Antenatally Detected Choledochal Malformation: What Are We Waiting For?

INTRODUCTION: An increasing proportion of congenital choledochal malformation (CCM) are being detected on antenatal ultrasound. However, the actual timing of its surgical correction remains controversial with some series showing an excess of complications the earlier the operation. The aim of this study was to characterize the pathophysiological aspects of this cohort from the perspective of age at surgery in order to inform a more rational basis for clinical decision-making. METHODS: We analysed a prospective database of CCM acquired over a 26-year period (Jan. 1997 to Dec. 2022) for patient demography; details of pre- and post-natal imaging; age at surgical intervention; operative complications (Clavien-Dindo classification) and outcome. Data are quoted as median (IQR). All comparisons are non-parametric. A P value of 0.05 was accepted as significant. RESULTS: There were 58 (72% female) children with an antenatally-detected CCM from a total of 265 (21.8%) in the series. These were classified as Type 1C (n = 47; 81%), type 4C (n = 3; 5%) and Type 5 (n = 8; 14%). There were no Type 1F lesions in this cohort. Median age at surgery was 113 (IQR 57-198) days. Postnatal cyst (US) size varied from 12 to 130 mm but there was little evidence of a relationship between this and post-natal liver biochemistry (e.g. bilirubin rS = 0.01, P = 0.44; AST rS = 0.14, P = 0.19). Choledochal pressure measurements (n = 46) showed resting pressures of 12 (9-21) mmHg with no significant correlation with age (P = 0.4) or aspartate aminotransferase (P = 0.2) or γ-glutamyl transferase (P = 0.06). The cohort was divided into 2 groups (Early and Late) based on the median age at surgery (all open) (113 days). Biliary obstruction was more common in the Early group (10 vs. 2; P = 0.01). Two perforations occurred, both in the Early group. With a deliberate policy of regular ultrasound-based follow-up we have seen no anastomotic complications (leak, stenosis, persistent intrahepatic biliary dilatation or stones) or post-operative cholangitis in any child [median follow-up 3.42 (1.30-8.05) years]. CONCLUSIONS: This is one of the largest series documenting the outcomes of antenatally-detected CCMs, certainly in Europe and North America. Such lesions are invariably cystic in nature, and either Types 1C, 4C or 5. The absence of complications using a policy of early intervention (where possible) in experienced hepatobiliary units was shown. EVIDENCE LEVEL: II.

The AST-to-Platelet Ratio Index (APRi) at Kasai Portoenterostomy: Standing the Test of Time.

AIMS: The outcomes following surgical treatment of infants with biliary atresia (BA) varies across the world with many possible confounding factors. APRi (AST-to-platelet ratio index) is a simple surrogate marker of liver fibrosis and we sought to determine its long-term relationship (if any) with outcome post-Kasai portoenterostomy (KPE). METHODS: Prospectively acquired database (Jan 1998-Dec 2021). Clearance of jaundice was defined as achieving <20 umol/L post-KPE. Categorical and survival data were tested using Chi2 tests and a log rank test respectively. P ≤ 0.05 was regarded as significant. Data are quoted as median (interquartile range) unless otherwise stated. RESULTS: There were 473 infants with a calculated APRi at time of KPE [0.70 (IQR 0.45-1.2)] and known outcomes. There was significant but moderate correlation with age at KPE (rS = 0.43; P < 0.0001). APRi was divided into quartiles (1st 0.11-0.44, n = 120; 2nd 0.45-0.69, n = 120; 3rd 0.70-1.18, n = 115 and 4th 1.2-15.1; n = 118). There was a clear distinction in APRi levels between CMV + ve BA and the other groups (Syndromic BA, Cystic BA, Isolated BA), with an overrepresentation of CMV IgM + ve BA in the higher APRi quartiles (Χ2 = 26.6; P = 0.0002). Clearance of jaundice showed a stepwise decrease across the quartiles (67%; 58%; 55%; 49%; overall Χ2 = 7.8, P = 0.049 and P = 0.005 for trend). Decreasing native liver survival also showed a significant trend (P = 0.01). CONCLUSION: APRi appears to be of fundamental prognostic value in stratifying the BA population. In our series, CMV status was associated with higher APRi score and appears to be different. This simple variable offers an objective method of assessing the biological status of BA at presentation and variability between different series. LEVEL OF EVIDENCE: II (prospective comparison).

Advances in understanding of biliary atresia pathogenesis and progression - a riddle wrapped in a mystery inside an enigma.

INTRODUCTION: Biliary atresia is a potentially fatal condition of the bile ducts - both intra- and extrahepatic, for which we have no cure. Though principally a cholestatic condition, much of its pathology stems from its tendency to aggressively induce liver fibrosis and ultimately cirrhosis, only partially restrained by the portoenterostomy. AREAS COVERED: This review is based on the current literature exploring the heterogeneous nature of biliary atresia. Thus, there are various phenotypes or variants of biliary atresia, each potentially with different etiological backgrounds caused by a number of hypothetical pathological mechanisms thought to be important in the genesis of the condition. Search methodology: the review (Oct. - Nov. 2022) is based on a search of PubMed (NLM) using main keyword 'biliary atresia' with supplementary searches using 'fibrosis'; 'inflammation'; 'BASM'; 'genetics'; 'surgery'; 'experimental'; 'etiology'; 'virology'; 'cases'; and 'syndromes.' EXPERT OPINION: Future developments will be made on matching clinical variants with a more distinct pathophysiological discrimination and those pathways linking the initial cholestatic phase of biliary atresia to the early stages of fibrosis.

Insights into the pathophysiology and classification of type 4 choledochal malformation.

INTRODUCTION: Type 4 choledochal malformations (CMs) can be defined as extra- and intrahepatic biliary dilatation. They are of uncertain etiology but make up about 20% of most series. The aim of this study was to investigate the pathophysiology and their natural history following surgical intervention. METHODS: Ambispective review of a single-center series of type 4 CM between 1996 and 2017. Perioperative imaging, intraoperative pressure monitoring, bile amylase, and long-term follow-up data were analyzed based on extrahepatic morphology [(cystic (C), fusiform (F)]. Data were expressed as median (range). Statistical analysis was performed with nonparametric tests. P < 0.05 was considered significant. RESULTS: 37 children had type 4 CM in the study period [age at surgery 4 (0.2-16) years] and could be further subdivided into cystic (4C) (n = 22) or fusiform (4F) (n = 15). There was significantly greater dilatation of the extrahepatic component in the cystic group [30 (11-94) versus 15 (8-90) mm; P = 0.0002] though there was no difference in left duct diameter [cystic 7.5 (0-17) mm versus fusiform 7.5 (3-16) mm; P = 0.86]. There was a trend to higher choledochal pressure in the cystic group [19 (4-40) versus 9 (6-25) mmHg; P = 0.09] and those in the fusiform group had higher bile amylase [8650 (3-890,000) versus 592 (1-123,000) IU/L; P = 0.01] and were older [4.1 (0.92-16.43) versus 2.4 (0.15-15.48) years; P = 0.03]. Children with type 4 CM were then separated simply on the basis of bile amylase into LOW (characterized by high pressure, cystic morphology and young age at surgery) and HIGH bile amylase (low pressure, fusiform morphology and older at time of surgery). CONCLUSIONS: We propose further division of type 4 CM into 4C and 4F on clinical and pathophysiological grounds. LEVEL OF EVIDENCE: II (prospective cohort).

Enteric neurospheres are not specific to neural crest cultures: implications for neural stem cell therapies.

OBJECTIVES: Enteric neural stem cells provide hope of curative treatment for enteric neuropathies. Current protocols for their harvesting from humans focus on the generation of 'neurospheres' from cultures of dissociated gut tissue. The study aims to better understand the derivation, generation and composition of enteric neurospheres. DESIGN: Gut tissue was obtained from Wnt1-Cre;Rosa26Yfp/Yfp transgenic mice (constitutively labeled neural crest cells) and paediatric patients. Gut cells were cultured either unsorted (mixed neural crest/non-neural crest), or following FACS selection into neural crest (murine-YFP+ve/human-p75+ve) or non-neural crest (YFP-ve/p75-ve) populations. Cultures and resultant neurospheres were characterized using immunolabelling in vitro and following transplantation in vivo. RESULTS: Cultures of (i) unsorted, (ii) neural crest, and (iii) non-neural crest cell populations generated neurospheres similar in numbers, size and morphology. Unsorted neurospheres were highly heterogeneous for neural crest content. Neural crest-derived (YFP+ve/p75+ve) neurospheres contained only neural derivatives (neurons and glia) and were devoid of non-neural cells (i.e. negative for SMA, c-Kit), with the converse true for non-neural crest-derived (YFP-ve/p75-ve) 'neurospheres'. Under differentiation conditions only YFP+ve cells gave rise to neural derivatives. Both YFP+ve and YFP-ve cells displayed proliferation and spread upon transplantation in vivo, but YFP-ve cells did not locate or integrate within the host ENS. CONCLUSIONS: Spherical accumulations of cells, so-called 'neurospheres' forming in cultures of dissociated gut contain variable proportions of neural crest-derived cells. If they are to be used for ENS cell replacement therapy then improved protocols for their generation, including cell selection, should be sought in order to avoid inadvertent transplantation of non-therapeutic, non-ENS cells.

Neonatal stomas: does a separate incision avoid complications and a full laparotomy at closure?

PURPOSE: Enterostomy formation is a common outcome in emergency neonatal laparotomy. No consensus exists regarding optimal stoma site. This study aims to identify incidence of complications and closure details related to position of stomas. METHODS: This study is a retrospective case note review of emergency neonatal enterostomy formation over 11 years at a single institution. Patients were separated into two groups: stomas created through the laparotomy wound and stomas created through a separate incision. Demographic details, complications and closure details were ascertained. Differences between groups were analysed (Mann-Whitney test for continuous variables, Chi-squared test or Fisher's exact test for categorical variables). RESULTS: One hundred and thirteen stoma formations were examined in 106 patients (71 within laparotomy wound, 42 through a separate incision). Age, gestation, weight, wound-related and stoma-related complications were not significantly different between the groups. A trend towards a higher rate of full laparotomy at closure with stomas through the wound (p = 0.09) was seen. If stomas were sited adjacently, there was no difference in avoidance of full laparotomy at closure (p = 0.97). CONCLUSION: Stomas sited adjacently within the laparotomy wound are not related to increased complications and offer the same advantage of circumexcision at closure as stomas sited through a separate wound, without an additional abdominal wound.

Intestinal atresia in association with gastroschisis: a 26-year review.

PURPOSE: We reviewed our experience with gastroschisis (GS) complicated by intestinal atresia over the last 26 years. Our aim was to determine the effect of different management strategies employed and the morbidity associated with this condition in our unit. METHODS: A retrospective casenote review was carried out. Data regarding the operative management of the GS and atresia was recorded. Primary outcome measures included time to commence and establish full enteral feeds, duration of parenteral nutrition, complications and outcome. RESULTS: Of 179 neonates with GS, 23 also had intestinal atresia. 13 underwent primary closure of the defect, 5 had patch closure and 5 had a silo placed. 4 atresias were 'missed' at first operation. The 19 recognised atresias were managed either by stoma formation, primary anastomosis or deferred management with subsequent primary anastomosis. There was wide variation in the outcomes of patients in each group. CONCLUSION: Differences in outcome between the management strategies are likely to reflect an inherent variability in patient condition, site of atresia, and bowel suitability for anastomosis at first surgery, rather than the mode of surgical management. Individual management plans should be tailored to the clinical condition of each patient.