Liver Transplantation for Urea Cycle Disorder - A Case Study

1. Anesthesiology Conference Liver Transplantation for Urea Cycle Disorder - A Case Study Sep. 26, 2003 Presented and Edited by Ri 吳智君, 楊翔惟Directed by Vs 詹光政 , CR 郭書麟

2. Case Presentation (Liver transplantation) Ri 楊翔惟

3. Brief history • A 2y/o+ boy • Poor activity, poor appetite, short of breath, unconsciousness and one episode of seizure with fever noted in Aug. 2002./08/20. • Initial ammonia=629, (<33 µmol./l) • After enzyme study (discussed later), UCD (urea cycle disorder) was impressed. • Receive liver transplantation on Sep. 8, 2003.

4. Laboratory studies 9/5 9/8 9/14 • Alb. 2.1 4.6 • PT 11.6 18.7 15.7 • PTT 27.3 45.4 30.4 • BUN 2.1 3.7 10.9 • Ammonia 53.8 53.8 30.8 • T-bil. 8.1 1.1 1.1 • ALT 41 405 210

5. Orthotopic Liver Transplantation

6. Preanhepatic phase • Hemodynamic instability • hypovolemia, hemorrhage from venous collaterals, citrate-induced hypocalcemia, hyperkalemia (rapid transfusion), hemolysis, diminished venous return (abd. retraction) • Aminocaproic acid (Amicar) help control hemorrhage secondary to fibrinolysis • Relation to UCD: • May induce CNS infarction, Seizure attack, worse the situation of hepatic encephalopathy.

7. Preanhepatic phase

8. Anhepatic phase • Ischemic injury: • Oliguria: dopamine (2 to 5 mug/kg/min) • Metabolic acidosis: sodium bicarbonate • Hypercoagulation: heparin • Retraction near the right hemidiaphragm: • Respiratory distress: PEEP • Relation to UCD: • Coagulopathy may occur in UCS(J. of Pediatrics No.138 Vol.1) • Hyperammonemia triggers respiration

9. Anhepatic phase

10. Neohepatic phase • Elevate O2 consumption and CO2 elimination: • Oxygen debt from graft tissue and GI systems • Hypotention, Arrhythmia, Thromboembolism • From ischemic metabolites (reperfusion injury), air embolism of reperfusion tissue • Avoid cardiovascular depressant anesthetics

11. Neohepatic phase

12. Discussion Ri 吳智君

13. Urea Cycle Disorder • Enzymes: • (1) carbamylphosphate synthetase (CPS) • (2) ornithine transcarbamylase (OCT) • (3) argininosucccinic acid synthetase • (4) argininosuccinic acid lyase • (5) arginase • (6) ornithine 5-aminotransferase • (7) N-acetylglutamate synthetase

14. Urea Cycle Disorder • Enzyme deficiency→ hyperammonemia • Clinical presentation: (1)Nearly identical clinical presentations: despite the course with the exception of arginase, the last enzyme of the cycle (2)Neonatal period: refusal to eat, vomiting, tachypnea, lethergy, quickly progress to a deep coma (3)Infants and older children: vomiting and nurologic abnormalities: ataxia, mental confusion, agitation, irritability, combativeness

15. Urea Cycle Disorder

16. In Our Patient • Plasma: • High glutamine, mild elevation of alanine(secondary to hyperammonemia) • Borderline low citrulline. • Tendam mass: low arginine level • Urine GC-mass: • No orotic peak • High hippuric acid. hippuric acid Benzoate

17. The Natural History of CPS (Carbamylphosphate synthetase) deficiency • A wide variation in severity of symptoms and the age presentation • Most commonly symptoms occur during the first few days: early-onset lethargy and seizures often are the first sign of abnormality • Coma and death may occur during these hyperammonic episodes

18. Current strategies for the management of neonatal urea cycle disorders • Early supportive treatment • Bulk ammonia removal—dialysis • Pharmacologic management go to --Phenylacetate --Benzoate --Arginine supplement • Long term correction --orthotopic liver transplantation --gene therapy Indications ~The journal of pediatrics vol138,no1,s30~38

20. Indications for Liver Transplantation for urea cycle disorder • Who cannot follow the necessary dietary restrictions • Who has recurrent episodes of hyperammonemia despite optimal medical management • Patients with CPS and OTC deficiency need early transplantation due to more difficult control of the natural history • Rigid dietary and pharmacotherapy regimen vs immunosuppression regimen

21. Contraindications to Liver Transplantation • Positive immunodeficiency virus culture • Severe irreversible neurologic injury

22. Indications for liver transplantation • Urea cycle disorder, r/o CPS deficiency,r/o N-acetylglutamate synthetase deficiencydifficult control of the natural course • Delayed growth of motor function, but no irreversible neurologic injury

23. Donor options • Donor allograft size reduction • Living-donor liver transplantation • Split-liver transplantation • The mortality of potential recipients<20kg await for OLT have reduced from 25%~50% to 2~5%

24. Outcome of Liver Transplantation • The overall patient survival rate • The goal of liver transplantation: (1) Preservation of neurologic function, (2) Rehabilitation, (3) A relatively normal quality of life

25. Outcome of Liver Transplantation • resulted in correction of hyperammonaemia in all patients. • The neurological outcome after transplantation correlated closely with the condition prior to transplantation. • relatively few problems in the long term related to the liver transplant itself. • The quality of life seems to be much improved ~Journal of Inherited Metabolic Disease. 21 Suppl 1:112-8, 1998. ,Acta Gastroenterologica Belgica. 62(3):300-5, 1999 Jul-Sep.,

26. Comparison of outcome after pediatric liver transplantation for metabolic diseases and biliary atresia. • Pediatric OLT: cholestatic liver disorders ranking first, followed by hepatic based metabolic disorders • The mean infection, complication, intervention, and retransplantation rate was equal in both groups. • Mortality and morbidity are not different despite the better starting point for children with MD.~European Journal of Pediatric Surgery. 11(1):28-35, 2001 Feb.

27. Donation from a donor with ornithine transcarbamylase deficiency. • The donor's OTC deficiency was diagnosed retrospectively since the liver graft recipient developed cerebral edema postoperatively due to extremely hyperammonemia(3793 micromol/l), but was not accompanied by general liver dysfunction • In contrast to the fatal course of the liver graft recipient, the kidney, lung, and heart transplantations were successful. ~. Transplant International. 14(3):196-201, 2001 Jun.

28. Thank you~