Histopathological findings from the investigation of paediatric acute hepatitis of unknown aetiology, United Kingdom 2022.

In 2022, there were global reports of increased numbers of acute hepatitis not explained by hepatitis A-E virus infection in children. This manuscript summarises histopathology results from 20 patients in the United Kingdom who underwent liver transplant or had a liver biopsy as part of aetiological investigations. All available histopathological samples were reviewed centrally as part of the outbreak investigation. A working group comprised of infection specialists, hepatologists and histopathologists met virtually to review the cases, presentation, investigations and histopathology. All 20 liver samples had evidence of inflammation without significant interface activity, and submassive confluent pan-lobular or multilobular hepatocellular necrosis. Overall, the predominant histopathological findings were of acute nonspecific hepatitis with submassive hepatic necrosis and central vein perivenulitis and endothelitis. Histopathological findings were a poor indicator of aetiology.

Noninvasive scores are poorly predictive of histological fibrosis in paediatric fatty liver disease.

OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children. Roughly a quarter of paediatric patients with NAFLD develop nonalcoholic steatohepatitis and fibrosis. Here, we evaluated the diagnostic accuracy of previously published noninvasive fibrosis scores to predict liver fibrosis in a large European cohort of paediatric patients with NAFLD. METHODS: The 457 patients with biopsy-proven NAFLD from 10 specialized centers were included. We assessed diagnostic accuracy for the prediction of any (F ≥ 1), moderate (F ≥ 2) or advanced (F ≥ 3) fibrosis for the AST/platelet ratio (APRI), Fibrosis 4 score (FIB-4), paediatric NAFLD fibrosis score (PNFS) and paediatric NAFLD fibrosis index (PNFI). RESULTS: Patients covered the full spectrum of fibrosis (F0: n = 103; F1: n = 230; F2: n = 78; F3: n = 44; F4: n = 2). None of the scores were able to accurately distinguish the presence of any fibrosis from no fibrosis. For the detection of moderate fibrosis, area under the receiver operating characteristic curve (AUROC) were: APRI: 0.697, FIB-4: 0.663, PNFI: 0.515, PNFS: 0.665, while for detection of advanced fibrosis AUROCs were: APRI: 0.759, FIB-4: 0.611, PNFI: 0.521, PNFS: 0.712. Fibrosis scores showed no diagnostic benefit over using ALT ≤ 50/ > 50 IU/L as a cut-off. CONCLUSIONS: Established fibrosis scores lack diagnostic accuracy to replace liver biopsy for staging of fibrosis, giving similar results as compared to using ALT alone. New diagnostic tools are needed for Noninvasive risk-stratification in paediatric NAFLD.

Paediatric acute hepatitis of unknown aetiology: a national investigation and adenoviraemia case-control study in the UK.

BACKGROUND: An increase in acute severe hepatitis of unknown aetiology in previously healthy children in the UK in March, 2022, triggered global case-finding. We aimed to describe UK epidemiological investigations of cases and their possible causes. METHODS: We actively surveilled unexplained paediatric acute hepatitis (transaminase >500 international units per litre) in children younger than 16 years presenting since Jan 1, 2022, through notifications from paediatricians, microbiologists, and paediatric liver units; we collected demographic, clinical, and exposure information. Then, we did a case-control study to investigate the association between adenoviraemia and other viruses and case-status using multivariable Firth penalised logistic regression. Cases aged 1-10 years and tested for adenovirus were included and compared with controls (ie, children admitted to hospital with an acute non-hepatitis illness who had residual blood samples collected between Jan 1 and May 28, 2022, and without known laboratory-confirmed diagnosis or previous adenovirus testing). Controls were frequency-matched on sex, age band, sample months, and nation or supra-region with randomised selection. We explored temporal associations between frequency of circulating viruses identified through routine laboratory pathogen surveillance and occurrence of cases by linear regression. SARS-CoV-2 seropositivity of cases was examined against residual serum from age-matched clinical comparison groups. FINDINGS: Between Jan 1 and July 4, 2022, 274 cases were identified (median age 3 years [IQR 2-5]). 131 (48%) participants were male, 142 (52%) were female, and one (<1%) participant had sex data unknown. Jaundice (195 [83%] of 235) and gastrointestinal symptoms (202 [91%] of 222) were common. 15 (5%) children required liver transplantation and none died. Adenovirus was detected in 172 (68%) of 252 participants tested, regardless of sample type; 137 (63%) of 218 samples were positive for adenovirus in the blood. For cases that were successfully genotyped, 58 (81%) of 72 had Ad41F, and 57 were identified as positive via blood samples (six of these were among participants who had undergone a transplant). In the case-control analysis, adenoviraemia was associated with hepatitis case-status (adjusted OR 37·4 [95% CI 15·5-90·3]). Increases in the detection of adenovirus from faecal samples, but not other infectious agents, in routine laboratory pathogen surveillance correlated with hepatitis cases 4 weeks later, which independently suggested an association (ß 0·06 [95% CI 0·02-0·11]). No association was identified for SARS-CoV-2 antibody seropositivity. INTERPRETATION: We observed an association between adenovirus 41F viraemia and paediatric acute hepatitis. These results can inform diagnostic testing recommendations, clinical management, and exploratory in vitro or clinical studies of paediatric acute hepatitis of unknown aetiology. The role of potential co-factors, including other viruses and host susceptibility, requires further investigation. FUNDING: None.

Impact of long-term administration of maralixibat on children with cholestasis secondary to Alagille syndrome.

There is growing interest in, but limited data about, intestinal bile acid transport inhibitors as treatment for cholestatic liver disease. The current analyses combine two similar randomized placebo-controlled trials with subsequent extension phases investigating the impact of maralixibat in children with severe cholestasis secondary to Alagille Syndrome (n = 57). The primary outcomes were measures of pruritus (ItchRO[Obs]) and clinician scratch scale (CSS), both increasing in severity from 0 to 4) and quality of life (QoL) (Parent PedsQL and Multidimensional Fatigue Scale module [MFS] scaled 0-100 with increased QoL) at week 48 of the extension phase relative to the baseline of the placebo-controlled trials (week 13). Secondary assessments included other clinical and biochemical parameters assessed in participants at week 72 or end of treatment (after week 48). At week 48, statistically and clinically significant least square mean (95% CI) improvements in pruritus and QoL were observed (ItchRO[Obs] -1.59 [-1.81, -1.36], CSS -1.36 [-1.67, -1.05], PedsQL +10.17 [4.48, 15.86], and multidimension fatigue [MFS] +13.97 [7.85, 20.08]). At week 48, serum bile acids, platelet count, and cholesterol decreased, whereas alanine aminotransferase (ALT) increased and total bilirubin (TB) and albumin were stable. Changes were durable at week 72 and end of treatment. There were no deaths; 2 participants underwent liver transplantation. Study drug was discontinued in 9 participants after treatment-emergent adverse events, 6 of which were events of increased ALT or TB. Conclusion: Maralixibat administration was associated with marked improvement in pruritus and QoL. Interpretation of these findings is complicated by the complex natural history of severe cholestasis in Alagille syndrome.

European paediatric non-alcoholic fatty liver disease registry (EU-PNAFLD): Design and rationale.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder in children and has the potential to progress to advanced fibrosis/cirrhosis, end-stage liver disease and hepatocellular carcinoma. However, the natural history of the condition is poorly understood and there are no approved treatments. The European Paediatric Non-Alcoholic Fatty Liver Disease Registry (EU-PNAFLD) is a multi-centre registry of paediatric NAFLD that will serve as a prospective, observational, natural history study and provide a tractable back-bone to support recruitment into subsequent interventional trials. Collection of samples into a bio-repository will facilitate translational studies, including genome sequencing and metabolomics. EU-PNAFLD will work closely alongside the existing adult European NAFLD Registry to obtain data on clinical outcomes after 20-30 years. Through an international, well-characterised large-scale cohort, EU-PNAFLD will address the key questions in paediatric NAFLD and benefit patients with the condition.

Liver Failure in Early Infancy: Aetiology, Presentation, and Outcome.

OBJECTIVE: Acute liver failure (ALF) in early infancy is rare and challenging to recognize and manage. We aim to describe the presentation and outcome of infants with ALF according to their final aetiology to elucidate features to facilitate early recognition leading to prompt diagnosis and management. METHODS: All infants presenting within 120 days from birth with liver failure were included in a retrospective review over a 19-year period. The aetiology, clinical features, presenting investigations, and outcome were collected. RESULTS: Seventy-eight young infants presented with ALF. The aetiology was established in 94% and included metabolic disease (36%), hypoxic-ischaemic (HI) insult (19%), infection (17%), neonatal haemochromatosis (9%), and infiltrative disease (9%). Infections, infiltrative disease, and acute HI insult usually resulted in higher transaminases and international normalized ratio, whereas neonatal haemochromatosis and tyrosinaemia were characterized by lower or near normal transaminases. Overall jaundice was not visible in 24% of infants at presentation. Forty-five (58%) infants were alive at discharge from hospital. Survival at 1 year was 53% and survival with native liver 50%. Later deaths occurred in infants with mitochondrial disease. Six infants received a liver transplant and 4 subsequently died from their underlying disease. CONCLUSION: ALF should be considered in any young infant with a coagulopathy as transaminases and/or bilirubin levels can be near normal at presentation. Better intensive care and the judicious use of liver transplantation may have contributed to the improved outcomes for this group compared with previous decades.

Histologic oddities at the porta hepatis in biliary atresia.

PURPOSE: Highly unusual histologic findings at the porta hepatis in 3 infants who underwent Kasai portoenterostomy for biliary atresia are reported. METHODS: Portoenterostomy was performed using a standard operative technique. Serial transverse sections of the excised portal plate were examined by light microscopy along with sections from the distal extrahepatic biliary remnants, gallbladder, and liver biopsy. RESULTS: Of 61 consecutive infants who underwent Kasai portoenterostomy for biliary atresia, 3 were found to have highly unusual histologic features at the porta hepatis. All had type 3 biliary atresia. Two had hilar biliary ductules lined in part by squamous epithelium, and the third had a focus of mature hyaline cartilage surrounded by perichondrium adjacent to biliary ductules. In each case, these unusual histologic features were localized to the porta hepatis in the region of the transected portal plate. CONCLUSIONS: The presence of hyaline cartilage at the portal plate is likely to be an expression of defective morphogenesis, thus supporting the concept of disordered embryogenesis in the etiology of biliary atresia. Squamous epithelium within biliary ductules might also reflect a similar mechanism but could alternatively be an unusual metaplastic response to inflammation at this site.

Kasai portoenterostomy: 12-year experience with a novel adjuvant therapy regimen.

AIM: The role of adjuvant therapy with corticosteroids and choleretics after Kasai portoenterostomy for biliary atresia (BA) remains uncertain. Experience with a novel postoperative adjuvant therapy regimen is reported. METHODS: Between 1994 and 2006, 71 infants with BA were referred. Four died from uncorrectable congenital heart disease/cardiorespiratory failure without undergoing portoenterostomy, 7 underwent primary liver transplantation (3 referred > or = 19 weeks of age), and 60 underwent portoenterostomy at a median of 51 (10-104) days. Of these, 55 (92%) had type 3 BA and 6 had the BA splenic malformation syndrome. Fifty (83%) received the following adjuvant therapy beginning on postoperative day 5: oral dexamethasone 0.3 mg/kg bd for 5 days, 0.2 mg/kg bd for 5 days, and 0.1 mg/kg bd for 5 days together with oral ursodeoxycholic acid 5 mg/kg bd and phenobarbitone 5 mg/kg nocte, both of which were continued for 1 year. All infants received routine perioperative prophylactic antibiotics. RESULTS: Overall, 42 of 60 (70%) infants cleared their jaundice (bilirubin < 20 micromol/L): 38 of 50 (76%) with the dexamethasone/ursodeoxycholic acid regimen compared with 4 of 10 (40%) not receiving this adjuvant treatment. There were 4 late deaths after portoenterostomy: 2 from associated congenital disorders and 2 after liver transplantation. Of the remaining 56 children, 39 (70%) are currently alive with their native liver at a median follow-up of 3.3 years and 17 are alive after liver transplantation. Surgical complications occurred in 3 after portoenterostomy: adhesive bowel obstruction (2) and an anastomotic leak. One infant had gastrointestinal bleeding that may have been related to dexamethasone, but this resolved with ranitidine. There were no perioperative septic complications. CONCLUSION: In this series, adjuvant postoperative treatment with a short course of oral dexamethasone and longer-term ursodeoxycholic acid significantly improved the outcome after Kasai portoenterostomy.

Immediate extubation of children following liver transplantation is safe and may be beneficial.

BACKGROUND: Immediate tracheal extubation of selected adult patients after orthotopic liver transplant (OLT) is common practice. We hypothesized that selected children may be safely extubated immediately after OLT and avoid potentially deleterious effects of artificial ventilation and sedation. METHODS: After June 2002, we chose immediate extubation unless a specific contraindication was identified. Charts of all children undergoing OLT between June 2002 and February 2005 were reviewed to audit safety and outcome of this approach. Comparative data were obtained for children undergoing first elective OLT at other UK centers. RESULTS: Forty-six cadaveric liver transplants were performed in 40 patients: 26 of 34 (76%) elective transplants and 4 of 12 (33%) urgent transplants were extubated immediately after surgery. Eight of 14 (57%) children weighing less than 10 kg were successfully extubated. One child required reintubation after developing transfusion-related acute lung injury. There were no other events compromising patient or graft. Small recipient size, split/reduced grafts, preexisting respiratory disease, retransplantation, and acute liver failure did not individually preclude successful immediate extubation. After elective OLT, the mean duration of intensive care stay was significantly shorter in the extubated group than in those who were ventilated (2.5 vs. 6.1 days, P<0.01). All children receiving a liver transplant at other UK centers in 2003 were ventilated postoperatively. However, the median duration of intensive care stay (2 days) was the same as in our series. CONCLUSIONS: Immediate extubation of selected children after OLT is safe. It may enhance patient recovery, benefit graft physiology, and reduce intensive care requirement.

Multidisciplinary management of surgical disorders of the pancreas in childhood.

OBJECTIVES: To describe the frequency and range of pancreatic disorders in children requiring surgical intervention and to highlight the importance of multidisciplinary management. METHODS: An audit of all children under 17 years of age referred with surgical disorders of the pancreas or pancreatitis to a regional pediatric gastroenterology unit in the United Kingdom during a 10-year period. A retrospective chart review of clinical features, pathology and outcome was undertaken. RESULTS: Surgical intervention was required for the following pancreatic disorders: persistent hyperinsulinemic hypoglycemia of infancy (n = 4), pancreatic tumors (n = 5), pancreaticobiliary malunion (n = 12), pancreatic trauma (n = 6) and pancreatitis (n = 10). The indications for surgery in acute pancreatitis were a persistent pseudocyst (n = 1) and treatment of an underlying cause of pancreatitis (n = 4); in chronic pancreatitis, surgery was used to treat symptomatic pancreatic duct strictures (n = 4). One child died of a progressive lymphoma but all others who underwent surgery are alive and well. All 33 children with acute pancreatitis, including four with pancreatic necrosis, survived. CONCLUSIONS: Surgery for pancreatic disorders in children is rarely required but may be necessary a) for definitive management of primary pancreatic pathology, b) to treat sequelae of acute or chronic pancreatitis and c) to treat an underlying cause of pancreatitis. There is a broad spectrum of potential pathologies. These patients are best managed by a multidisciplinary team approach.

The use of recalcified citrated whole blood -- a pragmatic approach for thromboelastography in children.

BACKGROUND: Thromboelastography (TEG) is an established way of monitoring the coagulation status of children and adults requiring blood products during surgery. Serial measurements are performed using a nearside machine and blood product prescription may be titrated against changes in TEG. There may also be useful applications when the patient is remote from the TEG machine but these are limited because TEG is usually performed on fresh native whole blood within 6 min of venepuncture. Citrated whole blood can be used for TEG if transport time is more than 6 min. We wished to establish whether TEG parameters for citrated whole blood were comparable with those of native whole blood in healthy children. METHODS: Blood was obtained from 14 healthy children undergoing minor surgical procedures, at the time of intravenous cannula insertion for anaesthesia. Each sample was divided: TEG was performed on part of the sample in its fresh native state at 6 min and second portion of the sample was citrated, kept at room temperature and TEG was performed at 30 min after recalcification. RESULTS: There was a significant difference in TEG parameters (r, k, alpha, MA and LY30) for fresh native whole blood and recalcified citrated whole blood (paired t-test). CONCLUSIONS: The normal range for fresh native whole blood TEG parameters is well established, which is routinely used in practice. There was a significant difference between TEG parameters for fresh native whole blood and citrated whole blood. We recommend that a specific normal range be established for citrated whole blood to enable it to be used in clinical practice.

Endoscopic rectal sparing in children with untreated ulcerative colitis.

BACKGROUND: Ulcerative colitis (UC) typically is associated with a confluent proctitis, whereas rectal sparing may be seen in large bowel Crohn disease (CD). A few studies have reported rectal sparing in UC and suggested that this might indicate a more severe form of the disease. This study aimed to determine the prevalence and prognostic significance of rectal sparing in children with newly diagnosed, untreated UC. METHODS: The records of all children with untreated UC presenting to a regional pediatric gastroenterology service between January 1996 and December 2001 were retrospectively reviewed. Patients were divided into two groups according to the endoscopic appearance of the rectum: Group 1 (proctitis) and Group 2 (rectal sparing). Clinical features, intractability index (duration of active disease as a proportion of length of follow-up), response to treatment, relapse index (number of recurrences per year), and the need for surgery were compared. RESULTS: Thirty children with untreated UC were identified. Seven (23%) had rectal sparing at initial endoscopy, but disease distribution was otherwise similar in both groups. Presenting symptoms were similar in those with and without rectal sparing. In Group 1, 20 (87%) children achieved remission with initial medical treatment, compared with 3 (43%) in Group 2 (P < 0.05). The intractability index was higher in children with rectal sparing, but the difference was not statistically significant (P = 0.22). During a median follow-up period of 2 years, one (4%) child in Group 1 and two (29%) children in Group 2 experienced primary sclerosing cholangitis, and two (29%) children with rectal sparing required colectomy, compared with none in Group 1. CONCLUSIONS: Endoscopic rectal sparing was seen in 23% of children with newly diagnosed, untreated UC, but this feature did not correlate with presenting symptoms. However, the presence of rectal sparing may indicate more aggressive disease that is less responsive to medical treatment.