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Quality of life after liver transplantation. A systematic review
Journal of Hepatology 48 (2008) 567–577 www.elsevier.com/locate/jhep
Quality of life after liver transplantation. A systematic reviewq Santiago Tome1,*, Jennifer T. Wells2, Adnan Said2, Michael R. Lucey2 1
Liver Unit, Internal Medicine Department, Complejo Hospitalario Universitario de Santiago, C/Choupana s/n, Santiago de Compostela 15705, Spain 2 Section of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
Background/Aims: Although many studies have reported significant improvements in quality of life (QOL) after liver transplantation (LT), consistent data on areas of improvement are lacking. To perform a systematic review on medical literature of QOL after LT paying particular attention to studies that utilized the most commonly adopted study instrument, Short Form-36 (SF-36). Methods: To collect studies focused on QOL in adult LT recipients, from 1963 to 2007, cited in Pub Med, Embase or Cochrane databases. From an initial identification of 613 articles, we selected 44 longitudinal studies with pre- and postLT data that we assessed using a sign test, and 19 used SF-36, which we analyzed separately. Results: Longitudinal data showed remarkable improvement of common domains of QOL comparing pre- and posttransplant items. However, analysis of 16 SF-36 cross-sectional studies comparing post-LT patient domains with control population showed significantly higher ratings for controls in six while no differences were found in two. Conclusions: This review suggests that whereas general QOL improves after LT, when compared with healthy controls, LT recipients have significant deficits in QOL. Consequently, the previously reported QOL benefits after LT may have been overstated. Ó 2008 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Keywords: Quality of life; Liver transplantation; SF-36
1. Introduction Liver transplantation (LT) is a life-saving intervention for many patients with end-stage liver disease. Assessment of the success of LT has traditionally been related to patient survival. Currently, patient survival rates at 1 and 5 years approach 90% and 70%, respectively. For some specific indications, such as those due to chronic cholestatic liver disease, survival is even better [1]. However, as concern about survival has diminished with improved surgical success, greater attention Received 24 October 2007; accepted 19 December 2007; available online 28 January 2008 Associate Editor: P.-A. Clavien q The authors declare that they do not have anything to disclose regarding funding from industries or conflict of interest with respect to this manuscript. * Corresponding author. E-mail address: [email protected] (S. Tome).
has been placed on issues related to medical management of the long-term liver transplant survivor. Recurrence of the underlying disease, complications of immunosuppression and onset of ‘‘de novo” diseases are frequent and impair both quantity and quality of life (QOL) among survivors. Any analysis of QOL after LT will be constrained by several limitations inherent to this field of study. For example, all published studies for obvious reasons do not take into account patients who have died, and also tend to exclude patients in poor condition at the time of assessment, thereby introducing a favorable bias [2]. Additionally measurement of health-related QOL will be affected by cultural, economical and social factors related to the population being studied. A reliable assessment tool that balances these factors is lacking. In a meta-analysis published in 1999 by Bravata et al. that included 49 studies, the assessment tools ranged from Karnofsky Performance Status (KPS) in 11 studies to self-designed questionnaires,
0168-8278/$34.00 Ó 2008 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jhep.2007.12.013
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lacking prior validation in 16 studies. Unfortunately, the frequent use of non-validated assessment tools is a significant impediment to comparison between studies. While it is clear that we lack a perfect tool to assess health-related QOL after LT, several validated tools have been utilized in studies of post-LT QOL, among which the Short Form-36 (SF-36) is the most often used. The SF-36 was developed to measure eight of the most important areas of health. The use of SF-36 enables comparisons across a broad range of conditions and between studies of healthrelated QOL in the same setting [4]. We believe that this is an opportune moment to undertake a systematic review of QOL after LT, in which particular attention is paid to studies using SF36 to assess health-related QOL after LT. We will review specific aspects of QOL after LT, including the available data on whether etiology of liver disease or gender influences post-LT QOL, review employment as a marker of QOL, and finally consider studies assessing sexual function after LT. Where studies are too scanty to allow a cumulative statistical analysis, we will provide a summary without statistical analysis.
manual search. The articles revealed by the search technique were included in the analysis if they used a validated tool or contained enough information to infer an appropriate assessment of the main domains of QOL. Similarly, articles which did not use validated tools were also included if relevant information related to a specific domain, such as sexual functioning, was collected in a prospective fashion. We adopted the following selection criteria for longitudinal studies: use of a validated QOL-assessment tool and inclusion of pre- and post-transplant items in the analysis. The studies were grouped in two different ways: longitudinal studies meeting our selection criteria, and all cross-sectional studies and longitudinal studies utilizing the SF-36 as a QOL-assessment tool (Fig. 1). Two different researchers (JW and ST) independently collected the papers. The coordinate-words used were ‘‘liver transplantation”, ‘‘quality of life”, ‘‘employment”, ‘‘sexuality”, ‘‘gender” and ‘‘health status”. We restricted our search to articles written in English and covering the time frame from when the first liver transplant data appeared (1963) to January 2007. The search was also limited to adults receiving livers from a deceased donors.
2.1. Statistical analysis The collected articles were entered in an electronic data base (Microsoft Excel 2003) in two different files: longitudinal studies containing pre- and post-transplant items using different tools, and a specific file gathering all the studies using SF-36, both cross-sectional as well as longitudinal studies. A sign test was performed on these longitudinal studies where different QOL-assessment tools were used. This test assesses the general trend of the effect without consideration of either the sample size or magnitude of effect. The specific domains of health-related QOL were assessed when a significant effect was found. If the magnitude of a specific effect was not displayed in the paper, but could be inferred, it was also considered for the global assessment. For example, the social functioning domain, in some circumstances, could be inferred by considering the rate of employment
2. Materials and methods The medical literature search was focused on three medical databases Pub Med, Embase, Cochrane, which we supplemented with a
Medical databases and manual search n:613
Relevant information n:93
Longitudinal studies n:54
Cross sectional Studies n:39
Excluded Studies:10 ( Non validated tool)
Individualized study n:5
Longitudinal studies using SF-36 n:4
Cross-sectional studies using SF-36 n:16
Specific SF-36 assessment Fig. 1. Study design.
Excluded Studies:18 ( living donor:13; not enough information:5)
S. Tome et al. / Journal of Hepatology 48 (2008) 567–577 (Table 1). A level of significance was estimated by comparing the proportion of positive or negative studies with the binomial distribution. A second part of our analysis was to calculate the size effect in those studies using the SF-36 as an assessment tool (Table 2). The analysis was performed by comparing pre-transplant and post-transplant items among longitudinal studies. We performed homogeneity tests in all summary effects.
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The assessment of the magnitude of the effect of transplantation for cross-sectional and longitudinal studies (where post-transplant and control population domains were not reported from the same study) was performed by calculating univariated weighted means for posttransplantation and control population domains. The difference of weighted means of different domains between transplant recipients in the post-transplant period and the control population was then calculated for a summary meta-analysis. We also calculated the magnitude
Table 1 Longitudinal studies comparing pre- and post-transplant items N
Author/year
Number of patients
Mean age
Followup
Tools
MMPI 16PF, SIP Sexual and Endocrine function WAIS, WMS, CMIF, SCL90-R CIS, Shipley WAIS EORT SBAS, SIP PAIS AUSQUAL BDI, STAI, SIP, MMSE, CVLT, WCST, TMT, IMI NHP, Karnofsky, PIWB, STAI, SrDS SBI SIP Karnofsky MOS-SF Karnofsky Z-E-WHO UNOS score CIS, MMSE, NHP, GHQ NIDDK Sexual, endocrine function Gynecological assessment PAIS KARNOFSKY WBI, BSF LZI SEB ALL ACSA POMS AUSQUAL LTDQOL, PIGW, Karnofsky, MOS QLI-LT
1 2
Tarter/1984 [52] Van Thiel/1990 [29]
10 150
48
36 18
3
Hockerstedt/1992 [55]
8
40
12
4 5 6 7 8
Arria/1991 [56] Kuchler/1991 [57] Tarter/1988, 1991 [53] Moore/1992 [30] Riether/1992 [58]
13 67 53 22 61
40 40 41 44.5 45
12 36 51 9 12
9
Bonsel/1992 [59]
26
43
120
10 11 12 13 14 15 16
Beresford/1992 [60] Tarter/1992 [54] Gish/1993 [61] Knechtle/1993 [10] Chen/1994 [62] Lundgren/1994 [63] Collis/1995 [64]
61 130 29 60 7 108 11
45 58 47 49 20.2 39 44
18 24 24 NA 38 12 9
17 18
213 10
49 42
60 11.6
19
Levy/1995 [65] Madersbacher/ 1995 [31] Mass/1996 [39]
84
37
12
20 21
Payne/1996 [32] Scholler/1997 [66]
50 171
43 NA
36 12
22 23
Moore/1997 [67] Belle/1997 [68]
32 346
44.1 48
9 12
24
41
50
12
25 26
Lobiondo-wood/ 1997 [69] Gevarghese/1998 [33] Gross/1999 [23]
100 157
46 50
72 12
27
Singh/1998 [13]
59
48
12
28
Moore/2000 [26]
27
44
9
29 30
De Bona/2000 [15] Caccamo/2001 [34]
141 33
46 46
60 12
31 32
Walter/2002 [70] Ratcliffe/2002 [48]
82 455
46 46–60
36 24
Karnofsky PAIS Karnofsky, IWB, IGA NIDDK LTD-QOL, Functioning composite (MOS, NHP) BDI, WCS, POMS, Karnofsky, Likert scale AUSQUAL, WAIS, REY Benton’s Controlled Oral word Association Test LEIPAD, BSI SCL-90R mFLIC, PAIS, WCQ ACSA, BSF, GBB SF-36, EQ-5D
Studied domains Gral QOL
Physical health
Social function
Sexual function
Psychological health
+ NA
+ NA
+ NA
NA +
+ NA
NA
NA
NA
NA
NA
NA + + + +
NA + + + +
NA NA + + +
NA NA NA 0 NA
+ 0 + + +
+
+
+
NA
+
+ + + + + + +
+ + + + + + +
+ + + + + + +
NA NA NA NA NA NA NA
– + + + 0 NA +
+ NA
+ NA
+ NA
NA +
+ NA
NA
NA
NA
0
NA
+ NA
+ NA
0 NA
+ NA
0 NA
+ +
+ +
+ +
NA NA
+ +
+
+
+
NA
+
+ +
+ +
0 +
+ +
0 +
+
+
NA
NA
+
+
+
+
NA
+
+ +
+ +
0 +
NA +
+ 0
+ +
+ +
NA +
NA + NA 0 (continued on next page)
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Table 1 (continued) N
Author/year
Number of patients
Mean age
Followup
Tools
NIDDK MOS-20, NHP, Karnofsky, Bradburng’s single item WHOQOL-100 EQ-5D Karnofsky, SF-36a LEIPAD, BSI LEIPAD, BSI Sexual function SF-36 SF-36, F-SOZU, FLZ, HADS-D Sexual function Sexual function
33 34
Karam/2003 [35] Cowling/2004 [28]
67 149
51 Median: 50
12 24
35 36 37 38 39 40 41 42
O’Carrol/2003 [71] Longworth/2003 [24] Moore/2004 [72] Burra/2005 [73] Sainz Barriga/2005 [19] Ho/2006 [36] Pieber/2006 [74] Goetzmann/2006 [49]
70 208 413 25 126 150 15 26
50 Median: 50 47 46.3 61 54 45 49
12 12 49 12 42 12–60 2 12
43 44
Sorrel/2006 [37] Gomez Lobo/2006 [38]
39 276
51 50
16 NA
Foot notes: +, improvement; 0, no improvement; a No data comparing pre and post with SF36.
Studied domains Gral QOL
Physical health
Social function
Sexual function
Psychological health
+ +
+ +
+ +
+ +
+ +
+ + + + + NA + +
+ NA NA + + NA 0
NA NA NA 0 NA NA + +
NA NA NA NA NA _ NA NA
+ NA NA + 0 NA + 0
NA NA
NA NA
NA NA
0 0
NA NA
, deterioration. See abbreviations in Appendix.
of the effect according to Spiegel et al. [3] using the following equation ES (effect size) = HR QOL group 1 HR QOL group 2/SD (standard deviation) group 1. An effect size <0.2 is considered a small effect, 0.5 a moderate effect and >0.8 a large effect according to Cohen et al. [11].
3. Results The medical literature search revealed 613 articles, of which 93 studies were informative (Fig. 1). There were 54 that contained longitudinal information including QOL items from pre- and post-transplant patients, whereas 39 were cross-sectional studies, most commonly including a control population for comparison. Among the longitudinal studies, 10 were excluded on account of the use of a non-validated tool, leaving 44 studies that met our selection criteria for longitudinal studies for the final analysis. Among the 39 cross-sectional studies identified, we rejected 18 studies either because the information provided was related to living donation (n = 13) or because the provided information was insufficient to allow a full analysis (n = 5). After 16 studies were included in the analysis specific to SF-36, there remained five cross-sectional studies that were analyzed separately. For the second part of the present review 16 crosssectional studies and three longitudinal studies, all using the SF-36 as a common instrument, were considered for a specific analysis. 3.1. Longitudinal studies using a variety of QOLassessment tools From the 44 longitudinal studies including pre- and post-transplant items, data on 4381 patients were pooled. The mean age was 45 years and mean followup was 25 months (2–120). The sign test performed for common domains showed that post-transplant improve-
ment was statistically significant for the domains related to general QOL (p < 0.0001), social functioning (p < 0.0001), physical health (p < 0.0001) and psychological health (p = 0.014) but not for sexual functioning (p = 0.58) (Fig. 2). 3.2. Cross-sectional studies using SF-36 Analysis of the 16 studies that used SF-36, in which the eight patient domains were compared with controls from the general population, included 1615 LT recipients with a mean age of 49 years and mean follow up of 43 months (6–120), showed significantly higher ratings for controls in six domains: physical functioning: 21.15 (p: 0.008); role physical: 30.54 (p < 0.0001); role emotional: 11.18 (p: 0.003); social functioning: 11.2 (p < 0.0001); energy mean diff: 10.45 (p: 0.02) and general health: 16.34 (p < 0.0001). The mean differences for the two remaining domains, body pain: 10.08 (p: 0.19); and mental health: 1.68 (p: 0.11), were similar between the two groups (Table 3). 3.3. Longitudinal studies using SF-36 Four studies [48–51] utilizing SF-36 were performed in a longitudinal fashion, including both pre- and post-transplant items. We were able to retrieve enough data to build an effects model from two [49,50]. From these studies, 76 patients were pooled with a mean age of 50 years and mean follow-up of 24 and 12 months, respectively. Enough data were available to compare trends in four domains. There was a statistically significant improvement of general health while the variation in physical function, role physical function and role emotional shown did not reach significance (Table 4).
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571
Longitudinal Studies Comparing Pre and Post-transplant QOL Domains (using different tools) N=44 Deterioration
Improvement
P values: the Sign Test Psychological health p=0.014
Physical functioning p<0.0001
Sexual functioning p=0.58
Psychosocial adaptation p=0.0001 General QOL -10
0
10
20
30
40 p<0.0001
Fig. 2. Sign test. Longitudinal studies comparing pre- and post-transplant items using different tools.
3.4. Assessment of specific issues 3.4.1. Etiology of liver disease While it seems likely that the etiology of liver disease would affect QOL after LT, evidence for a determinative effect of pre-transplant etiology is less clear. Among the conditions that have been investigated are alcoholic liver disease (ALD), HCV infection, acute liver failure (ALF), and chronic cholestatic syndromes. Several studies have reported on QOL after LT in patients trans-
planted for ALD [5–9]. While the majority of the studies have shown striking impairment before LT and significant improvement after LT, there remains debate about the QOL responses in ALD recipients when compared to patients transplanted for other conditions. An early study by Knechtle et al. [10] did not identify any differences between ALD recipients and patients transplanted for other etiologies, and subsequent authors have concurred with this conclusion[7–9]. However, recently Aadahl et al. reported on a cross-sectional
Table 2 Studies using SF-36 n
Author/year
Year’s data collection
Country
Follow up(mo)
Type of the study
PreTx Items
Number of patients
Mean age
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Littlefield/1996 [75] Hunt/1998 [76] Bryan/1998 [77] Hellgren/1998 [78] Fosberg/1999 [79] Pereira/2000 [8] Younossia/2000 [51] Rothenhausler/2002 [80] Painter/2001 [16] Aadahl/2002 [21] Ratcliffe/2002 [48] Van der Plas/2003 [81] Sutcliffe/2003 [82] Beilby/2003 [83] Kanwal/2004b [84] Krasnoff/2005 [50] Sargent/2006 [20] Goetzmann/2006 [49] Van den Berg-Emons/2006 [85] Sahota/2006 [5]
1993 1992–1995 1986–1994 1985–1995 1995–1997 1987–1996 1998 1996–1997 – 1990–1998 1996–1998 2000 1988–2000 1998–2001 1997–1998 – – 2000–2003 2003 1996–2001
Canada USA UK Sweden Sweden UK USA Germany USA Denmark UK Netherlands UK NZ USA USA UK Switzerland Netherlands USA
32 14 12–60 39 6–24 6–120 4 46 72 12–60 24 – 92 50 – 24 35 12 54 34
Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Longitudinal Cross-sectional Cross-sectional Cross-sectional Longitudinal Cross-sectional Cross- sectional Cross-sectional Cross-sectional Longitudinal Cross-sectional Longitudinal Cross-sectional Cross-sectional
N N N N N N Y N N N Y N N N Y N N Y N N
149 42 121 120 23 47 22 75 180 130 455 186 24 54 203 50 60 26 96 105
50 48 51 50 49 50 50 54 55 50 46–60 49 16.5 52 51 51 49 49 52 54.5
a b
CLDQ. Only including end-stage liver disease SF-36 scores.
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Table 3 Effects model in 16 cross-sectional studies using SF-36 Statistic/ domain
Physical functioning
Role physical
Role emotional
Social function
Pain
Energy
General health
Mental health
Mean diff. CI 95%
21.15 ( 32.64 to 9.66) 3.3 0.008 91%
30.5 ( 40.55 to 0.54) 3.2 <0.0001 64.8%
11.18 ( 18.66 to 3.70) 0.68 0.003 53.9%
11.27 ( 15.69 to 6.85) 0.94 <0.0001 33.9%
10.08 ( 25 to 4.8) 1.56 0.19 93.9%
10.45 ( 18.94 to 1.96) 1.62 <0.0001 77.3%
16.34 ( 22.02 to 10.66) 4.83 <0.0001 65.1%
1.68 ( 3.74 to .38) 0.98 0.11 0%
a ES p I2 a
ES, effect size according to Spiegel et al. An effect size <0.2 is considered a small effect, 0.5 a moderate effect and >0.8 a large effect.
QOL-study of 130 liver transplant recipients, who had survived at least 1 year, assessed using SF-36, and found significantly impaired QOL scores for ALD patients (who were grouped with cryptogenic cirrhosis) compared to patients transplanted for other conditions [21]. The role of HCV infection on QOL and specifically the effect of recurrence of the infection after LT has been the focus of several studies [12–19]. Singh et al. have documented a significant impairment of QOL assessed by different tools in HCV-infected LT recipients, with significant impairment related to physical functioning and fatigue [12,13]. Sargent and Wainwright used the UK version of SF-36 to compare QOL in 26 patients with ALF, 34 patients transplanted for chronic liver disease and the standard UK population [20]. They did not find any statistical differences between the post-LT groups although the scores were significantly lower than the standard UK population. In addition, they did not find any differences between those patients transplanted because of acetaminophen overdose compared to other ALF etiologies. A similar conclusion regarding the outcome after LT for ALF was reached by Aadahl et al. [21]. Among patients with cholestatic liver disease, Navasa et al. identified a great improvement in well being assessed by Karnosfky and Nottingham Health Profile [22]. Gross et al. confirmed these results using different tools in a later study [23]. An economic assessment in terms of cost effectiveness using QALYs for PBC, PSC and ALD as indications for liver transplant demonstrated that cholestatic liver disease displayed the best cost-effectiveness ratio [24]. 3.5. Gender differences An early study, published by Kober et al. [25], reported that men had lower QOL scores after LT than women recipients. In a composite analysis published in Table 4 Effects model in two SF-36 longitudinal studies Domain
Pooled mean diff. (CI 95%)
Signification
Physical function Role physical function Role emotional General health
+10.60 +12.54 +10.25 +13.82
p = 0.19 p = 0.25 p = 0.26 p = 0.02
(+26.32 (+34.10 (+28.18 (+25.42
to 5.12) to 9.02) to 7.67) to +2.23)
1999, Bravata et al. [2] concluded that there were no differences between the sexes in post-LT QOL, although the authors commented on the scarcity of studies dealing with this topic. Moore et al. came to the same conclusion in a single-center prospective study of 10 LT recipients compared to normal controls [26]. But recently more focus has been placed on gender in post-LT QOL assessments. Cowling et al. have reported a study specifically designed to consider whether gender influences QOL outcome after LT [28]. Among 88 male and 61 female LT recipients, matched for prevalence of HCV infection, who received QOL assessment pre-LT, men displayed higher levels of health-related QOL than women at 1 and 2 years [28]. The differences were partially corrected after adjustment for educational level. A similar result was reported by Spanish investigators who reported that psychosocial adjustment after LT was rated higher in male compared to female recipients [27]. 3.6. Sexual function We have identified 12 studies dealing with sexual function after liver transplant [23,28–39]. Five studies reported no improvement or even deterioration after liver transplant. In the meta-analysis published in 1999 by Bravata et al., sexual functioning was a specific domain that resulted in significant improvement. In 2006, two studies were published focusing on this specific domain. Ho et al. from British Columbia studied 320 transplanted patients. Among 150 respondents, sexual dysfunction was present in 24% before transplant and in 15% of them after liver transplant. However, 32% of patients presented with sexual dysfunction de novo after LT [36]. Similar findings were reported by Sorrell et al. wherein sexual dysfunction discovered before liver transplant tended to continue after liver transplant [37]. In our analysis, combining data from longitudinal studies, we did not observe a perceptible improvement in sexual function after LT. 3.7. Employment Many different studies have dealt with employment after LT. In Table 5 we have collected some of the most representative studies performed across different coun-
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Table 5 Employment rate after liver transplant across different countries Author/year Ref.
Country
Number
Follow-up (months)
Mean age
Return to work
% Working full time
Knechtle/1993 [10] Adams/1995 [40] Loinaz/1999 [41] Newton/1999 [42] Paterson/1999 [17] Karam/2003 [43] Cowling/2004 [6] Blanch/2004 [27] Kichner/2006 [44] Sahota/2006 [5] Sargent/2006 [20]
USA Can Spain USA USA France USA Spain Germany USA UK
60 203 137 122 87 125 152 126 23 105 60
NA 9 3 60 48 120 53 12 62 34 36
49 46 49 47 48 51 53 56 48 54 35
56% 57% 41% 55% 45% 53% 36% 33.1 26% 49% 37%
40% 40% 38% 47% NA 39% 24% NA 17% NA NA
tries [6,10,17,40–42,27,43,44]. These showed considerable variation of the level of employment after LT, from 26% in a study performed in Germany [44] among women with polycystic liver disease to 57% reported by Adams et al. during a period of economic recession in Canada [40]. The latter study showed that patient’s age and duration of disability before LT were predictors of employment after LT. A recent study not only confirmed these predictors but also identified the link between unskilled workers, an income of less than 30,000 USD and a duration of disability of more than 6 months and unemployment status [5]. 4. Discussion Assessment of QOL not only addresses a more comprehensive overview of outcome than finite end-points such as patient- or allograft-survival, but also results in a more nuanced evaluation in terms of both effectiveness and cost effectiveness. Many studies in medical literature have dealt with QOL after LT. There are obvious potential biases in these reports. They usually exclude the very ill. Some studies have been performed too soon after the transplantation. Moreover, the absence of uniform design and the broad variety of instruments utilized to assess QOL has been a significant drawback (see Table 6). In the last 10 years, the Short Form-36 Health Status Survey (SF-36) has become the most frequently used QOL instrument in LT recipients. SF-36 is a non-disTable 6 QOL and specific subjects Issues
Refs.
Condition of liver transplantation Alcohol liver disease Hepatitis C PBC PSC Acute liver failure Gender differences Sexual function Employment
[5,7–10] [12–18] [22–24] [20,21] [25–28] [23,28–39] [6,10,17,40–42,27,43,44]
ease-specific instrument that contains a 36-item questionnaire of describing and valuing the health status of individuals across several dimensions (physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health). Scores on each dimension are obtained by adding up item responses and transforming these raw scores to a scale by means of a scoring algorithm in which 0 represents poor health and 100 represents good health. Among the disadvantages of SF-36 are the lack of an overall score, the absence of an assessment of cognitive function, and the lack of validation of the interpretive significance of changes in patient responses over time [2]. Nevertheless, the adoption of SF-36 in LT studies is an advance because it allows comparison between studies, and analysis of accumulated data from multiple studies. Consequently, we felt that it was appropriate to undertake a systematic survey of QOL after LT, with particular emphasis on studies utilizing SF-36. The main findings in this systematic review showed that general QOL improves dramatically after LT, compared to health status prior to transplantation. On the other hand, when compared with the general population, the vast majority of LT patients have significant deficiencies in most QOL domains. This observation is in contrast to that of Karam et al. who, in a comparative study encompassing recipients of different solid allografts after 10 years follow up, found that the index of well being was better in LT recipients than in the general population [43]. Also, Pereira et al. found that QOL among LT recipients, transplanted on account of ALD, showed scores broadly similar to the standard population [8]. Despite these previous reports, we conclude that the perception of improvement of QOL after LT may have been overstated. Additionally, the specific analyses performed in those longitudinal studies using SF-36 as a common instrument demonstrated a lack of immediate improvement in several domains. While these data might be explained by insufficient follow up and also by the fact there were only two longitudinal studies with available data, they also raise questions about the level of restoration of QOL after LT.
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When analyzing specific issues related to QOL in LT patients some clues emerge about why the improvement of QOL is less than we might have expected. A close relationship has been established between underlying liver disease and QOL (see Table 6). HCV infection seems to impair QOL mainly in those patients with recurrence of the disease [12,13]. The same trend, although at lower level, can be seen in those patients who start to drink heavily again after transplant [9]. Additionally, indefinite exposure to immunosuppression and ‘‘de novo” diseases results in impairment of both QOL and life expectancy [45,46]. A recent finding is that gender affects perceptions of QOL after LT. In the meta-analysis performed in 1999 by Bravata et al. [2] gender was not identified as a factor impairing QOL. However, recent data indicate that women demonstrate worse scores than men [27,28]. Explanations for the phenomenon of gender-associated differences in QOL after LT are speculative, but most of the studies have pointed to social and psychological issues. Another novel aspect in this research is that sexual function after liver transplant tends to show no improvement and in some cases even deteriorates [36,37]. Thus, five [30,37–40] of thirteen studies found no improvement, or even identified deterioration of sexual function indicating that the reported restoration of sexual health may have been overstated. To address this issue by self-assessment questionnaires is always difficult. As several authors have pointed out, encephalopathy may have compromised responses in the pretransplant period whereas after LT, respondents ‘‘might have found this a good opportunity to express their dissatisfaction” or disappointment [36]. Reasons to explain the lack of improvement in perceptions of sexual health are likely to be psychological rather than endocrine since endocrine function typically recovers after LT [29,31]. While employment is a useful global surrogate for social functioning, care is necessary in procuring and analyzing the data [5]. In one study, contrary to what might be expected, unemployed patients displayed better scores of QOL [5]. It is necessary to distinguish and account for full time remunerated work outside the home, unremunerated work such as attending school or university, household work and part-time work. The lowest rates of employment after LT tend to be explained by gender composition, transition to retirement and disability status after LT [27,44]. Adams reported that the interval without work prior to LT correlated with the likelihood of returning to work [40]. The pre-LT diagnosis may also influence the rate of employment after LT. For example, prior to LT alcoholic patients appear less likely to be involved in structured social activities and routine volunteering than non-alcoholic patients but the rate of employment does not display any differences [6,9]. Dickson et al. [18] have
described a lower rate of employment among patients transplanted due to HCV cirrhosis although there was no statistical difference compared with patients transplanted because of HVB cirrhosis. Our review has several inherent limitations. QOL is a subjective concept that is not easy to measure on account of cultural, social and economic differences. Indeed these difficulties may explain the numerous instruments developed for its measurement [47]. We addressed these limitations in the following ways. First, in order to avoid heterogeneity of study design, we collected only studies written in English, and only those in which a validated tool was used. In addition, we restricted our survey of cross-sectional studies to those using SF-36. Second, in those longitudinal studies using different instruments the common domains were directly assessed, and where necessary we inferred the trend to determine the result for that domain. Trying to eliminate the assessment bias, the two researchers who collected the papers also performed a simultaneous assessment of a random sample of the articles and the concordance in the assessment was 100%. Nevertheless, the burden of subjectivity is high in specific assessments, for example when inferring that good social functioning is expressed by the rate of employment. Third, in this review some cross-sectional studies were used to identify specific outcomes such as the influence of liver disease etiology [7,8] on QOL [27,28]. Fourth, while this review has some overlap with the meta-analysis published by Bravata et al. [2], we used a different methodology. We focused on studies with a common assessment tool, something that would have been impossible for Bravata et al. due to scarcity of studies using the same instrument at that time. In conclusion, in this systematic review, we observed a striking improvement of QOL after LT. However, compared to the standard population, LT patients showed considerable deficits, an observation that was supported by impaired QOL in specific patient cohorts and in particular domains. We suggest that attention in future studies should be paid to the QOL of female LT recipients, to the QOL outcomes in specific patient populations such as HCV-infected recipients, and to specific domains such as sexual function or psychological health. Acknowledgment Santiago Tome has a temporary appointment at the University of Wisconsin, supported by the Institute Carlos III-Spanish Health Department Grant BAE7 06/90040.
Appendix Abbreviations: ACSA, anamnestic comparative self assessment; AUSQUAL, austin quality of life scale;
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ALL, everyday-life abilities; BDI, Beck depression inventory score; BSF, Berlin questionnaire of current moods; BSI, brief symptom inventory; CIS, clinical interview schedule; CMIF, cornell medical index form; CVLT, California verbal learning test; EORTC, European organization for research and treatment of cancer; EQ-5D, EuroQoL classification system; FLZ, questionnaire of life satisfaction; F-SOZU, social support questionnaire; GHQ, general health questionnaire; GBB, giessen complaint questionnaire; HADS, hospital anxiety and depression scale; IGA, index of general affect; IMI, impact message inventory; LEIPAD, quality of life test; LTDQOL, liver transplant disease quality of life questionnaire; mFLIC, modified functional living index for cancer; MMSE, mini-mental state examination; MMPI, Minnesota multiphasic personality inventory; MOS, medical outcome survey; NIDDK LTD, national diabetes kidney disease liver transplant disease questionnaire; NHP, Nottingham health profile; PAIS, psychological adjustment to illness scale; POMS, profile of mood states scale; QLI-LT, quality of life index-liver transplant version; PGWI, psychological general wellbeing index; REY, the complex figure of Rey; SBAS, social behaviour adjustment schedule; SCL90-R, symptoms check list; SBI, strauss bacon index; SEB, social embedding; SIP, sicknes impact profile; 16PF, sixteen personality factor questionnaire; SrDS, self-rating depression scale; STAI, state-trait anxiety inventory; TMT, trailmaking test; UNOS score, united network of organ sharing; WAIS, Weschler adult intelligence scale; WCST, Wisconsin card sort test; WMS, Weschler memory scale; WCQ, ways of coping questionnaire; WHOQOL-100, world health organization quality of life scale.
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Quality of life after liver transplantation. A systematic reviewq Santiago Tome1,*, Jennifer T. Wells2, Adnan Said2, Michael R. Lucey2 1
Liver Unit, Internal Medicine Department, Complejo Hospitalario Universitario de Santiago, C/Choupana s/n, Santiago de Compostela 15705, Spain 2 Section of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
Background/Aims: Although many studies have reported significant improvements in quality of life (QOL) after liver transplantation (LT), consistent data on areas of improvement are lacking. To perform a systematic review on medical literature of QOL after LT paying particular attention to studies that utilized the most commonly adopted study instrument, Short Form-36 (SF-36). Methods: To collect studies focused on QOL in adult LT recipients, from 1963 to 2007, cited in Pub Med, Embase or Cochrane databases. From an initial identification of 613 articles, we selected 44 longitudinal studies with pre- and postLT data that we assessed using a sign test, and 19 used SF-36, which we analyzed separately. Results: Longitudinal data showed remarkable improvement of common domains of QOL comparing pre- and posttransplant items. However, analysis of 16 SF-36 cross-sectional studies comparing post-LT patient domains with control population showed significantly higher ratings for controls in six while no differences were found in two. Conclusions: This review suggests that whereas general QOL improves after LT, when compared with healthy controls, LT recipients have significant deficits in QOL. Consequently, the previously reported QOL benefits after LT may have been overstated. Ó 2008 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Keywords: Quality of life; Liver transplantation; SF-36
1. Introduction Liver transplantation (LT) is a life-saving intervention for many patients with end-stage liver disease. Assessment of the success of LT has traditionally been related to patient survival. Currently, patient survival rates at 1 and 5 years approach 90% and 70%, respectively. For some specific indications, such as those due to chronic cholestatic liver disease, survival is even better [1]. However, as concern about survival has diminished with improved surgical success, greater attention Received 24 October 2007; accepted 19 December 2007; available online 28 January 2008 Associate Editor: P.-A. Clavien q The authors declare that they do not have anything to disclose regarding funding from industries or conflict of interest with respect to this manuscript. * Corresponding author. E-mail address: [email protected] (S. Tome).
has been placed on issues related to medical management of the long-term liver transplant survivor. Recurrence of the underlying disease, complications of immunosuppression and onset of ‘‘de novo” diseases are frequent and impair both quantity and quality of life (QOL) among survivors. Any analysis of QOL after LT will be constrained by several limitations inherent to this field of study. For example, all published studies for obvious reasons do not take into account patients who have died, and also tend to exclude patients in poor condition at the time of assessment, thereby introducing a favorable bias [2]. Additionally measurement of health-related QOL will be affected by cultural, economical and social factors related to the population being studied. A reliable assessment tool that balances these factors is lacking. In a meta-analysis published in 1999 by Bravata et al. that included 49 studies, the assessment tools ranged from Karnofsky Performance Status (KPS) in 11 studies to self-designed questionnaires,
0168-8278/$34.00 Ó 2008 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jhep.2007.12.013
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lacking prior validation in 16 studies. Unfortunately, the frequent use of non-validated assessment tools is a significant impediment to comparison between studies. While it is clear that we lack a perfect tool to assess health-related QOL after LT, several validated tools have been utilized in studies of post-LT QOL, among which the Short Form-36 (SF-36) is the most often used. The SF-36 was developed to measure eight of the most important areas of health. The use of SF-36 enables comparisons across a broad range of conditions and between studies of healthrelated QOL in the same setting [4]. We believe that this is an opportune moment to undertake a systematic review of QOL after LT, in which particular attention is paid to studies using SF36 to assess health-related QOL after LT. We will review specific aspects of QOL after LT, including the available data on whether etiology of liver disease or gender influences post-LT QOL, review employment as a marker of QOL, and finally consider studies assessing sexual function after LT. Where studies are too scanty to allow a cumulative statistical analysis, we will provide a summary without statistical analysis.
manual search. The articles revealed by the search technique were included in the analysis if they used a validated tool or contained enough information to infer an appropriate assessment of the main domains of QOL. Similarly, articles which did not use validated tools were also included if relevant information related to a specific domain, such as sexual functioning, was collected in a prospective fashion. We adopted the following selection criteria for longitudinal studies: use of a validated QOL-assessment tool and inclusion of pre- and post-transplant items in the analysis. The studies were grouped in two different ways: longitudinal studies meeting our selection criteria, and all cross-sectional studies and longitudinal studies utilizing the SF-36 as a QOL-assessment tool (Fig. 1). Two different researchers (JW and ST) independently collected the papers. The coordinate-words used were ‘‘liver transplantation”, ‘‘quality of life”, ‘‘employment”, ‘‘sexuality”, ‘‘gender” and ‘‘health status”. We restricted our search to articles written in English and covering the time frame from when the first liver transplant data appeared (1963) to January 2007. The search was also limited to adults receiving livers from a deceased donors.
2.1. Statistical analysis The collected articles were entered in an electronic data base (Microsoft Excel 2003) in two different files: longitudinal studies containing pre- and post-transplant items using different tools, and a specific file gathering all the studies using SF-36, both cross-sectional as well as longitudinal studies. A sign test was performed on these longitudinal studies where different QOL-assessment tools were used. This test assesses the general trend of the effect without consideration of either the sample size or magnitude of effect. The specific domains of health-related QOL were assessed when a significant effect was found. If the magnitude of a specific effect was not displayed in the paper, but could be inferred, it was also considered for the global assessment. For example, the social functioning domain, in some circumstances, could be inferred by considering the rate of employment
2. Materials and methods The medical literature search was focused on three medical databases Pub Med, Embase, Cochrane, which we supplemented with a
Medical databases and manual search n:613
Relevant information n:93
Longitudinal studies n:54
Cross sectional Studies n:39
Excluded Studies:10 ( Non validated tool)
Individualized study n:5
Longitudinal studies using SF-36 n:4
Cross-sectional studies using SF-36 n:16
Specific SF-36 assessment Fig. 1. Study design.
Excluded Studies:18 ( living donor:13; not enough information:5)
S. Tome et al. / Journal of Hepatology 48 (2008) 567–577 (Table 1). A level of significance was estimated by comparing the proportion of positive or negative studies with the binomial distribution. A second part of our analysis was to calculate the size effect in those studies using the SF-36 as an assessment tool (Table 2). The analysis was performed by comparing pre-transplant and post-transplant items among longitudinal studies. We performed homogeneity tests in all summary effects.
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The assessment of the magnitude of the effect of transplantation for cross-sectional and longitudinal studies (where post-transplant and control population domains were not reported from the same study) was performed by calculating univariated weighted means for posttransplantation and control population domains. The difference of weighted means of different domains between transplant recipients in the post-transplant period and the control population was then calculated for a summary meta-analysis. We also calculated the magnitude
Table 1 Longitudinal studies comparing pre- and post-transplant items N
Author/year
Number of patients
Mean age
Followup
Tools
MMPI 16PF, SIP Sexual and Endocrine function WAIS, WMS, CMIF, SCL90-R CIS, Shipley WAIS EORT SBAS, SIP PAIS AUSQUAL BDI, STAI, SIP, MMSE, CVLT, WCST, TMT, IMI NHP, Karnofsky, PIWB, STAI, SrDS SBI SIP Karnofsky MOS-SF Karnofsky Z-E-WHO UNOS score CIS, MMSE, NHP, GHQ NIDDK Sexual, endocrine function Gynecological assessment PAIS KARNOFSKY WBI, BSF LZI SEB ALL ACSA POMS AUSQUAL LTDQOL, PIGW, Karnofsky, MOS QLI-LT
1 2
Tarter/1984 [52] Van Thiel/1990 [29]
10 150
48
36 18
3
Hockerstedt/1992 [55]
8
40
12
4 5 6 7 8
Arria/1991 [56] Kuchler/1991 [57] Tarter/1988, 1991 [53] Moore/1992 [30] Riether/1992 [58]
13 67 53 22 61
40 40 41 44.5 45
12 36 51 9 12
9
Bonsel/1992 [59]
26
43
120
10 11 12 13 14 15 16
Beresford/1992 [60] Tarter/1992 [54] Gish/1993 [61] Knechtle/1993 [10] Chen/1994 [62] Lundgren/1994 [63] Collis/1995 [64]
61 130 29 60 7 108 11
45 58 47 49 20.2 39 44
18 24 24 NA 38 12 9
17 18
213 10
49 42
60 11.6
19
Levy/1995 [65] Madersbacher/ 1995 [31] Mass/1996 [39]
84
37
12
20 21
Payne/1996 [32] Scholler/1997 [66]
50 171
43 NA
36 12
22 23
Moore/1997 [67] Belle/1997 [68]
32 346
44.1 48
9 12
24
41
50
12
25 26
Lobiondo-wood/ 1997 [69] Gevarghese/1998 [33] Gross/1999 [23]
100 157
46 50
72 12
27
Singh/1998 [13]
59
48
12
28
Moore/2000 [26]
27
44
9
29 30
De Bona/2000 [15] Caccamo/2001 [34]
141 33
46 46
60 12
31 32
Walter/2002 [70] Ratcliffe/2002 [48]
82 455
46 46–60
36 24
Karnofsky PAIS Karnofsky, IWB, IGA NIDDK LTD-QOL, Functioning composite (MOS, NHP) BDI, WCS, POMS, Karnofsky, Likert scale AUSQUAL, WAIS, REY Benton’s Controlled Oral word Association Test LEIPAD, BSI SCL-90R mFLIC, PAIS, WCQ ACSA, BSF, GBB SF-36, EQ-5D
Studied domains Gral QOL
Physical health
Social function
Sexual function
Psychological health
+ NA
+ NA
+ NA
NA +
+ NA
NA
NA
NA
NA
NA
NA + + + +
NA + + + +
NA NA + + +
NA NA NA 0 NA
+ 0 + + +
+
+
+
NA
+
+ + + + + + +
+ + + + + + +
+ + + + + + +
NA NA NA NA NA NA NA
– + + + 0 NA +
+ NA
+ NA
+ NA
NA +
+ NA
NA
NA
NA
0
NA
+ NA
+ NA
0 NA
+ NA
0 NA
+ +
+ +
+ +
NA NA
+ +
+
+
+
NA
+
+ +
+ +
0 +
+ +
0 +
+
+
NA
NA
+
+
+
+
NA
+
+ +
+ +
0 +
NA +
+ 0
+ +
+ +
NA +
NA + NA 0 (continued on next page)
570
S. Tome et al. / Journal of Hepatology 48 (2008) 567–577
Table 1 (continued) N
Author/year
Number of patients
Mean age
Followup
Tools
NIDDK MOS-20, NHP, Karnofsky, Bradburng’s single item WHOQOL-100 EQ-5D Karnofsky, SF-36a LEIPAD, BSI LEIPAD, BSI Sexual function SF-36 SF-36, F-SOZU, FLZ, HADS-D Sexual function Sexual function
33 34
Karam/2003 [35] Cowling/2004 [28]
67 149
51 Median: 50
12 24
35 36 37 38 39 40 41 42
O’Carrol/2003 [71] Longworth/2003 [24] Moore/2004 [72] Burra/2005 [73] Sainz Barriga/2005 [19] Ho/2006 [36] Pieber/2006 [74] Goetzmann/2006 [49]
70 208 413 25 126 150 15 26
50 Median: 50 47 46.3 61 54 45 49
12 12 49 12 42 12–60 2 12
43 44
Sorrel/2006 [37] Gomez Lobo/2006 [38]
39 276
51 50
16 NA
Foot notes: +, improvement; 0, no improvement; a No data comparing pre and post with SF36.
Studied domains Gral QOL
Physical health
Social function
Sexual function
Psychological health
+ +
+ +
+ +
+ +
+ +
+ + + + + NA + +
+ NA NA + + NA 0
NA NA NA 0 NA NA + +
NA NA NA NA NA _ NA NA
+ NA NA + 0 NA + 0
NA NA
NA NA
NA NA
0 0
NA NA
, deterioration. See abbreviations in Appendix.
of the effect according to Spiegel et al. [3] using the following equation ES (effect size) = HR QOL group 1 HR QOL group 2/SD (standard deviation) group 1. An effect size <0.2 is considered a small effect, 0.5 a moderate effect and >0.8 a large effect according to Cohen et al. [11].
3. Results The medical literature search revealed 613 articles, of which 93 studies were informative (Fig. 1). There were 54 that contained longitudinal information including QOL items from pre- and post-transplant patients, whereas 39 were cross-sectional studies, most commonly including a control population for comparison. Among the longitudinal studies, 10 were excluded on account of the use of a non-validated tool, leaving 44 studies that met our selection criteria for longitudinal studies for the final analysis. Among the 39 cross-sectional studies identified, we rejected 18 studies either because the information provided was related to living donation (n = 13) or because the provided information was insufficient to allow a full analysis (n = 5). After 16 studies were included in the analysis specific to SF-36, there remained five cross-sectional studies that were analyzed separately. For the second part of the present review 16 crosssectional studies and three longitudinal studies, all using the SF-36 as a common instrument, were considered for a specific analysis. 3.1. Longitudinal studies using a variety of QOLassessment tools From the 44 longitudinal studies including pre- and post-transplant items, data on 4381 patients were pooled. The mean age was 45 years and mean followup was 25 months (2–120). The sign test performed for common domains showed that post-transplant improve-
ment was statistically significant for the domains related to general QOL (p < 0.0001), social functioning (p < 0.0001), physical health (p < 0.0001) and psychological health (p = 0.014) but not for sexual functioning (p = 0.58) (Fig. 2). 3.2. Cross-sectional studies using SF-36 Analysis of the 16 studies that used SF-36, in which the eight patient domains were compared with controls from the general population, included 1615 LT recipients with a mean age of 49 years and mean follow up of 43 months (6–120), showed significantly higher ratings for controls in six domains: physical functioning: 21.15 (p: 0.008); role physical: 30.54 (p < 0.0001); role emotional: 11.18 (p: 0.003); social functioning: 11.2 (p < 0.0001); energy mean diff: 10.45 (p: 0.02) and general health: 16.34 (p < 0.0001). The mean differences for the two remaining domains, body pain: 10.08 (p: 0.19); and mental health: 1.68 (p: 0.11), were similar between the two groups (Table 3). 3.3. Longitudinal studies using SF-36 Four studies [48–51] utilizing SF-36 were performed in a longitudinal fashion, including both pre- and post-transplant items. We were able to retrieve enough data to build an effects model from two [49,50]. From these studies, 76 patients were pooled with a mean age of 50 years and mean follow-up of 24 and 12 months, respectively. Enough data were available to compare trends in four domains. There was a statistically significant improvement of general health while the variation in physical function, role physical function and role emotional shown did not reach significance (Table 4).
S. Tome et al. / Journal of Hepatology 48 (2008) 567–577
571
Longitudinal Studies Comparing Pre and Post-transplant QOL Domains (using different tools) N=44 Deterioration
Improvement
P values: the Sign Test Psychological health p=0.014
Physical functioning p<0.0001
Sexual functioning p=0.58
Psychosocial adaptation p=0.0001 General QOL -10
0
10
20
30
40 p<0.0001
Fig. 2. Sign test. Longitudinal studies comparing pre- and post-transplant items using different tools.
3.4. Assessment of specific issues 3.4.1. Etiology of liver disease While it seems likely that the etiology of liver disease would affect QOL after LT, evidence for a determinative effect of pre-transplant etiology is less clear. Among the conditions that have been investigated are alcoholic liver disease (ALD), HCV infection, acute liver failure (ALF), and chronic cholestatic syndromes. Several studies have reported on QOL after LT in patients trans-
planted for ALD [5–9]. While the majority of the studies have shown striking impairment before LT and significant improvement after LT, there remains debate about the QOL responses in ALD recipients when compared to patients transplanted for other conditions. An early study by Knechtle et al. [10] did not identify any differences between ALD recipients and patients transplanted for other etiologies, and subsequent authors have concurred with this conclusion[7–9]. However, recently Aadahl et al. reported on a cross-sectional
Table 2 Studies using SF-36 n
Author/year
Year’s data collection
Country
Follow up(mo)
Type of the study
PreTx Items
Number of patients
Mean age
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Littlefield/1996 [75] Hunt/1998 [76] Bryan/1998 [77] Hellgren/1998 [78] Fosberg/1999 [79] Pereira/2000 [8] Younossia/2000 [51] Rothenhausler/2002 [80] Painter/2001 [16] Aadahl/2002 [21] Ratcliffe/2002 [48] Van der Plas/2003 [81] Sutcliffe/2003 [82] Beilby/2003 [83] Kanwal/2004b [84] Krasnoff/2005 [50] Sargent/2006 [20] Goetzmann/2006 [49] Van den Berg-Emons/2006 [85] Sahota/2006 [5]
1993 1992–1995 1986–1994 1985–1995 1995–1997 1987–1996 1998 1996–1997 – 1990–1998 1996–1998 2000 1988–2000 1998–2001 1997–1998 – – 2000–2003 2003 1996–2001
Canada USA UK Sweden Sweden UK USA Germany USA Denmark UK Netherlands UK NZ USA USA UK Switzerland Netherlands USA
32 14 12–60 39 6–24 6–120 4 46 72 12–60 24 – 92 50 – 24 35 12 54 34
Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Longitudinal Cross-sectional Cross-sectional Cross-sectional Longitudinal Cross-sectional Cross- sectional Cross-sectional Cross-sectional Longitudinal Cross-sectional Longitudinal Cross-sectional Cross-sectional
N N N N N N Y N N N Y N N N Y N N Y N N
149 42 121 120 23 47 22 75 180 130 455 186 24 54 203 50 60 26 96 105
50 48 51 50 49 50 50 54 55 50 46–60 49 16.5 52 51 51 49 49 52 54.5
a b
CLDQ. Only including end-stage liver disease SF-36 scores.
572
S. Tome et al. / Journal of Hepatology 48 (2008) 567–577
Table 3 Effects model in 16 cross-sectional studies using SF-36 Statistic/ domain
Physical functioning
Role physical
Role emotional
Social function
Pain
Energy
General health
Mental health
Mean diff. CI 95%
21.15 ( 32.64 to 9.66) 3.3 0.008 91%
30.5 ( 40.55 to 0.54) 3.2 <0.0001 64.8%
11.18 ( 18.66 to 3.70) 0.68 0.003 53.9%
11.27 ( 15.69 to 6.85) 0.94 <0.0001 33.9%
10.08 ( 25 to 4.8) 1.56 0.19 93.9%
10.45 ( 18.94 to 1.96) 1.62 <0.0001 77.3%
16.34 ( 22.02 to 10.66) 4.83 <0.0001 65.1%
1.68 ( 3.74 to .38) 0.98 0.11 0%
a ES p I2 a
ES, effect size according to Spiegel et al. An effect size <0.2 is considered a small effect, 0.5 a moderate effect and >0.8 a large effect.
QOL-study of 130 liver transplant recipients, who had survived at least 1 year, assessed using SF-36, and found significantly impaired QOL scores for ALD patients (who were grouped with cryptogenic cirrhosis) compared to patients transplanted for other conditions [21]. The role of HCV infection on QOL and specifically the effect of recurrence of the infection after LT has been the focus of several studies [12–19]. Singh et al. have documented a significant impairment of QOL assessed by different tools in HCV-infected LT recipients, with significant impairment related to physical functioning and fatigue [12,13]. Sargent and Wainwright used the UK version of SF-36 to compare QOL in 26 patients with ALF, 34 patients transplanted for chronic liver disease and the standard UK population [20]. They did not find any statistical differences between the post-LT groups although the scores were significantly lower than the standard UK population. In addition, they did not find any differences between those patients transplanted because of acetaminophen overdose compared to other ALF etiologies. A similar conclusion regarding the outcome after LT for ALF was reached by Aadahl et al. [21]. Among patients with cholestatic liver disease, Navasa et al. identified a great improvement in well being assessed by Karnosfky and Nottingham Health Profile [22]. Gross et al. confirmed these results using different tools in a later study [23]. An economic assessment in terms of cost effectiveness using QALYs for PBC, PSC and ALD as indications for liver transplant demonstrated that cholestatic liver disease displayed the best cost-effectiveness ratio [24]. 3.5. Gender differences An early study, published by Kober et al. [25], reported that men had lower QOL scores after LT than women recipients. In a composite analysis published in Table 4 Effects model in two SF-36 longitudinal studies Domain
Pooled mean diff. (CI 95%)
Signification
Physical function Role physical function Role emotional General health
+10.60 +12.54 +10.25 +13.82
p = 0.19 p = 0.25 p = 0.26 p = 0.02
(+26.32 (+34.10 (+28.18 (+25.42
to 5.12) to 9.02) to 7.67) to +2.23)
1999, Bravata et al. [2] concluded that there were no differences between the sexes in post-LT QOL, although the authors commented on the scarcity of studies dealing with this topic. Moore et al. came to the same conclusion in a single-center prospective study of 10 LT recipients compared to normal controls [26]. But recently more focus has been placed on gender in post-LT QOL assessments. Cowling et al. have reported a study specifically designed to consider whether gender influences QOL outcome after LT [28]. Among 88 male and 61 female LT recipients, matched for prevalence of HCV infection, who received QOL assessment pre-LT, men displayed higher levels of health-related QOL than women at 1 and 2 years [28]. The differences were partially corrected after adjustment for educational level. A similar result was reported by Spanish investigators who reported that psychosocial adjustment after LT was rated higher in male compared to female recipients [27]. 3.6. Sexual function We have identified 12 studies dealing with sexual function after liver transplant [23,28–39]. Five studies reported no improvement or even deterioration after liver transplant. In the meta-analysis published in 1999 by Bravata et al., sexual functioning was a specific domain that resulted in significant improvement. In 2006, two studies were published focusing on this specific domain. Ho et al. from British Columbia studied 320 transplanted patients. Among 150 respondents, sexual dysfunction was present in 24% before transplant and in 15% of them after liver transplant. However, 32% of patients presented with sexual dysfunction de novo after LT [36]. Similar findings were reported by Sorrell et al. wherein sexual dysfunction discovered before liver transplant tended to continue after liver transplant [37]. In our analysis, combining data from longitudinal studies, we did not observe a perceptible improvement in sexual function after LT. 3.7. Employment Many different studies have dealt with employment after LT. In Table 5 we have collected some of the most representative studies performed across different coun-
S. Tome et al. / Journal of Hepatology 48 (2008) 567–577
573
Table 5 Employment rate after liver transplant across different countries Author/year Ref.
Country
Number
Follow-up (months)
Mean age
Return to work
% Working full time
Knechtle/1993 [10] Adams/1995 [40] Loinaz/1999 [41] Newton/1999 [42] Paterson/1999 [17] Karam/2003 [43] Cowling/2004 [6] Blanch/2004 [27] Kichner/2006 [44] Sahota/2006 [5] Sargent/2006 [20]
USA Can Spain USA USA France USA Spain Germany USA UK
60 203 137 122 87 125 152 126 23 105 60
NA 9 3 60 48 120 53 12 62 34 36
49 46 49 47 48 51 53 56 48 54 35
56% 57% 41% 55% 45% 53% 36% 33.1 26% 49% 37%
40% 40% 38% 47% NA 39% 24% NA 17% NA NA
tries [6,10,17,40–42,27,43,44]. These showed considerable variation of the level of employment after LT, from 26% in a study performed in Germany [44] among women with polycystic liver disease to 57% reported by Adams et al. during a period of economic recession in Canada [40]. The latter study showed that patient’s age and duration of disability before LT were predictors of employment after LT. A recent study not only confirmed these predictors but also identified the link between unskilled workers, an income of less than 30,000 USD and a duration of disability of more than 6 months and unemployment status [5]. 4. Discussion Assessment of QOL not only addresses a more comprehensive overview of outcome than finite end-points such as patient- or allograft-survival, but also results in a more nuanced evaluation in terms of both effectiveness and cost effectiveness. Many studies in medical literature have dealt with QOL after LT. There are obvious potential biases in these reports. They usually exclude the very ill. Some studies have been performed too soon after the transplantation. Moreover, the absence of uniform design and the broad variety of instruments utilized to assess QOL has been a significant drawback (see Table 6). In the last 10 years, the Short Form-36 Health Status Survey (SF-36) has become the most frequently used QOL instrument in LT recipients. SF-36 is a non-disTable 6 QOL and specific subjects Issues
Refs.
Condition of liver transplantation Alcohol liver disease Hepatitis C PBC PSC Acute liver failure Gender differences Sexual function Employment
[5,7–10] [12–18] [22–24] [20,21] [25–28] [23,28–39] [6,10,17,40–42,27,43,44]
ease-specific instrument that contains a 36-item questionnaire of describing and valuing the health status of individuals across several dimensions (physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health). Scores on each dimension are obtained by adding up item responses and transforming these raw scores to a scale by means of a scoring algorithm in which 0 represents poor health and 100 represents good health. Among the disadvantages of SF-36 are the lack of an overall score, the absence of an assessment of cognitive function, and the lack of validation of the interpretive significance of changes in patient responses over time [2]. Nevertheless, the adoption of SF-36 in LT studies is an advance because it allows comparison between studies, and analysis of accumulated data from multiple studies. Consequently, we felt that it was appropriate to undertake a systematic survey of QOL after LT, with particular emphasis on studies utilizing SF-36. The main findings in this systematic review showed that general QOL improves dramatically after LT, compared to health status prior to transplantation. On the other hand, when compared with the general population, the vast majority of LT patients have significant deficiencies in most QOL domains. This observation is in contrast to that of Karam et al. who, in a comparative study encompassing recipients of different solid allografts after 10 years follow up, found that the index of well being was better in LT recipients than in the general population [43]. Also, Pereira et al. found that QOL among LT recipients, transplanted on account of ALD, showed scores broadly similar to the standard population [8]. Despite these previous reports, we conclude that the perception of improvement of QOL after LT may have been overstated. Additionally, the specific analyses performed in those longitudinal studies using SF-36 as a common instrument demonstrated a lack of immediate improvement in several domains. While these data might be explained by insufficient follow up and also by the fact there were only two longitudinal studies with available data, they also raise questions about the level of restoration of QOL after LT.
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When analyzing specific issues related to QOL in LT patients some clues emerge about why the improvement of QOL is less than we might have expected. A close relationship has been established between underlying liver disease and QOL (see Table 6). HCV infection seems to impair QOL mainly in those patients with recurrence of the disease [12,13]. The same trend, although at lower level, can be seen in those patients who start to drink heavily again after transplant [9]. Additionally, indefinite exposure to immunosuppression and ‘‘de novo” diseases results in impairment of both QOL and life expectancy [45,46]. A recent finding is that gender affects perceptions of QOL after LT. In the meta-analysis performed in 1999 by Bravata et al. [2] gender was not identified as a factor impairing QOL. However, recent data indicate that women demonstrate worse scores than men [27,28]. Explanations for the phenomenon of gender-associated differences in QOL after LT are speculative, but most of the studies have pointed to social and psychological issues. Another novel aspect in this research is that sexual function after liver transplant tends to show no improvement and in some cases even deteriorates [36,37]. Thus, five [30,37–40] of thirteen studies found no improvement, or even identified deterioration of sexual function indicating that the reported restoration of sexual health may have been overstated. To address this issue by self-assessment questionnaires is always difficult. As several authors have pointed out, encephalopathy may have compromised responses in the pretransplant period whereas after LT, respondents ‘‘might have found this a good opportunity to express their dissatisfaction” or disappointment [36]. Reasons to explain the lack of improvement in perceptions of sexual health are likely to be psychological rather than endocrine since endocrine function typically recovers after LT [29,31]. While employment is a useful global surrogate for social functioning, care is necessary in procuring and analyzing the data [5]. In one study, contrary to what might be expected, unemployed patients displayed better scores of QOL [5]. It is necessary to distinguish and account for full time remunerated work outside the home, unremunerated work such as attending school or university, household work and part-time work. The lowest rates of employment after LT tend to be explained by gender composition, transition to retirement and disability status after LT [27,44]. Adams reported that the interval without work prior to LT correlated with the likelihood of returning to work [40]. The pre-LT diagnosis may also influence the rate of employment after LT. For example, prior to LT alcoholic patients appear less likely to be involved in structured social activities and routine volunteering than non-alcoholic patients but the rate of employment does not display any differences [6,9]. Dickson et al. [18] have
described a lower rate of employment among patients transplanted due to HCV cirrhosis although there was no statistical difference compared with patients transplanted because of HVB cirrhosis. Our review has several inherent limitations. QOL is a subjective concept that is not easy to measure on account of cultural, social and economic differences. Indeed these difficulties may explain the numerous instruments developed for its measurement [47]. We addressed these limitations in the following ways. First, in order to avoid heterogeneity of study design, we collected only studies written in English, and only those in which a validated tool was used. In addition, we restricted our survey of cross-sectional studies to those using SF-36. Second, in those longitudinal studies using different instruments the common domains were directly assessed, and where necessary we inferred the trend to determine the result for that domain. Trying to eliminate the assessment bias, the two researchers who collected the papers also performed a simultaneous assessment of a random sample of the articles and the concordance in the assessment was 100%. Nevertheless, the burden of subjectivity is high in specific assessments, for example when inferring that good social functioning is expressed by the rate of employment. Third, in this review some cross-sectional studies were used to identify specific outcomes such as the influence of liver disease etiology [7,8] on QOL [27,28]. Fourth, while this review has some overlap with the meta-analysis published by Bravata et al. [2], we used a different methodology. We focused on studies with a common assessment tool, something that would have been impossible for Bravata et al. due to scarcity of studies using the same instrument at that time. In conclusion, in this systematic review, we observed a striking improvement of QOL after LT. However, compared to the standard population, LT patients showed considerable deficits, an observation that was supported by impaired QOL in specific patient cohorts and in particular domains. We suggest that attention in future studies should be paid to the QOL of female LT recipients, to the QOL outcomes in specific patient populations such as HCV-infected recipients, and to specific domains such as sexual function or psychological health. Acknowledgment Santiago Tome has a temporary appointment at the University of Wisconsin, supported by the Institute Carlos III-Spanish Health Department Grant BAE7 06/90040.
Appendix Abbreviations: ACSA, anamnestic comparative self assessment; AUSQUAL, austin quality of life scale;
S. Tome et al. / Journal of Hepatology 48 (2008) 567–577
ALL, everyday-life abilities; BDI, Beck depression inventory score; BSF, Berlin questionnaire of current moods; BSI, brief symptom inventory; CIS, clinical interview schedule; CMIF, cornell medical index form; CVLT, California verbal learning test; EORTC, European organization for research and treatment of cancer; EQ-5D, EuroQoL classification system; FLZ, questionnaire of life satisfaction; F-SOZU, social support questionnaire; GHQ, general health questionnaire; GBB, giessen complaint questionnaire; HADS, hospital anxiety and depression scale; IGA, index of general affect; IMI, impact message inventory; LEIPAD, quality of life test; LTDQOL, liver transplant disease quality of life questionnaire; mFLIC, modified functional living index for cancer; MMSE, mini-mental state examination; MMPI, Minnesota multiphasic personality inventory; MOS, medical outcome survey; NIDDK LTD, national diabetes kidney disease liver transplant disease questionnaire; NHP, Nottingham health profile; PAIS, psychological adjustment to illness scale; POMS, profile of mood states scale; QLI-LT, quality of life index-liver transplant version; PGWI, psychological general wellbeing index; REY, the complex figure of Rey; SBAS, social behaviour adjustment schedule; SCL90-R, symptoms check list; SBI, strauss bacon index; SEB, social embedding; SIP, sicknes impact profile; 16PF, sixteen personality factor questionnaire; SrDS, self-rating depression scale; STAI, state-trait anxiety inventory; TMT, trailmaking test; UNOS score, united network of organ sharing; WAIS, Weschler adult intelligence scale; WCST, Wisconsin card sort test; WMS, Weschler memory scale; WCQ, ways of coping questionnaire; WHOQOL-100, world health organization quality of life scale.
[8]
[9]
[10]
[11] [12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
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