1. Acute Liver Failure (ALF) in Children Dan W
Acute Liver Failure (ALF) in Children Dan W. Thomas, MD Medical Director Hepatology & Liver Transplantation Children’s Hospital Los Angeles Professor of Clinical Pediatrics Keck/USC School of Medicine

2. Acute Liver Failure (ALF) in Children Dan W. Thomas, M.D.
I have no relevant financial relationships with the manufactured (s) or any commercial product (s) and/or provider of commercial products or services discussed in this CME activity. I do not intend to discuss unapproved/investigative use of commercial product (s) / device (s) in my presentation.

3. AASLD Practice Guidelines: The Management of Acute Liver Failure- Update Lee WL, Larson AM, Stravitz RT @

4. Objectives Definition Causes Prognostic factors Management
Encephalopathy (HE)
Outcome

5. Definition No evidence of pre-existing liver disease
Biochemical evidence of acute hepatic injury
Elevated bilirubin, abnormal LFT’s
Coagulopathy
INR > 2.0 not correctable by vitamin K +/-HE
INR > 1.5 in the presence of encephalopathy
Encephalopathy
May occur up to 2 months after onset of jaundice
< 4 year old: coma grade scale (GCS)
> 4 year old: stages 1-4

6. Objectives Definition Causes Prognostic factors Management
Encephalopathy
Outcome

7. Causes of Acute Liver Failure in Children
Developed countries
Indeterminate 49%
Acetaminophen 14%
Non-APAP drug %
Metabolic %
Autoimmune %
Infectious %
Circulatory 5%
Other %
J. Pediatr 2006; 148:652-8
JPGN 2005;40:
J Hepatol 2006; 44:
Undeveloped
Countries
Infection (viral) 90%
Other 10%
DDS 1998; 43:

8. Non-typable viral hepatitis
Aplastic Anemia - 30%
NK cell dysfunction

9. Acetaminophen toxicity (APAP)

10. Wilson’s Disease Excessive copper accumulation, low ceruloplasmin
Characteristic low alkaline phosphatase level
Kayser- Fleischer rings may NOT be present
Associated with hemolytic anemia & elevated unconjugated bilirubin level

11. Wilson’s – Clinical Diagnosis
KF rings
Low ceruloplasmin
Ur Cu ≥ 250 ug/24 hr
All 3 must be +
Q Cu with liver biopsy or genetic test if not
(AASLD recommendations)

12. Autoimmune hepatitis Elevated total serum protein
Usually have abn AIH antibody tests (ANA, smooth muscle, anti LKM, liver soluble antigen)
Response to medical therapy is variable

13. Objectives Definition Causes Prognostic factors Management
Encephalopathy
Outcome

14. Outcome - Children Overall transplant-free survival ≤ 40%
Etiology specific transplant-free survival
Acetaminophen 100%
Sepsis %
Autoimmune 50%
Viral %
Hematological 40%
Unknown %
Metabolic %
J Hepatol 2006;44:

15. Outcome - Adults Overall transplant-free survival ≥ 75%
20% increased use of I.V.
N-acetylcysteine regardless of etiology
Reuben A. et al, Ann Int Med; :

16. Use of N-acetylcysteine in Children with Non-APAP ALF
No benefit/worse TSF
Currently not recommended
Squires R et al, Hepatology 2013:57:

17. Prognosis Coagulation Factors Factor V < 20% Factor VII < 5%
% necrosis on liver biopsy
Liver biopsy is
controversial
> 70% necrosis =
non recovery

18. King’s College Criteria
Prognostic Factors
King’s College Criteria
K King’s College Criteria
(listed in 2011 AASLD update on ALF)

19. Objectives Definition Causes Prognostic factors Management
Encephalopathy
Outcome

20. Management of Acute Liver Failure
EARLY Transfer to Transplant Center
Coagulopathy
No correction unless active bleeding
Risk of bleeding increases if INR >4 or with interventional procedure
Encephalopathy
Risk of cerebral edema
Avoid benzodiazepines/opiates
Avoid electrolyte fluxes
?ICP monitoring
Normalize blood sugar
Broad spectrum antibiotics
High risk of serious infection
If child becomes unstable, has high WBC, or fever

21. Coagulopathy
Anticoagulant
Procoagulant

22. Objectives Definition Causes Prognostic factors Management
Encephalopathy of ALF
Outcome
hepatic encephalopathy

23. General Classification of Hepatic Encephalopathy
Class A
Associated with acute liver failure
Risk of cerebral edema
Class B
Associated with porto-systemic bypass
Class C
Associated with cirrhosis

24. Hepatic Encephalopathy
Stage II
Drowsiness/confusion
Inappropriate behavior
*asterixis (older children)
EEG: generalized slowing
Stage I
Slowness of mentation
Sleep-wake cycle disturbance
No EEG changes

25. Hepatic encephalopathy
Stage III
Sleepy but arousable
Delerious
Hyperreflexia/+ Babinsky
EEG: grossly abnormal
Stage IV
Unconscious
Decerebrate or decorticate posture
EEG: Delta wave

26. Pediatric GCS

28. Hepatic Encephalopathy of ALF
Vaquero J et al, Sem Liver Dis 2003 (23): 259Vaquero

29. Brain Edema is a preterminal event in Acute Liver Failure
Vaquero J et al, Sem Liver Dis 2003 (23): 259Vaquero

30. Stages of ALF Hepatic Encephalopathy in Children

31. Hepatic Encephalopathy
Frequent clinical assessment
NO definite correlation between NH3 levels with
Clinical assessment
Electrophysiological measurements
Hypoglycemia
Electrolyte abnormalities
Uremia
Infection
Administered sedatives/opiates
Underperfusion of the brain

32. Hepatic Encephalopathy- Pathogenesis
Normal hepatic metabolic & detoxification functions fail.
Mileau of neurotransmitters (e.g. GABA, serotonin, dopamine, glutamate, glutamine) becomes perturbed.
Benzodiazepine receptors are upregulated.
Disruption of the blood-brain barrier(BBB).
Desjardins P et al, J Clin Exp. Hepatol, 2012 (60): 690.

33. Broken Dam Theory Cirrhotic liver leak of molecules
and toxins into the systemic circulation
ALF/Necrotic liver flood of AA’s
(tyrosine, phenylalanine, tryptophan), SCFA, phenols, thiols, mercaptans, NH3 into the systemic circulation

34. Benzodiazepine-receptors
Synergestic effects of neurotransmitters Neurotransmitters Glutamine + Glutamate
GABA
increased GABA-Cl current/ brain water porosity
Benzodiazepine-receptors
Increased receptor number
Increased affinity
Serotonin & Dopamine
Increased glutamine results in increased tryptophan and tyrosine cross the BBB and are precursor neurotransmitters

35. Ammonia
(NH3 crosses BBB)

36. Effect of NH3 in Hepatic Encephalopathy
NH3 on PET scan
Increased cerebral extraction
Increased brain permeability
Increased metabolic rate
Increased glutamine
NH3 metabolism is astrocyte-dependent (Urea cycle is only in the liver)
NO LINEAR CORRELATION TO BLOOD AMMONIA

37. Pivotol role of astrocytes in NH3 metabolism and glutamine in HE

38. Altered Glial-Neuronal Crosstalk in HE Crosstalk in HE
astrocyte
neuron
Scott TR et al, World J Gastroenterol 2013 (19):9240

39. Why does cerebral edema occur in ALF ?
Butterworth RF, J Clin Exp Hepatol 2015 (5): S96

40. “Trojan Horse Effect”
Scott TR et al, World J Gastroenterol 2013 (19): 9240

41. Added negative effects in ALF HE: Increased water channel uptake - Astrocytes

42. Aquaporin 4 in Astrocytes in HE
Rao KVR et al, J Neuropath Exp Neurol 2010 (69): 869

43. ALF Other pathophysiologic considerations… Other factors contributing to brain damage and multi-organ failure

44. Role of SIRS – Activated by Liver Necrosis

45. Treatment of Hepatic Encephalopathy
Supportive
- Treat infection, electrolyte abnormalities, correct
blood glucose, avoid sedatives/opiates, normalize circulation
? Neomycin, ? Rifaximin, ? Lactulose
Future???

46. CVVH in ALF Hepatic encephalopathy Multi organ failure
- Hepatorenal syndrome
Excessive fluid accumulation
e.g. administration of blood products, clotting factors, FFP IV drip
Bridge to LVT
MARS

47. Hemofiltration

48. Objectives Definition Causes Prognostic factors Management
Encephalopathy
Outcome
Critical role of early referral to Pediatric Liver Transplant Center

49. Post transplant Outcome - ALF
Accounts for only 12% of all transplants
High mortality on waiting list (? LRD)
Six months survival: 74.5%
Compared to 89%
High risk patients
Grade 4 encephalopathy
Age less than 1
Renal failure
Liver transplantation 2004; 10:

50. Summary- ALF
All patients with acute liver failure require urgent referral to a pediatric liver transplant center
Hemofiltration plays a potential role in treatment and prevention of neurological complications
Sudden clinical decompensation due to acute hepatic encephalopathy (brain swelling), bleeding, and/or infection are common and lethal.
LVT is presently the only curative treatment for irreversible ALF.
N – acetylcysteine RX for non-APAP ALF in children currently is not recommended.

51. THANK YOU!