Frailty in Patients With Cirrhosis

  • Beverley Kok
  • Puneeta Tandon
Liver (J Bajaj, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Liver


Purpose of review

This review gives an overview of the evolving concept of physical frailty in patients with cirrhosis. As well as summarizing the available metrics that have been used to diagnose it, this review also examines the major recent trials that have investigated frailty in patients with cirrhosis. The complex relationship between sarcopenia and frailty is explored, and strategies to optimize frailty, such as including pharmacological and non-pharmacological therapies, are discussed.

Recent findings

Though there is heterogeneity between studies on how physical frailty in cirrhosis has been assessed, it is nonetheless becoming increasingly apparent that frailty in cirrhosis contributes to poor outcomes. A growing body of evidence strongly supports that frailty, as an entity distinct from comorbidity or measurable by laboratory-based liver disease severity, contributes to pre-transplant mortality and unplanned hospital admissions. If taken into account, frailty may improve pre-transplant mortality risk prediction.


Physical frailty in cirrhosis may be objectively assessed by a number of validated metrics though at present, we lack a uniform consensus on the most appropriate tool. Early identification of frailty may allow optimization of the patient with the potential to avoiding adverse outcomes. Further studies are awaited validating and exploring optimal approaches to diagnosing and reversing frailty.


Frailty Cirrhosis Sarcopenia 



Branched-chain amino acids


Clinical Frailty Scale




Computed tomography


Fried Frailty Criteria


Model for end-stage liver disease


Short Physical Performance Battery


6-min walking distance


Author Contributions

BK: Drafted the final manuscript.

PT: Revision of the final manuscript.

Compliance with Ethical Standards

Conflict of Interest

Beverley Kok declares that she has no conflict of interest.

Puneeta Tandon declares that she has no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001;56(3):M146–56.PubMedCrossRefGoogle Scholar
  2. 2.
    Angulo J, El Assar M, Rodriguez-Manas L. Frailty and sarcopenia as the basis for the phenotypic manifestation of chronic diseases in older adults. Mol Asp Med. 2016;50:1–32.CrossRefGoogle Scholar
  3. 3.
    Lai JC, Covinsky KE, Hayssen H, Lizaola B, Dodge JL, Roberts JP, et al. Clinician assessments of health status predict mortality in patients with end-stage liver disease awaiting liver transplantation. Liver Int. 2015;35(9):2167–73.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    •• Lai JC, Feng S, Terrault NA, Lizaola B, Hayssen H, Covinsky K. Frailty predicts waitlist mortality in liver transplant candidates. Am J Transplant. 2014;14(8):1870–9. Landmark study introducing the concept of frailty and its negative impact on outcomes in patients with cirrhosis.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    • Tandon P, Tangri N, Thomas L, Zenith L, Shaikh T, Carbonneau M, et al. A rapid bedside screen to predict unplanned hospitalization and death in outpatients with cirrhosis: a prospective evaluation of the Clinical Frailty Scale. Am J Gastroenterol. 2016;111(12):1759–67. Study supporting the use of a “clinic-friendly” global frailty scale to rapidly screen patients and identify whether they were at high risk of unplanned hospitalization or death.PubMedCrossRefGoogle Scholar
  6. 6.
    • Dunn MA, Josbeno DA, Tevar AD, Rachakonda V, Ganesh SR, Schmotzer AR, et al. Frailty as tested by gait speed is an independent risk factor for cirrhosis complications that require hospitalization. Am J Gastroenterol. 2016;111(12):1768–75. Study supporting the use of a single component assessment—gait speed—as a marker of hospitalization in patients with cirrhosis. Relevant discussion about the cost implications of frailty.PubMedCrossRefGoogle Scholar
  7. 7.
    •• Lai JC, Covinsky KE, Dodge JL, Boscardin WJ, Segev DL, Roberts JP, et al. Development of a novel frailty index to predict mortality in patients with end-stage liver disease. Hepatology. 2017;66(2):564–74. This study provides clinicians with a prospectively established battery of 3 tools—the “liver frailty index” for the prediction of waitlist mortality.PubMedCrossRefGoogle Scholar
  8. 8.
    Bruyere O, Buckinx F, Beaudart C, Reginster JY, Bauer J, Cederholm T, et al. How clinical practitioners assess frailty in their daily practice: an international survey. Aging Clin Exp Res. 2017;29(5):905–12.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    • Carey EJ, Steidley DE, Aqel BA, Byrne TJ, Mekeel KL, Rakela J, et al. Six-minute walk distance predicts mortality in liver transplant candidates. Liver Transpl. 2010;16(12):1373–8. A seminal study which highlighted the impact of muscle function on outcomes in patients with cirrhosis.PubMedCrossRefGoogle Scholar
  10. 10.
    Roberts RE, Vernon SW. The Center for Epidemiologic Studies Depression Scale: its use in a community sample. Am J Psychiatry. 1983;140(1):41–6.PubMedCrossRefGoogle Scholar
  11. 11.
    Rockwood K, Song X, MacKnight C, Bergman H, Hogan DB, McDowell I, et al. A global clinical measure of fitness and frailty in elderly people. CMAJ. 2005;173(5):489–95.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Mitnitski AB, Mogilner AJ, MacKnight C, Rockwood K. The mortality rate as a function of accumulated deficits in a frailty index. Mech Ageing Dev. 2002;123(11):1457–60.PubMedCrossRefGoogle Scholar
  13. 13.
    Teng EL, Chui HC. The Modified Mini-Mental State (3MS) examination. J Clin Psychiatry. 1987;48(8):314–8.PubMedGoogle Scholar
  14. 14.
    Guralnik JM, Simonsick EM, Ferrucci L, Glynn RJ, Berkman LF, Blazer DG, et al. A short physical performance battery assessing lower extremity function: association with self-reported disability and prediction of mortality and nursing home admission. J Gerontol. 1994;49(2):M85–94.PubMedCrossRefGoogle Scholar
  15. 15.
    Volpato S, Cavalieri M, Sioulis F, Guerra G, Maraldi C, Zuliani G, et al. Predictive value of the Short Physical Performance Battery following hospitalization in older patients. J Gerontol A Biol Sci Med Sci. 2011;66((1):89–96.CrossRefGoogle Scholar
  16. 16.
    ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002;166(1):111–7.Google Scholar
  17. 17.
    Lai JC, Dodge JL, Sen S, Covinsky K, Feng S. Functional decline in patients with cirrhosis awaiting liver transplantation: results from the functional assessment in liver transplantation (FrAILT) study. Hepatology. 2016;63(2):574–80.PubMedCrossRefGoogle Scholar
  18. 18.
    Sinclair M, Poltavskiy E, Dodge JL, Lai JC. Frailty is independently associated with increased hospitalisation days in patients on the liver transplant waitlist. World J Gastroenterol. 2017;23(5):899–905.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Tapper EB, Finkelstein D, Mittleman MA, Piatkowski G, Lai M. Standard assessments of frailty are validated predictors of mortality in hospitalized patients with cirrhosis. Hepatology. 2015;62(2):584–90.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Katz S, Ford AB, Moskowitz RW, Jackson BA, Jaffe MW. Studies of illness in the aged. The index of ADL: a standardized measure of biological and psychosocial function. JAMA. 1963;185:914–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Bergstrom N, Braden B, Kemp M, Champagne M, Ruby E. Predicting pressure ulcer risk: a multisite study of the predictive validity of the Braden Scale. Nurs Res. 1998;47(5):261–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Morse JM, Tylko SJ, Dixon HA. The patient who falls—and falls again: defining the aged at risk. J Gerontol Nurs. 1985;11(11):15–8.PubMedCrossRefGoogle Scholar
  23. 23.
    Cruz-Jentoft AJ, Baeyens JP, Bauer JM, Boirie Y, Cederholm T, Landi F, et al. Sarcopenia: European consensus on definition and diagnosis: report of the European Working Group on Sarcopenia in Older People. Age Ageing. 2010;39(4):412–23.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Rosenberg IH. Sarcopenia: origins and clinical relevance. J Nutr. 1997;127(5 Suppl):990s–1s.PubMedCrossRefGoogle Scholar
  25. 25.
    Dasarathy S, Merli M. Sarcopenia from mechanism to diagnosis and treatment in liver disease. J Hepatol. 2016;65(6):1232–44.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Carey EJ, Lai JC, Wang CW, Dasarathy S, Lobach I, Montano-Loza AJ, et al. A multicenter study to define sarcopenia in patients with end-stage liver disease. Liver Transpl. 2017;23(5):625–33.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Cederholm T, Barazzoni R, Austin P, Ballmer P, Biolo G, Bischoff SC, et al. ESPEN guidelines on definitions and terminology of clinical nutrition. Clin Nutr. 2017;36(1):49–64.PubMedCrossRefGoogle Scholar
  28. 28.
    Landi F, Calvani R, Cesari M, Tosato M, Martone AM, Bernabei R, et al. Sarcopenia as the biological substrate of physical frailty. Clin Geriatr Med. 2015;31(3):367–74.PubMedCrossRefGoogle Scholar
  29. 29.
    Kim G, Kang SH, Kim MY, Baik SK. Prognostic value of sarcopenia in patients with liver cirrhosis: a systematic review and meta-analysis. PLoS One. 2017;12(10):e0186990.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    van Vugt JL, Levolger S, de Bruin RW, van Rosmalen J, Metselaar HJ, Systematic Review JNIJ. Meta-analysis of the impact of computed tomography-assessed skeletal muscle mass on outcome in patients awaiting or undergoing liver transplantation. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg. 2016;16(8):2277–92.CrossRefGoogle Scholar
  31. 31.
    Merli M, Giusto M, Lucidi C, Giannelli V, Pentassuglio I, Di Gregorio V, et al. Muscle depletion increases the risk of overt and minimal hepatic encephalopathy: results of a prospective study. Metab Brain Dis. 2013;28(2):281–4.PubMedCrossRefGoogle Scholar
  32. 32.
    Nardelli S, Lattanzi B, Torrisi S, Greco F, Farcomeni A, Gioia S, et al. Sarcopenia is risk factor for development of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt placement. Clin Gastroenterol Hepatol. 2017;15(6):934–6.PubMedCrossRefGoogle Scholar
  33. 33.
    Goodpaster BH, Park SW, Harris TB, Kritchevsky SB, Nevitt M, Schwartz AV, et al. The loss of skeletal muscle strength, mass, and quality in older adults: the health, aging and body composition study. J Gerontol A Biol Sci Med Sci. 2006;61(10):1059–64.PubMedCrossRefGoogle Scholar
  34. 34.
    Tandon P, Low G, Mourtzakis M, Zenith L, Myers RP, Abraldes JG, et al. A model to identify sarcopenia in patients with cirrhosis. Clin Gastroenterol Hepatol. 2016;14(10):1473–80.e3.PubMedCrossRefGoogle Scholar
  35. 35.
    Wang CW, Feng S, Covinsky KE, Hayssen H, Zhou LQ, Yeh BM, et al. A comparison of muscle function, mass, and quality in liver transplant candidates: results from the functional assessment in liver transplantation study. Transplantation. 2016;100(8):1692–8.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Tsien C, Shah SN, McCullough AJ, Dasarathy S. Reversal of sarcopenia predicts survival after a transjugular intrahepatic portosystemic stent. Eur J Gastroenterol Hepatol. 2013;25(1):85–93.PubMedCrossRefGoogle Scholar
  37. 37.
    Hirsch S, Bunout D, de la Maza P, Iturriaga H, Petermann M, Icazar G, et al. Controlled trial on nutrition supplementation in outpatients with symptomatic alcoholic cirrhosis. JPEN J Parenter Enteral Nutr. 1993;17(2):119–24.PubMedCrossRefGoogle Scholar
  38. 38.
    Marchesini G, Bianchi G, Merli M, Amodio P, Panella C, Loguercio C, et al. Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a double-blind, randomized trial. Gastroenterology. 2003;124(7):1792–801.PubMedCrossRefGoogle Scholar
  39. 39.
    Ney M, Vandermeer B, van Zanten SJ, Ma MM, Gramlich L, Tandon P. Meta-analysis: oral or enteral nutritional supplementation in cirrhosis. Aliment Pharmacol Ther. 2013;37(7):672–9.PubMedCrossRefGoogle Scholar
  40. 40.
    Koretz RL, Avenell A, Lipman TO. Nutritional support for liver disease. Cochrane Database Syst Rev. 2012;(5):Cd008344.
  41. 41.
    Plauth M, Cabre E, Riggio O, Assis-Camilo M, Pirlich M, Kondrup J, et al. ESPEN guidelines on enteral nutrition: liver disease. Clin Nutr. 2006;25(2):285–94.PubMedCrossRefGoogle Scholar
  42. 42.
    Amodio P, Bemeur C, Butterworth R, Cordoba J, Kato A, Montagnese S, et al. The nutritional management of hepatic encephalopathy in patients with cirrhosis: International Society for Hepatic Encephalopathy and Nitrogen Metabolism Consensus. Hepatology. 2013;58(1):325–36.PubMedCrossRefGoogle Scholar
  43. 43.
    Tsien CD, McCullough AJ, Dasarathy S. Late evening snack: exploiting a period of anabolic opportunity in cirrhosis. J Gastroenterol Hepatol. 2012;27(3):430–41.PubMedCrossRefGoogle Scholar
  44. 44.
    • Plank LD, Gane EJ, Peng S, Muthu C, Mathur S, Gillanders L, et al. Nocturnal nutritional supplementation improves total body protein status of patients with liver cirrhosis: a randomized 12-month trial. Hepatology. 2008;48(2):557–66. Key study illuminating the beneficial effect on lean body mass in patients with cirrhosis by avoiding prolonged overnight fasting.PubMedCrossRefGoogle Scholar
  45. 45.
    Duarte-Rojo A, Ruiz-Margain A, Montano-Loza AJ, Macias-Rodriguez RU, Ferrando A, Kim WR. Exercise and physical activity for patients with end-stage liver disease: improving functional status and sarcopenia while on the transplant waiting list. Liver Transpl. 2018;24(1):122–39.PubMedCrossRefGoogle Scholar
  46. 46.
    Zenith L, Meena N, Ramadi A, Yavari M, Harvey A, Carbonneau M, et al. Eight weeks of exercise training increases aerobic capacity and muscle mass and reduces fatigue in patients with cirrhosis. Clin Gastroenterol Hepatol. 2014;12(11):1920–6.e2.PubMedCrossRefGoogle Scholar
  47. 47.
    Fiatarone MA, O’Neill EF, Ryan ND, Clements KM, Solares GR, Nelson ME, et al. Exercise training and nutritional supplementation for physical frailty in very elderly people. N Engl J Med. 1994;330(25):1769–75.PubMedCrossRefGoogle Scholar
  48. 48.
    Garcia-Pagan JC, Santos C, Barbera JA, Luca A, Roca J, Rodriguez-Roisin R, et al. Physical exercise increases portal pressure in patients with cirrhosis and portal hypertension. Gastroenterology. 1996;111(5):1300–6.PubMedCrossRefGoogle Scholar
  49. 49.
    Debette-Gratien M, Tabouret T, Antonini MT, Dalmay F, Carrier P, Legros R, et al. Personalized adapted physical activity before liver transplantation: acceptability and results. Transplantation. 2015;99(1):145–50.PubMedCrossRefGoogle Scholar
  50. 50.
    Roman E, Garcia-Galceran C, Torrades T, Herrera S, Marin A, Donate M, et al. Effects of an exercise programme on functional capacity, body composition and risk of falls in patients with cirrhosis: a randomized clinical trial. PLoS One. 2016;11(3):e0151652.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Neff GW, O'Brien CB, Montalbano M, Meyer D, DeManno A, Muslu H, et al. Beneficial effects of topical testosterone replacement in patients with end-stage liver disease. Dig Dis Sci. 2004;49(7–8):1186–9.PubMedCrossRefGoogle Scholar
  52. 52.
    Neff GW, O'Brien CB, Shire NJ, DeManno A, Kahn S, Rideman E, et al. Topical testosterone treatment for chronic allograft failure in liver transplant recipients with recurrent hepatitis C virus. Transplant Proc. 2004;36(10):3071–4.PubMedCrossRefGoogle Scholar
  53. 53.
    Yurci A, Yucesoy M, Unluhizarci K, Torun E, Gursoy S, Baskol M, et al. Effects of testosterone gel treatment in hypogonadal men with liver cirrhosis. Clin Res Hepatol Gastroenterol. 2011;35(12):845–54.PubMedCrossRefGoogle Scholar
  54. 54.
    Sinclair M, Grossmann M, Hoermann R, Angus PW, Gow PJ. Testosterone therapy increases muscle mass in men with cirrhosis and low testosterone: a randomised controlled trial. J Hepatol. 2016;65(5):906–13.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Gastroenterology (Liver Unit)University of AlbertaEdmontonCanada

Personalised recommendations