Monitoring Practices After Pediatric Liver Transplantation.

OBJECTIVES: This study sought to understand the current monitoring practices after pediatric liver transplantation (LT), specifically regarding follow-up clinic visits, outpatient laboratory testing, protocol biopsies, and diagnostic imaging, and to identify potential center and provider characteristics associated with such practices. METHODS: A cross-sectional survey of pediatric LT providers at centers participating in the Society of Pediatric Liver Transplantation (SPLIT) registry was conducted from February 2020 to April 2021. RESULTS: The overall response rate was 79% (38/48 SPLIT centers), with the majority representing large volume centers (>10 LTs per year). Frequency of clinic visits and laboratory monitoring varied by center, but all centers decreased frequency after the first post-transplant year. The most common practice included an annual clinic visit and laboratory sampling every 2-3 months. Surveillance liver biopsy is seldom done during the first post-transplant year, while being routinely performed by 50% of centers after this time period. Centers forgoing surveillance biopsies assert that the results would likely not change management. Only 39% of centers have a hepatologist perform the liver biopsy while the remaining centers consult interventional radiology. Most diagnostic imaging is obtained only as needed. Routine abdominal ultrasounds were obtained by only 50% of responding centers after the first year post-transplant. CONCLUSIONS: SPLIT centers vary widely in the routine management of LTs after the first year post-transplant. While common themes emerge, future studies will be needed to connect protocols to outcomes to determine best practice.

Variation in immunosuppression practices among pediatric liver transplant centers-Society of Pediatric Liver Transplantation survey results.

BACKGROUND: Variation in IS exists among pediatric liver transplant centers. While individual centers may publish their practice paradigms, current data on practices as a whole are lacking. This study sought to ascertain the IS protocols of pediatric liver transplant centers within the SPLIT to better understand variability and similarities among peer institutions. METHODS: A 27-item questionnaire was developed within the SPLIT Quality Improvement and Clinical Care Committee. The survey collected data regarding center demographics, IS practices, and treatment of acute cellular rejection. RESULTS: Twenty-eight (64%) SPLIT centers responded with 22 (79%) centers performing more than 10 transplants per year and 17 (61%) following more than 100 post-transplant recipients. All centers use a written protocol, and 25 (89%) have a dedicated transplant pharmacist/PharmD. Twenty-five (89%) centers use steroids for induction alone or in combination with thymoglobulin/interleukin-2 antibodies. All centers use tacrolimus for initial maintenance therapy. Most centers have specialized protocols for ABO-incompatible transplants, recipients with renal dysfunction, autoimmune liver diseases, and liver tumors. Treatment of rejection varied but was associated with escalation in IS. CONCLUSION: IS practices among pediatric liver transplant centers are similar including the use of written protocols, pharmacy involvement, steroids for induction, tacrolimus as initial IS, tacrolimus reduction/delay for renal dysfunction, and escalation of IS with rejection severity. However, other IS practices show wide variability including treatment for ABO-incompatible grafts and presumed rejection. This study serves as a foundation to guide prospective research linking IS practice to outcomes to determine best practice.

Severe Acute Respiratory Syndrome Coronavirus-2 Infection in Children With Liver Transplant and Native Liver Disease: An International Observational Registry Study.

OBJECTIVE: Increased mortality risk because of severe acute respiratory syndrome coronavirus-2 (SARS-CoV2) infection in adults with native liver disease (LD) and liver transplant (LT) is associated with advanced age and comorbid conditions. We aim to report outcomes for children with LD and LT enrolled in the NASPGHAN/SPLIT SARS-CoV2 registry. METHODS: In this multicenter observational cohort study, we collected data from 91 patients <21 years (LD 44, LT 47) with laboratory-confirmed SARS-CoV2 infection between April 21 and September 17, 2020. RESULTS: Patients with LD were more likely to require admission (70% vs 43% LT, P = 0.007) and pediatric intensive care unit (PICU) management (32% vs 4% LT, P = 0.001). Seven LD patients required mechanical ventilation (MV) and 2 patients died; no patients in the LT cohort died or required MV. Four LD patients presented in pediatric acute liver failure (PALF), 2 with concurrent multisystem inflammatory syndrome in children (MIS-C); all recovered without LT. Two LD patients had MIS-C alone and 1 patient died. Bivariable logistic-regression analysis found that patients with nonalcoholic fatty LD (NAFLD) (odds ratio [OR] 5.6, P = 0.02) and LD (OR 6.1, P = 0.01, vs LT) had higher odds of severe disease (PICU, vasopressor support, MV, renal replacement therapy or death). CONCLUSIONS: Although not directly comparable, LT recipients had lower odds of severe SARS-CoV2 infection (vs LD), despite immunosuppression burden. NAFLD patients reported to the registry had higher odds of severe SARS-CoV2 disease. Future controlled studies are needed to evaluate effective treatments and further stratify LD and LT patients with SARS-CoV2 infection.

Complications of Cryptosporidium infection after pediatric liver transplantation: Diarrhea, rejection, and biliary disease.

BACKGROUND: Cryptosporidium enteritis can be devastating in the immunocompromised host. In pediatric liver transplant recipients, infection may be complicated by prolonged carriage of the parasite, rejection, and biliary tree damage and fibrosis. Herein, we report on six patients and their long-term outcomes following cryptosporidiosis. METHODS: We reviewed all cases of cryptosporidiosis in a pediatric liver transplant population over a 17-year period at a single center. Six patients with infection were identified, and their outcomes were analyzed. RESULTS: Infection was associated with significant diarrhea and dehydration in all cases, and led to hospitalization in one-half of patients. Four of the six patients developed biopsy-proven rejection following infection, with three of those patients developing rejection that was recalcitrant to intravenous steroid treatment. Additionally, three patients developed biliary tree abnormalities with similarity to sclerosing cholangitis. In one patient, those biliary changes led to repeated need for biliary drain placement and advancing fibrotic liver allograft changes. CONCLUSIONS: Cryptosporidiosis in pediatric liver transplant recipients may lead to significant complications, including recalcitrant episodes of rejection and detrimental biliary tree changes. We advocate for increased awareness of this cause of diarrheal disease and the allograft injuries that may accompany infection.

Hepatopulmonary Syndrome in an Adolescent With Insidious Hypoxia and Small Intrahepatic Portal Venous Shunts: Posttransplant Benefit From Sildenafil.

We report a patient without known preexisting liver disease who presented with hepatopulmonary syndrome (HPS) due to aberrant intrahepatic portal venous development leading to portosystemic shunting. Liver transplantation resulted in resolution of portal hypertension and HPS and sildenafil was safely tolerated in the treatment of persistent fatigue and hypoxemia. Twelve months later, patient has normal allograft function and has returned to normal activity.

Pressure gradients, laboratory changes, and outcomes with transjugular intrahepatic portosystemic shunts in pediatric portal hypertension.

INTRODUCTION: Indications for TIPS are well described in adults and involve complications of PHTN. Complications from PHTN are associated with PSG of > 12 mm Hg in adults. It is unclear if these parameters apply to children with PHTN. OBJECTIVE: To assess whether adult criteria for TIPS placement can be utilized in children, describe laboratory changes over time, and report outcomes. METHODS: We performed a retrospective review of 34 pediatric patients who underwent TIPS, examining indications, radiology, PSG reductions, laboratory changes, and outcomes. RESULTS: Most patients had PHTN due to parenchymal liver disease including congenital hepatic fibrosis (n = 5), biliary atresia (n = 5), cystic fibrosis-related liver disease (n = 3) and cavernous transformation of the portal vein (n = 6). Indications for TIPS included variceal bleeding, recurrent ascites, and maintenance of portal vein flow following thrombolysis. Variceal bleeding was observed in six children with PSG < 12 mm Hg. Minor complications occurred in eight subjects. Continued bleeding occurred in one patient. Six patients were successfully bridged to transplantation, and three patients died secondary to end-stage disease. Standard laboratory tests stabilized after TIPS placement and hematocrit increased. CONCLUSION: TIPS placement in pediatric patients was performed for complications of PHTN. Unlike adult series, a substantial proportion of our cases treated extrahepatic PHTN from cavernous transformation of the portal vein. Children presented with sequelae of PHTN with PSG below 12 mm Hg, below the adult standard. We found TIPS in pediatrics to be safe and effective with laboratory stabilization and improvement in hematocrit.

Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations.

Germline loss-of-function mutations in the transcription factor signal transducer and activator of transcription 3 (STAT3) cause immunodeficiency, whereas somatic gain-of-function mutations in STAT3 are associated with large granular lymphocytic leukemic, myelodysplastic syndrome, and aplastic anemia. Recently, germline mutations in STAT3 have also been associated with autoimmune disease. Here, we report on 13 individuals from 10 families with lymphoproliferation and early-onset solid-organ autoimmunity associated with 9 different germline heterozygous mutations in STAT3. Patients exhibited a variety of clinical features, with most having lymphadenopathy, autoimmune cytopenias, multiorgan autoimmunity (lung, gastrointestinal, hepatic, and/or endocrine dysfunction), infections, and short stature. Functional analyses demonstrate that these mutations confer a gain-of-function in STAT3 leading to secondary defects in STAT5 and STAT1 phosphorylation and the regulatory T-cell compartment. Treatment targeting a cytokine pathway that signals through STAT3 led to clinical improvement in 1 patient, suggesting a potential therapeutic option for such patients. These results suggest that there is a broad range of autoimmunity caused by germline STAT3 gain-of-function mutations, and that hematologic autoimmunity is a major component of this newly described disorder. Some patients for this study were enrolled in a trial registered at www.clinicaltrials.gov as #NCT00001350.

Desmoid tumors complicating Familial Adenomatous Polyposis: a meta-analysis mutation spectrum of affected individuals.

BACKGROUND: Desmoid tumors are a group of benign, invasive, solid tumors that are relatively rare in the general population, but can occur in up to 21 % of patients with Familial Adenomatous Polyposis (FAP). They can be difficult to treat and have high rates of recurrence even after resection. Our goal with this study was to identify the genetic mutations that put certain patients with FAP at high risk for desmoid tumors and could be future targets for research. METHODS: We performed a search in Pubmed, Ovid Medline and Embase to identify subjects with desmoid tumors and FAP. As a reference group for APC mutations in the unselected FAP population, we used the UMD-APC database referenced in the Orphanet portal which includes APC mutation data on 2040 individuals with FAP. RESULTS: Mutations were able to be broken down into 7 regions based on previously published data. Mutations in the APC gene from codons 1310 to 2011 were the most common region encompassing 48 % of published desmoid cases and 40 % of the reference population. It had a slightly elevated odds ratio of 1.4 that was statistically significant along with codon region 543-713 that had an odds ratio of 2.0. Using a combination of p-value and CI, the remaining 5 regions did not meet statistical significance as either the p >0.05 or the CI included 1.0. The most common point mutation found was codon 1309 (13.1 %), but it was also the most commonly found mutation in our reference population (12.9 %) and had an odds ratio of 1.0. CONCLUSIONS: There is an increased risk for desmoid tumors in individuals with APC mutations between codons 543-713 and 1310-2011 when compared to a reference population. These patients may benefit from further study to develop surveillance protocols that could improve outcomes.

14-month-old female with anti-MDA5 juvenile dermatomyositis complicated by liver disease: a case report.

BACKGROUND: Juvenile Dermatomyositis (JDM) is a rare disorder with subtypes associated with different myositis-specific antibodies (MSAs) including anti-MDA5. Hepatic involvement in JDM is rare and has not previously been documented in anti-MDA5 JDM. There is a lack of formal research on treatment protocols for anti-MDA5 JDM, though tofacitinib is a highly regarded emerging therapy. CASE PRESENTATION: A previously healthy 14-month-old Hispanic female presented to a pediatric rheumatology clinic with eight months of worsening rash, weakness, periorbital edema, intermittent fevers, and weight loss. Her physical exam was notable for fever, thinning of hair, heliotrope rash, periorbital edema, violaceous macules on her bilateral elbows, forearms, arms, and knees, arthritis, Gottron's sign, and hepatomegaly. The patient was admitted, and symptoms progressed to include hypoxemia. Subsequent workup was notable for ground glass opacities of bilateral lung fields on chest CT, myositis visualized on MRI and confirmed with muscle biopsy, and liver biopsy showing nonspecific signs of liver injury. After a thorough infectious disease workup to rule out concomitant infection, the patient was started on high-dose steroids and induction with cyclophosphamide. She responded well with disease remission maintained with tofacitinib in the outpatient setting. DISCUSSION AND CONCLUSIONS: Our patient is notable due to her young age at presentation, histopathologically confirmed liver injury, and response to treatment. The case adds to the growing body of literature supporting tofacitinib for anti-MDA5 JDM in the pediatric population. Future research can better standardize effective treatment protocols and define the mechanism of liver involvement. For patients with nonspecific liver injury, muscular, and cutaneous disease, anti-MDA5 JDM should be considered in the differential diagnosis with treatment options including tofacitinib for confirmed cases.

Thyroid cancer complicating familial adenomatous polyposis: mutation spectrum of at-risk individuals.

BACKGROUND: Lifetime risk of thyroid cancer associated with FAP has been reported as 1-2%. The mean age at diagnosis of thyroid carcinoma in FAP has been reported at 28 years. The aims of this paper are to better understand gene mutations associated with thyroid cancer and refine surveillance recommendations for patients with FAP. METHODS: We performed a search in Pubmed, Ovid Medline and Embase with the terms ("Thyroid Gland"[Mesh] OR "Thyroid Neoplasms"[Mesh]) AND "Adenomatous Polyposis Coli"[Meshdenomatous Polyposis Coli"[Mesh] to identify subjects with thyroid cancer and FAP. As a reference group for APC mutations in the unselected FAP population, we used the UMD-APC database referenced in the Orphanet portal, which includes APC mutation data on 2040 individuals with FAP. RESULTS: There were 115 reported cases of thyroid cancer in patients with FAP (95 female: 11 male) with an average age of 29.2 years. Gene mutation testing results were reported in 48 patients. On comparing the prevalence of APC mutation in the population of FAP patients with thyroid cancer and the prevalence of the same mutation in the reference population an increased odds ratio was evident in individuals harboring an APC mutation at codon 1061 (OR: CI 4.1: 1.7-8.9). Analysis of the prevalence of thyroid cancer in individuals with FAP segregated by the region of the gene affected shows an increased risk of thyroid cancer in individuals harboring mutations proximal to codon 512 (OR 2.6, p 0.0099). CONCLUSIONS: There is increased risk for thyroid cancer in individuals with APC mutations at the 5' end (proximal to codon 528) along with the established high risk group harboring mutation at codon 1061. It is suggested that these patients might benefit from directed surveillance by annual ultrasound from age 18 years onwards.

Leukocyte cell-derived chemotaxin 2 correlates with pediatric non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD), newly renamed metabolic dysfunction-associated liver disease (MASLD), is a leading cause of liver disease in children and adults. There is a paucity of data surrounding potential biomarkers and therapeutic targets, especially in pediatric NAFLD. Leukocyte cell-derived chemotaxin 2 (LECT2) is a chemokine associated with both liver disease and skeletal muscle insulin resistance. Our aim was to determine associations between LECT2 and common clinical findings of NAFLD in pediatric patients. Enzyme-linked immunosorbent assay (ELISA) was used to measure serum LECT2 concentrations in children (aged 2-17 years) with and without NAFLD. LECT2 concentrations were then correlated to clinical parameters in NAFLD. Mean LECT2 was significantly elevated in children with NAFLD versus healthy controls (n = 63 vs. 42, 5.83 ± 1.98 vs. 4.02 ± 2.02 ng/mL, p < 0.005). Additionally, LECT2 had strong correlations with body mass index (BMI) (Pearson r = 0.301, p = 0.002). A LECT2 concentration of 3.76 mg/mL predicts NAFLD with a sensitivity of 90.5% and specificity of 54.8%. Principal component analysis and logistic regression models further confirmed associations between LECT2 and NAFLD status. This study demonstrates increased serum LECT2 concentrations in pediatric NAFLD, which correlates with BMI and shows strong predictive value within these patients. Our data indicate that LECT2 is a potential diagnostic biomarker of disease and should be further investigated in pediatric as well as adult NAFLD.

Use and safety of prophylactic endoscopy from a single center serving urban and rural children with portal hypertension.

Prophylactic endoscopy is routine in adults with portal hypertension (PHTN), but there is limited data in pediatrics. We sought to describe our experience with prophylactic endoscopy in pediatric PHTN. This is a retrospective study of 87 children who began surveillance endoscopy prior to gastrointestinal bleeding (primary prophylaxis) and 52 who began after an episode of bleeding (secondary prophylaxis) from 01/01/1994 to 07/01/2019. Patients who underwent primary prophylaxis had a lower mean number of endoscopies (3.897 vs 6.269, p = 0.001). The primary prophylaxis group was less likely to require a portosystemic shunt (6% vs 15%, p < 0.001) with no difference in immediate complications (1% vs 2%, p = 0.173) or 2-week complications (1% vs 2%, p = 0.097). No deaths were related to variceal bleeding or endoscopy. Kaplan-Meier Survival Curve suggests improved transplant and shunt free survival in the primary prophylaxis group (log-rank p < 0.001). Primary and secondary endoscopic prophylaxis should be considered safe for the prevention of variceal hemorrhage in pediatric portal hypertension. There are differences in outcomes in primary and secondary prophylaxis, but unclear if this is due to patient characteristics versus treatment strategy. Further study is needed to compare safety and efficacy to watchful waiting.

The effect of neuropsychiatric medication on pediatric nonalcoholic fatty liver disease.

Obese and overweight children are at risk of developing nonalcoholic fatty liver disease (NAFLD), which can lead to steatohepatitis, cirrhosis, and liver transplantation. Neuropsychiatric conditions affect an increasing proportion of children and often require neuropsychiatric medications (NPMs) that are associated with weight gain and/or drug-induced liver injury. We sought to evaluate the role that the extended use of NPMs play in pediatric NAFLD. Medical chart review was conducted for 260 patients with NAFLD (NPM = 77, non-NPM = 183) seen in the Liver Care Center at Children's Mercy Hospital between 2000 and 2016. Outcome measures included body mass index (BMI) percentile, BMI z-score, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, and gamma glutamyltransferase, and were collected at diagnosis, 6-18 month follow-up, and 18-36 months. Controlling for race and metformin, there was a significant increase over time in BMI z-score (p < 0.01) and total bilirubin (p = 0.03), with only initial decreases in ALT (p < 0.01) and AST (p < 0.01). Except for higher total bilirubin in the non-NPM group, no main effect of group or interaction effect was found. Similar patterns remained when subjects were analyzed by NPM drug class. Further study is needed to confirm these findings and to evaluate the effects of NPM dose and duration of exposure, by drug class, on pediatric NAFLD outcomes.

Readiness to Change and Prospective Effects of Weight Management Programs in Pediatric Nonalcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is an increasing problem in pediatrics with limited treatment options. We prospectively assessed outcomes in patients managed in a hepatology clinic (HC) alone vs. those managed in combination with a multidisciplinary weight management program (MWMP). We describe each group's readiness to change at the time of NAFLD diagnosis. Patients diagnosed with NAFLD were given a modified Stages of Change Readiness and Treatment Eagerness Scale (SOCRATES) at enrollment (T1) to assess readiness to change. They were then followed at 3-9 months (T2) and at 10-15 months (T3). Linear mixed models were used to evaluate changes in body mass index (BMI), BMI z-score, and transaminases over time and between the two groups. There were no significant treatment group main effects or treatment × time interactions for our primary end points for HC alone (n = 75) or with MWMP (n = 18). There was a significant main effect for time for BMI z-score, with BMI z-scores declining on average by 0.0568 (P = 0.004) from visit to visit. Low SOCRATES subscales scores in HC alone (n = 33) or with MWMP (n = 4) suggested a patient population with low recognition of disease and likelihood of taking steps for change. Patients with obesity and NAFLD had low scores on all three SOCRATES subscales. Despite this, both groups had improvement in BMI z-score without significant difference between the two treatment groups in other primary end points. Further study is needed to identify the most effective patient selection and treatment strategies for pediatric patients with NAFLD, including pharmacotherapy and surgery.

Variants in STXBP3 are Associated with Very Early Onset Inflammatory Bowel Disease, Bilateral Sensorineural Hearing Loss and Immune Dysregulation.

BACKGROUND AND AIMS: Very early onset inflammatory bowel disease [VEOIBD] is characterized by intestinal inflammation affecting infants and children less than 6 years of age. To date, over 60 monogenic aetiologies of VEOIBD have been identified, many characterized by highly penetrant recessive or dominant variants in underlying immune and/or epithelial pathways. We sought to identify the genetic cause of VEOIBD in a subset of patients with a unique clinical presentation. METHODS: Whole exome sequencing was performed on five families with ten patients who presented with a similar constellation of symptoms including medically refractory infantile-onset IBD, bilateral sensorineural hearing loss and, in the majority, recurrent infections. Genetic aetiologies of VEOIBD were assessed and Sanger sequencing was performed to confirm novel genetic findings. Western analysis on peripheral blood mononuclear cells and functional studies with epithelial cell lines were employed. RESULTS: In each of the ten patients, we identified damaging heterozygous or biallelic variants in the Syntaxin-Binding Protein 3 gene [STXBP3], a protein known to regulate intracellular vesicular trafficking in the syntaxin-binding protein family of molecules, but not associated to date with either VEOIBD or sensorineural hearing loss. These mutations interfere with either intron splicing or protein stability and lead to reduced STXBP3 protein expression. Knock-down of STXBP3 in CaCo2 cells resulted in defects in cell polarity. CONCLUSION: Overall, we describe a novel genetic syndrome and identify a critical role for STXBP3 in VEOIBD, sensorineural hearing loss and immune dysregulation.

Leukocyte cell derived chemotaxin-2 (Lect2) as a predictor of survival in adult acute liver failure.

BACKGROUND: One of the major issues in the field of acute liver failure (ALF) is the lack of reliable biomarkers that predict outcome. Many cases present with very limited treatment options and prognostic indicators are invaluable. We tested whether leukocyte cell derived chemotaxin 2 can be used as a prognostic biomarker to predict patient survival either alone or in combination with other routine clinical parameters. METHODS: Serum samples and associated clinical data from came from two independent sources, the Acute Liver Failure Study Group (ALFSG) registry and the University of Kansas Medical Center. We analyzed a total of 61 cases, each with individual time points collected over a period of 0 to 7 days after hospital admission. Analysis was developed to compare responses in survivors vs. non-survivors. RESULTS: The data indicate that survivors had significantly lower serum levels of leukocyte cell derived chemotaxin 2 compared to non-survivors (P=0.03). Further, it was able to predict patient survival when taken together with either international normalized ratio (INR) alone (71% concordance) or INR and bilirubin (76% concordance) or INR and serum albumin (77% concordance). Furthermore, when we analyzed data for each day, serum Lect2 and INR taken together were able to predict survival at day three after hospital admission with 86.3% concordance. CONCLUSIONS: These studies have revealed test batteries consisting of easily available serum tests that are concordant with survival status of ALF patients early during the clinical course.