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- Authors' Contributions
- Supporting Information
During the last 25 years, survival rates after pediatric liver transplantation (Ltx) have increased steadily, with survival rates currently ranging from 85% to 97% among liver transplanted children [1, 2]. Today, pediatric Ltx is a well-established treatment for a variety of liver diseases in their final stage. Even in relative indications (i.e. certain metabolic diseases), liver transplantation is a promising treatment option that actually is becoming increasingly important in clinical practice [3, 4].
Despite these major advances, (neuro)psychological research on the cognitive and emotional development of liver transplanted children as well as the process of adapting to a life with a chronic health condition has lagged far behind. Only recently has the focus shifted from mere survival to long-term health outcomes such as chronic kidney defects, chronic implant failure or psychosocial functioning [4, 5]. Cognitive performance constitutes an important developmental prerequisite. Importantly, childhood cognitive ability is highly predictive for educational achievement and later occupational outcomes  as well as health behavior . Furthermore, average to high intelligence is considered to be one of the most important resilience factors for mental health [8, 9].
Current research indicates that liver transplanted children are at higher risk for developing cognitive deficits compared to the age-matched normal population [10, 11]. However, our understanding of the association between cognitive deficits and certain disease-related variables is still limited. Infantile onset of liver disease [12-14], longer pretransplant duration of disease, postmortem donation [15, 16], elevated serum calcineurin inhibitor level, lower pretransplant growth percentile and elevated serum ammonia  have all been suggested as potential risk factors for cognitive deficits in liver transplanted children. However, these findings are based on only a few studies with small samples or date back to the 1980s. Moreover, comparisons between different diagnoses have not yet been performed.
Given the immediate clinical relevance of delayed or impaired cognitive development in children undergoing Ltx, a better understanding of disease-related, therapy-associated and environmental risk factors could contribute to optimizing clinical care of these patients. In particular, more information about the long-term impact on postoperative cognitive abilities is urgently needed.
The current prospective cross-sectional study assessed 64 school-aged, liver transplanted children and compared four areas of cognitive performance as well as Total IQ with that of age- and gender-matched children without a chronic health condition. To this end, the re-edited, newly published German version of the Wechsler Intelligence Scale for Children (WISC-IV)  was applied. We expected that liver transplanted children late postoperatively would perform worse compared to the reference group. Furthermore, we hypothesized that the profile of cognitive impairment would differ depending on the primary diagnosis with more severe dysfunction in genetic–metabolic diseases. Moreover, we expected that the cognitive performance would be associated with certain disease-related variables such as age at Ltx, height at Ltx, pretransplant duration of disease or type of donation.
- Top of page
- Authors' Contributions
- Supporting Information
The present findings demonstrate long-term cognitive dysfunction in liver transplanted children compared to an age- and gender-matched reference group of children without a chronic health condition as well as compared to the normal population. In comparison to the reference group, twice as many patients displayed serious cognitive delay. Children with a primary diagnosis of genetic–metabolic disease exhibited the lowest scores. Height percentile at Ltx proved to be the most relevant predictor of posttransplant cognitive performance. These findings support our hypothesis and confirm and expand previous research in this area [10, 11, 20, 21].
While several studies to date have demonstrated a lower IQ in pediatric Ltx patients [20, 22, 23], only one of these specifically addressed verbal deficits . Moreover, all studies were conducted in very small patient groups with a sample size ranging from N = 15 to N = 28. In our study, we found substantial impairments across several domains of cognitive function such as verbal comprehension, perceptual reasoning and processing speed. This should be emphasized as the revised version of the Wechsler battery (WISC-IV) is better suited to differentiate between these subdomains of cognition compared to the WISC-III  used in previous reports. In addition, our data may provide a more accurate estimate of cognitive impairment in pediatric Ltx patients by limiting the Flynn effect (i.e. norms become outdated with an increase of approximately 3 IQ-points per 10 years) : several studies have demonstrated that the WISC-III indeed appears to overestimate a child's intelligence because of this shift in norm values . Therefore, the results of previous studies in liver transplanted children utilizing the WISC-III [11, 20, 24] likely underestimated the degree of cognitive impairment in this population. Against this background, the present results gained with the WISC-IV are even more meaningful. In addition, the new 4-factor structure enables clinicians to evaluate a specific intellectual profile of every child . Combined with guidelines for interpretation, this may serve as a basis for individually tailored interventions . Moreover, the newly added Index Working Memory allows for comparisons with our previous studies on attention and executive functioning .
Although differences in Working Memory between patients and the selected reference group fell short of statistical significance, the difference to the population mean was significant. Therefore, this finding confirms our earlier reports. We have previously demonstrated substantial impairment in a Working Memory task of a computer-based assessment tool in 59 liver transplanted children . Yssaad-Fesselier et al  also found Working Memory scores significantly below the population mean. Furthermore, Sorensen et al  detected impaired Working Memory performance based on a rating of executive functioning completed by parents and teachers. Thus, Working Memory may be particularly affected in pediatric liver transplant recipients. Neurobiologically, this is plausible as corticosteroids are toxic to the hippocampus, a limbic structure relevant for learning and memory .
Our results support the assumption that liver transplanted children with different diagnoses show significant differences of cognitive performance. Children who received Ltx following a primary genetic–metabolic disease scored much worse compared to the others. Wilson's disease, hyperoxaluria, Crigler Najjar syndrome and especially urea cycle defects are known to affect the brain. Our results are in line with recently published work by Stevenson et al  who demonstrated significant mental deficits in a group of 33 pediatric liver transplant recipients with metabolic disorders. As children with a genetic–metabolic disease also suffered from the longest duration of disease preoperatively, our results may argue for early transplantation in these children. Our results might be of special relevance, as “after biliary atresia, metabolic conditions […] are the second most common disease category leading to liver transplantation in children” (, p. 59). However, at present, these findings have to be interpreted with caution due to the heterogeneity of diseases included in our study and the small sample size in the genetic–metabolic group. Therefore, larger, multicenter studies are warranted to further explore these associations.
We expected duration of disease, age and height at Ltx, and type of donation to predict cognitive performance. This hypothesis was partially confirmed since only height at Ltx significantly contributed to all cognitive indices except for Processing Speed. Available previous studies have rarely included laboratory parameters, usually examined small samples [11, 24, 32], or were published more than 20 years ago [12, 13, 22]. Therefore, we also performed exploratory stepwise regression analysis by including disease-related variables and laboratory parameters in order to detect combinations of variables that might contribute to cognitive deficits after Ltx. This procedure confirmed the impact of height at Ltx as a significant predictor. As this is in line with earlier findings , children with lower height percentile at Ltx should be carefully monitored posttransplant regarding cognitive performance. Growth might be interpreted as a marker for nutritional status. Several studies in the recent literature have shown that malnutrition, especially in early childhood, is highly interrelated to cognitive and behavioral dysfunction and adult mental disorders [33, 34].
Apart from height at Ltx, other previously suggested disease-related factors that may contribute to cognitive impairment were only partially confirmed. For example, in line with Krull et al , we found that more days spent in the intensive care unit after the Ltx was correlated with verbal delays. However, regarding the impact of age at Ltx, our results are contradictory to those obtained by other research groups. Young age at onset of disease and consecutively at Ltx was associated with an increased risk for cognitive delay . In our study, half of the liver transplanted children received their transplant within the first year of life and their cognitive performance did not differ significantly from the population mean. Additionally, age at Ltx was only related to Processing Speed, with younger age predicting better performance. These findings are in line to our previously published reports [16, 35]. However, it has clearly been demonstrated that adverse early biological and environmental experiences exert dramatic influences on the developing brain . It is therefore conceivable that, similarly, there might be a critical window for liver disease to affect the brain during early childhood. On the other hand, if Ltx is performed very early in life, neuronal plasticity might alleviate potential toxic influences. Therefore, the contradictory results might be due to a vague definition of “younger” and “older.” Usually this is only defined within the examined respective samples. Instead, further studies should compare groups of liver transplanted children with the same primary disease, but with clearly different ages at Ltx.
We did not find any laboratory parameter to serve as a significant predictor of cognitive performance. Moreover, there was no relation between daily dosage of immunosuppressive medication or CNI levels (measured at 1-year posttransplant, or time of assessment) and cognitive performance. However, these findings are limited as blood levels were only determined once, either 1-year posttransplant and at the time of assessment.
The degree of cognitive impairment detected in our cohort is similar to the results obtained in pediatric kidney and heart transplant recipients. A recent study found cognitive impairment in 49 children after kidney transplantation with a reported Total IQ of M = 83.9, SD = 20.0 . Older studies mainly showed deficits regarding nonverbal abilities [38, 39]. IQs of children after heart transplantation are relative consistently reported to be 10–15 IQ points below nonclinical comparison groups [40, 41]. In children with biliary atresia, cognitive deficits can already be detected preoperatively [42, 43]. Given the starkly different etiologies and pathogenetic processes leading to organ failure in these diseases, the underlying neuropsychological and -biological mechanisms remain to be elucidated. Further research should also take into account that stress  and anesthesia [45, 46] in early childhood may negatively affect brain development and consequently cognitive function.
The obtained interrelations between parental education level and some IQ Indices are within the expectable scope in the population .
In summary, our current study provides clear evidence for substantial cognitive impairment in a relatively large cohort of pediatric liver transplant recipients. These results were obtained in a cohort representative of the clinical heterogeneity of children undergoing Ltx as different types of primary diagnoses were considered. In addition, our results are further strengthened by the fact that all patients were school aged and were assessed with the same instrument. Furthermore, children with known mental retardation disorders were excluded in order to minimize confounding effects of outliers. We also included an appropriate reference group and used a newly revised assessment method.
Cognitive deficits have tremendous consequences for future development and well-being, especially in children, as cognitive performance impacts daily life as well as educational success. Ltx in children is meant to result not only in survival but in the best achievable health status in the long term. Therefore, cognitive performance should be regarded as equally important measure of therapeutic success in addition to medical outcomes.
The high prevalence of cognitive deficits demonstrated in the present study emphasizes the urgent need to implement (neuro)psycholocial screening procedures using appropriate and standardized assessment methods into routine clinical care. Counseling for the parents should also be offered on a regular basis. Importantly, further research should explore (neuro)psychological treatment options in order to develop evidence-based intervention strategies.