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Keywords:

  • adult;
  • liver transplantation;
  • long-term;
  • quality of life

Abstract

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. Acknowledgements
  8. References
  9. Supporting Information

Background & Aims

Liver transplantation is the only curative intervention for terminal liver disease. Accurate long-term quality of life (QOL) data are required in the context of improved surgical outcomes and increasing post-transplant survival. This study reviews the long-term QOL after primary liver transplantation in adult patients surviving 5 or more years after surgery.

Methods

A literature search was conducted on PubMed for all studies matching the eligibility criteria between January 2000 and October 2013. Bibliographies of included studies were also reviewed. Two authors independently performed screening of titles and abstracts. Consensus for studies included for review was achieved by discussion between authors based on predetermined eligibility criteria. Quality appraisal and data tabulation were performed using predetermined forms. Results were synthesized by narrative review.

Results

Twenty-three studies (5402 patients) were included. QOL following liver transplantation remains superior to preoperative status up to 20 years post-operatively. More post-operative complications predicted worse QOL scores especially in physical domains. Benefits in functional domains persist long-term with independence in self-care and mobility. Employment rates recover in the short-term but decline after 5 years, and differ significantly between various aetiologies of liver disease. Overall QOL improves to a similar level as the general population, but physical function remains worse. Participation in post-operative physical activity is associated with superior QOL outcomes in liver transplant recipients compared to the general population. QOL improvements are similar compared to lung, kidney and heart transplantation. Heterogeneity between studies precluded quantitative analysis.

Conclusions

Liver transplantation confers specific long-term QOL and functional benefits when compared to preoperative status. This information can assist in providing a more complete estimate of the overall health of liver transplant recipients and the effectiveness of surgery. Guidelines for future studies are provided.

Abbreviations
CLD

chronic liver disease

CLDQ

Chronic Liver Disease Questionnaire

NHP

Nottingham Health Profile

NIDDKQOL

National Institute of Diabetes, Digestive and Kidney Diseases Liver Transplantation Questionnaire

QOL

Quality of life

SF-36

Medical outcomes short form 36

TxEQ-D

Transplant Effects Questionnaire

Liver transplantation is a well-established therapy with curative intent for the terminal stages of chronic liver disease (CLD). It was initially a high risk procedure, but advances in surgical techniques and emerging immunosuppressive therapy has resulted in significant improvements in post-transplantation survival. Contemporary studies report 1-year, 10-year and 18-year survival at 83–88% [1, 2], 68–72% [3, 4], and 48–56% [4, 5] respectively.

As survival and clinical outcomes of liver transplantation improve, the focus has shifted to quality of life (QOL) outcomes after surgery [6-8]. This is particularly important since patients' QOL is already greatly diminished before surgery due to symptoms, and emotional and social stress [9, 10]. Many patients are more concerned about QOL than longevity, which is key to the importance of QOL assessments [11, 12].

Transplantation procedures carry significant morbidity and potentially serious complications including acute or chronic rejection of the donor organ, infections, biliary complications, reoperation and recurrence of disease [6]. Given the operative morbidity and long-term immunosuppression required, purely prolonging life may not be the best outcome for patients.

Previous reviews have demonstrated significant improvements in post-transplant QOL, but patients appear to have ongoing deficits when compared to healthy controls [11, 12]. To date there has been no systematic review on the long-term effects on QOL. This is critical in outcome evaluation, in assessing the overall health status of transplant recipients and the cost-effectiveness of the procedure. QOL data allow clinicians to inform prospective transplant recipients of the expected projector of their post-operative QOL and aid in their decision to undertake surgery.

We conducted a systematic review of publications from the start of this millennium to investigate long-term QOL after liver transplantation in adults compared to (i) preoperative patients, (ii) the general population, and (iii) other organ transplantations. QOL outcomes assessed included physical, mental and functional health such as employment and sexual health.

Methods

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. Acknowledgements
  8. References
  9. Supporting Information

The structure of this systematic review followed the PRISMA guidelines [13].

Definition and measurement of quality of life

Quality of life is a ‘multidimensional construct that is affected by physical health, psychological health, functional status, social relationships, personal beliefs’ [14] QOL may be classified as disease-specific or generic.

In CLD, disease-specific QOL assesses a patient's physical and mental state related to the symptoms, treatment and prognosis of CLD. Common disease-specific QOL assessment tools for liver transplant recipients are Chronic Liver Disease Questionnaire (CLDQ) [15], Liver Disease Quality of Life (LDQOL) [16], Transplant Effects Questionnaire (TxEQ-D) [17], the Ferrans and Powers Questionnaire [18] and National Institute of Diabetes, Digestive and Kidney Diseases Liver Transplantation Questionnaire (NIDDKQOL) [19].

Generic QOL instruments such as Medical Outcomes Short Form-36 (SF-36) [20], Euro-QOL [21] and Nottingham Health Profile (NHP) [22] are used to assess broad domains of QOL. Generic and disease-specific assessments of QOL in parallel facilitate holistic and quantitative analysis of QOL.

Detailed descriptions of all scoring systems and QOL instruments are outlined in the supplemental digital content (Table S1).

Eligibility criteria

Studies considered for review had the following characteristics: (i) adult recipients of primary single-organ liver transplantation, (ii) both cadaveric and living donor transplantations (iii) disease-specific and/or generic QOL data recorded using a validated QOL assessment instrument, (iv) post-operative QOL compared to preoperative state or other preoperative patients, general population and/or other organ transplants, and (v) follow-up period of at least 5 years. These studies were restricted according to the following report characteristics: (i) publication date after January 2000, (ii) English language, and (iii) original articles.

Long-term follow-up was defined as at least 5 years duration based on mean, median or final recorded time of follow-up. The rationale for 5 years as a cut-off is based on previous studies which defined long-term survival after liver transplantation as 5 years [23-26].

Information sources and search strategy

On October 2013, a literature search was conducted using MeSH keyword search on PubMed (MEDLINE) for all studies which matched the eligibility criteria above (Fig. 1). An additional manual search of OVID (MEDLINE) and EBSCOhost (EMBASE) as well as bibliographies of each included study was conducted to identify studies not covered by the initial MeSH keyword search. All identified articles were retrieved from the aforementioned databases.

image

Figure 1. Search algorithm.

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Study selection

Following the search, two reviewers independently performed screening of titles and abstracts after MeSH keyword and manual searches. Studies were excluded if they did not meet eligibility criteria. Consensus for studies included for review was achieved by discussion between reviewers based on the predetermined eligibility criteria.

Data items and extraction

All data items for assessment of study quality (Table 1) and study results (Table 2) were predetermined. Data extraction was then performed by 2 reviewers using standardized pilot forms.

Table 1. Quality appraisal
Author yearStudy designPatientsAverage ageAetiologyFollow-up durationDisease-specific HRQOLGeneric HRQOLResponse rate (%)Comparison groupsLevel of evidence
  1. ADS, Hospital Anxiety And Depression Scale; AI-C, autoimmune cirrhosis; ALF, acute liver failure; BA, biliary atresia; BSI, Brief Symptom Inventory; CLD, chronic liver disease; CLDQ, Chronic Liver Diseases Questionnaire; Crypt-C, cryptogenic cirrhosis; EQ-6D, European Quality Of Life Questionnaire 6 Dimensional; ETOH-C, alcoholic cirrhosis; EuroQOL, European Quality Of Life Questionnaire; FAP, familial adenomatous polyposis; FLF, fulminant liver failure; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HOCF, high output cardiac failure; IPAQ, International Physical Activity Questionnaire; LDQOL, Liver Disease Quality of Life; LT, liver transplantation; Metabolic, metabolic disease; MMSE, Mini Mental State Examination; MOS 20, Medical Outcomes Survey 20; NHP, Nottingham Health Profile; NIDDKQOL, National Institute of Diabetes and Digestive and Kidney Disease Transplantation Quality of Life Questionnaire; NR, not reported; P, prospective; PBC, primary biliary cirrhosis; PLD, polycystic liver disease; PSC, primary sclerosing cholangitis; R, retrospective; SBC, secondary biliary cirrhosis; SIP, sickness impact profile; Vir-C, viral cirrhosis.

Zahn et al. [52]R28153HCC 24%, Vir-C 16%, ETOH-C 26%, Cholestatic liver disease 10%, Other 24%42 (2–136) monthsSF-36, Employment Survey70Wait listIII
Sirivatanauksorn et al. [43]R11653.4HBV 20.8%, HCV 23.4%, HBV + HCV 3.4%, ETOH-C 11.2%, HCC 1.7%, HBV +  HCC 14.6%, HCV + HCC 4.3%, HBV + ETOH-C 1.7%, HCV + ETOH-C 4.3%, ETOH-C + HCC 0.9%, Other 14.7%8 yearsCLDQSF-36NRPre-LTIII
Aberg et al. [32]R40142–55 (mean age reported by aetiologyPSC 16%, PBC 20%, ALF 22%, ETOH-C 11%, Tumours 5%, Other 25%8 (5–11) years15D89Between aetiologiesIII
Masala et al. [33]R17055.2NR1–8 yearsSF-36, International Physical Activity Questionnaire95ControlsIII
Morales et al. [40]R147955NR6.4 yearsStudy's own questionnaireEuroQOL99Renal transplantIII
Rongies et al. [41]RCT31Group A 55.2, Group B 56NRGroup A 7.8 ± 4 years, Group B 6.7 ± 1.5 yearsSF36100Group A (no physical activity), Group B (physical activity at least once a week)II
Lasker et al. [39]R10058PBC 100%5.2 yearsNIDDKQOL, PBC-40SF-36NRPBCs on wait listIII
Duffy et al. [5]P29328HCV 21%, BA 20%, PBC 13%, HBV 9%, PSC 8%, Metabolic 7%, Crypt-C 5%, HCC 4%, ETOH-C 3%, ALF 2%, AI-C 2%, Others 6.4%20 yearsLDQOLSF-36, Neuropsychological Impairment Scale42US population, CLDII
Dupuis-Girod et al. [36]R1351.8Isolated HOCF 69%, biliary necrosis 15%, both HOCF and biliary necrosis 7.7%, haemobilia 7.7%109 (1–200) monthsSF-36100Pre-LTIII
Ruppert et al. [42]P38148.9HBV or HBV + HDV 3.7%, HCV 14.2%, ETOH-C 10%, ETOH-C + HCV 5.2%, AI-C 68%, Crypt-C 10.2%, PBC 16.5%, PSC 23.9%, Other 9.4%9.7 ± 1.5 yearsNIDDKQOL1001 year and 12 years post-LTIII
Drent et al. [35]P952FAP 100%6 (4–12) yearsSF-36100Non-FAP liver transplant groupIV
Desai et al. [34]R10236.9PBC 25%, BA 12%, AI-C 11%, Met 11%, ETOH-C 9%, PSC 9%, Budd-Chiari 7%, FLF 7%, Tumours 3%, Crypt-C 2%, Vir-C 2%, SBC 2%14.2 (10–30) yearsThe Ferrans and Powers questionnaireSF-3660UK population normsIII
Goetzmann et al. [54]R370 (liver 117)48.8HCV 23%, HBV 18%, HCC 10%, Crypt-C 9%, PBC 9%, ETOH-C 8%, FLF 8%, Other 15%66 (4–229) monthsTxEQ-DSF-3664Heart, Lung, Kidney transplantsIII
Kousoulas et al. [38]R13738Crypt-C 16.3%, Budd-Chiari 15.3%, HBV 9.6%, PBC 7.6%, PSC 6.7%, HCV 6.7%, ETOH-C 3.8%, Others 29.8%, HCC 8.7%, PLD 7.6%, Metabolic 8%, Benign liver tumours 2.9%>15 yearsSF-3676German populationIII
de Kroon et al. [44]R4938.5PBC (35%), PSC 16%, AI-C 14%, Crypt-C 11%, Budd-Chiari 8%, Other 16%18.8 (15.0–26.8) yearsEQ-6DNRNoneIII
Ho et al. [49]R32054ALF caused by toxin ingestion 11%, HBV 7%, HCV 23%, AI-C 28%, Metabolic 3%, ETOH-C 9%, HCC 3%, Other 12%

<12 months 7%

1–5 years 33%

>5 years 60%

Sexual health questionnaire42NoneIII
Kirchner et al. [51]P3648PLD 100%62 (5–156) monthsSF-36100Combined liver and kidney transplantation, age-matched German populationIII
Sainz-Barriga et al. [31]P15259.4HCV 38%, Other 62%3.5 (1–8) years

LEIPAD

BSI

83Wait listIII
Kizilisik et al. [45]R105Male 49.1, Female 51.9HCV, BA, PSC, PBC, ETOH-C, chronic active hepatitis, congenital hepatic fibrosis, Budd-Chiari177 (139–217) monthsModified SF-36, Karnofsky performance scale, Psychosocial adjustment to illness scaleNRAge-matched general populationIII
Karam et al. [46]P126 (liver)49.3NR>10 yearsNIDDKQOL86General population, kidney transplantation and heart transplantationIII
Lewis and Howdle [47]R3649.5PBC, AI-C, SBC, ETOH-C, Budd-Chiari, Crypt-C, hepatoblastoma, primary oxalosis, paracetamol overdose149 (135.5–164.5) monthsEuroQOL, ADS, MMSE80ControlsIII
Painter et al. [48]R32055NR7.1 ± 1.5 yearsSF3659Active group, Inactive groupIII
Cowling et al. [50]P62851–54 (mean age reported by aetiology)(Laennec's/non-Laennec's): ETOH-C 21%/0%, AI-C 0%/6%, Crypt-C 0%/18%, FLF 0%/5%, HBV 0%/6%, HCC 0%/2%, HCV 8.3%/19%, Met 8.3%/2%, Other 0%/6%, Other malignancy 0%/2%, PBC 0%/20%, PSC 0%/14%2 and 5 yearsModified NIDDKQOL, liver transplantation QOL form

Karnofsky Performance

Status Scale, the Index of Well-Being, MOS, NHP

20Laennac, Non-LaennecIII
Table 2. Results of included studies
Author yearComparison groupsDisease-specific HRQOLGeneric HRQOL 
  1. ALF, acute liver failure; BP, bodily pain; CAD, coronary artery disease; CLD, chronic liver disease; ETOH-C, alcoholic cirrhosis; FAP, familial adenomatous polyposis; GH, general health; IQR, Inter-quartile range; LEIPAD, The Leiden and Padua questionnaire; LT, liver transplantation; MCS, Mental Composite Scale; MH, mental health; MI, myocardial infarction; NR, not reported; OR, odds ratio; PBC, primary biliary cirrhosis; PCS, Physical Composite Scale; PF, physical function; PSC, primary sclerosing cholangitis; PTDM, post-transplantation diabetes mellitus; QOL, quality of life; RE, role emotional; RP, role physical; SF, social function; VT, vitality.

  2. a

    Values estimated from graph.

  3. b

    Unable to interpret data.

  4. c

    Follow-up duration >10 years.

Zahn et al. [52]a5–10 years post-LT vs >10 years post-LT Physical health:PF (70 vs 69); BP (80 vs 58); GH (59 vs 63); VT (58 vs 51)
Mental health:RE (72 vs 74); MH (70 vs 68)
Social health:SF (55 vs 72)
Functional health:RP (60 vs 61)
Sirivatanauksom et al. [43]Key points:QOL improvements plateaued at 3 years post-LT and persisted long-term
Pre-LT vs Post-LTFatigue (3.98 vs 4.97); Activity (4.25 vs 5.08); Emotional function (4.59 vs 5.19); Abdominal symptoms (4.52 vs 5.22); Systemic symptoms (4.44 vs 5.25); Worry (4.60 vs 5.54)Physical health:PF (51.75 vs 71.35); BP (57.14 vs 75.63); GH (44.30 vs 70.48); VT (59.52 vs 71.52);
Mental health:RE (43.86 vs 86.44); MH (56.43 vs 75.45)
Social health:SF (61.62 vs 76.69)
Functional health:RL (39.47 vs 80.93)
Key points:Patients post-LT scored better SF-36 and CLDQ scores in all domains compared to pre-LT patients up to the final follow-up duration of 8 years
Aberg et al. [32]Aetiologies of CLDPhysical health:GH (PSC 0.886; PBC 0.882; ALF 0.882; ETOH-C 0.883); Miscellaneous (0.911); Liver tumour (0.873)
Mental health:
Social health:

Likelihood of resuming work (OR) (reference: PBC)

PSC 2.44 (1.07–5.58); ALF 0.87 (0.39–1.95); ETOH-C 2.47 (1.01–6.08); Miscellaneous 1.88 (0.85–4.16); Liver tumour 2.09 (0.70–6.26)

Early retirement (%): (PSC 83; PBC 63; ALF 64, ETOH-C 80; CLD 66; liver tumour 69)

Functional health:
Key points:QOL scores late after LT were below population norms but remained relatively high and comparable between aetiologies. Lowest rates of employment were observed in ALF and PBC
Masala et al. [33]Post-LT vs ControlsPhysical health:PF (71.48 ± 22.60 vs 82.63 ± 22.66); GH (62.12 ± 20.76 vs 59.05 ± 22.29); VT (58.14 ± 19.84 vs 59.49 ± 17.94); PCS (46.02 ± 8.79 vs 47.27 ± 9.54)
Mental health:RE (59.87 ± 40.63 vs 74.07 ± 33.28); MH (65.11 ± 20.01 vs 71.77 ± 19.55); MCS (45.26 ± 10.06 vs 47.75 ± 9.20)
Social health:SF (72.68 ± 23.55 vs 74.42 ± 23.33)
Functional health:RP (56.94 ± 41.61 vs 72.22 ± 35.57); Metabolic Equivalent (MET) (2880.05 ± 3863.32 vs 3719.01 ± 4980.22)
Key points:Post-LT patients have full recovery of health status but score lower than the general population. Physical and social problems can persist. MET positively associate with all domains of SF-36 scores
Morales et al. [40]RT vs LTVAS Scale (72.7 ± 18.3 vs 76.4 ± 17.6)Physical health:EQ index score (0.73 ± 0.16); EQ-5D Mobility (70% vs 74.8%); Pain (43.8% vs 31.6%)
Mental health:Anxiety/Depression (2.3% vs 3.7%)
Social health:
Functional health:Self-care (93.1 vs 91.8); usual activities (70.9% vs 66.9%)
Key points:Majority (94.2%) of patients reported continued improvement in QOL up to over 6 years post-LT. High-intensity immunosuppressive treatment is associated with poorer QOL outcomes
Rongies et al. [41]Group A (0 days/week of physical activity) vs Group B (3.9 ± 2.5 days/week of physical activity)Physical health:PF (49.2 ± 20.4 vs 80.4 ± 21); BP (47.9 ± 11.6 vs 62.9 ± 22.1); GH (31.2 ± 13.9 vs 48.8 ± 23.9); PCS (36.4 ± 9.6 vs 59.1 ± 12.4)
Mental health:RE (20.5 ± 34.8 vs 82 ± 35); MCS (45.11 ± 11.5 vs 68.1 ± 10.2)
Social health:SF (57.7 ± 18.8 vs 74 ± 17.3)
Functional health:
Key points:All aspects of QOL including physical Function, body problems, general health, social function, and emotional health were significantly improved in patients who engaged in regular physical exercise more than 5 years after LT
Lasker et al. [39]Waiting list vs Post-LTSymptoms (5.05 vs 1.84); Fatigue (83.2 vs 46.3); Uncertainty (91.19 vs 78.95); Depression (23.5 vs 14.9)Physical health:PCS (34.4 vs 40.5)
Mental health:MCS (38.4 vs 46.2)
Social health:Social and family involvement (5.71 vs 7.03)
Functional health:
Key points:Better QOL was observed in patients who were physically active after LT
Duffy et al. [5]c20 years post-LT vs US norms vs Pre-LTSymptoms (77 ± 18 vs 55 ± 21); effects of liver disease (89 ± 17 vs 60 ± 24); stigmata of liver disease (88 ± 22 vs 71 ± 25)Physical health:PF (79 ± 26 vs 84 ± 23 vs 51 ± 29); BP (72 ± 28 vs 75 ± 24 vs 50 ± 32); GH (62 ± 23 vs 72 ± 20 vs 54 ± 27); VT (63 ± 22 vs 61 ± 21 vs 52 ± 28); PCS (46 ± 12 vs 50 ± 10 vs NR)
Mental health:

RE (75 ± 39 vs 81 ± 33 vs 58 ± 20); MH (80 ± 20 vs 74 ± 18 vs 34 ± 22); MCS (52 ± 11 vs 50 ± 10 vs NR)

Cognition: Global (63.92 ± 48.3 vs 47.5 ± 30.9); Memory (5.60 ± 5.3 vs 7.1 ± 4.6); Cognitive efficiency (5.10 ± 7.1 vs 5.2 ± 5.2 vs NR); Attention (6.27 ± 7.0 vs 7.3 ± 5.2 vs NR)

Social health:SF (77 ± 26 vs 83 ± 23 vs 33 ± 21); Sexual functioning (84 ± 20 vs NR vs 52 ± 39); Quality of social interaction (78 ± 17 vs NR vs 67 ± 18)
Functional health:RP (67 ± 42 vs 81 ± 34 vs 38 ± 31)
Key points:Over 50% survived 20 years post-LT and report QOL superior to patients with CLD
Dupuis-Girod et al. [36]aPre-LT vs Post-LTPhysical health:PF (30 vs 80); BP (45 vs 75); GH (40 vs 60); VT (25 vs 60)
Mental health:RE (20 vs 52); MH (50 vs 70)
Social health:SF (40 vs 75)
Functional health:RP (20 vs 45); Physical Activity (16 vs 26)
Key points:All patients reported improvement in QOL at 7 years post-LT
Ruppert et al. [42]Physical health:

Physical distress (high score = bad QOL): [14.9 (13.4, 16.3)]

Health perception (higher score = better QOL): [8.2 (7.96, 8.44)]

Mental health:Anxiety and Depression [4.82 (4.27, 5.37)]
Social health:Social and role function (high score = good QOL) 15.9 (15.4, 16.3)
Functional health:Personal function (high score = good QOL) 1.95 (1.77, 2.13)
Key points:QOL improves within 1 year post-LT but decline with time in most areas. QOL remains higher than pre-LT status. Patients with concomitant ETOH-C and HCV report worse QOL and greatest rate of decline
Drent et al. [35]aPost-LT non-FAP vs post-LT FAP vs Dutch PopulationPhysical health:PF (30 vs 75 vs 85); BP (60 vs 93 vs 78); GH (34 vs 79 vs 72); VT (48 vs 80 vs 72)
Mental health:RE (50 vs 99 vs 82); MH (69 vs 91 vs 78)
Social health:SF (48 vs 99 vs 85)
Functional health:RP (25 vs 98 vs 78)
9–12 years post-LTPhysical health:PF (11 ± 9); BP (60 ± 39); GH (25 ± 21); VT (50 ± 11)
Mental health:RE (33 ± 58); MH (74 ± 9.6)
Social health:SF (32 ± 13)
Functional health:RP (0)
Key points:QOL improvements remained stable for first 4 years post-LT. Long-term, patients with FAP score lower QOL than non-FAP transplanted patients and Dutch controls. Physical well-being is most significantly affected
Desai et al. [34]b,c10 years post-LT vs Population means

Quality of life index 25

Health functioning 25

Social 26

Psychological/Spiritual 25

Family 28

Physical health:
Mental health:
Social health:
Functional health:
Key points:QOL 10 or more years after liver transplantation is generally good, although physical functioning is reduced
Goetzmann et al. [54]Post-LT vs Mean of all organ transplantationsWorry (2.60 vs 2.56); Guilt (1.78 vs 1.71); Disclosure (4.46 vs 4.42); Adherence (4.07 vs 4.35); Responsibility (3.07 vs 3.00)Physical health:PF (45.83 ± 9.85 vs 47.11 ± 9.71); BP (49.48 ± 12.02 vs 50.54 ± 11.71); GH (46.12 ± 11.55 vs 45.13 ± 10.52); VT (47.03 ± 12.27 vs 49.02 ± 10.92); PCS (45.78 ± 10.90 vs 46.49 ± 10.63)
Mental health:RE (47.28 ± 11.92 vs 49.24 ± 10.58); MH (48.71 ± 11.85 vs 49.79 ± 10.60); MCS (48.65 ± 11.85 vs 50.28 ± 10.34)
Social health:SF (48.16 ± 12.03 vs 48.96 ± 10.88)
Functional health:RP (44.25 ± 12.66 vs 45.88 ± 11.97)
Key points:Transplant patients report lower QOL scores compared to the general population. QOL post-LT is comparable with kidney, heart and lung transplant patients
Kousoulas et al. [38]cPost-LT vs CLDPhysical health:PF (85 ± 22 vs 67 ± 26); BP (79 ± 27 vs 72 ± 29); GH (68 ± 20 vs 56 ± 21); VT (63 ± 18 vs 53 ± 20)
Mental health:RE (90 ± 25 vs 72 ± 41); MH (73 ± 16 vs 69 ± 19)
Social health:SF (88 ± 18 vs 78 ± 26); Employed vs Unemployed SF (76 ± 23 vs 60 ± 27); RP (68 ± 38 vs 44 ± 45)
Functional health:RP (83 ± 31 vs 55 ± 43)
Key points:Patients who returned to work within 1 year post-LT score higher in physical domains of SF 36. At 15 years of follow-up post-LT, patients report higher QOL compared to patients with CLD but lower QOL compared to general population
De Kroon et al. [44]cPhysical health:Pain/discomfort 37.1%; self-perceived health status: 7/10 (4–10/10); Charlson Comorbidity index (CCI): 3 (0–7)
Mental health:Anxiety/depression 77.1%; Cognition 71.4%
Social health:
Functional health:Mobility 42.9%; Self-care 82.9%; Usual activities 54.3%
Key points:Survival rate 15 years post-LT was 78%. QOL remained satisfactory but some limitations in mobility and pain associated with long-term medical complications
Ho et al. [49]Laennec's (ETOH-C) vs Non-Laennec'sPhysical health:QOL (70 ± 18 vs 72 ± 16); Health perception (64 ± 19 vs 66 ± 16)
Mental health:
Social health:
Functional health:

Function (69 ± 25 vs 73 ± 22)

Performance Scale (%): (Minor signs or symptoms of disease 61 vs 62; Self-care but not normal activity or do active work 39 vs 38; Employment (full and/or part time) 40 vs 58

Key points:Satisfactory sexual function was reported in 59% of patients. Immunosuppressive medication is one of the main contributors to sexual dysfunction post-LT. Sexual function post-LT is a poorly studied area and requires further prospective studies
Kirchner et al. [51]aNormal population vs Post-LTPhysical health:PF (84 vs 65); BP (75 vs 70); GH (60 vs 60); VT (61 vs 50)
Mental health:RE (92 vs 78); MH (77 vs 62)
Social health:SF (90 vs 79)
Functional health:

RP (81 vs 60)

Physical activity (%) LT vs combined Liver-kidney: (67 vs 27)

Key points:Fatigue, physical fitness, loss of appetite, and vomiting improved significantly after LT. Both single liver and combined liver-kidney transplantation present excellent survival rates and QOL improvements at 5 year follow-up
Sainz-Barriga et al. [31]Pre-op waiting list, 1–2 years post-LT, 3–4 years post-LT, 5–8 years post-LTPhysical health:

Pre-op LEIPAD (24.3 ± 11.3); 1–2 years post-LT LEIPAD (20 ± 10.3); 3–4 years post-LT LEIPAD (20.3 ± 10.1); 5-8 years post-LT LEIPAD (20.4 ± 12.2)

Pre-op BSI (26.1 ± 21.2); 1-2 years post-LT BSI (19.2 ± 13.3); 3–4 years post-LT BSI (22.7 ± 19.2); 5–8 years post-LT BSI (21.9 ± 22.6)

Mental health:
Social health:
Functional health:

Work (%)

Waiting list vs 5–8 years (50 vs 19)

Key points:Physical functioning and life satisfaction continue to improve up to 8 years post-LT. Physical function is significantly superior to pre-LT patients
Kizilisik et al. [45]cPhysical health:

Overall Health 7.17 ± 2.22 (out of 10)

Satisfaction with life: 8.95 ± 1.02 (21% better than before LT)

Mental health:
Social health:
Functional health:

Self-care: (8.04 ± 2.28) (45% better than before LT)

Activity: (5.91 ± 2.50) (15% better than before LT)

Key points:Post-LT comorbidities include hypertension, diabetes mellitus, osteoporosis and heart disease. Most patients report all domains of QOL to be equal if not better than age-matched controls
Karam et al. [46]cGeneral population vs LTPhysical health:Physical distress [15 (0–65) vs 20 (1–58)]; General health perception [7 (4–10) vs 7 (3–10)]; Well-being [11 (5–14.7) vs 12 (6–14.7)]
Mental health:Psychological distress [5 (0–20) vs 5 (0–18)]
Social health:
Functional health:Personal function [4 (0–4) vs 2 (0–4)]
Key points:QOL beyond 10 years after LT is quite similar to the general population and is the best when compared to heart and lung transplantation patients
Lewis and Howdle [47]cPost-LT vs Control PopulationPhysical health:

EuroQol visual analogue scale (IQR) 70 (60–75) vs N/A (not significantly different)

Median EuroQol: [0.74 (0.60–0.83), vs 1.00 (0.85–1.00)]

Mental health:

Anxiety (6 (4.5–8) vs Not reported

Depression [3.5 (2–5) vs not reported]

Social health:
Functional health:

MMSE: [29 (29–30) vs 30 (29–30)]

Rey Auditory Verbal Learning Test: [54 (50–58) vs 36.5 (33.5–49)]

Key points:Survivors 10 years post-LT report significant cognitive dysfunction and poor health-related QOL
Painter et al. [48]aGeneral Population vs Active vs InactivePhysical health:PF (80 vs 85 vs 60); BP (75 vs 80 vs 70); GH (72 vs 70 vs 55); VT (60 vs 65 vs 48); PCS (50 vs 48 vs 42)
Mental health:RE (80 vs 77 vs 75); MH (75 vs 77 vs 75); MCS (50 vs 50 vs 49)
Social health:SF (80 vs 80 vs 75)
Functional health:RP (90 vs 70 vs 55)
Key points:Regular physical activity post-LT is associated with better QOL and health outcomes compared to pre-LT patients and the general population
Cowling et al. [50]aETOH-C vs Non-ETOH-CPhysical health:QOL overall (70 ± 18 vs 72 ± 16); Health Perception (64 ± 19 vs 66 ± 16); Symptom distress (72 ± 17 vs 73 ± 18)
Mental health:Feelings about life (69 ± 24 vs 79 ± 19)
Social health:Normal activity w minor signs of disease (61% vs 62%); Employment (40% vs 58%)
Functional health:Ability to function (69 ± 25 vs 73 ± 22)
Key points:Overall QOL and employment levels appear similar between patients transplanted for alcoholic and non-alcoholic liver disease. This similarity appears to extend to 5 years post-LT

Synthesis of results

Qualitative analysis was performed according to previous guidelines where QOL outcomes were categorized into physical, emotional, social and functional health domains which could be disease-specific or generic [27].

Risk of bias

The risk of bias in individual studies was assessed by a qualitative analysis based on study quality and data tabulated in Table 1. Given that meta-analysis was not feasible because of clinical heterogeneity between the studies, specific tools were not utilized to assess bias within each study. Each study was assessed for significant selection, performance, detection or reporting bias. This is supported by the Cochrane guidelines on systematic reviews [28] and assessment of bias was also performed according to the PRISMA guidelines [13, 29]. Levels of evidence of for individual studies were assessed using previously outlined guidelines (NHMRC Evidence Hierarchy) [30].

Results

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. Acknowledgements
  8. References
  9. Supporting Information

Study selection

Twenty-three studies were included in this systematic review (Fig. 1) [5, 31-52]. Heterogeneous data precluded meta-analysis. Key factors were statistical (no preoperative data, data not expressed as mean ± standard deviation), methodological (different QOL scoring systems) and clinical heterogeneity (diverse range of comparison groups). Full details and results of the reviewed articles are provided in Tables 1 and 2.

Study characteristics and risk of bias within studies

The strength of evidence was analysed systematically in this review (Table 1). We aimed to minimize reporting bias with a comprehensive search of the literature for all studies that meet our eligibility criteria. There was a diverse range of aetiologies for end-stage CLD that included primary and other malignancies, alcoholic liver disease, infectious hepatitis, autoimmune diseases of the biliary tract and genetic diseases. This is a potential source of bias as different aetiologies may have impact QOL differently. The sample size ranged between 13 and 1479 and the mean or median age at time of transplantation was between 28 and 59.

Follow-up was conducted over a period of 5 months to 20 years. The majority of studies analysed in this review had follow-up duration of 5–10 years. Follow-up consistency was variable. According to previous guidelines, a response rate of >85% (loss to follow-up <15%) is considered ideal for treatment received analyses [53]. Ten studies did not achieve this [5, 31, 34, 38, 47-50, 52, 54] and five studies did not report their response rates [39, 43-45, 55]. Patients who failed to respond may be more likely to be unwilling or unable to because of illness or being deceased, which may skew the data positively [56, 57].

There were eight prospective studies [5, 31, 35, 41, 42, 50, 51, 58] and 15 retrospective studies [32-34, 36-40, 43-45, 47-49, 52]. Only three studies included patients' own preoperative QOL data [32, 36, 43]. The lack of patients' respective preoperative QOL data is attributed to a retrospective study design and may preclude information on direction and magnitude of change in QOL. However, indirect comparison of QOL data to preoperative cohorts provides this information in the absence of direct data.

Disease-specific QOL tools were used in nine studies [5, 34, 39, 40, 42, 43, 46, 50, 54]. SF-36 was the most commonly utilized generic QOL instrument [5, 33-39, 41, 43, 45, 48, 51, 52]. Two studies tailored previously validated QOL assessment tools to patients undergoing liver transplantation [40, 50].

Mortality and morbidity in included studies

The studies included in this review reported survival rates of 51–92% [36, 45, 59] at 10 years after liver transplantation and 37–56% [5, 44] at 18–20 years.

Complications specific to liver transplantation were assessed in five studies [5, 31, 34, 36, 42]. Disease recurrence was 17% in one study over a mean follow-up of 109 months [42]. Sainz-Barriga et al. reported recurrence of chronic hepatitis C infection in up to 90% of patients whose 5-year survival rate was 10–28% [31]. Early rejection (22–52%) was more common than late rejection (9–4%) [5, 34]. Biliary complications such as biliary leak, common hepatic artery thrombosis and anastomotic biliary stenosis occurred in up to 32% of patients [5, 36]. Reoperations occurred in 15–35% in these studies [34, 36]. New comorbidities after surgery such as osteoporosis (48%), skin cancer (33%), non-skin cancers (38%) hypertension (64%) and diabetes (20%) are common [44, 45].

Quality of life outcomes

Complete results of qualitative analysis are provided in Table 2 with data at latest follow-up tabulated.

Compared to preoperative group

All included studies found that liver transplantation improved overall QOL when compared with preoperative or equivalent waitlisted preoperative patients [5, 31, 33, 34, 36, 38, 41-43, 46, 48, 51, 52, 59]. QOL improved after liver transplantation compared to patients' own preoperative status in all domains [32, 36, 43]. Physical function is a strong benefactor of surgery [36]. Patients report improvement in feelings of loneliness, anxiety and hopelessness, allowing higher quality of social interactions [5]. Sainz-Barriga et al. reported improvements in all domains of QOL except the psychological domain [31]. The Leiden and Padua Questionnaire [60] (LEIPAD) and the Brief Symptom Inventory scores improved most dramatically in the first 2 years after liver transplantation and remained better than the waitlisted group after 8 years [31].

Overall QOL remained satisfactory up to 20 years after surgery particularly in social interaction and emotional and psychosocial function [5, 32, 34, 38, 44, 45, 58].

Compared to general population

Seven studies compared SF-36 scores with age-matched controls [5, 33-35, 38, 46, 47]. Data are conflicted. Four studies found QOL is relatively similar to the general population except for physical functioning [33-35, 46, 48]. In one study, liver transplantation patients scored slightly higher QOL in all domains including mental, social and functional health [35]. However, physical functioning had no change. Twenty-year survivors had worse, but comparable QOL compared with the general population [5]. The greatest deficit was in physical functioning. However, mental composite scores persisted higher than both preoperative status and general population. In contrast, two studies reported cognitive dysfunction and poor overall QOL [38, 47].

Compared to recipients of other organ transplants

Four studies compared QOL with recipients of kidney, heart and/or lung transplants [40, 46, 51, 54]. TxEQ-D and SF-36 scores in all subcategories did not significantly differ between heart, kidney, lung and liver transplants [54]. Psychological health, perceived social and role function were similar to the general population and between organs [46]. Liver transplantation scored highest in general health perception and personality scale [46]. Overall QOL was also better in liver transplantation than kidney transplantation [40, 46]. QOL of patients following liver, kidney and heart transplantations was worse than the general population, especially in physical health and personal function [40, 46, 51, 54]. Poorer QOL is associated with high-intensity immunosuppressant regimens [40].

Functional status

The majority of patients undergoing liver transplantation are of working age (28–59 years) at the time of surgery [31, 32]. Up to half were employed at the time of follow-up [31, 32]. The overall rate of employment declines after 5 years with 67% retired by 8 years [31, 59]. Across the studies assessing employment, patients returning to work post-operatively reported higher QOL scores [31, 50, 59]. Employment status differed according to aetiology of liver disease [32, 50]. Rates of resumption of work were highest in primary sclerosing cholangitis, and lowest in acute liver failure, primary biliary cirrhosis and alcoholic liver disease [49].

Ho et al. assessed sexual function in liver transplantation patients [49]. Preoperative sexual dysfunction was present in 24% of respondents and persisted in 15% after surgery. The incidence of sexual problems in both men and women increased by about 25% after transplantation. New sexual problems were reported in 32% of the patients. Incidence of sexual problems in men and women increased from 23.8% and 24.1% prior to transplantation to 51.1% and 40.3% after transplantation. Thirty-six per cent attributed this to immunosuppressive medications. However, Duffy et al. reported improved overall sexual function after transplantation compared to CLD patients [5].

Physical activity levels were acceptable and contribute to better QOL [33, 36, 41, 48, 51]. Greater involvement in social and physical activities is attributed to amelioration of physical symptoms, fatigue and worry related to CLD [43]. Active patients achieved better scores in domains of physical functioning, bodily pain, general health, social functioning, role limitations caused by emotional problems, and physical and mental component summary scores. The physical component summary score of active individuals achieved similar levels as the general population. Physical activity after surgery is also associated with health benefits in addition to QOL such as decreased surgical complications and new onset comorbidities after surgery [33, 48].

Discussion

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. Acknowledgements
  8. References
  9. Supporting Information

Summary of evidence and interpretation

Liver transplantation is beneficial for long-term QOL with persistent relief of symptoms, emotional benefit and improved functional capacity compared to preoperatively. The improvement in these domains is therefore important in the context of decreased life-expectancy and a likely long period of poor physical health prior to transplantation.

Functional domains such as employment, social role and physical activity are critical for liver transplant patients who are often young and of working age. The findings in this review are consistent with current data[8] and shows functional status is at least as good as preoperatively for up to 5 years [5, 34, 42]. Independence of self-care and mobility is also favourable. The ability to return to work is an important indicator of functional recovery as reflected by higher QOL scores in employed patients [32, 38, 50, 52]. Re-employment in first 5 years following surgery is positive in the context of the morbidity of previous disease and the operation. There are cultural, socio-economical and clinical factors contributing to the different employment status depending on aetiology of liver disease. Patients with PSC in this study by Aberg et al. were recruited in Finland where they are transplanted at earlier stages of disease to prevent progression to cholangiocellular carcinoma [32]. Saab et al. also discussed lack of disability and number of hours worked prior to transplantation as an indicator for post-transplantation employment [61].

Studies in this review showed long-term employment declines quickly after 8 years. This may reflect a combination of declining health and patient motivation caused by chronic illness. The majority of those returning to work after transplantation do so within the first 6 months to 2 years. Patients requiring longer post-operative recuperation may have poorer QOL, be closer to retirement age or lack motivation to return to work. This leads to decreasing probability of re-employment after the initial critical window period. Long-term follow-up studies on outcomes of post-LT employment will be valuable data.

Overall QOL scores and general health perception remain enhanced and comparable to the general population in the long-term. However, physical functioning continues to be inferior to the general population despite marked improvement from preoperative physical functioning. This is indicative of the severe preoperative morbidity and impairments associated with CLD. Complications such as late rejection leading to graft failure, recurrence of liver disease and de-novo medical complications related to intensive immunosuppressive therapy become more common with increased survival [62]. The frequency of surgical morbidity, both early and late, is likely to be a major contributor to suboptimal physical health compared to the general population. Given the well-established preoperative as well as post-operative morbidity of CLD and liver transplantation, as well as ongoing medical therapy after surgery, subnormal physical functioning is an expected finding of this study. Despite this, the significant physical improvement for patients is reflective of the benefits of surgery for a highly morbid condition.

Quality of life after liver transplantation appears to be similar to kidney, heart and lung transplantation. In particular, liver transplant recipients reported better QOL in the long-term when compared to kidney transplant recipients. Dialysis support has been postulated as a potential contributor to superior outcomes within the first 2 years of post-operative period [63]. However, kidney transplant recipients reported limited improvement in health-related QOL, likely associated with a higher incidence of diabetes and elevated serum creatinine. For all organ transplant patients, QOL is worse than the general population especially in physical function. Immunosuppressive therapy has been identified as a major contributor. However, organ transplant recipients, including liver transplants have similar psychological and social function to the general population post-operatively and this is in keeping with the emotional and social benefits for patients.

Data on predictors of QOL benefits remain limited and controversial. Greater degree of improvement has been reported in patients with poorer preoperative QOL scores [64], namely those with alcoholic or viral hepatitis and preoperative Child–Pugh C score [64, 65]. This may reflect subjectivity in perception of improvement in patients with chronically impaired standards of health. There are conflicting data on the influence of aetiology on QOL outcomes. Some studies have speculated that viral hepatitis is associated with poorest improvement in QOL, perhaps because of patient demographics and their negative perception of health [64, 66, 67]. Others concluded no differences between aetiologies in influencing post-operative QOL [65, 68].

This review adds other potential associations with QOL outcomes from the included studies. Physical symptoms are reported more commonly in long-term survivors of liver transplantation and seem to be proportionately related to intensity of immunosuppressive therapy [38, 40]. Increased physical activity was associated with less medical comorbidities and a greater QOL. The level of physical activity following transplantation is also an indicator of patients' freedom from disease and capacity beyond undertaking normal daily activities. Clinicians may consider encouraging physical activity after surgery to improve QOL in addition to the well-known benefits of physical activity. Inpatient rehabilitation post-operatively to optimize physical function would be a useful consideration [69, 70].

Post-operative QOL is becoming an increasingly important and recognized outcome of organ transplantation [63, 71]. It is a critical consideration for patients in addition to purely prolonging life. In addition, liver transplantation is a resource-intensive and expensive procedure. Long-term data on QOL can help facilitate informed decisions for prospective transplant recipients and assist clinicians in designing specific post-operative treatments that target poorly scored QOL domains for future patients. Studies show that liver transplantation is a cost-effective treatment for end-stage CLD [72-74] and provides curative benefits and QOL improvements. Persistent improvements in QOL following liver transplantation is likely to further validate its importance as a widely accepted therapy for cirrhosis.

There are two previous systematic reviews that show liver transplantation improves general QOL remarkably compared to patients with CLD [7, 8]. However, the mean follow-up durations of these studies were 27.5 months and 25 months respectively. With improved post-operative care with more effective and less toxic immunosuppressants, the majority of patients survive more than 10 years following liver transplantation [75]. To our knowledge, this is the first systematic review on long-term QOL outcomes following liver transplantation and provides a synthesized modern reference.

Review limitations

The main limitation of this study was that meta-analysis could not be performed because of statistical, methodological and clinical heterogeneity. However, this review summarizes the best available evidence and provides useful information on QOL after surgery. Even though language bias may be present because of the eligibility criteria, we found 4 articles written in French [76], Italian [77] and Portuguese [78, 79] that were relevant to this review (Fig. 1). Available English abstracts were reviewed and none of the four articles met our eligibility criteria. However, the abstract results were similar to our findings.

Guidelines for future research

This review demonstrates the lack of preoperative compared to post-operative QOL results of the same patients as well as appropriate data for meta-analysis. Prospective studies with predetermined follow-up time points that accurately reflect current survival rates and consistent use of previously validated QOL instruments are recommended. Multi-centre involvement is ideal. Further investigation is required on defining the predictors of better QOL outcomes and to define strategies for improvement.

Conclusion

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. Acknowledgements
  8. References
  9. Supporting Information

The most important finding of this review is that there are specific improvements in QOL following liver transplantation that persist long-term. Bodily pain, physical function, mental health and functional status domains benefit most. In particular, functional gains reflect the significant QOL benefits and patients' ability to return to a normal lifestyle despite ongoing morbidity. This morbidity associated with CLD, immunosuppression and surgical complications results in worse QOL compared to reference populations especially in physical health. Studies on long-term QOL are limited by the fact that patients who fail to respond are often those with poorer QOL. Nonetheless, post-operative survival is improving and long-term QOL data provide valuable information for both patients and clinicians when considering liver transplantation.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. Acknowledgements
  8. References
  9. Supporting Information

There are no further acknowledgements to disclose for this manuscript.

Conflict of interest: The authors do not have any disclosures to report.

References

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. Acknowledgements
  8. References
  9. Supporting Information

Supporting Information

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. Acknowledgements
  8. References
  9. Supporting Information
FilenameFormatSizeDescription
liv12553-sup-0001-TableS1.docxWord document28KTable S1. Description of Quality of Life Scoring Systems.

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