Overall, children with BA are at risk of impaired HrQoL, both physically and psychologically, significantly when younger, whether they are native liver survivors or received an LT during disease progression (Figure 2). Whereas bilirubin levels, the number of cholangitis episodes, variceal bleeding, and nutritional status mainly define the pretransplant HrQoL, the HrQoL posttransplant is mainly affected by the number of prescribed immunosuppressive medications. Interestingly, age at surgery and associated malformations seem not to affect the HrQoL (Figure 4). However, children at higher ages score higher in HrQoL than their younger peers. This might be a result of their long-term adaption to their disease. This phenomenon is known as "response shift," a change in individuals' perceptions of their HrQoL based on their individual experiences Moreover, children who already had reached school age are clinically stable, with a similar or even improved health status compared with the years before, most likely score their HrQoL higher. Also, the score can be affected by the reporter. Parents might tend to report a lower HrQoL because of the intense years after their child was diagnosed with BA and their experience coping with the disease.
An important finding is the often neglected aspect of gender difference in HrQoL. In our study, we found that females had lower scores in all domains of HrQol questionnaires. Especially in bodily pain, females show increased sensitivity to nociceptive stimuli . Studies reported that the hormones like estrogen or testosterone had a direct impact on perceived pain. For instance, estrogen increases the nervous system activity, which increases the transmission of pain stimuli and pain sensitivity of a woman .
On the other hand, testosterone has an analgesic effect and can reduce pain sensitivity in men [26, 27]. Also, in another study concerning "fatigue" after LT, Berg-Emons et al. concluded that the female gender perceives "fatigue" with greater severity, suggesting impaired HrQol . However, although females score lower in "physical function" and "physical role functioning," studies are suggesting that females score higher in domains "emotional role functioning" and "mental health," suggesting females have a better ability to manage stress and psychosocial demands in the posttransplant setting . However, these findings could not be substantiated in the present study.
Nevertheless, gender differences also exist in response to painful situations in teenagers and adolescents. Males would primarily seek out distracting behaviors while females use social support and positive self-statements [26, 29]. Hence, it is essential to recognize gender differences in the setting of chronic liver disease to direct attention to being active, thinking positively, and expressing emotions positively, which will be correlated with higher scores in HrQol questionnaires. However, among all pretransplant clinical covariates, serum bilirubin following HPE appears to be the most predictive biomarker of the outcome . With increasing levels of bilirubin, the likelihood of the need for LT increases. For example, children with Bilirubin levels > 50 µl/ml at 2- and five years had a transplant-free survival of 4.8 % and 0, respetively . Cholangitis is one factor that has a direct impact on HrQol in patients with BA. In the present study, the pooled prevalence of cholangitis was 33% which correlates with the incidence of cholangitis reported in the literature (40 % and 90 %)(Figure ). In general, most patients experience at least one episode prior to 2 years of age. Recurrent cholangitis may predict the need for LT as it can lead to progressive cirrhosis [30, 32]. On the other hand, one episode of cholangitis does not predict early LT . Also, other liver disease-associated symptoms like therapy refractory ascites with accompanying risk of spontaneous bacterial peritonitis or increased portal hypertension with the risk of gastrointestinal hemorrhage, which is present throughout the lives of children with BA, are often correlated with a poor outcome and early liver transplantation needs. However, HrQol is mainly dependent on whether adequate bile drainage is achieved after HPE [30, 34].
A significant common clinical problem in BA is poor nutrition and, along nondrainage of the HPE, the most common indication for LT. Unfortunately, nutritional problems in BA are challenging to overcome. Children with BA have a constant caloric deficit and need to be supplemented with extra calories, fat-soluble vitamins, and medium-chain triglycerides (MCT) to prevent weight loss and failure to growth . The perceived dependency from external nutritional support is also reflected by the correlation of a low HrQoL and the number of prescribed drugs. We found that immunosuppression polytherapy and the number of prescribed medications were associated with a significantly lower HrQoL [11, 20]. Immunosuppressive medications are necessary post-LT because of the risk of organ rejection and graft loss, and the need for re-transplantation is a lifelong danger. However, those drugs produce side effects that need to be monitored. First, early post-transplant use of corticosteroids raises the risk of post-transplant hyperglycemia and diabetes. The weight gain may result in long-standing post-transplant metabolic syndrome as well. The most common side effects are nephrotoxicity and hypertension because of Calcineurin inhibitors such as tacrolimus or ciclosporin. To reduce nephrotoxicity, other immunosuppressive drugs like the antimetabolites mycophenolate mofetil, azathioprine, or mTOR inhibitors like sirolimus and everolimus increased the armamentarium of immunosuppressive drugs .
In one study, the ideal survivor after liver transplantation was on single-agent immunosuppression, not receiving prednisone, antihypertensive or antiseizure medications with no impact on linear growth or immunosuppression-related comorbid conditions . A condition that is barely achieved in those patients who received an LT. So, it is not a surprise that Miserachs et al. reported significantly lower HrQoL scores in liver transplant recipients with biliary atresia (p < 0.001) than healthy peers in physical, psychosocial, social, and family functioning domains . Despite the constant improvement of the survival rates following LT, future research on immunosuppression withdrawal will be necessary to improve the HrQoL of children with BA.
Although we found that the HrQoL of those who lived with their native livers and BA patients who received an LT is comparable to healthy peers, the survival of BA patients with their native liver is poor and reported in the literature between 30% - 55%, 30% - 40%, and 20% - 40% at 5, 10, and 20 years respectively . Most patients will develop chronic liver disease and require an LT. In the present study, the pooled prevalence of having an LT after a "failed HPE" was 59 %,which is in line with the reported literature . It has been suggested that LT as a primary approach for managing patients with BA is possible. However, HPE remains to be the most reasonable initial approach. If the patient is stable, it is better to delay the LT to increase the chances of a successful liver transplant .
One often-overlooked factor is that patients with BA often show a history of neurodevelopmental delay, especially in early childhood . Also, motor impairments or behavioral problems are common. Additionally, up to 25 % f the patients are suffering from anxiety and depression. While addressing the numerous liver disease complications, it is essential to identify patients with neurodevelopmental and psychological issues as early as possible for timely referral to a psychosocial health care provider .