Biochemical testing and pathology reveal rare cause of pediatric acute liver failure: Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome.

Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare metabolic condition that can cause lethargy, ataxia, tachypnea, nausea, vomiting, seizures, coma, and acute liver failure. We present a 26-month-old female with acute liver failure who was diagnosed with HHH 1 week after admission. Histology revealed an acute hepatitic pattern of liver injury with numerous acidophils and glycogenated nuclei without zonal distribution, the former a rarely discussed feature. Acute management included intravenous dextrose and intralipids, with chronic management requiring a protein-restricted diet, glycerol phenylbutyrate for nitrogen scavenging, and citrulline supplementation to support the urea cycle. This case contributes to our growing understanding of the phenotypic presentation of HHH, a rare genetic cause of liver failure not included on newborn screening but with specific treatment implications. We also highlight the importance of collecting biochemical genetics labs and liver biopsy early in the disease course and discuss how a patient's voluntary self-restriction of protein can offer helpful clues in the diagnostic evaluation.