Title: Utility of transcranial Doppler and reversed jugular venous saturations for neuromonitoring in children with acute liver failure  

Source: European Journal of Pediatrics 2025, 185 (1): 39  

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Date of publication: December 2025

Publication type: Single centre observational study

Abstract: Paediatric Acute Liver Failure (PALF) is associated with high morbidity and mortality, with cerebral oedema a key contributor to mortality. The aim of our study was to examine the association between the findings of two neuromonitoring modalities (transcranial Doppler (TCD) and reverse venous jugular oxygen saturation (SjvO₂) and mortality, as well as ammonia levels, in children with acute liver failure who received neuroprotection within 7 days of paediatric intensive care unit (PICU) admission. Retrospective observational cohort study. Sixteen-bed PICU in a UK university-affiliated tertiary care hospital. Patients admitted to the PICU with PALF were reviewed between January 2013 and October 2023. Seventy-eight children, who were intubated and ventilated, had neuromonitoring either with TCD/SjvO₂ or both during the first week of hospital admission (before liver transplantation), and were included in the study.

Interventions: None. The median (IQR) age of the study population was 64 (25-144) months. Among the 78 children, 24 (30.8%) survived without liver transplant, 39 children (50.0%) survived post-liver transplant, 5 (6.4%) died post-transplant, and 10 (12.8%) died without transplant. Patients who died had a lower meanvelocity in the right middle cerebral artery (RMCA Vm) (Median: 34 cm/s vs 55 cm/s, p-value: 0.01) and higher pulsatility index (PI) than those who survived (Median: 2.1 vs 1.6, p: 0.001). SjvO₂ was also lower in non-survivors than in survivors (Mean: 39.0% vs 56.1%, p-value: 0.002). The PI had a weak positive correlation with ammonia (Rho: 0.25, p: 0.005). RMCA Vm and SjvO₂ had a negative correlation with ammonia (Rho: – 0.21, p-value: 0.022; Rho – 0.22; p-value: 0.017 respectively).

Conclusion: Patients with acute liver failure who died had a high RMCA PI, lower RMCA Vm, and lower SjvO₂. TCD and SjvO₂ may serve as useful adjuncts to the overall neurological assessment in critically ill children with PALF.

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Title: Phenotype and long-term outcome in recurrent paediatric acute liver failure: systematic review and individual participant data analysis

Source: Liver International 2025, 45 (11): e70412

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Date of publication: November 2025

Publication type: Systematic review

Abstract: Background and aims: Recurrent acute liver failure (RALF) in children is defined as two or more episodes of acute liver failure with complete recovery in between. Several genetic mutations are associated with this condition, including NBAS, RINT1, LARS1 and SCYL1. We have reported liver transplant and mortality rates to help providers make informed management decisions.

Methods: We conducted a systematic review and one-stage individual participant analysis using EMBASE, MEDLINE and Web of Science for English-language studies of RALF occurring in children with NBAS, RINT1, LARS1 or SCYL1 mutations published on or prior to May 14th, 2025.

Results: Our search query identified 62 articles, including 38 (66%) case reports, 13 (22%) case series and 6 (11%) cohort studies. A total of 168 (males, 40%) patients were identified, with first presentation at a median age of 9 months (range 1 week-18 years) and preceded by fever in 110/114 (98%) children. The last episode was documented at a median of 4 years (2 months to 21 years). Patients had a median of 4 (range 2-30) episodes, with only 8 (5%) patients experiencing events after age 10 years. Commonest mutated genes identified were NBAS (66%, n = 111) and LARS1 (18.4%, n = 31). Liver transplant was undertaken in 18 (11%) patients, with no recurrences reported post-transplant. Death was reported in 29 (17.3%) patients.

Conclusions: Most patients with RALF present in the first year of life and have a self-limiting course. Episodes of acute liver failure are often associated with febrile illness. Liver transplantation for RALF remains controversial and may be less appealing in etiologies that tend to resolve with age. We recommend whole-exome sequencing with a targeted search for NBAS, SCYL1, RINT1 and LARS1 for patients presenting with unexplained acute liver failure in the setting of a febrile illness.

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Title: Interpreting liver function markers in children on continuous renal replacement therapy for acute liver failure  

Source: European Journal of Pediatrics 2025, 184 (11): 675

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Date of publication: October 2025  

Publication type: Review article  

Abstract: Children with acute liver failure (ALF) often experience hyperammonaemia, fluid overload, metabolic derangements, and multi-organ failure. Continuous renal replacement therapy (CRRT) is commonly used for renal and non-renal indications, particularly in those with hyperammonaemia and hepatic encephalopathy. However, the non-selective nature of CRRT can result in the clearance of beneficial metabolites and liver-related biomarkers, which are important for monitoring disease progression or improvement. Therefore, understanding the kinetic principles governing molecular clearance during CRRT is crucial for accurate interpretation of liver biochemistry to inform clinical decision-making. By considering the kinetic properties of hepatic markers, including bilirubin, bile acids, liver enzymes, metabolites, waste products, inflammatory markers, albumin, and coagulation proteins, we describe the impact of CRRT on the plasma levels of these markers. In addition, we discuss various CRRT attributes, and the removal of these markers is also discussed. Metabolites and waste products, including ammonia, lactate, and urea, are the most useful markers to inform CRRT responsiveness, owing to their small molecular size, low degree of protein binding, and small volume of distribution; whereas bilirubin, bile acids, coagulation factors, and albumin remain true indicators of hepatic function and clinical condition. It should be noted that the overall plasma levels of any molecules reflect the balance between production and clearance, even for molecules with a high degree of CRRT removal. Awareness of these properties helps clinicians differentiate dialytic response versus genuine hepatic recovery or deterioration, guiding a more rational interpretation of clinical progression in ALF with liver transplant/spontaneous native recovery or mortality as the outcomes.Conclusion: Understanding the kinetic behaviour of liver-related markers during CRRT is essential to distinguish between dialytic clearance and true changes in hepatic function. This knowledge enables more accurate clinical interpretation, guiding decision-making in children with acute liver failure and optimizing management strategies toward recovery or timely transplantation.

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Title: Continuous kidney replacement therapy for management of hyperammonemia and hepatic encephalopathy in pediatric acute liver failure

Source: Journal of Pediatric Gastroenterology and Nutrition 2025, Oct 13. [E–publication]

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Date of publication: October 2025

Publication type: Retrospective analysis 

Abstract: Objectives: This study aimed to evaluate the impact of continuous kidney replacement therapy (CKRT) on the outcomes of pediatric acute liver failure (PALF).

Methods: This was a retrospective analysis of PALF presenting to a tertiary care pediatric hepatology center between January 2012 and August 2024. Cases of PALF where CKRT was initiated within 24 h of admission for nonrenal indications (hyperammonemia, hepatic encephalopathy [HE]) were identified and outcomes compared to a propensity-matched cohort of controls not receiving CKRT. The primary outcome measures were native liver survival (NLS) and overall survival (OS) at Day 28.

Results: A total of 448 patients with PALF were admitted during the study period, of which 94 had received CKRT. Thirty-eight (40.4%) of them who received CKRT for renal indications were excluded. The remaining 56 (59.6%) received CKRT for hyperammonemia and HE. The NLS in the CKRT and no CKRT groups were 46.4%, and 52.1%, respectively, while the OS in the two groups was 53.6%, and 61.3%, respectively. In the propensity-matched cohort (52 in each arm), there was a statistically insignificant trend toward higher NLS (46.2% vs. 36.5%, p = 0.304) and OS (53.8% vs. 44.2%, p = 0.291) in CKRT group compared to controls. Patients receiving CKRT had lower ammonia (p = 0.016) and bilirubin (p = 0.008) levels on Day 4, while international normalized ratio and lactate levels remained comparable.

Conclusion: CKRT led to significant reduction in ammonia on Day 4 in PALF; however, this did not translate into improved NLS and OS.

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Title: Absence of pupillary reflexes in pediatric acute liver failure and neurological outcome after liver transplantation  

Source: Pediatric Transplantation 2025, 29 (3): e70076

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Date of publication: April 2025  

Publication type: Retrospective observational study  

Abstract: Background: Pediatric Acute Liver Failure (PALF) frequently requires liver transplantation (LTx). The neurological condition can deteriorate rapidly, but the difficulty in assessing the (ir)reversibility of neurological symptoms can hamper therapeutic decision-making, including transplantation. We aimed to determine the association between pupillary reflexes (PR), brain stem reflexes (BSR), radiological signs of brain herniation, and subsequent neurological outcome.

Methods: We analyzed a retrospective, observational cohort of PALF patients with severe hepatic encephalopathy (grade III-IV), admitted to our national pediatric liver transplantation center between 1993 and 2023. We subdivided the patients into groups with PR present or PR absent. We compared the two groups for pre-treatment neurological and neuro-radiological parameters and related the findings to neurological outcomes.

Results: Survival rate in patients with PR present was higher compared to patients with PR absent [70% (26/37) and 29% (4/14); resp., p = 0.008]. In the absence of PR, neurological outcome could still be favorable after LTx (n = 3/6). Presence or absence of BSR was not related to the outcome in terms of survival or death. Radiologically proven brain herniation was associated with mortality (6/7) or minimally conscious state (1/7), irrespective of undergoing a LTx or not.

Conclusions: Although absence of PR is associated with a poor prognosis, the neurological outcome can still be favorable after LTx. Radiological signs of brain herniation are strongly associated with mortality or severe neurological outcomes, irrespective of subsequent transplantation. We therefore advocate that absence of PR should be an indication for radiological imaging to assess brain herniation before making major treatment decisions.

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Title: Molecular adsorbent recirculating system (MARS®) and continuous renal replacement therapy for the treatment of paediatric acute liver failure – two-centre retrospective cohort study

Source: European Journal of Pediatrics 2025, 184 (3): 192

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Date of publication: February 2025

Publication type: Retrospective cohort study 

Abstract: To describe outcomes of a cohort of patients with paediatric acute liver failure (PALF) treated with either one of two extracorporeal therapies (ECT) – continuous renal replacement therapy (CRRT) and molecular adsorbent recirculatory system (MARS®). Retrospective, observational, cohort study at two European paediatric intensive care units (PICUs) – UK (2006-2017, CRRT) and the Netherlands (2003-2017, MARS® and CRRT). Patients were children (0-18 years) admitted to the PICU with PALF who required CRRT or MARS®. Between each group, we compared baseline characteristics, biochemical parameters at 0 and 24 h after commencing MARS®/CRRT, and clinical outcomes. In total, 95 patients (23 MARS®, 72 CRRT) were included. The median age at admission for the whole cohort was 4.3 years (interquartile range (IQR) 1.0-12.1), and 47/95 (49.5%) of patients had an indeterminate aetiology. A lower proportion of patients in the MARS® group were on inotropes or were ventilated at admission, and they had a lower Pediatric Index of Mortality 3 risk % than the CRRT group (14.5% (7.5-22) vs 20.4% (16.8-26.4), p = 0.002). After treatment, there were no significant differences detected between groups in survival with native liver, or overall survival (15/23 (65.2%) for MARS® and 49/72 (68.1%) for CRRT, p = 0.998).

Conclusion: We did not detect a significant difference in clinical outcomes between PALF patients treated with CRRT or MARS®, despite a relatively sicker cohort in the CRRT group. Further high-quality evidence is necessary regarding the role of extracorporeal therapies in PALF, with consideration of clinical outcomes, feasibility, and cost.

What is known: Outcomes for children with paediatric acute liver failure (PALF) have improved in recent years secondary to improved supportive care aimed at avoiding liver transplantation. • Extracorporeal therapies, in particular continuous renal replacement therapy (CRRT), are increasingly applied in the management of these children; however few studies have compared outcomes between different extracorporeal therapies.

What is new: In this retrospective study across two centres, outcomes between patients with PALF treated with CRRT were compared to patients treated with MARS®. • There was no significant difference in key clinical outcomes between groups, including survival with native liver and overall survival.

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Title: The management of paediatric acute liver failure: results from an international multi-centre survey across Europe

Source: Intensive Care Medicine – Paediatric and Neonatal 2024, 2 (32)

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Date of publication: November 2024

Publication type: Article

Abstract: Background: Paediatric acute liver failure (PALF) is a rare condition with high morbidity and mortality. The liver transplant era, and improvements in medical management, have transformed outcomes. However, differences in aetiology, management, experience and resources are reported across single-centre case series. This study aimed to survey current practices in the critical care of children with PALF across Europe.

Methods: Cross-sectional survey of PICUs in European countries was created and distributed by the Liver Failure Working Group of the European Society of Paediatric and Neonatal Intensive Care (ESPNIC) and ERN Rare-Liver. Participants were intensivists and hepatologists across PICUs in Europe. The survey was distributed using the EUSurvey platform April-June 2023.

Results: 25 centres from 16 countries participated (response rate 66% of 38 relevant centres). Most centres (56%, n = 14) managed 1–6 cases of PALF per year. Therapeutic strategies varied across the participating centres. Overall, 80% (n = 20) routinely prescribed antibiotics. Invasive intracranial pressure monitoring was practiced by 20% (n = 5) of centres; cerebral perfusion pressure was targeted by 68% of centres (n = 17). All centres used renal replacement therapy (88% for hyperammonaemia, 50% hepatic encephalopathy); 64% (n = 16) made use of plasma exchange. Most centres used the King’s College Hospital Criteria (68%, n = 17) for listing.

Conclusions: This survey across Europe highlighted varied aetiologies in different settings, and variations in key aspects of management, for patients with PALF. International collaboration is needed to standardise guidelines to improve equity of access to treatment, and to foster research collaborations to improve outcomes, for this high-risk patient group.

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Title: Missense variants in the TRPMr7 α-kinase domain are associated with recurrent pediatric acute liver failure

Source: Hepatology Communications 2024, 8 (12): e0598

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Date of publication: November 2024

Publication type: Article

Abstract: Background: Pediatric acute liver failure (PALF) is a rare and life-threatening condition. In up to 50% of PALF cases, the underlying etiology remains unknown during routine clinical testing. This lack of knowledge complicates clinical management and liver transplantation decisions. Recently, whole-exome sequencing has identified genetic disorders in a large number of cases without specific laboratory biomarkers or metabolic fingerprints.

Methods: We describe how further analysis of whole-exome sequencing data combined with proteomic analyses in 5 previously unsolved PALF patients, where no pathogenic variants in genes previously associated with acute liver failure were identified, revealed rare biallelic variants in transient receptor potential cation channel subfamily M member 7 (TRPM7).

Results: We establishe TRPM7 as a novel disease gene for PALF. Yet, the cation channel kinase TRPM7 has not been associated with any Mendelian disorder. No homozygous loss-of-function variants were found in in-house exomes or publicly available databases. Rare biallelic TRPM7-variants were significantly enriched in the PALF cohort compared with a pediatric control cohort. Viral infections preceded the majority of PALF episodes. Recurrent PALF episodes characterized the disease course with rapid progression, leading to early death in 3 cases. Proteomic analyses of patient fibroblasts unveiled significantly reduced TRPM7 protein levels, indicative of functional impairment. Severely reduced Mg2+ levels in one individual with a mutation in the channel domain suggests a potential interaction between disturbed Mg2+ homeostasis and PALF. The consistent presence of mutations in the TRPM7 protein-kinase-domain across all patients suggests its specific relevance in PALF.

Conclusions: Our data extend the genetic spectrum of recurrent PALF and prompt consideration of TRPM7 in children with unexplained liver failure.

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Title: Paediatric acute liver failure: a multidisciplinary perspective on when a critically ill child is unsuitable for liver transplantation

Source: The Lancet. Child & Adolescent Health 2024, 8 (12): 921-932

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Date of publication: December 2024  

Publication type: Review article

Abstract: Paediatric acute liver failure is a devastating condition with high morbidity and mortality, which is challenging to manage for the hepatologist, intensivist, and associated specialists. Emergency liver transplantation is required for 10-20% of patients, but for 10% of critically ill children, liver transplantation is deemed unsuitable; the child might be too unwell, or the underlying cause might carry a poor prognosis. Other social, logistical, or ethical considerations are often relevant. Liver transplantation when a patient is too unwell creates perioperative risk to the child that could lead to morbidity, mortality, and potential graft wastage, which is detrimental for others on the waiting list. Donor liver scarcity should prompt an evaluation of whether a transplant is justified through a holistic multidisciplinary lens that considers medical, social, logistical, and ethical concerns. In this Review, we explore, from a multidisciplinary perspective, why a critically unwell child with paediatric acute liver failure might be unsuitable for liver transplantation.

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Title: Outcomes and management in paediatric autoimmune hepatitis presenting as acute liver failure: individual patient data meta-analysis

Source: Liver International 2024, May 3. [E–publication]

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Date of publication: May 2024

Publication type: Article

Abstract: Background and aims: Autoimmune hepatitis (AIH) in children presenting in acute liver failure (ALF) can be fatal and often requires liver transplantation (LTx). This individual patient data meta-analysis (IPD) aims to examine management and outcomes of this population, given the lack of large cohort studies on paediatric AIH first presenting as ALF (AIH-ALF).

Methods: A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses of IPD statement using PubMed and Excerpta Medica dataBASE, and included English studies published between 2000 and 2020. The study included patients under 21 years of age, diagnosed with type 1 or 2 AIH and presenting with ALF. Data extracted included clinical and biochemical characteristics, interventions, and outcomes.

Results: Three hundred and thirty eligible patients from 61 studies were identified, with an additional five patients from our institution. The majority were female (66.8%), with a median age of 10. Overall, 59.7% achieved native liver survival (NLS), 35% underwent LTx, and 5% died before LTx. The use of corticosteroids with non-steroid immunomodulators increased the likelihood of NLS by 2.5-fold compared to corticosteroids alone. AIH-1 was associated with 3.3-fold odds for NLS, compared to AIH-2. However, on multivariate analysis, only AIH-1 was identified as an independent predictor for NLS (OR 3.8 [95% CI 1.03-14.2], p = .04).

Conclusion: While corticosteroids and non-steroid immunomodulators treatment may offer enhanced probability of achieving NLS, treatment regimens for AIH-ALF may need to consider patient-specific factors, especially AIH type. This highlights the potential for NLS in AIH-ALF and suggest a need to identify biomarkers which predict the need for combination immunosuppression to avoid LTx.

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