, J. P. (2019) · Clinical Liver Disease · doi:10.1002/cld.818 · Cited by 2
Development of a Motility Frailty Index in Patients with Gastroparesis
Winston, J. T., Rojas, P. G., Stocker, A. M., Mathur, P., Lorenz, D. J., Daniels, M. W., & Abell, T. L. (2021) · Gastrointestinal Disorders · doi:10.3390/gidisord3020008 · Cited by 2
“evaluated diverse physical performance tests, such as grip strength, chair stands, and balances [10], and from these created a liver frailty index.”
BackgroundAnálisis del impacto del trasplante hepático como condicionante de salud
Fernández‐Alonso, V., Hernández-Matías, A. M., Díaz-Serrano, M. T., Hernández-Caballero, A. B., & Pérez-Gómez, M. (2022) · Enfermería Clínica · doi:10.1016/j.enfcli.2022.03.006 · Cited by 2
Towey, J., Ngonadi, C., Rajoriya, N., Holt, A. P., Greig, C. A., & Armstrong, M. J. (2022) · BMJ Open Gastroenterology · doi:10.1136/bmjgast-2022-001052 · Cited by 2
MELD-Na: Does This Leave Anyone Behind?
Choden, T., & Satoskar, R. S. (2017) · Current Hepatology Reports · doi:10.1007/s11901-017-0356-8 · Cited by 2
PRO: Older Adults Should Be Offered Liver Transplantation
Haque, L., Palumbo, C. S., & Batisti, J. (2019) · Clinical Liver Disease · doi:10.1002/cld.821 · Cited by 2
Tapper, E. B. (2019) · Springer eBooks · doi:10.1007/978-3-030-26226-6_3 · Cited by 2
The Pathogenesis of Physical Frailty and Sarcopenia
Dasarathy, S. (2019) · Springer eBooks · doi:10.1007/978-3-030-26226-6_4 · Cited by 2
Fan, H., & Zhu, J. (2018) · Hepatology · doi:10.1002/hep.29813 · Cited by 2
“,((1)) in which the authors aimed to develop a frailty index to capture the extrahepatic complications of cirrhosis and enhance mortality prediction in patients who have cirrhosis.”
BackgroundMuscle abnormalities in cirrhosis: Calling for more strength in evaluation and prevention
Becchetti, C., & Bosch, J. (2019) · Digestive and Liver Disease · doi:10.1016/j.dld.2019.08.015 · Cited by 2
The impact of late liver allograft dysfunction on physical activity of liver transplant recipients
Malinovskaya, Y. O., Kokina, K. Y., Moysyuk, Y. G., & Сумцова, О. В. (2021) · Transplantologiya The Russian Journal of Transplantation · doi:10.23873/2074-0506-2021-13-4-356-366 · Cited by 1
Assessment of advanced age candidates for liver transplantation warrants more caution
Parente, A., & Ronca, V. (2022) · World Journal of Transplantation · doi:10.5500/wjt.v12.i2.24 · Cited by 1
The Impact of Sarcopenia, Frailty, and Malnutrition on Further Decompensation
Wang, S., & Tandon, P. (2022) · Springer eBooks · doi:10.1007/978-3-031-08552-9_50 · Cited by 1
Ernährung bei fortgeschrittener Leberzirrhose und perioperativ bei Lebertransplantation
Weiler, N., & Bojunga, J. (2023) · Die Gastroenterologie · doi:10.1007/s11377-023-00706-2 · Cited by 1
Clinical Application of Frailty in the Evaluation of Solid Organ Transplant Patients
Cimeno, A., Madariaga, M. L. L., Basu, A., Pezzuto, D., Parsons, R. F., & Huisingh-Scheetz, M. J. (2024) · Current Transplantation Reports · doi:10.1007/s40472-024-00436-6 · Cited by 2
Expanding the liver donor pool worldwide with hepatitis C infected livers, is it the time?
Hashem, M., Medhat, M. A., Abdeltawab, D., & Makhlouf, N. A. (2024) · World Journal of Transplantation · doi:10.5500/wjt.v14.i2.90382 · Cited by 1
The Role of Palliative Care in the Management of Patients with Hepatocellular Carcinoma
Mohy‐ud‐din, N., & Babich, M. (2024) · Clinics in Liver Disease · doi:10.1016/j.cld.2024.08.005 · Cited by 1
Modern views on the diagnosis of sarcopenia in patients with diffuse liver diseases
Ахмедов, В. А., & Исаева, А. С. (2024) · Medical alphabet · doi:10.33667/2078-5631-2024-26-24-27 · Cited by 1
Hepatocellular carcinoma management in older adults and its relation with frailty
Messina, G., & Palmieri, V. O. (2025) · Geriatric Care · doi:10.4081/gc.2025.13157 · Cited by 1
Skladaný, Ľ., Líška, D., Mesíková, K., Havaj, D. J., Adamcová-Selčanová, S., Sulejova, K. K., Žilinčanová, D., & Kohout, P. (2025) · BMJ Open · doi:10.1136/bmjopen-2025-100171 · Cited by 1
Shamaa, T. M., Allenspach, L. L., Shamaa, O., Hage‐Hassan, O., Kitajima, T., Shimada, S., Bajjoka‐Francis, I., Abouljoud, M. S., & Nagai, S. (2025) · Clinical Transplantation · doi:10.1111/ctr.70230 · Cited by 1
“LFI consists of handgrip strength, chair stands, and balance testing and measures the physical reserve and strength of patients [11, 12].”
Benítez, C., Reyes, D., Grandy, C., Thomas, I., Lavados, N., Kim, N. J., Gálvez, A., Valdés, S., Contreras, S., & Cândia, R. (2025) · Annals of Hepatology · doi:10.1016/j.aohep.2025.102114 · Cited by 1
Wang, S., Wei, H., Aihemaiti, Y., Ma, L., Tong, Y., & Li, F. (2025) · Transplant Immunology · doi:10.1016/j.trim.2025.102327 · Cited by 1
Metadata
- Authors
- Lai, J. C., Covinsky, K. E., Dodge, J. L., Boscardin, W. J., Segev, D. L., Roberts, J. P., & Feng, S.
- Affiliations
- University of California, San Francisco (US)
- Johns Hopkins University (US)
- Corresponding author
- Lai, Jennifer C.
- ORCID
- Venue
- Hepatology
- Published
- 2017-06-28
- Volume
- 66
- Issue
- 2
- Pages
- 564-574
- ISSN
- 0270-9139 (ISSN-L)
- 1527-3350
- PMC
- PMC5519430
- OpenAlex
- W2606209221
- Cited by
- 556
- References
- 34
- Citations by year
- 2026: 75 · 2025: 62 · 2024: 71 · 2023: 62 · 2022: 50 · 2021: 69 · 2020: 60 · 2019: 59 · 2018: 35 · 2017: 10
- FWCI
- 27.72
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- American College of Gastroenterology (K23AG048337, P30 DK026743, P30AG044281)
- National Institutes of Health
- University of California, San Francisco (P30 AG044281, P30DK026743)
- National Institute on Aging (K23AG048337, R01AG042504, R03AG045072, P30AG044281)
- National Institute of Diabetes and Digestive and Kidney Diseases (K24DK101828, P30DK026743)
- Liver Center, University of California, San Francisco (P30 DK026743, DK026743)
- Topics
- Health Sciences › Medicine › Hepatology › Liver Disease and Transplantation
- Health Sciences › Medicine › Geriatrics and Gerontology › Frailty in Older Adults
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Keywords
- frailty index, end-stage liver disease, liver cirrhosis, waitlist mortality, MELD-Na, liver transplantation, mortality prediction, grip strength, chair stand, balance, net reclassification improvement, instrumental activities of daily living, walking speed, exhaustion, physical activity
- MeSH terms
- Activities of Daily Living, Cause of Death, Disability Evaluation, Female, Humans, Liver Cirrhosis, Male, Middle Aged, Physical Fitness, Predictive Value of Tests, Prognosis, Retrospective Studies, Severity of Illness Index, Waiting Lists, Reproducibility of Results, Cohort Studies, Survival Rate, Liver Transplantation, Databases, Factual, Risk Assessment, End Stage Liver Disease
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