Long-term nutritional and cognitive outcomes after liver transplantation in childhood

Abstract

Introduction: Malnutrition is common in children with end-stage liver disease but recovery is expected after transplantation. Early childhood under-nutrition is recognised to contribute to adult disease. There is however, limited information on long-term outcomes and nutritional recovery after childhood liver transplantation. Aims: The aims of this thesis therefore were to examine several long-term outcomes in survivors of childhood liver transplantation, which potentially may have been impacted by malnutrition prior to liver transplant. The specific areas examined were: Specific Aim 1: Growth and anthropometry; Specific Aim 2: Body cell mass (BCM); Specific Aim 3: Bone mineral density (BMD); and Specific Aim 4: Cognition, behaviour, and academic function. Methods: All patients transplanted aged l18 years, who survived g3 years after initial transplant, with ongoing review by the Queensland Liver Transplant Service were eligible. Since testing was only available in Brisbane, most participants were resident in Queensland. SA 1: Patients with g2 measurements, of which one was g5 years post-transplant, were considered. Height, weight, and body mass index data were collected at transplant, 1, 5, 10, and 15 years post-transplant to assess longitudinal growth and anthropometry. WHO reference ranges were used for Z-scores. SA 2: Total Body Potassium (TBK) measurements, were obtained pre-transplant, and at long-term follow up to examine longitudinal change post-transplant. BCM was calculated from TBK and adjusted for height raised to the power p depending on gender (BCM/Heightp). SA 3: Cross-sectional assessment of BMD in patients g5 years post-transplant, was performed using Dual Energy X-ray Absorptiometry (DXA). Wrist X-ray was performed to assess bone age. SA 4: Patients surviving g5 years post-transplant, and still attending school were eligible. Hearing and comprehensive neuro-psychometric tests were undertaken by participants, and sibling controls. Results: SA 1: Longitudinal height and weight data were available on 98 and 104 patients respectively. 58% were Australian, and the rest Japanese. Height recovery continued for g10 years, reaching the 26th centile, although Australian patients did better and attained 47th centile. Weight recovery was most marked in the first year and continued for 15 years even in the well nourished. Growth impaired and malnourished children had the best recovery, but remained shorter and lighter. Gender and age at transplant did not affect height or weight recovery. Dichotomous growth recovery between Australian and Japanese patients was likely due to post-transplant factors. At 10-15 years post-transplant, 9% were overweight but none obese. SA 2: TBK measurements were performed in 32 patients at median 7.23 (range 3.28-14.99) years when they were aged 10.12 (range 4.56-20.77) years. This cohort attained mean Z-scores for height -0.41, weight -0.26, and BMI 0.04. BCM/Heightp was low pre-transplant, but further reduced post-transplant (pl0.001) despite normalization of height and weight, implying that weight recovery was from fat, not BCM. Growth impairment was associated with greater reduction in post-transplant BCM/Heightp (p=0.02). On multivariate analyses, only older age at transplant predicted reduced post-transplant BCM/Heightp (p=0.02). SA 3: 42 patients were assessed at median 10.10 (5.01-25.98) years post-transplant, aged 14.64 (6.59-38.07) years. BMD normalized with lumbar spine Z-score -0.15p1.07, 44th centile, and total body Z-score -0.76p1.14. Reduced BMD was noted in four patients (10%), with ongoing steroid use a significant factor, p=0.049. Age at transplant, time from transplant, and reduced BCM did not predict BMD. Overall fracture incidence, including post-traumatic was 12%; pathologic fractures only occurred within 18 months of transplant. SA 4: 13 children were assessed at median 10.89 (range 5.16-16.37) years post-transplant, at age 13.08 (6.52-16.99) years. 6 siblings were also tested. All subjects had full scale intelligence quotient (IQ) within normal, with mean IQ 97 and 105 for transplanted children and siblings respectively. No difficulties were identified in intellect, cognition, academic function, memory and learning, although both groups had reduced mathematical ability compared to normal. Transplanted patients had difficulties in self-regulation, planning, organisation, problem solving, and visual scanning. Four transplant survivors (31%), and no siblings, scored in the clinical range for attention deficit hyperactivity disorder (ADHD). Emotional difficulties noted in transplanted patients were also found in their siblings. Conclusions: SA 1: Children can expect height and weight recovery for at least 10-15 years after liver transplant. Growth impairment at transplant and post-transplant care significantly impact on final height attained. SA 2: Weight recovery after childhood liver transplant is likely due to increased fat since BCM remains reduced. SA 3: BMD normalises at 10 years post-transplant, but reduced BMD is more likely in those still on steroids. SA 4: Long-term liver transplant survivors have intact intellect and cognition, but exhibit subtle difficulties in executive function and are more likely to have ADHD. Long-term survivors after childhood liver transplantation can expect excellent medical outcomes with normalization of weight, height, BMD, IQ and cognition, but remain at risk of ongoing problems including sarcopenic obesity, executive function difficulties and ADHD. Nutritional compromise persists in long-term survivors of childhood liver transplantation.