Secondary Ammonia Scavenge With Glycerol Phenylbutyrate Improves Hyperammonemia Following Portosystemic Shunting

**Background:** Portosystemic shunts (PSS) allow intestinal blood to bypass the liver, predisposing children to minimal hepatic encephalopathy (MHE) and altered neurodevelopmental outcomes. Treatment options for MHE are limited and typically extrapolated from cirrhosis management. Glycerol phenylbutyrate, an oral medication used in urea cycle disorders, provides a secondary pathway for ammonia elimination via renal excretion of phenacetylglutamine. This case describes its use in a noncirrhotic patient with PSS and MHE refractory to conventional therapies.

**Methods:** A 3-year-old boy with a history of preterm delivery at 33 weeks gestational age and umbilical catheterization developed extrahepatic portal vein obstruction with cavernous transformation. He underwent distal splenorenal shunt for refractory variceal bleeding. One month postoperatively, he developed suspected MHE (ammonia 54 µmol/L) and was treated with lactulose. His condition worsened with behavioral changes, sleep disturbance, and ammonia levels of 80–100 µmol/L. He presented to the emergency department with acute neurologic decompensation (ammonia 148 µmol/L). Lactulose was increased and rifaximin 200 mg PO BID was added. Over 12 months, additional measures included cycling rifaximin with lactulose, a vegan diet, dietetic review to prevent catabolism, and a seven-strain probiotic. Serum amino acid profile was normal except for low branched-chain amino acids. Urea cycle disorder was ruled out via plasma amino acids, urine amino acids, urine orotic acid, ornithine transcarbamylase gene sequencing, and MLPA. Hyperammonemia remained refractory with three episodes of ammonia exceeding 100 µmol/L. Glycerol phenylbutyrate was initiated at 2.5 mL TID (11 mL/m² and 12.1 g/m²), then reduced to maintenance of 1.8 mL TID (8 mL/m² and 8.8 g/m²).

**Key Results:** Following glycerol phenylbutyrate initiation, median serum ammonia decreased from 64.0 µmol/L (IQR 49.0–81.0) pretreatment to 55.0 µmol/L (IQR 45.0–68.5) post-treatment (P = 0.0268). Three post-treatment ammonia values exceeded 100 µmol/L but were deemed spurious as they were asymptomatic and normalized within 24 hours without intervention. Clinically, the patient showed marked and sustained improvement in behavior, concentration, school performance, and fine motor skills. No hepatic encephalopathy events occurred in the 24 months following treatment initiation. Amino acid profile remained unchanged.

**Clinical Implications:** This case demonstrates that glycerol phenylbutyrate can effectively reduce ammonia levels and improve clinical outcomes in noncirrhotic patients with PSS and MHE refractory to standard therapies including lactulose, rifaximin, dietary modifications, and probiotics. The mechanism leverages a non-urea cycle pathway for renal nitrogen excretion, which is particularly advantageous when portal blood bypasses the liver. Given the risk of long-term cognitive impairment from uncontrolled hyperammonemia in children with PSS, glycerol phenylbutyrate represents a promising therapeutic option for this population. Further studies are needed to confirm these findings in larger cohorts.