EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Key words : Diagnostic tools, Neuropsychological tests, Pediatric transplant

A liver transplant is a treatment option that provides long-term survival for patients with chronic liver diseases. Although posttransplant survival increases, recent studies indicate that liver transplant recipients perform poorly in physical, psychological, and social functions versus healthy populations.¹

Malnutrition, metabolic irregularities, and elect-rolyte irregularities are generally seen in liver diseases, and posttransplant medications can expose children to many conditions that may be toxic for the brain. The infantile onset of liver disease, longer pretransplant duration of disease, deceased organ transplant, elevated serum calcineurin inhibitor level, lower pretransplant growth percentile, and elevated serum ammonia have been suggested as potential risk factors for cognitive deficits in pediatric liver transplant recipients. In addition, stress and anesthesia in early childhood may negatively affect brain development and consequently cognitive functions.^2-6 Attention functions are also impaired in patients with liver disease. It has been reported that selective attention is more affected in patients with minimal hepatic encephalopathy.^7,8

Attention-deficit and hyperactivity disorder (ADHD) is a neurodevelopmental disorder identified with attention deficit, hyperactivity, and impulsivity. Executive functions are impaired in this disorder. Executive functions are part of the larger group of cognitive functions, but in ADHD, generally, the intelligence quotient is in a normal range.⁹

For diagnosis of ADHD, health care providers use the guidelines in the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), and a thorough evaluation by a health care provider or mental health professional is necessary to determine the cause of the symptoms and identify effective treatments.

Although there are many cognitive function studies in children with liver transplants in the literature, studies related to ADHD are rare. Therefore, we aimed to investigate the prevalence of ADHD and to discover the best diagnostic tool for accurate diagnosis of ADHD in children with liver transplants. We hypothesized that the incidence of ADHD in children with liver transplant is higher than in the general population.

Materials and Methods

Our study included 62 children from 6 to 18 years old who underwent liver transplant at least 1 year previous to this study and who were followed up in the Department of Pediatric Gastroenterology at Baskent University.

Primary diagnoses, Child-Pugh score, and Pediatric End-Stage Liver Disease (PELD) or the Model For End-Stage Liver Disease (MELD) scores, age of transplant, duration of pretransplant illness, duration of hospitalization before and after transplant, and donor type were recorded. In addition, prematurity, history of low birth weight, convulsion, familial epilepsy, and maternal smoking history during pregnancy were recorded.

The patients were first assessed by the pediat-rician for ADHD based on DSM-5 criteria, and then the patients were assessed according to the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS), Turkish version. The K-SADS and Conners Parent Rating Scale (CPRS) were applied to the parents of children. The Conners Teacher Rating Scale (CTRS) was given to the children’s teachers, who completed the forms.

The K-SADS is a semi-structured diagnostic interview developed by Kaufman and colleagues according to DSM-5 diagnostic criteria for the detection of psychopathologies of children and adolescents aged 6 to 18 years.¹⁰ In Turkey, the validity and reliability study has been established by Gökler and colleagues.¹¹ The K-SADS was given to 62 pediatric liver transplant recipients and their parents.

The CPRS is a subtest composed of questions regarding symptoms of distractibility, hyperactivity, disorientation, and impaired behavior.¹² The Turkish adaptation, validity, and reliability study of the CPRS was performed by Dereboy and colleagues.¹³ In our study, the CPRS was given to 61 of the 62 parents of the pediatric liver transplant recipients. According to the protocols for these diagnostic scales, when the total score for the attention deficit subscale exceeds 5, the total score for the hyperactivity subscale exceeds 6, the total score for the oppositional defiant problems subscale exceeds 7, and the total score for the behavioral problems subscale exceeds 18, then the child is considered to have ADHD.

The CTRS is a tool that is given to teachers to assess students’ classroom behavior, and it can be used to screen for “attention deficit and disruptive behavior disorders.”^13,14 The CTRS scale was applied to 54 of 62 teachers of the liver transplant recipients. According to the CTRS protocol, when the total score of the attention-deficit/passiveness subscale exceeds 18, the total score of the hyperactivity subscore exceeds 16, and the behavioral problem subscore exceeds 18, then the child is considered to have ADHD. Information was obtained from classroom teachers for primary school students and from arithmetic and literature teachers for adolescent students.

Clinical assessment
All patients were clinically examined by a psychiatrist specializing in child and adolescent patients, and the psychiatric examination assessed writing skills, reading skills, mathematic skills, drawing skills, and reading comprehension skills.

Parents and children were interviewed and finally assessed in the context of information from all of the aforementioned sources. The ADHD diagnosis was made unanimously by clinical evaluation, K-SADS, and CPRS, and CTRS results. When all of these evaluation tools produced results that indicated ADHD, then the patient was diagnosed with ADHD. The Wechsler Intelligence Scale for Children-Revised was applied to patients as deemed necessary by the psychiatrist.

Our study design was approved by the ethics committee of our university (project No. KA16/35). Before enrollment, written informed consent was obtained from the primary caretaker of each patient.

Statistical analyses
In the evaluation of the data, we used mean values ± SD, median values, and minimum and maximum values for numerical measurements from descriptive statistics. Numbers and percentages are given for qualitative features. Whether the measurements obtained in patients with ADHD and liver transplant showed normal distribution was tested with the Shapiro-Wilk test, and the results showed that the data did not show normal distribution. In the comparison of numerical values between 2 groups, the Mann-Whitney U test was used in independent groups. Chi-square analysis, the Fisher exact test, and the Fisher-Freeman-Halton test were used for the comparison of qualitative features in the 2 groups. The Spearman correlation coefficient was used for the relationships between numerical properties. P < .05 was considered statistically significant, and the IBM SPSS (version 21.0) for Windows package was used for all statistical analyses.

Our study group included 62 children, composed of 37 (59.7%) male patients and 25 (40.3%) female patients. The average age of the patients was 11.6 ± 3.1 years. The mean age at transplant was 4.8 ± 3.2 years (range, 0.6-16.6 years). The mean duration of the disease before transplant was 3.48 ± 3.83 years (range, 0.06-16 years). Ninety-three percent of the patients received transplants from a living donor, and all of these donors were first-degree relatives. All patients diagnosed with ADHD received their organs from a living donor. Age at transplant and duration of disease before transplant were not statistically significant with regard to ADHD diagnosis (P = .435 and P = .999, respectively). Before the transplant, only 1 patient had a psychiatric history, and the diagnosis was intellectual disability.

The K-SADS test was given to 62 patients, and the results were positive for ADHD in 15 (24.5%) patients. The CPRS scale was given to 61 of the patients’ parents. According to the results of the CPRS scale from the parents, hyperactivity was present in 26 (42.6%) of these patients and attention deficit in 28 (45.9%). The CTRS scale was used by the teachers to assess 54 patients. According to the CTRS results from the teachers, 13 (24%) of these patients had hyperactivity and 22 (40.7%) had attention deficit (Table 1).

Psychiatric examinations and final clinical evaluations showed that 6 patients (9.67%) had ADHD, including 4% (1 of 25) of female patients and 13.5% (5 of 37) of male patients. There was no statistically significant association between patient sex and ADHD (P = .387).

Two patients with familial hypercholesterolemia were diagnosed with ADHD (hyperactivity-impulsivity predominant type, combined type). Two patients with Alagille syndrome were diagnosed with ADHD (attention deficit predominant type, combined type). One patient with biliary atresia and another patient with tyrosinemia were both diagnosed with ADHD (combined type). There was no statistically significant association between ADHD and primary liver disease. The PELD or MELD scores and Child-Pugh scores of liver disease could not be associated with ADHD (P = .999 and P = 0.534, respectively). Pretransplant ammonia levels were found to be significantly higher in the group without ADHD (P = .042).

All 6 patients with ADHD had received their transplants from living donors. There was no pos-ttransplant history of encephalopathy or posterior reversible encephalopathy syndrome in children diagnosed with ADHD. There was no statistically significant association between ADHD and duration of hospitalization after transplant (P = .898).

Eight (12.9%) patients were diagnosed with intel-lectual disability, 4 (6.5%) patients were diagnosed with border intelligence, 3 (4.8%) patients were diagnosed with a specific learning disability, and 1 (1.6%) patient was diagnosed with autism spectrum disorder.

In our investigation of the prevalence of ADHD in pediatric and adolescent liver transplant recipients, a 9.7% ADHD rate was found, which is compatible with the rate of the community-based studies. In a study conducted in 2015, the prevalence of ADHD in Turkey was found to be 8%.6 When considering individual studies to determine the prevalence of ADHD, the results were found to be between values as low as 0.2% and 0.4% and as high as 23.4% and 27%.¹⁵ In 2 of the more extensive meta-analyses conducted in recent years, the average prevalence of ADHD worldwide was reported as 5.29% and 5.9% to 7.1%.^16,17 As a result of these 2 meta-analyses, the authors concluded that substantial variability of ADHD prevalence reported among the large number of previous studies was mainly the result of the differences in methodologies, not geographical and racial differences.^15-17

In one of their studies, Kaller and colleagues found the prevalence of ADHD was 4% among pediatric liver transplant recipients, and in another study, they reported that attention problems were seen in 47% of pediatric liver transplant recipients.^4,18 This suggests that the liver does not have an effect on cognitive function and attention of course. The Study of Pediatric Liver Transplant (SPLIT) reported 14% of the patients had ADHD among 93 children with liver disease.¹⁹ The ADHD diagnosis for the SPLIT report was provided by the children’s own doctors, and the sample size for the SPLIT project was larger than the sample size in our study. The results from the SPLIT project may indicate that ADHD occurs at a higher rate in larger-scale studies. Ee and colleagues diagnosed ADHD in 4 of 13 (31%) liver transplant recipients.²⁰ In a study by Lee and colleagues, the ADHD rate was found to be 32.5% in 43 pediatric liver and kidney transplant recipients.²¹ The reason for these high ratios could be that the diagnoses were based only on the CPRS results and only clinicians’ interviews, respectively. Kaller and colleagues observed that 137 pediatric liver transplant recipients were in the low-normal range of attention tests, especially in the assessments of subdivided attention, functioning memory, and excitability, scalability, and sustainable attention.¹⁸ The main difference of our study from other studies in the literature is that our study is not only based on clinical opinion or scales but benefits from both of these aspects.

Studies for which the diagnoses rely solely on the scales show significantly higher rates of ADHD versus the clinical assessment constructs. It has been determined that the prevalence of ADHD is lower in studies conducted with scales, in clinical interviews conducted with scales, and with information obtained from more sources versus results from studies that use a single source of information.²² The best-estimated procedure is that all information, including the clinical psychiatric evaluation of the pediatric and adolescent patients, is assessed and diagnosed by an experienced clinician, but the examination is the most preferred method. In the case of patients with ADHD, the rate of ADHD may vary, although it shown to be high.

Batstra and colleagues proposed an investigation into the assessment about clinical impairment decreases ADHD prevalence rates in 2014.²² The population of this study already had chronic diseases and related low functionality, and therefore a conclusive diagnosis of ADHD is difficult to obtain for this group. Children who have received a solid-organ transplant do not usually return to their school, and in cases where these patients are able to resume attendance in the classroom, their guardians may likely maintain low expectations for academic performance from these children.²³ Impaired intellectual function due to brain damage is a likely outcome for these patients, and cognitive impairment was detected in 15 patients in this study, and the functionality in these patients decreases.²³ In addition, intellectual dysfunction impairs attention functions. Unlike other studies, the low rate of ADHD in our present study was thought to be caused by the consideration of all these in the clinical evaluation. For this reason, it is thought that detailed clinical examination is more important than neuropsychological tests and scales to diagnose these patients.

Hyperactivity scores reported in the CTRS results from teachers increase as the duration of hospita-lization increases in the posttransplant period. Hyperactivity is more common in children with chronic diseases and also with living in child welfare institutions due to lack of stimuli.²⁴ In our study group, it is also possible that adherence to long-term hospitalization may have increased the risk of hyperactivity by creating a lack of stimuli in the same way.

Deterioration of any of the 4 areas (attention deficit, hyperactivity, behavior disorder, and oppositional disorder) in the evaluation of the CPRS poses a risk for detecting disorder in the other 3 areas. This is due to the frequent occurrence of comorbid disorders in ADHD. In addition, when the questions within the CPRS test were examined, it appeared that some questions could be seen in more than 1 disorder and that the parents could not completely separate the situation.

The small sample size was a limitation of the study. Patients were not evaluated for ADHD before transplant. Therefore, future evaluation of these patients before and after transplant and screening them for ADHD will enable us to see the possible results of the transplant procedure. Due to the very low age of transplant, even if a psychiatric history was taken about pretransplant details, these pieces of information were not helpful for the assessment of ADHD. However, this is the first study, to our knowledge, to comprehensively examine liver transplant recipients for the diagnosis of ADHD.

Detailed clinical examination is more important than neuropsychological tests and diagnostic screening scales for diagnosis of ADHD in patients with liver disease or in pediatric liver transplant recipients. Multidisciplinary assessment is crucial for these groups.

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