Ten-year follow-up of cavoportal hemitransposition in pediatric liver transplantation for complete portomesenteric venous thrombosis: A case report and literature review.

BACKGROUND: Portal vein thrombosis is a potentially devastating complication following pediatric liver transplantation. In rare instances of complete portomesenteric thrombosis, cavoportal hemitransposition may provide graft inflow. Here we describe long-term results following a case of pediatric cavoportal hemitransposition during liver transplantation and review the current pediatric literature. METHODS: A 9-month-old female with a history of biliary atresia and failed Kasai portoenterostomy underwent living donor liver transplantation, which was complicated by portomesenteric venous thrombosis. The patient underwent retransplantation with cavoportal hemitransposition on postoperative day 12. OUTCOME: The patient recovered without further complication, and 10 years later, she continues to do well, with normal graft function and no clinical sequelae of portal hypertension. CT scan with 3-D vascular reconstruction demonstrated recanalization of the splanchnic system, with systemic drainage to the inferior vena cava via an inferior mesenteric vein shunt. The cavoportal anastomosis remains patent with hepatopetal flow. Of the 12 previously reported cases of pediatric cavoportal hemitransposition as portal inflow in liver transplantation, this is the longest-known follow-up with a viable allograft. Notably, sequelae of portal hypertension were also rare in the 12 previously reported cases, with no cases of long-term renal dysfunction, lower extremity edema, or ascites. CONCLUSIONS: Long-term survival beyond 10 years with normal graft function is feasible following pediatric cavoportal hemitransposition. Complications related to portal hypertension were generally short-lived, likely due to the development of robust collateral circulation. Additional reports of long-term outcomes are necessary to facilitate informed decision making when considering pediatric cavoportal hemitransposition for liver graft inflow.

Overview of Physical, Neurocognitive, and Psychosocial Outcomes in Pediatric Intestinal Failure and Transplantation.

PURPOSE OF REVIEW: Intestinal failure and transplantation may significantly impact physical, neurocognitive, and psychosocial development in pediatric patients. Currently, there is a paucity of literature on the effects of intestinal failure and transplantation on these aspects of development. This article will review the current literature and discuss the short and long-term impacts as well as interventions to improve clinical outcomes in children with intestinal failure or those undergoing transplantation. RECENT FINDINGS: Psychological disorders, neurodevelopmental delay, and social maladaptation are frequently encountered in this patient population. While the main focus is often on medical management, equal emphasis should be placed on other aspects of development such as increasing social support and improving school performance. The transition to adulthood also presents many obstacles for patients and healthcare providers should anticipate challenges such as childbirth, employment, and raising a family. The pre-operative, perioperative, and post-operative periods all represent opportunities for medical intervention. Frequent monitoring of physical, psychosocial, and neurocognitive status helps to improve clinical outcomes and long-term quality of life. Future research should emphasize continued development of multidisciplinary programs and specialized services to help address the physical and psychosocial needs of children with intestinal failure as well as transplant recipients.

Homozygosity for a mutation affecting the catalytic domain of tyrosyl-tRNA synthetase (YARS) causes multisystem disease.

Aminoacyl-tRNA synthetases (ARSs) are critical for protein translation. Pathogenic variants of ARSs have been previously associated with peripheral neuropathy and multisystem disease in heterozygotes and homozygotes, respectively. We report seven related children homozygous for a novel mutation in tyrosyl-tRNA synthetase (YARS, c.499C > A, p.Pro167Thr) identified by whole exome sequencing. This variant lies within a highly conserved interface required for protein homodimerization, an essential step in YARS catalytic function. Affected children expressed a more severe phenotype than previously reported, including poor growth, developmental delay, brain dysmyelination, sensorineural hearing loss, nystagmus, progressive cholestatic liver disease, pancreatic insufficiency, hypoglycemia, anemia, intermittent proteinuria, recurrent bloodstream infections and chronic pulmonary disease. Related adults heterozygous for YARS p.Pro167Thr showed no evidence of peripheral neuropathy on electromyography, in contrast to previous reports for other YARS variants. Analysis of YARS p.Pro167Thr in yeast complementation assays revealed a loss-of-function, hypomorphic allele that significantly impaired growth. Recombinant YARS p.Pro167Thr demonstrated normal subcellular localization, but greatly diminished ability to homodimerize in human embryonic kidney cells. This work adds to a rapidly growing body of research emphasizing the importance of ARSs in multisystem disease and significantly expands the allelic and clinical heterogeneity of YARS-associated human disease. A deeper understanding of the role of YARS in human disease may inspire innovative therapies and improve care of affected patients.

Restriction of congenital portosystemic shunt using the modified microvascular plug.

Congenital portosystemic shunts (CPSS) may produce a variety of severe, clinically detrimental presentations. When indicated, closure is recommended; however, if the intrahepatic portal venous system (IPVS) is underdeveloped complete closure may not be possible and may result in severe acute portal hypertension. Staged restriction of CPSS flow by both surgical and complex transcatheter interventions has been successful in augmenting development of the IPVS such that complete occlusion of the CPSS can be performed. We report use of a modified microvascular plug to restrict CPSS flow with subsequent IPVS development and safe complete occlusion of CPSS.

Rare genetic mutation triggering acute liver failure in a toddler requiring a liver transplant.

APS-1 is an extremely rare, autosomal recessive condition that often presents with candidiasis, adrenal insufficiency, and hypoparathyroidism. This condition is associated with autoimmune hepatitis in less than 20% of cases, and there have only been a few reports of children with the condition who developed ALF. We present a unique case of an infant with APS-1 who developed ALF and subsequently required liver transplantation.

Overview of Albumin Physiology and its Role in Pediatric Diseases.

PURPOSE OF REVIEW: Albumin plays a critical role in a wide range of disease processes; however, the role of albumin in pediatric patients has not been well described. This article aims to review albumin physiology and kinetics in children, albumin's impact on pediatric diseases, and the utility of albumin as a predictor of clinical outcome. RECENT FINDINGS: Hypoalbuminemia is seen in a wide range of conditions, including protein-losing enteropathy, hepatic synthetic failure, malnutrition, inflammatory states, and renal disease. While the impact of hypoalbuminemia has been more extensively studied in adult patients, there is a relative paucity of literature in the pediatric population. Hypoalbuminemia is a marker of poor outcome in critically ill children and those undergoing a wide range of medical interventions. Albumin infusions may be an effective therapy for fluid resuscitation and for patients with severe hypoalbuminemia.

Heterozygous CTLA4 splice site mutation c.458-1G > C presenting with immunodeficiency and variable degree of immune dysregulation in three generation kindred of Caribbean descent.

Cytotoxic T-lymphocyte-associated protein 4 (CTLA4) is an immune checkpoint, which downregulates T cell activation and T regulatory cell function. CTLA4 haploinsufficiency (CTLA4 HI) leads to T cell hyperactivation, immunodeficiency and variable degree of immune dysregulation. Furthermore, CTLA4 HI predisposes affected individuals to development of various cancers. Less well understood is the penetrance and expressivity of CTLA4 mutations. We describe five members of a single family with heterozygous CTLA4 splice site mutation c.458-1G > C, previously shown to result in CTLA-4 HI, who presented with immunodeficiency and variable degree of immune dysregulation. The host, environmental and the epigenetic factors affecting the penetrance and expressivity of CTLA4 mutations merits further investigation.

Assessment of Gastric Emptying Times Between Pediatrics and Adults With Cyclic Vomiting Syndrome.

BACKGROUND & AIMS: Cyclic vomiting syndrome (CVS) is characterized by episodes of nausea and vomiting separated by symptom-free intervals. Rome IV guidelines have now distinguished CVS from other disorders such as cannabinoid hyperemesis. The pathogenesis of CVS, however, is poorly understood. Limited data exist on gastric emptying (GE) in patients with CVS. Therefore, the authors aim to measure the GE profile in pediatrics and adults with CVS. MATERIALS AND METHODS: Patients with the diagnosis of CVS (per NASPGHAN and Rome IV) between December 1998 and March 2017 who underwent gastric emptying study (GES) and without documented cannabis use were included. Clinical features including demographics, medication use, and comorbidities were also recorded. Frequency of rapid, normal, and delayed emptying was reported, and multinomial univariate logistic regression was used to identify factors associated with each type of emptying. KEY RESULTS: Sixty-seven subjects were included (50.7% female individuals, pediatrics n=15, adults n=52). At 2-hour retention, 40% of pediatric patients met criteria for rapid, 33.3% for normal, and 26.7% for delayed GE. In adults, 50% met criteria for rapid, 46.2% for normal, and 3.8% for delayed GE. For every 5-year increase in age, odds of rapid emptying on GES increased. CONCLUSIONS: (1) GE is predominantly rapid at 2 hours in pediatrics and adults with CVS. (2) Rapid GE seems to increase with age. (3) Current guidelines do not recommend GE in the initial management, however, further studies may play a role to help differentiate CVS from other functional gastric disorders.

Incidence Trends, Comorbidities, and Outcomes of Pyogenic Liver Abscess Among Children: A Nationwide Population-based Analysis.

OBJECTIVES: Population-based analysis of incidence, comorbid conditions, microbiological characteristics, and outcomes of pyogenic liver abscess (PLA) in children. METHODOLOGY: Retrospective analysis of National Inpatient Sample (NIS) and Kids Inpatient database (KID) database from 2003 to 2014 and included patients between 1 and 20 years of age. Using ICD-9 codes, we identified all hospitalizations with PLA and compared them with 1 : 10 age- and gender-matched controls. Amebic liver abscess and Candida infections were excluded. RESULTS: Total number of PLA admissions is 4075. The overall incidence of PLA is 13.5 per 100,000 hospitalizations, which increased by 60% between 2003 and 2014. The mean age of patients was 13.03 ±â€Š6.1 years and were predominantly boys-61%. Of the comorbid conditions, hepatobiliary malignancy had the highest odds ratio (OR 71.8) followed by liver transplant (OR 38.4), biliary disease (OR 29.9), inflammatory bowel disease (IBD) (OR 5.35), other GI malignancies (OR 4.74), primary immune deficiency disorder (OR 4.13). Patients with PLA had 12 times increased odds of having associated severe sepsis. Infective endocarditis (IE) (OR 4.5), appendicitis (OR 1.8), and diverticulitis (OR 8.1) were significantly associated with PLA. Almost 39% (1575) of the PLA patients had positive culture, whereas Streptococcus (10.8%) and Staphylococcus spp (9.2%) were the most common pathogens. About 45% of PLA patients underwent percutaneous liver abscess aspiration whereas 4.1% had hepatic resection for PLA. The mortality rate of PLA was 0.8% (n = 32). CONCLUSIONS: The incidence of PLA is steadily increasing over the last decade among pediatric population in the United States. Hepatobiliary malignancy and liver transplant are the most common comorbid conditions associated with PLA.

A Review of Autoimmune Enteropathy and Its Associated Syndromes.

Autoimmune enteropathy is an extremely rare condition characterized by an abnormal intestinal immune response which typically manifests within the first 6 months of life as severe, intractable diarrhea that does not respond to dietary modification. Affected individuals frequently present with other signs of autoimmunity. The diagnosis is made based on a characteristic combination of clinical symptoms, laboratory studies, and histological features on small bowel biopsy. Autoimmune enteropathy is associated with a number of other conditions and syndromes, most notably immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome and autoimmune polyglandular syndrome type 1 (APS-1). Diagnosis and treatment is challenging, and further research is needed to better understand the pathogenesis, disease progression, and long-term outcomes of these conditions.

Management of Five Hundred Patients With Gut Failure at a Single Center: Surgical Innovation Versus Transplantation With a Novel Predictive Model.

OBJECTIVE(S): To define the evolving role of integrative surgical management including transplantation for patients gut failure (GF). METHODS: A total of 500 patients with total parenteral nutrition-dependent catastrophic and chronic GF were referred for surgical intervention particularly transplantation and comprised the study population. With a mean age of 45 ±â€Š17 years, 477 (95%) were adults and 23 (5%) were children. Management strategy was guided by clinical status, splanchnic organ functions, anatomy of residual gut, and cause of GF. Surgery was performed in 462 (92%) patients and 38 (8%) continued medical treatment. Definitive autologous gut reconstruction (AGR) was achievable in 378 (82%), primary transplant in 42 (9%), and AGR followed by transplant in 42 (9%). The 84 transplant recipients received 94 allografts; 67 (71%) liver-free and 27 (29%) liver-contained. The 420 AGR patients received a total of 790 reconstructive and remodeling procedures including primary reconstruction, interposition alimentary-conduits, intestinal/colonic lengthening, and reductive/decompressive surgery. Glucagon-like peptide-2 was used in 17 patients. RESULTS: Overall patient survival was 86% at 1-year and 68% at 5-years with restored nutritional autonomy (RNA) in 63% and 78%, respectively. Surgery achieved a 5-year survival of 70% with 82% RNA. AGR achieved better long-term survival and transplantation better (P = 0.03) re-established nutritional autonomy. Both AGR and transplant were cost effective and quality of life better improved after AGR. A model to predict RNA after AGR was developed computing anatomy of reconstructed gut, total parenteral nutrition requirements, cause of GF, and serum bilirubin. CONCLUSIONS: Surgical integration is an effective management strategy for GF. Further progress is foreseen with the herein-described novel techniques and established RNA predictive model.

Improved Survival Following Living Donor Liver Transplantation for Pediatric Acute Liver Failure: Analysis of 20 Years of US National Registry Data.

This study estimated the utility of technical variant grafts (TVGs), such as split/reduced liver transplantation (SRLT) and living donor liver transplantation (LDLT), in pediatric acute liver failure (PALF). PALF is a devastating condition portending a poor prognosis without liver transplantation (LT). Pediatric candidates have fewer suitable deceased donor liver transplantation (DDLT) donor organs, and the efficacy of TVG in this setting remains incompletely investigated. PALF patients from 1995 to 2015 (age <18 years) were identified using the Scientific Registry of Transplant Recipients (n = 2419). Cox proportional hazards model and Kaplan-Meier curves were used to assess outcomes. Although wait-list mortality decreased (19.1% to 9.7%) and successful transplantations increased (53.7% to 62.2%), patients <1 year of age had persistently higher wait-list mortality rates (>20%) compared with other age groups (P < 0.001). TVGs accounted for only 25.7% of LT for PALF. In the adjusted model for wait-list mortality, among other factors, increased age (subhazard ratio [SHR], 0.97 per year; P = 0.020) and access to TVG were associated with decreased risk (SHR, 0.37; P < 0.0001). LDLT recipients had shorter median waiting times compared with DDLT (LDLT versus DDLT versus SRLT, 3 versus 4 versus 5 days, respectively; P = 0.017). In the adjusted model for post-LT survival, LDLT was superior to DDLT using whole grafts (SHR, 0.41; P = 0.004). However, patient survival after SRLT was not statistically different from DDLT (SHR, 0.75; P = 0.165). In conclusion, despite clear advantages to reduce wait-list mortality, TVGs have been underutilized in PALF. Early access to TVG, especially from LDLT, should be sought to further improve outcomes.

Cardiovascular risk factors and cardiac disorders in long-term survivors of pediatric liver transplantation.

The MetS and cardiovascular disease are leading causes of late morbidity in adult liver transplantation recipients; however, limited data are available in pediatric liver transplantation. A single-center retrospective review was undertaken for patients who had a liver transplantation before 18 yr of age and were >5 yr post-transplantation, to study the prevalence of MetS, its components, and cardiac disorders. Fifty-eight patients were included in the study with a mean age at transplantation of 6.3 ± 6.1 yr and mean follow-up of 14.1 ± 6.0 yr. Of the study group, 41.4% were overweight or obese, with ongoing prednisone use and increased duration of follow-up being significant risk factors. Fifty-three patients had sufficient data for determining MetS, which was present in 17% of the patients. Although the prevalence of MetS is low in pediatric liver transplant recipients, it is associated with CKD and prednisone therapy (p < 0.05). Echocardiography data were available for 23 patients, of whom 43.4% had LVH and 13% had evidence of PH. The spectrum of cardiac disorders in this population is much wider than in adults.

Low Gamma-Glutamyl Transferase Cholestasis in a Patient With X-Linked Myotubular Myopathy and Crohn's Disease.

X-linked myotubular myopathy (XLMTM) is a neuromuscular disorder manifesting at birth with hypotonia and respiratory distress. We describe the XLMTM case presenting at birth who developed normal gamma-glutamyl transferase cholestasis at 1 year of age. He was also diagnosed with Crohn's disease 4 years later. His cholestasis could be attributed to progressive familial intrahepatic cholestasis (PFIC) or primary sclerosing cholangitis in the setting of Crohn's disease. However, genetic testing ruled-out PFIC, and his radiographic and liver biopsy findings were not suggestive of primary sclerosing cholangitis. We believe that this cholestasis is related to XLMTM leading to a PFIC-like state.

Health-related quality of life in children with autoimmune liver disease.

BACKGROUND AND AIM: Health-related quality of life (HRQOL), a pivotal outcome indicator of health care interventions, has not been evaluated in children with autoimmune liver disease (AILD). The aim of this study was to determine HRQOL in children with AILD and the factors affecting it. METHODS: The Pediatric Quality Of Life Inventory, generic core scale, was used to collect HRQOL data on children with AILD. Specific liver disease-related questions were added. RESULTS: Survey responses were received from 30 of 40 patients. Patients' mean age at diagnosis was 11.6 ± 4.5 years, with M:F ratio of 1:1.3, and AILD for average of 4.6 ± 4.3 years. Seventy-three percent of patients had advanced liver disease. Mean overall health summary scores for the group per child and parent reports were 71.6 ± 19.0 and 71.3 ± 17.1, respectively, which were lower than healthy controls: 83.9 ± 12.5 and 82.3 ± 15.6 (P = 0.002). Frequent liver-related symptoms were associated with impaired physical and school functioning by child (P = 0.034 and 0.047) and parent reports (P = 0.051 and P = 0.018). Abdominal pain, fatigue, and psychological symptoms were found to adversely affect the HRQOL. Although it was difficult to estimate the effect of individual features of advanced liver disease such as cirrhosis, history of upper gastrointestinal bleed, and portal hypertension on the HRQOL, because of a relatively small sample size, the presence of ascites revealed lower social functioning score per parent report (P = 0.036). In an analysis of patients with any of the above complications versus those without, however, children reported lower social functioning scores (P = 0.018). There were no differences in HRQOL scores in children with autoimmune hepatitis versus primary sclerosing cholangitis versus autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome. CONCLUSIONS: First study to date shows that AILD in children significantly affects HRQOL, especially with frequent liver disease-related symptoms, even in early stages of disease. Findings need to be validated in larger, multicenter studies and will help practitioners understand their patients better and optimize care.

Metabolic-Associated Fatty Liver Disease in Childhood and Adolescence.

Metabolic-associated fatty liver disease (MAFLD) has become the most common cause for chronic liver disease among children and adolescents globally. Although liver biopsy remains the gold standard for diagnosis, emerging technology, like velocity controlled transient elastography, a noninvasive method, is being utilized to evaluate degree of fibrosis in these patients. The discovery of multiple gene polymorphisms has brought new hope for possible treatment targets. However, this research is still ongoing, making lifestyle changes and weight reduction the current mainstay of treatment. This review briefly reviews the most recent data regarding the epidemiology, pathophysiology, diagnostic modalities, and treatment of pediatric MAFLD.

Segmental Arterial Mediolysis Presenting as a Pancreatic Mass in a Pediatric Patient: A Case Report.

We describe a case of segmental arterial mediolysis (SAM) in a 2-year-old male who presented with symptoms of acute pancreatitis. SAM is a vascular entity of unknown etiology that involves medium-sized arteries in which the integrity of the vessel wall is compromised, resulting in increased susceptibility to ischemia, hemorrhage, and dissection. The clinical presentation is variable and can range from abdominal pain to more ominous findings of abdominal hemorrhage or organ infarction. This entity should be considered in the correct clinical setting and after other vasculopathies have been excluded. We aim to bring awareness to pediatric providers given this is a rare entity with variable presentation, which could be potentially life threatening.

Longitudinal Analysis of Cancer Risk in Children and Adults With Germline PTEN Variants.

Importance: Identifying hereditary cancer predisposition facilitates high-risk organ-specific cancer surveillance and prevention. In PTEN hamartoma tumor syndrome (PHTS), longitudinal studies remain lacking, and there are insufficient data on cancers in children and young adults, as well as individuals with neurodevelopmental disorders (NDD). Objective: To evaluate lifetime cancer risks, including second malignant neoplasms (SMN), among patients with PHTS. Design, Setting, and Participants: Prospective longitudinal cohort study (September 1, 2005, through January 6, 2022). General population risks from the Surveillance, Epidemiology, and End Results database. Patients with PHTS, molecularly defined as carrying germline PTEN variants, were accrued from community and academic medical centers throughout North America, South America, Europe, Australia, and Asia. Data were analyzed from July 2022 to February 2023. Exposures: Review of physical and electronic medical records, and follow-up through clinical visits or telephone interviews. Main Outcomes and Measures: Lifetime cancer risks in PHTS relative to the general population. Results: A total of 7302 patients were prospectively accrued, 701 of whom had germline PTEN variants (median [IQR] age at consent, 38 [12-52] years; 413 female patients [59%]). Longitudinal follow-up data could be obtained for 260 patients (37%), with a median (IQR) follow-up of 4 (2-8) years. Of the 701 patients, 341 (49%) received at least 1 cancer diagnosis, with 144 (42%) of those having SMN. The study found significantly elevated lifetime risks for breast (91%), endometrial (48%), thyroid (33%), kidney (30%), and colorectal cancers (17%), as well as melanoma (5%). Cancer diagnoses were also observed in children and young adults with PHTS (15%) and in patients with PHTS with neurodevelopmental disorders (11%). Elevated risks (P < .001) of thyroid (age-adjusted standardized incidence ratios [SIR], 32.1; 95% CI, 26.0-39.0), kidney (SIR, 26.5; 95% CI, 18.8-36.3), endometrial (SIR, 26.0; 95% CI, 19.5-34.1), breast (SIR, 20.3; 95% CI, 17.3-23.7), and colorectal (SIR, 7.9; 95% CI, 5.2-11.7) cancers, and melanoma (SIR, 6.3; 95% CI, 3.5-10.5) were observed. Of the 341 patients with PHTS with cancer, 51 (15%) had 1 or more cancers diagnosed at age 29 years or younger, and 16 (31.4%) of those developed SMN at final follow-up. Twenty-three patients with PHTS with NDD and cancer were identified, with 5 (22%) having developed SMN at final follow-up. Individuals with PHTS and NDD showed higher lifetime cancer risks compared with individuals with PHTS but without NDD (hazard ratio, 2.7; 95% CI, 1.7-4.2; P < .001). Conclusions and Relevance: This cohort study found consistently elevated lifetime cancer risks in PHTS. Organ-specific surveillance should continue in patients with PHTS. Additional study is required to ascertain elevated cancer risks in patients with PHTS with NDD.

Glycogen storage disease type 1a in the Ohio Amish.

Glycogen storage disease type 1a (GSD1a) is an inborn error of glucose metabolism characterized by fasting hypoglycemia, hepatomegaly, and growth failure. Late complications include nephropathy and hepatic adenomas. We conducted a retrospective observational study on a cohort of Amish patients with GSD1a. A total of 15 patients cared for at a single center, with a median age of 9.9 years (range 0.25-24 years) were included. All patients shared the same founder variant in GCPC c.1039 C > T. The phenotype of this cohort demonstrated good metabolic control with median cohort triglyceride level slightly above normal, no need for continuous overnight feeds, and a higher quality of life compared to a previous GSD cohort. The most frequent complications were oral aversion, gross motor delay, and renal hyperfiltration. We discuss our unique care delivery at a single center that cares for Amish patients with inherited disorders.