Development and validation of pFIB scores for exclusion of significant liver fibrosis in pediatric MASLD.

BACKGROUND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent pediatric liver disease, yet accurate risk scores for referral of children/adolescents with suspected clinically significant liver fibrosis are currently lacking. APPROACH RESULTS: Clinical and biochemical variables were collected in a prospective cohort of 327 children and adolescents with severe obesity, in whom liver fibrosis was evaluated by transient elastography. Logistic regression was performed to establish continuous (pFIB-c) and simplified (pFIB-6) diagnostic scores that accurately exclude significant (≥F2) fibrosis. Performance for each was compared to established non-invasive fibrosis scores. These scores were validated in elastography (n=504) and multiple biopsy-proven MASLD (n=261) cohorts. Patient sex, ethnicity, weight z-score, HOMA-IR index, ALT, and presence of hypertension were included in the scores. The pFIB-c and pFIB-6 exhibited good discriminatory capacity (c-statistic of 0.839 and 0.826), outperforming existing indices. Negative predictive values (NPV) were >90% for both scores in the derivation and elastography validation cohorts. Performance in the histological cohorts varied (AUROCs for the pFIB-c between 0.710 and 0.770), as the scores were less accurate when applied to populations in tertiary referral centers characterized by a high prevalence of significant fibrosis and high ALT levels. CONCLUSIONS: Analyzing several cohorts totaling approximately 1100 children and adolescents, we developed novel risk scores incorporating readily available clinical variables. In accordance with the aim of excluding pediatric MASLD-associated fibrosis, the scores performed better in non-selected cohorts of children and adolescents living with obesity than in patients referred to tertiary liver units.

Preservation of fat mass at the expense of lean mass in children with end-stage chronic liver disease.

BACKGROUND: Sarcopenia predicts morbidity and mortality in end-stage chronic liver disease (ESCLD). Here, we describe changes in body composition in children with ESCLD before and after liver transplantation (LT). METHODS: Retrospective analysis of whole body DXA scans performed before and after LT over 4 years. Appendicular and whole-body fat mass and lean mass were expressed as fat mass (FMI) and lean mass (LMI) index z-scores. Sarcopenia was defined as leg LMI z-score <-1.96. RESULTS: Eighty-three DXA scans of children before or after LT were studied. Sarcopenia had a positive correlation with weight (0.8, p < .01), height (0.48, p < .05), and BMI z-score (0.77, p < .01), as well as arm, trunk, and total mean mass indices. It correlated negatively with indices of hypersplenism: PLTs (-0.57, p < .01), Neu (-0.50, p < .05), WCC (-0.44, p < .05), and days to discharge (-0.46, p < .05). At baseline: 13/25 (52%) children were sarcopenic and stayed in the hospital after LT for longer. Eight were stunted with a higher WCC and Ne/Ly ratio. All had normal FM indices. One year after LT, 12/26 children remained sarcopenic. Seven were stunted. Two years after LT, 5/15 were sarcopenic, and 5 were stunted. Three years after LT, 1/10 was sarcopenic, and 2 were stunted. By 4 years after LT, 1/7 was sarcopenic, and the same one was stunted. FM indices remained normal. CONCLUSIONS: Sarcopenic patients stayed longer in the hospital after LT. Lean mass indices were mostly within the normal range by 4 years after LT. 32% of children were stunted, and markers of inflammation were correlated with stunting. Fat mass was preserved at the cost of lean mass.

Clinical outcomes of ABCB4 heterozygosity in infants and children with cholestatic liver disease.

OBJECTIVES: Biallelic variants in the adenosine triphosphate binding cassette subfamily B member 4 (ABCB4) gene which encodes the multidrug resistance 3 protein (MDR3) leads to progressive familiar intrahepatic cholestasis type 3. However, monoallelic variants are increasingly recognized as contributing to liver disease in adults. Our aim was to describe the clinical characteristics of MDR3 heterozygous variants in a large cohort of infants and children with cholestatic liver disease. METHODS: The clinical and genotypic data on pediatric patients seen at King's College Hospital, London, between 2004 and 2022 and found to harbour heterozygous variants in ABCB4 were reviewed. RESULTS: Ninety-two patients amongst 1568 tested were identified with a monoallelic variant (5.9%). The most common presenting problem was conjugated hyperbilirubinemia (n = 46; 50%) followed by cholelithiasis (n = 12; 13%) and cholestatic hepatitis (n = 10; 11%). The median values of liver biochemistry at presentation were: GGT 105 IU/L and total bilirubin 86 µmol/L. Thirty-two genetic variants were identified including 22 missense (69%), 4 deletions (13%), 5 splice site (16%) and 1 termination (3%). At a median follow up of 1 year there was resolution of liver disease. CONCLUSIONS: Rare variants in ABCB4 were found amongst infants and children with cholestatic liver disease. The presenting problems were variable and abnormalities tended to normalize over time. Those with severe mutations could develop liver disease later in life when exposed to further insult and should be counseled appropriately.

Acute hepatitis of unknown aetiology in children: a clinical update on the recent outbreak with mechanistic insights.

Since April 2022, over 1000 children across 35 countries have developed episodes of acute hepatitis of unknown origin. At King's College Hospital, a total of 65 children were referred with acute hepatitis of unknown etiology, with 10 of these children presenting with acute liver dysfunction leading to acute liver failure. Multiple hypotheses have been proposed and continue to be investigated worldwide. In this review, we explore the current understanding of potential aetiologies for this outbreak. We further characterize the proposed immunological mechanisms of liver injury in these cases.

Predictors of patient and graft survival following pediatric liver transplantation: Long-term analysis of more than 300 cases from single centre.

BACKGROUND: Pediatric liver transplant (PLT) activity has flourished over time although with limited expansion in the graft pool. The study aims to identify pre-transplant factors that predict post-transplant patient and graft survival in the PLT population. METHODS: Retrospective review of PLTs at a single tertiary transplant unit from 2000 to 2019. Univariate and multivariate analyses of pre-transplant factors were performed to identify predictors of patient and graft survival. RESULTS: Two hundred and seventy-six patients received 320 PLTs. The most common cause of graft loss was hepatic artery thrombosis (n = 13, 29.6%). The most common cause of mortality was sepsis (n = 11, 29.7%). Univariate analysis showed that the following variables had a significant (p < .05) impact on patient survival: recipient age, weight, height, graft type (technical variant graft), transplant category (acute liver failure), the era of transplant, and invasive ventilation. The following variables had a significant (p < .05) impact on graft survival: recipient age, weight, height, transplant category (acute liver failure), and the era of transplant. Multivariate analysis precluded the era of transplant as the only significant factor for patient survival; patients transplanted after 2005 had significantly higher patient survival. No independent factor predicting graft survival was identified. For children transplanted after 2005, the only factor that predicted patient survival was pre-transplant invasive ventilation. CONCLUSIONS: Our study suggests that the learning curve and pre-transplant invasive ventilation in the recipient have a significant impact on patient survival. The traditional view of worse outcomes of smaller PLT candidates should be changed.

Sclerosing Cholangitis in Pediatric Inflammatory Bowel Disease: Early Diagnosis and Management Affect Clinical Outcome.

OBJECTIVE: To describe the characteristics and clinical course of children and young persons with inflammatory bowel disease (IBD) and sclerosing cholangitis (SC). STUDY DESIGN: Retrospective analysis of clinical characteristics, management, and outcome of two separate cohorts of children and young persons with IBD-SC managed in a tertiary pediatric gastroenterology center and in a tertiary pediatric hepatology center in the UK. RESULTS: Eighty-two pediatric patients (31% female) with IBD-SC and a mean age at diagnosis of 11.9 ± 2.8 years were followed up for a mean of 6.8 ± 3.3 years. The most common type of IBD was ulcerative colitis (55%), followed by unclassified IBD (30%) and Crohn's disease (15%). Autoimmune SC (ASC) was diagnosed in 72%, and small duct SC was diagnosed in 28%. Complication-free and native liver survival were 96% and 100%, respectively, at 5 years after diagnosis and 75% and 88%, respectively, at 10 years after diagnosis. Patients in the gastroenterology center, who were diagnosed with liver disease sooner after diagnosis of IBD compared with the hepatology center cohort (mean, 2.7 ± 6.1 months vs 9.3 ± 19.4 months; P = .03), did not develop liver-related complications during follow-up. CONCLUSIONS: Our data suggest that children with IBD-SC have better clinical outcomes than have been reported previously, particularly if diagnosed early. We recommend prompt assessment for SC, including liver biopsy and biliary imaging, when liver function abnormalities are detected in a children diagnosed with IBD.

Resting Energy Expenditure of Children With End-stage Chronic Liver Disease Before and After Liver Transplantation.

OBJECTIVES: Our objective was to test the hypothesis that children with end-stage chronic liver disease (ESCLD) are hypermetabolic when compared to healthy children, and that this hypermetabolism persists for at least 6 months after liver transplant. METHODS: Seventeen patients with end-stage chronic liver disease and 14 healthy controls had their resting energy expenditure measured (mREE) by indirect calorimetry. Weight, height, and body mass index were converted to standard deviation (SD) scores. Children older than 5 years had air displacement plethysmography and patients older than 5 years also had whole body dual-energy X-ray absorptiometry with characterization of fat mass (FM), fat-free mass (FFM), and bone-free fat free (lean) mass. RESULTS: When compared to the prediction equation 44% of the patients and 50% of the healthy controls were hypermetabolic. The younger patients (0-5 years) had a lower mREE than the healthy controls but were significantly lighter and shorter than their healthy counterparts. mREE correlated strongly for all children with age, weight, height, and FFM. There was a strong negative correlation between age and mREE/kg in both patients (rs = -0.94, P < 0.01) and controls (rs = -0.91, P < 0.01). Almost 84% of the variance in mREE was explained by age (P < 0.001). There were no significant differences between resting energy expenditure (REE)/FFM between the 2 groups. mREE/kg before liver transplant correlated with mREE/kg after transplant (Pearson r = 0.83, P < 0.01). CONCLUSIONS: REE mostly reflected the size of the child. The patients were not hypermetabolic when compared to the healthy children. The main determinant of REE/kg after transplant was REE/kg before transplant.

Value of Serum Zinc in Diagnosing and Assessing Severity of Liver Disease in Children With Wilson Disease.

OBJECTIVES: Wilson disease (WD) is a rare inborn error of copper metabolism with diverse manifestations. There has been no study of zinc (Zn), the copper's antagonist, in WD diagnosis and severity so far. Our aims were to evaluate serum Zn in WD and its correlation with the disease severity score (revised WD index). Although the ATP7B mutation analysis is highly accurate for WD diagnosis, it may not be readily available in a resource-limiting setting. We proposed a disease diagnostic score (Proposed WD diagnostic score) which incorporates serum Zn. METHODS: Medical records of WD and non-WD children seen at King's College Hospital from 2005 to 2015 were reviewed for the selected parameters using the Proposed WD diagnostic score. Available serum Zn data in WD children before disease diagnosis and the calculated severity score were statistically analyzed. Diagnostic values of the Proposed WD diagnostic score were evaluated. RESULTS: Serum Zn level was significantly lower in 8 WD-acute liver failure (ALF) (5.8 [4.1-8.3] µmol/L) compared to 18 WD-non-ALF (13.5 [6.1-22.2] µmol/L) and 9 ALF from indeterminate cause (9.8 [7.0-12.1] µmol/L) (P < 0.001). Serum Zn significantly correlated with the revised WD index (r = -0.554, P = 0.004). The Proposed WD diagnostic score that included serum Zn level as 1 of the parameters had sensitivity and specificity of 87% and 99.2%, respectively. CONCLUSIONS: Serum Zn is a novel parameter for diagnosis and correlates with severity of WD. The Proposed WD diagnostic score is useful while awaiting ATP7B mutation analysis.

Primary Budd-Chiari Syndrome in Children: King's College Hospital Experience.

Primary Budd-Chiari syndrome is a rare cause of liver disease in children in the western world. Here we present a retrospective review of children with Primary Budd-Chiari syndrome presenting from January 2001 to November 2015 to our hospital. Seven children were identified. Their presentation was mostly chronic. All had predisposing factors for thrombosis and were started on anticoagulation. Radiological interventions (2 transjugular intrahepatic portosystemic shunts and 1 hepatic vein stenting), liver transplant and mesocaval shunt were done in 3, 2, and 1 patients, respectively; 1 child underwent bone marrow transplantation following transjugular intrahepatic portosystemic shunts and 1 child was managed only medically. After liver transplantation, one child died 3 years later as a result of subarachnoid haemorrhage, whereas others remain well at a median follow-up of 6 years. Despite high morbidity, the disease can have a good long-term outcome with a multidisciplinary approach.

Omega-3 Fatty Acid-Rich Parenteral Nutrition: Is It a Double-Edged Sword?

Parenteral nutrition (PN) has been strongly associated with intestinal failure-associated liver disease. Cholestasis, liver steatosis, and liver fibrosis are features of this liver injury, which can progress to end stage liver disease. Omega-3 fatty acid rich PN has been shown to alleviate cholestasis and steatosis. There have been reports although suggesting that it may not be able to arrest or reverse the progression to liver fibrosis. In this article, we develop a hypothesis of the mechanism of how Ω-3 fatty acid rich PN may influence the progression of fibrosis.

Fatty liver disease in children (MAFLD/PeFLD Type 2): unique classification considerations and challenges.

In children, fatty liver disease is a group of disorders that often overlaps with inherited metabolic disorders (IMDs), which requires prompt diagnosis and specific management. Metabolic dysfunction-associated fatty liver disease (MAFLD) or, formerly, non-alcoholic fatty liver disease (NAFLD) is the hepatic component of a multisystemic disease that requires a positive criteria in metabolic dysfunction for diagnosis. However, in children, the diagnosis of MAFLD is one of the exclusions of an IMD [paediatric fatty liver disease (PeFLD) type 1] including the possibility that an IMD can be identified in the future following investigations that may be negative at the time. Therefore, while children with fatty liver with metabolic dysfunction could be classified as MAFLD (PeFLD type 2) and managed that way, those who do not fulfil the criteria for metabolic dysfunction should be considered separately bearing in mind the possibility of identifying a yet undiagnosed IMD (PeFLD type 3). This concept is ever more important in a world where MAFLD is the most common cause of liver disease in children and adolescents in whom about 7% are affected. The disease is only partially understood, and awareness is still lacking outside hepatology and gastroenterology. Despite its increasing pervasiveness, the management is far from a one-size-fits-all. Increasing complexities around the genetic, epigenetic, non-invasive modalities of assessment, psychosocial impacts, therapeutics, and natural history of the disease have meant that an individualised approach is required. This is where the challenge lies so that children with fatty liver are considered on their own merits. The purpose of this review is to give a clinical perspective of fatty liver disease in children with relevance to metabolic dysfunction.

Transient elastography and von Willebrand factor as predictors of portal hypertension and decompensation in children.

Background & Aims: Von Willebrand factor antigen (vWFAg), a protein measured to test the level of vWF released from the vascular endothelium has gained much attention as a marker for portal hypertension (PHT) severity. The objectives of this study were to investigate the use of vWFAg as a biomarker along with liver and spleen stiffness measurements by transient elastography as potential predictors of clinically significant varices (CSV), variceal bleeding (VB) and decompensation in children with PHT. Methods: This observational prospective cohort study included 117 children (median age 10 [IQR 6-14] years) who underwent oesophagogastroduodenoscopy between January'2012 to November'2021 and a validation group of 33 children who underwent the same procedure between December'2021 to March'2023. Measurements of vWFAg and glycoprotein Ib binding activity of VWF (GPIbR) were available in 97 patients in the study group and in all patients in the validation group.Results: vWFAg and GPIbR were significantly higher in children with CSV (223 IU/dl and 166 IU/dl; p = 0.015 and p = 0.04, respectively) and VB (218 IU/dl and 174 IU/dl; p = 0.077 and p = 0.03, respectively) than in those without CSV or VB, respectively. Ninety-six patients had liver and spleen stiffness measurements. Spleen stiffness was significantly higher in patients with CSV compared to those without CSV (p = 0.003). In a chronic liver disease subgroup, a predictive scoring tool based on vWFAg, GPIbR, platelet count, and spleen/liver stiffness measurements could predict CSV with an AUROC of 0.76 (p = 0.04). Conclusions: This study suggests the predictive value of vWF for CSV and VB increases when combined with spleen stiffness, with AUROCs of 0.88 and 0.82, respectively. Hence, a combination of biomarkers could assist clinicians in diagnosing CSV, preventing unnecessary invasive procedures. Impacts and implications: Surveillance endoscopies in children with portal hypertension (PHT) have their own risks and non-invasive markers, such as von Willebrand factor antigen, glycoprotein Ib binding activity of VWF (GPIbR), and transient elastography could be used to predict clinically significant varices, variceal bleeding and disease compensation in children with PHT. Such non-invasive markers for PHT and varices are lacking in the paediatric population. The results show that von Willebrand factor and GPIbR along with transient elastography can be used to formulate a scoring system which can be used as a clinical tool by paediatric hepatologists to monitor the progression of PHT and risk of bleeding, and hence to stratify the performance of invasive endoscopic procedures under general anaesthesia. However, there is a need to validate the scoring system in children with portal vein thrombosis and for hepatic decompensation in a multi-centre registry in the future.

Long-term outcomes of pediatric liver transplantation in acute liver failure vs end-stage chronic liver disease: A retrospective observational study.

BACKGROUND: Children with acute liver failure (ALF) who meet the criteria are eligible for super-urgent transplantation, whereas children with end-stage chronic liver disease (ESCLD) are usually transplanted electively. Pediatric liver trans plantation (PLT) in ALF and ESCLD settings has been well described in the literature, but there are no studies comparing the outcomes in these two groups. AIM: To determine if there is a difference in post-operative complications and survival outcomes between ALF and ESCLD in PLT. METHODS: This was a retrospective observational study of all primary PLTs performed at a single center between 2000 and 2019. ALF and ESCLD groups were compared for pretransplant recipient, donor and operative parameters, and post-operative outcomes including graft and patient survival. RESULTS: Over a 20-year study period, 232 primary PLTs were performed at our center; 195 were transplanted for ESCLD and 37 were transplanted for ALF. The ALF recipients were significantly older (median 8 years vs 5.4 years; P = 0.031) and heavier (31 kg vs 21 kg; P = 0.011). Living donor grafts were used more in the ESCLD group (34 vs 0; P = 0.006). There was no difference between the two groups concerning vascular complications and rejection, but there were more bile leaks in the ESCLD group. Post-transplant patient survival was significantly higher in the ESCLD group: 1-, 5-, and 10-year survival rates were 97.9%, 93.9%, and 89.4%, respectively, compared to 78.3%, 78.3%, and 78.3% in the ALF group (P = 0.007). However, there was no difference in 1-, 5-, and 10-year graft survival between the ESCLD and ALF groups (90.7%, 82.9%, 77.3% vs 75.6%, 72.4%, and 66.9%; P = 0.119). CONCLUSION: Patient survival is inferior in ALF compared to ESCLD recipients; the main reason is death in the 1st year post-PLT in ALF group. Once the ALF children overcome the 1st year after transplant, their survival stabilizes, and they have good long-term outcomes.

Pancreatitis in RYR1-related disorders.

Mutations in RYR1 encoding the ryanodine receptor (RyR) skeletal muscle isoform (RyR1) are a common cause of inherited neuromuscular disorders. Despite its expression in a wide range of tissues, non-skeletal muscle manifestations associated with RYR1 mutations have only been rarely reported. Here, we report three patients with a diagnosis of Central Core Disease (CCD), King-Denborough Syndrome (KDS) and Malignant Hyperthermia Susceptibility (MHS), respectively, who in addition to their (putative) RYR1-related disorder also developed symptoms and signs of acute pancreatitis. In two patients, episodes were recurrent, with severe multisystem involvement and sequelae. RyR1-mediated calcium signalling plays an important role in normal pancreatic function but has also been critically implicated in the pathophysiology of acute pancreatitis, particularly in bile acid- and ethanol-induced forms. Findings from relevant animal models indicate that pancreatic damage in these conditions may be ameliorated through administration of the specific RyR1 antagonist dantrolene and other compounds modifying pancreatic metabolism including calcium signalling. These observations suggest that patients with RYR1 gain-of-function variants may be at increased risk of developing acute pancreatitis, a condition which should therefore be considered in the health surveillance of such individuals.

Sarcopenia and Fat Mass in Children With Chronic Liver Disease and Its Impact on Liver Transplantation.

In adults, weight loss and sarcopenia are prognostic indicators of poor outcomes for patients awaiting liver transplant (LT). We tested the hypothesis that sarcopenia in children awaiting LT was related to poor outcomes. Methods: Children with end-stage chronic liver disease undergoing assessment for LT were recruited into an observational longitudinal study. Anthropometry and body composition (BC; whole-body dual-energy x-ray absorptiometry scan) were assessed before and, on average, 1 year after LT. Results: Eleven children (6 females:5 males) were assessed (4.7 to 17.2 years; median, 9.9) at baseline. Nine children went on to have an LT. The aspartate aminotransferase-to-platelet ratio index had a significant positive correlation with trunk lean mass and trunk lean mass index (LMI) SD score (SDS). At baseline, 4 patients were sarcopenic with appendicular LMI SDS less than -1.96. All fat mass and fat mass index (FMI) SDSs were within the normal range (above -1.96). There was a strong negative correlation between FMI SDS and height SDS. After transplant, there was a significant reduction in trunk LMI from 1.20 to -0.51 (95% CI, 1.03-2.4; P < 0.01). Body mass index SDS had a negative correlation with days to discharge after transplant. The majority of patients discharged after 16 days were sarcopenic. One year after transplantation, all patients were alive with normal graft function regardless of BC before LT. Conclusion: FMIs were normal regardless of LMIs and correlated negatively with height. BC was related to days to discharge after LT but not to outcomes a year after LT.

Clinical management of sickle cell liver disease in children and young adults.

Liver involvement in sickle cell disease (SCD) is often referred to as sickle cell hepatopathy (SCH) and is a complication of SCD which may be associated with significant mortality. This review is based on a round-table workshop between paediatric and adult hepatologists and haematologists and review of the literature. The discussion was prompted by the lack of substantial data and guidance in managing these sometimes very challenging cases. This review provides a structured approach for the diagnosis and management of SCH in children and young adults. The term SCH describes any hepatobiliary dysfunction in the context of SCD. Diagnosis and management of biliary complications, acute hepatic crisis, acute hepatic sequestration and other manifestations of SCH are discussed, as well as the role of liver transplantation and haemopoietic stem cell transplantation in the management of SCH.

The International Liver Transplantation Society Living Donor Liver Transplant Recipient Guideline.

Living donor liver transplantation (LDLT) has been increasingly embraced around the world as an important strategy to address the shortage of deceased donor livers. The aim of this guideline, approved by the International Liver Transplantation Society (ILTS), is to provide a collection of expert opinions, consensus, and best practices surrounding LDLT. Recommendations were developed from an analysis of the National Library of Medicine living donor transplantation indexed literature using the Grading of Recommendations Assessment, Development and Evaluation methodology. Writing was guided by the ILTS Policy on the Development and Use of Practice Guidelines (www.ilts.org). Intended for use by physicians, these recommendations support specific approaches to the diagnostic, therapeutic, and preventive aspects of care of living donor liver transplant recipients.