Thomas Starzl and colleagues from Denver, Colorado, reported the first series of liver transplants (LTs) in adults and children in December 1963 [1], sparking an upsurge in enthusiasm for the procedure in a number of centres throughout the world. Such programmes withered and ultimately failed on the lack of effective immunosuppression, and long-term survivors were rare. However, with the resumption in transplant activity during the 1980s, it is now clear that we are seeing successful paediatric cohorts of not only 10- but also 20-year survivors. There are reported 20-year survival rates of 52% from an American multicentre cohort transplanted between 1984 and 1988 [2] and 10- and 20-year survival rates of 83% and 80%, respectively, from a more recent Japanese paediatric living donor LT programme between 1989 and 2010 [2]. There is now a significant cohort of patients transplanted in childhood moving into adulthood, or as adolescents and young adults, where transplant outcome is poorer [3,4]. These young people deserve specialist attention and dedicated care to provide improved and excellent long-term outcomes. The onus of care has been on providing a good quality of life through the provision of appropriate transition from paediatrics to adult services.

41.2 ADOLESCENCE AND LIVER TRANSPLANTATION

Adolescence is characterised by a combination of biological, psychological and social challenges leading to the development of autonomy and self-identity and is often defined by the onset of puberty. Despite the excellent survival data post–liver transplantation, data on health-related quality of life (HRQL) in adolescents shows that they share many characteristics similar to those other chronic health conditions, rather than with the general population [5,6].

Whereas most of the current literature focuses on adolescence, it is now well demonstrated that structural and functional changes continue to take place in the brain into adulthood [7], and that the focus should be on ‘young people’, defined by the World Health Organization (WHO) as aged 10–24 years; this includes adolescents (aged 10–19 years) as well as young adults (aged 15–24 years), as a separate population who are neither ‘big children’ nor ‘small adults’ and deserve specialist care [8], shared by paediatric and adult professionals (Box 41.1).

41.3 BIOLOGICAL AND PSYCHOSOCIAL ASPECTS OF ADOLESCENCE

Growth impairment is common following LT, with the Studies of Pediatric Liver Transplantation (SPLIT) registry reporting that 20% of 8- to 18-year-old recipients have linear growth impairment [9]. Risk factors for growth impairment include prolonged steroid exposure, pretransplant failure to thrive, metabolic liver disease retransplantation and nonwhite race. Data on pubertal delay in young people with chronic liver disease is currently lacking; however, it is well documented in other chronic conditions, including inflammatory bowel disease, nephrotic syndrome, asthma and cystic fibrosis. of 353 children post-LT, pubertal delay was reported in 39% of girls and 42% of boys who had not reached Tanner 5 development between the ages of 16 and 18 years, compared with 100% of the general population [9]. The psychosocial effect on quality of life and long-term outcome should not be underestimated. Young people with pubertal and growth delay will find it more difficult to be managed in an age-appropriate fashion and struggle to become independent. Recombinant growth hormone has been used in the renal transplant population with a positive effect on linear growth and psychosocial well-being; however, larger studies are needed to assess its safety in the post-LT setting [10].

BOX 41.1 New definitions

• Young people Aged 10–24 years

• Adolescents Aged 10–19 years

• Young adults Aged 15–24 years

World Health Organization

• Transition

• ‘Purposeful, planned process that addresses the medical, psychosocial and educational/vocational needs of adolescents and young adults with chronic physical and medical conditions from child-centered to adult-orientated healthcare systems’.

Blum et al. (1993) [33]

Cosmetic side effects of medications such as steroids and cyclosporine (now less commonly used), as well as surgical scars, impact on body image and subsequently adherence to treatment; however, the literature is scarce on this topic. We recently investigated body image in a cohort of 80 patients aged between 16 and 24 years of whom 30% had undergone liver transplantation and found that body image perception was poorer in this group, although this did not appear to be associated with a surgical scar or side effects of immunosuppressive medication.

End-stage liver disease alters the normal physiology of the hypothalamic–pituitary–gonadal axis and disturbs oestrogen metabolism, affecting sexual function. Menstrual irregularities are common in women with chronic liver disease and typically improve following LT. A survey of menstrual function and obstetric history before and after LT reported irregular menses in 28% and amenorrhoea in 30% of 64 patients pretransplant, with 95% of 51 women younger than 46 years observing a normal menstrual cycle within the first year after LT [11].

With the median age at first intercourse being 16 years in developed countries, with 20%–30% of young people reporting sexual intercourse before the age of 15, comprehensive sex education is essential and even more important in young people with chronic health conditions. Sexuality and pregnancy should therefore be part of the consultation with young people with liver disease both pre- and post-LT.

Oestrogens, and typically the synthetically produced ethinylestradiol used in the combined hormonal preparations, are more potent, with a potential effect on the liver irrespective of the route of administration. Progestogens do not have receptors on liver cells and are commonly given at a lower dose and are well tolerated. Although not contraindicated in patients with compensated cirrhosis, in both pre- and post-LT settings, the current contraceptive recommendation is that progesterone-only preparations, such as the mini pill (e.g. Cerazette®), medroxyprogesterone injection or etonogestrol implants, and, if sexually active, a levonogestrol-releasing intrauterine system (e.g. Mirena®) [12], should be utilised.

Pregnancy following LT has been reported to have largely favourable outcomes for the allograft, mother and fetus (Box 41.2). We have reported on the outcome of 115 pregnancies in 84 patients, between 1988 and 2010 [13]. There were 71% live births, with prematurity reported in 34% and very low birth weight in 6%, which is higher than that of the general population. More recently, in a UK national cohort study between 2007 and 2012, live birth rates in LT recipients were 92%, with similar prematurity rates (42%) [14]. Maternal complications such as hypertension and preeclampsia were more common. In our series, graft rejection was noted in 16% and was considerably higher in patients conceiving within 12 months of LT, although there was no graft loss. Delivery by caesarean section is certainly more common. Current recommendations are to delay pregnancy until at least 1 year following liver transplantation and use appropriate contraception in the interim (Box 41.2) [12,15].

Liver transplantation will impact on the psychosocial aspects of adolescence and vice versa. Data available on cognitive development post-LT confirms an increased incidence of learning difficulties in this population. of 144 patients, aged 5–7 years, from the SPLIT registry who were >2 years posttransplant, mild to moderate cognitive delay was recorded in 26% and serious cognitive delay in 4%. The authors reported that 25% were having learning difficulties with reading and math skills and a relevant executive functioning deficit which would potentially affect independent management of their health condition in adult life [16]. Further research identified height centile at transplantation and genetic-metabolic conditions as having a high impact on long-term cognitive functioning. More studies are needed to assess cognitive function in young people long term after LT and its effect on outcome and quality of life.

BOX 41.2 Pregnancy and liver transplantation: recommendations

• Delay pregnancy for at least 1 year following LT (if possible).

• Immunosuppression (acceptable and safe)

• Tacrolimus

• Cyclosporine

• Prednisolone

• Azathioprine

• Immunosuppression (avoid because of adverse fetal outcomes)

• Mycophenolate mofetil

• Sirolimus

Self-efficacy and sufficiency in various chronic conditions predict regimen adherence and more effective disease management and are relevant to quality of life [17]. Health professionals therefore should encourage all young people to take more responsibility and initiative for the management of their condition after assessment of their psychosocial and educational needs, as these can affect the patient’s ability to do so. Cognitive delay, infantilisation and long-term dependence on parents or carers, as well as social isolation and educational failure, can all interfere with the development of self-efficacy. Whereas overall HRQL in young people after LT seems to be good, poorer physical functioning and general health than the general population are reported, as well as delay in educational achievement and a higher incidence of psychological problems [18,19]. A report from our centre of 55 adolescents concluded that overall HRQL was reduced, but comparable to that observed in other chronic health conditions and related to the side effects of immuno-suppression and associated psychosocial factors [20].

Adherence to treatment is a challenge for all patients and can become more challenging during adolescence. Although difficult to measure, reported nonadherence (NA) in the adolescent transplant population is as high as 50%, and the causes are often multifactorial. Its association with poor outcome is well described. Nonintentional NA is most common and related to a variety of factors, with simply forgetting the most common one, but includes a lack of knowledge of their medical condition and treatment, the burden of the amount and timing of medications, a chaotic lifestyle and the lack of a routine for taking medications. Not experiencing immediate adverse side effects when missing medication does not reinforce adherence. Health professionals should try to explore this issue when seeing young recipients and distinguish nonintentional from intentional NA, which is more complex and requires input from other health professionals, including a clinical psychologist and a social worker to be able to manage the problem effectively. At times, NA is not disclosed; however, if suspected, it is important to adopt a nonjudgemental approach and acknowledge that NA is relatively developmentally appropriate during adolescence [21]. Simplifying medical treatment and conversion to once-daily preparations of immunosuppression have been reported to improve adherence and treatment satisfaction [22]. A recent publication on the use of long-acting tacrolimus showed a decline in intrapatient variability, accompanied by reduction in acute rejection in a cohort of patients who were electively converted from twice-daily to once-daily tacrolimus [23] (Table 41.1).

Table 41.1 Summary of the potential barriers to adherence and suggested strategies to manage them

Barrier to adherence	Strategies
Non-intentional NA
• Lack of knowledge and naive about risks of NA • Burden of medication regime (amount of tablets and timing of medications) • Lifestyle related (forgetting, chaotic lifestyle, etc.)	• Individualised education about condition and medication • Education with regard to individual medicines • Simplification of regime • Reminders (pillboxes, charts, alarms, mobile apps, etc.)
Intentional NA
• Related to patient’s belief with regard to condition and treatment • Related to practical barriers such as housing, finances and parental support	• Explore beliefs, including benefits of NA to the individual • Assess mood • Referral to clinical psychologist • Assess potential barriers • Referral to social worker

NA is often complex and can be seen in association with posttraumatic stress disorder [24] and other psychosocial stressors [25]. In our service, a case-note review of the more complex cases NA referred to our clinical psychologist and specialist social worker revealed a significant minority with entrenched relational difficulties who had experienced childhood abuse [26]. Effective identification of NA and the factors contributing to it are essential to ensure access to the appropriate services.

41.4 TRANSITION FROM PAEDIATRIC TO ADULT-CENTRED HEALTH SERVICES

Box 41.1 gives a definition of transition given by the Adolescent Health Society in 1993, to which the American Academy of Pediatrics added the following: ‘The goal of transition in health care for young adults with special health care needs is to maximise lifelong functioning and potential through the provision of high-quality developmentally appropriate health care services that continue uninterrupted as the individual moves from adolescence to adulthood’ [27].

Poorer outcome for patients transplanted during adolescence and as young adults supports the concept that maturation and complete development continue beyond the age of 18 years [28]. Currently, the development of dedicated young people’s services is mainly driven by paediatric specialists, with no consensus on the measurement of success or implementation of guidelines. Adult health professionals often lack the skills or experience to care for young adults with chronic childhood conditions.

An example of a successful transition programme is set in a renal transplant service in the United Kingdom where the introduction of an integrated paediatric and young adult joint transition clinic and care pathway showed improved outcomes over a 4-year period, with no episodes of late acute rejection or graft loss compared with 35% graft loss in a group of patients who did not benefit from this service [29]. This format might not be applicable to all centres, as the group of patients was small and living in the vicinity of the transplant centre; however, young adult and transition care should be developed depending on the setup of the paediatric and adult care in each institution, ensuring continuity of care is provided.

Ideally, the timing of the transition process should be flexible and aimed at the patient’s needs and readiness. However, in practice, lack of age-appropriate inpatient facilities or paediatric and adult services being on different sites means that patients aged over 18 years cannot be admitted to paediatric inpatient facilities, emphasising the importance of starting the transition process early. This is particularly relevant in patients with special health care needs where the transition process becomes more complicated, as the patient might not be able to advocate for their care, consent for procedures and manage an inpatient stay on an adult ward independently. In these cases, the multiprofessional team should ensure a well-documented care pathway is discussed prior to transition to adult services [30].

Experience from a sickle cell disease transition programme looking after young adults from ages 15 to 24 years showed that those who were older when attending their first transition clinic or with clinical markers of mild disease severity were at higher risk of an unsuccessful transition [4]. Gender, race or insurance income did not influence transition outcome, whereas travel distance to the adult sickle cell disease centre did. Useful tools to assess transition readiness have been developed in various health settings and can be adapted to an individual centre’s setup. Even where integrated care with the adult service is not available, an individual detailed document is useful for the patient and the adult team looking after him or her in the future.

Patients and their families should be given realistic expectations of the adult health care systems where patients are expected to advocate for themselves and the development of self-management skills should be included in the transition process. Support from a multidisciplinary team of professionals is desirable during this process. A recent pilot study of 20 LT recipients whose care was coordinated by a transition coordinator showed that when compared with a historic group of 14 patients, improved adherence to treatment during the year before transfer to adult services could be observed. After transfer, tacrolimus standard deviation (SD) scores remained stable in the group supported by the transition coordinator compared with the historic group, where the tacrolimus SD increased, suggesting poorer adherence [31]. It is important to engage the young person and personalise his or her care. Standard administrative policies with regard to appointments and nonattendance might not be useful and disengage the young person. Nonattendance to clinic appointments is a common problem, and there are various reports of higher nonattendance to first appointments in adolescent or young adult’s clinics, which is of concern. By contacting patients referred to the liver transition clinic prior to their appointment and giving them additional information with regard to the service, as well as sending out written information, we have managed to decrease nonattendance for new appointments from 25% to 10%, and feedback from patients and their carers was excellent.

Peer support and mentoring programmes are being used in various health care settings. In LT, a study involving 22 patients who took part in a mentoring programme showed it to be safe, feasible and acceptable, with improvement in adherence in the patient as well as in the mentor population [32].

41.5 CONCLUSION

Despite excellent outcomes following LT, young people are a vulnerable cohort of patients, dealing with the challenges of adolescence and of having a chronic health condition. This often coincides with moving on from family-centred paediatric services to adult-orientated services. The onus is on ‘getting it right’ by engaging the young person and encouraging self-management at the same time as identifying aspects of care that could complicate the transition process, such as learning difficulties, NA to treatment and clinic appointments and potential complicating psychosocial factors. Having a nonjudgemental approach and support from a multidisciplinary team of health professionals is essential.