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Emergencies in paediatric hepatology

Published:January 02, 2022DOI:https://doi.org/10.1016/j.jhep.2021.12.027

      Summary

      The aetiology of several liver diseases in children is age specific and many of these conditions have significant and potentially long-term clinical repercussions if not diagnosed early and managed in a timely fashion. We address 5 clinical scenarios that cover most of the diagnostic and therapeutic emergencies in children: infants with liver disease; acute liver failure; management of bleeding varices; liver-based metabolic disorders; and liver tumours and trauma. A wide spectrum of conditions that cause liver disease in infants may present as conjugated jaundice, which could be the only symptom of time-sensitive disorders – such as biliary atresia, metabolic disorders, infections, and haematological/alloimmune disorders – wherein algorithmic multistage testing is required for accurate diagnosis. In infantile cholestasis, algorithmic multistage tests are necessary for an accurate early diagnosis, while vitamin K, specific milk formulae and disease-specific medications are essential to avoid mortality and long-term morbidity. Management of paediatric acute liver failure requires co-ordination with a liver transplant centre, safe transport and detailed age-specific aetiological work-up – clinical stabilisation with appropriate supportive care is central to survival if transplantation is indicated. Gastrointestinal bleeding may present as the initial manifestation or during follow-up in patients with portal vein thrombosis or chronic liver disease and can be managed pharmacologically, or with endoscopic/radiological interventions. Liver-based inborn errors of metabolism may present as encephalopathy that needs to be recognised and treated early to avoid further neurological sequelae and death. Liver tumours and liver trauma are both rare occurrences in children and are best managed by a multidisciplinary team in a specialist centre.

      Keywords

      Introduction

      In the practice of paediatric hepatology, conditions considered as emergencies vary from seriously unwell children requiring immediate intensive care to stable thriving infants requiring the urgent diagnosis of a liver disease. Timely recognition and appropriate multidisciplinary management of these disorders can result in favourable outcomes. A comprehensive discussion on all emergencies is beyond the scope of this article. We have focused on common emergency scenarios that cover the vast majority of general paediatric hepatology. We opted to focus on 5 clinical scenarios: infants with liver disease; acute liver failure; management of bleeding varices; liver-based metabolic disorders; and liver tumours and trauma. While it is to be acknowledged that the understanding and approach to some of these emergencies are heavily influenced by data from adult literature, many disorders causing liver disease are unique to children or manifest differently in this population. Unlike in adults, many diagnoses in children are age dependent. We discuss the available evidence or the lack of it in this age group and highlight variations in practice between children and adults. The review will be of interest to practising paediatric hepatologists, gastroenterologists, adult hepatologists caring for patients with childhood liver diseases and other healthcare professionals involved in the management of children with liver disease.
      Emergencies in paediatric hepatology include both seriously unwell children with acute liver failure, variceal bleed, liver trauma or encephalopathy and seemingly well children with neonatal cholestasis or a liver mass that require urgent diagnosis.

      Infant with liver disease – a diagnostic emergency

      Infants presenting a new diagnosis of liver disease constitute the largest group in paediatric hepatology. An infant presenting with liver disease should be managed as an emergency even if the child does not look acutely unwell. Establishing a correct diagnosis and recognising and treating complications like coagulopathy, hypoglycaemia and other metabolic derangements in a timely fashion could prevent life-limiting or life-changing sequelae. Some of the time-sensitive diagnoses include metabolic disorders (such as galactosemia and tyrosinemia type 1), haemophagocytic lymphohistiocytosis, herpes simplex infection, gestational alloimmune disease (GALD) and biliary atresia, which constitutes around 25% of all causes of neonatal-onset cholestasis managed in liver centres.
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      • Jagadisan B.
      Referral patterns and factors influencing age at admission of infants with cholestasis in India.
      Infants with biliary atresia look deceptively well but delayed diagnosis and treatment beyond 2 months of age is generally associated with poor native liver survival. Of infants with biliary atresia who undergo a Kasai portoenterostomy at an age of <30 days, 70% survive with their native liver to an age of 2 years, with a bilirubin of <6 mg/dl, while this number is reduced to 50% and 0% when surgery is performed beyond 90 and 120 days of age.
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      A multicenter study of the outcome of biliary atresia in the United States, 1997 to 2000.
      The diagnostic challenge stems from the fact that about 60% of term and 80% of preterm new born babies develop physiological unconjugated jaundice.
      The recognition of conjugated jaundice or infantile cholestasis (IC) is often missed amongst these cases. Prolonged jaundice longer than 2 weeks of age in a term infant and 3 weeks in a premature infant should trigger investigations for IC.
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      Guideline for the evaluation of cholestatic jaundice in infants: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition.
      This includes any child in whom the parent or the healthcare worker reports pale stools or yellow diaper staining of urine. Around 37% of doctors and nurses and 66% of parents do not identify pale stools correctly in the absence of a stool colour card as a guide.
      • Mathiyazhagan G.
      • Jagadisan B.
      Referral patterns and factors influencing age at admission of infants with cholestasis in India.
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      • Vadamalayan B.
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      How reliably can paediatric professionals identify pale stool from cholestatic newborns?.
      Infant stool colour cards can improve recognition of pale stools by parents from 66% to 87%.
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      Early detection of neonatal cholestasis: inadequate assessment of stool color by parents and primary healthcare doctors.
      Stool colour cards have been shown to be a cost-effective population-level screening tool for biliary atresia.
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      • Wu T.C.
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      Universal screening for biliary atresia using an infant stool color card in Taiwan.
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      Home-based screening for biliary atresia using infant stool colour cards: a large-scale prospective cohort study and cost-effectiveness analysis.

      Emergency interventions before definitive diagnosis

      Infants with liver disease may present acutely with complications such as bleeding (due to vitamin K deficiency or liver failure) or metabolic decompensation (e.g. hypoglycaemia). These complications are managed in parallel to the rapid diagnostic work-up. Vitamin K deficiency induced coagulopathy can lead to cutaneous haematomas, gastrointestinal bleeds and intracranial bleeds. Intracranial bleeding due to vitamin K deficiency is more common if the diagnosis of biliary atresia is delayed, occurring at a frequency of up to 11% in Japanese infants, and it may result in serious neurological sequelae.
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      • Matsuura T.
      • Yoshimaru K.
      • Yanagi Y.
      • Hayashida M.
      • Taguchi T.
      Comparison of biliary atresia with and without intracranial hemorrhage.
      Hypoglycaemia may occur as a result of neonatal acute liver failure or endocrine disorders. It tends to be out of proportion to the liver dysfunction in galactosemia where one-fourth of children present with hypoglycaemia.
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      • Bosch A.M.
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      • Coelho A.I.
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      • et al.
      The natural history of classic galactosemia: lessons from the GalNet registry.
      Hypoglycaemia in the setting of preserved liver synthetic function may suggest endocrine disorders such as panhypopituitarism with or without septo-optic dysplasia.
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      • Sawathiparnich P.
      • Nimkarn S.
      • Likitmaskul S.
      • Santiprabhob J.
      • Aanpreung P.
      Anterior pituitary hormone effects on hepatic functions in infants with congenital hypopituitarism.
      In neonates with liver failure, prompt administration of acyclovir to treat herpes simplex infection and switching feeds to a lactose-free formulation to treat galactosemia are early interventions to improve outcomes while awaiting confirmatory test results.
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      • Dhawan A.
      • Zuckerman M.
      • Hadzic N.
      • Baker A.J.
      • Mieli-Vergani G.
      Neonatal herpes simplex virus infection presenting as acute liver failure: prevalent role of herpes simplex virus type I.

      Diagnosis

      In view of the broad aetiological spectrum in infants with liver disease, diagnostic protocols often employ multistage tests while taking into account the urgency of each diagnosis and their relative frequency. Clinical features and other organ involvement could provide clues to the cause of neonatal cholestasis (Table 1). Cholestasis may be multifactorial, as in neonates with a history of prematurity, sepsis, necrotizing enterocolitis, intestinal surgeries and parenteral nutrition. A family history of affected siblings is usually seen in inherited disorders. Patients with GALD, though not inherited, also present with a history of affected siblings. A thorough history and examination for dysmorphisms and other organ involvement (e.g. endocrine, cardiac, and neurological) can help to determine aetiology.
      Table 1Clinical clues to diagnosis in an infant with liver disease.
      Clinical featuresDiagnosis
      Facial dysmorphismDown syndrome, Zellweger syndrome, ARC syndrome, Smith Lemli Opitz syndrome, Alagille syndrome (difficult to appreciate in neonates)
      Abnormalities in eye examinationCataract - Congenital rubella, galactosemia, Zellweger syndrome, Wolman disease

      Posterior embryotoxon and Drusen – Alagille syndrome

      Cherry-red spot – Gaucher's and Niemann-Pick disease

      Septo-optic dysplasia - Hypopituitarism
      Skin changesIcthyosis, hypotrichosis – Neonatal sclerosing cholangitis

      Cutaneous laxity – ARC syndrome, transaldolase deficiency

      Lymphoedema – Aagenaes syndrome
      Congenital cardiovascular defectsPulmonary and peripheral pulmonary stenosis, tetrology of Fallot - Alagille syndrome

      Atrial and ventricular Septal Defects, preduodenal portal vein, absent Inferior vena cava – Biliary atresia
      Skeletal abnormalitiesVertebral anomalies – Alagille syndrome

      Patellar stippling on X-ray – Zellweger syndrome
      Neuromuscular involvementHypotonia – Down syndrome, Zellweger syndrome, Wolman syndrome, congenital disorders of glycosylation, mitochondrial disorders, Gaucher and Niemann-Pick disease

      Seizures – Congenital intrauterine infections, disseminated herpes infection, hypoglycaemia due to any cause of liver failure, galactosemia, fructosemia

      Arthrogrypopsis – ARC syndrome
      Massive splenomegalyGaucher’s and Niemann-Pick's disease
      AscitesAscites without liver failure – Spontaneous rupture of bile duct

      Ascites with liver dysfunction – Any cause of neonatal liver failure
      Genital abnormalitiesMicropenis - Septo-optic dysplasia

      Ambigous genitalia - Smith-Lemli-Opitz syndrome
      Renal anomaliesCysts – ciliopathies

      Dysplasia – ARC syndrome
      ARC, arthrogryposis-renal dysfunction-cholestasis.
      Elevated transaminases in isolation are less useful in reaching a diagnosis. However, very high serum transaminase values may suggest a viral aetiology (herpes simplex in infants) or ischaemic hepatitis. Normal transaminases disproportionate to the liver dysfunction may be seen with extensive parenchymal loss in neonatal liver failure (e.g. in cases of GALD).
      • Borovsky K.
      • Banc-Husu A.M.
      • Saul S.A.
      • Neighbors K.
      • Kelly S.
      • Alonso E.M.
      • et al.
      Applying an age-specific definition to better characterize etiologies and outcomes in neonatal acute liver failure.
      A normal or low gamma-glutamyltransferase (GGT) raises the possibility of progressive familial intrahepatic cholestasis type 1 and 2, tight junction protein-2 disease, NR1H4 or MYO5B gene mutations or bile acid synthetic disorder.
      • Amirneni S.
      • Haep N.
      • Gad M.A.
      • Soto-Gutierrez A.
      • Squires J.E.
      • Florentino R.M.
      Molecular overview of progressive familial intrahepatic cholestasis.
      Low serum bile acid levels with a low/normal GGT may suggest a defect in bile acid synthesis. An algorithm and clinical cues that can be used to guide diagnosis are provided in Fig. 1 and Table 2.
      Figure thumbnail gr1
      Fig. 1Aetiology in infantile cholestasis and the algorithmic approach.
      Table 2Disease-specific investigations for infants with liver disease.
      DisorderInvestigations
      Sepsis, urinary tract infectionBlood culture, urine culture.
      Congenital intrauterine infectionsReview of maternal serology, history of infection during pregnancy, In the neonate – urine CMV PCR, Guthrie card blood spot DNA, VDRL serology test, toxoplasma serology, Rubella serology
      Neonatal herpes simplex infectionSerum HSV PCR
      Hemophagocytic lymphohistiocytosisFull blood count, serum triglycerides, ferritin, fibrinogen, soluble CD25, bone marrow aspiration and trephine biopsy, perforin expression, Natural killer cell degranulation and cytotoxicity, perforin mutations, SAP and XIAP expression
      Gestational alloimmune diseaseBuccal mucosal biopsy for salivary gland iron staining, MRI abdomen, serum ferritin, total iron binding capacity
      GalactosemiaRBC galactose-1-phosphate uridyl transferase levels before any RBC transfusion
      Tyrosinemia type 1Urine succinyl acetone, mutational analysis
      Hereditary fructose intolerance, arthrogryposis renal dysfunction cholestasis syndrome, Dubin-Johnson syndrome, GRACILE syndrome, McCune Albright syndrome, citrin deficiency, Down syndrome, transaldolase deficiency, ciliopathiesGenetic testing
      Mitochondrial hepatopathySerum lactate, pyruvate, genetic testing
      Ornithine transcarbamylase deficiencySerum ammonia, plasma and urine amino acids, genetic testing
      Spontaneous rupture of bile ductHepatobiliary radioisotope scan
      Lipid storage disorders - Gaucher's, Niemann-Pick type A, B, CWhite cell enzymes, skin biopsy for fibroblast culture and filipin staining, genetics, eye examination, bone marrow aspiration and biopsy
      Panhypopituitarism, hypothyroidismRandom serum cortisol, If low short synacthen test, thyroid function test, MRI brain, genetic mutations
      Congenital leukaemiaFull blood count, bone marrow aspiration, biopsy, flow cytometry
      Biliary atresiaUltrasound – Cyst at the porta, triangular cord sign, small irregular gallbladder, polysplenia/asplenia, situs inversus

      Liver biopsy – Expanded portal tract with fibrosis and inflammation, bile ductular reaction, bile plugs

      Operative cholangiogram to confirm the diagnosis
      Choledochal cyst, choledocholithiasisUltrasound, MRCP
      Neonatal sclerosing cholangitis, NISCH syndromeLiver biopsy, genetic studies
      Bile acid transporter defectsGGT, genetics, liver immunohistochemistry
      Syndromic paucity of bile ducts (Alagille syndrome)Echocardiography, eye examination, vertebral radiography, liver biopsy and genetics
      Bile acid synthetic disordersGGT, serum bile acid, urine bile acid profile, genetics
      Alpha-1-antitrypsin deficiencyAlpha-1-antitrypsin level and phenotype
      Cystic fibrosisImmunoreactive trypsinogen, genetics
      Cholesteryl ester storage diseaseSerum cholesterol, triglycerides, lysosomal acid lipase levels, genetics
      Zellweger syndromeVery long-chain fatty acid, genetics
      Congenital disorder of glycosylationTransferrin electrophoresis, genetics
      CMV, cytomegalovirus; GGT, gamma glutamyltransferase; HSV, herpes simplex virus; MRCP, magnetic resonance cholangiopancreatography; NISCH, neonatal ichthyosis sclerosing cholangitis hypotrichosis; RBC, red blood cell; VDRL, Venereal Research Disease Laboratory.
      Children with biliary atresia, neonatal presentation of choledochal cyst, neonatal sclerosing cholangitis, choledocholithiasis and inspissated bile duct syndrome invariably present with pale stools. Demonstration of pigmented stools rules out biliary atresia at that point in time. The role of hepatobiliary scintigraphy is restricted to children in whom the stools are ambiguous but where there may be a benefit in avoiding a liver biopsy, such as in preterm infants. Other disorders with severe cholestasis may also present with pale stools.
      • Lai M.W.
      • Chang M.H.
      • Hsu S.C.
      • Hsu H.C.
      • Su C.T.
      • Kao C.L.
      • et al.
      Differential diagnosis of extrahepatic biliary atresia from neonatal hepatitis: a prospective study.
      ,
      • Mowat A.P.
      • Psacharopoulos H.T.
      • Williams R.
      Extrahepatic biliary atresia versus neonatal hepatitis. Review of 137 prospectively investigated infants.
      Liver biopsy has played a central role in the rapid diagnosis of biliary atresia with accuracy rates of 88-96.8%.
      • Lai M.W.
      • Chang M.H.
      • Hsu S.C.
      • Hsu H.C.
      • Su C.T.
      • Kao C.L.
      • et al.
      Differential diagnosis of extrahepatic biliary atresia from neonatal hepatitis: a prospective study.
      ,
      • Rastogi A.
      • Krishnani N.
      • Yachha S.K.
      • Khanna V.
      • Poddar U.
      • Lal R.
      Histopathological features and accuracy for diagnosing biliary atresia by prelaparotomy liver biopsy in developing countries.
      It also provides clues regarding biliary ductal paucity and transporter defects when immunohistochemistry is used. Ultrasound is most useful for the diagnosis of choledochal cyst where a cyst and/or biliary dilatation is demonstrated. Magnetic resonance cholangiopancreatography may be required to further investigate choledochal cysts and biliary dilatation. The role of ultrasound in the diagnosis of biliary atresia is quite variable across centres. A small gallbladder with poor contractility, cyst at the porta hepatis, triangular cord sign, subcapsular plexus and dominant hepatic artery are described as diagnostic features in biliary atresia. The presence of a triangular cord sign can be determined objectively by measuring the echogenic anterior wall of the right portal vein.
      • Lee H.J.
      • Lee S.M.
      • Park W.H.
      • Choi S.O.
      Objective criteria of triangular cord sign in biliary atresia on US scans.
      A meta-analysis of the role of ultrasound in diagnosing biliary atresia showed that the combination of the triangular cord sign and an abnormal gallbladder achieved a summary sensitivity of 0.95 (95% CI 0.70–0.99) and a summary specificity of 0.89 (95% CI 0.79–0.94).
      • Zhou L.
      • Shan Q.
      • Tian W.
      • Wang Z.
      • Liang J.
      • Xie X.
      Ultrasound for the diagnosis of biliary atresia: a meta-analysis.
      Yet this data from specialised units is not universally replicated. Endoscopic retrograde cholangiopancreatography (ERCP) examination in centres with the expertise may help avoid laparotomy by demonstrating biliary tree patency in cases where diagnosis remains doubtful even after liver biopsy. The reported successful ERCP completion rate is 89.2% with no procedure-related complications, positive predictive value of 92.2% and negative predictive value of 97.1%.
      • Negm A.A.
      • Petersen C.
      • Markowski A.
      • Luettig B.
      • Ringe K.I.
      • Lankisch T.O.
      • et al.
      The role of endoscopic retrograde cholangiopancreatography in the diagnosis of biliary atresia: 14 Years' experience.
      In infantile cholestasis, algorithmic multistage tests are necessary for early and accurate diagnoses, while addressing complications of fat-soluble vitamin deficiencies, via administration of vitamin K and specific milk formulae, is crucial.
      The advent of next-generation sequencing has improved recognition of genetic disorders such as Alagille syndrome, bile acid transporter defects, bile acid synthetic disorders, storage and other metabolic disorders. The availability of targeted gene panels has decreased the need for diagnostic biopsy in many of these disorders.
      • D’Antiga L.
      Next-generation sequencing in paediatric hepatology.

      Acute liver failure

      Acute liver failure (ALF), though uncommon in the population, is an important cause of mortality. About 12.5% of all liver transplants in children are performed for ALF.
      • Kim W.R.
      • Lake J.R.
      • Smith J.M.
      • Skeans M.A.
      • Schladt D.P.
      • Edwards E.B.
      • et al.
      OPTN/SRTR 2013 annual data report: liver.
      • Psacharopoulos H.T.
      • Mowat A.P.
      • Davies M.
      • Portmann B.
      • Silk D.B.
      • Williams R.
      Fulminant hepatic failure in childhood: an analysis of 31 cases.
      • Sundaram V.
      • Shneider B.L.
      • Dhawan A.
      • Ng V.L.
      • Im K.
      • Belle S.
      • et al.
      King's College Hospital Criteria for non-acetaminophen induced acute liver failure in an international cohort of children.
      Paediatric acute liver failure (PALF) differs from adult in its: i) definition; ii) aetiology and iii) selection criteria for liver transplantation (LT). Challenges in the management of PALF include: i) timely transfer to a specialist liver centre; ii) establishing aetiology; iii) predicting need for LT; iv) supportive management while awaiting LT or native liver recovery to minimise mortality and long-term complications like neurological injury.

      Recognition, referral and transfer

      PALF is defined as a hepatic-based coagulopathy with biochemical evidence of acute liver injury leading to an international normalized ratio (INR) ≥1.5 not correctable by vitamin K in the presence of clinical hepatic encephalopathy (HE), or an INR ≥2.0 irrespective of the presence of encephalopathy, in patients with no known evidence of chronic liver disease.
      • Squires Jr., R.H.
      • Shneider B.L.
      • Bucuvalas J.
      • Alonso E.
      • Sokol R.J.
      • Narkewicz M.R.
      • et al.
      Acute liver failure in children: the first 348 patients in the pediatric acute liver failure study group.
      Behavioural changes of children in the hospital environment may be difficult to differentiate from early HE. Many children may not be regarded as encephalopathic until much later in the course of their liver failure. Thus, PALF differs from the definition of ALF in adults where HE is a mandatory criterion.
      • Lee W.M.
      • Stravitz R.T.
      • Larson A.M.
      Introduction to the revised American Association for the Study of Liver Diseases Position Paper on acute liver failure 2011.
      Some of the disorders presenting as PALF, like Wilson disease (WD), autoimmune liver disease (AILD), GALD and tyrosinemia type 1, may exhibit a degree of fibrosis and chronicity on histopathology. Thus, they may not fit the classic definition of ALF in the strict sense. Yet their current classification as PALF is driven by the presentation and natural history that mimics ALF.
      Patients with worsening coagulopathy should be discussed with, or transferred to, the nearest liver centre with liver transplant facilities. The criteria for transfer varies based on the local healthcare setup and aetiology (e.g., higher INR threshold for paracetamol toxicity). Suggested transfer criteria to a specialist centre are, (i) paracetamol toxicity with an INR >3 and increasing or any degree of extrahepatic dysfunction, or (ii) non-paracetamol ALF with INR persistently >2.

      Aetiology and diagnosis of PALF

      The aetiology of PALF is largely different from that in adults. It also varies between the various age-groups in paediatrics while retaining a geographical variation. Table S1 lists the various aetiologies reported in children across various age groups and geographical areas.
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      • Shneider B.L.
      • Bucuvalas J.
      • Alonso E.
      • Sokol R.J.
      • Narkewicz M.R.
      • et al.
      Acute liver failure in children: the first 348 patients in the pediatric acute liver failure study group.
      ,
      • Lee W.S.
      • McKiernan P.
      • Kelly D.A.
      Etiology, outcome and prognostic indicators of childhood fulminant hepatic failure in the United Kingdom.
      • Poddar U.
      • Thapa B.R.
      • Prasad A.
      • Sharma A.K.
      • Singh K.
      Natural history and risk factors in fulminant hepatic failure.
      • Sundaram S.S.
      • Alonso E.M.
      • Narkewicz M.R.
      • Zhang S.
      • Squires R.H.
      Characterization and outcomes of young infants with acute liver failure.
      • Ciocca M.
      • Ramonet M.
      • Cuarterolo M.
      • López S.
      • Cernadas C.
      • Alvarez F.
      Prognostic factors in paediatric acute liver failure.
      Hepatitis A still continues to be an important cause of PALF in countries from South America and South-East Asia.
      • Poddar U.
      • Thapa B.R.
      • Prasad A.
      • Sharma A.K.
      • Singh K.
      Natural history and risk factors in fulminant hepatic failure.
      ,
      • Ciocca M.
      • Ramonet M.
      • Cuarterolo M.
      • López S.
      • Cernadas C.
      • Alvarez F.
      Prognostic factors in paediatric acute liver failure.
      A thorough aetiological work-up allows for disease-specific treatment and also helps in prognostication.
      • Di Giorgio A.
      • Bartolini E.
      • Calvo P.L.
      • Cananzi M.
      • Cirillo F.
      • Della Corte C.
      • et al.
      Diagnostic approach to acute liver failure in children: a position paper by the SIGENP liver disease working group.
      Data suggest wide variability in the work-up of PALF, especially regarding screening for autoimmune and metabolic liver diseases.
      • Narkewicz M.R.
      • Dell Olio D.
      • Karpen S.J.
      • Murray K.F.
      • Schwarz K.
      • Yazigi N.
      • et al.
      Pattern of diagnostic evaluation for the causes of pediatric acute liver failure: an opportunity for quality improvement.
      Limitations to this work-up include the limited time available for investigations, turnaround times and the availability of investigations. There is room for quality improvement in the form of standardised age-appropriate aetiological work-up (Table 3).
      Table 3Evaluation for aetiology in paediatric acute liver failure.
      AetiologyInvestigations
      Drugs/ toxins
      Tools to measure serum paracetamol adducts are not widely available.
      Serum paracetamol level, urine screen for toxins/drugs
      Autoimmune liver diseaseSerum total IgG, anti-smooth muscle antibody, anti-liver kidney microsomal antibody, anti-nuclear antibody, anti-liver cytosol antibody, antibody to soluble liver antigen, liver biopsy
      Role of liver biopsy is controversial.
      Viral infectionsSerum PCR for herpes simplex virus, serology for acute EBV infection, EBV PCR, adenovirus PCR, parvovirus PCR, enterovirus PCR, cytomegalovirus PCR, HBV DNA PCR, HBsAg, IgM anti-HBcAb, IgM anti-HAV, anti-HEV antibody
      Haematological disorders – haemophagocytic lymphohistiocytosis, congenital leukaemia, lymphomatous infiltrationFull blood count, blood film, lactate dehydrogenase, serum triglycerides, serum ferritin, serum fibrinogen, soluble CD25, granzyme B, bone marrow aspiration and trephine biopsy, NK cell activity, perforin mutations
      Metabolic and genetic work-upRed blood cell – galactose-1-phosphate uridyl transferase

      Urine – succinyl-acetone, organic acids, plasma amino acids

      Serum – lactate, pyruvate

      Genetic analysis for mitochondrial genetics and Wilson’s disease: serum caeruloplasmin, 24-hour urine copper, serum carnitine and acyl carnitine profile, urine ketones

      Disorders causing recurrent acute liver failure.
      Genetics for mutations suggesting NBAS deficiency, E3 deficiency, Wolcott-Rallison syndrome, CALFAN syndrome (SCYL1 mutations), TRMU mutations, MARS, LARS, RINT1, PCK1 mutations, fatty acid oxidation disorders
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      • Peters B.
      • Wagner M.
      • Alameer S.
      • Barić I.
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      Defining clinical subgroups and genotype-phenotype correlations in NBAS-associated disease across 110 patients.
      • Brassier A.
      • Ottolenghi C.
      • Boutron A.
      • Bertrand A.M.
      • Valmary-Degano S.
      • Cervoni J.P.
      • et al.
      Dihydrolipoamide dehydrogenase deficiency: a still overlooked cause of recurrent acute liver failure and Reye-like syndrome.
      • Julier C.
      • Nicolino M.
      Wolcott-Rallison syndrome.
      • Li J.Q.
      • Gong J.Y.
      • Knisely A.S.
      • Zhang M.H.
      • Wang J.S.
      Recurrent acute liver failure associated with novel SCYL1 mutation: a case report.
      • Zeharia A.
      • Shaag A.
      • Pappo O.
      • Mager-Heckel A.M.
      • Saada A.
      • Beinat M.
      • et al.
      Acute infantile liver failure due to mutations in the TRMU gene.
      • van Meel E.
      • Wegner D.J.
      • Cliften P.
      • Willing M.C.
      • White F.V.
      • Kornfeld S.
      • et al.
      Rare recessive loss-of-function methionyl-tRNA synthetase mutations presenting as a multi-organ phenotype.
      • Casey J.P.
      • McGettigan P.
      • Lynam-Lennon N.
      • McDermott M.
      • Regan R.
      • Conroy J.
      • et al.
      Identification of a mutation in LARS as a novel cause of infantile hepatopathy.
      • Cousin M.A.
      • Conboy E.
      • Wang J.S.
      • Lenz D.
      • Schwab T.L.
      • Williams M.
      • et al.
      RINT1 Bi-allelic variations cause infantile-onset recurrent acute liver failure and skeletal abnormalities.
      • Vieira P.
      • Cameron J.
      • Rahikkala E.
      • Keski-Filppula R.
      • Zhang L.H.
      • Santra S.
      • et al.
      Novel homozygous PCK1 mutation causing cytosolic phosphoenolpyruvate carboxykinase deficiency presenting as childhood hypoglycemia, an abnormal pattern of urine metabolites and liver dysfunction.


      Whole-exome sequencing for indeterminate aetiology group
      VascularUltrasound with Doppler of hepatic veins
      Gestational alloimmune diseaseBuccal mucosal biopsy, serum ferritin, transferrin saturation, MRI abdomen for iron deposition in the viscera.
      EBV, Epstein-Barr virus; NK, natural killer.
      Tools to measure serum paracetamol adducts are not widely available.
      $ Role of liver biopsy is controversial.
      ∗∗ Disorders causing recurrent acute liver failure.
      Serum caeruloplasmin and 24-hour urine copper are unreliable for the diagnosis of WD presenting as PALF. An alkaline phosphatase to total bilirubin ratio of <4 and an aspartate aminotransferase/alanine aminotransferase ratio >2.2 yielded an AUROC of 0.98. If present, Coombs negative haemolytic anaemia supports the diagnosis.
      • Korman J.D.
      • Volenberg I.
      • Balko J.
      • Webster J.
      • Schiodt F.V.
      • Squires Jr., R.H.
      • et al.
      Screening for Wilson disease in acute liver failure: a comparison of currently available diagnostic tests.
      AILD presenting as PALF (AI-PALF) constitutes 2-6% of all PALF.
      • Squires Jr., R.H.
      • Shneider B.L.
      • Bucuvalas J.
      • Alonso E.
      • Sokol R.J.
      • Narkewicz M.R.
      • et al.
      Acute liver failure in children: the first 348 patients in the pediatric acute liver failure study group.
      ,
      • Lee W.S.
      • McKiernan P.
      • Kelly D.A.
      Etiology, outcome and prognostic indicators of childhood fulminant hepatic failure in the United Kingdom.
      ,
      • Aydoğdu S.
      • Ozgenç F.
      • Yurtsever S.
      • Akman S.A.
      • Tokat Y.
      • Yağci R.V.
      Our experience with fulminant hepatic failure in Turkish children: etiology and outcome.
      ,
      • Jain V.
      • Srivastava A.
      • Yachha S.K.
      • Kumari N.
      • Kathuria R.
      • Sarma M.S.
      • et al.
      Autoimmune acute liver failure and seronegative autoimmune liver disease in children: are they different from classical disease?.
      Type 2 AILD with anti-liver kidney microsomal type 1 (anti-LKM-1) antibody positivity is more likely to present as PALF.
      • Gregorio G.V.
      • Portmann B.
      • Reid F.
      • Donaldson P.T.
      • Doherty D.G.
      • McCartney M.
      • et al.
      Autoimmune hepatitis in childhood: a 20-year experience.
      Among children with AILD, those with anti-LKM-1 positivity are typically younger (median 7.4 [0.8-14.2] years-old) than those expressing anti-smooth muscle antibody (anti-SMA) (10.5 [2.3-14.9] years-old).
      • Gregorio G.V.
      • Portmann B.
      • Reid F.
      • Donaldson P.T.
      • Doherty D.G.
      • McCartney M.
      • et al.
      Autoimmune hepatitis in childhood: a 20-year experience.
      The diagnosis is complicated by the fact that autoantibodies may be present in 20% of indeterminate PALF (ID-PALF) cases and 22% of PALF cases caused by another aetiology, especially WD. Anti-LKM-1 positivity is more specific to an autoimmune aetiology than anti-nuclear antibody or anti-SMA positivity.
      • Narkewicz M.R.
      • Horslen S.
      • Belle S.H.
      • Rudnick D.A.
      • Ng V.L.
      • Rosenthal P.
      • et al.
      Prevalence and significance of autoantibodies in children with acute liver failure.
      IgG level may be normal in 14-20% of patients with AI-PALF.
      • Jain V.
      • Srivastava A.
      • Yachha S.K.
      • Kumari N.
      • Kathuria R.
      • Sarma M.S.
      • et al.
      Autoimmune acute liver failure and seronegative autoimmune liver disease in children: are they different from classical disease?.
      ,
      • Di Giorgio A.
      • Bravi M.
      • Bonanomi E.
      • Alessio G.
      • Sonzogni A.
      • Zen Y.
      • et al.
      Fulminant hepatic failure of autoimmune aetiology in children.
      Diagnostic testing should use an extended panel, including anti-liver cytosol and anti-soluble liver antigen antibodies. In up to 36% of cases with type 2 AILD, anti-liver cytosol antibody could be the only positive antibody.
      • Villalta D.
      • Girolami E.
      • Alessio M.G.
      • Sorrentino M.C.
      • Tampoia M.
      • Brusca I.
      • et al.
      Autoantibody profiling in a cohort of pediatric and adult patients with autoimmune hepatitis.
      All patients labelled as AI-PALF were positive for autoantibodies in 2 studies on AI-PALF, even though children with AILD are known to have negative autoantibodies at the time of diagnosis.
      • Jain V.
      • Srivastava A.
      • Yachha S.K.
      • Kumari N.
      • Kathuria R.
      • Sarma M.S.
      • et al.
      Autoimmune acute liver failure and seronegative autoimmune liver disease in children: are they different from classical disease?.
      ,
      • Gregorio G.V.
      • Portmann B.
      • Reid F.
      • Donaldson P.T.
      • Doherty D.G.
      • McCartney M.
      • et al.
      Autoimmune hepatitis in childhood: a 20-year experience.
      ,
      • Di Giorgio A.
      • Bravi M.
      • Bonanomi E.
      • Alessio G.
      • Sonzogni A.
      • Zen Y.
      • et al.
      Fulminant hepatic failure of autoimmune aetiology in children.
      Coagulopathy precludes a liver biopsy even though transjugular biopsy is an option. Massive hepatic necrosis, presence of lymphoid follicles, a plasma cell-enriched inflammatory infiltrate, and central perivenulitis are considered distinctive features of fulminant presentations of AILD.
      • Stravitz R.T.
      • Lefkowitch J.H.
      • Fontana R.J.
      • Gershwin M.E.
      • Leung P.S.
      • Sterling R.K.
      • et al.
      Autoimmune acute liver failure: proposed clinical and histological criteria.
      Massive hepatic necrosis type 4 and 5, considered more specific for autoimmune aetiology in adults, varies in frequency from 0-66% in paediatric series.
      • Jain V.
      • Srivastava A.
      • Yachha S.K.
      • Kumari N.
      • Kathuria R.
      • Sarma M.S.
      • et al.
      Autoimmune acute liver failure and seronegative autoimmune liver disease in children: are they different from classical disease?.
      ,
      • Di Giorgio A.
      • Bravi M.
      • Bonanomi E.
      • Alessio G.
      • Sonzogni A.
      • Zen Y.
      • et al.
      Fulminant hepatic failure of autoimmune aetiology in children.
      ,
      • Stravitz R.T.
      • Lefkowitch J.H.
      • Fontana R.J.
      • Gershwin M.E.
      • Leung P.S.
      • Sterling R.K.
      • et al.
      Autoimmune acute liver failure: proposed clinical and histological criteria.
      The validity of such histological patterns is doubtful in children.
      ID-PALF constitutes 43-49% of PALF.
      • Squires Jr., R.H.
      • Shneider B.L.
      • Bucuvalas J.
      • Alonso E.
      • Sokol R.J.
      • Narkewicz M.R.
      • et al.
      Acute liver failure in children: the first 348 patients in the pediatric acute liver failure study group.
      ,
      • Di Giorgio A.
      • Bravi M.
      • Bonanomi E.
      • Alessio G.
      • Sonzogni A.
      • Zen Y.
      • et al.
      Fulminant hepatic failure of autoimmune aetiology in children.
      This is probably a heterogenous group that includes unknown or undetected viral infections, drug-induced liver injury, undiagnosed metabolic/genetic disorders and disorders of immune dysregulation. ID-PALF is associated with low rates of native liver survival. Occult paracetamol toxicity is probably an important cause. Paracetamol adducts have been reported in 11% of patients with an ID-PALF. Adduct-positive ID-PALF was associated with a spontaneous survival rate of 76% compared to 44% for adduct-negative ID-PALF (p = 0.03).
      • Alonso E.M.
      • James L.P.
      • Zhang S.
      • Squires R.H.
      Acetaminophen adducts detected in serum of pediatric patients with acute liver failure.
      Metagenomic next-generation sequencing and whole-exome sequencing in ID-PALF are expected to identify subgroups of infective and metabolic/genetic disorders, respectively, possibly leading to more individualised care. The role of liver biopsy is controversial in the diagnosis of PALF. Although transjugular biopsy may be safe, the need for general anaesthesia is usually a deterrent in children who are not already on assisted ventilation. Liver biopsy could assist clinical decision making in conditions like AILD and WD where clinical features or biomarkers have not been helpful,
      • Chapin C.A.
      • Mohammad S.
      • Bass L.M.
      • Taylor S.A.
      • Kelly S.
      • Alonso E.M.
      Liver biopsy can Be safely performed in pediatric acute liver failure to aid in diagnosis and management.
      though Di Giorgio et al. advise against liver biopsy in differentiating AI-PALF and ID-PALF.
      • Di Giorgio A.
      • Bravi M.
      • Bonanomi E.
      • Alessio G.
      • Sonzogni A.
      • Zen Y.
      • et al.
      Fulminant hepatic failure of autoimmune aetiology in children.

      Management of PALF

      Management of PALF should always involve a multi-disciplinary approach that includes liaising with the nearest specialist liver centre. Transfer to specialist liver centres with facilities for LT depends on local expertise and the availability of intensive care facilities.
      Disorders for which aetiology-specific treatment is available are listed in Table 4. Supportive non-transplant care attempts to alleviate the extrahepatic dysfunction resulting from liver failure, in order to sustain life until the liver regenerates while at the same time maintaining the appropriate metabolic milieu and perfusion to allow for hepatic regeneration. This involves monitoring liver dysfunction, including INR and extrahepatic dysfunction, while appropriately timing interventions. (Table 5)
      Table 4Disorders causing paediatric acute liver failure for which there are aetiology-specific treatment options.
      AetiologyTreatment
      Tyrosinemia type 1Nitisinone
      Paracetamol toxicityN-acetyl cysteine
      Haemophagocytic lymphohistiocytosisImmunosuppression protocols
      HSV infectionAcyclovir
      Drug-induced liver injuryWithdrawal of offending drug
      GalactosemiaGalactose-free formula
      Fatty acid oxidation disordersDextrose infusion
      NBAS deficiencyDextrose/lipid infusion
      Gestational alloimmune liver diseaseDouble volume exchange transfusion and intravenous immunoglobulin administration
      Acute HBVAnti HBV antivirals
      Acute Budd-Chiari syndromeHepatic venoplasty and stenting
      Table 5Supportive care in paediatric acute liver failure.
      Systems needing supportMonitoring/investigationsIntervention and remarks
      Airway and respiratory supportSpO2, pO2, pCO2 and pH
      • Assisted ventilation in Grade III/IV encephalopathy or agitation with lower encephalopathy grades
      • Atracurium not dependent on hepatic elimination and useful when needing paralysis
        • Ward S.
        • Neill E.A.
        Pharmacokinetics of atracurium in acute hepatic failure (with acute renal failure).
      Fluid, electrolyte and metabolic management

      Renal support
      Serum sodium, serum potassium, serum phosphate, serum magnesium, serum calcium, CVP, urine output, serum urea and serum creatinine, plasma glucose, plasma lactate, pH. Hypophosphatemia/hyperphosphatemia more common with paracetamol toxicity.
      • Schmidt L.E.
      • Dalhoff K.
      Serum phosphate is an early predictor of outcome in severe acetaminophen-induced hepatotoxicity.
      Hypomagnesemia more common with plasmapheresis.
      • Kamochi M.
      • Aibara K.
      • Nakata K.
      • Murakami M.
      • Nandate K.
      • Sakamoto H.
      • et al.
      Profound ionized hypomagnesemia induced by therapeutic plasma exchange in liver failure patients.
      Hypocalcaemia and acidosis possible if regional citrate anticoagulation is used for CRRT
      • Rodriguez K.
      • Srivaths P.R.
      • Tal L.
      • Watson M.N.
      • Riley A.A.
      • Himes R.W.
      • et al.
      Regional citrate anticoagulation for continuous renal replacement therapy in pediatric patients with liver failure.
      • Target euvolemia to ensure cerebral perfusion
      • Start with 80% maintenance fluid for age and weight
      • Rapid fluid boluses can worsen cerebral oedema
      • Dextrose infusion to prevent hypoglycemia
      • Early CRRT with combination of factors – oliguria/anuria, fluid overload, hyponatremia <130 meq/L, hyperkalaemia, high lactate/metabolic acidosis unresponsive to fluid therapy, Persistent hyperammonaemia >150 umol/L after adequate hydration
      • Epoprostenol may be used for CRRT to prevent clotting
        • Deep A.
        • Zoha M.
        • Dutta Kukreja P.
        Prostacyclin as an anticoagulant for continuous renal replacement therapy in children.
      • No evidence for use of lactulose for lowering ammonia in case of constipation. May result in gaseous gut distention that may affect transplantation surgery
      • No evidence to support use of LOLA/Rifaximin
      Cardiovascular supportHeart rate, blood pressure, invasive arterial blood pressure, urine output, capillary refill time, temperature gradient, mixed venous oxygen saturation in patients on inotropes, trend in CVP, stroke volume variations, pulse pressure variations and response to fluid administration in hypotension
      • Noradrenaline after a trial of fluid is often the inotrope of choice to treat hypotension in PALF.
      • Relative adrenal insufficiency is known to occur. Corticosteroids may alleviate refractory hypotension
        • Harry R.
        • Auzinger G.
        • Wendon J.
        The effects of supraphysiological doses of corticosteroids in hypotensive liver failure.
      • Plasmapheresis in those with high inotrope requirement
        • Ide K.
        • Muguruma T.
        • Shinohara M.
        • Toida C.
        • Enomoto Y.
        • Matsumoto S.
        • et al.
        Continuous veno-venous hemodiafiltration and plasma exchange in infantile acute liver failure.
        • Chevret L.
        • Durand P.
        • Lambert J.
        • Essouri S.
        • Balu L.
        • Devictor D.
        • et al.
        High-volume hemofiltration in children with acute liver failure.
        • Larsen F.S.
        • Schmidt L.E.
        • Bernsmeier C.
        • Rasmussen A.
        • Isoniemi H.
        • Patel V.C.
        • et al.
        High-volume plasma exchange in patients with acute liver failure: an open randomised controlled trial.
      • With escalating inotrope requirement (features of ‘toxic-liver’) hepatectomy while awaiting emergency liver transplantation
      Neurological monitoring and support
      • Kamat P.
      • Kunde S.
      • Vos M.
      • Vats A.
      • Gupta N.
      • Heffron T.
      • et al.
      Invasive intracranial pressure monitoring is a useful adjunct in the management of severe hepatic encephalopathy associated with pediatric acute liver failure.
      ,
      • Hunt A.
      • Tasker R.C.
      • Deep A.
      Neurocritical care monitoring of encephalopathic children with acute liver failure: a systematic review.
      GCS/AVPU, HE staging, features of raised ICP – bradycardia, dystonia and hypertension, pupillary abnormalities, any focal neurological deficits, seizures. Rule out hypoglycaemia with altered sensorium. Limited data on invasive ICP monitoring. 7% bleeding complications.
      • Kamat P.
      • Kunde S.
      • Vos M.
      • Vats A.
      • Gupta N.
      • Heffron T.
      • et al.
      Invasive intracranial pressure monitoring is a useful adjunct in the management of severe hepatic encephalopathy associated with pediatric acute liver failure.
      ONSD not reliable to monitor ICP. Reverse jugular venous oxygen saturation measurement is intermittent, prone to jugular venous thrombosis and is an indirect measure of ICP, the interpretation of which is influenced by confounding factors. Transcranial doppler – quantitative assessment of waveforms, particularly the Windkessel effect or quantitative estimates using the pulsatility index, mean blood flow velocity and arterial pressure. This lacks correlation across the various phases of raised ICP and intermittent nature of measurement is a drawback. Any sudden worsening of sensorium/focal signs – cross-sectional imaging for intracranial bleed
      • Prevention of raised ICP/neurological injury – Fever control, head end elevation to 30 degrees, sedation, minimise stimulation, avoid fluid overload while ensuring good CPP, maintain serum sodium between 145-150 mEq/L. Nurse with minimal stimulation in a quiet environment
      • Sedation in agitated or ventilated patient. Avoid benzodiazepines. Morphine/fentanyl preferred. Adequate sedation during airway suction
      • Early CRRT with renal impairment or presence of HE >grade 2 with ammonia >150 μmol/L or an absolute serum ammonia value of >200 μmol/L after fluid resuscitation
        • Cardoso F.S.
        • Gottfried M.
        • Tujios S.
        • Olson J.C.
        • Karvellas C.J.
        Continuous renal replacement therapy is associated with reduced serum ammonia levels and mortality in acute liver failure.
      • Ammonia scavengers such as sodium benzoate and sodium phenyl butyrate are beneficial in ALF secondary to urea cycle disorders.
      • 3% saline, 20% mannitol (contraindicated in AKI) and transient hyperventilation may be used for spurt in ICP. Monitor serum sodium, osmolarity or pCO2
      • No sufficient evidence for use of anticonvulsants to prevent subclinical seizures in higher grades of HE.
        • Ellis A.J.
        • Wendon J.A.
        • Williams R.
        Subclinical seizure activity and prophylactic phenytoin infusion in acute liver failure: a controlled clinical trial.
      • Hepatectomy in a very select patient where necrotic liver is believed to be causing raised intracranial hypertension.
      Coagulation and haematological supportBleeding manifestations, Prothrombin time (INR), plasma fibrinogen level, platelet counts. INR does not predict bleeding risk
      • Correction of INR by coagulation factors affects monitoring and decision-making for listing for liver transplantation
      • Coagulation factor support only for bleeding and invasive procedures
      • No evidence for threshold of INR for transfusion of factors.
      • Platelet count above 50,000 platelets/ml could minimise bleeding risk
      • Plasma exchange for life threatening bleeds or increased requirement for coagulation factor support (>30ml/kg of FFP in 24 h)
        • Akcan Arikan A.
        • Srivaths P.
        • Himes R.W.
        • Tufan Pekkucuksen N.
        • Lam F.
        • Nguyen T.
        • et al.
        Hybrid extracorporeal therapies as a bridge to pediatric liver transplantation.
      • Stress ulcer prevention – proton pump inhibitor
      Secondary infectionFever, features of SIRS. SIRS non-specific and could be a result of liver failure/necrosis. CRP unreliable as a marker of sepsis. Daily surveillance cultures.
      • Lee W.M.
      • Stravitz R.T.
      • Larson A.M.
      Introduction to the revised American Association for the Study of Liver Diseases Position Paper on acute liver failure 2011.
      Suspect infection in case of sudden worsening/hypotension/ unexplained AKI/encephalopathy/SIRS
      • Prophylactic broad-spectrum antibiotics and antifungals decrease frequency of infections. Effect on mortality not known
        • Godbole G.
        • Shanmugam N.
        • Dhawan A.
        • Verma A.
        Infectious complications in pediatric acute liver failure.
        • Mekala S.
        • Jagadisan B.
        • Parija S.C.
        • Lakshminarayanan S.
        Surveillance for infectious complications in pediatric acute liver failure - a prospective study.
        • Rolando N.
        • Harvey F.
        • Brahm J.
        • Philpott-Howard J.
        • Alexander G.
        • Gimson A.
        • et al.
        Prospective study of bacterial infection in acute liver failure: an analysis of fifty patients.
      • Selective gut decontamination not recommended
      Nutrition
      • Enteral feed when possible, with 1 g/kg/day of protein
      Aetiology non-specific supportive care
      • N-acetyl cysteine infusion – when there is a suspicion of paracetamol toxicity.
      AKI, acute kidney injury; AVPU scale, alert verbal painful unresponsiveness; CPP, cerebral perfusion pressure; CRP, C-reactive protein; CRRT, continuous renal replacement therapy; CVP, central venous pressure; FFP, fresh frozen plasma; GCS, Glasgow coma scale; HE, hepatic encephalopathy; ICP, intracranial pressure; INR, international normalised ratio; ONSD, optic nerve sheath diameter; pCO2, partial pressure of carbon dioxide; pO2, partial pressure of oxygen; SIRS, systemic inflammatory response syndrome; SpO2, oxygen saturation.
      Only 1 in 13 patients with fulminant WD survive without LT despite albumin dialysis and chelation.
      • Markiewicz-Kijewska M.
      • Szymczak M.
      • Ismail H.
      • Prokurat S.
      • Teisseyre J.
      • Socha P.
      • et al.
      Liver transplantation for fulminant Wilson's disease in children.
      Plasmapheresis has been used in patients with WD-related PALF who present with haemolysis and renal dysfunction,
      • Kido J.
      • Matsumoto S.
      • Momosaki K.
      • Sakamoto R.
      • Mitsubuchi H.
      • Inomata Y.
      • et al.
      Plasma exchange and chelator therapy rescues acute liver failure in Wilson disease without liver transplantation.
      • Asfaha S.
      • Almansori M.
      • Qarni U.
      • Gutfreund K.S.
      Plasmapheresis for hemolytic crisis and impending acute liver failure in Wilson disease.
      • Kiss J.E.
      • Berman D.
      • Van Thiel D.
      Effective removal of copper by plasma exchange in fulminant Wilson's disease.
      • Matsumura A.
      • Hiraishi H.
      • Terano A.
      Plasma exchange for hemolytic crisis in Wilson disease.
      • Nagata Y.
      • Uto H.
      • Hasuike S.
      • Ido A.
      • Hayashi K.
      • Eto T.
      • et al.
      Bridging use of plasma exchange and continuous hemodiafiltration before living donor liver transplantation in fulminant Wilson's disease.
      • Zhang Y.
      • Li L.
      • Zhang X.
      • Xu W.
      • Guo Q.
      • Zhou J.
      Plasmapheresis combined with continuous plasma filtration adsorption rescues severe acute liver failure in Wilson's disease before liver transplantation.
      • Schwartz J.
      • Padmanabhan A.
      • Aqui N.
      • Balogun R.A.
      • Connelly-Smith L.
      • Delaney M.
      • et al.
      Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the Writing Committee of the American Society for Apheresis: the seventh special issue.
      but single pass albumin dialysis and plasmapheresis to remove circulating copper are at best bridges to LT.
      • Collins K.L.
      • Roberts E.A.
      • Adeli K.
      • Bohn D.
      • Harvey E.A.
      Single pass albumin dialysis (SPAD) in fulminant Wilsonian liver failure: a case report.
      The new Wilson index can be used to predict death without LT, with a score of ≥11 having a positive predictive value of 88% for death without LT.
      • Dhawan A.
      • Taylor R.M.
      • Cheeseman P.
      • De Silva P.
      • Katsiyiannakis L.
      • Mieli-Vergani G.
      Wilson's disease in children: 37-year experience and revised King's score for liver transplantation.
      Collating results from the literature, 12 of the 29 (41.4%) cases of AI-PALF showed a response to steroids.
      • Jain V.
      • Srivastava A.
      • Yachha S.K.
      • Kumari N.
      • Kathuria R.
      • Sarma M.S.
      • et al.
      Autoimmune acute liver failure and seronegative autoimmune liver disease in children: are they different from classical disease?.
      ,
      • Gregorio G.V.
      • Portmann B.
      • Reid F.
      • Donaldson P.T.
      • Doherty D.G.
      • McCartney M.
      • et al.
      Autoimmune hepatitis in childhood: a 20-year experience.
      ,
      • Di Giorgio A.
      • Bravi M.
      • Bonanomi E.
      • Alessio G.
      • Sonzogni A.
      • Zen Y.
      • et al.
      Fulminant hepatic failure of autoimmune aetiology in children.
      ,
      • Herzog D.
      • Rasquin-Weber A.M.
      • Debray D.
      • Alvarez F.
      Subfulminant hepatic failure in autoimmune hepatitis type 1: an unusual form of presentation.
      ,
      • Maggiore G.
      • Porta G.
      • Bernard O.
      • Hadchouel M.
      • Alvarez F.
      • Homberg J.C.
      • et al.
      Autoimmune hepatitis with initial presentation as acute hepatic failure in young children.
      The comparative response in adults is 10-41%.
      • Ichai P.
      • Duclos-Vallée J.C.
      • Guettier C.
      • Hamida S.B.
      • Antonini T.
      • Delvart V.
      • et al.
      Usefulness of corticosteroids for the treatment of severe and fulminant forms of autoimmune hepatitis.
      ,
      • Mendizabal M.
      • Marciano S.
      • Videla M.G.
      • Anders M.
      • Zerega A.
      • Balderramo D.C.
      • et al.
      Fulminant presentation of autoimmune hepatitis: clinical features and early predictors of corticosteroid treatment failure.
      While interpreting such data, one must remember that nearly 10-50% of children do not receive steroids in view of their advanced state of liver failure.
      • Jain V.
      • Srivastava A.
      • Yachha S.K.
      • Kumari N.
      • Kathuria R.
      • Sarma M.S.
      • et al.
      Autoimmune acute liver failure and seronegative autoimmune liver disease in children: are they different from classical disease?.
      ,
      • Di Giorgio A.
      • Bravi M.
      • Bonanomi E.
      • Alessio G.
      • Sonzogni A.
      • Zen Y.
      • et al.
      Fulminant hepatic failure of autoimmune aetiology in children.
      Early grades of HE (<grade 3) and lower model for end-stage liver disease score (<27) were associated with response to steroids, suggesting that AI-PALF probably offers a narrow window for responsiveness to treatment prior to loss of a critical hepatocyte mass.
      • Mendizabal M.
      • Marciano S.
      • Videla M.G.
      • Anders M.
      • Zerega A.
      • Balderramo D.C.
      • et al.
      Fulminant presentation of autoimmune hepatitis: clinical features and early predictors of corticosteroid treatment failure.
      In adults, response to a 2-week course of steroids is considered a more definitive proof but there is no equivalent paediatric data.
      • Czaja A.J.
      • Rakela J.
      • Ludwig J.
      Features reflective of early prognosis in corticosteroid-treated severe autoimmune chronic active hepatitis.
      The role of plasma exchange as a specific treatment for AI-PALF is not well established.
      • Liu L.L.
      • Feng M.L.
      • Wang L.N.
      • Li X.L.
      • Yao L.
      A case report of successful treatment with plasma exchange for adult-onset Still's disease with autoimmune hepatitis.
      The pattern of activated CD8 infiltration reflecting a process akin to haemophagocytic lymphohistiocytosis has been demonstrated in ID-PALF.
      • Chapin C.A.
      • Melin-Aldana H.
      • Kreiger P.A.
      • Burn T.
      • Neighbors K.
      • Taylor S.A.
      • et al.
      Activated CD8 T-cell hepatitis in children with indeterminate acute liver failure: results from a multicenter cohort.
      Immunosuppression protocols based on a demonstration of CD8+ cytotoxic T cell-predominant liver injury on biopsy led to spontaneous survival in 5 children with indeterminate hepatitis and PALF, of whom only one was ever listed for LT.
      • McKenzie R.B.
      • Berquist W.E.
      • Nadeau K.C.
      • Louie C.Y.
      • Chen S.F.
      • Sibley R.K.
      • et al.
      Novel protocol including liver biopsy to identify and treat CD8+ T-cell predominant acute hepatitis and liver failure.
      The role of corticosteroids in ID-PALF and hepatitis-associated aplastic anaemia is doubtful considering that the outcomes are no different from those in historical controls.
      • Chapin C.A.
      • Horslen S.P.
      • Squires J.E.
      • Lin H.
      • Blondet N.
      • Mohammad S.
      • et al.
      Corticosteroid therapy for indeterminate pediatric acute liver failure and aplastic anemia with acute hepatitis.
      Among other therapies, the use of N-acetyl cysteine (NAC) in non-acetaminophen liver failure is controversial. Data from a prospective adult study showed that NAC conferred a transplant-free survival benefit in patients with coma grade I–II.
      • Lee W.M.
      • Hynan L.S.
      • Rossaro L.
      • Fontana R.J.
      • Stravitz R.T.
      • Larson A.M.
      • et al.
      Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure.
      A retrospective paediatric study showed improved transplant-free survival, lower length of stay and improved post-LT survival.
      • Kortsalioudaki C.
      • Taylor R.M.
      • Cheeseman P.
      • Bansal S.
      • Mieli-Vergani G.
      • Dhawan A.
      Safety and efficacy of N-acetylcysteine in children with non-acetaminophen-induced acute liver failure.
      However, in a prospective study, NAC did not lead to improvements in 1-year survival in PALF (73% vs. placebo 82%, p = 0.19).
      • Squires R.H.
      • Dhawan A.
      • Alonso E.
      • Narkewicz M.R.
      • Shneider B.L.
      • Rodriguez-Baez N.
      • et al.
      Intravenous N-acetylcysteine in pediatric patients with nonacetaminophen acute liver failure: a placebo-controlled clinical trial.
      The role of plasmapheresis in adult ALF was studied by Larsen et al. in an open, randomised, controlled study, which showed that high volume plasmapheresis with fresh-frozen plasma increases transplant-free survival after 3 months in patients who did not undergo emergency LT, especially in those who fulfilled the criteria for poor prognosis but were not listed for LT due to contraindications.
      • Larsen F.S.
      • Schmidt L.E.
      • Bernsmeier C.
      • Rasmussen A.
      • Isoniemi H.
      • Patel V.C.
      • et al.
      High-volume plasma exchange in patients with acute liver failure: an open randomised controlled trial.
      Studies in children involve fewer patients without a control group and hence have not demonstrated a survival advantage. In a non-controlled study by Chevret et al., a group of 15 children with PALF requiring emergency LT with HE grade >2 and/or haemodynamic instability requiring vasopressors underwent high-volume haemofiltration therapy (ultrafiltrate flow >80 ml/kg/hour), which improved mean arterial pressure, serum creatinine and HE grade. Survival outcomes in this specific group are not available as the study also involved children with acute-on-chronic liver failure and primary non-function of the transplanted graft.
      • Chevret L.
      • Durand P.
      • Lambert J.
      • Essouri S.
      • Balu L.
      • Devictor D.
      • et al.
      High-volume hemofiltration in children with acute liver failure.
      Ide et al. reported a similar decrease in catecholamine index with a combination of continuous veno-venous haemodiafiltration and plasma exchange.
      • Ide K.
      • Muguruma T.
      • Shinohara M.
      • Toida C.
      • Enomoto Y.
      • Matsumoto S.
      • et al.
      Continuous veno-venous hemodiafiltration and plasma exchange in infantile acute liver failure.
      Similarly marginal benefit from the use of plasma exchange in the setting of life threatening bleeds or increased requirement for coagulation factor support was reported in a small paediatric study.
      • Akcan Arikan A.
      • Srivaths P.
      • Himes R.W.
      • Tufan Pekkucuksen N.
      • Lam F.
      • Nguyen T.
      • et al.
      Hybrid extracorporeal therapies as a bridge to pediatric liver transplantation.
      Data from other paediatric series do not confirm its efficacy, suggesting the need for further studies.
      • Singer A.L.
      • Olthoff K.M.
      • Kim H.
      • Rand E.
      • Zamir G.
      • Shaked A.
      Role of plasmapheresis in the management of acute hepatic failure in children.
      ,
      • Jørgensen M.H.
      • Rasmussen A.
      • Christensen V.B.
      • Jensen A.B.
      • Fonsmark L.
      • Andreassen B.U.
      • et al.
      Safety of high-volume plasmapheresis in children with acute liver failure.
      The use of extracorporeal liver support systems in children is the subject of a few case series, but its use in routine clinical practice cannot be recommended based on the lack of available evidence.
      • Jain V.
      • Dhawan A.
      Extracorporeal liver support systems in paediatric liver failure.

      Prognostication and listing for LT

      Advances in medical management and LT have decreased short-term mortality in PALF (from 72% in the pre-LT era to 14% currently).
      • Psacharopoulos H.T.
      • Mowat A.P.
      • Davies M.
      • Portmann B.
      • Silk D.B.
      • Williams R.
      Fulminant hepatic failure in childhood: an analysis of 31 cases.
      ,
      • Sundaram V.
      • Shneider B.L.
      • Dhawan A.
      • Ng V.L.
      • Im K.
      • Belle S.
      • et al.
      King's College Hospital Criteria for non-acetaminophen induced acute liver failure in an international cohort of children.
      Every patient admitted with PALF is assessed for their risk of mortality without transplant. Available prognostication systems associate single point or multi-point assessments to outcome events (either death or LT).
      • Jain V.
      • Dhawan A.
      Prognostic modeling in pediatric acute liver failure.
      In paediatric acute liver failure it is essential to establish the diagnosis and provide expert supportive and disease-specific care while coordinating with liver transplant centres.
      The available prognostic markers include those indicating degree of liver dysfunction, extrahepatic dysfunction, systemic inflammatory response syndrome, age and aetiology.
      • Psacharopoulos H.T.
      • Mowat A.P.
      • Davies M.
      • Portmann B.
      • Silk D.B.
      • Williams R.
      Fulminant hepatic failure in childhood: an analysis of 31 cases.
      ,
      • Squires Jr., R.H.
      • Shneider B.L.
      • Bucuvalas J.
      • Alonso E.
      • Sokol R.J.
      • Narkewicz M.R.
      • et al.
      Acute liver failure in children: the first 348 patients in the pediatric acute liver failure study group.
      ,
      • Lee W.S.
      • McKiernan P.
      • Kelly D.A.
      Etiology, outcome and prognostic indicators of childhood fulminant hepatic failure in the United Kingdom.
      ,
      • Poddar U.
      • Thapa B.R.
      • Prasad A.
      • Sharma A.K.
      • Singh K.
      Natural history and risk factors in fulminant hepatic failure.
      ,
      • Ciocca M.
      • Ramonet M.
      • Cuarterolo M.
      • López S.
      • Cernadas C.
      • Alvarez F.
      Prognostic factors in paediatric acute liver failure.
      ,
      • Dhawan A.
      • Cheeseman P.
      • Mieli-Vergani G.
      Approaches to acute liver failure in children.
      • Rivera-Penera T.
      • Moreno J.
      • Skaff C.
      • McDiarmid S.
      • Vargas J.
      • Ament M.E.
      Delayed encephalopathy in fulminant hepatic failure in the pediatric population and the role of liver transplantation.
      • Bhaduri B.R.
      • Mieli-Vergani G.
      Fulminant hepatic failure: pediatric aspects.
      • Ng V.L.
      • Li R.
      • Loomes K.M.
      • Leonis M.A.
      • Rudnick D.A.
      • Belle S.H.
      • et al.
      Outcomes of children with and without hepatic encephalopathy from the pediatric acute liver failure study group.
      The various parameters known to affect outcomes and the scoring systems (combining these parameters) that are validated in PALF are detailed in Tables S2 and S3.
      • Psacharopoulos H.T.
      • Mowat A.P.
      • Davies M.
      • Portmann B.
      • Silk D.B.
      • Williams R.
      Fulminant hepatic failure in childhood: an analysis of 31 cases.
      • Sundaram V.
      • Shneider B.L.
      • Dhawan A.
      • Ng V.L.
      • Im K.
      • Belle S.
      • et al.
      King's College Hospital Criteria for non-acetaminophen induced acute liver failure in an international cohort of children.
      • Squires Jr., R.H.
      • Shneider B.L.
      • Bucuvalas J.
      • Alonso E.
      • Sokol R.J.
      • Narkewicz M.R.
      • et al.
      Acute liver failure in children: the first 348 patients in the pediatric acute liver failure study group.
      ,
      • Lee W.S.
      • McKiernan P.
      • Kelly D.A.
      Etiology, outcome and prognostic indicators of childhood fulminant hepatic failure in the United Kingdom.
      ,
      • Poddar U.
      • Thapa B.R.
      • Prasad A.
      • Sharma A.K.
      • Singh K.
      Natural history and risk factors in fulminant hepatic failure.
      ,
      • Ciocca M.
      • Ramonet M.
      • Cuarterolo M.
      • López S.
      • Cernadas C.
      • Alvarez F.
      Prognostic factors in paediatric acute liver failure.
      ,
      • Dhawan A.
      • Cheeseman P.
      • Mieli-Vergani G.
      Approaches to acute liver failure in children.
      ,
      • Bhaduri B.R.
      • Mieli-Vergani G.
      Fulminant hepatic failure: pediatric aspects.
      • Ng V.L.
      • Li R.
      • Loomes K.M.
      • Leonis M.A.
      • Rudnick D.A.
      • Belle S.H.
      • et al.
      Outcomes of children with and without hepatic encephalopathy from the pediatric acute liver failure study group.
      • Liu E.
      • MacKenzie T.
      • Dobyns E.L.
      • Parikh C.R.
      • Karrer F.M.
      • Narkewicz M.R.
      • et al.
      Characterization of acute liver failure and development of a continuous risk of death staging system in children.
      • Lu B.R.
      • Gralla J.
      • Liu E.
      • Dobyns E.L.
      • Narkewicz M.R.
      • Sokol R.J.
      Evaluation of a scoring system for assessing prognosis in pediatric acute liver failure.
      • Rajanayagam J.
      • Frank E.
      • Shepherd R.W.
      • Lewindon P.J.
      Artificial neural network is highly predictive of outcome in paediatric acute liver failure.
      • Lu B.R.
      • Zhang S.
      • Narkewicz M.R.
      • Belle S.H.
      • Squires R.H.
      • Sokol R.J.
      Evaluation of the liver injury unit scoring system to predict survival in a multinational study of pediatric acute liver failure.
      Median waiting times for LT vary among centres. While patients await LT, focus is on keeping them stable with the measures listed in Table 5. Children listed for LT will need ongoing monitoring for features of clinical improvement or worsening that will necessitate delisting. Untreated or progressive infection despite 48 hours of appropriate antimicrobial treatment, invasive fungal infections, rapidly escalating inotrope requirements, objective evidence of brain death and acute respiratory distress syndrome indicate possible futility of LT.
      • Donnelly M.C.
      • Hayes P.C.
      • Simpson K.J.
      The changing face of liver transplantation for acute liver failure: assessment of current status and implications for future practice.
      Pre-existing advanced or progressive neurological impairment, mitochondrial disorders, active extrahepatic malignancy and multisystem disease may preclude children from LT.
      The UK National Health Service Blood and Transplant listing criteria for super-urgent listing for PALF is based on the King’s College Hospital score.
      (Table S4) The Clichy-Villejuif criteria that incorporates factor V levels is more often used in Europe and was predominantly validated in adults with viral hepatitis.
      • Ciocca M.
      • Ramonet M.
      • Cuarterolo M.
      • López S.
      • Cernadas C.
      • Alvarez F.
      Prognostic factors in paediatric acute liver failure.
      ,
      • Bernuau J.
      • Goudeau A.
      • Poynard T.
      • Dubois F.
      • Lesage G.
      • Yvonnet B.
      • et al.
      Multivariate analysis of prognostic factors in fulminant hepatitis B.

      Management of acute variceal bleeding

      Causes of variceal bleeding in children

      Variceal bleeding in children could result from cirrhotic or non-cirrhotic causes of portal hypertension. Among children who present with variceal bleeding, the causes of paediatric portal hypertension in developed and developing countries are, respectively, portal venous obstruction in 33% and 84.5%, intrahepatic non-cirrhotic portal hypertension in 12% and 5.5% and cirrhosis in 55% and 10%. Among intrahepatic causes of non-cirrhotic portal hypertension, congenital hepatic fibrosis is the single most common cause, accounting for 44-92% of cases. In developing countries, non-cirrhotic portal fibrosis and Budd-Chiari syndrome are also significant aetiological factors.
      • Poddar U.
      • Thapa B.R.
      • Rao K.L.
      • Singh K.
      Etiological spectrum of esophageal varices due to portal hypertension in Indian children: is it different from the West?.
      ,
      • Howard E.R.
      • Stringer M.D.
      • Mowat A.P.
      Assessment of injection sclerotherapy in the management of 152 children with oesophageal varices.
      Among patients with cirrhosis evaluated for LT, at least one-fourth have been known to have had an episode of variceal bleeding.
      • Sokal E.M.
      • Van Hoorebeeck N.
      • Van Obbergh L.
      • Otte J.B.
      • Buts J.P.
      Upper gastro-intestinal tract bleeding in cirrhotic children candidates for liver transplantation.
      Biliary atresia is a common cause of chronic liver disease in children and the onset of portal hypertension is often rapid and disproportionate to the liver synthetic dysfunction. Hence, biliary atresia is the aetiology responsible for one-third of bleeding cases in children with cirrhosis in the developed world.
      • Howard E.R.
      • Stringer M.D.
      • Mowat A.P.
      Assessment of injection sclerotherapy in the management of 152 children with oesophageal varices.
      Nearly 20% of patients with biliary atresia present with variceal bleeding during follow-up compared to 3% of patients with Alagille syndrome.
      • Lykavieris P.
      • Gauthier F.
      • Hadchouel P.
      • Duche M.
      • Bernard O.
      Risk of gastrointestinal bleeding during adolescence and early adulthood in children with portal vein obstruction.
      ,
      • Duché M.
      • Ducot B.
      • Tournay E.
      • Fabre M.
      • Cohen J.
      • Jacquemin E.
      • et al.
      Prognostic value of endoscopy in children with biliary atresia at risk for early development of varices and bleeding.
      Three-fourths of children with biliary atresia who bleed do so before 2.5 years of age. The risk of bleeding is related to the presence of ascites, total serum bilirubin concentration, prothrombin time, and portal vein diameter.
      • Duché M.
      • Ducot B.
      • Tournay E.
      • Fabre M.
      • Cohen J.
      • Jacquemin E.
      • et al.
      Prognostic value of endoscopy in children with biliary atresia at risk for early development of varices and bleeding.

      Management of variceal bleeding

      Children presenting with large volume gastrointestinal bleeding should have their airway, breathing, circulation and blood glucose assessed. Airway intubation may be required in view of encephalopathy, shock or the use of a balloon tamponade (BT) device. Intravenous access should be secured at ≥2 points. Intravenous delivery of a crystalloid bolus is required in those who are hypotensive. Rapid pushes of a bolus can precipitate or increase bleeding in a normotensive child, so caution should be exercised. A restrictive transfusion strategy with a target haemoglobin between 7–8 g/dl is recommended based on the experience in adults.
      • Villanueva C.
      • Colomo A.
      • Bosch A.
      • Concepción M.
      • Hernandez-Gea V.
      • Aracil C.
      • et al.
      Transfusion strategies for acute upper gastrointestinal bleeding.
      Early control of variceal bleeding can be achieved by pharmacotherapy with octreotide. Octreotide infusion at 1-5 μg/kg/hour after a single bolus of 1 μg/kg helps to decrease portal pressure by causing splanchnic vasoconstriction. Reports on the use of octreotide in paediatric portal hypertension are restricted to case series. Octreotide controls bleeding in around 70% of patients, with hyperglycaemia and abdominal pain being the only adverse events.
      • Zargar S.A.
      • Javid G.
      • Khan B.A.
      • Yattoo G.N.
      • Shah A.H.
      • Gulzar G.M.
      • et al.
      Endoscopic ligation compared with sclerotherapy for bleeding esophageal varices in children with extrahepatic portal venous obstruction.
      • Siafakas C.
      • Fox V.L.
      • Nurko S.
      Use of octreotide for the treatment of severe gastrointestinal bleeding in children.
      • Lam J.C.
      • Aters S.
      • Tobias J.D.
      Initial experience with octreotide in the pediatric population.
      Terlipressin has the advantage of subcutaneous intermittent administration but experience in children is limited. Abdominal cramps, diarrhoea and hypertension are potential complications with terlipressin, with similar or lower rates of bleeding control compared to octreotide.
      • Zhou X.
      • Tripathi D.
      • Song T.
      • Shao L.
      • Han B.
      • Zhu J.
      • et al.
      Terlipressin for the treatment of acute variceal bleeding: a systematic review and meta-analysis of randomized controlled trials.
      Children with chronic liver disease and coagulopathy may require transfusions of coagulation factors in addition to vitamin K. The use of coagulation factors should be restricted to those with variceal bleeding who are unresponsive to pharmacological and endoscopic therapy. Platelet transfusion is also restricted to such patients with a platelet count of <50,000 platelets/μl. The use of proton pump inhibitors is recommended for prophylaxis of gastric mucosal bleeding.
      Endoscopic therapy is recommended in patients once haemodynamic stability is achieved. A patient who is refractory to pharmacological therapy and unstable haemodynamically may require BT and the choice of device is usually dictated by local expertise. As 75% of children respond to octreotide infusion and endoscopic therapy can usually control bleeding in the rest, BT is rarely needed.
      • Zargar S.A.
      • Javid G.
      • Khan B.A.
      • Yattoo G.N.
      • Shah A.H.
      • Gulzar G.M.
      • et al.
      Endoscopic ligation compared with sclerotherapy for bleeding esophageal varices in children with extrahepatic portal venous obstruction.
      The high complication rates associated with BT are a major deterrent to its overenthusiastic use. Endoscopy should preferably be performed electively within 24 hours if the bleed is controlled pharmacologically but may be required as an emergency if not controlled by octreotide alone.
      • Garcia-Tsao G.
      • Sanyal A.J.
      • Grace N.D.
      • Carey W.D.
      Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis.
      ,
      • Lau J.Y.W.
      • Yu Y.
      • Tang R.S.Y.
      • Chan H.C.H.
      • Yip H.C.
      • Chan S.M.
      • et al.
      Timing of endoscopy for acute upper gastrointestinal bleeding.
      In practice, only 28% of endoscopies are performed within 24 hours and this has not been associated with adverse outcomes.
      • Carneiro de Moura M.
      • Chen S.
      • Kamath B.M.
      • Ng V.L.
      • Ling S.C.
      Acute variceal bleeding causes significant morbidity.
      Endoscopic variceal ligation (EVL) is the preferred modality of therapy when the oesophageal varices are big and a banding device can be passed into the oesophagus (usually in children >10-12 kg),
      • Liu J.
      • Petersen B.T.
      • Tierney W.M.
      • Chuttani R.
      • Disario J.A.
      • Coffie J.M.
      • et al.
      Endoscopic banding devices.
      with 100% bleeding control reported.
      • McKiernan P.J.
      • Beath S.V.
      • Davison S.M.
      A prospective study of endoscopic esophageal variceal ligation using a multiband ligator.
      In small children where banding is not possible, sclerotherapy is an effective option. Sclerotherapy of oesophageal varices has been shown to control bleeding in 97% of cases.
      • Goenka A.S.
      • Dasilva M.S.
      • Cleghorn G.J.
      • Patrick M.K.
      • Shepherd R.W.
      Therapeutic upper gastrointestinal endoscopy in children: an audit of 443 procedures and literature review.
      Octreotide infusion may be tapered gradually over a day or two following endotherapy. The median period of octreotide infusion was 4 days in a paediatric series of 70 variceal bleeding episodes.
      • Carneiro de Moura M.
      • Chen S.
      • Kamath B.M.
      • Ng V.L.
      • Ling S.C.
      Acute variceal bleeding causes significant morbidity.
      Gastric variceal bleeding requires a different management approach. Gastro-oesophageal varices on the lesser curvature may be managed with EVL but gastro-oesophageal varices on the greater curvature and isolated gastric varices in the fundus should not be banded or sclerosed. Cyanoacrylate glue injection is the standard of care. The use of lipiodol along with glue may result in delayed polymerisation and higher chances of embolisation. In a series including 28 children who underwent sessions for bleeding gastric varices, haemostasis was achieved in all patients.
      • Poddar U.
      • Borkar V.
      • Yachha S.K.
      • Srivastava A.
      Endoscopic management of bleeding gastric varices with N-butyl, 2-cyanoacrylate glue injection in children with non-cirrhotic portal hypertension.
      Early rebleeding is known to occur from ulceration and incomplete obliteration. Late bleeding may also occur due to glue cast extrusion. A repeat endoscopy within a week may be required to ensure complete obliteration. All patients who have received glue injection are kept on proton pump inhibitors until follow-up endoscopies confirm the absence of a gastric ulceration.
      Endoscopic ultrasound-guided transluminal glue injection may be required in those in whom bleeding prohibits adequate visualisation by conventional endoscopy. This may be combined with coil injection of the varix to act as a scaffold that facilitates polymerisation of the glue and limits the amount of glue required for obliteration and also the chances of systemic embolisation. This may be more relevant in large gastric varices >20 mm. Yet the size of endoscopic ultrasound scopes and the limited availability of expertise has limited the widespread adoption of this technique. Also, there is no evidence to show that it is superior to the conventional endoscopic technique of glue injection.
      • Thiruvengadam S.S.
      • Sedarat A.
      The role of endoscopic ultrasound (EUS) in the management of gastric varices.
      In patients in whom pharmacotherapy and endotherapy have failed, transjugular intrahepatic portosystemic shunt (TIPS) should be considered to control variceal bleeding, especially in Budd-Chiari syndrome and congenital hepatic fibrosis.
      • Ghannam J.S.
      • Cline M.R.
      • Hage A.N.
      • Chick J.F.B.
      • Srinivasa R.N.
      • Dasika N.L.
      • et al.
      Technical success and outcomes in pediatric patients undergoing transjugular intrahepatic portosystemic shunt placement: a 20-year experience.
      • Di Giorgio A.
      • Agazzi R.
      • Alberti D.
      • Colledan M.
      • D'Antiga L.
      Feasibility and efficacy of transjugular intrahepatic portosystemic shunt (TIPS) in children.
      • Nagral A.
      • Hasija R.P.
      • Marar S.
      • Nabi F.
      Budd-Chiari syndrome in children: experience with therapeutic radiological intervention.
      • Huppert P.E.
      • Goffette P.
      • Astfalk W.
      • Sokal E.M.
      • Brambs H.J.
      • Schott U.
      • et al.
      Transjugular intrahepatic portosystemic shunts in children with biliary atresia.
      • Heyman M.B.
      • LaBerge J.M.
      • Somberg K.A.
      • Rosenthal P.
      • Mudge C.
      • Ring E.J.
      • et al.
      Transjugular intrahepatic portosystemic shunts (TIPS) in children.
      • Hackworth C.A.
      • Leef J.A.
      • Rosenblum J.D.
      • Whitington P.F.
      • Millis J.M.
      • Alonso E.M.
      Transjugular intrahepatic portosystemic shunt creation in children: initial clinical experience.
      • Lorenz J.M.
      Placement of transjugular intrahepatic portosystemic shunts in children.
      In patients with cirrhosis, TIPS usage could lead to encephalopathy.
      • Ghannam J.S.
      • Cline M.R.
      • Hage A.N.
      • Chick J.F.B.
      • Srinivasa R.N.
      • Dasika N.L.
      • et al.
      Technical success and outcomes in pediatric patients undergoing transjugular intrahepatic portosystemic shunt placement: a 20-year experience.
      Hence it should be offered to children with minimal synthetic dysfunction of the liver or as a bridge to LT. In very young children, TIPS is limited by the availability of appropriate size stents and technical expertise.
      It is desirable to use prophylactic antibiotics in all children with cirrhosis with variceal bleeding to cover for gram-negative infections. In the absence of guidelines in children, only 54% receive prophylactic antibiotics after variceal bleeding.
      • Carneiro de Moura M.
      • Chen S.
      • Kamath B.M.
      • Ng V.L.
      • Ling S.C.
      Acute variceal bleeding causes significant morbidity.
      New onset ascites or an increase in ascites often follows variceal bleeding in patients with cirrhosis. This is often a reflection of the degree of synthetic dysfunction in these patients. Children with portal vein obstruction who have massive bleeding leading to low albumin may also develop transient ascites. Restricting sodium administration, and an early switch to oral feeds and diuretics once the bleed has been controlled, help in ascites management. Mortality due to uncontrolled bleeding and in the first 6 weeks following variceal bleeding can be up to 8% in patients with biliary atresia and other causes of cirrhosis.
      • Carneiro de Moura M.
      • Chen S.
      • Kamath B.M.
      • Ng V.L.
      • Ling S.C.
      Acute variceal bleeding causes significant morbidity.
      ,
      • Wanty C.
      • Helleputte T.
      • Smets F.
      • Sokal E.M.
      • Stephenne X.
      Assessment of risk of bleeding from esophageal varices during management of biliary atresia in children.
      Mortality is uncommon in patients with portal vein obstruction (1.7%).
      • Poddar U.
      • Thapa B.R.
      • Rao K.L.
      • Singh K.
      Etiological spectrum of esophageal varices due to portal hypertension in Indian children: is it different from the West?.
      Almost 57% developed morbidity associated with a prolonged hospital stay, including ascites (34%), infection (30%), respiratory complications (24%), intensive care unit admission (20%), re-bleeding (11%), encephalopathy (7%), acute kidney injury (6%) and failure to control bleeding (4%). Serum total bilirubin values predicted morbidity in patients with variceal bleeding.
      • Carneiro de Moura M.
      • Chen S.
      • Kamath B.M.
      • Ng V.L.
      • Ling S.C.
      Acute variceal bleeding causes significant morbidity.
      While we await innovative approaches to primary phrophylaxis in young children, variceal bleeding must be effectively managed in children to decrease mortality and morbidity.

      Liver mass

      The finding of liver mass/masses in infants and children necessitates urgent investigations to determine the nature of the lesion. Diagnoses include liver abscesses, malignancies and vascular tumours. Tumour markers like alpha-fetoprotein and axial imaging CT and/or MRI usually establish the diagnosis, with liver biopsy only occasionally required. This review focuses on the emergency presentations of tumours, including symptomatic hepatic haemangioma in infants and bleeding in a liver mass.
      Rapid work-up of liver masses is essential to identify malignancies, vascular tumours/malformations and infective lesions in order to offer aetiology-specific treatments.
      Infants with hepatic haemangioma may present with large or multifocal lesions that are symptomatic with high output cardiac failure. Abdominal distention may lead to respiratory compromise and abdominal compartment syndrome. This may be accompanied by consumptive thrombocytopenia and hypothyroidism. Initial stabilisation may include judicious use of diuretics in those with early symptoms or inotropes and ventilation in those with significant haemodynamic and respiratory compromise. Use of propranolol at 1-3 mg/kg/day is beneficial in children without heart failure.
      • Léauté-Labrèze C.
      • Hoeger P.
      • Mazereeuw-Hautier J.
      • Guibaud L.
      • Baselga E.
      • Posiunas G.
      • et al.
      A randomized, controlled trial of oral propranolol in infantile hemangioma.
      Pre-operative cross-sectional imaging could delineate the blood supply to the tumour. The most established treatment is selective transcatheter embolisation of the arterial supply of the haemangioma.
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      Depending on the centre’s expertise and preference, hepatic artery ligation could also be helpful. Liver transplantation may be required in rare cases.
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      Bleeding from liver tumours may result from intraperitoneal rupture of the tumour, intra-tumoral bleeding or very rarely haemobilia, as in adults with hepatocellular carcinoma (HCC) and cholangiocarcinoma.
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      Management of bleeding liver tumors.
      Intra-tumoral bleeding without rupture presents as an incidental imaging finding or as sudden onset abdominal pain and distension. In very young infants, this could result in significant haemodynamic compromise. In contrast, intraperitoneal rupture is often catastrophic. Unlike adults where HCC and telangiectatic adenomas are common causes of intraperitoneal rupture, in the paediatric age group this is often seen with hepatoblastoma (HB) and infantile haemangioma.
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      Management of bleeding liver tumors.
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      Aetio-pathogenesis and the management of spontaneous liver bleeding in the West: a 16-year single-centre experience.
      The reported incidence of HB rupture is variable (5-16%) in view of the unclear definitions of rupture in the earlier co-operative study groups.
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      ,
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      The Children's Hepatic tumors International Collaboration (CHIC): novel global rare tumor database yields new prognostic factors in hepatoblastoma and becomes a research model.
      The 2017 PRETEXT staging system for the PHITT trial proposed a clearer definition for rupture.
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      Clinically manifest intraperitoneal rupture presents as pallor, abdominal pain, sudden abdominal distention and haemodynamic compromise. Intraperitoneal rupture in HB is spontaneous in 82% of cases and may precede or follow chemotherapy. Other cases may be due to liver biopsy (18%) or an undefined cause of trauma.
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      Tumor rupture in hepatoblastoma: a high risk factor?.
      Rupture after biopsy is often seen in those with a subcapsular haematoma prior to biopsy.

      Stages of management

      Stabilisation: Children presenting with hypovolemia and anaemia are resuscitated with adequate volume replacement, transfusions and inotropes when necessary. Shock and abdominal distention leading to respiratory compromise may necessitate respiratory support. Coagulopathy and thrombocytopenia are often seen in adults with rupture of HCC occurring on the background of a chronic liver disease with hepatic insufficiency. This can be seen in children with ruptured HB – as a result of massive transfusions, shocked liver with decreased hepatic reserve or chemotherapy – and necessitates blood product support.
      Early diagnostic investigations: Ultrasound can detect liver masses, haematomas within a mass or within the subcapsular area and evidence of haemorrhage in the intraperitoneal fluid. Triple phase abdominal CT angiography should be performed as soon as the child is haemodynamically stable to confirm the haemoperitoneum and any liver haematoma (including any subcapsular component). Contrast extravasation indicates active bleeding and identifies the vessel supplying the bleeding tumour, which could be targeted for intervention. When spontaneous rupture is the initial presentation of HB, it also poses a diagnostic challenge. Characterising the tumour could be more difficult at this stage because of the haematoma and could be better done with a subsequent contrast MRI.
      • Darnis B.
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      • Mohkam K.
      • Ducerf C.
      • Mabrut J.Y.
      Management of bleeding liver tumors.
      Definitive management: Transarterial embolisation (including the transumblical route in neonates) is now the intervention of choice in ruptured hepatic tumours with ongoing bleeding.
      • Chan K.L.
      • Tam P.K.
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      • Lee S.C.
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      Successful transumbilical embolization of congenitally ruptured hepatoblastoma.
      • Kitahara S.
      • Makuuchi M.
      • Ishizone S.
      • Terada M.
      • Kawasaki S.
      • Nakahata T.
      • et al.
      Successful left trisegmentectomy for ruptured hepatoblastoma using intraoperative transarterial embolization.
      • Krauel L.
      • Albert A.
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      • Cruz O.
      • Mortera C.
      • et al.
      Use of angioembolization as an effective technique for the management of pediatric solid tumors.
      Embolisation is possible in 90% of adults but success rates in children are not known, as few cases have been reported. Small calibre tortuous vessels and anatomical variation could increase procedural complexity.
      • Darnis B.
      • Rode A.
      • Mohkam K.
      • Ducerf C.
      • Mabrut J.Y.
      Management of bleeding liver tumors.
      ,
      • Battula N.
      • Tsapralis D.
      • Takhar A.
      • Coldham C.
      • Mayer D.
      • Isaac J.
      • et al.
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      ,
      • Lau K.
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      • Kan W.K.
      • Leung J.L.
      • Lee A.S.
      • et al.
      Emergency transcatheter embolization of ruptured hepatocellular carcinomas with tortuous conventional or aberrant hepatic vascular anatomy, or parasitic supply.
      In patients who cannot be stabilised haemodynamically or with failed radiological embolisation, emergency laparotomy is indicated, sometimes just with sonographic evidence of haemoperitoneum. Emergency liver resection is rarely performed, as it may be associated with higher mortality and morbidity. Haemostasis is achieved with perihepatic packing and temporary clamping of the hepatic pedicle.
      • Darnis B.
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      ,
      • Madanur M.A.
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      Once stabilised, staged procedures are planned.
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      and could include attempts at intraoperative or post-operative radiological embolisation.
      • Kitahara S.
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      Successful left trisegmentectomy for ruptured hepatoblastoma using intraoperative transarterial embolization.

      Liver trauma

      Liver trauma in children results from blunt or penetrating injuries and can affect other organs as well. Increasingly liver trauma is managed conservatively. In a single centre study, 90% of liver injuries were successfully managed non-operatively.
      • Koyama T.
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      • Gaarder C.
      • Naess P.A.
      Surgical intervention for paediatric liver injuries is almost history - a 12-year cohort from a major Scandinavian trauma centre.
      However easy access to interventional radiology and ERCP is essential.
      • van As A.B.
      • Millar A.J.
      Management of paediatric liver trauma.
      An algorithm for management of blunt and penetrating liver injuries is outlined in Fig. 2.
      • Koyama T.
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      • Engelsen P.
      • Eken T.
      • Gaarder C.
      • Naess P.A.
      Surgical intervention for paediatric liver injuries is almost history - a 12-year cohort from a major Scandinavian trauma centre.
      • van As A.B.
      • Millar A.J.
      Management of paediatric liver trauma.
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      Liver trauma: WSES 2020 guidelines.
      After the initial stabilisation and control of bleeding, children will need to undergo follow-up for biliary and vascular complications.
      Figure thumbnail gr2
      Fig. 2Management of liver trauma in children.

      Metabolic encephalopathy due to liver-based inborn errors of metabolism (IEM)

      Manifestations and diagnosis

      Metabolic encephalopathies resulting from IEM typically present early in life in infants and children, even though disorders such as ornithine transcarbamylase deficiency could present for the first time as encephalopathy in adulthood. Having ruled out other causes of encephalopathy (infections, toxins and primary neurological conditions), a family history of metabolic disorders, unexplained infant deaths, consanguinity, neonatal onset encephalopathy, recurrent episodes and associated neurodevelopmental impairment could suggest IEM as a possible aetiology. These episodes may have an abrupt onset in a previously healthy child or may present initially as only behavioural changes, ataxia and vomiting. The encephalopathy may progress with a fulminant course to coma or may have a fluctuating course that is mistaken for improvement.
      Liver-based inborn errors of metabolism causing hyperammonaemia, hypoglycaemia, acidosis or aminoacidopathies may present with encephalopathy that needs to be recognised early – prompt metabolic stabilisation improves neurological outcomes.
      Common IEM that can present as emergencies are urea cycle disorders, organic acidemias, aminoacidopathies, fatty acid oxidation disorders, mitochondriopathies and glycogen storage disorders. Even though many of these disorders may manifest across the entire spectrum of the paediatric age group, aminoacidopathies, organic acidemias and urea cycle disorders have an onset early in the neonatal period. Fatty acid oxidation disorders more often manifest in childhood when longer periods of starvation (than in early infancy) and superimposed illness precipitate encephalopathy.
      Children with suspected metabolic encephalopathy should have plasma glucose, serum electrolytes, plasma ammonia, liver function tests with prothrombin time and blood gas analysis for acid-base imbalances measured immediately. Markedly elevated plasma ammonia levels in the absence of severe liver dysfunction suggest an IEM as the aetiology. Ornithine transcarbamylase deficiency may present as abnormal transaminase levels unlike in other urea cycle disorders, but the degree of liver dysfunction may not explain the very high plasma ammonia levels. Further interpretation might require quantitative plasma amino acid levels, plasma and urine acyl-carnitine profile, serum lactate and urine organic acids analysis.
      Hypoglycaemia in a newborn could be the result of severe systemic illness or sepsis. Early onset hypoglycaemia could be part of decreased reserves in a small for gestational age baby or an infant of a diabetic mother. Endocrine disorders can present as hypoglycaemia in a newborn. In the absence of the above, IEM should be suspected. The evaluation usually includes liver function tests, serum insulin, growth hormone and cortisol levels, C-peptide, serum beta-hydroxybutyrate, urine ketones and reducing substances, plasma amino acids, urine organic acids, plasma free fatty acid levels, acyl carnitine profile, plasma lactate and pyruvate levels(Fig. 3).
      • Guerrero R.B.
      • Salazar D.
      • Tanpaiboon P.
      Laboratory diagnostic approaches in metabolic disorders.
      • Schillaci L.P.
      • DeBrosse S.D.
      • McCandless S.E.
      Inborn errors of metabolism with acidosis: organic acidemias and defects of pyruvate and ketone body metabolism.
      • Häberle J.
      • Boddaert N.
      • Burlina A.
      • Chakrapani A.
      • Dixon M.
      • Huemer M.
      • et al.
      Suggested guidelines for the diagnosis and management of urea cycle disorders.
      Figure thumbnail gr3
      Fig. 3Approach to diagnosis in an infant with metabolic encephalopathy.

      Early management and stabilisation

      The emergency management of these disorders is aimed at rapid normalisation of metabolic derangement to improve survival and decrease neurological morbidity. Immediate correction of hypoglycaemia, ensuring adequate hydration and treatment of suspected infections is highly recommended. Hyperammonaemia is treated with sodium phenylbutyrate, sodium benzoate, arginine, carnitine and avoidance of alkalosis. High anion-gap acidosis is treated with intravenous glucose and insulin, corrections of acidosis, intravenous carnitine, vitamin B12 and biotin. Haemofiltration is necessary if plasma ammonia is >300 μmol/L or in the presence of severe acidosis (e.g. pH <7.2 or plasma leucine level >1,500-2,000 μmol/L). At least 100 kcal/kg/day is provided to avoid endogenous protein breakdown and protein is introduced at 1 g/kg body weight and gradually increased. Parenteral nutrition is necessary to ensure an anabolic state where enteral feeding is not possible.

      Conclusions

      The conditions discussed above constitute most of the common diagnostic and therapeutic challenges that present as emergencies in paediatric hepatology. In infants with cholestasis, early diagnosis of biliary atresia and other time-sensitive disorders improve outcomes. Simple interventions such as vitamin K administration can prevent neurological morbidity. Patients with PALF require stabilisation and investigations in consultation with a liver transplant centre. The use of octreotide in variceal bleeding achieves effective bleeding control and stabilisation before endoscopy or transfer to a liver centre. Liver trauma and liver tumours are better managed by a multidisciplinary approach in specialist centres. Several IEM can present with liver dysfunction, their early identification and treatment in collaboration with metabolic experts is essential to improve outcomes.

      Abbreviations

      AILD, autoimmune liver disease; AI-PALF, AILD presenting as PALF; ALF, acute liver failure; anti-LKM-1, anti-liver kidney microsomal type 1; anti-SMA, anti-smooth muscle antibody; BT, balloon tamponade; EVL, endoscopic variceal ligation; GALD, gestational alloimmune disease; HCC, hepatocellular carcinoma; HE, hepatic encephalopathy; IC, infantile cholestasis; ID-PALF, indeterminate PALF; IEM, inborn errors of metabolism; INR, international normalised ratio; LT, liver transplantation; NAC, N-acetyl cysteine; PALF, paediatric acute liver failure; TIPS, transjugular intrahepatic portosystemic shunt; WD, Wilson disease.

      Financial support

      The authors received no financial support to produce this manuscript.

      Authors’ contributions

      All authors contributed to the manuscript and approved the final manuscript.

      Conflict of interest

      The authors declare no conflicts of interest that pertain to this work.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following are the supplementary data to this article:

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