High Prevalence of Hemophagocytic Lymphohistiocytosis in Acute Liver Failure of Infancy

J Pediatr. 2022 Nov:250:67-74.e1. doi: 10.1016/j.jpeds.2022.07.006. Epub 2022 Jul 11.


Objectives: To investigate the prevalence of hemophagocytic lymphohistiocytosis (HLH) syndrome in pediatric acute liver failure (PALF) of infancy and assess the diagnostic role of rapid immunologic tests, genotype/phenotype correlations, and clinical outcomes.

Study design: We retrospectively analyzed 78 children with PALF aged <24 months referred over almost 2 decades. The studied patients with a phenotype of HLH syndrome had a comprehensive immunologic workup, including additional genetic analysis for primary immunologic causes.

Results: Thirty of the 78 children had the HLH phenotype and underwent genetic assessment, which demonstrated positive findings in 19 (63.3%), including 9 (30%) with biallelic primary HLH mutations and 10 (33.3%) with heterozygous mutations and/or polymorphisms. The most common form of primary HLH was familial hemophagocytic lymphohistiocytosis (FHL)-2, diagnosed in 6 children, 4 of whom had a c.50delT (p.Leu17ArgfsTer34) mutation in the PRF1 gene. Three patients with primary HLH received genetic diagnoses of FHL-3, Griscelli syndrome, and LRBA (lipopolysaccharide-responsive vesicle trafficking, beach- and anchor-containing) protein deficiency. Overall mortality in the series was 52.6% (10 of 19), and mortality in children with a documented biallelic pathogenic HLH mutation (ie, primary HLH) was 66.6% (6 of 9). Two children underwent liver transplantation, and 4 children underwent emergency hematopoietic stem cell transplantation; all but 1 child survived medium term.

Conclusions: Primary HLH can be diagnosed retrospectively in approximately one-third of infants with indeterminate PALF (iPALF) who meet the clinical criteria for HLH, often leading to their death. The most common HLH type in iPALF is FHL-2, caused by biallelic mutations in PRF-1. The clinical relevance of observed heterozygous mutations and variants of uncertain significance requires further investigation. Prompt hematopoietic stem cell transplantation could be life-saving in infants who survive the liver injury.

Keywords: hemophagocytic lymphohistiocytosis; liver transplantation; pediatric acute liver failure; perforin deficiency; primary immune deficiency.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Humans
  • Liver Failure, Acute* / diagnosis
  • Liver Failure, Acute* / epidemiology
  • Liver Failure, Acute* / etiology
  • Lymphohistiocytosis, Hemophagocytic* / complications
  • Lymphohistiocytosis, Hemophagocytic* / diagnosis
  • Lymphohistiocytosis, Hemophagocytic* / epidemiology
  • Mutation
  • Perforin / genetics
  • Prevalence
  • Retrospective Studies


  • Perforin
  • LRBA protein, human
  • Adaptor Proteins, Signal Transducing