Long-term morbidity and follow-up after choledochal malformation surgery; A plea for a quality of life study

Much about the aetiology, pathophysiology, natural course and optimal treatment of choledochal malformation remains under debate. Surgeons continuously strive to optimize their roles in the management of choledochal malformation. Nowadays the standard treatment is complete cyst excision followed by Rouxen-Y hepaticojejunostomy, be it via a laparotomy, laparoscopy or robot-assisted procedure. Whatever surgical endeavor is undertaken, it will be a major operation, with significant morbidity. It is important to realize that especially in asymptomatic cases, this is considered prophylactic surgery, aimed at preventing symptoms but even more important the development of malignancy later in life. A clear overview of long-term outcomes is therefore necessary. This paper aims to review the long-term outcomes after surgery for choledochal malformation. We will focus on biliary complications such as cholangitis, the development of malignancy and quality of life. We will try and identify factors related to a worse outcome. Finally, we make a plea for a large scale study into quality and course of life after resection of a choledochal malformation, to help patients, parents and their treating physicians to come to a well-balanced decision regarding the treatment of a choledochal malformation. (C) 2020 The Authors. Published by Elsevier Inc

Current Concepts of Biliary Atresia and Matrix Metalloproteinase-7:A Review of Literature

Biliary atresia (BA) is a rare cholangiopathy of infancy in which the bile ducts obliterate, leading to profound cholestasis and liver fibrosis. BA is hypothesized to be caused by a viral insult that leads to over-activation of the immune system. Patients with BA are surgically treated with a Kasai portoenterostomy (KPE), which aims to restore bile flow from the liver to the intestines. After KPE, progressive liver fibrosis is often observed in BA patients, even despite surgical success and clearance of their jaundice. The innate immune response is involved during the initial damage to the cholangiocytes and further differentiation of the adaptive immune response into a T-helper 1 cell (Th1) response. Multiple studies have shown that there is continuing elevation of involved cytokines that can lead to the progressive liver fibrosis. However, the mechanism by which the progressive injury occurs is not fully elucidated. Recently, matrix metalloproteinase-7 (MMP-7) has been investigated to be used as a biomarker to diagnose BA. MMPs are involved in extracellular matrix (ECM) turnover, but also have non-ECM related functions. The role of MMP-7 and other MMPs in liver fibrosis is just starting to be elucidated. Multiple studies have shown that serum MMP-7 measurements are able to accurately diagnose BA in a cohort of cholestatic patients while hepatic MMP-7 expression correlated with BA-related liver fibrosis. While the mechanism by which MMP-7 can be involved in the pathophysiology of BA is unclear, MMP-7 has been investigated in other fibrotic pathologies such as renal and idiopathic pulmonary fibrosis. MMP-7 is involved in Wnt/beta-catenin signaling, reducing cell-to-cell contact by shedding of E-cadherin, amplifying inflammation and fibrosis via osteopontin (OPN) and TNF-alpha while it also appears to play a role in induction of angiogenesis This review aims to describe the current understandings of the pathophysiology of BA. Subsequently, we describe how MMP-7 is involved in other pathologies, such as renal and pulmonary fibrosis. Then, we propose how MMP-7 can potentially be involved in BA. By doing this, we aim to describe the putative role of MMP-7 as a prognostic biomarker in BA and to provide possible new therapeutic and research targets that can be investigated in the future

Meta-analysis of risk of developing malignancy in congenital choledochal malformation

BackgroundCholedochal malformations comprise various congenital cystic dilatations of the extrahepatic and/or intrahepatic biliary tree. Choledochal malformation is generally considered a premalignant condition, but reliable data on the risk of malignancy and optimal surgical treatment are lacking. The objective of this systematic review was to assess the prevalence of malignancy in patients with choledochal malformation and to differentiate between subtypes. In addition, the risk of malignancy following cystic drainage versus complete cyst excision was assessed. MethodsA systematic review of PubMed and Embase databases was performed in accordance with the PRISMA statement. A meta-analysis of the risk of malignancy following cystic drainage versus complete cyst excision was undertaken in line with MOOSE guidelines. Prevalence of malignancy was defined as the rate of biliary cancer before resection, and malignant transformation as new-onset biliary cancer after surgery. ResultsEighteen observational studies were included, reporting a total of 2904 patients with a median age of 36 years. Of these, 312 in total developed a malignancy (107 per cent); the prevalence of malignancy was 73 per cent and the rate of malignant transformation was 34 per cent. Patients with types I and IV choledochal malformation had an increased risk of malignancy (P = 0016). Patients who underwent cystic drainage had an increased risk of developing biliary malignancy compared with those who had complete cyst excision, with an odds ratio of 397 (95 per cent c.i. 240 to 655). ConclusionThe risk of developing malignancy among patients with choledochal malformation was almost 11 per cent. The malignancy risk following cystic drainage surgery was four times higher than that after complete cyst excision. Complete surgical resection is recommended in patients with choledochal malformation. Choledochal cysts should be resecte

Predicting intestinal recovery after necrotizing enterocolitis in preterm infants

Background: Intestinal recovery after NEC is difficult to predict in individuals. We evaluated whether several biomarkers predict intestinal recovery after NEC in preterm infants. Methods: We measured intestinal tissue oxygen saturation (rintSO2) and collected urinary intestinal-fatty acid binding protein (I-FABPu) levels 0–24 h and 24–48 h after NEC onset, and before and after the first re-feed. We assessed intestinal recovery in two ways: time to full enteral feeding (FEFt; below or equal/above group’s median) and development of post-NEC complications (recurrent NEC/post-NEC stricture). We determined whether the rintSO2, its range, and I-FABPu differed between groups. Results: We included 27 preterm infants who survived NEC (Bell’s stage ≥ 2). Median FEFt was 14 [IQR: 12–23] days. Biomarkers only predicted intestinal recovery after the first re-feed. Mean rintSO2 ≥ 53% combined with mean rintSO2range ≥ 50% predicted FEFt < 14 days with OR 16.7 (CI: 2.3–122.2). The rintSO2range was smaller (33% vs. 51%, p < 0.01) and I-FABPu was higher (92.4 vs. 25.5 ng/mL, p = 0.03) in case of post-NEC stricture, but not different in case of recurrent NEC, compared with infants without complications. Conclusion: The rintSO2, its range, and I-FABPu after the first re-feed after NEC predicted intestinal recovery. These biomarkers have potential value in individualizing feeding regimens after NEC

Time to full enteral feeding after necrotizing enterocolitis in preterm-born children is related to neurodevelopment at 2-3 years of age

BACKGROUND: Necrotizing enterocolitis (NEC) is associated with poorer neurodevelopment. It is, however, unclear which factors besides surgery affect neurodevelopment in preterm-born children surviving NEC. AIMS: We determined whether time to full enteral feeding (FEFt) and post-NEC complications after NEC were associated with neurodevelopment. STUDY DESIGN: Prospective observational cohort study. SUBJECTS: Two to three year old preterm-born children who survived NEC (Bells stage ≥ 2). We categorized children in two groups, one group shorter and equal and one group longer than the group's median FEFt. Post-NEC complications included recurrent NEC and/or post-NEC stricture. OUTCOME MEASURES: Bayley Scales of Infants and Toddler Development III (Bayley-III) and Child Behavior Checklist (CBCL). Associations between Bayley-III and CBCL scores with FEFt and Post-NEC complications were determined using linear regression analyses, adjusted for severity of illness and potential confounders. RESULTS: We included 44 children, median gestational age of 27.9 [IQR: 26.7-29.3] weeks, birth weight 1148 [IQR: 810-1461] grams. Median FEFt after NEC was 20 [IQR: 16-30] days. Median follow-up age was 25.7 [IQR: 24.8-33.5] months. FEFt > 20 days was associated with lower cognitive and lower motor composite scores of the Bayley-III (B: -8.6, 95% CI -16.7 to -0.4, and B: -9.0, 95% CI, -16.7 to -1.4). FEFt was not associated with CBCL scores. Post-NEC complications (n = 11) were not associated with Bayley-III scores nor with CBCL scores. CONCLUSIONS: Prolonged FEFt after NEC in preterm-born children surviving NEC is associated with lower cognitive and lower motor composite scores at the age of 2-3 years. These results show the importance of limiting the duration of the nil per mouth regimen if and when possible

The effect of enteral bolus feeding on regional intestinal oxygen saturation in preterm infants is age-dependent:a longitudinal observational study

Background The factors that determine the effect of enteral feeding on intestinal perfusion after preterm birth remain largely unknown. We aimed to determine the effect of enteral feeding on intestinal oxygen saturation (r(int)SO(2)) in preterm infants and evaluated whether this effect depended on postnatal age (PNA), postmenstrual age (PMA), and/or feeding volumes. We also evaluated whether changes in postprandial r(int)SO(2) affected cerebral oxygen saturation (r(c)SO(2)). Methods In a longitudinal observational pilot study using near-infrared spectroscopy we measured r(int)SO(2) and r(c)SO(2) continuously for two hours on postnatal Days 2 to 5, 8, 15, 22, 29, and 36. We compared preprandial with postprandial values over time using multi-level analyses. To assess the effect of PNA, PMA, and feeding volumes, we performed Wilcoxon signed-rank tests or logistic regression analyses. To evaluate the effect on r(c)SO(2), we also used logistic regression analyses. Results We included 29 infants: median (range) gestational age 28.1 weeks (25.1-30.7) and birth weight 1025 g (580-1495). On Day 5, r(int)SO(2) values decreased postprandially: mean (SE) 44% (10) versus 35% (7), P = .01. On Day 29, r(int)SO(2) values increased: 44% (11) versus 54% (7), P = .01. Infants with a PMA >= 32 weeks showed a r(int)SO(2) increase after feeding (37% versus 51%, P = .04) whereas infants with a PMA = 32 weeks when greater volumes of enteral feeding are tolerated. We speculate that at young gestational and postmenstrual ages preterm infants are still unable to increase intestinal oxygen saturation after feeding, which might be essential to meet metabolic demands. Trial registration: For this prospective longitudinal pilot study we derived patients from a larger observational cohort study: CALIFORNIA-Trial, Dutch Trial Registry NTR4153

Clinical usefulness of splanchnic oxygenation in predicting necrotizing enterocolitis in extremely preterm infants:a cohort study

Background: Impaired intestinal microcirculation seems to play an important role in the pathogenesis of necrotizing enterocolitis (NEC). A previous study showed that a SrSO2 &lt; 30% is associated with an increased risk of developing of NEC. We aimed to determine the clinical usefulness of the cut off &lt; 30% for SrSO2 in predicting NEC in extremely preterm neonates.Methods: This is a combined cohort observational study. We added a second cohort from another university hospital to the previous cohort of extremely preterm infants. SrSO2 was measured for 1–2 h at days 2–6 after birth. To determine clinical usefulness we assessed sensitivity, specificity, positive and negative predictive values for mean SrSO2 &lt; 30. Odds ratio to develop NEC was assessed with generalized linear model analysis, adjusting for center.Results: We included 86 extremely preterm infants, median gestational age 26.3 weeks (range 23.0-27.9). Seventeen infants developed NEC. A mean SrSO2 &lt; 30% was found in 70.5% of infants who developed NEC compared to 33.3% of those who did not (p = 0.01). Positive and negative predictive values were 0.33 CI (0.24–0.44) and 0.90 CI (0.83–0.96), respectively. The odds of developing NEC were 4.5 (95% CI 1.4–14.3) times higher in infants with SrSO2 &lt; 30% compared to those with SrSO2 ≥ 30%.Conclusions: A mean SrSO2 cut off ≥ 30% in extremely preterm infants between days 2–6 after birth may be useful in identifying infants who will not develop NEC.</p

Necrotizing Enterocolitis Associated with Congenital Heart Disease:a Different Entity?

Background: Necrotizing enterocolitis (NEC) predominantly occurs in preterm infants (PT-NEC). In term neonates, NEC occurs more frequently when a congenital heart disease is present (CHDNEC). Our aim was to evaluate differences and similarities in disease characteristics of PT-NEC versus CHD-NEC.Methods: In this retrospective case-control study we identified all CHD infants who developed NEC Bell's stage &gt;= 2 in our center from 2004 to 2014. We randomly selected (1:2 ratio) PT-NEC infants from the same period. Biochemical and clinical variables were retrieved from patient files.Results: We found 18 CHD-NEC infants and selected 36 PT-NEC infants (gestational age 28.3 [25-35.6] weeks vs. 38.6 [31.7-40.7] weeks). Postnatal age at onset was significantly lower in CHD-NEC patients (4 [2-24] vs. 11 [4-41] days, p &lt;0.001). Lowest pH levels were lower (7.21 [7.01-7.47] vs. 7.27 [6.68-7.39], p = 0.02), and highest CRP levels were higher (112.5 mg/L [5.0-425.0] vs. 66.0 [52-189.0], p = 0.05) in PT-NEC vs. CHD-NEC. Anatomic localisation of the disease differed: the colon was significantly more often involved in CHD-NEC versus PT-NEC (86% vs. 33%, p = 0.03). Mortality caused by NEC was not different (22% vs. 11%, p = 0.47).Conclusion: While outcome of NEC in both groups is similar, the predominant NEC localisation differed between CHD-NEC and PT-NEC patients. This suggests that both variants of the disease have a different underlying pathophysiological mechanism that predisposes different intestinal regions to develop NEC.Type of Study: Retrospective Case-Control Study. (C) 2018 Elsevier Inc. All rights reserved.</p

Gut Microbiota Composition of Biliary Atresia Patients Before Kasai Portoenterostomy Associates With Long-term Outcome

BACKGROUND AND AIMS: Biliary atresia (BA) is a cholestatic, fibro-obliterative cholangiopathy of unknown etiology. BA is primarily treated by a surgical approach, i.e. the Kasai portoenterostomy (KPE), to obtain clearance of jaundice (COJ). The gut microbiota (GM) composition has been associated with the course of several cholestatic liver diseases. It is largely unknown, however, whether GM composition associates with the outcome of KPE. We compared the GM composition of BA patients and controls and assessed if GM composition before KPE was related to COJ after KPE. METHODS: We compared feces of term born BA patients before KPE and controls (patients undergoing inguinal hernia repair) by 16S rRNA sequencing. Composition and alpha diversity of the GM were compared between BA and controls before KPE and after KPE, between patients with COJ vs. without COJ (total serum bilirubin < or ≥ 20 μmol/L < 6mo post-KPE). RESULTS: Alpha diversity was comparable between BA (n = 12, age 1.6[1.3-1.8]mo) and controls (n = 6, age 2.0[1.4-2.1]mo; P = 0.22). Compared to controls, BA patients had lower abundances of Bifidobacteriaceae (β=-1.98, P < 0.001) and Lachnospiraceae (β=-1.84, P = 0.007), and higher abundances of Streptococcus (β=1.13, P = 0.003). The alpha diversity prior to KPE correlated negatively with COJ (R = -0.63, P = 0.03). Lower alpha diversity pre-KPE was associated with COJ [+] (βlogit = -0.64, P = 0.04). We observed greater abundances of genus Acinetobacter (β=1.27, P = 0.03) and family Clostridiaceae (β=1.45, P = 0.03) and lower abundances of the family Enterobacteriaceae, (genera Klebsiella (β=-1.21, P = 0.01), Salmonella (β=-1.57, P = 0.02)) in COJ [+] vs. COJ [-]. CONCLUSIONS: The gut microbiota of biliary atresia patients prior to Kasai portoenterostomy associates with outcome, clearance of jaundice, suggestive of predictive and mechanistic roles of the gut microbiota composition in bile homeostasis