The use of once-daily LCP-Tacrolimus with adolescent and young adult solid organ transplant recipients.

BACKGROUND: Adolescent and young adult (AYA) solid organ transplant (SOT) recipients experience increased rates of rejection and graft loss surrounding the time of health care transition, in part due to poor medication adherence. This study aims to examine the impact of a once-daily formulation of tacrolimus, LCP-tacrolimus (LCPT), on medication adherence for AYA SOT patients. METHODS: A retrospective descriptive analysis was performed for all patients who underwent SOT and were prescribed LCPT after the age of 12 at our single-center pediatric hospital. Medication adherence was assessed via provider documentation and the medication level variability index (MLVI). RESULTS: Twenty-nine patients were prescribed LCPT as part of their immunosuppression regimen. Twenty patients were converted to LCPT from immediate-acting (IR) tacrolimus; six patients were initiated immediately following transplant, and three patients were unable to receive LCPT due to insurance denial. There was a numeric improvement in medication adherence for converted patients when measured by provider assessment (45.0% vs. 68.4%, p = .140) and MLVI (40.0% vs. 71.4%, p = .276), though these did not reach statistical significance. There were no differences in episodes of rejection or adverse effects. LCPT prescription was not associated with decreased medication burden, and two patients transitioned back to IR tacrolimus due to increased cost. CONCLUSIONS: LCPT use did not significantly improve patient adherence; however, it resulted in numerically higher perceived and measured adherence rates. LCPT appears to be safe and effective in the management of SOT recipients; however, it may not affect pill burden and may result in a higher financial burden. Use may be considered for a select group of AYA SOT recipients.

Pragmatic strategies to address health disparities along the continuum of care in chronic liver disease.

Racial, ethnic, and socioeconomic disparities exist in the prevalence and natural history of chronic liver disease, access to care, and clinical outcomes. Solutions to improve health equity range widely, from digital health tools to policy changes. The current review outlines the disparities along the chronic liver disease health care continuum from screening and diagnosis to the management of cirrhosis and considerations of pre-liver and post-liver transplantation. Using a health equity research and implementation science framework, we offer pragmatic strategies to address barriers to implementing high-quality equitable care for patients with chronic liver disease.

Quality measures in pre-liver transplant care by the Practice Metrics Committee of the American Association for the Study of Liver Diseases.

The liver transplantation (LT) evaluation and waitlisting process is subject to variations in care that can impede quality. The American Association for the Study of Liver Diseases (AASLD) Practice Metrics Committee (PMC) developed quality measures and patient-reported experience measures along the continuum of pre-LT care to reduce care variation and guide patient-centered care. Following a systematic literature review, candidate pre-LT measures were grouped into 4 phases of care: referral, evaluation and waitlisting, waitlist management, and organ acceptance. A modified Delphi panel with content expertise in hepatology, transplant surgery, psychiatry, transplant infectious disease, palliative care, and social work selected the final set. Candidate patient-reported experience measures spanned domains of cognitive health, emotional health, social well-being, and understanding the LT process. Of the 71 candidate measures, 41 were selected: 9 for referral; 20 for evaluation and waitlisting; 7 for waitlist management; and 5 for organ acceptance. A total of 14 were related to structure, 17 were process measures, and 10 were outcome measures that focused on elements not typically measured in routine care. Among the patient-reported experience measures, candidates of LT rated items from understanding the LT process domain as the most important. The proposed pre-LT measures provide a framework for quality improvement and care standardization among candidates of LT. Select measures apply to various stakeholders such as referring practitioners in the community and LT centers. Clinically meaningful measures that are distinct from those used for regulatory transplant reporting may facilitate local quality improvement initiatives to improve access and quality of care.

Caregiver Perceptions of Social Risk Screening in Pediatric Liver Transplantation: From the Multicenter SOCIAL-Tx Study.

BACKGROUND: The social determinants of health contribute to adverse post-liver transplant outcomes. Identifying unmet social risks may enable transplant teams to improve long-term outcomes for at-risk children. However, providers may feel uncomfortable asking about household-level social risks in the posttransplant period because they might make their patients/families uncomfortable. METHODS: We conducted a mixed-methods analysis of caregiver participants (ie, parents/guardians of pediatric liver transplant recipients) in the Social and Contextual Impact on Children Undergoing Liver Transplantation study to assess their perceptions of provider-based social risk screening. Participants (N = 109) completed a 20-min social determinants of health questionnaire that included questions on the acceptability of being asked intimate social risk questions. A subset of participants (N = 37) engaged in an in-depth qualitative interview to share their perceptions of social risk screening. RESULTS: Of 109 participants across 9 US transplant centers, 60% reported financial strain and 30% reported at least 1 material economic hardship (eg, food insecurity, housing instability). Overall, 65% of respondents reported it very or somewhat appropriate and 25% reported being neutral to being screened for social risks in a liver transplant setting. In qualitative analyses, participants reported trust in the providers and a clear understanding of the intention of the screening as prerequisites for liver transplant teams to perform social risk screening. CONCLUSIONS: Only a small minority of caregivers found social risk screening unacceptable. Pediatric liver transplant programs should implement routine social risk screening and prioritize the patient and family voices when establishing a screening program to ensure successful implementation.

The impact of health literacy on adolescent and young adult pediatric liver transplant recipients.

Pediatric liver transplant recipients have increased rates of morbidity and mortality following transfer to adult health care providers. The role of health literacy (HL) has not been adequately assessed in this population and may be an unrecognized barrier to successful health care transition. We sought to determine the impact of HL for patients and their caregivers on measures of transition readiness (TR), adherence, health-related quality of life, and medical outcomes following pediatric liver transplant. This is a single-center study of pediatric liver transplant recipients transplanted between the ages of 12 and 26 from October 2016 through August 2020. Patients and caregivers completed 4 surveys to evaluate TR, health-related quality of life, and HL. Clinical outcomes were stratified based on the presence or absence of adequate HL. Limited HL was identified in 57.0% of recipients and 47.4% of caregivers. Patients with limited HL were more likely to be younger in age ( p = 0.004), Hispanic ( p = 0.003), and less likely to have obtained a high school diploma or equivalent ( p < 0.001). Patients with adequate HL demonstrated significantly higher levels of TR ( p < 0.001). Patient HL did not impact health-related quality of life, adherence, or medical outcomes. Caregiver HL did not impact patient outcomes or adherence, though higher levels of caregiver education were associated with adequate patient HL ( p = 0.049). This study demonstrates that limited HL is associated with decreased measures of TR. Inadequate HL may be an unrecognized barrier to a successful health care transition. Regular assessment of HL may provide an opportunity for intervention prior to transfer of care. Future studies should investigate the impact of these interventions on long-term medical outcomes.

The diagnostic yield of exome sequencing in liver diseases from a curated gene panel.

Exome sequencing (ES) has been used in a variety of clinical settings but there are limited data on its utility for diagnosis and/or prediction of monogenic liver diseases. We developed a curated list of 502 genes for monogenic disorders associated with liver phenotypes and analyzed ES data for these genes in 758 patients with chronic liver diseases (CLD). For comparison, we examined ES data in 7856 self-declared healthy controls (HC), and 2187 patients with chronic kidney disease (CKD). Candidate pathogenic (P) or likely pathogenic (LP) variants were initially identified in 19.9% of participants, most of which were attributable to previously reported pathogenic variants with implausibly high allele frequencies. After variant annotation and filtering based on population minor allele frequency (MAF ≤ 10-4 for dominant disorders and MAF ≤ 10-3 for recessive disorders), we detected a significant enrichment of P/LP variants in the CLD cohort compared to the HC cohort (X2 test OR 5.00, 95% CI 3.06-8.18, p value = 4.5e-12). A second-level manual annotation was necessary to capture true pathogenic variants that were removed by stringent allele frequency and quality filters. After these sequential steps, the diagnostic rate of monogenic disorders was 5.7% in the CLD cohort, attributable to P/LP variants in 25 genes. We also identified concordant liver disease phenotypes for 15/22 kidney disease patients with P/LP variants in liver genes, mostly associated with cystic liver disease phenotypes. Sequencing results had many implications for clinical management, including familial testing for early diagnosis and management, preventative screening for associated comorbidities, and in some cases for therapy. Exome sequencing provided a 5.7% diagnostic rate in CLD patients and required multiple rounds of review to reduce both false positive and false negative findings. The identification of concordant phenotypes in many patients with P/LP variants and no known liver disease also indicates a potential for predictive testing for selected monogenic liver disorders.

Treatment of Cholestasis in Infants and Young Children.

PURPOSE OF REVIEW: Cholestasis is characterized by a conjugated hyperbilirubinemia secondary to impaired bile synthesis, transport, or excretion from the liver. It is always pathologic and can be indicative of an underlying hepatobiliary, genetic, or metabolic disorder, several of which require timely diagnosis to ensure proper management and optimal outcomes. This review provides an overview of the evaluation of cholestasis with a focus on current and emerging treatment strategies. RECENT FINDINGS: Increased accessibility of next generation sequencing (NGS) allows for utilization of genetic testing early in the diagnostic process. This may alter the clinical algorithm for diagnosis of cholestatic disorders. An enhanced understanding of the underlying pathophysiology may help guide future development of targeted therapies, such as ileal bile acid transporter (IBAT) inhibitors. These were recently approved for treatment of cholestatic pruritus in patients with Alagille syndrome and Progressive Familial Intrahepatic Cholestasis. Current management of cholestasis is aimed at the biochemical consequences of impaired bile flow, including malnutrition, pruritus, and progressive fibrosis. NGS has led to an enhanced understanding of biliary pathology and may guide development of future treatment modalities based on specific gene mutations. Rapid discernment of the underlying etiology is essential as new treatment modalities emerge.

Interim results from an ongoing, open-label, single-arm trial of odevixibat in progressive familial intrahepatic cholestasis.

Background & Aims: PEDFIC 2, an ongoing, open-label, 72-week study, evaluates odevixibat, an ileal bile acid transporter inhibitor, in patients with progressive familial intrahepatic cholestasis. Methods: PEDFIC 2 enrolled and dosed 69 patients across two cohorts; all received odevixibat 120 µg/kg per day. Cohort 1 comprised children from PEDFIC 1, and cohort 2 comprised new patients (any age). We report data through 15 July 2020, with Week 24 of PEDFIC 2 the main time point analysed. This represents up to 48 weeks of cumulative exposure for patients treated with odevixibat from the 24-week PEDFIC 1 study (cohort 1A) and up to 24 weeks of treatment for those who initiated odevixibat in PEDFIC 2 (patients who received placebo in PEDFIC 1 [cohort 1B] or cohort 2 patients). Primary endpoints for this prespecified interim analysis were change from baseline to Weeks 22-24 in serum bile acids (sBAs) and proportion of positive pruritus assessments (≥1-point drop from PEDFIC 2 baseline in pruritus on a 0-4 scale or score ≤1) over the 24-week period. Safety monitoring included evaluating treatment-emergent adverse events (TEAEs). Results: In cohort 1A, mean change from PEDFIC 1 baseline to Weeks 22-24 of PEDFIC 2 in sBAs was -201 µmol/L (p <0.0001). For cohort 1B and cohort 2, mean changes from odevixibat initiation to weeks 22-24 in sBAs were -144 and -104 µmol/L, respectively. The proportion of positive pruritus assessments in the first 24-week period of PEDFIC 2 was 33%, 56%, and 62% in cohorts 1A, 1B, and 2, respectively. Most TEAEs were mild or moderate. No drug-related serious TEAEs occurred. Conclusions: Odevixibat in patients with progressive familial intrahepatic cholestasis was generally well tolerated and associated with sustained reductions in sBAs and pruritus. Clinical Trials Registration: This study is registered at ClinicalTrials.gov (NCT03659916). Impact and Implications: Disrupted bile flow is a hallmark feature of patients with progressive familial intrahepatic cholestasis and can result in build-up of bile constituents in the liver with spill over into the bloodstream; other effects that patients can experience include extremely itchy skin, and because not enough bile reaches the gut, patients can have problems digesting food, which may lead to poor growth. Odevixibat is an orally administered medication that shunts bile acids away from the liver. The current study, called PEDFIC 2, suggested that odevixibat can improve the problematic signs and symptoms of progressive familial intrahepatic cholestasis and was generally safe for patients.

Current approach to health care transition and integration into adult care for pediatric liver transplant recipients: A call for partnership.

Despite the increased risk of non-adherence, allograft rejection, and mortality following transfer from pediatric to adult care in liver transplantation (LT), there is no standardized approach to health care transition (HCT). Two electronic national surveys were developed and distributed to members of the Society for Pediatric Liver Transplantation and all adult LT programs in the United States to examine current HCT practices. Responses were received from 40 pediatric and 79 adult centers. Pediatric centers were more likely to focus on HCT noting the presence of a transition/transfer policy (60.2% vs. 39.2%), transition clinic (51.6% vs. 16.5%), and the routine use of transition readiness assessment tools (54.8% vs. 10.2%). Perceived barriers to HCT were similar among pediatric and adult respondents and included patient willingness to transfer and participate in care, failure to show for appointments, and lack of sufficient time and staffing. These results highlight the need for an increased awareness of HCT at both pediatric and adult LT centers. The path to improvement requires a partnership between pediatric and adult providers. Recognizing the importance of a comprehensive HCT program initiated in pediatrics and continued throughout young adulthood with ongoing support by the adult team is essential.

Health Care Transition for Adolescents and Young Adults With Pediatric-Onset Liver Disease and Transplantation: A Position Paper by the North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition.

Advances in medical therapies and liver transplantation have resulted in a greater number of pediatric patients reaching young adulthood. However, there is an increased risk for medical complications and morbidity surrounding transfer from pediatric to adult hepatology and transplant services. Health care transition (HCT) is the process of moving from a child/family-centered model of care to an adult or patient-centered model of health care. Successful HCT requires a partnership between pediatric and adult providers across all disciplines resulting in a transition process that does not end at the time of transfer but continues throughout early adulthood. Joint consensus guidelines in collaboration with the American Society of Transplantation are presented to facilitate the adoption of a structured, multidisciplinary approach to transition planning utilizing The Six Core Elements of Health Care Transition TM for use by both pediatric and adult specialists. This paper provides guidance and seeks support for the implementation of an HCT program which spans across both pediatric and adult hepatology and transplant centers.

Caregivers' and providers' perspectives of social and medical care after pediatric liver transplant: Results from the multicenter SOCIAL-Tx study.

Disparities exist in pediatric liver transplant (LT). We characterized barriers and facilitators to providing transplant and social care within pediatric LT clinics. This was a multicenter qualitative study. We oversampled caregivers reporting household financial strain, material economic hardship, or demonstrating poor health literacy. We also enrolled transplant team members. We conducted semistructured interviews with participants. Caregiver interviews focused on challenges addressing transplant and household needs. Transplant provider interviews focused on barriers and facilitators to providing social care within transplant teams. Interviews were recorded, transcribed, and coded according to the Capability, Opportunity, Motivation-Behavior model. We interviewed 27 caregivers and 27 transplant team members. Fifty-two percent of caregivers reported a household income <$60,000, and 62% reported financial resource strain. Caregivers reported experiencing (1) high financial burdens after LT, (2) added caregiving labor that compounds the financial burden, (3) dependency on their social network's generosity for financial and logistical support, and (4) additional support being limited to the perioperative period. Transplant providers reported (1) relying on the pretransplant psychosocial assessment for identifying social risks, (2) discomfort initiating social risk discussions in the post-transplant period, (3) reliance on social workers to address new social risks, and (4) social workers feeling overburdened by quantity and quality of the social work referrals. We identified barriers to providing effective social care in pediatric LT, primarily a lack of comfort in assessing and addressing new social risks in the post-transplant period. Addressing these barriers should enhance social care delivery and improve outcomes for these children.

Risk Factors for 30-Day Unplanned Readmission After Hepatectomy: Analysis of 438 Pediatric Patients from the ACS-NSQIP-P Database.

BACKGROUND: Hepatic resections are uncommon in children. Most studies reporting complications of these procedures and risk factors associated with unplanned readmissions are limited to retrospective data from single centers. We investigated risk factors for 30-day unplanned readmission after hepatectomy in children using the American College of Surgeons National Surgical Quality Improvement-Pediatric database. METHODS: The database was queried for patients aged 0-18 years who underwent hepatectomy for the treatment of liver lesions from 2012 to 2018. Chi-squared tests were performed to evaluate for potential risk factors for unplanned readmissions. A multivariate regression analysis was performed to identify independent predictors for unplanned 30-day readmissions. RESULTS: Among 438 children undergoing hepatectomy, 64 (14.6%) had unplanned readmissions. The median age of the hepatectomy cohort was 1 year (0-17); 55.5% were male. Patients readmitted had significantly higher rates of esophageal/gastric/intestinal disease (26.56% vs. 14.97%; p=0.022), current cancer (85.94% vs. 75.67%; p=0.012), and enteral and parenteral nutritional support (31.25% vs. 17.65%; p=0.011). Readmitted patients had significantly higher rates of perioperative blood transfusion (67.19% vs. 52.41%; p=0.028), organ/space surgical site infection (10.94% vs. 1.07%; p<.001), sepsis (15.63% vs. 3.74%; p<.001), and total parenteral nutrition at discharge (9.09% vs. 2.66%; p=0.041). Organ/space surgical site infection was an independent risk factor for unplanned readmission (OR=9.598, CI [2.070-44.513], p=0.004) by multivariable analysis. CONCLUSION: Unplanned readmissions after liver resection are frequent in pediatric patients. Organ/space surgical site infections may identify patients at increased risk for unplanned readmission. Strategies to reduce these complications may decrease morbidity and costs associated with unplanned readmissions.

Bone Fractures in Children With Cholestatic Liver Disease May Mimic Those Seen in Child Abuse.

ABSTRACT: Certain fractures in children are highly specific for child abuse. Metabolic bone disease frequently develops in patients with cholestatic liver disease (CLD); this can result in weakened bones and a predisposition to pathologic fractures. Fractures that occur in patients with rickets and osteopenia may mimic a bone response to inflicted injury, which in children raise the concern of child abuse. Here we report a series of 15 patients with CLD who developed pathologic fractures in the setting of metabolic bone disease. During initial evaluation, the caretakers of 5 of these 15 patients were reported to child protective services and investigated for child abuse. Pediatricians should be aware that children with CLD have an increased incidence of pathologic fractures, even after the cholestasis has resolved.

Concomitant tacrolimus and ketorolac therapy in pediatric liver transplant recipients: Teaching old dogma new tricks.

Nonsteroidal anti-inflammatory drugs (NSAIDs), such as ketorolac, are effective analgesic medications, but concerns for nephrotoxicity have limited their role for pain control following pediatric liver transplantation (LT). Calcineurin inhibitors (CNIs) and NSAIDs share a similar mechanism of nephrotoxicity, and concomitant administration is traditionally discouraged. A retrospective review of pediatric LT recipients was conducted between 1/1/2015 and 12/31/2019 at a single center. Patients were stratified based on receipt of ketorolac. The primary outcome was the incidence of acute kidney injury (AKI). Secondary outcomes included serum creatinine, urine output, estimated glomerular filtration rate, bleeding incidence, oral morphine milligram equivalents, and hospital length of stay (LOS). The incidence of AKI was similar between the two groups with 25.8% of patients in the ketorolac group versus 29.2% of patients in the nonketorolac group (p = .475) meeting criteria in the first 10 days post-transplant. Opioid requirements were less in the ketorolac group (p < .001), who also demonstrated shorter LOS compared with nonketorolac patients (p = .033). Concurrent CNI and ketorolac use did not result in an increased incidence of AKI in the early post-LT period and resulted in significantly lower opioid requirements along with a decreased hospital LOS.

Health Care Transition: A Time of Increased Vulnerability for Pediatric Liver Transplant Recipients.

Improvements in pediatric liver transplantation (LT) have led to an increased number of patients reaching young adulthood. Young adult LT recipients transferring from pediatric to adult models of care have increased rates of rejection, graft loss, and medical complications. The goal of a health care transition program is to optimize health and assist youth in reaching their full potential. The means to achieve this goal requires an organized transition process to support youth in acquiring independent health care skills, preparing for an adult model of care, and transferring to new providers without disruption in treatment. This can only be achieved through a multidisciplinary approach to transition planning. This is often a labor and resource-intensive undertaking, which may not receive the necessary support from local institutions. Widespread implementation requires the assistance and endorsement from governing organizations at the national and international level.

Recent advances in understanding and managing pediatric nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of disease that can range from isolated macrovesicular hepatocellular steatosis to nonalcoholic steatohepatitis (NASH) with or without fibrosis to cirrhosis. The prevalence of NAFLD has increased over several decades, mirroring the global obesity pandemic. NAFLD currently represents the most common etiology of chronic liver disease in children and adolescents worldwide. Disease presentation in childhood strongly suggests that these children may have unique susceptibilities and more severe long-term consequences. Emerging data demonstrate that the pathogenesis of early-onset NAFLD is secondary to a complex interplay involving genetic, metabolic, environmental, and microbiological factors. Such influences may begin in utero. Dietary and lifestyle modifications remain the primary effective therapeutic interventions, although long-term efficacy is limited by poor adoption or adherence. Advances in the development and validation of non-invasive biomarkers and imaging modalities will facilitate diagnosis for affected children and adolescents and facilitate long-term natural history studies and the development of therapeutic interventions.

A case of an Infant with SARS-CoV-2 hepatitis early after liver transplantation.

We present a case of a pediatric liver transplant recipient diagnosed with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection four days after receiving a living donor liver allograft from her mother. The recipient was a 6-month-old with end-stage liver disease due to biliary atresia and failed Kasai. The infant had an uncomplicated implantation, excellent graft function and down-trending liver enzymes until developing fevers, diarrhea, and moderate respiratory distress requiring non-invasive respiratory support. SARS-CoV-2 testing (nasal swab Polymerase Chain Reaction) was positive on post-operative day (POD) 4. Liver enzymes peaked ~1000 U/L (5-fold higher than the previous day) on POD 6. Histology demonstrated a mixed picture of moderate acute hepatitis and classical elements of mild to moderate acute cellular rejection. Her hepatitis and respiratory symptoms improved coincident with completing treatment with hydroxychloroquine, reduced immunosuppression, and intravenous gamma globulin (IVIG).

Role of Budesonide for the Treatment of Rejection in Pediatric Liver Transplantation.

INTRODUCTION: Corticosteroids are an integral part of liver transplant (LT) immunosuppression regimens but are often accompanied by many adverse effects. Budesonide is an oral corticosteroid with extensive (80%-90%) hepatic first-pass metabolism and minimal systemic absorption. The aim of this study was to examine the safety and efficacy of budesonide for management of acute cellular rejection (ACR) in pediatric LT recipients. METHODS: A retrospective descriptive analysis was performed for all pediatric patients who underwent LT at our center and were prescribed oral budesonide for the treatment of ACR. Alanine aminotransferase (ALT) values and documented adverse effects were reviewed. RESULTS: Twenty-nine patients were prescribed budesonide for the treatment of ACR; 65.5% with biopsy-proven acute rejection and 34.5% with presumed ACR. There was a significant decrease in ALT noted from the time of rejection when compared to values 1 month (P = 0.0011), 3 months (P = 0.0003), and 6 months (P = 0.0001) after treatment with budesonide. There was no difference noted between patient baseline ALT levels before rejection when compared to 1, 3, and 6 months posttreatment values suggesting resolution of rejection. Three patients required conversion from budesonide to systemic steroids. There were no discontinuations of budesonide secondary to adverse effects. CONCLUSION: Oral budesonide may be a promising alternative to systemic corticosteroids for the management of mild/moderate ACR and for empiric treatment of ACR in select pediatric LT recipients. Data from this study may provide the foundation for larger, prospective, multicenter trials to assess the effectiveness of budesonide in the treatment of ACR.