Paracetamol toxicity in classic homocystinuria: Effect of N‐acetylcysteine on total homocysteine

• Published in: JIMD reports Vol. 64; no. 3; pp. 238 - 245
• Main Authors: Elkhateeb, Nour, Hyde, Sarah, Hogg, Sarah L., Allsop, Daniel, Shankar, Arun, Deegan, Patrick, Tan, Chong Y.
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01-05-2023; Wiley
• Subjects: acute liver failure; Analgesics; Asymptomatic; Biopsy; Blood tests; Case Report; Case Reports; classical homocystinuria; Diet; Edema; Gallbladder diseases; glutathione depletion; Homocysteine; Liver; Medical imaging; Medical screening; N‐acetylcysteine; paracetamol toxicity; Patients; Phosphatase; Plasma; plasma total homocysteine; Toxicity; Visual impairment; paracetamol toxicity; classical homocystinuria; acute liver failure; plasma total homocysteine; N‐acetylcysteine; glutathione depletion
• ISSN: 2192-8312; 2192-8304; 2192-8312
• DOI: 10.1002/jmd2.12363

Classical homocystinuria (HCU) is caused by cystathionine β‐synthase deficiency leading to impaired homocysteine transsulfuration and accumulation of homocysteine and methionine. Patients present with a wide spectrum of manifestations including ocular, skeletal, neuropsychiatric, and vascular manifestations. We report a 48‐year‐old female with pyridoxine‐unresponsive HCU treated with betaine, cyanocobalamin, and folate. Her diet was non‐restricted due to intolerance of low‐methionine diet. She was admitted to hospital following a fall, with multiple fractures and subsequently developed acute liver failure with encephalopathy. Shock, sepsis, and liver ischaemia/thrombosis were excluded. In the context of glutathione depletion expected in HCU, hepatic dysfunction was presumed to be due to iatrogenic paracetamol toxicity, despite paracetamol intake at conventional therapeutic dose, with role of hypermethioninemia as a contributing factor being uncertain. Betaine was discontinued on hospital admission. N‐Acetylcysteine (NAC) infusion was initiated. Plasma total homocysteine (tHcy) was 3.4 μmol/L 9 days following initiation of NAC treatment with a markedly elevated plasma methionine of 1278 μmol/L. tHcy concentration returned to pre‐admission baseline after NAC was discontinued. Recovery following this episode was slow with a prolonged cholestatic phase and gradual improvement in jaundice and coagulopathy. We recommend that paracetamol should be administered cautiously in HCU patients due to underlying glutathione depletion and risk of toxicity even at therapeutic doses. NAC is clearly effective in lowering tHcy in classical HCU in the short‐term however further research is required to assess clinical efficacy and use as a potential therapy in classical HCU.