EASL Clinical Practice Guidelines

Lifestyle in the long-term follow-up

Quality of life

The goal of transplantation is not only to ensure a patient’s survival, but also to offer the patient the same state of health that he or she enjoyed before the disease and achieve a balance between the functional efficacy of the graft and the patient’s psychological and physical integrity. This is the reason that a change has taken place in the evaluation of medical interventions in the field of organ transplantation, just as in other medical fields [[464], [465]].

Previously used parameters, such as clinical judgment, biochemical and instrumental tests, and survival rates, have been integrated with new indicators that evaluate the relationship between the costs (both human and economic) and benefits of any intervention in terms of QoL [[466], [467]].

Unfortunately, the measurement of QoL in liver transplant recipients has not been rigorously studied and is not standardized as reported by a recent review of instruments used to assess QoL after LT. More than 50 different instruments are available for assessing QoL in liver transplant candidates or recipients, and among these, generic health assessment questionnaires are the most widely used [468].

Several studies have assessed QoL during the first few years after LT and have shown encouraging results; however, studies of the long-term evaluation of the QoL after LT are less optimistic.

Somatization, depression, and anxiety usually improve during the first year after transplantation, but they worsen again during the long-term follow-up, especially at 1 and 2 years. This is mainly due to the fact that in the early post-transplant, patients experience the perception of a new life, whereas in the long-term side effects of medication, especially of immunosuppression, can develop. Conversely, mental functioning, physical functioning and life satisfaction scores improve significantly during the first year after transplantation, and this improvement persist over time [469]. Another factor that can influence long-term QoL after LT is the aetiology of liver disease. Considering HCV liver transplanted patients, histological abnormalities, commonly seen at post-transplant protocol biopsies, have been considered a potential cause of anxiety in patients at 1 to 2 years after transplant. Although a specific correlation between HCV recurrence after LT and a decrease in the physical domain of QoL has never been shown, patients with HCV recurrence can show significantly greater levels of depression, anxiety, phobic anxiety, and paranoid ideation in comparison with HCV negative patients [470].

Considering patients transplanted for alcoholic liver disease, no differences in returning to society with active and productive lives have been compared with non-alcohol-related liver transplanted recipients [471].

Interestingly, a recent study found that patients who underwent transplantation for autoimmune disease had decreased QoL in the physical, social/role function, personal function, and general health perception domains [472].

QoL has been considered at 10 and 30 years after LT, and patients’ perception of their QoL was generally good, being reduced only in older individuals who can develop a reduction in their ability to carry out physical activity in comparison with the general population [473].

As far as gender is concerned, data on the different QoL after LT in male and female recipients are still controversial [474]. Usually no difference in terms of post-transplant QoL between male and female patients is seen, but a study reported a higher degree of overall QoL in male compared with female recipients [475].

Recommendation

Adherence

It is widely reported that the effectiveness of any treatment depends not only on the correct choice of therapy, but also, and considerably, on active cooperation by the patient [476]. Adherence can be defined as the extent to which a person’s behaviour corresponds with the agreed recommendations from a healthcare provider [[477], [478], [479]]. In patients before and after transplantation, adherence to medical prescriptions and immunosuppressive therapy in particular is crucial to prevent medical complications that negatively influence graft function and patient survival and increase costs. Across all types of transplantation, average non-adherence rates ranged from 1 to 4 cases per 100 patients per year for substance use (tobacco, alcohol, illicit drugs), to 19 to 25 cases per 100 patients per year for non-adherence to immunosuppressants, diet, exercise, and other healthcare requirements. Demographics, social support, and perceived health showed little correlation with non-adherence, whereas pre-transplant substance use predicted post-transplant use [480]. Assessing patient adherence to medical regimens and lifestyle recommendations is the first step towards understanding the reasons for poor adherence or non-adherence [[481], [482]].

Although poor adherence is a common phenomenon among liver transplant patients, the literature on the topic is still scarse. Most of these studies have been based on small numbers of patients and have assessed adherence with different methods; this has often prevented any comparisons of the results.

Non-adherence rates range between 20% and 50% in published studies. Among a sample of organ transplanted patients a non-adherence to immunosuppressive therapy, to correct lifestyle, and to general medical prescriptions of 38%, 39%, and 13% respectively has been reported. Non-adherent patients to immunosuppressive therapy and to general medical prescriptions displayed a longer interval from transplantation compared with adherent patients. In addition, non-adherent patients to the correct lifestyle, the rates of men and of patients with disability pension were significantly higher compared to adherent patients [483].

The alarming picture emerging from these studies is that poor adherence is an issue for nearly one of every two liver transplant patients, and this coincides with substantial increases in the rates of graft loss and death. This phenomenon seems to particularly affect young liver transplant recipients, who are more prone to this behaviour for several reasons. Healthcare providers dealing with liver transplant patients, therefore, need to be properly trained to address non-adherence and be able to use all available means to improve their patients’ adherence. Patient education alone is apparently not enough to ensure adherence, so multidisciplinary measures developed by professional educators, supported by psychologists, and coordinated by physicians are warranted [484].

Adherence in adolescents

The outcome of LT is usually reported in terms of graft and patient survival, medical and surgical complications, and QoL, but when it comes to transplanted adolescents such conventional parameters are unable to give a full account of their life with a new liver, and their transition from adolescence to adulthood is a time when they are particularly vulnerable.

Adolescents with liver transplants have excellent survival rates, over 80% of them surviving more than 10 years. Graft loss is most often associated with complications such as chronic rejection, hepatic artery thrombosis, and biliary complications. CNIs may have various side effects, including hypertension and nephrotoxicity. Liver transplanted adolescents are also exposed to viral infections, among which the EBV is very common and associated with the onset of PTLD. Growth retardation may also be an issue in some liver transplant recipients. Future studies will determine the best way to assess the functional immune status of adolescents with a transplanted liver with a view to ensuring the best treatment to induce tolerance without the complications of excessive immunosuppression. Schooling may be disrupted due to adolescent transplant recipients’ poor adherence. Non-adherence is associated with a poor medical outcome. Both physical and psychosocial functioning is reportedly lower among young liver transplant recipients than in the general population [485].

Schooling

Liver transplant adolescents are at a higher risk for developing cognitive deficits compared to the age-matched normal population [[486], [487]].

Schooling may be negatively affected by poor adherence to prescribed medication. In a recent study, when data on adherence were pooled together, it emerged that at least 3 in 4 adolescent liver transplant recipients were non-adherent on at least one measure of adherence. It was clear that the group of non-adherent recipients experienced more severe limitations on their school activities and their mental health suffered more; they also had a worse perception of their health and a lower self-esteem and family cohesion [488].

School performance is an important aspect of functional outcomes in the adolescent population. An interesting longitudinal survey on school attendance, performance, and educational outcomes (including the need for targeted educational programs) was recently published [489]. This retrospective study had been performed on 823 liver transplant recipients whose median age at the time of their transplant surgery ranged from 0.05 to 17.8 years. These 823 cases came from 39 liver transplant centres in the US. A third of the children and adolescents had missed more than 10 days of school a year, and absences were higher for older recipients and for shorter times elapsing since LT. More than a third of the sample needed extra teaching and one in five had repeated a school year. The type of immunosuppression taken 6 months after the transplant, the occurrence of CMV infection and the teaching services used before the transplant were the main factors associated with the need for special support. The most striking predictor was the pre-transplant need for extra teaching (OR 22.46), suggesting that most neurocognitive impairments seen after transplantation originated beforehand [488].

An editorial on this topic published in the same journal as the survey emphasised that the article looked at functional outcomes, as well as surgical and biological results, in survivors of paediatric LT, and congratulated the authors on their contribution to moving the field towards a broader approach to outcome assessment [490].

A multicentre study on cognitive and academic outcomes was recently performed in 5–7 year-old children two years after their transplantation: it confirmed that these young liver transplant recipients performed significantly below test norms in terms of their IQ and achievement measures, and 26% had mild-to-moderate IQ delay, whereas the normally expected rate is 14%. Four percent had severe mental delays and learning difficulties [487].

Recommendations

Employment

The percentage of liver transplant recipients who return to work after transplantation ranges from 26% to 57%, with the rates differing with the length of the follow-up period considered. Employed patients have a significantly better QoL than those who are unemployed [491].

Among working-aged patients, employment rates were highest in the PSC (56%) group and lowest in the acute liver failure (39%) and PBC (29%) groups. In age-adjusted logistic regression, patients with PSC or alcoholic cirrhosis were 2.4- and 2.5-fold more likely to resume work after LT than patients with PBC [492].

The opposite was reported from the UNOS database, where the authors found that patients with alcoholic liver disease had a significantly lower rate of employment than patients with other aetiologies of liver disease [493].

Recommendation

Sexual function and pregnancy

Successful LT leads to improvements in sex hormone disturbances in both men and women, but immunosuppressive drugs may interfere with hormone metabolism [494].

A significant improvement of sexual function after transplantation has been shown in a meta-analysis based on seven studies. When sexual activity was evaluated in female liver transplant subjects, 70% of sexually active patients reported satisfaction with their sexual health [495].

However, recent studies described less favourable data. In one of the studies, 23% of men and 26% of women reported decreased libido, and 33% of men and 26% of women reported difficulty in reaching orgasm with intercourse [496]. In the other study, 40% of the patients who underwent LT reported a decreased frequency of sexual intercourse, and among men, partial and complete erectile dysfunction was reported by 20.6% and 34.3%, respectively [497].

Male population

Usually the proportion of sexually inactive men decreases after transplantation, but erectile dysfunction may remain unchanged. Cardiovascular disease, diabetes, alcohol abuse, antidepressants, and angiotensin II receptor blockers were associated with erectile dysfunction after LT [498]. When the erectile dysfunction was compared between pre- and post-LT, the percentage for severe erectile dysfunction was significantly greater in patients with cirrhosis vs. liver transplant patients (43% vs. 22%, p <0.04). Moreover, a worse International Index Erectile Function score was seen in patients with cirrhosis vs. patients who underwent transplantation (14.3 vs. 19.5, p <0.04). Sexual dysfunction correlated with old age (p <0.03), whereas after transplantation, it was greater in patients with depression (p <0.02). Therefore sexual dysfunction, despite improvement, was still present after LT, with depression being the major risk factor [499]. The role of immunosuppression on erectile function has been studied; however, data concerning the impact of different drugs on erectile function and fertility are still lacking and mainly reported in kidney transplant recipients. Laboratory studies on rats and primates seem to demonstrate a direct link between SRL and decreased spermatogenesis [500], but in a recent cross-sectional study, despite lower total testosterone levels and higher follicle stimulating hormome and luteinizing hormone levels, no significant difference in sexual scores was found between patients treated with SRL and a control group [501].

Female population

The prevalence of sexual dysfunction was reported from a single centre analysis, to be broadly similar for patients who underwent transplantation and patients with cirrhosis (65% vs. 60%). After transplantation, sexual dysfunction was correlated with depression (p <0.01) and reduced QoL (p = 0.02) [499]. Women achieve normal menstrual function and fertility a few months after transplantation. In the year before transplantation, 42% of women reported regular menstrual cycles, 28% reported irregular and unpredictable bleeding, and 30% reported amenorrhea, whereas after transplantation, 48% experienced regular menses, 26% experienced irregular bleeding, and 26% experienced amenorrhea [502]. When liver transplant recipients are of reproductive age, they must be counselled about the possibility of pregnancy and the use of contraception, and pregnancy should be avoided for the first 6 to 12 months after transplantation, although some centres advocate waiting 24 months [499]. Barrier contraception seem to be the safest option for these patients [503]. Pregnancy is often successful after LT, despite the potentially toxic effects of immunosuppressive drug therapy. Acute cellular rejection may occur in pregnant liver transplant recipients, but no difference is generally reported in comparison with non-pregnant recipients. The treatment is usually based on an increase in immunosuppression or on the use of intravenous boluses of steroids [503]. Liver transplant recipients with recurrent hepatitis C nonetheless appear to be at risk of worse graft function in the event of pregnancy, and antiviral drugs are generally contraindicated in pregnancy because of their teratogenic effects. The use of immunosuppressive drugs should be maintained during pregnancy since CNIs, azathioprine and steroids have not been found to be teratogenic. MMF has been reported to cause malformations in animal models and is not recommended in pregnancy in humans. mTOR inhibitors have been reported to affect spermiogenesis in males. Immunosuppressive drug concentrations should be carefully monitored [503]. The US Food and Drug Administration categorizes the safety of drugs in pregnancy on the basis of available evidence as reported in Table 7 [504]. Fetal loss, prematurity, and low birth weight have been reported in women who have undergone transplantation, and maternal risks include hypertension, preeclampsia, gestational diabetes, and graft dysfunction. The rate of caesarean section is considerably higher in post-LT patients. It is crucial for post-transplant patients who conceive, to be managed by centres with multidisciplinary care teams including a liver transplant hepatologist and surgeon, an obstetrician, and a paediatrician [499]. After delivery, most transplant physicians advise against breastfeeding because of concerns over the safety of neonatal exposure to immunosuppressive drugs [499].

Table 7
US Food and Drug Administration pregnancy categories for commonly used immunosuppressive drugs in liver transplantation [504].


*FDA category definition: A = controlled studies show no risk: adequate, well-controlled studies in pregnant women have failed to demonstrate risk to the fetus; B = no evidence of risk in humans: either animal findings show risk (but human findings do not) or, if no adequate human studies have been performed, animal findings are negative; C = risk cannot be ruled out: human studies are lacking and animal studies are either positive for fetal risk or lacking as well. However, potential benefits may justify the potential risk; D = positive evidence of risk: investigational or postmarketing data show risk to the fetus. Nevertheless, potential benefits may outweigh the risk; X = contraindicated in pregnancy: studies in animals or humans or investigational or postmarketing reports have shown fetal risk that outweighs any possible benefit to the patient.

Recommendations

Physical activity and weight control

After transplantation patients have an improved functional capacity and can perform tasks independently [505]. The use of a structured exercise program increased exercise capacity and fitness for the first six months after transplant followed by a plateau [506], and exercise performance remains lower than in age-matched controls [[506], [507]]. Only a quarter of patients were found to be physically active after transplant [508].

There are little data regarding nutritional composition and caloric intake after transplantation and up to two-thirds of subjects were found to have more than the recommended energy intake [509].

The influence of LT on physical fitness during the first post-operative year was studied in 23 men with a mean age of 45.1 years and 15 women with a mean age of 44.6 years. Preoperative maximal oxygen uptake during graded ergometer bicycling, isokinetic knee extension/flexion moments, and functional performance was measured. Preoperative fitness and strength was 40 to 50% less than expected in the age-matched general population. All post-LT patients underwent a supervised exercise program for 8 to 24 weeks. Follow-up data showed a significant increase in all tested physical performance parameters after LT. Six months post-transplant, patients’ maximal oxygen uptake had increased by 43%; knee strength 60 to 100%; and functional performance 22 to 27%. One year post-surgery, general health was improved and perceived as excellent or good in all patients. All patients were independent in activities of daily living, and the level of physical activity increased after LT. No further improvement in either physical performance parameters or self-assessed parameters was seen beyond 6 months after transplantation. In conclusion, these findings indicate that LT combined with a supervised post-transplant exercise program improves physical fitness, muscle strength, and functional performance [506]. There are no data regarding the impact of an exercise program on the prevalence of the metabolic syndrome or singular components after transplant [510], but no specific recommendations regarding the prevention or treatment of NAFLD or NASH in liver transplant recipients can be made other than general recommendations to avoid excessive gain in body weight and control hypertension and diabetes [437]. A single randomized trial evaluated the effects of exercise and dietary counselling after LT, it reported an improvement in cardiorespiratory fitness in the intervention group, but no changes were noted in body composition or muscle strength [507]. Exercise training is effective in improving the cardiovascular risk profiles of non-transplanted patients, but the health benefits and potential harms of routine exercise training after solid organ transplantation are unclear. A systematic review of all RCTs comparing the outcomes of exercise training programs in solid organ recipients against standard care was published. In total, 15 eligible RCTs involving 643 patients were included. Among non-heart transplant recipients, no significant improvements in exercise capacity or cardiovascular risk factors such as incidence of new onset diabetes after transplantation were observed, but all effect estimates were very imprecise. Therefore the authors concluded that exercise training is a promising but unproven intervention for improving the cardiovascular outcomes of solid organ transplant recipients. Existing trials are small, of relatively short duration, and focus on surrogate outcomes therefore large-scale RCTs are required [511].

In another study, the authors reported that those that were physically active had less hypertension and decreased BMI [508]. Obesity is common after LT. A study performed on 597 patients reported that the median weight gain at 1 and 3 years was 5.1 and 9.5 kg above dry weight pre-transplant. By 1 and 3 years, 24% and 31% had become obese (defined as a BMI >30 kg/m2). There was no significant difference in weight gain between the sexes, those who were obese before transplantation or those who received corticosteroids for >3 months. Weight gain was significantly greater in patients aged >50 years and those transplanted for chronic liver disease compared with fulminant liver failure. A pre-transplant BMI >30 was a strong indicator that the patient would still have a BMI >30 at 3 years. There was no effect of the type of immunosuppression on weight gain, therefore confirming that it seems to be unrelated to any specific immunosuppressive drug. The greatest weight gain occurs after the first 6 months and intervention with dietary advice at this point could be implemented to minimize the long-term morbidity and mortality risks associated with obesity [512].

Recommendation