Living donor liver paired exchange between pediatric and adult recipients due to donor graft size mismatch.

Living donor liver transplantation is an effective means to decrease organ shortage. However, many potential living donors are currently being denied due to ABO incompatibility or inadequate donor liver volume. Liver paired exchange (LPE) provides a practical solution to overcome these obstacles, and yet the first case of LPE in the United States was only recently reported in 2020. Here, we report world's first case of LPE involving pediatric and adult recipients to avoid surgical complexity of the pediatric recipient and to increase the graft-to-recipient weight ratio of the adult recipient between 2 ABO compatible pairs. As living donor liver transplantation becomes more widely adopted, the need for pair exchange to improve surgical safety and postoperative outcomes between 2 ABO compatible pairs is likely to increase.

Predictors of survival following liver transplantation for pediatric hepatoblastoma and hepatocellular carcinoma: Experience from the Society of Pediatric Liver Transplantation (SPLIT).

Management of unresectable pediatric hepatoblastoma (HB) and hepatocellular carcinoma (HCC) remains challenging. The Society of Pediatric Liver Transplantation (SPLIT) database was used to study survival predictors in pediatric liver transplantation (LT) for HB and HCC. Event-free survival (EFS), associated risk factors, and postoperative complications were studied in children requiring LT for HB/HCC at 16 SPLIT centers. Three-year EFS was 81% for HB (n = 157) and 62% for HCC (n = 18) transplants. Of HB transplants, 6.9% were PRETEXT II and 15.3% were POST-TEXT I/II. Tumor extent did not impact survival (p = NS). Salvage (n = 13) and primary HB transplants had similar 3-year EFS (62% versus 78%, p = NS). Among HCC transplants, 3-year EFS was poorer in older patients (38% in ≥8-year-olds vs 86% <8-year-olds) and those with larger tumors (48% for those beyond versus 83% within Milan criteria, p = NS). Risk of infection (HR 1.5, 95% CI 1.1-2.2, p = .02) and renal injury (HR 2.4, 95% CI 1.7-3.3, p < .001) were higher in malignant versus nonmalignant LT. Survival is favorable for pediatric HB and HCC LT, including outcomes after salvage transplant. Unexpected numbers of LTs occurred in PRE/POST-TEXT I/II tumors. Judicious patient selection is critical to distinguish tumors that are potentially resectable; simultaneously, we must advocate for patients with unresectable malignancies to receive organs.

Pediatric acute liver failure: Reexamining key clinical features, current management, and research prospects.

This review aims to synthesize the most updated research, outcomes, and trends in the field of pediatric liver transplantation (LT), specifically focusing on children who have suffered from acute liver failure. Pediatric acute liver failure is a dynamic, life-threatening condition that can either self-resolve or lead to death. LT is a lifesaving intervention. With the introduction of technical variant grafts and recent immunosuppression modifications, overall patient survival, graft survival, and waitlist mortality have improved. Furthermore, recent advances in the knowledge of immunologic mediators of acute liver failure offer the possibility of more detailed understanding of the pathophysiology and new areas for research. Given the success of living donor LT for pediatric patients with acute liver failure, this option should continue to be actively considered as an alternative treatment option for patients who are listed for transplantation and are managed at a multidisciplinary tertiary care transplant center.

Clinical Value of Surveillance Biopsies in Pediatric Liver Transplantation.

Although pediatric liver transplantation (LT) results in excellent long-term outcomes, a high incidence of early acute cellular rejection and late graft fibrosis persists. Routine measurement of allograft enzymes may not reliably detect rejection episodes, identify candidates for immunosuppression minimization, or indicate allograft fibrosis. Surveillance biopsies (SBs) can provide valuable information in this regard, but their role in pediatric LT is not fully established. A retrospective cohort of 236 pediatric LT recipients from a high-volume center was studied to characterize the risks and benefits of SB versus for-cause biopsies (FCBs). The study population was 47.1% male and 54.7% Hispanic, and 31% received living donor grafts. Our data suggest that patients in the SB group had better transplant outcomes (rejection-free, graft, and patient survival) compared with patients who had FCBs or who never underwent biopsy. Among 817 biopsies obtained from 236 patients, 150 (18.4%) were SBs. Only 6 patients had a biopsy-related complication, and none were observed in the SB subset. Graft biochemical blood tests did not accurately predict rejection severity on biopsy, with aspartate aminotransferase area under the receiver operating characteristic curve (AUROC) 0.66, alanine aminotransferase AUROC 0.65 (very poor predictions), and gamma-glutamyltransferase AUROC 0.58 (no prediction). SBs identified subclinical rejection in 18.6% of biopsies, whereas 63.3% of SBs had evidence of fibrosis. SBs prompted changes in immunosuppression including dose reduction. Our experience suggests that SB in pediatric LT is safe, offers valuable information about subclinical rejection episodes, and can guide management of immunosuppression, including minimization. Improved outcomes with SB were likely multifactorial, potentially relating to a more favorable early posttransplant course and possible effect of management optimization through SB. Further multicenter studies are needed to examine the role of SBs on long-term outcomes in pediatric LT.

Immunologic benefits of maternal living donor allografts in pediatric liver transplantation: fewer rejection episodes and no evidence of de novo allosensitization.

BACKGROUND: Pediatric liver transplant (LT) recipients of maternal living liver donor (LLD) grafts have been reported to experience fewer rejection episodes. However, it is unclear whether this benefit translates to reduction in developing donor-specific antibody (DSA) among maternal-LLD recipients. The aim of this study was to compare immunologic outcomes among maternal-LLD, non-maternal-LLD, and deceased donor liver transplant (DDLT) recipients. METHODS: Children (≤18 years) who underwent LT between 1/1998 and 12/2019 at two high-volume LT centers in North America were evaluated. Patients were divided into three groups by type of graft received (maternal-LLD, non-maternal LLD, and DDLT). Clinical variables and outcomes were compared according to each graft type. RESULTS: A total of 450 pediatric primary LT were analyzed: 275 (61.1%) DDLT, 73 (16.2%) maternal-LLD, and 102 (22.6%) non-maternal-LLD. Children receiving LLD grafts were less likely to develop rejection when compared to the DDLT group (DDLT 46.9% vs. maternal-LLD 31.5% vs. non-maternal-LLD 28.4%, p = 0.001). There was no difference in rejection rates between maternal and non-maternal-LLD recipients. A higher percentage of maternal-LLD recipients were on immunosuppression monotherapy compared to non-maternal-LLD and DDLT recipients (6.7% vs. 1.2 vs. 2.4%, respectively). A subgroup of 68 patients were tested for DSA post-LT. Maternal-LLD recipients were less likely to develop de novo DSA (maternal-LLD 11.8% vs. non-maternal-LLD 19.3% vs. DDLT 43%, p = 0.018). None of the maternal-LLD recipients developed antibody-mediated rejection. CONCLUSIONS: These data support the concept of immunologic benefit of maternal-LLD in pediatric LT, with lower rates of rejection and allosensitization post-LT when compared to DDLT recipients.

Outcomes following liver transplantation in young infants: Data from the SPLIT registry.

Liver transplantation (LT) in young patients is being performed with greater frequency. We hypothesized that objective analysis of pre-, intra-, and postoperative events would help understand contributors to successful outcomes and guide transplant decision processes. We queried SPLIT registry for pediatric transplants between 2011 and 2018. Outcomes were compared for age groups: 0-<3, 3-<6, 6-<12 months, and 1-<3 years (Groups A, B, C, D respectively) and by weight categories: <5, 5-10, >10 kg; 1033 patients were available for analysis. Cholestatic disease and fulminant failure were highest in group A and those <5 kg; and biliary atresia in group C (72.8%). Group A had significantly higher life support dependence (34.6%; P < .001), listing as United Network for Organ Sharing status 1a/1b (70.4%; P < .001), and shortest wait times (P < .001). The median (interquartile range) for international normalized ratio and bilirubin were highest in group A (3.0 [2.1-3.9] and 16.7 [6.8-29.7] mg/dL) and those <5 kg (2.6 [1.8-3.4] and 13.5 [3.0-28.4] mg/dL). A pediatric end -stage liver disease score ≥40, postoperative hospital stays, rejection, and nonanastomotic biliary strictures were highest in group A with lowest survival at 93.1%. Infants 0 to <3 months and those <5 kg need more intensive care with lower survival and higher complications. Importantly, potential LT before reaching status 1a/1b and aggressive postoperative management may positively influence their outcomes.

Mycophenolate Mofetil Hepatotoxicity Associated With Mitochondrial Abnormality in Liver Transplant Recipients and Mice.

OBJECTIVES: Mycophenolate mofetil (MMF) is a widely used immunosuppressive agent. MMF hepatotoxicity has been reported in non-transplant and renal transplant patients with minimal histologic description. This is the first study describing detailed histology and ultrastructure of MMF hepatotoxicity. METHODS: Four liver-transplant recipients (Cases 1-4) were suspected to have MMF hepatotoxicity. Cases 1-3 (two females and one male; 4-17 years) had multiple biopsies for liver function test (LFT) abnormalities. Case 4 (female; 16 years) had a surveillance biopsy. Electron-microscopic examination (EM) was requested on Cases 1-3 for unexplained, persistent LFT elevation and histologic abnormalities despite therapy and Case 4 for unexplained histologic abnormalities despite a stable clinical course. To confirm the pathologic changes in the human allografts, livers from MMF-treated and untreated mice were also reviewed. RESULTS: While the allograft biopsies showed nonspecific histologic changes, EM revealed unequivocal mitochondrial abnormalities similar to those seen in primary and secondary mitochondrial disorders. In Cases 1 and 2, LFTs improved after stopping and reducing MMF, respectively. In Case 3, pre- and post-MMF treatment biopsies were performed and only the post-MMF biopsy demonstrated mitochondrial abnormalities. Mitochondrial abnormality in Case 4 was subclinical. The mouse study confirmed that MMF caused various stress changes in the mitochondria; number of mitochondria/cell (mean ± standard deviation; untreated group: 58.25 ±â€Š8.426; MMF-treated group: 76.37 ±â€Š18.66), number of lipid droplets/cell (untreated: 0.9691 ±â€Š1.150; MMF-treated: 3.649 ±â€Š4.143) and sizes of mitochondria (µm, untreated: 0.8550 ±â€Š0.3409; MMF-treated: 0.9598 ±â€Š0.5312) were significantly increased in hepatocytes in the MMF-treated mice compared with the untreated mice (P < 0.0001). CONCLUSIONS: Although MMF is safe for the majority of patients, MMF can cause mitochondrial stress, which may trigger more severe mitochondrial abnormalities in a small subset. MMF hepatotoxicity should be considered for MMF-treated patients with unexplained, persistent LFT abnormalities and nonspecific histologic findings. EM should be requested for these cases.

Case series and systematic review of acquired diaphragmatic hernia after liver transplantation.

BACKGROUND: ADH is a rare and potentially fatal complication following LT. In this study, a systematic review was completed to identify risk factors which may contribute to ADH. METHODS: Transplant databases at three LT programs were reviewed. Four pediatric and zero adult cases were identified. Next, a systematic review was completed. Fourteen studies describing 41 patients with ADH were identified. Patient demographics, transplant characteristics, and features of ADH diagnosis were examined. RESULTS: The majority (90.2%) of ADH were in children. In pediatric LT, 95.1% received a segmental allograft. ADH occurred in the right P diaphragm 92.7% of the time, and 87.8% were repaired primarily. Patient demographics, post-transplant complications, and immunosuppression regimens were broad and failed to predict ADH. Most patients presented with either respiratory or gastrointestinal symptoms. There were two pediatric deaths related to undiagnosed ADH. The combined worldwide incidence of ADH in pediatric LT is 1.5% (34/2319 patients). CONCLUSION: ADH is a rare complication post-LT that primarily occurs in pediatric recipients. When diagnosed early, ADH can be repaired primarily with good outcomes.

'De novo' and 'recurrent' autoimmune hepatitis after liver transplantation: A comprehensive review.

Autoimmune Hepatitis (AIH) is a chronic progressive inflammatory disease of the liver that responds to immunosuppressive therapy. In patients with AIH who have an acute liver failure presentation or those who develop end stage liver disease despite medical therapy, liver transplantation (LT) may become necessary. Despite good outcomes after LT, AIH can develop/recur in the allograft with an estimated incidence of recurrence between 8 and 12% at 1 year and 36-68% at 5 years. The presence of non-organ specific autoantibodies, elevated serum aminotransferases and immunoglobulin G as well as the characteristic histologic features of interface hepatitis (peri-portal plasma cell infiltration) characterize recurrence of disease. De novo AIH is the development of features of classical AIH in the allograft of patients who have not been transplanted for AIH. There are several reports in the pediatric transplant population, where administering immunosuppressive therapy in the regimen used to treat AIH has stabilized graft function in de novo AIH. In adults, hepatitis C (HCV) is the most common indication for LT and HCV often recurs after LT, requiring treatment with Interferon and Ribavirin. Labeling the graft dysfunction 'de novo AIH' can be problematic in this context, particularly if HCV RNA is positive at that time. Some have chosen to give other names like 'graft dysfunction mimicking AIH' and 'plasma cell hepatitis'. Regardless of the nomenclature, autoimmune liver graft dysfunction, if managed appropriately with the treatment regimen used to treat AIH, can save grafts and patients. The mechanism causing recurrent or de novo AIH after LT remains unknown. Several mechanisms have been implicated in this loss of self-tolerance including impaired thymic regulation, impaired activity of T regulatory cells, molecular mimicry, calcineurin inhibitors, glutathione-s transferase and genetic polymorphisms. While the phenotype of de novo AIH in pediatrics has been uniform, it has been more variable in adults, highlighting the need for uniform diagnostic criteria or scoring system post LT. Better understanding of the development of autoimmunity and its difference from classical rejection after LT will allow better therapeutic strategies and improved outcome.

Complications of gastrojejunal feeding tubes in children.

BACKGROUND: Long-term gastrojejunal (GJ) feeding is an increasingly popular alternative to gastric fundoplication for children with pathologic reflux, particularly those with neurologic impairment. We sought to evaluate morbidity associated with GJ feeding tubes in a large population of children. MATERIALS AND METHODS: The records of all children who underwent placement of a GJ feeding tube in a large children's hospital between January 2005 and September 2013 were reviewed. Indications for GJ feedings were noted. Events including a requirement for tube replacement and intestinal complications attributable to a GJ tube that required a laparotomy were evaluated. Risk factors for morbidity were assessed. RESULTS: A total of 124 children underwent GJ tube placement at an average age of 5.0 y (2 mo-16 y). Of the total, 83 (66%) subjects were neurologically impaired and 108 (87%) had gastroesophageal reflux. Of those, 55 (44%) had undergone prior laparoscopic fundoplication. Persistent reflux symptoms occurred in 22 (17.6%). Subjects underwent an average of 2.75 tube replacements per year and those under 2 y old had almost four. Four children (3.2%) required emergent laparotomy for intestinal perforation due to a GJ tube. These subjects were significantly younger (12 mo) than those without perforations (60.6 mo, P < 0.005). CONCLUSIONS: GJ feeding tubes were associated with notable morbidity ranging from persistent reflux to dislodgement and intestinal perforation. Together with issues of inconvenience with continuous feedings, these complications should be taken into account in children and particularly infants, in whom GJ feedings are being considered as an alternative to fundoplication.

Hepatopulmonary syndrome associated with nodular regenerative hyperplasia after liver transplantation in a child.

HPS is a significant complication of portal hypertension in children with chronic liver disease and is an established indication for LT. It is characterized clinically by the triad of pulmonary vascular dilatation causing hypoxemia in the setting of advanced liver disease. NRH, a cause of non-cirrhotic portal hypertension, is characterized by diffuse benign transformation of the hepatic parenchyma into small regenerative nodules with minimal or no fibrosis. Development of NRH and HPS in pediatric LT recipients has not been reported, although occasional cases have been reported in adult LT recipients. In this report, we discuss a case of a three-yr-old male who developed HPS, two yr after LT. Pulmonary and cardiac causes for hypoxemia were ruled out by appropriate investigations including a chest X ray, echocardiogram, cardiac catheterization, and a CT angiographic study. The diagnosis of HPS was confirmed via bubble echocardiogram that demonstrated intrapulmonary shunting. Open liver biopsy revealed marked NRH. The patient underwent liver retransplantation that resulted in complete reversal of his pulmonary symptoms and normal oxygen saturations within three months after LT.

A Case of Pediatric Alcohol-Associated Hepatitis Evaluated for Liver Transplant Listing.

Alcohol-associated hepatitis (AH) refers to liver injury from alcoholic intake that usually occurs after years of heavy alcohol abuse. Frequent, heavy alcohol consumption causes hepatic inflammation, fibrosis, and cirrhosis. Some patients develop severe AH, which carries high short-term mortality and is the second most common reason for adult liver transplants (LTs) worldwide. We present one of the first cases of a teenager diagnosed with severe AH that led to LT evaluation. Our patient was a 15-year-old male who presented with epistaxis and 1 month of jaundice after 3 years of heavy daily alcohol abuse. In collaboration with our adult transplant hepatologist colleagues, we initiated a management plan that consisted of treating acute alcohol withdrawal, steroid utilization, mental health support, and LT evaluation.

Non-invasive biomarkers of Fontan-associated liver disease.

BACKGROUND & AIMS: Fontan-associated liver disease (FALD) has emerged as an important morbidity following surgical palliation of single ventricle congenital heart disease. In this study, non-invasive biomarkers that may be associated with severity of FALD were explored. METHODS: A retrospective cohort of paediatric patients post-Fontan who underwent liver biopsy at a high volume at a paediatric congenital heart disease centre was reviewed. RESULTS: Among 106 patients, 66% were male and 69% were Hispanic. The mean age was 14.4 ± 3.5 years, and biopsy was performed 10.8 ± 3.6 years post-Fontan. The mean BMI was 20.8 ± 5 kg/m2, with 27.4% meeting obesity criteria. Bridging fibrosis was observed in 35% of patients, and 10.4% of all patients had superimposed steatosis. Bridging fibrosis was associated with lower platelet counts (168.3 ± 58.4 vs. 203.9 ± 65.8 K/µl for congestive hepatic fibrosis score [CHFS] 0-2b, p = 0.009), higher bilirubin (1.7 ± 2.2 vs. 0.9 ± 0.7 mg/dl, p = 0.0090), higher aspartate aminotransferase-to-platelet ratio index [APRI] and fibrosis-4 [FIB-4] scores (APRI: 0.5 ± 0.3 vs. 0.4 ± 0.1, p <0.01 [AUC: 0.69] and FIB-4: 0.6 ± 0.4 vs. 0.4 ± 0.2, p <0.01 [AUC: 0.69]), and worse overall survival (median 2 years follow-up post-biopsy, p = 0.027). Regression modelling of temporal changes in platelet counts before and after biopsy correlated with fibrosis severity (p = 0.005). CONCLUSIONS: In this large, relatively homogeneous adolescent population in terms of age, ethnicity, and Fontan duration, bridging fibrosis was observed in 35% of patients within the first decade post-Fontan. Bridging fibrosis was associated with worse survival. Changes in platelet counts, even years before biopsy, and APRI/FIB-4 scores had modest discriminatory power in identifying patients with advanced fibrosis. Steatosis may represent an additional risk factor for disease progression in obese patients. Further prospective studies are necessary to develop strategies to screen for FALD in the adolescent population. LAY SUMMARY: In this study, the prevalence of Fontan-associated liver disease (FALD) in the young adult population and clinical variables that may be predictive of fibrosis severity or adverse outcomes were explored. Several lab-based, non-invasive markers of bridging fibrosis in FALD were identified, suggesting that these values may be followed as a prognostic biomarker for FALD progression in the adolescent population.

Frequency and methods of gastrojejunal tube replacement in children.

Gastrojejunal (GJ) tubes are increasingly used for enteral feeding in children in whom gastric feeding either is not tolerated or is contraindicated. The most common complications associated with GJ tube use are mechanical failure (clogging, cracking, deterioration) and dislodgement. Less common, but more significant, complications are bowel perforation, aspiration, and feeding intolerance. Some of these complications may be prevented by replacing GJ tubes at regular intervals. Methods to direct a GJ tube include 1) guidewire, 2) gastroduodenoscopy-guidewire, 3) esophagogastroduodenoscopy-forceps, and 4) fluoroscopy-guidewire. Clinical experience to determine the ideal method and optimal timing of GJ tube replacement is evolving. GJ tube replacement using a guidewire through the prior GJ tube, without endoscopy, fluoroscopy, or sedation, is the least risky method, but is also the least likely to be successful.

Severe Late-Onset Acute Cellular Rejection in a Pediatric Patient With Isolated Small Intestinal Transplant Rescued With Aggressive Immunosuppressive Approach: A Case Report.

Small intestinal transplantation is performed for patients with intestinal failure who failed other surgical and medical treatment. It carries notable risks, including, but not limited to, acute and chronic cellular rejection and graft malfunction. Late severe acute intestinal allograft rejection is associated with increased risk of morbidity and mortality and, in the majority of cases, ends with total enterectomy. It usually results from subtherapeutic immunosuppression or nonadherence to medical treatment. We present the case of a 20-year-old patient who underwent isolated small bowel transplant for total intestinal Hirschsprung disease at age 7. Due to medication nonadherence, she developed severe late-onset acute cellular rejection manifested by high, bloody ostomy output and weight loss. Ileoscopy showed complete loss of normal intestinal anatomic landmarks and ulcerated mucosa. Graft biopsies showed ulceration and granulation tissue with severe architectural distortion consistent with severe intestinal graft rejection. She initially received intravenous corticosteroids and increased tacrolimus dose without significant improvement. Her immunosuppression was escalated to include infliximab and finally antithymocyte globulin. Graft enterectomy was considered repeatedly; however, clinical improvement was noted eventually with evidence of histologic improvement and salvage of the graft. The aggressive antirejection treatment was complicated by development of post-transplant lymphoproliferative disorder that resolved with reducing immunosuppression. Her graft function is currently maintained on tacrolimus, oral prednisone, and a periodic infliximab infusion. We conclude that a prompt and aggressive immunosuppressive approach significantly increases the chance of rescuing small bowel transplant rejection.

Undifferentiated embryonal sarcoma of the liver successfully treated with chemotherapy and liver resection.

Undifferentiated embryonal sarcoma is the third most common malignant tumor of the liver in children, accounting for 13% of hepatic malignancies in this age group. It has been considered an aggressive neoplasm with very poor prognosis until the late 1980s, when long-term survivors were reported after multiagent chemotherapy followed by resection. We, herein, report two pediatric cases of undifferentiated embryonal sarcoma treated successfully with surgical resection after neoadjuvant chemotherapy based on therapy used in childhood soft tissue sarcomas and in childhood hepatic malignancies. The first patient also had a concurrent cerebellar tumor (pilocytic astrocytoma), for which he first underwent craniotomy and resection, delaying the liver tumor resection by 10 weeks. They are alive and tumor free at 48 months (case no. 1) and 18 months (case no. 2) following neoadjuvant chemotherapy and liver resection.