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Orthotopic liver transplantation (OLT) in the care of children with inborn errors of metabolism (IEM) is well established and represent the second most common indication for pediatric liver transplantation in most centers worldwide, behind biliary atresia. OLT offers cure of disease when a metabolic defect is confined to the liver, but may still be transformative on a patient's quality of life reducing the chance of metabolic crises causing neurological damage in children be with extrahepatic involvement and no "functional cure." Outcomes post‐OLT for inborn errors of metabolism are generally excellent. However, this benefit must be balanced with consideration of a composite risk of morbidity, and commitment to a lifetime of post‐transplant chronic disease management. An increasing number of transplant referrals for children with IEM has contributed to strain on graft access in many parts of the world. Pragmatic evaluation of IEM referrals is essential, particularly pertinent in cases where progression of extra‐hepatic disease is anticipated, with long‐term outcome expected to be poor. Decision to proceed with liver transplantation is highly individualized based on the child's dynamic risk‐benefit profile, their family unit, and their treating multidisciplinary team. Also to be considered is the chance of future treatments, such as gene therapies, emerging in the medium term. [ABSTRACT FROM AUTHOR]

Background: Alagille syndrome is a rare genetic disease that often presents with severe cholestasis and pruritus. There are no approved drugs for management. Maralixibat, an apical, sodium-dependent, bile acid transport inhibitor, prevents enterohepatic bile acid recirculation. We evaluated the safety and efficacy of maralixibat for children with cholestasis in Alagille syndrome.Methods: ICONIC was a placebo-controlled, randomised withdrawal period (RWD), phase 2b study with open-label extension in children (aged 1-18 years) with Alagille syndrome (NCT02160782). Eligible participants had more than three times the normal serum bile acid (sBA) levels and intractable pruritus. After 18 weeks of maralixibat 380 μg/kg once per day, participants were randomly assigned (1:1) to continue maralixibat or receive placebo for 4 weeks. Subsequently, all participants received open-label maralixibat until week 48. During the long-term extension (204 weeks reported), doses were increased up to 380 μg/kg twice per day. The primary endpoint was the mean sBA change during the RWD in participants with at least 50% sBA reduction by week 18. Cholestastic pruritus was assessed using observer-rated, patient-rated, and clinician-rated 0-4 scales. The safety population was defined as all participants who had received at least one dose of maralixibat. This trial was registered with ClinicalTrials.gov, NCT02160782, and is closed to recruitment.Findings: Between Oct 28, 2014, and Aug 14, 2015, 31 participants (mean age 5·4 years [SD 4·25]) were enrolled and 28 analysed at week 48. Of the 29 participants who entered the randomised drug withdrawal period, ten (34%) were female and 19 (66%) were male. In the RWD, participants switched to placebo had significant increases in sBA (94 μmol/L, 95% CI 23 to 164) and pruritus (1·7 points, 95% CI 1·2 to 2·2), whereas participants who continued maralixibat maintained treatment effect. This study met the primary endpoint (least square mean difference -117 μmol/L, 95% CI -232 to -2). From baseline to week 48, sBA (-96 μmol/L, -162 to -31) and pruritus (-1·6 pts, -2·1 to -1·1) improved. In participants who continued to week 204 (n=15) all improvements were maintained. Maralixibat was generally safe and well tolerated throughout. The most frequent adverse events were gastrointestinal related. Most adverse events were self-limiting in nature and mild-to-moderate in severity.Interpretation: In children with Alagille syndrome, maralixibat is, to our knowledge, the first agent to show durable and clinically meaningful improvements in cholestasis. Maralixibat might represent a new treatment paradigm for chronic cholestasis in Alagille syndrome.Funding: Mirum Pharmaceuticals. [ABSTRACT FROM AUTHOR]

Despite a century of research, bilirubin metabolism and the transport mechanisms responsible for homeostasis of bilirubin in serum remain controversial. Emerging evidence on the hepatic membrane transporters and inherited disorders of bilirubin metabolism have contributed to a greater understanding of the various steps involved in bilirubin homeostasis and its associated excretory pathways. We discuss these recent research findings on hepatic membrane transporters and evaluate their significance on the newborn bilirubin metabolism and excretion. New insights gained speculate that a proportion of conjugated bilirubin is excreted via the renal system, as an alternative to the intestinal excretion, even in normal physiological jaundice with no associated pathological concerns. Finally, this paper discusses the clinical relevance of targeting the altered renal excretory pathway, as bilirubin in urine may hold diagnostic importance in screening for neonatal jaundice. [ABSTRACT FROM AUTHOR]

Homozygous familial hypercholesterolaemia (FH) causes severe cardiovascular disease from childhood. Conventional drug therapy is usually ineffective; lipoprotein apheresis (LA) is often required. Liver transplantation (LT) can correct the metabolic defect but is considered a treatment of last resort. Newer drugs including lomitapide and evinacumab might reduce the need for apheresis and LT. We sought to determine the long-term outcomes following LT in Australia and New Zealand. We analysed demographic, biochemical and clinical data from all patients in Australia and New Zealand who have received LT for homozygous FH, identified from the Australia and New Zealand Liver and Intestinal Transplant Registry. Nine patients (five female; one deceased; seven aged between 3 and 6 years at the time of LT and two aged 22 and 26 years) were identified. Mean follow-up was 14.1 years (range 4–27). Baseline LDL-cholesterol off all treatment was 23 ± 4.1 mmol/L. Mean LDL-cholesterol on medical therapy (including maximal statin therapy in all patients, ezetimibe in three and LA in five) was 11 ± 5.7 mmol/L (p < 0.001). After LT, mean LDL-cholesterol was 2.6 ± 0.9 mmol/L (p = 0.004) with three patients remaining on statin therapy and none on LA. One patient died from acute myocardial infarction (AMI) three years after LT. Two patients required aortic valve replacement, more than 10 years after LT. The remaining six patients were asymptomatic after eight to 21 years of follow-up. No significant adverse events associated with immunosuppression were reported. LT for homozygous FH was highly effective in achieving substantial long-term reduction in LDL-cholesterol concentrations in all nine patients. LT remains an option for severe cases of homozygous FH where drug therapy combined with apheresis is ineffective or unfeasible. [Display omitted] • Liver transplantation has low morbidity in experienced centres. • Modern immunosuppression facilitates long-term graft survival. • Liver transplantation lowers LDL-cholesterol more than any other treatment. • Aortic stenosis can progress despite liver transplantation. • Post-transplant familial hypercholesterolaemia cardiovascular guidelines are needed. [ABSTRACT FROM AUTHOR]

Liver transplantation has become the standard of care for children with end‐stage liver disease. In Australia and New Zealand, there are four paediatric liver transplant units, in Sydney, Melbourne, Brisbane and Auckland. Over the past 30 years, there have been significant changes to indications for transplant, as well as medical and surgical advances. In this paper, using retrospective data from the Australia and New Zealand Liver Transplant Registry, we review 977 children (less than 16 years of age) who underwent liver transplant from 1985 to 2018. The most common indication was biliary atresia (54%), although there has been an increase in other indications, including inborn errors of metabolism, fulminant hepatic failure and malignant liver tumours. Over the past 3 decades, areas of change and innovation include: the use of 'split grafts' to enable an adult and a child to receive the same donor liver, live donation, improvements in immunosuppressive regimens and infectious prophylaxis protocols and innovative surgical techniques allowing transplantation in smaller infants. The outcomes for children who undergo liver transplant in ANZ are excellent, with current 10‐year patient survival rates of 95%, comparable to other larger centres around the world. [ABSTRACT FROM AUTHOR]

Hepatitis viruses A to E can cause abnormal liver function tests in children. Although, overall, they are relatively uncommon in children in Australia, epidemiology diagnosis and treatment modalities for these viruses have evolved over the last decade. This review provides an update on the diagnosis and treatment of viral hepatitis in children. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 2.5-month-old girl with cough, coryza, and increased work of breathing. Topics discussed include results of various medical tests; complications of immunodeficiency, cough and coryza; and the usage of duodenal biopsy and co-trimoxazole therapy in the treatment.

Abstract: Introduction: Bleeding and thrombotic complications contribute to morbidity and mortality following paediatric orthotopic liver transplantation (OLT). However, the pathophysiology of haemostasis during paediatric OLT is not well understood. This report consists of two complimentary studies examining the frequency of haemostatic complications before and after the introduction of a post-operative thrombin inhibitor replacement therapy protocol at a single institution. Materials and Methods: A retrospective study of 40 patients who underwent 43 liver transplants between July 1992 and July 2002, identified bleeding to be the most frequent complication associated with OLT (30%), however thrombotic complications were also common (12.5%). In 2003, following a detailed analysis of haemostatic profiles of children undergoing OLT, a thrombin inhibitor replacement protocol was introduced. A prospective clinical outcome audit was undertaken from April 2003 to September 2008 to determine the effect of the new protocol on haemostasis. Results: Commencement of the thrombin inhibitor replacement protocol significantly reduced the incidence of thrombosis (from 5 to 1, p<0.05), graft loss (from 4 to none, p<0.05), mortality due to thrombosis or bleeding (from 3 to none, p<0.05) and was associated with a 50% reduction in frequency of major bleeding. Conclusion: In conclusion, the introduction of a post-operative thrombin inhibitor replacement therapy protocol following paediatric OLT significantly improved haemostasis-related morbidity and mortality outcomes in children. [ABSTRACT FROM AUTHOR]

Aim: A Macrogol 3350-based, iso-osmotic laxative has become available for the treatment of chronic constipation in adults. This open-label, non-randomised study aimed to evaluate the safety and efficacy of this preparation in the treatment of chronic constipation in children. Methods: Seventy-eight children, aged 2–11 years, with chronic constipation for greater than 3 months were enrolled. All children received Macrogol 3350 plus electrolytes for 12 weeks. The primary efficacy variable was the number of spontaneous defaecations per week. Secondary efficacy variables were faecal form, abdominal pain, rectal bleeding, pain on defaecation, straining, soiling, amount of stool, stool withholding and assessments of efficacy by the investigators and parents. Safety and compliance were also assessed. Results: The mean number of spontaneous defaecations per week increased from 1.4 ± 0.55 (SD) at baseline to 6.8 ± 3.45 after 14 days, and 7.1 ± 3.45 at 12 weeks ( P < 0.001). Similar improvements were found in the secondary efficacy variables. There was a significant reduction in reported abdominal pain from 53 (69%) children at baseline to 3 (4%) at the final visit ( P < 0.0001). Similarly, 61 (79%) children had pain on defaecation at baseline, compared with 7 (9%) at the final visit ( P < 0.0001). Treatment was well tolerated. Of 318 adverse events, 262 (82%) were considered mild, and 241 (76%) were deemed unrelated to treatment. Only 3 (4%) children were withdrawn because of poor compliance. Conclusions: Macrogol 3350 plus electrolytes is a safe and effective treatment for constipation in children aged 2–11 years. [ABSTRACT FROM AUTHOR]

To determine the natural history of perinatally acquired hepatitis C virus (HCV) infection, clinical and laboratory outcomes among 31 children with HCV infection were retrospectively reviewed. Fifteen children had acquired HCV by blood transfusion (BT) prior to 6 months of age and 16 had vertically acquired (VT) HCV.Demographic data, clinical symptoms and signs, liver biochemistry, HCV antibody, HCV-RNA and liver histology were evaluated.Mean age at last visit was 13.0 years (range 9.0–16.8 years) in the BT group and 8.6 years (range 0.5–18.1 years) in the VT group. There were no abnormal clinical findings of chronic liver disease in either group. Estimated HCV-RNA clearance rate was 19%, with no significant difference between the groups. In HCV-RNA-negative children (n = 6), two lost anti-HCV antibody and two developed indeterminate anti-HCV antibody results, while all HCV-RNA-positive children (n = 25) remained both anti-HCV antibody positive and HCV-RNA positive throughout follow up. The alanine aminotransferase level was significantly higher in the VT group than in the BT group during the first 5 years of life. Liver biopsy, which was carried out in four children, revealed mild to moderate fibrosis and/or necroinflammatory activity, but no cirrhosis.Outcomes among children with HCV acquired in infancy demonstrate asymptomatic and slowly progressive disease, at least for the initial decade of infection. Mode of acquisition appears to have a limited impact on outcomes, with similar viral clearance and anti-HCV antibody seroreversion rates in vertical and transfusion acquired infection. [ABSTRACT FROM AUTHOR]

Hepatic venous outflow obstruction, known as Budd-Chiari syndrome, is a rare but serious complication of orthotopic liver transplantation and may lead to graft loss. Our aim was to describe a single center experience of percutaneous interventional management of hepatic outflow obstruction post liver transplantation in children. Three children with post-transplant hepatic venous outflow obstruction were treated successfully with percutaneous stent placement. This resulted in long-term resolution of symptoms and was superior to balloon angioplasty both in our series and in cases reported in the literature. Stenting may be the treatment of choice for hepatic venous obstruction after pediatric liver transplantation, particularly if there is a recurrence of stenosis after balloon dilatation. [ABSTRACT FROM AUTHOR]

Here we identify a previously unreported cause of rectal bleeding (juvenile polyposis) in a patient with cystic fibrosis (CF). We believe this patient most likely has two coexisting genetic diseases. It also raises many issues about organ transplantation in a patient with medical conditions that individually increase the risk of gastrointestinal malignancy and stresses the diagnostic value of endoscopy in CF patients with rectal bleeding. [ABSTRACT FROM AUTHOR]

The article describes the case of a 5-year-old boy who had elevated lead levels after having swallowed a fishing sinker. Topics discussed include the removal of lead foreign bodies either by endoscopy or with the help of laxatives, the unpredictability of lead levels in children who ingest a lead object, and the importance of chelation prior to foreign body removal.

Haemophagocytic syndrome (HPS) following orthotopic liver transplantation is a rare event which is often fatal. We report here a case of HPS in association with cytomegalovirus (CMV) reactivation. The patient was treated with a combination of antiviral agents, immunomodulatory and supportive therapy which resulted in suppression of CMV infection and resolution of the haemophagocytosis. [ABSTRACT FROM AUTHOR]

Pediatric hepatitis C is a chronic infection in the majority of children and hence confers a lifetime risk of development of cirrhosis and hepatocellular carcinoma, potentially with a younger age of onset. Several recent studies have examined the natural history of HCV infection in children and although fibrosis is seen frequently, the majority of patients remain clinically well over three or more decades. Therapeutic options in children have not been studied fully but may play a role in certain patients. Well conducted, sufficiently powered studies are desperately needed to provide data on which sound therapeutic judgements can be made. [ABSTRACT FROM AUTHOR]

Summary: Background: Azathioprine and mercaptopurine are considered safe during pregnancy. However, the pharmacokinetic effects of pregnancy on thiopurine metabolism are undefined. Aims: To characterise thiopurine metabolism in pregnancy and measure infant metabolite levels and outcomes. Methods: Women with IBD who were taking a thiopurine and pregnant or trying to conceive were recruited. Maternal thiopurine metabolites were measured pre‐conception, in each trimester, at delivery and post‐partum. Infant metabolite levels, full blood examination and liver function testing were performed at birth, and repeated until levels undetectable and haematological and biochemical abnormalities resolved. Results: Forty patients were included with measurements on at least two occasions, and two with only mother‐baby levels at delivery. The median maternal 6‐TGN level dropped in the second trimester compared with post‐partum (179.0 vs 323.5 pmol/8 × 108 RBCs, P < 0.001) and the median 6‐MMP level increased in the second trimester compared with post‐partum (1103.0 vs 329.5 pmol/8 × 108 RBCs, P < 0.01). At delivery, the median 6‐TGN level was lower in infants (n = 20) than mothers (78.5 vs 217 pmol/8 × 108 RBCs) (P < 0.001). Metabolites were not detected at 6 weeks in any infants. Anaemia was not seen, but thrombocytosis and abnormal liver biochemistry were detected in 80% of infants from 6 weeks, which gradually improved. Conclusions: 6‐TGN levels decrease and 6‐MMP levels increase in the second trimester of pregnancy. Infants are exposed to thiopurine metabolites at low levels with clearance by 6 weeks and no anaemia. The cause of infant thrombocytosis and abnormal liver biochemistry in the absence of metabolites is unclear. [ABSTRACT FROM AUTHOR]

Patients with high model for end‐stage liver disease (MELD) scores waiting for liver transplantation in Australia and New Zealand (ANZ) have had limited access to deceased donor livers and therefore binational sharing of livers, for patients with a MELD score ≥35 was introduced in February 2016. Waiting list mortality, post‐transplant outcomes and intention‐to‐treat survival were compared between patients whose MELD score reached 35 on the waiting list between October 2013 and April 2015 (Pre‐Share 35 group, n = 23) and patients who were Share 35 listed between February 2016 and May 2022 (Share 35 group, n = 112). There was significantly reduced waiting list mortality in share 35 listed patients in comparison to the pre‐Share 35 group (11.7% vs. 52.2%, OR.120 95% CI.044–.328, P <.001). Post‐transplant patient and graft survival were not significantly different between the groups (5‐year patient survival 82% vs. 84%, P =.991, 5‐year graft survival 82% vs. 76%, P =.543). Intention‐to‐treat survival was superior in the Share 35 group (HR.302, 95% CI.149–.614, P <.001). Introduction of Share 35 in ANZ resulted in a 78% risk reduction in waiting list mortality, equivalent post‐transplant survival and an improvement in intention‐to‐treat survival. [ABSTRACT FROM AUTHOR]

Bright rectal bleeding in a neonate is most commonly due to necrotising enterocolitis, gastrointestinal infection or cows milk protein intolerance. We present here an infant who developed PR bleeding after cardiac surgery. Bleeding persisted despite presumptive treatment for the most common causes. A colonic intramural haematoma was identified on colonoscopy most likely related to anticoagulation in the setting of cardiac surgery. [ABSTRACT FROM AUTHOR]

Discusses the case of a four-year-old male child with fulminant hepatic failure that was probably induced by herbal medication. Details of the medical case; Symptoms and treatment procedures; Implications on pediatrics and child health.

Introduction: Chronic liver disease causes a disruption of procoagulant and anticoagulant factors, resulting in a fragile state, prone to increased rates of both bleeding and thrombosis. Currently, there is limited literature describing the changes observed in pediatric liver disease and extrahepatic portal vein obstruction or shunt. This study aimed to describe the changes that occur in children with chronic liver disease and extrahepatic portal vein obstruction or shunt.Materials and methods: We measured the concentration and activity of key procoagulant and anticoagulant factors in children with liver disease, children with extrahepatic portal vein obstruction or shunt, and healthy children.Results: Children with severe liver disease had coagulopathic changes, including either decreased concentration or activity of factor II, factor V, and factor VII. Nineteen percent (8/42) of the cohort had significant bleeding. Thrombophilic changes were also observed, including decreased concentration or activity of protein C, protein S, and antithrombin and increased concentration and activity of factor VIII and Von Willebrand factor. Similar coagulation factor changes were observed in children with extrahepatic portal vein obstruction or shunt. There was a trend toward greater changes in coagulation factor activity compared to concentration.Conclusion: This study provides a detailed description of the changes in both the concentration and activity of coagulation factors in pediatric liver disease and extrahepatic portal vein obstruction or shunt. Interestingly, procoagulant and anticoagulant factors were deranged in portal vein obstruction or shunt to a similar degree as in liver disease. An improved understanding of the coagulation profile in the pediatric setting will contribute to the improved management of liver disease and extrahepatic portal obstruction or shunt. Abbreviations:PELD: pediatric end-stage liver disease score; MELD: model for end-stage liver disease score; ELISA: enzyme-linked immunosorbent assay; MCRI: Murdoch Childrens Research Institute; FII: factor II; FV: factor V; FVII: factor VII; FVIII: factor VIII; AT: antithrombin III; A2M: alpha-2-macroglobulin; vWF: Von Willebrand factor; PC: protein C; PS: protein S; ISTH-BAT: International Society on Thrombosis and Haemostasis Bleeding Assessment Tool [ABSTRACT FROM AUTHOR]

Abstract The approach of a pediatric hepatologist in managing children with hepatitis C virus (HCV) differs from adult practice, because the pediatric hepatologist is dealing with the beginning of a chronic illness in which long-term outcomes will not occur for 20 or 40 years, and it is not possible to predict in the early stages of the infection which patients have a more sinister prognosis. The prevalence of chronic HCV in children is low, but varies between different countries in the Asia–Pacific region. In most countries, screening of blood products for HCV has virtually eliminated the risk of post-transfusion HCV, so that in Australia children aged less than 11 years will not have acquired HCV from blood transfusion or extracorporeal membrane oxygenation. The risk of perinatal transmission of this virus is only about 6%, but this remains virtually the only source of HCV transmission for children in most countries. While available data are limited, mild histological changes are present in the majority of children with hepatitis C, and cirrhosis is rare. Unfortunately, long-term natural history studies of the course of HCV infection in children have not been reported. Individual decisions on antiviral treatment are more difficult in childhood, not because the treatment is any less effective or because of the severity of side-effects (which tend to be less severe than for adults), but because the long-term outcome of infection is unclear. At present, treatment should be confined to those with significant hepatic fibrosis and continued moderate to severe necroinflammatory change. Measures to prevent HCV infection in childhood center on whether, as recently suggested, elective cesarean section may reduce the risk of transmission. Despite the presence of HCV-RNA in some breast milk samples, there is no evidence that breast-feeding confers any risk of HCV infection. © 2002 Blackwell Publishing Asia Pty Ltd. [ABSTRACT FROM AUTHOR]

Aim: Primary sclerosing cholangitis (PSC) is a chronic progressive cholestatic disorder associated with ulcerative colitis (UC). Although the inflammatory bowel disease phenotype has been characterised in patients with PSC, the impact of UC on the course and progression of PSC‐UC is less clear. We aimed to evaluate the effects of UC on liver‐related outcomes in children with PSC. Methods: Retrospective analysis of children aged ≤18 years diagnosed with PSC with/without UC at a single tertiary paediatric liver unit between January 1998 and May 2016. Patients were followed up until transition to an adult service. Outcomes studied included biliary complications, clinically significant portal hypertension, need for liver transplantation and post‐transplantation recurrence. Results: Fifty‐one children (31 female) were diagnosed with PSC (median age – 11.3 years (interquartile range 7)), follow‐up median duration 54 months (interquartile range 56). Thirty‐seven (73%) patients had concurrent UC, of which 26 had their diagnosis confirmed prior to or within 6 months of PSC diagnosis (early‐onset). PSC complications were more common in children with PSC‐UC compared with PSC alone (24/37 (65%) vs. 2/14 (14%); P = 0.001). Furthermore, children with endoscopically mild or moderate UC at diagnosis showed a greater propensity for liver‐related complications compared with children with severe UC (24/32 vs. 0/5; P = 0.003). Children with late‐onset UC had higher rates of clinically significant portal hypertension (5/11 (45%) vs. 3/26 (12%); P = 0.007) and liver transplantation (5/11(45%) vs. 2/26 (8%); P = 0.02). Children with PSC‐UC had significantly higher rates of pancolitis, rectal sparing and milder colitis than those with UC alone. Conclusion: The presence and a later‐onset of UC are associated with more significant progression to end‐stage liver disease. There is an inverse trend between UC severity and PSC severity in children with concurrent PSC‐UC. [ABSTRACT FROM AUTHOR]

Background: This study aimed to evaluate the transition to adult care program instituted for liver transplant recipients (LTRs) at a large tertiary pediatric hospital in Melbourne, Australia. Evaluation included the change in a Global Assessment Measure (GAM) before and after the transition program, satisfaction with the program, and measures of transition success including rejection rates and attendance at appointments post‐transfer. We hypothesized that the introduction of our structured transition program would improve disease understanding, health system understanding, and self‐care. We also hypothesized that those who had undergone the transition program would have lower failure to attend rates and lower rates of rejection than historical controls. Methods: A LTR transition program was instituted at our service from 2013 to 2015. The program involved initial assessment of competencies with a Global Assessment Measure (GAM), followed by the introduction of a personalized goal setting program addressing issues identified in dedicated transition clinics. Assessment of competencies was compared between the commencement of the program and immediately prior to transfer. Patient satisfaction with the transition process was assessed at an interview 6–12 months after transfer to the adult service. Rejection rates and failure to attend rates were compared between the intervention group and a group of LTRs who did not receive the intervention. Results: Twenty‐eight LTRs participated in the study; 20 received the transition intervention and 8 served as controls. Within the intervention group, all domains of transition competency and reported anxiety regarding transferring had significantly improved at the conclusion of the intervention and all reported satisfaction with the transition program with most (81%) reporting readiness to transfer. There were no significant differences in rejection rates or failure to attend rates between those who did and did not receive the transition intervention. Conclusion: A longitudinal holistic transition program has the potential to positively impact the competencies and readiness of LTRs to successful transition and transfer to adult care. [ABSTRACT FROM AUTHOR]

Nourishing children with liver disease is a challenging task; however, appropriate assessment and well-timed nutritional interventions are paramount for a good long-term outcome in these patients. An appropriate balance of macronutrients, micronutrients, and vitamins is important, as is the route of administration. This review aims to highlight the practical points in nutrition assessment and also provides a guide to the various nutritional interventions available for children with chronic liver disease. [ABSTRACT FROM AUTHOR]

Background and Aim: Autoimmune hepatitis (AIH) is a chronic disease of unknown etiology, which usually progresses to cirrhosis if not diagnosed and treated promptly. Data on long-term follow up in children with AIH are scant. The aim of this study is to assess the long-term outcome of autoimmune hepatitis in children with respect to clinical and laboratory features at presentation. Methods: Data were extracted from the medical records of patients presenting over a 28-year period (1972-2000) to the Royal Children's Hospital, Melbourne, Australia. Additional information was obtained by interviewing patients, and their current physicians. Of the 30 patients (22 females, mean age 9 years) identified, 18 had type I, three had type II, four had autoimmune-polyendocrinopathy syndrome type 1, one had infantile giant-cell hepatitis associated with Coomb's-positive hemolytic anemia, and four were seronegative (antinuclear antibody (ANA), smooth muscle antibody (SMA) and liver-kidney microsomal antibody (LKM)). Results: Clinical features at presentation included hepatomegaly (86%), jaundice (66%) and splenomegaly (50%). Initial investigations revealed a median serum bilirubin level of 55 μmol/L (range 6-425), median aspartate aminotransferase level of 678 IU (range 70-2548), and abnormal clotting in 33% of patients. Liver biopsies were performed on all patients at presentation and 11 showed cirrhosis (36%). The mean follow-up period was 10.0 ± 7.8 years with 43% being followed for > 10 years. Only two patients died and one required transplantation. Fourteen (50%) patients continue to be on low dose prednisolone with azathioprine, two (7%) are on prednisolone alone, and six (21%) are on no therapy. When the cirrhotic and non-cirrhotic patients were compared, the albumin level at presentation was significantly lower in the cirrhotic group (P = 0.01). Of the patients who were cirrhotic at presentation, six (54%) remain compensated with a mean follow-up period of 8... [ABSTRACT FROM AUTHOR]

Crigler–Najjar syndrome type 1 (CNS1) is characterized by a severe unconjugated hyperbilirubinemia from birth. Intensive blue-light phototherapy is the standard method for management; however, it imposes severe restrictions on the child and their family's lifestyle. We describe here the use of a novel sit-up phototherapy unit in a child with CNS1. The unit allowed a 50% reduction in phototherapy time while maintaining efficacy, thus enabling the child to attend school. [ABSTRACT FROM AUTHOR]

Changes in the coagulation profile in children with liver disease and extrahepatic portal vein obstruction or shunt result in both bleeding and thrombosis. Routine coagulation tests do not accurately predict bleeding risk, as they are not sensitive to changes in anticoagulant factors. The thrombin generation assay could be suitable for describing the overall balance of coagulation in children with liver disease. This study aims to characterise the mechanism of thrombin generation in this population, focusing on prothrombin conversion and thrombin inhibition. Patients were categorised as: severe (paediatric end stage liver disease score > 15) and mild disease, or portal vein obstruction or shunt. Age and gender matched healthy controls were used. The thrombin generation assay was performed in plasma samples from patients and controls with and without exogenous thrombomodulin and the results were further analysed with the computational thrombin dynamics method. A total of 42 patients (severe, n = 5; mild, n = 29, obstruction/shunt, n = 8) and 20 controls were included in this study. The total prothrombin conversion, thrombin-antithrombin formation and the thrombin decay capacity, in the presence and absence of thrombomodulin were reduced in children with severe liver disease. The rate of prothrombin conversion was increased and thrombin decay capacity was decreased in patients with portal vein obstruction or shunt compared to controls. This study demonstrates changes in the mechanism in thrombin generation seen in severe chronic liver disease. The changes vary in parenchymal versus non parenchymal liver disease and further study assessing the clinical significance of these variations in mechanism is required. • The thrombin generation assay represents an alternative to traditional coagulation tests in paediatric chronic liver disease. • Children with liver disease have a reduction in both the rate of prothrombin conversion and thrombin decay capacity. • In extrahepatic portal vein obstruction or shunt the balance of haemostatic changes tend towards a pro-thrombotic state. [ABSTRACT FROM AUTHOR]

The Fontan circulation describes the circulatory state resulting from an operation in congenital heart disease where systemic venous return is directed to the lungs without an intervening active pumping chamber. As survival increases, so too does recognition of the potential health challenges. This document aims to allow clinicians, people with a Fontan circulation, and their families to benefit from consensus agreement about management of the person with a Fontan circulation. The document was crafted with input from a multidisciplinary group of health care providers as well as individuals with a Fontan circulation and families. It is hoped that the shared common vision of long-term wellbeing will continue to drive improvements in care and quality of life in this patient population and eventually translate into improved survival. KEYPOINTS. [ABSTRACT FROM AUTHOR]

Thrombosis is a major postoperative complication in pediatric liver transplantation. There is marked heterogeneity in prophylactic antithrombotic therapies used, without established guidelines. This review summarizes current worldwide incidence of thrombotic events and compares antithrombotic therapies in children post–liver transplant, with comparison to our institution's experience. Of the twenty‐three articles with sufficient detail to compare antithrombotic regimens, the overall incidence of thrombosis ranged from 2.4% to 17.3%. Incidence of HAT ranged from 0% to 28.1%, of HVT from 0% to 4.7%, of PVT from 1.5% to 11.2%, and of IVC thrombosis from 0% to 2.8%. Re‐transplantation due to thrombosis ranged from 0% to 4.8%. Prophylactic antithrombotic therapies varied between studies, and bleeding complications were infrequently reported. Since 2010, 96 children underwent 100 liver transplants at our institution with thrombosis incidence comparable to international literature (HAT 6%, PVT 5%, IVC 1%, and HVT 0%). Re‐transplantation due to thrombosis occurred in 2% and major bleeding occurred in 10%. The prophylactic antithrombotic therapies used post–liver transplantation in children remain varied. Low rates of thrombosis have been reported with antiplatelet use both with and without anticoagulation. Standard definitions and consistent reporting of bleeding complications are required, in addition to thrombosis rates, so that true risk‐benefit assessment of reported regimes can be understood. [ABSTRACT FROM AUTHOR]

Abstract Background Hepatic and renal dysfunction have been observed in survivors of the Fontan procedure, however their incidence and associated factors remain poorly defined. Methods A total of 152 participants from a Registry of 1528 patients underwent abdominal ultrasound, transient elastography (FibroScan), serum fibrosis score (FibroTest), in vivo Tc-99m DTPA measurement of glomerular filtration rate (mGFR), and urine albumin-creatinine ratio (ACR). Results Mean age and time since Fontan were 19.8 ± 9.3 and 14.1 ± 7.6 years, respectively. Features suggestive of hepatic fibrosis were observed on ultrasound in 87/143 (61%) and no patient was diagnosed with hepatocellular carcinoma. FibroScan median kPa was ≥10 in 117/133 (88%), ≥15 in 75/133 (56%), and ≥20 in 41/133 (31%). Fifty-four patients (54/118, 46%) had a FibroTest score ≥0.49 (equivalent to ≥F2 fibrosis). FibroTest score correlated with FibroScan value (r = 0.24, p = 0.015) and ACR (r = 0.29, p = 0.002), and patients with ultrasound features of hepatic fibrosis had a higher FibroScan median kPa (19.5 vs 15.4, p = 0.002). Renal impairment was mild (mGFR 60–89 ml/min/1.73 m2) in 46/131 (35%) and moderate (mGFR 30–59 ml/min/1.73 m2) in 3/131 (2%). Microalbuminuria was detected in 52/139 participants (37%). By multivariable analysis, time since Fontan was associated with increased FibroScan median kPa (β = 0.89, 95% CI 0.54–1.25, p = 0.002) and decreased mGFR (β = −0.77, 95% CI −1.29–0.24, p = 0.005). Conclusions In the second decade after Fontan hepatic and renal structure and function are abnormal in a significant number of patients: close to 60% have ultrasonographic evidence of structural hepatic abnormalities, 46% have elevated serum hepatic fibrosis scores, and 57% have either reduced glomerular filtration rate or microalbuminuria. Hepatic and renal function should be monitored for potential impacts on outcomes after Fontan completion. Highlights • In the second decade after the Fontan procedure, abnormalities in hepatic and renal structure and function are common. • Close to two-thirds of patients have ultrasonographic evidence of hepatic fibrosis. • Almost 50% of patients have an elevated serum-based hepatic fibrosis (FibroTest) score. • More than 50% of patients have either a reduced glomerular filtration rate or microalbuminuria. • Hepatic and renal structure and function should be monitored for potential impacts on outcomes after Fontan completion. [ABSTRACT FROM AUTHOR]

Background Oesophageal achalasia is well-recognized but relatively rare in children, occasionally appearing as the 'triple A' syndrome (with adrenal insufficiency and alacrima). Treatment modalities, as in adult practice, are not curative, often needing further interventions and spurring the search for better management. The outcome for syndromic variants is unknown. We sought to define the efficacy of treatments for children with achalasia with and without triple A syndrome. Methods We conducted a retrospective analysis of presentation and outcomes for 42 children with achalasia presenting over three decades to a major pediatric referral center. Long term impact of the diagnosis was assessed by questionnaire. Results We identified 42 children including six with triple A syndrome. The median overall age at diagnosis was 10.8 years and median follow-up 1593 days. Initial Heller myotomy in 17 required further interventions in 11 (65%), while initial treatment with botulinum toxin ( n = 20) was ultimately followed by myotomy in 17 (85%). Ten out of 35 patients who underwent myotomy required a repeat myotomy (29%). Patients with triple A syndrome developed symptoms earlier, but had delayed diagnosis, were more underweight at diagnosis and at last follow up. Questionnaire results suggested a significant long term deleterious impact on the quality of life of children and their families. Conclusion Many children with achalasia relapse after initial treatment, undergoing multiple, different procedures, despite which symptoms persist and impact on quality of life. Symptoms develop earlier in patients with triple A syndrome, but the diagnosis is delayed and this has substantial nutritional impact. [ABSTRACT FROM AUTHOR]

Hepatitis B during pregnancy presents unique management issues for both the mother and fetus. These include the lack of a current cohesive strategy for treatment and follow-up of mothers and their babies; the uncertain risk of postpartum HBV flares; the lack of randomised trial data on the safety and efficacy of antiviral treatment in pregnancy; the lack of head-to-head studies comparing different antivirals in pregnancy; and the lack of epidemiologic information regarding infection across different populations globally. This position paper provides a comprehensive review of the management of women with HBV infection prior to conception, throughout each stage of pregnancy and postpartum, as well as recommendations and clinical approaches for the follow-up of children born to infected mothers, based on available evidence in the literature and recommendations from international experts. Prevention of perinatal transmission is an important component of global efforts to reduce the burden of chronic HBV since vertical transmission is responsible for most of the chronic infection worldwide. [ABSTRACT FROM AUTHOR]

Aim: An estimated 1.1% of Australian adults are infected with hepatitis C virus (HCV). Many develop chronic liver disease, and some develop liver failure or hepatocellular carcinoma. HCV infection in Australian children is poorly defined. We aimed to determine the reported incidence, clinical and epidemiological features of newly diagnosed HCV infection in Australian children presenting to paediatricians.Methods: We undertook prospective active national surveillance, using the Australian Paediatric Surveillance Unit, of incident HCV cases in children aged <15 years between 1(st) January 2003, and 31(st) December 2007.Results: There were 45 confirmed cases of newly diagnosed HCV infection over five years (<1 per 100,000 children aged <15 years per year). Median age at diagnosis was 2.9 years. Positive maternal HCV serostatus was the most frequent reported risk factor for HCV infection in children (40/45). Three children (all aged > 14), were exposed through their own IV drug use. No children were co-infected with HIV and only one child was co-infected with HBV. All children were asymptomatic at diagnosis, although many had minor elevations in liver transaminases. Many clinicians reported difficulties with follow-up.Conclusions: Childhood HCV infection is uncommon in Australia, although our data likely underestimate the incidence. Only a small number of children aged <18 months was identified, despite known perinatal exposure. Opportunistic investigation of children at risk for HCV, improved education regarding vertical transmission for health care providers, and increased coordination of childhood HCV services are required to improve recognition and management of children with HCV. [ABSTRACT FROM AUTHOR]

Background & Aims Despite the mortality associated with liver disease observed in patients with short bowel syndrome (SBS), mechanisms underlying the development of SBS-associated liver disease (SBS-ALD) are poorly understood. This study examines the impact of bacterially-mediated bile acid (BA) dysmetabolism on farnesoid X receptor (FXR) signalling pathways and clinical outcome in a piglet model of SBS-ALD. Methods 4-week old piglets underwent 75% small bowel resection (SBR) or sham operation. Liver histology and hepatic inflammatory gene expression were examined. Abundance of BA biotransforming bacteria was determined and metabolomic studies detailed the alterations in BA composition of stool, portal serum and bile samples. Gene expression of intestinal and hepatic FXR target genes and small heterodimer partner (SHP) transrepression targets were assessed. Results Histological evidence of SBS-ALD included liver bile duct proliferation, hepatocyte ballooning and fibrosis. Inflammatory gene expression was increased. Microbiota changes included a 10-fold decrease in Clostridium and a two-fold decrease in Bacteroides in SBS-ALD piglets. BA composition was altered and reflected a primary BA dominant composition. Intestinal and hepatic regulation of BA synthesis was characterised by a blunted intestinal FXR activation response and a failure of SHP to repress key hepatic targets. Conclusions We propose a pathological scenario in which microbial dysbiosis following SBR results in significant BA dysmetabolism and consequent outcomes including steatorrhoea, persistent diarrhoea and liver damage. Furthermore alterations in BA composition may have contributed to the observed disturbance in FXR-mediated signalling pathways. These findings provide an insight into the complex mechanisms mediating the development of liver disease in patients with SBS. [ABSTRACT FROM AUTHOR]

OBJECTIVES:Assessment of treatment response in children with celiac disease (CD) after commencing a strict gluten-free diet (GFD) is generally based on the resolution of clinical features and normalization of serology. Recent adult studies have shown that serologic markers do not correlate with mucosal recovery. We aimed (i) to determine whether anti-tissue transglutaminase immunoglobulin (Ig)A (tTG) and anti-deamidated gliadin peptide IgG (DGP) antibodies are sensitive and specific markers of mucosal recovery in children with CD on a GFD for at least 12 months, and (ii) to determine whether a validated dietary questionnaire of compliance can identify patients with mucosal recovery.METHODS:A total of 150 children with biopsy-proven CD were prospectively evaluated with duodenal biopsies at ≥12 months on GFD, paired with repeat tTG and DGP serology. The biopsies were reviewed in a blinded manner by two histopathologists and graded by Marsh criteria. A validated questionnaire of dietary compliance was also administered.RESULTS:Of 150 children recruited, 27 (18%) had positive serology, 97 (65%) had negative serology, and 26 (17%) had equivocal serology. Of the 97 children with negative serology, none had Marsh type 3 enteropathy. Of the 27 patients with positive serology, only 6 had Marsh type 3 changes. The sensitivity and specificity of serology as a marker of significant mucosal pathology was 75 and 85%, respectively, with a positive predictive value of 22% but a negative predictive value of 98%. Of the 129 (86%) questionnaires completed, 88% reported good or excellent compliance with a GFD (negative predictive value 97%).CONCLUSIONS:This study suggests that follow-up using two serological tests in children with CD on a GFD may obviate the need for repeat mucosal biopsy in the majority of patients. A standardized dietary questionnaire may be useful in identifying patients who require further evaluation. [ABSTRACT FROM AUTHOR]

Aim The aim of this study is to determine the demographic, clinical and serological patterns of hepatitis B in children in Victoria over a 17-year period. Methods Retrospective analysis of medical records of all patients <18 years of age with positive hepatitis B surface antigen referred to the Gastroenterology, Immigrant Health and Infectious Diseases clinics between 1992 and 2009. Results Of the 164 children identified, 76% were born overseas, with vertical transmission the most likely source in 84%. Most were asymptomatic, with no signs of chronic liver disease. Forty children infected with hepatitis B virus ( HBV) were born in Australia prior to universal vaccination. There was poor documentation of vaccination or response to vaccination in siblings at risk within families where at least one child was infected. An increasing number of referrals was noted from 2006 to 2009 compared with the preceding 4 years ( P < 0.001). Of an expected 200 follow-up visits from new referrals, 78% were attended. Conclusion These findings suggest that the number of children with HBV in our population is increasing and that models of health care designed to integrate primary with specialist care are required to minimise the overall health care burden of this chronic infection. [ABSTRACT FROM AUTHOR]

Denny B, Beyerle K, Kienhuis M, Cora A, Gavidia-Payne S, Hardikar W. New insights into family functioning and quality of life after pediatric liver transplantation. Abstract: Thorough research of the medical aspects of pediatric liver transplantation has given way to recent interest in the impact of the transplantation process on the QOL of recipients and their families. In this cross-sectional study, we compared the family functioning and QOL of children (n = 30) aged between three and 16 yr ( M = 10.10, s.d. = 3.62) who had received a liver transplant in the previous 1-12 yr ( M = 5.31, s.d. = 3.44) with non-transplant children (n = 33), as reported via parent proxy. Results showed that parents of pediatric liver transplant recipients made significantly more adjustments to family routines to accommodate their children, particularly in relation to childcare. Impaired family functioning was also found to be associated with decreased QOL. These preliminary findings of relative deficits in family functioning may inform psychosocial interventions to assist pediatric liver transplant patients and their families. Further investigation beyond a single-center study incorporating subjective information from pediatric patients and their parents is recommended. [ABSTRACT FROM AUTHOR]

Increasing numbers of children are surviving into adulthood following surgery to correct or palliate congenital heart disease. This surgery can occasionally result in long-standing elevated right heart pressures and chronic hepatic venous congestion leading to cardiac cirrhosis. We report the first paediatric case of hepatocellular carcinoma in the setting of cardiac cirrhosis. A 13-year-old girl developed inoperable hepatocellular carcinoma and was treated with transarterial embolization with lipiodol and doxorubicin eluting microbeads. Promoting awareness of this association, even in younger patients, will hopefully result in better surveillance and screening of hepatic complications in survivors of complex cardiac surgery. [ABSTRACT FROM AUTHOR]

Aims: The first aim of this study was to determine the health-related quality of life (HRQoL) of children with chronic hepatitis C virus (HCV) infection and compare HRQoL as reported by parents. The second aim was to ascertain parents' perceptions and concerns about current and future life for their child with HCV, and compare these findings with those reported by adolescents. Methods: The study group comprised children attending a tertiary pediatric HCV-clinic in Melbourne, Australia, who acquired HCV prior to 12 months of age by vertical transmission or blood transfusion. Two validated (parent- and self-reported) questionnaires of HRQoL were completed (CHQ-PF 50 and CHQ-CF 50). Scores for children with HCV were compared with normative data (representative sample of 3119 age-matched Victorian children). A study-designed questionnaire relating to the impact of the diagnosis of HCV on parent and child perceptions of current and future health was administered. Results: In total, 83% (19/23) questionnaires were returned. Physical and psychosocial summary scores were significantly lower in HCV than non-HCV children (45.3 vs 49.6 and 44.0 vs 50.1, respectively). Nine out of 11 scale scores were significantly lower in children with HCV, most notably the General health (49.9 vs 77.1; P < 0.001) and Parent impact–emotional (45.6 vs 80.3; P < 0.001) scales. Children reported reduced physical functioning (82.8% vs 94.4%) but were otherwise less concerned than their parents about their future health. Conclusions: Despite being “asymptomatic” on routine medical history, children with early acquired HCV have significantly poorer health status than community controls. These findings suggest the need for services currently available for adult HCV patients to support families and children with HCV. [ABSTRACT FROM AUTHOR]

Abstract Background: Injection of botulinum toxin (BTx) into the lower esophageal sphincter (LES) of adult patients with achalasia results in the effective relief of symptoms. The aim of the present study was to examine the effectiveness of BTx in pediatric patients suffering from achalasia. Methods: Seven patients suffering from achalasia with or without prior treatment were treated with intrasphincteric injection of BTx. The median duration of follow up was 15 months. Results: All seven patients improved. The median interval before recurrence of symptoms was 4 months (range 1–14 months). There was an inverse relationship between the pretreatment LES pressure and the duration of response (r = –0.6). The mean pretreatment LES pressure in the subgroup with a response greater than 6 months was 38 ± 10 mmHg compared with 61 ± 12 mmHg in the other four patients (P = 0.05). All seven patients required retreatment. Conclusion: Botulinum toxin is effective in relieving symptoms in pediatric patients suffering from achalasia, producing a sustained response beyond 6 months in 43% of patients. [ABSTRACT FROM AUTHOR]

We present the case of a 14-year-old boy presented with a recent history of progressive neurologic decline and extrapyramidal features. The history and findings with illustrative figures are detailed, and a diagnostic approach to the presentation is considered. The therapeutic options and broader management issues are briefly reviewed. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 19-month-old toddler with perinatally acquired hepatitis C infection. The child is positive with hepatitis C virus (HCV) RNA and HCV antibody and got her infection from her mother who had a history of intravenous drug use. The article discusses the use of steroids as a treatment for type 2 autoimmune hepatitis which may exacerbate the HCV infection.

A letter to the editor about the basal expression of toll-like receptors TLR2 and TLR 4 on peripheral blood monocytes (PBMC) in healthy children is presented.