Clinical Spectrum of Children with Acute Hepatitis of Unknown Cause.

BACKGROUND: Since January 2022, there has been an increase in reports of cases of acute hepatitis of unknown cause in children. Although cases have been reported across multiple continents, most have been reported in the United Kingdom. Investigations are ongoing to identify the causative agent or agents. METHODS: We conducted a retrospective study involving children referred to a single pediatric liver-transplantation center in the United Kingdom between January 1 and April 11, 2022. These children were 10 years of age or younger and had hepatitis that met the case definition of the U.K. Health Security Agency for confirmed acute hepatitis that was not hepatitis A through E and did not have a metabolic, inherited or genetic, congenital, or mechanical cause, in the context of a serum aminotransferase level greater than 500 IU per liter. We reviewed medical records and documented demographic characteristics, clinical features, and results of liver biochemical, serologic, and molecular tests for hepatotropic and other viruses, as well as radiologic and clinical outcomes. The outcomes were classified as an improving condition, liver transplantation, or death. RESULTS: A total of 44 children had hepatitis that met the confirmed case definition, and most were previously healthy. The median age was 4 years (range, 1 to 7). Common presenting features were jaundice (in 93% of the children), vomiting (in 54%), and diarrhea (in 32%). Among the 30 patients who underwent molecular testing for human adenovirus, 27 (90%) were positive. Fulminant liver failure developed in 6 patients (14%), all of whom received a liver transplant. None of the patients died. All the children, including the 6 who received liver transplants, were discharged home. CONCLUSIONS: In this series involving 44 young children with acute hepatitis of uncertain cause, human adenovirus was isolated in most of the children, but its role in the pathogenesis of this illness has not been established.

The Outcome of A Centralization Program in Biliary atresia: 20 years and beyond.

OBJECTIVE: Biliary atresia (BA) is a rare disease and reported outcomes of surgical management, typically a Kasai portoenterostomy (KPE), vary considerably across the world. Centralization has been proposed to improve this. SUMMARY BACKGROUND DATA: A national centralization programme was started in Jan. 1999, involving 3 English units with co-located liver transplant facilities. As the program has now reached the 20-year point, the main aim was to update outcome statistics and identify trends. METHODS: Prospective registry and database. The main measures of outcome were (i) time to KPE, (ii) Clearance of Jaundice (CoJ), defined as reaching a bilirubin value of <20µmol/L (≈1.5 mg/dL), and (iii) actuarial native liver survival (NLS) and overall survival (OS). Data are quoted as median (IQR) and non-parametric statistical comparison used with P<0.05 regarded as significant. RESULTS: 867 infants were born with BA and managed between January 1999 and December 2019. Death occurred without intervention (n=10, 1.1%) or were subject to primary transplant (n=26, 3.0%); leaving 831 (95.9%) infants who underwent KPE at median age of 51 (IQR 39-64) days. Age at KPE reduced over the period (P=0.0001) becoming 48(35-57) days in the last 5-year era. CoJ was achieved in 505/831 (60.6%), also increasing over the period (P=0.002). 42 (5.0%) died post-KPE and 384 were transplanted, leaving 405 alive with their native livers at last follow-up. Of the 412 children transplanted, there were 23 (5.6%) deaths, leaving 387 alive. 5-year and 10-year native liver survival were 51.3% (95% CI 54.8-47.8) and 46.5% (95% CI 50.1 - 42.9) and overall survival were 91.5% (95% CI 93.2 - 89.4) and 90.5% (95% CI 92.3 - 88.2%) respectively. CONCLUSIONS: There have been continued improvements in efficiency over the period of centralization with a significant reduction in time to KPE and improved CoJ following KPE. Overall survival in this disease remains >90%.

Long-term outcomes of pediatric liver transplantation using organ donation after circulatory death: Comparison between full and reduced grafts.

BACKGROUND: The shortage of donors' livers for pediatric recipients inspired the search for alternatives including donation after cardiac death (DCD). METHODS: Retrospective review of pediatric liver transplant (PLT) using DCD grafts. Patients were divided into either FLG or RLG recipients. Pre-transplant recipient parameters, donor parameters, operative parameters, post-transplant recipient parameters, and outcomes were compared. RESULTS: Overall, 14 PLTs from DCD donors between 2005 and 2018 were identified; 9 FLG and 5 RLG. All donors were Maastricht category III. Cold ischemia time was significantly longer in RLG (8.2 h vs. 6.2 h; p = .038). Recipients of FLG were significantly older (180 months vs. 7 months; p = .012) and waited significantly longer (168 days vs. 22 days; p = .012). Recipients of RLG tended to be sicker in the immediate pre-transplant period and this was reflected by the need for respiratory or renal support. There was no significant difference between groups regarding long-term complications. Three patients in each group survived more than 5 year post-transplant. One child was re-transplanted in the RLG due to portal vein thrombosis but failed to survive after re-transplant. One child from FLG also died from a non-graft-related cause. CONCLUSIONS: Selected DCD grafts are an untapped source to widen the donor pool, especially for sick recipients. In absence of agreed criteria, graft and recipient selection for DCD grafts should be undertaken with caution.

Acute-on-chronic liver failure: A 20-year retrospective review of a tertiary paediatric liver centre.

AIM: Acute-on-chronic liver failure (ACLF) is an acute deterioration of pre-existing chronic liver disease related to a precipitating event. We characterised paediatric ACLF at Birmingham Children's Hospital (BCH) utilising European Association of Liver Disease CLIF criteria, including prevalence, triggers and outcomes. METHODS: All BCH patients from 2000 to 2020 with CLD who underwent initial liver transplant or died on the transplant waiting list or whilst too unwell to be listed were reviewed. RESULTS: From 2000 to 2020, 24 (4%) children with ACLF were identified. Death occurred in 18 (75%). Transplant occurred in 9 (36%), 3 of which died. ACLF triggers were sepsis organism negative 11 (46%), sepsis organism positive 8 (33%) and GI bleed 5 (17%). Bilirubin at the time of transplant/death in those with ACLF who lived compared with those who died was 529 umol/L (381) versus 665 (210) (p=0.38), creatinine 138 umol/L (147) versus 67 (46) (p=0.41), PT 33 sec (14) versus (32 (15) (p = 0.72), Grade 3, 4 hepatic encephalopathy 1 (17%) versus 10 (56%) (p = 0.17), vasopressor use 1 (17%) versus 17 (94%) (p = 0.001) and ventilation 3 (50%) versus 17 (94%) (p = 0.035). CONCLUSION: Acute-on-chronic liver failure whilst infrequent has high rates of mortality. The use of vasopressors and ventilation is more frequent in those who die from ACLF.

Hepatopulmonary Syndrome in Children: A 20-Year Review of Presenting Symptoms, Clinical Progression, and Transplant Outcome.

Hepatopulmonary syndrome (HPS) in stable patients with cirrhosis can easily be overlooked. We report on the presenting symptoms, disease progression, and outcomes after liver transplantation (LT) in children with HPS. Twenty patients were diagnosed with HPS between 1996 and 2016. The etiologies were as follows: biliary atresia (n = 9); alpha-1-antitrypsin deficiency (n = 2); cryptogenic liver disease (n = 3); and others (n = 6). HPS presentations were as follows; dyspnea (n = 17) and pneumonia (n = 3). For diagnostic confirmation, the following techniques were used: technetium-99m-labeled macroaggregated albumin lung perfusion scan (n = 13) or contrast echocardiogram (n = 7). There were 16 patients listed for LT, with a median age at HPS diagnosis of 10 years and an average wait from listing to LT of 9 weeks. A marked rise in hemoglobin (Hb; median, 125-143.5 g/L) and modest decrease in oxygen saturation (SpO2 ; median 91% to 88% room air) were evident over this time. Patients' need for assisted ventilation (1 day), pediatric intensive care unit (PICU) stay (3 days), and total hospital stay (20 days) were similar to our general LT recipients-the key difference in the postoperative period was the duration of supplementary O2 requirement. Hb of ≥130 g/L on the day of LT correlated with a longer PICU stay (P value = 0.02), duration of supplementary O2 (P value = 0.005), and the need for the latter beyond 7 days after LT (P value = 0.01). Fifteen patients had resolution of their HPS after LT. The 5-, 10-, and 20-year survival rates were unchanged at 87.5%. None had a recurrence of HPS. In conclusion, HPS is a life-threatening complication of cirrhosis which usually develops insidiously. This combined with the often-stable nature of the liver disease leads to delays in diagnosis and listing for LT. Progressive polycythemia extends the need for supplementary O2 and PICU stay. We advocate screening for HPS with a combination of SpO2 and Hb monitoring to facilitate earlier recognition, timely LT, and shortened recovery periods.

Intention to Split Policy: A Successful Strategy in a Combined Pediatric and Adult Liver Transplant Center.

OBJECTIVE: The primary aim of this study is to evaluate the role of split liver transplantation (SLT) in a combined pediatric and adult liver transplant center. The secondary aim is to reflect on our clinical practice and discuss strategies to build a successful split program using an "intention to split policy." BACKGROUND: SLT is an established procedure to expand the organ pool and reduce wait list mortality; however, technical and logistic issues are limiting factors. METHODS: Prospectively collected data and outcomes of SLT procedures performed between November 1992 and March 2014 were analyzed retrospectively. To assess the effect of standardization and learning curve, the experience was divided into 2 time periods. RESULTS: Out of 3449 liver transplant procedures performed, 516(15%) were SLT. The recipients included 266 children (290 grafts; 56%) and 212 adults (226 grafts; 44%). The median donor age was 25(7-63 years) and the median weight was 70(22-111 kg). The cold and warm ischemic times improved significantly during the second period (SP) (2001-2014). With experience, there was a significant reduction in the biliary complications for both grafts. The introduction of "intention to split policy" resulted in a significantly increased usage of SLT. There was no mortality on the pediatric wait list for last 4 years. Over the last decade 65% of our pediatric transplants were SLT. The overall 1-, 5-, 10-year patient and graft survival of left graft recipients was 91%, 90%, and 89% and 90%, 87%, and 86%. For right grafts it was 87%, 82%, and 81% and 82%, 81%, and 79%, respectively. CONCLUSIONS: SLT is an effective surgical strategy to meet the demands in a combined adult and pediatric transplant center. Good outcomes can be achieved with a standardized technique.

The Broad Spectrum of Paediatric Pancreatic Disease: A Single-center 26-years Retrospective Review.

BACKGROUND: Paediatric pancreatic pathology and its management is rarely described. We present our experience. METHODS: A retrospective case-note review of all patients with pancreatic disease from 1995 to 2021 was completed. Data are quoted as median (range). RESULTS: Two hundred and twelve patients were identified with 75.9% presenting with pancreatitis. Referrals for pancreatitis increased during the study period and affected a wide age range (2 months-15.6 years). Acute pancreatitis (n = 118) (age 10.6 (0.18-16.3) years). The most common causes were idiopathic (n = 60, 50.8%) and biliary (n = 28, 23.8%). About 10% required treatment for complications or underlying biliary causes. Recurrent pancreatitis (n = 14) (11.6 (0.3-14.3) years). The most common cause was hereditary pancreatitis (n = 6, 42.9%). One patient required endoscopic drainage of pseudocyst. Chronic pancreatitis (n = 29) (16 (0.38-15.5) years). The underlying diagnosis was idiopathic (n = 14, 48.4%) or hereditary pancreatitis (n = 10, 34.5%). 13 patients required active management, including pancreaticojejunostomies (n = 5). Blunt Trauma (n = 34) was managed conservatively in 24 (70.5%). 6 patients required open surgery, but 4 were managed by either endoscopy or interventional radiology. Pancreatic tumours (n = 13) presented at 11.2 (2.3-16) years. Pathology included pancreaticoblastomas (n = 3), solid pseudopapillary tumours (n = 3), neuroendocrine tumours (n = 2), acinar cell cystadenoma (n = 1), intraductal papillary mucinous neoplasm (n = 1), pancreatic insulinoma (n = 1), pancreatic ductal adenocarcinoma (n = 1), and embryonal rhabdomyosarcoma (n = 1). OTHERS (N = 4): Pancreatic cyst (n = 3) and annular pancreas (n = 1). CONCLUSION: Paediatric pancreatic disease spans a wide spectrum of both benign and malignant disease and benefits from access to specialist medical, surgical, endoscopic, and interventional radiology expertise. Referrals for paediatric pancreatitis are increasing, but aetiology is different to that seen in adults. LEVEL OF EVIDENCE: IV.

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.

Interventional radiology and open surgery: An effective partnership for solid organ trauma.

BACKGROUND: Management algorithms of paediatric blunt abdominal solid organ injury (BASOI) are evolving to include interventional radiology, but there are few studies documenting the application and clinical outcomes of cases in children. METHODS: A retrospective case note review of all paediatric BASOI at a single Paediatric Major Trauma Centre was completed. CT scans and injuries have been retrospectively graded according to AAST guidelines. RESULTS: In the period February 2012 - October 2019, there were 106 children (median age 10.6 years (range 10 days - 16 years)) with BASOI. Of these, 71% (n = 75) suffered liver injuries, 29% (n = 31) spleen, and 27% (n = 29) renal. 95 children (89.6%) were treated with non-operative management, of which 15% (n = 14) went on to require secondary operative management (surgery, n = 1 & interventional radiology, n = 14). There were no deaths or loss of organ in the group which required secondary operative management, regardless of the grade of injury. CONCLUSION: The majority of BASOI can be successfully treated conservatively, but IR is a useful additional tool in management for all grades of injury and is complementary to open surgery. LEVEL OF EVIDENCE: Level IV Case Series.

Fifteen-Year Single-Center Experience of Biliary Complications in Liver Trauma Patients: Changes in the Management of Posttraumatic Bile Leak.

INTRODUCTION: Management of posttraumatic bile leak has evolved over time in our unit, from endoscopic retrograde cholangiopancreatography (ERCP) stenting to intraperitoneal drainage (IPD) alone as first-line treatment for intraperitoneal bile leak. MATERIALS AND METHODS: Retrospective review of liver trauma patients from 2002 to 2017. Demographics, time and mode of diagnosis of bile leak, management, and outcome were analyzed of the box plot. RESULTS: In 118 patients, there were 28 traumatic bile leaks. Eighteen were free intraperitoneal and 10 were localized bilomas. The median time of diagnosis was 6 days following injury. The modes of diagnosis were preemptive hepatobiliary scintigraphy (18), computed tomography (CT) or ultrasound (7), and laparotomy (3). Free intraperitoneal biliary leak management included 11 IPD alone, 3 IPD plus ERCP, 2 IPD plus transcystic biliary stent (TBS), 1 operative cholangiogram, and 1 no intervention. Median time of IPD duration was 7 days (4-95) in IPD alone versus 14 days (6-40) in IPD + ERCP/TBS (p = 0.3). Median inpatient length of stay was 13 days (8-44) in IPD alone versus 12 days (8-22) in IPD + ERCP/TBS (p = 0.4). CONCLUSION: Placement of IPD alone, as first-line treatment, is safe and effective in the management of intraperitoneal bile leaks, avoiding the costs and potential complications of ERCP.

Effect of previous abdominal surgery and gallbladder appearance on biliary atresia outcomes.

BACKGROUND: Biliary atresia (BA) is typically treated by Kasai portoenterostomy (KPE), and there is a relationship between age at surgery and outcome. We hypothesize that previous abdominal surgery (PAS) for associated congenital intestinal conditions could be used to identify BA earlier, perhaps improving prognosis. METHODS: A retrospective case note review was performed of all BA patients at a single centre from 1999 to 2016. Demographics and clinical outcome data were collected. Additional data on laparotomy, parenteral nutrition, and referral were collected from patients who underwent PAS. Data are median (range). MAIN RESULTS: Two-hundred-and-fifty-seven children were reviewed. Of these, 16 (6.2%) underwent PAS on day 3 (0-23), during which 5 atretic gallbladders were noted. Gallbladder appearance was not referenced in the operation notes of 8 infants. Jaundice and acholic stools were noted at 4 (0-56) days and 21 (0-60) days, respectively. Age at KPE was comparable between PAS and the other patients (50 vs. 51days; P=0.78), but native liver survival was significantly lower after PAS (p<0.0001). Mortality rate was higher in PAS patients (25% vs. 4.5%; P=0.0007). Survival was unaffected by early referral of patients on finding an atretic gallbladder at surgery. CONCLUSION: About 6% of infants have already undergone abdominal surgery for biliary atresia associated intestinal anomalies. Routine gallbladder examination at time of laparotomy could have aided earlier diagnosis and treatment of biliary atresia in up to 80% of patients in this cohort. However, our data suggest that clinical outcome is poorer in biliary patients who undergo prior abdominal surgery and is not improved by earlier referral. LEVEL OF EVIDENCE: Prognostic study: Level III.

Selective intraoperative cholangiography during laparoscopic cholecystectomy in children is justified.

AIMS: Intraoperative cholangiograms (IOC) during laparoscopic cholecystectomy have been advocated to detect biliary anomalies and intraductal calculi. However, IOC increases operative time and patient irradiation, and therefore is not universally used. We hypothesise selective IOC may be a valuable tool in children. METHODS: A retrospective case note review was performed of all children who underwent laparoscopic cholecystectomy at a single institution by a single surgeon between January 2011 and March 2017. Demographics, radiological imaging, indications for surgery and IOC, and clinical outcomes were collected. Chi-Squared and Wilcoxon Rank Sum tests were used for comparisons. RESULTS: Sixty-two patients were reviewed. Median follow-up was 2 months (0.1-60), and 53 (85%) had complete symptom resolution following surgery. Twenty-two patients underwent IOC. Six (27%) had anomalies undetected by preoperative imaging. IOC identified common bile duct (CBD) stones in 2 patients which were cleared at laparoscopy. One patient required subsequent ERCP for impacted stones. One patient has a long common channel and pancreatitis. Two patients have CBD strictures. These last 3 are awaiting biliary reconstruction. Presence of CBD dilatation or ductal stones on preoperative ultrasound were significantly associated with positive findings at IOC. No complications resulted from IOC. Patients who did not undergo IOC did not represent with missed anomalies. CONCLUSIONS: Despite using multimodal preoperative imaging, IOC detected biliary anomalies requiring further treatment in 6/62 (10%) of patients undergoing laparoscopic cholecystectomy. Our data support the use of IOC in selective patients with CBD dilatation or suspicion of ductal stones on preoperative imaging. LEVEL OF EVIDENCE: Study of Diagnostic Test: Level III.

An investigation of minimisation criteria.

BACKGROUND: Minimisation can be used within treatment trials to ensure that prognostic factors are evenly distributed between treatment groups. The technique is relatively straightforward to apply but does require running tallies of patient recruitments to be made and some simple calculations to be performed prior to each allocation. As computing facilities have become more widely available, minimisation has become a more feasible option for many. Although the technique has increased in popularity, the mode of application is often poorly reported and the choice of input parameters not justified in any logical way. METHODS: We developed an automated package for patient allocation which incorporated a simulation arm. We here demonstrate how simulation of data can help to determine the input parameters to be used in a subsequent application of minimisation. RESULTS: Several scenarios were simulated. Within the selected scenarios, increasing the number of factors did not substantially adversely affect the extent to which the treatment groups were balanced with respect to the prognostic factors. Weighting of the factors tended to improve the balance when factors had many categories with only a slight negative effect on the factors with fewer categories. When interactions between factors were included as minimisation factors, there was no major reduction in the balance overall. CONCLUSION: With the advent of widely available computing facilities, researchers can be better equipped to implement minimisation as a means of patient allocation. Simulations prior to study commencement can assist in the choice of minimisation parameters and can be used to justify those selections.

A study on sensory properties of sodium reduction and replacement in Asian food using difference-from - control test.

This study examined the effects of sodium reduction and flavor enhancers on the sensory profile of two types of hawker foods commonly consumed in Singapore, namely chicken rice and mee soto broth. The 'difference-from-control' test was the method adopted in this study involving 24-29 trained panelists. Combinations included blind control, two levels of sodium reduction, and two levels of flavor enhancers in sodium-reduced recipes. In the sodium-reduced recipes, two levels of NaCl, 0.48% and 0.55%, for chicken rice, and 0.76% and 0.86% for mee soto (equivalent to 31% and 22% reduction in NaCl), were used. Monosodium glutamate (MSG) or Ajiplus (®) (a blend of MSG and nucleotides) at 0.20% and 0.40% were added to the recipes comprising a reduction of 40% in NaCl (equivalent to 31% and 22% reduction in sodium, respectively) compared with the control. It was found that the inclusion of MSG or Ajiplus (®) in 40% NaCl-reduced recipe resulted in a significant increase in perception of umami taste (P < 0.05) when compared to the control. By adding flavor enhancers into the 40%-reduced salt chicken rice recipes, the perception of saltiness was significantly increased when compared to 22% and 31% sodium reduced recipes. Similarly for mee soto broth, there was a significant increase in perception of chicken flavor, umami taste, mouthfeel sensation, and sweet taste (P < 0.05) with a decrease in the perception of sour and bitter taste when compared to control. By adding 0.40% MSG into the 40%-reduced salt recipes, the perception of saltiness was maintained when compared with control.

Biliary atresia in England and Wales: results of centralization and new benchmark.

INTRODUCTION: Biliary atresia (BA) is a rare, potentially life-threatening condition of the newborn presenting with conjugated jaundice. Typically, it is treated by an initial attempt to restore bile flow (the Kasai portoenterostomy [KP]) as soon as possible after diagnosis and, if this fails, liver transplantation. Since 1999, the treatment of BA has been centralized to 3 centers in England and Wales able to offer both treatment options. The aim of this study was to review the outcome of this policy change and provide a national benchmark. METHODS: The management of all infants born within England and Wales during the period January 1999 to December 2009 was assessed using 3 key performance indicators such as median time to KP, percentage clearance of jaundice (≤20 mol/L) post-KP, and 5- and 10-year native liver and true survival estimates. Data are quoted as median (range), and P < .05 was considered significant. RESULTS: A total of 443 infants had confirmed BA; and of these, most were isolated BA (n = 359), with 84 having other significant anomalies (but predominantly BA splenic malformation syndrome). Four infants died before any biliary intervention. Kasai portoenterostomy was performed in 424 infants (median age, 54 [range 7-209] days), and a primary liver transplant was performed in 15. Clearance of jaundice post-KP was achieved in 232 (55%). There were 41 deaths, including 4 (10%) without any intervention, 24 (58%) post-KP usually because of end-stage liver disease and mostly on a transplant waiting list, and 13 (32%) post-LT usually because of multiorgan failure. Overall, the 5- and 10-year native liver survival estimates were 46% (95% confidence interval [CI], 41-51) and 40% (95% CI, 34-46), respectively. The 5- and 10-year true patient survival estimates were 90% (95% CI, 88-93) and 89% (95% CI, 86-93), respectively. Outcome was worse for those with other anomalies (lower clearance of jaundice post-KP [43% vs 57%; odds ratio, 1.7; 95% CI, 1.04-2.8]; P = .02) and an increased mortality overall (eg, at 5 years, 72 [95% CI, 64-83] vs 94 [95% CI, 91-96]; χ(2) = 33; P < .0001). CONCLUSIONS: National outcome measures in BA appear better than those from previously published series from comparable countries and may be attributed to centralization of surgical and medical resources.