Thirty-one publications met our criteria for the PubMed search, including 24 original articles and 7 reviews (Figure 1 and Table 1). The last search was performed September 1^st , 2015.

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Figure 1 Summary of the search method. LT: Liver transplantation; LDLT: Living donor liver transplantation; QoL: Quality of life.

Overall QoL: In general, health related QoL (HRQoL) improves and remains stable throughout the years after transplantation, but does not reach the level of the general population. This can be explained by the presence of comorbidities, the severity of the disease and the transplant procedure[3,8,10-14].

HRQoL tends to increase rapidly during the first two years, and remains stable afterwards once almost normal values have been reached[8,15]. Some authors report a more fluctuating evolution with a rapid increase of QoL during the first six months, followed by a stabilization during the remainder of the first year and a rebound effect during the second year due to adaption to certain psychosocial conditions. Patients are confronted with their new health status and can experience problems with re-enrolment in society and more particular difficulties in their professional life. The rebound effect is due to the fact that patients slowly retrieve peer acceptance and can participate in professional and social activities. After two years, in these patients, an improvement can be found until the fifth year after LT[10].

Overall, many studies have proven significant improvements in general and mental health, vitality, social and physical functioning[1,16].

Physical QoL: Overall, physical health starts improving after the first month after transplantation. This effect lasts the first six months, up to 2 years after transplantation[17]. Fluctuations are not uncommon due to the rebound effect[10,13,16]. A lower physical activity can be seen 10 to 30 years post-transplantation in comparison to the general population. This can be explained by the effect of ageing[11,14]. Due to the rapid evolution in the field of LT, older studies do not reflect the common medical practice and should be read with caution.

In summary, an improvement is seen in physical functioning after LT after the first year, if major medical complications are absent, e.g., cytomegalovirus reactivation, rejection and revision[1,18-22].

Mental QoL: The World Health Organisation defines mental health as “a state of well-being in which every individual realizes his or her own potential, can cope with the normal stresses of life, can work productively and fruitfully, and is able to make a contribution to her or his community”[23]. This vague definition complicates the assessment of mental health QoL after liver and impedes the comparison of different studies. Some authors assessed the mental QoL by measuring anxiety and depression, because of the high correlation with these mental diseases. Burra and Germani[14] showed in their systematic review an increase of depression and anxiety scores during the first year, followed by a decrease afterwards. However, another study reported a significant improvement of depression and anxiety rates especially during the first year after LT in the absence of complications such as biliary events, endocrine disorders, physical and psychiatric problems[11,15]. The relief of the stressful time-lapse awaiting transplantation combined with a better physical health status could be a logical explanation. Furthermore, differences might be related to the presence of underlying psychiatric morbidities. Affective illness, maladjustment and severe anxiety have been diagnosed in 19%-54% of patients during psychiatric evaluation. Obsessive-compulsive, somatization, anxiety and depression symptoms were frequently found. The transplantation and stay at intensive care unit have been considered as traumatic stressors that diminish QoL and can cause overall mental distress. These patients are prone to some psychiatric disorders (e.g., anxiety and affective disorders, posttraumatic stress disorder) and a low QoL after LT[21,24-31].

The short form-36 questionnaire (SF-36) is extensively used to assess the health-related QoL, which is a reliable and standardized tool comparing as well the mental [the mental component summary score (MCS)] as the physical [physical component summary score (PCS)] aspects of QoL. During the first month after liver transplantation, studies show a rapid improvement of the MCS; the improvement of the PCS is slower though more durable and remains at higher levels six to twelve months after transplantation[13,15]. Side effects of immunosuppressive drugs and unmet expectations after liver transplantation can also hamper the improvement of MCS[17].

In summary an improvement is seen in the mental health status within the first months after transplantation and can be influenced by complications such as rejection, infections and biliary events. These are interesting targets for improvement[13-15,27].

Aetiology of liver disease: The original liver disease leading might influence QoL afterwards. Patients transplanted for non-cholestatic liver diseases report a significantly lower QoL after LT in comparison to those with a cholestatic liver disease[12]. Patients with viral hepatitis tend to suffer more from anxiety after LT than patients with alcoholic liver disease[13]. However, others challenge these data[10,14,21]. The influence of aetiology on QoL needs further investigation, since it influences all aspects of QoL[2,14].

Socio-demographic factors: The influence of gender on QoL remains a matter of debate, and data are conflicting[8,11,18].

Relational status however, does impact QoL. Married patients have a better QoL after liver transplantation than single or non-married patients[8,19,28]. This might be explained by a better social support.

Employment after LT is a crucial factor influencing QoL. Unfortunately, only 25% will return to work after two years. Restarting an active professional life after LT generates an income, but also restores the functional role of the patient in society. In employed patients, physical functioning is also improved and this results in an overall better QoL[10,12-14,21].

Early retirement, which is often observed in these patients, negatively impacts QoL. Patients with former alcoholic liver disease have a lower chance to return to work after transplantation, compared to other aetiologies, which can be related to the psychosocial burden present before liver transplantation. This can be explained by the psychosocial burden attached to addiction.

Professional activity before transplantation has a major impact on the general outcome after LT, which improves the activation grade after LT. As one might expect, the type of activities will determine the possibility to return to work, favouring higher educated patients compared to lower educated patients involved in physically demanding manual labour[1,3,13].

Patients regaining professional activities after only one year had a better QoL on the long term with less emotional problems[1,3,8,10,28]. A possible bias could be that only patients in good general condition will resume work. Unemployment leads to a circulus vitiosus: Unemployed patients are less active, therefore less motivated which leads to reduced physical functioning and to lower employment. Professional reactivation should be stimulated after liver transplantation and is an interesting target for improvement of QoL.

Depression and anxiety: Patients with anxiety disorders or depression before LT report a lower QoL. Generally, it is assumed that mental disorders such as anxiety disorders and depression are mostly correlated with the severity of the disease pre-transplant and the occurrence of complications. However, some studies show that the acceptance of the disease is more predictive for a good or bad QoL than the severity of the disease[13,32].

Importantly, high levels of depression may double the chances of mortality. More than half of the recipients experience at least one episode of anxiety disorder or depression within the first two years after transplantation. This negatively impacts MCS[8,11].

Sexual function: An aspect of QoL that often remains taboo, is sexual function after LT. We found some conflicting results. As expected, sexual dysfunction seems to be related to old age, a positive post-transplant status and the presence of depression[14]. In a study of Cannesson et al[13], 70% of the liver transplant recipients declare to have a satisfactory sexual life after LT, even though a decrease is seen in libido, sexual potency and starting of new sexual relationships, caused by bodily changes and immunosuppressive side effects. This high percentage may be caused by a reserve of patients to communicate openly about this topic. Sexual function after liver transplantation is a research area with unmet needs.

Immunosuppressive therapy: Intensified immunosuppressive therapy during the first six months after transplantation can cause uncomfortable side effects[5]. These side effects are common and remain a challenge on the long term[3]. Transplant recipients take a variation of immunomodulating drugs, such as mTOR and calcineurin inhibitors. Their side effects include diabetes mellitus, renal failure, hypertension, tremor, obesity and hypercholesterolemia[4,11,15]. Furthermore, corticosteroids, often used in the first 3 mo can cause insomnia, mood swings and anxiety[15]. Especially high doses of corticosteroids are associated with physical and mental health, however this correlation is not seen with low-dose corticosteroids. Corticosteroid restricting strategies can reduce long-term complications and support QoL[4,15]. Noteworthy, some observations report better QoL in patients using cyclosporines than patients using tacrolimus[8]. However, rejection and re-transplantation affect QoL, and should be avoided by proper immunosuppressive therapy[8,12,13]. We can conclude that the maximal reduction of side effects has a beneficial effect on QoL[12,33,34].

Waiting list: Waiting for a liver transplantation can be long and stressful. The QoL of patients on the waiting list is significantly lower than the QoL of the general population. Length of time spent on the waiting list has a negative impact on QoL. Thirty-eight percent of these patients are fearful (for rejection, death, recurrence of illness), 53% struggle with keeping up with their work-related functions and 23% experience social isolation. Anxiety and negative mood are known to get worse with increasing waiting time[13]. Nevertheless, some authors do not describe an increase in psychosocial stress[28]. More than half of the patients on the waiting list express a need for psychological counselling, which decreases during the waiting time[27].

Areas for further investigation: Although QoL has been extensively studied, we identified several areas of ambiguity. Identifying influencing factors of QoL is crucial to increase QoL after liver transplantation and needs further research[3,12]. In this line some interesting areas of research are: The influence of the underlying condition on QoL, gender, length of stay, immunosuppressive regimens, the influence of the recurrence of the initial liver disease, sexual function and professional reactivation. The development of more liver transplant specific outcome measures could be helpful[13,14].

Self-report QoL questionnaires: For the assessment of QoL more than 50 different instruments are used, measurement is not standardized and generic health assessment questionnaires are very commonly used. The largest part of these instruments has not been designed to evaluate the health status of liver transplant patients. Consequently it is difficult to interpret the results of these questionnaires in a meaningful way[9,14]. The SF-36 is the most commonly used generic questionnaire. It offers broad-spectrum questions applicable to a variety of patient groups and enables comparison between different populations[1,9]. These questionnaires can be distributed before and after LT.

Alternative questionnaires are the Transplant Effects Questionnaire, the Positive Effects of Transplant Scale, the schedule for the evaluation of individual expects of QoL - direct weighting (SEIQoL-DW)... The SEIQoL-DW allows patients to name areas important for him/herself and weigh each area to the relative importance and fulfilment level. On the downside, it is a qualitative interview-based assessment with his inherent disadvantages[21]. This complicates its use in clinical studies and does not enable repeated questioning of the same patient. Other questionnaires are the International Physical Activity Questionnaire and the Chronic Liver Disease Questionnaire. Only 16% of the reported authors used disease-specific instruments[1,9,16].

In conclusion, the best way to measure QoL after LT is the combination of generic questionnaires and disease-specific questionnaires, which offers a broad and thorough assessment of QoL. Jay et al[9] proposed the consistent use of validated, treatment-specific QoL instruments. This will result in a more accurate assessment of QoL in LT and lead to an increasing number of studies with comparable endpoints.