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Phenotype and Long-Term Outcome in Recurrent Paediatric Acute Liver Failure: Systematic Review and Individual
Harry Sutton1, Or Steg Saban1, Jessie Cunningham2
1Division of Gastroenterology Hepatology and Nutrition, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
Insights
Recurrent acute liver failure (RALF) in children, often linked to genetic mutations, typically presents in infancy and may resolve spontaneously. Genetic testing for NBAS, SCYL1, RINT1, and LARS1 is recommended for unexplained cases.
Area of Science:
- Pediatric Hepatology
- Clinical Genetics
- Genomic Medicine
Background:
- Recurrent acute liver failure (RALF) in children involves multiple episodes of liver failure with full recovery between events.
- Genetic mutations in NBAS, RINT1, LARS1, and SCYL1 are associated with RALF.
- Understanding transplant and mortality rates is crucial for managing pediatric RALF.
Purpose of the Study:
- To systematically review and analyze individual patient data for RALF in children with specific genetic mutations.
- To determine transplant and mortality rates in this patient population.
- To inform clinical decision-making for managing pediatric RALF.
Main Methods:
- Systematic review and one-stage individual participant analysis.
- Searched EMBASE, MEDLINE, and Web of Science for English-language studies up to May 14th, 2025.
- Included studies on pediatric RALF with NBAS, RINT1, LARS1, or SCYL1 mutations.
Main Results:
- 168 patients with RALF were identified, with a median first presentation at 9 months.
- NBAS (66%) and LARS1 (18.4%) were the most common mutated genes.
- 11% underwent liver transplant, and 17.3% died; no recurrences post-transplant were noted.
Conclusions:
- RALF in children often presents in the first year of life and can have a self-limiting course, frequently triggered by febrile illness.
- Liver transplantation for RALF is controversial and may be less indicated for conditions that resolve with age.
- Whole-exome sequencing targeting NBAS, SCYL1, RINT1, and LARS1 is recommended for unexplained acute liver failure in febrile children.
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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