Acute Liver Failure in Children

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Acute Liver Failure in Children

  1. 1. Giorgina Mieli-Vergani Paediatric Liver, GI & Nutrition Centre King’s College London School of Medicine King’s College Hospital London, UK Acute Liver Failure in Children
  2. 2.  < 1960s ? liver disease in children  1970s liver disease in children  1980s tertiary centres  1990s liver transplant Paediatric Hepatology: a young subspecialty
  3. 3. Acute liver failure in childhood  rare  … but pathology different from adults … a paediatric hepatologist’s headache  definition  management borrowed from adult experience
  4. 4. Acute liver failure Fulminant liver failure versus
  5. 5. Definition? Acute/Fulminant liver failure in childhood  important for treatment decision  important for result comparison
  6. 6. massive liver necrosis with encephalopathy developing within 8 weeks from the first signs of illness in a patient without underlying chronic liver disease Fulminant hepatic failure in adults
  7. 7. massive liver necrosis with encephalopathy developing more than 8 weeks from the first signs of illness in a patient without underlying chronic liver disease Late onset (subacute) hepatic failure in adults
  8. 8. Encephalopathy  often late, terminal event Acute liver failure in childhood  difficult to diagnose, particularly in infants
  9. 9. the most common presentation is subacute Acute liver failure in childhood if encephalopathy is a major criterium for definition…
  10. 10. King’s prognostic indicators (non paracetamol patients) Fulminant hepatic failure  prothrombin time > 100 sec (irrespective of grade of encephalopathy) or  any 3 of the following variables (irrespective of grade of encephalopathy): age <10 or >40 years nonA-nonB, halothane, idiosyncratic drug reactions jaundice to encephalopathy > 7 days prothrombin time > 50 sec bilirubin >300 mmol/l O’Grady et al, Gastroenterology 1989;97:439-45
  11. 11. Underlying liver disease Acute liver failure in childhood  frequent in paediatrics tyrosinaemia neonatal haemochromatosis Wilson autoimmune mitochondrial disorders etc
  12. 12. King’s Definition - 1996 Multisystem disorder in which severe acute impairment of liver function, with or without encephalopathy, occurs in association with hepatocellular necrosis in patients with no recognised underlying chronic liver disease Acute liver failure in childhood Bhaduri & Mieli-Vergani, Sem Liver Dis 1996;16:349-355
  13. 13.  no known evidence of chronic liver disease  biochemical evidence of acute liver injury  hepatic-based coagulopathy (not corrected by vitamin K): PT > 15s or INR > 1.5 with encephalopathy or PT >20s or INR >2.0 with or without encephalopathy Acute liver failure in childhood Acute Liver Failure Study Group, USA -1996
  14. 14. ALF Symposium, London 2005 Acute hepatocellular injury with severe impairment of liver function (INR >2, not responsive to vitamin K), with or without encephalopathy in patients without known underlying liver disease Acute liver failure in childhood
  15. 15. Acute liver failure in childhood  without underlying liver disease  with underlying liver disease different prognosis and management
  16. 16. Acute liver failure in childhood Liver transplant  what criteria should be used?
  17. 17. Acute liver failure in childhood  adult criteria?  aetiology based criteria Criteria for liver transplant
  18. 18. Transplant  if cause of ALF treatable by LT  if predicted outcome of LT better than that of underlying disease  if no severe brain damage Acute liver failure in childhood
  19. 19. Acute liver failure in childhood  encephalopathy → poor prognosis  young children may die with no obvious encephalopathy without underlying liver disease
  20. 20. with underlying liver disease Acute liver failure  response to medical treatment possible even in the presence of encephalopathy (e.g. mitochondrial disorders)  prognosis and management depend on the cause of underlying liver disease
  21. 21. Acute liver failure in childhood prognostic criteria other than encephalopathy are needed
  22. 22. When to list for transplant?  15 survived  29 died Acute liver failure in childhood King’s: 44 children with ALF not transplanted …prognostic indicators? Bhaduri & Mieli-Vergani, Sem Liver Dis 1996;16:349-355
  23. 23. Indicators of poor prognosis Acute liver failure in childhood  age < 2 years  max INR ≥4  max bilirubin ≥ 235 mmol/l  WBC ≥ 9x109/l
  24. 24. Prognostic indicators Acute liver failure in childhood age, max INR, max bilirubin, WBC % mortality any 1 indicator 76 any 2 indicators 93 any 3 indicators 96 all 4 indicators 100
  25. 25. Prognostic indicators King’s: 44 children with ALF not transplanted  aetiology  presence of encephalopathy Acute liver failure in childhood no correlation with: correlation with:  max degree of encephalopathy grade I-II = 44% mortality grade III-IV = 78% mortality P<0.02
  26. 26. Acute liver failure in childhood Prognostic indicators - INR  dead  alive P<0.001 0 5 10 15 20 25 INR < 4 INR ≥ 4
  27. 27.  still valid with improved paediatric intensive care?  impossible to determine in the era of transplantation Acute liver failure in childhood King’s prognostic indicators
  28. 28.  potential for the liver to regenerate  lifelong immunosuppression if LT Acute liver failure in childhood Ethical dilemma if no underlying liver disease
  29. 29.  extra-corporeal assist devices  hepatocyte transplantation Acute liver failure in childhood New approaches  auxiliary liver transplantation
  30. 30. Auxiliary liver transplant
  31. 31. Acute liver failure – Auxiliary transplant
  32. 32. Acute liver failure – Auxiliary transplant time 0 6 months 18 months
  33. 33. Acute liver failure – Auxiliary transplant 1 month 6 months 18 months 24 months
  34. 34.  survival 85%  off drugs 29%  weaning 53% Acute liver failure – Auxiliary transplant
  35. 35. Hepatocyte transplant for acute liver failure  transient synthetic and detoxifying function  site accessible in coagulopathic patients  no immunosuppression
  36. 36. 2.5 x 106 cells/ml Alginate beads
  37. 37. ~400-450µm  Encapsulated hepatocytes
  38. 38.  liver Site of injection Hepatocyte transplant for acute liver failure  peritoneum  spleen
  39. 39. before Tx retrieved microbeads
  40. 40. Hepatocyte in alginate beads for acute liver failure First human application – King’s  Herpes simplex FHF  hepatocyte transplant aged 2 weeks – March 2011 “Liver implant gives boy another chance of life”NEWS 8 months
  41. 41.  5 patients Herpes simplex 1 neonatal haemochromatosis 2 indeterminate 2 Hepatocyte in alginate beads for acute liver failure King’s, 2011-13  outcome 2 alive without liver transplant 2 bridge to liver transplant 1 care withdrawn (Down syndrome with cardiac failure, stable INR) clinical condition improved in all
  42. 42.  early referral to specialised centres  transplant when necessary Acute liver failure in childhood The message – The future  Rx related to aetiology  development of effective bridges to recovery

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