The aim of the study was to identify factors affecting health-related quality of life (HRQL) in adolescents after liver transplantation. HRQL was measured using the CHQ-CF87 in 55 adolescents, aged 12–18 years. Factors associated with HRQL included allograft morbidity, psychological and family-related variables measured through standardized questionnaires. The domains of the CHQ-CF87 were reduced using factor analysis to give physical, psychological and social domains. Impacting factors were identified through stepwise, multiple regression analysis. Adolescents had significantly lower HRQL in every domain except for role/social-behavior and family cohesion compared to the general population. Adolescents experienced median 18 (range 4–31) symptoms related to immunosuppression, 40(75%) had one or more chronic illnesses related to immunosuppression and 12(22%) had a history of emotional difficulties. Self-esteem and emotional health were similar to the general population but behavior and aspects of family function were lower. Following regression analysis, the factors associated with HRQL were: age at transplant, secondary chronic illness, symptom distress, headaches, history of emotional difficulties, self-esteem and family conflict. These explained 57% of the variance in physical function, 61% of psychological function and 39% of social function. HRQL is significantly reduced in adolescents after transplantation, which could be related to immunosuppression and psychosocial factors.
Liver transplantation (LT) has become the standard treatment for end-stage liver disease, acute liver failure (ALF) and liver-based metabolic disease. Advances in surgical techniques and improved medical aftercare have led to a survival of 81% at 5 years and 78% at 10 years (1). However, long-term immunosuppression is a double-edged sword that is responsible for many of the medical conditions that transplant recipients develop. While the physical consequences of transplantation have been well described (2,3), there is limited knowledge of the psychosocial effects. Only a few studies have shown improvements in neurocognitive function (4,5) as well as behavioral difficulties and reduced social function (6,7).
More recently, research has focused on the wider concept of health-related quality of life (HRQL) that incorporates physical, psychological and social function. A critical review of this literature suggests HRQL is reduced in children and adolescents (young people) after liver transplantation compared to the general population but similar to those with other chronic illnesses (8). This has been confirmed in later studies (9–11). However, these studies fail to take neurodevelopment into consideration and assume the psychological perception of a child is the same as that of an adolescent. Furthermore, a majority of studies rely on parent report rather than self-report, which has shown to be an unreliable method of assessing HRQL (12,13). The limitations of published studies notwithstanding, attempts to identify factors associated with reduced quality of life (QoL) have been described previously (9,14–16). However, there are paucity of data that measure the personal and family-related factors that could affect HRQL. The aims, therefore, of this study were to measure self-reported HRQL in adolescent LT recipients and to examine the influence of transplant-related, personal and family-related variables on HRQL.
Material and Methods
This was a prospective, cross-sectional descriptive study guided by an adaptation of a conceptual model of HRQL in cancer survivors (17) and was based on a structured definition of HRQL specific to young people (18). The conceptual model proposed that HRQL was influenced by variables related not only to the transplant (health issue) but also to the young person (psychosocial factors).
A total of 539 children received LT at King's College Hospital between January 1988 and December 2004. Young people were eligible to participate if they were literate in English and were at least 6 months post isolated LT. Young people who had severe developmental delay or who had undergone formal psychological or psychiatric treatment within 6 months of recruitment were excluded. This latter group was excluded as mental illness is known to reduce HRQL and would therefore skew the results (19). The study was approved by the Local Research Ethics Committee. Informed, written consent was obtained from parents and young people >16 years, and written assent from those <16 years.
Health-related quality of life: No HRQL instrument specific to LT was available; instead, a generic questionnaire was used. The Child Health Questionnaire (CHQ) is a widely used and well-validated generic measure of HRQL for children and young people aged 4–18 years (20) and has been used in previous studies of HRQL in children after LT (9–11,14–16,21). The self-report version (CHQ-CF87) is valid for young people aged 10–18 years and contains 87 items contained in 11 domains. Completion of the CHQ-CF87 is based on a 4-week recall. Scores for each domain range from 0 to 100, with the higher score indicating better HRQL.
Transplant-related variables: The transplant-related variables that might affect HRQL were derived from a literature review (14–16,22). These included pretransplant clinical course (diagnosis, presentation, age at diagnosis, physical symptoms, type of transplant and waiting time) and posttransplant clinical course (complications, comorbidity, number of transplants and admissions to hospital).
To determine the impact of the side effects of immunosuppression, the Modified Transplant Symptom Occurrence and Symptom Distress scale (MTSOSD) (23) was used. The MTSOSD is an adaptation of the Transplant Symptom Distress Scale, primarily reporting complications of prednisolone and azathioprine in adult heart transplant recipients (24), updated to include the side effects of ciclosporin, tacrolimus and mycophenolate mofetil (25,26). The MTSOSD has been used in adult liver, heart and renal transplant recipients (23,27,28). In order for the MTSOSD to be used in young people, the language of the questionnaire was adapted and additional items added based on reported symptoms in children (22). The MTSOSD Adolescent version therefore contained 35 items. These changes were evaluated as appropriate by a panel of five independent experts in pediatric development and LT and pilot-tested in a sample of five young people to evaluate understanding and ease of completion. The symptom frequency items are scored on a 5-point Likert-type scale to measure frequency as ‘never’ to ‘always’, or ‘not at all’ to ‘very severely’, and the symptom distress items are scored on a 5-point scale from ‘not distressing at all’ to ‘terribly distressing’. A total distress score is also calculated by computing the sum of all the distress scores.
Person-related variables included mental health history and three aspects of emotional health: self-esteem, emotional state and behavior.
Mental health history
A record was made of mental health history from a review of the medical records. This included attendance to a psychiatrist, psychologist or counselor, reason for referral and type and duration of treatment.
The Piers-Harris Children's Self-Concept Scale (PH2) was used to measure self-esteem (29). The PH2 is a self-report questionnaire for adolescents aged 7–18 years and contains 60 items covering 6 domain scales and a total score. Higher scores indicate a greater level of self-esteem. While the PH2 is relatively new, the PH1 has been used in studies of children following LT (30,31) and renal transplantation (32).
The Children's Depression Inventory (CDI) was used to measure emotional state (33) and has previously been used in research in children post-LT (31). The CDI is a self-report questionnaire for adolescents aged 12–17 years. It contains 27 items covering five factors reflecting cognitive and somatic symptoms of depression. The higher the score reflects the greater the severity of emotional problem.
The Strengths and Difficulties Questionnaire (SDQ) was used to measure behavior (34). The SDQ focuses not just on the negative aspects of behavior but also the positive attributes. The SDQ is a self-report instrument developed for use in adolescents aged 11–16 years. It contains 25 items with five dimensions and a total score. The SDQ has been used as a screening tool for emotional problems in adolescents with chronic illness (35). A higher score reflects more behavioral difficulties.
The social climate of the family was measured using the Family Environment Scale (FES). The FES measures positive (e.g. cohesion) and negative (e.g. conflict) aspects of family life (36). Young people over 12 years can complete the FES. The 90 items of the FES cover three main dimensions, which have 10 subscales. The FES has been used in adult studies of liver and renal transplantation (37,38) and in pediatric studies of bone marrow (39), renal (40) and LT (9).
The questionnaires were administered by a single researcher (RMT), who was not involved in clinical care. After gaining written consent/assent, the questionnaires were mailed to young people a week before their routine outpatient clinic appointment and returned in a sealed envelop to the outpatient clinic clerk for later collection by the researcher. Questionnaires were administered in random order to reduce the risk of response bias.
Data were analyzed using SPSS (version 13.0, SPSS Inc., Chicago, IL). If more than 10% of the questions were incomplete, it was removed from the analysis. Differences between the scores of the CHQ-CF87, PH2, CDI, SDQ and FES and the published norms or values for adolescents with other chronic illnesses were made using two-tailed, one-sample t-tests. Unlike the parent version of the CHQ (CHQ-PF50), the CHQ-CF87 did not have summary scores, therefore, an exploratory factor analysis was performed to examine how the items were related to each other (20). Principle components analysis was used for extraction and varimax rotation was used in order that the loading of each component could be identified. The derived CHQ-CF87 summary scores were then used as outcome variables in bivariate and multiple regression analysis. Pearson's correlation coefficient was used in the bivariate analysis and stepwise multiple regressions were used with variables noted to be significant in the bivariate analyses to p ≤ 0.07. Separate models were developed for transplant-, personal- and family-related factors. Finally, all those variables forming the models for each of these factors were entered into a single regression model to identify overall models explaining variance in physical, psychological and social function. Clinical data are presented as median and range and questionnaire data as mean ± standard deviation to allow comparison to other populations, unless specified, p < 0.05 was considered significant.
Of the 81 young people eligible to participate, questionnaires were returned by 55(68%). Reasons for not participating included: questionnaire not returned (n = 11), nonattendance to clinic (n = 7), refusal (n = 4) and unable to understand the questionnaires (n = 4). A comparison of the demographic characteristics of the study sample and eligible nonparticipants is shown in Table 1. Young people were predominantly Caucasian, with a history of chronic liver disease. Nine (16%) had liver function tests outside the normal range, due to nonadherence to immunosuppression in six (as reported in the medical records). One young person had chronic rejection and was relisted for transplant.
Table 1. Demographic characteristic of young people after liver transplantation
Participants N = 55
Eligible nonparticipants N = 26
*p < 0.05.
Age at time of study (years)1
Acute liver failure
Chronic liver disease
Idiopathic acute liver failure
Autoimmune liver disease
Other metabolic liver disease
Drug-induced liver failure
Age at diagnosis (years)1
Age at transplantation (years)1
Time since transplantation (years)1
Health-related quality of life
The mean scores on the CHQ-CF87 are shown in Table 2. In comparison to the general population, young people after LT scored significantly lower in every domain apart from role/social–behavioral and family cohesion. However, they had similar scores to young people with other chronic illnesses. Young people had similar scores to young people transplanted at a single centre in the United States (10) in the physical domains; however, young people in this study scored lower than the US population in the domains of behavior, self-esteem, general health perceptions and family activities and higher in the domains of role/social–behavioral and family cohesion.
Table 2. CHQ-CF87 comparison between the young people after liver transplantation, the general population and those with other chronic illnesses
Domain of the CHQPhysical function
Liver transplantation N = 5588.6 ± 14.4
General population1 N = 39297.8 ± 7.6***
Liver transplantation2 N = 2890.2 ± 14.1
Asthma1 N = 26092.2 ± 11.6
Diabetes3 N = 128 95.2 ± 8.7***
*p < 0.05; **< 0.01; ***< 0.001.
1Waters et al. (43), 2Fredericks et al. (10) and 3Wake et al. (41).
86.0 ± 22.7
96.8 ± 10.1***
87.6 ± 20.9
84.1 ± 21.3
88.7 ± 19.3
93.8 ± 12.5
96.8 ± 10.3
87.6 ± 21.6***
89.5 ± 19.4**
92.4 ± 20.5
86.8 ± 20.5
97.7 ± 10.6***
88.4 ± 21.9
91.3 ± 18.8
92.7 ± 14.5*
68.7 ± 25.0
84.4 ± 15.2***
72.4 ± 23.7
66.8 ± 21.2
75.2 ± 21.2
77.3 ± 12.4
85.3 ± 12.6***
81.0 ± 15.1*
75.0 ± 14.7
77.5 ± 14.3
73.1 ± 17.0
77.2 ± 18.7
71.6 ± 18.4
77.0 ± 16.6
74.1 ± 17.2
87.4 ± 11.8***
81.8 ± 12.1**
72.1 ± 18.5
75.1 ± 18.0
General health perceptions
54.5 ± 16.6
77.2 ± 13.5***
60.3 ± 13.3**
61.2 ± 16.0**
62.0 ± 17.7***
71.7 ± 23.4
78.9 ± 13.1*
79.7 ± 16.6*
69.3 ± 17.5
68.4 ± 18.6
75.8 ± 23.9
80.8 ± 21.5
68.6 ± 22.8*
69.0 ± 26.2*
68.3 ± 26.9*
The exploratory factor analysis that showed a 3-factor solution accounted for 76.9% of common variance. The loading for the three components aligned clearly with the physical, psychological and social domains of HRQL. The three components were therefore labeled psychological summary score (PsySS) incorporating behavior, mental health and self-esteem; physical summary score (PhSS) incorporating physical function, role/social–physical, bodily pain and general health perceptions; and social summary score (SocSS) incorporating role/social–emotional and role/social–behavioral. These three outcome variables were used in all subsequent analyses.
Transplant-related factors are summarized in Table 3. An associated condition or secondary chronic illness was present in 7(13%) prior to transplantation including ulcerative colitis (n = 2) and one each had a cardiac defect, epilepsy, deafness, cystic fibrosis and juvenile rheumatoid arthritis. Fourteen young people required a hospital admission in the 6 months prior to participating in the study, for up to three occasions (range 1–20 days). In 41 (75%), other chronic medical conditions (1 to 4 per young person) developed after LT, including poor renal function, hypertension, gastrointestinal complaints, recurrent skin infections, asthma, epilepsy, diabetes and growth delay. Many of these could be clinically attributed to immunosuppression.
Table 3. Transplant-related characteristics of young people after liver transplantation
Type of transplant
Pretransplant co-chronic illness (yes)
0.12 (−4.00 to 3.63)
Overweight (z-score >2)
Underweight (z-score < –2)
−0.50 (−3.73 to 2.77)
Stunted (z-score < –2)
Current calcineurin inhibitors
Other current medical problems
Number of admissions in the last 6 months
Number of days in hospital in the last 6 months
Over 50% of the young people were taking tacrolimus as their primary immunosuppression, although three were receiving no calcineurin inhibitors and were maintained on mycophenolate mofetil. Medical records indicated that eight (15%) young people self-reported as being nonadherent to immunosuppression in the previous year. The occurrence of side effects of immunosuppression and associated level of distress, as measured by the MTSOSD score, are shown in Figure 1. The median number of symptoms each young person experienced was 18 (range 4–31). The median total symptom distress score was 26 (0–104). Three (6%) young people had a total distress score >64 (denoting severe distress). Figure 1 shows the symptoms occurring most frequently were not necessarily those that caused the most distress. For example, ‘bruises easily’ occurred frequently (n = 40, 73%) but only one found this moderately/severely distressing. Weight gain, on the other hand, occurred in 14(25%) but 7(50%) found this moderately or severely distressing.
Mental health history: Twelve (22%) young people had received some form of psychiatric or psychological support since transplantation but not within the last 6 months. This was at a median age of 12.5 (8–17) years, 3.5 (1–14) years from the time of transplantation. Seven had been seen by a psychologist, four were treated by a psychiatrist and one had been in family therapy. The reason for therapy was not known in 1 young person, 4 had behavioral problems, 2 were treated for depression, 2 were self-harming and 1 each suffered with stress, panic attacks and anger management.
Self-esteem, emotional state and behavior: The levels of self-esteem (PH2), emotional state (CDI) and behavior (SDQ) are shown in Table 4. Young people after LT had comparable total scores to the general population for self-esteem and emotional state; however, they scored significantly worst on the measure of behavior (total score).
Table 4. Comparison between the measurement of self-esteem (PH2), emotional state (CDI) and behavior (SDQ) between young people after liver transplantation and those in the general population
Young people after liver transplantation
*p < 0.05; **< 0.01; ***< 0.001.
1Data from general adolescent population: PH2 (29), CDI (33) (only mean provided in the handbook) and SDQ (http://www.sdqinfo.com).
11.4 ± 3.2
11.2 ± 2.9
PH2— intellectual and school status
10.6 ± 3.4**
11.9 ± 3.4
PH2— physical appearance and attributes
7.5 ± 2.7
7.8 ± 2.6
PH2— freedom from anxiety
9.0 ± 3.9
10 ± 3.4
8.9 ± 2.5
8.4 ± 2.7
PH2—happiness and satisfaction
7.9 ± 2.1
8.1 ± 2.2
42.7 ± 10.3
44.6 ± 10.2
2.0 ± 2.3
0.8 ± 0.9
1.4 ± 1.6*
2.7 ± 2.3*
1.3 ± 1.5*
8.1 ± 6.2
3.7 ± 2.5**
2.8 ± 2.1
2.1 ± 1.5
2.2 ± 1.7
4.1 ± 1.9
3.8 ± 2.2
1.9 ± 1.6
1.5 ± 1.4
8.0 ± 1.5
8.0 ± 1.7
19.6 ± 4.7***
10.3 ± 5.2
Family-related variables: The majority of young people, 40 (73%), were in a two-parent family. A summary of scores for each domain of the FES is shown in Table 5. Young people rated their family environment lower in the relationship domains of achievement-orientation and moral–religious emphasis, and in the family structure domains in comparison to the general population of adolescents.
Table 5. Comparison of scores on the family environment (FES) between young people after liver transplantation to those in the general population
Multiple regression analyses: The transplant-, personal- and family-related variables significantly related to one or more of the HRQL summary scores (Table 6) were entered into stepwise multiple regression analyses to create models to explain the variance in the three dimensions of HRQL (2). A 4-factor model best predicted PhSS, adjusted R2= 0.569 indicating that these factors explain 57% of the variance (df= 45, F = 17.2, p < 0.001). A 6-factor model best predicted PsySS, adjusted R2= 0.613 indicating that these factors explain 61% of the variance (df= 32, F = 11.0, p < 0.001). A 3-factor model best predicted SocSS, adjusted R2= 0.392 indicating that these factors explain 39% of the variance (df= 44, F = 11.1, p < 0.001).
Table 6. Significant factors in the bivariate analysis included in the stepwise multiple regression analysis
We found that adolescent's self-reported HRQL after LT was an average 10 points lower than the general population in every domain except role/social–behavioral and family cohesion, indicating moderate to severely impaired HRQL. Similar to reports in adults, this was irrespective of acute or chronic presentation (42). This finding is unlike reports of young people from other centers who show similar HRQL to the general population (10,16,43). Possible explanations are the use of incentive payments to participate (10) and the use of different normative reference groups. We used data from a group of adolescents within the same age range as our sample (44). Fredericks et al., on the other hand, used normative data from those aged 10–15 years (45), which would not reflect HRQL of those in late adolescence, approximately 25% of our population.
In comparison to other chronic illnesses, our study showed young people had comparable HRQL. Chronic illness is well known to impact negatively on psychological function (46). The fact that psychological function is similarly low in all chronic disorders supports the notion that it is the chronic illness per se and not the actual diagnosis that affects young people's view of their HRQL. While HRQL may be comparable, this overlooks the fundamental aim of transplantation, being a treatment and not another disease. Hence, it is more appropriate to compare HRQL after LT against that of the general population rather than other chronic illnesses so that the risk and benefits of the treatment can be more objectively determined.
We identified transplant-, personal- and family-related factors associated with a poorer HRQL and found that the older the age at transplantation, the poorer the HRQL, which is similar to a previous parent-report of HRQL (14). This was not explained by pretransplant morbidity and may be proxy measure of other more significant but as yet unmeasured factors such as prolonged absences from school or cognitive developmental effects (47).
This is the first time the impact of the side effects of immunosuppression has been investigated in adolescents after LT in relation to HRQL. Similar to adult studies (24), the most frequent symptoms did not necessarily result in the most distress, but both the frequency of symptoms and symptom distress were related to lower HRQL. Symptom distress reflects the emotional anguish experienced through developing symptoms (25) and therefore further study of symptoms occurring after transplantation should focus on those that young people find most distressing and burdensome, such as weight gain, difficulty sleeping, painful joints and headaches. Our study confirms previous reports showing headaches are a common problem in young people after transplantation (48). We also showed that the occurrence of headaches had a significant impact on HRQL. The occurrence of headaches is common in adolescence with reported incidence of 10–30% depending upon the definition, that is, tension headache or migraine (49). In this study, more than twice as many young people (69%) experienced headaches. While the impact of headaches on HRQL has not been shown previously in young people after LT, the impact of headache frequency and intensity have both been found to be predictive of poor HRQL (50–52).
Development of a secondary chronic illness after transplantation as a result of immunosuppression had the greatest negative impact on HRQL. This is not surprising as many of the chronic illnesses developed after transplantation are already known to negatively impact on HRQL, including asthma (53–55), diabetes (56,57) and epilepsy (58,59). A high proportion of the young people in this study developed secondary renal dysfunction. None required dialysis but treatment affected their daily life, for example, increased hospital attendance and additional medications. The reason this has not been identified in previous studies (14) is because they used a numerical measure of renal function (glomerular filtration rate) rather than the treatment burden.
A striking finding in this study was the strong negative association previous psychological treatment had with the psychological domain of current HRQL. Psychological treatment occurred some time after transplantation in most young people. There was limited information about mental health history available and therefore the cause or trigger for this could not be ascertained. Nevertheless, the high incidence of mental health problems was nearly double the UK national average (http://www.statistics.gov.uk/cci/nugget.asp?id=853), suggesting some relation to the transplant and/or the effects of subsequent treatment. While there is limited research into psychopathologies after LT during adolescence, the onset of depression and other psychopathologies are known to occur during adolescence due to the demands of developmental tasks. In conjunction with a chronic illness, one could surmise that young people after LT were at a greater risk of developing problems. Young people had comparable emotional health and self-esteem to the general population. Higher self-esteem was associated with more positive HRQL, which has not been reported before in young people after transplantation. However, this has been noted in other chronic illnesses. For example, low self-esteem, strait–trait anxiety and behavior were related to reduced HRQL in adolescents with asthma (60).
Young people's lives are entwined with that of their family and therefore we also investigated the impact of family environment. We found no difference in the family cohesion domain of the CHQ, and similar to proxy reports (9), our young people scored similarly to the general population in the relationship domains of the FES. However, family conflict had a negative impact on HRQL. The relationship between HRQL and family function is important because others have shown it may have an impact on treatment adherence (9). We had no direct measure of adherence, therefore, the relationship to HRQL could not be quantified. However, a small study in children after renal transplantation showed a complex link between parental distress, child's attitude and behavior with adherence and HRQL (61) and thus further investigation is warranted.
There were a number of limitations to this study. As with other HRQL studies in LT, ours was single centre. A hierarchical approach was used in the regression analysis to account for the relatively small sample size in relation to the number of variables of interest, but a larger sample size is desirable. While a response rate of 68% is acceptable, there is potential for bias as HRQL maybe different in those who did not respond. The only demographic difference was a greater number of males in the group who did not participated. However, data were not available for other important factors such as family composition or level of education. Furthermore, all participants were English speaking and a majority were Caucasians, therefore, the results may not be generalizable. The number of potentially influencing variables that were measured was limited in number to reduce questionnaire overload. Other potentially important aspects of psychological function, such as coping or neurodevelopment may therefore have a stronger relationship to HRQL. This requires further examination. Finally, we used the CHQ to measure HRQL as it was the most appropriate instrument available at the time of study conception. We have since found that this does not necessarily reflect the things that are important to young people (Taylor, unpublished data). Further work is required to identify the most suitable instrument to measure HRQL in young transplant recipients. This may be the development of a transplant-specific instrument rather than adopting an existing generic questionnaire.
Despite the limitations, this is the largest conceptually robust study of HRQL in young people after LT. Furthermore, this is the first time a possible explanation for the variance in HRQL can be proposed. Either directly or indirectly, reduced HRQL stems from the necessity of having to take life-long immunosuppression. All young people with chronic illness requiring life-long medications find this burdensome (62,63). However, the side-effect profile of immunosuppression is far greater than many medications used in other chronic illnesses. In fact, immunosuppression can result in the development of a secondary chronic illness, for example, diabetes, epilepsy and asthma, which then necessitates the young person to take further medications. The physical impact aside, a number of young person-related variables also stem from the need to take life-long medications: for example, aspects of emotional health.
To improve HRQL the aim would therefore be to eliminate the need for immunosuppression. Promoting immunotolerance has become an important focus of research in the transplant community. However, it will be a number of years before this is achieved, therefore, subsequent research on HRQL in young people after LT should focus on interventions to lessen the burden of immunosuppression. Possibilities include adapting immunosuppression regimens to accommodate lifestyle and lessen the number of side effects, understanding the symptom experience and teaching coping mechanisms. Furthermore, relieving symptoms caused by immunosuppression may be a way of reducing the high incidence of nonadherence currently reported in these patients (10,64).
In summary, HRQL is significantly reduced in young people after LT but comparable to those with other chronic illnesses. Reduced HRQL is related to the side effects of immunosuppression and associated psychosocial factors. Further research is needed and should investigate mediating and moderating factors.