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.

Expenditure and survival of adult patients with intestinal failure due to short bowel syndrome: real-world evidence from Southern Finland.

OBJECTIVES: Comprehensive follow-up data from the largest hospital district in Finland was used to assess hospital-based healthcare resource utilization (HCRU) and expenses, incidence and prevalence, survival, and effect of comorbidities/complications on survival of adult patients with intestinal failure due to short bowel syndrome (SBS-IF). METHODS: This study utilized electronic healthcare data covering all ≥18-year-old patients with SBS-IF at the Hospital District of Helsinki and Uusimaa in Finland between 2010 and 2019. Patients were followed from SBS-IF onset until the end of 2020 or death and compared to birth year and sex-matched control patients without SBS-IF. RESULTS: The study included 77 patients with SBS-IF (cases) and 363 controls. Cases had high HCRU; the cumulative expenses were about tenfold compared to the controls, at the end of the study (€123,000 vs. €14,000 per patient). The expenses were highest during the first year after SBS-IF onset (€53,000 per patient). Of the cases with a median age 62.5 years, 51.9% died during study time. The median survival was 4.4 years from SBS-IF onset and cases died 13.5 times more likely during the follow-up compared to controls. Mortality risk was lower in female cases (hazard ratio (HR) 0.46; 95% confidence intervals (CI) 0.24, 0.9) and higher with presence of comorbidities (Charlson comorbidity index HR 1.55; 95% CI 1.2, 2.0) and mesenteric infarction (HR 4.5; 95% CI 1.95, 10.36). The incidence of adult SBS-IF was 0.6 per 100,000 adults. CONCLUSION: Our study demonstrates a high demand for healthcare support and elevated mortality in adult SBS-IF-patients. Our results suggest that the presence of comorbidities is a key driver for mortality.

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.

Long-Term Outcomes After Autologous Intestinal Reconstructive Surgery in Children With Short Bowel Syndrome.

OBJECTIVES: Autologous intestinal reconstructive (AIR) surgery is frequently utilized in the management of pediatric short bowel syndrome (SBS). However, little is known about the long-term sequela of these procedures. METHODS: We undertook a retrospective follow-up study addressing parenteral nutrition (PN) dependence, nutritional status, intestinal morbidity, and related complications in SBS patients having undergone AIR surgery (SBS-AIR, n = 19). We compared results with conservatively treated control SBS patients (SBS-C, n = 45). Eligible patients were identified from our institutional intestinal failure registry during 1985-2019. RESULTS: After median 11.4 follow-up years, 42% of SBS-AIR patients received PN in relation to 36% in SBS-C group ( P = 0.6210), and overall PN duration was significantly longer (35.4 vs 10 months, P = 0.0004) in SBS-AIR group. Although symptoms of intestinal dysfunction improved in majority (62%) of patients after AIR surgery, their symptoms remained more frequent and severe at latest follow-up compared to SBS-C group (39% vs 5%, P = 0.0015). Although bacterial overgrowth was more frequent in SBS-AIR group (53% vs 24%, P = 0.0416), latest endoscopy findings and fecal calprotectin levels as well as occurrence of anastomotic/staple line ulcerations were comparable between groups. Histological liver steatosis (50% vs 18%, P = 0.042) and impaired bone health (26% vs 6.7%, P = 0.042) were more frequent in SBS-AIR patients. CONCLUSIONS: While AIR surgery improved gastrointestinal symptoms and transition to enteral autonomy in majority of patients, a noteworthy proportion of them continued to suffer from clinically significant intestinal dysfunction and related complications. Close long-term follow-up of pediatric AIR surgery patients is mandatory.

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.

Pediatric Short Bowel Syndrome: Real-World Evidence on Incidence and Hospital Resource Use From a Finnish Data Lake.

OBJECTIVES: Little is known about the epidemiology and healthcare burden of pediatric intestinal failure (IF). We aimed to assess the incidence, prevalence, healthcare resource utilization (HCRU), and related costs of pediatric short bowel syndrome (SBS) using follow-up data from the largest hospital district in Finland. METHODS: This retrospective registry study utilized electronic healthcare data covering all pediatric patients with SBS-IF born between 2010 and 2019 at the Hospital District of Helsinki and Uusimaa in Finland. Patients were followed from birth until the end of 2020 and compared to control patients, all from the same hospital system. RESULTS: In total, 38 patients with SBS-IF and 1:5 matched controls were included, with median follow-up time of almost 6 years from birth. Over half of the patients were born early preterm (gestational age ≤30 weeks). The incidence of pediatric SBS-IF was 24 per 100,000 live births. The HCRU was higher compared to controls and most of the inpatient days incurred during the first year of the SBS-IF patients' life. The average hospital-based HCRU costs were €221,000 for the first year and €57,000 for whole follow-up annually. The costs were higher for the early preterm patients and accumulated mainly from inpatient days. CONCLUSIONS: SBS-IF is a rare disease with a relatively low number of patients treated at each hospital district. The burden on the hospital system, as well as the patient's family, is especially high at the onset as the newborns with SBS-IF spend a significant part of their first year of life in the hospital.

Efficacy and Safety of Teduglutide in Infants and Children With Short Bowel Syndrome Dependent on Parenteral Support.

OBJECTIVES: Our objective was to evaluate the short- and long-term safety and efficacy of teduglutide treatment in infants and children with short bowel syndrome with intestinal failure (SBS-IF). METHODS: Two open-label phase 3 studies and 1 extension study investigated the short- and long-term safety and efficacy of teduglutide (0.05 mg/kg/day) in infants and children with SBS-IF: NCT03571516, 24-week study of infants who were randomized to receive teduglutide or standard of care (SoC); NCT02980666, 24-week study of infants and children who all received teduglutide; and NCT03268811, 24-week extension study of patients who completed NCT02980666 (patients could receive up to 48 weeks of total treatment). RESULTS: Twelve infants and 8 children enrolled in the core studies, and 2 infants and 7 children in the extension study. After 24 weeks of treatment, parenteral support (PS) requirements reduced by ≥20% from baseline for 4 infants (57.1%) and 4 children (66.7%) receiving teduglutide and for 2 infants receiving SoC (50.0%). One infant (50.0%) and 4 children (80.0%) receiving teduglutide maintained the ≥20% reduction in PS at 48 weeks of treatment. Two children receiving teduglutide achieved enteral autonomy, after 12 weeks and 28 weeks of treatment, respectively. All adverse events (AEs) were in line with known impacts of SBS-IF and adverse reactions to teduglutide. Only one serious AE (abdominal pain) was considered related to teduglutide. CONCLUSIONS: Short- and long-term treatment with teduglutide resulted in clinically meaningful reductions in PS requirements for infants and children with SBS-IF. Teduglutide was well tolerated, and efficacy improved with longer-term treatment.

Infant liver biochemistry is different than current laboratory accepted norms.

The purpose is to study liver biochemistry in a well-defined cohort of term infants. The methods include healthy term infants (n = 619) provided blood samples at 3 and 6 months of age when participating to the DIABIMMUNE study. The infants were followed up at clinical study visits 3, 6, 12, 18, 24, and 36 months the participation rate being 88.6% at the end of follow-up, while none disclosed any signs of a liver disease. The serum levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), total bilirubin (BIL), and conjugated bilirubin (BIL-conj) were determined using Siemens Atellica CH 930 analyzers. The results are at 3 months of age, the upper 90% CI for ALT, AST, ALP, GGT, BIL, and BIL-conj were higher than the current upper reference limits in our accredited hospital laboratory. At 6 months, the upper 90% CIs for ALT had declined but was still higher than the cut-offs for a raised value. The upper 90% CI for AST remained as high as at 3 months, whereas ALP, BIL-conj, and GGT had decreased close to the current cut-offs. The type of feeding was associated with the levels of liver biochemistry. Exclusively or partially breastfed infants showed higher ALT, AST, BIL, and BIL-conj values at 3 months than formula-fed. Breastfed infants had higher AST, Bil, and Bil-conj values also at 6 months.  Conclusion: We encourage setting appropriate reference ranges for liver biochemistry for the first year of life and to note the type of feeding. What is Known: • Healthy infants may show higher values of liver biochemistry during their first year of life than in later life. • It has been speculated that type of feeding may play a role in liver biochemistry levels among infants. What is New: • In a cohort of healthy infants, several analytes of liver biochemistry were higher than the currently used upper reference limits at 3 and 6 months of age, and exclusively or partially breastfed infants showed higher values than formula-fed. • The findings address the importance of setting appropriate reference ranges for liver biochemistry for the first year of life.

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.

Longitudinal evolution of catheter-related bloodstream infections, kidney function and liver status in a nationwide adult intestinal failure cohort.

OBJECTIVES: The development of intestinal failure-related complications in Finnish adults is unknown. This study aimed to investigate the incidence of catheter-related bloodstream infections (CRBSI), and the longitudinal changes in biochemical liver and kidney tests in a nationwide cohort. MATERIALS AND METHODS: The search for Finnish adults with intestinal failure (IF) utilized a survey to Finnish health-care providers (n = 111) with the potential to provide long-term parenteral support (PS) for adult IF. Our nationwide, cross-sectional cohort included all IF patients aged ≥ 18 years who had received PS for ≥ 120 d in 2017. Data regarding CRBSI and biochemical liver and kidney tests were collected from patient records at the start of PS up to the latest available measurement in 2017. RESULTS: In the nationwide cohort of 52 patients, the CRBSI incidence was 1.35/1000 catheter days. Seventy-three percent of CRBSI in a long-term catheter led to catheter replacement. During a median PS duration of 27.5 (interquartile range [IQR] 11.3-57.3) months, a statistically significant median change occurred in estimated glomerular filtration rate (eGFR; -8.5 ml/min/1.73 m2, IQR -30-7, p = .005) and alkaline phosphatase (ALP; 26 U/l, IQR -11-95, p = .019). In a multiple regression model for eGFR at data collection, baseline eGFR and age were strong explanatory variables. CONCLUSIONS: Incidence of CRBSI, but not treatment strategies, in this nationwide adult IF population correspond well to those reported from specialized centers. Decreased kidney function and abnormal liver test results are frequent findings, and even more so over time, emphasizing the importance of regular monitoring.

Prediction, identification and progression of histopathological liver disease activity in children with intestinal failure.

BACKGROUND & AIMS: Diagnostic criteria, progression risk and optimal monitoring for intestinal failure (IF)-associated liver disease (IFALD) remain undefined. We assessed predictors, non-invasive markers and progression of histopathological liver disease in patients with IF. METHODS: In total, 77 children with IF and median age of 1.7 years underwent diagnostic liver biopsy, which was repeated in 48 patients after 2.9 years with simultaneous evaluation of liver biochemistry, liver stiffness, serum citrulline (a surrogate for viable enterocyte mass), spleen size, esophageal varices and clinical data. Patients were staged according to histopathological liver disease activity: active IFALD (cholestasis and/or inflammation), chronic IFALD (significant fibrosis and/or steatosis), or no IFALD (none of these features). RESULTS: Diagnostic liver biopsy revealed active, chronic or no IFALD in 48%, 21% and 31% of patients. Active IFALD was segregated by low serum citrulline, parenteral nutrition (PN) dependency and young age, while weaning off PN and older age predicted chronic IFALD. Although the liver histopathology in most patients either normalized (52%) or transformed to a less reactive (chronic) disease stage (23%), 19% of patients retained and 6.3% progressed to an active cholestatic/inflammatory IFALD phenotype. Decreased serum citrulline and PN-dependency also predicted active IFALD in follow-up biopsies. Increased median liver biochemistry values and liver stiffness only associated with active IFALD, which was accurately identified by gamma-glutamyltransferase (GGT), citrulline and liver stiffness, their combinations reaching diagnostic and follow-up AUROC values above 0.90. CONCLUSIONS: Active IFALD, essentially predicted by intestinal disruption and PN-dependency, was accurately detected by GGT, liver stiffness and citrulline, which together with recent advances in clinical management options, provides new avenues for monitoring and targeted liver protection in patients with IF. LAY SUMMARY: Liver disease is a common and critical complication in patients with intestinal failure, who require intravenous nutrition for survival due to severe intestinal dysfunction. We showed that both intravenous nutrition dependency and intestinal disruption essentially predicted development of active histopathological liver disease, which persisted in 25% of patients during long-term follow-up and could be accurately detected without the need for liver biopsy. Identification of the active and potentially progressive histopathology offers new possibilities for monitoring and targeted liver protection in patients with intestinal failure.

Expression of fibrosis-related genes in liver allografts: Association with histology and long-term outcome after pediatric liver transplantation.

BACKGROUND: Unexplained graft fibrosis and inflammation are common after pediatric liver transplantation (LT). OBJECTIVE: We investigated the graft expression of fibrogenic genes and correlated the findings with transplant histopathology and outcome. METHODS: Liver biopsies from 29 recipients were obtained at a median of 13.1 (IQR: 5.0-18.4) years after pediatric LT. Control samples were from six liver-healthy subjects. Hepatic expression of 40 fibrosis-related genes was correlated to histological findings: normal histology, fibrosis with no inflammation, and fibrosis with inflammation. Liver function was evaluated after a subsequent follow-up of 9.0 years (IQR: 8.0-9.4). RESULTS: Patients with fibrosis and no inflammation had significantly increased gene expression of profibrotic TGF-ß3 (1.17 vs. 1.02 p = .005), CTGF (1.64 vs. 0.66 p = .014), PDGF-α (1.79 vs. 0.98 p = .049), PDGF -ß (0.99 vs. 0.76 p = .006), integrin-subunit-ß1 (1.19 vs. 1.02 p = .045), α-SMA (1.12 vs. 0.58 p = .013), type I collagen (0.82 vs. 0.53 p = .005) and antifibrotic decorin (1.15 vs. 0.99 p = .045) compared to patients with normal histology. mRNA expression of VEGF A (0.84 vs. 1.06 p = .049) was lower. Only a few of the studied genes were upregulated in patients with both fibrosis and inflammation. The gene expression levels showed no association with later graft outcome. CONCLUSIONS: Altered hepatic expression of fibrosis-related genes is associated with graft fibrosis without concurrent inflammation.

Neurocognitive and Motor Functions in Biliary Atresia Patients: A Cross-sectional, Prospective National Cohort Study.

OBJECTIVES: The aim of the study was to evaluate the neurocognitive and motor development of biliary atresia (BA) patients in childhood and adolescence and to identify risk factors for impaired outcome. METHODS: We invited all BA patients between ages 1 and 20 years followed up at Helsinki University Children's Hospital in Finland between 1 January 2019 to 31 January 2020 to participate. All participants underwent age-appropriate validated neurocognitive tests. Participants between 3.0 and 16.9 years of age were assessed with the Movement Assessment Battery for children, version 2. Guardians of participants between ages 5 and 17 years filled the Five-to-Fifteen-Revised (5-15R) parental questionnaire. RESULTS: The mean (±standard deviation [SD]) total intelligence quotient (IQ) of the 39 participants was 91 ±â€Š15, lower compared with test norms (mean IQ 100 ±â€Š15, P < 0.01). Earlier clearance of jaundice (COJ) had a positive effect on mean (±SD) total IQ (COJ <3 months 96 ±â€Š13 vs COJ ≥3 months post-portoenterostomy 84 ±â€Š13, P < 0.05). Out of 30 participants assessed, 13 (43%) were either at risk or fulfilled the criteria for impaired motor development. Guardians reported elevated rates of functional difficulties affecting everyday life. There were no significant differences between native liver and liver transplanted (16/41%) groups. CONCLUSIONS: IQ is moderately, and motor scores markedly impaired in BA patients compared with normative data. Standardised cognitive and motor assessment before school-age for all BA patients is advisable to identify individuals in need of additional support.

Outcomes in Hirschsprung's disease with coexisting learning disability.

This study describes functional and health-related quality of life (HRQoL) outcomes in patients with Hirschsprung's disease (HSCR) with associated learning disability or neurodevelopmental delay (LD), completing a core outcome set for HSCR. This was a cross-sectional study from a tertiary pediatric surgery center. Patients treated between 1977 and 2013 were prospectively contacted to complete an outcomes survey. Children under 12 and older patients with LD were assisted to complete these by a proxy. Bowel and urologic function were assessed (Rintala's BFS and modified DanPSS) along with HRQoL (PedsQL/GIQLI/SF-36). Thirty-two patients with LD were compared to 186 patients with normal cognition. Patients with LD had 76% survival over the follow-up period, compared to 99% in the remainder of the cohort. Poor functional outcomes were common in the patients with LD, considerably higher than cognitively normal patients: with weekly issues withholding stool, soiling and fecal accidents in over half of patients surveyed (44-60%), and urinary incontinence in 46%. Use of permanent stoma was significantly higher (22% vs. 4%; p = 0.001). HRQoL was worse in domains of physical functioning in adults and children but not for social or emotional domains in adults. Subgroup analysis of patients with Down syndrome suggested similar functional results but better QoL. Multivariate analysis demonstrated a dramatically higher incidence of poor continence outcomes in patients with LD (adjusted OR 9.6 [4.0-23]).Conclusions: We provide LD-specific outcomes showing inferior function but similar HRQoL to other patients with HSCR, this is much needed in the counselling of families of these children. What is Known: • Hirschsprung's disease is commonly associated with syndromes or other anomalies with resultant cognitive impairments. • The outcomes for these patients specifically have been poorly described in the literature. What is New: • Objective functional and quality of life surveys demonstrate significant differences from patients without cognitive impairment. • Patients with learning disability Patients with associated LD were almost ten times more likely to have an associated poor functional outcome, with very little impact on proxy-reported quality of life.

Long-term Outcomes and Health Perceptions in Pediatric-onset Portal Hypertension Complicated by Varices.

OBJECTIVES: Outcomes of pediatric-onset portal hypertension are poorly defined. We aimed to assess population-based long-term outcomes of pediatric-onset portal hypertension complicated by varices. METHODS: All children with esophageal varices (n = 126) were identified from 14,144 single nationwide referral center endoscopy reports during 1987 to 2013, and followed up through national health care and death registers. A questionnaire was sent to survivors (n = 94) of whom 65 (69%) responded. RESULTS: Nineteen underlying disorders included biliary atresia (35%), extrahepatic portal vein obstruction (35%), autosomal recessive polycystic kidney disease (7%), and other disorders (23%). During median follow-up of 15.2 (range 0.5-43.1) years patients underwent median 9 (1-74) upper gastrointestinal endoscopies. Esophageal varices were first observed at a median age of 4.0 (0.3-18.2) years, 112 (89%) patients underwent median 6 (1-56) sclerotherapy/banding sessions, and 61 (48%) experienced median 2 (range 1-20) variceal bleeding episodes. Forty-eight surgical shunt procedures were performed to 41 (36%) patients and 38% underwent liver transplantation. Portal hypertensive biliopathy was diagnosed in 4 patients. Hepatopulmonary syndrome necessitated liver transplantation in 2 patients, hepatic encephalopathy in 2, and hepatorenal syndrome in 1. No patient died of variceal bleeding. Patient-reported perception of health on a scale of 1 to 10 was 9 (range 4-10), and 86% reported no current symptoms attributable to esophageal varices. CONCLUSIONS: Pediatric-onset portal hypertension is a heterogeneous disease with significant long-term morbidity, requiring multimodal approach with considerable resources and continuation of follow-up in adulthood. Although mortality to variceal bleeding was avoided, bleeding episodes recurred also in adulthood, while patient-reported health of long-term survivors was encouraging.

Impaired Bone Health in Children With Biliary Atresia.

OBJECTIVES: The aim of the study was to examine the frequency of rickets and bone fractures and to assess areal bone mineral density (aBMD) in childhood among patients with biliary atresia (BA). METHODS: We gathered data on all patients diagnosed with BA in Finland that survived to ≥1 year of age between 1 January 2000 to 30 June 2018. Data on gestational age, birth weight, postsurgical medications, and history of rickets and bone fractures were collected retrospectively. Serum levels of 25-hydroxyvitamin D [25(OH)D] postportoenterostomy (PE) were collected. Plain radiographs and dual energy X-ray absorptiometry (DXA) measurements of study subjects were reviewed. RESULTS: Out of 49 patients, 7 (14%) were diagnosed with rickets during infancy. Clearance of jaundice [odds ratio 0.055, 95% confidence interval [CI] 0.00266-0.393; P < 0.01] was a protective factor against rickets. Sufficient 25(OH)D levels were reached 3 months post-PE. Eleven (22%) patients suffered at least one bone fracture (range 1-9) during childhood and adolescence. In DXA measurements, median lumbar spine aBMD anthropometrically adjusted z-scores were as follows: in native liver survivors 0.8 (interquartile range [IQR] -1.9 to 1.4) at 5 and -0.3 (IQR -1.3 to 0.8) at 10 years and for liver transplanted patients 0.4 (IQR -0.2 to 1.1) at 5 and 0.6 (IQR -0.1 to 1.3) at 10 years. CONCLUSIONS: BA patients have an increased risk for rickets and bone fractures compared with the normal population. Most BA patients have aBMD within normal range between 5 and 10 years of age irrespective of liver transplantation status.

Neonatal Intestinal Failure Is Independently Associated With Impaired Cognitive Development Later in Childhood.

OBJECTIVE: The impact of pediatric intestinal failure (IF) on neurodevelopment beyond infancy has not been systematically studied. Our aim was to evaluate cognitive and motor impairment and to identify risk factors for adverse outcomes among children with IF. METHODS: We conducted a cross-sectional single-center study at the Helsinki University Children's Hospital. Patients with IF with >60 days of parental nutrition (PN) dependency aged between 3 and 16 years (n = 40) were invited to participate. The cognitive and motor skills were evaluated using validated tests: Wechsler Preschool and Primary Scale of Intelligence, 3rd edition, Wechsler Intelligence Scale for Children, 4th edition, and Movement Assessment Battery for Children, 2nd edition. RESULTS: All the patients attending the study tests (n = 30, males = 24) were included. Their median age, gestational age, and birth weight was 7.5 (range 3-16) years, 35 (interquartile range [IQR] 28-38) weeks and 2238 (IQR 1040-3288) grams, respectively. Median duration of PN was 13 (IQR 5-37) months and 9 patients were currently on PN. Median intelligence quotient was 78 (IQR 65-91) and 10 (35%) patients had an intelligence quotient under 70 (-2 standard deviation). Significant motor impairment was detected in 10 patients (36%) and milder difficulties in 8 (28%). Adverse cognitive outcome was associated with neonatal short bowel syndrome, number of interventions under general anesthesia, and length of inpatient status, whereas adverse motor outcome was associated with prematurity. CONCLUSION: Clinically significant cognitive and motor impairments are alarmingly common among neonatal patients with IF. We recommend early neurodevelopmental follow-up for all children with IF.

Cancer morbidity and mortality after pediatric solid organ transplantation-a nationwide register study.

BACKGROUND: The prevalence of malignancies after pediatric solid organ transplantation was evaluated in a nationwide study. METHODS: All patients who had undergone kidney, liver, or heart transplantation during childhood between the years 1982 and 2015 in Finland were identified. The inclusion criteria were age under 16 years at transplantation and age over 18 years at the last follow-up day. A total of 233 (137 kidney, 53 liver, and 43 heart) transplant recipients were enrolled. Controls (n = 1157) matched by the year of birth, gender, and hometown were identified using the Population Register Center registry. The cancer diagnoses were searched using the Finnish Cancer Registry. RESULTS: Altogether 26 individuals diagnosed with cancer were found, including 18 transplant recipients. Cancer was diagnosed at a median of 12.0 (IQR 7.8-17.8) years after the transplantation. The transplant recipients' risk for cancer was significantly higher when compared with the controls (HR 14.7; 95% CI 6.4-33.9). There was no difference for different graft types. Sixty-one percent of cancers among the transplant recipients were diagnosed at age older than 18 years. CONCLUSION: The risk for cancer is significantly higher among young adults having undergone solid organ transplantation during childhood in comparison with population controls. Careful follow-up and attention to prevent cancers throughout adulthood are warranted.

Incidence and long-term outcomes of surgically treated childhood hepatic malignancies in Finland.

AIM: To analyse incidence, treatment and outcomes of paediatric liver malignancies in Finland during 1987-2017. METHODS: Medical records and national cancer registry data of 47 children with liver malignancies were reviewed. Survival was calculated with the Kaplan-Meier method. RESULTS: During follow-up, liver malignancy incidence remained stable at 1.1:106 . Altogether, 42 patients with hepatoblastoma (n = 24), hepatocellular carcinoma (n = 11) and undifferentiated embryonal sarcoma (n = 7) underwent surgery at median age 4.6 (interquartile range, 2.0-9.6) years and were followed up for 13 (7.0-19) years. Cumulative 5-year survival was 86% for hepatoblastoma, 41% for hepatocellular carcinoma and 67% for undifferentiated embryonal sarcoma. Five-year survival was decreased among hepatoblastoma patients aged ≥ 2.4 years (73% versus 100%, P = .040), with PRETreatment EXTent of disease IV (PRETEXT, 60% vs 100%, P = .004), and with recurrent disease (67% vs 88%, P = .029). Recurrent/residual disease associated with decreased 5-year survival in hepatocellular carcinoma (0% vs 83%, P = .028). Survival was similar among 19 transplanted and 23 resected patients. In total, 14 deaths occurred either for the underlying malignancy (n = 8), adverse effects of chemotherapy (n = 5) or unrelated reasons (n = 1). CONCLUSION: Outcomes for PRETEXT I-III hepatoblastoma and un-metastasized hepatocellular carcinoma were encouraging. Adverse effects of chemotherapy significantly contributed to mortality.

Management strategies and treatment results of pediatric choledochal malformations in the Nordic countries.

BACKGROUND: Incidence and long-term outcomes of choledochal malformations (CMs) in children remain unclear. METHODS: Clinical characteristics, operative details, complications, and follow-up data were collected from eight pediatric surgical centers in Sweden, Norway, Denmark, and Finland, which also answered a questionnaire addressing management practices. RESULTS: During 2000-2017, 126 pediatric CMs were diagnosed, corresponding an incidence of 1:37,400. Diagnostic, treatment, and follow-up practices varied markedly. Of patients with complete clinical data (n = 119), 85% and 11% had type I and IV CMs and were managed by open hepaticojejunostomy at median age of 2.5 (interquartile range 0.46-5.8) years. Associated malformations were more common in fusiform and type IV (23%) than cystic CMs (8%, p = 0.043). Pancreaticobiliary maljunction was more frequently confirmed in patients presenting with pancreatitis (26% vs. 7%, p = 0.005) and with fusiform CMs (56% vs. 25%, p = 0.001). Cholangitis/pancreatitis episodes, occurring in 12% during postoperative follow-up of 4.0 (2.0-7.9) years, associated with longer surveillance (OR 1.32, 95% CI 1.13-1.54, p < 0.001). However, only two thirds of centers continued follow-up until adulthood. No malignancies were reported. CONCLUSIONS: CM incidence was higher than traditionally reported among Western populations. Although open hepaticojejunostomy carries good short-term outcomes, long-term morbidity is noteworthy. Standardized evidence-based management strategies and long-term follow-up are encouraged.