A Retrospective Study of Long-Term Outcomes in 16 ABO-Incompatible Deceased Donor Pediatric Liver Transplants from a National Transplant Center at Helsinki University Hospital, Finland, 1987-2022.

BACKGROUND The use of ABO-incompatible liver transplants (ABO-ILTs) from deceased donors has become more common due to the shortage of available donor livers and increased transplant waiting times. This retrospective study from a national transplant center at Helsinki University Hospital, Finland, aimed to assess the long-term outcomes of ABO-incompatible deceased donor pediatric liver transplants between 1987 and 2022. MATERIAL AND METHODS Sixteen (9.5%) of the 169 pediatric liver transplantations were ABO-ILTs. The median age at transplantation was 5.0 (0.5-15.4) years. Reasons for ABO-ILTs were acute liver failure (18.75%), malignancy (12.5%), small body size and long waiting time (25%), and other reasons (43.75%). The median post-transplant follow-up time was 147 (0.72-353) months. Patient and graft survival and occurrence of surgical complications were compared to ABO-identical transplants, and anti-ABO antibody titers were analyzed. RESULTS The 1-, 3-, and 5-year patient survivals were comparable between the ABO-I and ABO-compatible groups, being 81.3%, 73.9%, and 73.9% (ABO-I) and 87.5%, 82.5%, 77.9% (ABO-compatible), respectively. Three patients with ABO-ILTs died of sepsis and multiorgan failure during the first 3 months after transplantation. The occurrence of biliary complications and early vascular thrombosis (<30 days after transplantation) did not differ significantly between recipients with an ABO-ILT vs ABO-compatible liver graft. CONCLUSIONS The findings from this study support findings from previous studies that outcomes after ABO-incompatible liver transplants in children were comparable to outcomes from ABO-identical liver transplants.

Deep learning quantification reveals a fundamental prognostic role for ductular reaction in biliary atresia.

BACKGROUND: We aimed to quantify ductular reaction (DR) in biliary atresia using a neural network in relation to underlying pathophysiology and prognosis. METHODS: Image-processing neural network model was applied to 259 cytokeratin-7-stained native liver biopsies of patients with biliary atresia and 43 controls. The model quantified total proportional DR (DR%) composed of portal biliary epithelium (BE%) and parenchymal intermediate hepatocytes (PIH%). The results were related to clinical data, Sirius Red-quantified liver fibrosis, serum biomarkers, and bile acids. RESULTS: In total, 2 biliary atresia biopsies were obtained preoperatively, 116 at Kasai portoenterostomy (KPE) and 141 during post-KPE follow-up. DR% (8.3% vs. 5.9%, p=0.045) and PIH% (1.3% vs. 0.6%, p=0.004) were increased at KPE in patients remaining cholestatic postoperatively. After KPE, patients with subsequent liver transplantation or death showed an increase in DR% (7.9%-9.9%, p = 0.04) and PIH% (1.6%-2.4%, p = 0.009), whereas patients with native liver survival (NLS) showed decreasing BE% (5.5%-3.0%, p = 0.03) and persistently low PIH% (0.9% vs. 1.3%, p = 0.11). In Cox regression, high DR predicted inferior NLS both at KPE [DR% (HR = 1.05, p = 0.01), BE% (HR = 1.05, p = 0.03), and PIH% (HR = 1.13, p = 0.005)] and during follow-up [DR% (HR = 1.08, p<0.0001), BE% (HR = 1.58, p = 0.001), and PIH% (HR = 1.04, p = 0.008)]. DR% correlated with Sirius red-quantified liver fibrosis at KPE (R = 0.47, p<0.0001) and follow-up (R = 0.27, p = 0.004). A close association between DR% and serum bile acids was observed at follow-up (R = 0.61, p<0.001). Liver fibrosis was not prognostic for NLS at KPE (HR = 1.00, p = 0.96) or follow-up (HR = 1.01, p = 0.29). CONCLUSIONS: DR predicted NLS in different disease stages before transplantation while associating with serum bile acids after KPE.

Cutoffs and Characteristics of Abnormal Bowel Dilatation in Pediatric Short Bowel Syndrome.

OBJECTIVES: Although excessive intestinal dilatation associates with worsened outcomes in pediatric short bowel syndrome (SBS), little is known about the natural history and definition of pathological dilatation. We addressed fore-, mid-, and hind-gut dilatation in children with SBS, who had not undergone autologous intestinal reconstructive (AIR) surgery, in relation to controls. METHODS: SBS children without history of AIR surgery (n = 59) and age-matched controls without any disclosed intestinal pathology (n = 140) were included. Maximum diameter of duodenum, small bowel (SB), and colon were measured in each intestinal contrast series during 2002 to 2020 and expressed as diameter ratio (DR) to L5 vertebrae height. Predictive ability of DR for weaning off parenteral nutrition (PN) was analyzed with Cox proportional hazards regression models using multiple cutoffs. RESULTS: Duodenum (DDR), SB (SBDR), and colon (CDR) DR were 53%, 183%, and 23% higher in SBS patients compared to controls ( P < 0.01 for all). The maximal DDR and SBDR measured during follow-up is associated with current PN dependence and young age. DDR correlated with SBDR ( r = 0.586, P < 0.01). Patients with maximal DDR less than 1.5, which was also the 99th percentile for controls, were 2.5-fold more likely to wean off PN ( P = 0.005), whereas SBDR and CDR were not predictive for PN duration. CONCLUSIONS: All segments of remaining bowel, especially SB, dilate above normal levels in children with SBS. In SBS children without AIR surgery, PN dependence and young age is associated with duodenal and small intestinal dilatation, while duodenal dilatation also predicted prolonged PN.

Bacterial translocation markers and toll-like receptors in biliary atresia following successful portoenterostomy.

AIM: The gut-liver axis may contribute to pathophysiology of cholestatic liver disorders like biliary atresia (BA) by bacterial translocation (BT). Toll-like receptors (TLR) are pattern recognition receptors known to activate innate immunity and secretion of inflammatory cytokines. Herein, we examined BT-associated biomarkers and TLRs in relation to liver injury after successful portoenterostomy (SPE) in BA. METHODS: Serum levels of lipopolysaccharide-binding protein (LBP), CD14, LAL, TNF-α, IL-6 and FABP2 along with liver expression of TLRs (TLR1, TLR4, TLR7 and TLR9), LBP and CD14 were measured during median 4.9 (1.7-10.6) years follow-up after SPE in 45 BA patients. RESULTS: Serum LBP, CD14, TNF-α and IL-6 all increased after SPE whereas LAL and FABP-2 remained unchanged. Serum LBP correlated positively with CD14 and markers of hepatocyte injury and cholestasis, but not with Metavir fibrosis stage, transcriptional markers for fibrosis (ACTA2) or ductular reaction. Serum CD14 concentration was significantly higher in patients with portal hypertension than without. While liver expression of TLR4 and LBP remained low, TLR7 and TLR1 showed marked BA-specific increases, and TLR7 correlated with Metavir fibrosis stage and ACTA2. CONCLUSION: BT does not seem to play a significant role in liver injury after SPE in our series of BA patients.

Characteristics, management and outcomes of choledochal malformations in Finnish adult patients.

CONCLUSIONS: Nearly half of operated patients developed long-term postoperative complications. A novel association between CMs and IBD was observed. Although no hepatobiliary malignancies regardless of treatment modality were encountered, the number of patients and length of follow-up remained limited.

Incidence of Isolated Biliary Atresia during the COVID Lockdown in Europe: Results from a Collaborative Project by RARE-Liver.

BACKGROUND: Biliary atresia (BA) is a rare cholangiopathy where one of the proposed aetiological mechanisms is an infectious viral trigger. Coronavirus disease-19 (COVID) lockdown restrictions were implemented to reduce the transmission of infections. Strictness of lockdown varied across European countries. This study aimed to investigate if there was an association between strictness of lockdown and change in isolated BA (IBA) incidence in Europe. METHODS: We approached European centres involved in the European Reference Network RARE-LIVER. We included IBA patients born between 2015 and June 2020. We calculated the number of IBA patients born per centre per month. The Stringency Index (SI) was used as lockdown strictness indicator. The association between percentage change of mean number of IBA patients born per month and the SI was assessed. RESULTS: We included 412 IBA patients from thirteen different centres. The median number of patients per month did not change: 6 (1-15) pre-lockdown and 7 (6-9) during lockdown (p = 0.34). There was an inverse association between SI and percentage change in IBA (B = -0.73, p = 0.03). Median age at Kasai portoenterostomy (days) did not differ between time periods (51 (9-179) vs. 53 (19-126), p = 0.73). CONCLUSION: In this European study, a stricter COVID-lockdown was seemingly accompanied by a simultaneous larger decrease in the number of IBA patients born per month in the lockdown. Results should be interpreted with caution due to the assumptions and limitations of the analysis.

Serum FGF19 predicts outcomes of Kasai portoenterostomy in biliary atresia.

BACKGROUND AND AIMS: Outcomes after Kasai portoenterostomy (KPE) for biliary atresia remain highly variable for unclear reasons. As reliable early biomarkers predicting KPE outcomes are lacking, we studied the prognostic value of FGF19. APPROACH AND RESULTS: Serum and liver specimens, obtained from biliary atresia patients (N=87) at KPE or age-matched cholestatic controls (N=26) were included. Serum concentration of FGF19 and bile acids, liver mRNA expression of FGF19 , and key regulators of bile acid synthesis were related to KPE outcomes and liver histopathology. Immunohistochemistry and in situ hybridization were used for the localization of liver FGF19 expression. Serum levels (223 vs. 61 pg/mL, p <0.001) and liver mRNA expression of FGF19 were significantly increased in biliary atresia. Patients with unsuccessful KPE (419 vs. 145 pg/mL, p =0.047), and those subsequently underwent liver transplantation (410 vs. 99 pg/mL, p =0.007) had significantly increased serum, but not liver, FGF19, which localized mainly in hepatocytes. In Cox hazard modeling serum FGF19 <109 pg/mL predicted native liver survival (HR: 4.31, p <0.001) also among patients operated <60 days of age (HR: 8.77, p =0.004) or after successful KPE (HR: 6.76, p =0.01). Serum FGF19 correlated positively with increased serum primary bile acids ( R =0.41, p =0.004) and ductular reaction ( R =0.39, p =0.004). CONCLUSIONS: Increased serum FGF19 at KPE predicted inferior long-term native liver survival in biliary atresia and was associated with unsuccessful KPE, elevated serum primary bile acids, and ductular reaction.

Dextranomer Endoscopic Injections for the Treatment of Urinary Incontinence in Bladder Exstrophy-epispadias Complex.

PURPOSE: Since bladder neck dextranomer/hyaluronic acid copolymer (Deflux) injections can improve urinary incontinence of various etiologies, we hypothesized that incontinent children with bladder exstrophy-epispadias complex would benefit from dextranomer/hyaluronic acid copolymer. We aimed to analyze dextranomer/hyaluronic acid copolymer efficacy and predictors of treatment success in bladder exstrophy-epispadias complex. MATERIALS AND METHODS: Incontinent bladder exstrophy-epispadias complex children aged >4 years undergoing dextranomer/hyaluronic acid copolymer injections in our hospital between October 1997 and January 2021 were included. Medical history, continence, and bladder capacity before injections were recorded. Postoperatively, patients were categorized as "dry," "significantly improved," or "failure." Postoperative complications, bladder emptying mode, and bladder capacity were reported. Failure-free survival was estimated by Kaplan-Meier models. RESULTS: Altogether, 58 patients (27 male epispadias, 9 female epispadias, 22 bladder exstrophy) underwent 105 injections at median age of 8.5 (interquartile range 5.8-12) years. Previous bladder neck reconstruction had been performed in 38 (66%) and 33 (57%) received multiple injections. Complications occurred in 9%. Five-year failure-free survival was 70% (standard error 9.1) in males epispadias compared to 45% (9.0) in females and exstrophy patients (P = .04). Previous bladder neck reconstruction associated with improved 5-year failure-free survival in females and exstrophy patients (58%, SE 11) but not in male epispadias (75%, SE 11). CONCLUSIONS: Dextranomer/hyaluronic acid copolymer injections provided satisfactory and lasting continence in over half of bladder exstrophy-epispadias complex patients. While injections were successful in male epispadias regardless of bladder neck reconstruction timing, results were better in bladder exstrophy and female epispadias after previous bladder neck reconstruction.

Antithrombin supplementation for prevention of vascular thrombosis after pediatric liver transplantation.

AIMS: After liver transplantation (LT), synthesis of coagulation factors by the graft recovers faster for pro thrombotic than anti thrombotic factors, resulting in a potential pro thrombotic imbalance. We studied the thrombotic and hemorrhagic complications in our pediatric LT series, providing supplementation of fresh frozen plasma (FFP) and/or antithrombin (AT) in the prophylactic antithrombotic regimen. METHODS: This was a retrospective observational single center study. All isolated pediatric LTs performed between 1/11/2009 and 31/12/2019 (n = 181) were included. Postoperatively, in addition to low molecular weight heparin, 22 patients (12%) received FFP (10 ml/kg twice daily for 10 days), 27 patients (15%) were given FFP (reduced duration) and AT (50-100 IU/kg/day if AT activity remained <70%), and 132 (73%) received AT only. Complications, outcome, and coagulation profiles in postoperative days 0-10 were analyzed. RESULTS: In all three treatment groups, AT activity normalized by day 4 while prothrombin remained <70% of normal until day 9. Hepatic artery thrombosis (HAT), portal vein thrombosis (PVT), and hemorrhagic complications occurred in 2.8%, 3.3%, and 3.9% of LTs. One- and 5-year patient and graft survival were 88% (±2.4% Standard Error) and 84% (±2.5%), and 86% (±2.6%) and 84% (±2.7%), respectively, without difference between groups. HAT were associated with low AT on days 0 and 1, and PVT with low AT on day 0. CONCLUSIONS: Low antithrombin activity after LT was associated with postoperative thromboses. FFP and/or AT supplementation allowed early normalization of AT activity, while thrombotic or hemorrhagic complications were rare, suggesting efficient and safe management of post-LT coagulopathy.

Liver secretin receptor predicts portoenterostomy outcomes and liver injury in biliary atresia.

Biliary atresia (BA) is a chronic neonatal cholangiopathy characterized by fibroinflammatory bile duct damage. Reliable biomarkers for predicting native liver survival (NLS) following portoenterostomy (PE) surgery are lacking. Herein we explore the utility of 22 preidentified profibrotic molecules closely connected to ductular reaction (DR) and prevailing after successful PE (SPE), in predicting PE outcomes and liver injury. We used qPCR and immunohistochemistry in a BA cohort including liver samples obtained at PE (n = 53) and during postoperative follow-up after SPE (n = 25). Of the 13 genes over-expressed in relation to cholestatic age-matched controls at PE, only secretin receptor (SCTR) expression predicted cumulative 5-year NLS and clearance of jaundice. Patients in the highest SCTR expression tertile showed 34-55% lower NLS than other groups at 1-5 years after PE (P = 0.006-0.04 for each year). SCTR expression was also significantly lower [42 (24-63) vs 75 (39-107) fold, P = 0.015] among those who normalized their serum bilirubin after PE. Liver SCTR expression localized in cholangiocytes and correlated positively with liver fibrosis, DR, and transcriptional markers of fibrosis (ACTA2) and cholangiocytes (KRT7, KRT19) both at PE and after SPE. SCTR is a promising prognostic marker for PE outcomes and associates with liver injury in BA.

Variability of Care and Access to Transplantation for Children with Biliary Atresia Who Need a Liver Replacement.

Background & Aims: Biliary atresia (BA) is the commonest single etiology indication for liver replacement in children. As timely access to liver transplantation (LT) remains challenging for small BA children (with prolonged waiting time being associated with clinical deterioration leading to both preventable pre- and post-transplant morbidity and mortality), the care pathway of BA children in need of LT was analyzed­from diagnosis to LT­with particular attention to referral patterns, timing of referral, waiting list dynamics and need for medical assistance before LT. Methods: International multicentric retrospective study. Intent-to-transplant study analyzing BA children who had indication for LT early in life (aged < 3 years at the time of assessment), over the last 5 years (2016−2020). Clinical and laboratory data of 219 BA children were collected from 8 transplant centers (6 in Europe and 2 in USA). Results: 39 patients underwent primary transplants. Children who underwent Kasai in a specialist -but not transplant- center were older at time of referral and at transplant. At assessment for LT, the vast majority of children already were experiencing complication of cirrhosis, and the majority of children needed medical assistance (nutritional support, hospitalization, transfusion of albumin or blood) while waiting for transplantation. Severe worsening of the clinical condition led to the need for requesting a priority status (i.e., Peld Score exception or similar) for timely graft allocation for 76 children, overall (35%). Conclusions: As LT currently results in BA patient survival exceeding 95% in many expert LT centers, the paradigm for BA management optimization and survival have currently shifted to the pre-LT management. The creation of networks dedicated to the timely referral to a pediatric transplant center and possibly centralization of care should be considered, in combination with implementing all different graft type surgeries in specialist centers (including split and living donor LTs) to achieve timely LT in this vulnerable population.

Long-term outcomes of biliary atresia patients surviving with their native livers.

Portoenterostomy (PE) has remained as the generally accepted first line surgical treatment for biliary atresia (BA) for over 50 years. Currently, close to half of BA patients survive beyond 10 years with their native livers, and most of them reach adulthood without liver transplantation (LT). Despite normalization of serum bilirubin by PE, ductular reaction and portal fibrosis persist in the native liver. The chronic cholangiopathy progresses to cirrhosis, complications of portal hypertension, recurrent cholangitis or hepatobiliary tumors necessitating LT later in life. Other common related health problems include impaired bone health, neuromotor development and quality of life. Only few high-quality trials are available for evidence-based guidance of post-PE adjuvant medical therapy or management of the disease complications. Better understanding of the pathophysiological mechanisms connecting native liver injury to clinical outcomes is critical for development of accurate follow-up tools and novel therapies designed to improve native liver function and survival.

Prognostic and Pathophysiologic Significance of IL-8 (CXCL8) in Biliary Atresia.

Interleukin (IL)-8 (CXCL8), a chemokine involved in neutrophil recruitment, has been implicated in ductular reaction and liver fibrogenesis. We studied liver and serum IL-8 expression in a large biliary atresia (BA) cohort and explored its prognostic and pathophysiological potential. IL-8 expression was assessed in liver utilizing quantitative polymerase chain reaction (qPCR), immunohistochemistry and in situ hybridization and in serum using an enzyme-linked immunosorbent assay, among 115 BA patients, 10 disease controls and 68 normal controls. Results were correlated to portoenterostomy (PE) outcomes, biochemical and histological liver injury, transcriptional markers of fibrosis and cholangiocytes, and expression of other related cytokines. IL-8 was markedly overexpressed in liver and serum of BA patients at PE (n = 88) and in serum samples obtained during postoperative follow-up (n = 40). IL-8 expression in the liver was predominantly in cholangiocytes within areas of ductular reaction. Liver IL-8 mRNA expression correlated positively with its serum concentration, bile ductular proliferation, Metavir fibrosis stage, and transcriptional markers of activated myofibroblasts (ACTA2) and cholangiocytes (KRT19). Taken together, IL-8 may mediate liver injury in BA by promoting ductular reaction and associated liver fibrogenesis. Prognostic value of serum IL-8 to predict native liver survival was limited and confined to the postoperative period after PE.

Evolving Up-regulation of Biliary Fibrosis-Related Extracellular Matrix Molecules After Successful Portoenterostomy.

Successful portoenterostomy (SPE) improves the short-term outcome of patients with biliary atresia (BA) by relieving cholestasis and extending survival with native liver. Despite SPE, hepatic fibrosis progresses in most patients, leading to cirrhosis and a deterioration of liver function. The goal of this study was to characterize the effects of SPE on the BA liver transcriptome. We used messenger RNA sequencing to analyze global gene-expression patterns in liver biopsies obtained at the time of portoenterostomy (n = 13) and 1 year after SPE (n = 8). Biopsies from pediatric (n = 2) and adult (n = 2) organ donors and other neonatal cholestatic conditions (n = 5) served as controls. SPE was accompanied by attenuation of inflammation and concomitant up-regulation of key extracellular matrix (ECM) genes. Highly overexpressed genes promoting biliary fibrosis and bile duct integrity, such as integrin subunit beta 6 and previously unreported laminin subunit alpha 3, emerged as candidates to control liver fibrosis after SPE. At a cellular level, the relative abundance of activated hepatic stellate cells and liver macrophages decreased following SPE, whereas portal fibroblasts (PFs) and cholangiocytes persisted. Conclusion: The attenuation of inflammation following SPE coincides with emergence of an ECM molecular fingerprint, a set of profibrotic molecules mechanistically connected to biliary fibrosis. The persistence of activated PFs and cholangiocytes after SPE suggests a central role for these cell types in the progression of biliary fibrosis.

Comparison of antegrade and retrograde endoscopic injection techniques for neurogenic sphincteric incontinence in children with neurogenic bladder.

INTRODUCTION/BACKGROUND: Urinary incontinence is common in children with neuropathic bladder. Results of endoscopic injections of bulking agents in the bladder neck are promising but it remains unclear whether they should be performed an antegrade or retrograde fashion. OBJECTIVE: Our aim was to compare the antegrade and retrograde endoscopic injection techniques for the treatment of urinary incontinence. STUDY DESIGN: A prospective study evaluating bladder neck dextranomer-hyaluronic acid polymer injections for urinary incontinence in children with neurogenic bladder was initiated in 1997. Children with normal bladder capacity and compliance and without uncontrolled detrusor overactivity or previous bladder neck surgery were included. Patients were classified as success (dry or significantly improved, the latter defined as no need for more than one pad per day, continent during night, and patient seeking no further treatment) or failure at regular follow-up visits. RESULTS: During 1997-2016, 34 children underwent endoscopic treatment in a retrograde while 17 children in antegrade fashion (mean age 11 years, range 5-20). Most patients (n = 47/51) had neuropathic bladder due to congenital malformations, 13 (25%) had had previous bladder augmentation, and 19 (37%) were in wheelchair. Sex, age, etiology of neurogenic bladder, degree of physical impairment, or era of treatment (1997-2012 vs. 2012-2016) had no influence on success rates (Summary Table). After mean follow-ups of 69 (range 12-156) months, success rates were 71% for the antegrade and 53% for the retrograde technique (p = 0.366). Mean number of injections to obtain success was similar between the techniques (1.4 vs. 1.2). While the proportion of dry patients was similar between the two techniques (35%), the proportion of significantly improved patients tended to be higher after antegrade than retrograde injections (35% vs. 18%, p = 0.181). DISCUSSION: Better visualization of the bladder neck may explain the tendency for improved results of antegrade compared to retrograde technique. Further studies in larger patient samples are needed to define the optimal endoscopic injection technique. CONCLUSION: Long-term results of the antegrade endoscopic bladder neck injections of dextranomer-hyaluronic acid polymer for urinary incontinence in children with neurogenic bladder are promising.

Long-term Morbidity of Choledochal Malformations in Children.

OBJECTIVE: The aim of the study was to assess long-term morbidity in children operated for choledochal malformation (CM) by relating clinical complications to liver histopathology, follow-up imaging, liver stiffness, and biochemistry. METHODS: A single-center retrospective follow-up study including all CM patients (n = 55, 71% girls) treated during 1976 to 2018 was performed. Mann-Whitney U test and Spearman rank correlation were used for statistical analyses. RESULTS: During median follow-up of 5.8 (interquartile range, 2.5-12) years, 1 patient was lost to follow-up whereas all survived. Intraoperative liver biopsies showed fibrosis in 32%, and patients with Metavir stage ≥2 were younger at surgery (0.36 [0.11-1.9] vs 3.8 [0.72-10.5] years, P = 0.024) than those without fibrosis. Overall, 21% had long-term complications including cholangitis in 9 (>2 episodes in 5) patients, anastomotic stricture in 2 referred patients and adhesive volvulus or hepatocellular carcinoma in 1 each. Anastomotic strictures were successfully managed nonoperatively and hepatocellular carcinoma with thermoablation. In postoperative magnetic resonance cholangiography (MRCP) performed 6.4 (3.6-16) years after hepaticojejunostomy, diameters of both main intrahepatic ducts had decreased significantly to 3.0 (2.5-3.5) mm (P = 0.0001) but a distal cyst stump was remaining in 30% with a length of 6.0 (4.0-20) mm that associated with operation age (r = 0.71, P = 0.015) and fusiform CM type. Follow-up ultrasound revealed mild dilation of intrahepatic bile ducts in 6.3% and mildly to moderately elevated liver biochemistry in 23%, and liver stiffness (>7 kPa) in 22%. CONCLUSIONS: Whilst cholangitis was the most common postoperative problem, individual patients experienced other more significant complications and one quarter of patients showed evidence of underlying liver dysfunction.

Partial Biliary Diversion May Promote Long-Term Relief of Pruritus and Native Liver Survival in Children with Cholestatic Liver Diseases.

INTRODUCTION: Rare cholestatic liver diseases may cause debilitating pruritus in children. Partial biliary diversion (PBD) may relieve pruritus and postpone liver transplantation which is the only other alternative when conservative treatment fails. The aim was to report long-term outcome after PBD in a population of 26 million people during a 25-year period. MATERIALS AND METHODS: This is an international, multicenter retrospective study reviewing medical journals. Complications were graded according to the Clavien-Dindo classification system. RESULTS: Thirty-three patients, 14 males, underwent PBD at a median of 1.5 (0.3-13) years at four Nordic pediatric surgical centers. Progressive familial intrahepatic cholestasis was the most common underlying condition. Initially, all patients got external diversion, either cholecystojejunostomy (25 patients) or button placed in the gallbladder or a jejunal conduit. Early complications occurred in 14 (42%) patients, of which 3 were Clavien-Dindo grade 3. Long-term stoma-related complications were common (55%). Twenty secondary surgeries were performed due to stoma problems such as prolapse, stricture, and bleeding, or conversion to another form of PBD. Thirteen children have undergone liver transplantation, and two are listed for transplantation due to inefficient effect of PBD on pruritus. Serum levels of bile acids in the first week after PBD construction were significantly lower in patients with good relief of pruritus than in those with poor effect (13 [2-192] vs. 148 [5-383] µmol/L; p = 0.02). CONCLUSION: PBD may ensure long-term satisfactory effect on intolerable pruritus and native liver survival in children with cholestatic liver disease. However, stoma-related problems and reoperations are common.

Compromised duodenal mucosal integrity in children with short bowel syndrome after adaptation to enteral autonomy.

BACKGROUND: Intestinal adaptation has been extensively studied experimentally, but very limited data is available on human subjects. In this study we assessed intestinal adaption in humans with short bowel syndrome (SBS). METHODS: We comparatively evaluated mucosal hyperplasia, inflammation, barrier function and nutrient transport using histology, immunohistochemistry and qPCR for selected 52 key genes in duodenal biopsies obtained from children with SBS after weaning off parenteral nutrition (n = 33), and matched controls without intestinal pathology (n = 12). Small bowel dilatation was assessed from contrast small bowel series. RESULTS: Duodenal mucosa of SBS children showed increased histologic inflammation of lamina propria (p = 0.033) and mucosal mRNA expression of tumor necrosis factor (p = 0.027), transforming growth factor (TGF)-ß2 (p = 0.006) and caveolin-1 (CAV1; p = 0.001). Villus height, crypt depth, enterocyte proliferation, apoptosis and expression of proliferation and nutrient transport genes remained unchanged. Pathologic small bowel dilatation reduced crypt depth (p = 0.045) and downregulated mRNA expression of interleukin (IL)-6 by three-fold (p = 0.008), while correlating negatively with IL6 (r = -0.609, p = 0.004). Loss of ileocecal valve (ICV) upregulated mRNA expression of toll-like receptor 4 (TLR4), TGF-ß1, CAV1, several apoptosis regulating genes, and mRNA expression of zonulin (p < 0.05 for all). CONCLUSIONS: Despite successful adaptation to enteral autonomy, duodenal mucosa of SBS children displayed histologic and molecular signs of abnormal inflammation and regulation of epithelial permeability, whereas no structural or molecular signs of adaptive hyperplasia or enhanced nutrient transport were observed. Excessive dilatation of the remaining small bowel paralleled impaired duodenal crypt homeostasis, while absence of ICV modified regulation of mucosal inflammation, regeneration and permeability. LEVEL OF EVIDENCE: II.