seminar on acute liver failure/ fulminant hepatic failure in children

3. Functions of liver

4. Acute liver failure: Definition
Acute liver failure in children includes
(1)Biochemical evidence of acute liver (usually <8 wks
duration)
(2) no evidence of a known chronic liver disease;
(3)hepatic-based coagulopathy that is not corrected by
parenteral administration of vitamin K;
(4) hepatic encephalopathy must be present if the
uncorrected prothrombin time (PT) is ≥ 15 seconds or
international normalized ratio (INR) is1.5 to 1.9,
respectively; and
(5) hepatic encephalopathy is not required if the PT
is ≥ 20 seconds or INR ≥2.0, respectively.
Squires et al.J Pediatr 2006;148:652–658

5. Acute Hepatic Failure: Background
Acute hepatic failure in children is a relatively rare
clinical syndrome
Mortality rate is high – 60 to 80%.
Among the different causes,
In western countries:
Viral cause – 12%
Drugs & Chemicals – 52%
Miscellaneous – 18%
Mixed: 10-22%
But in south-east Asia hepatitis is the most
predominant cause of ALF (50-70%)

6. Epidemiology
The incidence of fulminant hepatic failure appears to
be low in the United States, with approximately 2000
cases annually. Drug-related hepatotoxicity accounts
for more than 50% of acute liver failure cases,
including acetaminophen toxicity (42%) and
idiosyncratic drug reactions (12%). Nearly 15% of
cases remain of indeterminate etiology.

8. Etiology of ALF In different age group
Neonates Infants
Infection
Inborn errors of
metabolism
Immune mediated
Ischemia
& abnormal
Perfusion
Drugs & toxins
other
HSV, Adeno virus
HBV
Galatosemia, tyrosinaemia,
Hereditary fructose
Intolerance.
Neonatal
Hemochromatosis
Congestive heart failure,
severe aspyxia
Hemophagocytic syndrome
HAV, HBV, HSV
hereditary fructose
Intolerance, others.
Auloimmune hepatitis
Congestive heart
Failure,
Acetaminophen,INH,
valproate malignancy

9. Etiology Cont….
2-10 year old 10-18 yrs old
Infection
Drugs & toxins
Immune mediated
Ischemia
& abnormal
Perfusion
Metabolic
other
HAV, HBV, HSV
Acetaminophen,INH,
valproate
Autoimmune hepatitis,
hemophagocytic
syndrome
Budd-Chiari syndrome,
Heart failure, cardiac
Surgery, myocarditis
Wilson’s disease, Reye’s
syndrome, Hemophagocytic
syndrome, septicemia, heat
stroke
HAV, HBV, HSV, HCV
Acetaminophen,INH,
valproate
Autoimmune hepatitis,
hemophagocytic
syndrome
Budd-Chiari syndrome,
Heart failure, cardiac
Surgery, myocarditis
Wilson’s disease, Reye’s
syndrome, Hemophagocytic
syndrome, septicemia, heat
stroke

11. MMeecchhaanniissmmss ooff hheeppaattiicc iinnjjuurryy

12.  Immune mediated hepatocellular injury
- Viral infections
- Drug hepatotoxicity (dihydralazine,
halothane)
 Direct hepatocellular injury
- Hepatotrophic virus family-HAV, HBV, HCV
- Toxic or reactive metabolites- acetaminophen
- Toxic metabolites of compounds-metabolic
diseases
 Ischemic hepatocellular Injury
- Shock states, SIRS

13. Effects are:
• Impaired hepatocyte regeneration
• Altered parenchymal perfusion
• Endotoxemia
• Decreased hepatic reticulo-endothelial function
Hepatic failure

14. Acute liver Failure in neonate
The highest incidence of acute liver failure is
seen in newborns.
Dhawan et al, Clinics and Research in Hepatology and Gastroenterology
(2012) 36, 278—283.
Viral infections
 HSV infection most common.
 Infection acquired usually during perinatal
period.
 HSV induced ALF carries high mortality & is
rarely accompanied by skin lesions.

15.  It should be considered in all sick babies with
coagulopathy and raised transaminases.
Usually presented with poor feeding, lethargy,
coagulopathy within 2wks after birth.
Acyclovir should be started in all neonates with liver
failure, as herpes virus infection is the predominant
viral cause.
Dhawan et al, Clinics and Research in Hepatology and Gastroenterology
(2012) 36, 278—283.

16. Cont….
Metabolic disease:
Most common metabolic diseases that may
presented as neonatal ALF are:
Galactosemia, hereditary fructose intolerance,
Tyrosinaemia, neonatal iron storage disease.
Ischemic injury:
Due to hypovolaemia/hypotension, congestive
cardiac failure.

17. Viral causes are:
 Hepatitis A,B,C,D,E: also may present as ALF
 Hepatitis C: rare in children.
 Dengue causes ALF in children in thailand.(40
cases with 66% mortality)
Poovorawan Y et al. Dengue virus infection: a major cause
of AHF in Thai children. Ann Trop Paediatr 2006, 26:17-23.
 Other virus-CMV,HSV, EBV, Influenzae type A.

18. Non viral cause-rare
 Severe sepsis
Bacterial infections- Salmonella,
Shigella, E.coli etc
Miliary TB
Leptospirosis
Plasmodium falciparum infection

19. Hepatitis
Direct cytopathic immune-mediated injury
 necrosis in the centri-lobular areas


 diffuse kupffer cell hyperplasia and
parenchymal collapse fulminant hepatic
 failure

20. Important drugs responsible for ALF
•Dose dependant:
Acetamenophen
CCI
Mushroom
•Idiosyncratic:
INH
Valproic acid
Phenytoin
Carbamazepine
Propylthiouracil
Halothane
Nitrofurantoin

21. AAcceettaammeennoopphheenn ttooxxiicciittyy

22. Most imp. drug of dose dependant toxicity.
Acute toxic Dose:
> 200 mg/kg within a 24 hour period in <12
yrs of age.
Patient with acetamenophen induced ALF
have a higher rate of spontaneous recovery
than do pt. with viral hepatitis.

24. Clinical evidence of toxicity
Phase 1: 0.5-24 hours
- Nausea, vomiting
Phase 2: 24 – 48 hours
-RUQ pain &tenderness,oliguria.
Phase-3:72-96 hours
-Hepatic necrosis, encephalopathy,
coagulopathy,ATN .
Phase 4 : 4 days – 2 weeks
-Resolution of hepatic dysfunction or complete
liver failure.

25. Wilson disease
It is an autosomal recessive disorder.
The condition is due to mutations in the Wilson
disease protein (ATP7B) gene
May present as ALF in older child.
ALF due to wilson disease should be suspected in any
pt with.
-ALF + Coomb’s negative hemolytic anemia.

28. History
Duration of illness.Onset of jaundice and
encephalopathy.
Risk factors for hepatitis: eg- street food,
sanitation, BT, surgery.
Drug & immunization history
Family history and consanguinity
H/O any bleeding episode.
Systemic enquiry
Features of hepatic encephalopathy

29. Stages of encephalopathy
Encephalopathy Symptoms Signs
Stage I (mild)
Stage II
Stage III
Stage IV
Alert, euphoric, occasionally depression.
Poor concentration,
slow mentation and affect,reversed
sleep rhythm.
Drowsiness, lethargic, inappropriate
behavior, disorientation
Stuporous but easily arousable, marked
confusion, incoherent speech
Coma, unresponsive but may respond to
painful stimulus.
Trouble drawing figures,
performing mental task,
EEG-normal
Asterexis,fetor
hepaticus,EEG slowing of
wave.
Asterexis, hyperreflexia,
rigidity, EEG-Triphasic
wave
Planter extensor,
Rigidity ,Areflexia,
Flacidity.EEG-delta wave.

30. Aggravating factors of HE
GI bleeding
Hypovolemia
Hypokalemia
Hypoglycemia
Sedatives
Uremia
Sepsis
High protein diet
Constipation
Paracentesis

31. Physical examination
Jaundice
Anaemia
Vital signs: Hypotension, tachycardia, tachypnoea.
Mental status.
Hepatomegaly
Spleenomegaly
Stigmata of chronic liver disease.
Ascities
Features of raised ICP
Nervous system examination.

33. Investigation
a. Complete blood count: Leucocytosis ,
thrombocytopenia
b. LFT: S. bilirubin ­
ALT: raised
AST :raised
Alkaline phospatase: may be normal or ­
PT and INR: to see the severiry of coagulopathy
and to asses prognosis.
c. Blood grouping and cross matching
d. C/S blood, urine etc.

34. Inv.continued
E . Biochemical test:
 S. Electrolytes- Hypokalaemia and others.
 S. Glucose- Hypoglycaemia.
 S. Creatinine
 S. Ammonia- ­
 S. Calcium , Phosphate, Magnesium
 S. lactate: At 4 hours(>3.5) or at 12 hours(>3)
are early predictors of outcome in
acetamenophan induced ALF.
F . Blood gas analysis.

35. To detect cause
G . Serological marker
Anti HAV IgM
HBsAg, AntiHBcIgM
Anti HEV IgM
Screening for other viruses- HSV, CMV etc.

36. Immunological test
S. immunoglobulin, ANA, anti SMA,
antiLKM1
J . S acetamenophen level
K . USG of HBS
L . Screening for metabolic disease.
M . EEG
N . Liver biopsy :in auto-immune, metabolic
causes of liver failure.

37. Screening for Wilsons disease
Eye examination for KF ring & cataract
S.copper
S. Ceruloplasmin
24 hours urinary copper

39. Management of ALF
Medical: To maintain physiological functions of liver
 Supportive care
 Specific treatment
Surgical:
 Extracorporeal systems
 Liver transplantation

40. Supportive care.
Nursing in a quiet environment.
ICU.
Avoid sedation and stimulation.
Fluid restriction- 60-80% of daily requirement.
Choice of fluid: 0.225% Nacl in 10% dextrose.
Prevention of hypoglycemia(maintain glucose level
>4 mmol/L).

41. IV H2 blocker or PPI.
Antibiotic: Cefuroxim, amoxycillin, fluconazole.
(King’s College protocol)
Cefotaxime+ flucoxacillin-Indian protocol.
Anaemia should be corrected to ensure maximum
oxygen supply to tissue.
Lactulose
Management of complication:

42. Close Monitoring
Continous O2 saturation
Clinical status: Pulse & BP hourly, liver size 12 hrly
Strict input-output chart : Avoid fluid overload
CVP, Foley’s and arterial line : MAP >60 mmHg
Frequent evaluation of blood glucose and
neurological status.
• 12 hourly electrolyte and coagulation studies

43. ALF: common complication
Encephalopathy
cerebral edema
Raised ICP
Infection
Coagulapathy
Hypoglycemia
Dyselectrolytemia
Acid base disturbance.
Multi-organ failure

44. Management of complication

45. Encephalopathy
Treatment
Low protein by month.
Lactulose 10-50ml 2-4 hourly
Acid enema: Lactulose enema, vinegar-can be given
6 hourly
Treat sepsis, bleeds and electrolyte imbalance.
Avoid sedation
Flumazenil : Short lived results.

46. Cerebral Edema
Treatment
• Nurse the child 20-30° elevated ¯ ICP
• IV mannitol
• Hypertonic saline
• Hyperventilation may help ¯ ICP
• Hypothermia ¯ ICP
• Avoid hyperthermia.

47. Bleeding
Treatment
Inj. Vitamin K
Fresh frozen plasma (FFP).
Platelet transfusion -If platelet<10000/mm3 or
platelet count<50000 with bleeding.
Fresh whole blood transfusion.
Recombinant factor VII.

48. Acid Base Changes
Treatment
• Volume expansion.
• Dopamine infusion.
• NaHCO3.
• Mechanical ventilation for R.acidosis.
• Plan for liver transplantation.

49. Septicaemia
:
Gram-positive (in 2/3rd cases):
Staphylococcus
Streptococci
Gram-negative (in 1/3rd cases):
Fungal infection

50. Septicemia
• Septic workup : culture blood, sputum & urine
• Cefuroxime, Amoxycillin, Fluconazole.
• Fungal infection : IV amphoterecin .
• We use fluconazole orally.
• Iv cefuroxime and flucloxacillin

51. Renal complication
Renal failure may occur in 50% pt. with ALF
Due to
Hepatorenal syndrome.
ATN by due to sepsis, endotoxemia, bleeding
hypotension.
Directly by nephrotoxic drug.

52. Treatment
• Dopamine infusion.
• Correct fluid overload, acidosis & hyperkalemia.
• Avoid nephrotoxic drugs.
• Dialysis

53. Specific treatment

54. Infections Interventions
Malaria, Typhoid, Leptospirosis
Herpes family Acyclovir
Enterovirus Pleconaril (?)
Parvovirus Immune globulin (?)
HBV Lamivudine, .
Drug and Toxin
Medication induced Remove offending drug
Acetaminophen N-acetylcysteine
Metabolic Disease
Wilson’s disease Liver transplant
Galactosemia Remove dietary lactose
Fatty acid oxidation IV glucose, avoid fasting
Immune Dysregulation
Autoimmune hepatitis Corticosteroids
Neonatal hemochromatosis Antioxidant cocktail
.

55. N- Acetylcysteine (NAC)
N- acetyl derivative of cysteine
Anti-oxidant: Reactive O2 & N2 species
Replenishes depleted Glutathione
Improves oxygen carrying capacity
Anti-inflammatory effects

56. Extracorporeal Liver Assisted Device(ELAD)
Artificial
Bioartificial
To bridge liver transplantation or
regeneration of native liver
To remove toxic substances to
improve survival and HE

57. Liver transplantation

58. King’s College Criteria For liver transplantation.
Acetaminophen cases
Arterial PH < 7.3 or
Arterial lactate>3.5 at 4
hrs or
Arterial lactate>3 at 12
hrs
INR>6.5 &
Cr>3.4 &
Stage 3 or 4
encephalopathy
Non-acetaminophen
cases
INR>6.5 or
Any 3 of the followings:
Age<10 or >40 yrs
Duration of jaundice>7
d
Total Bili>17.5
INR>3.5
Etiology: idiosyncratic
drug, halothane,
idiopathic, non-A non-
B hepatitis

59. Liver Transplantation
Survival increased from 20% to 60-80% in various
studies
Has changed the outlook & the natural course

60. Prognosis

61.  Overall mortality with supportive care exceeds
70 percent.
With intensive medical support survival rate 50-
60 % in acetaminophen overdose and fulminant
HAV or HBV infections.
In idiopathic form of ALF or acute onset of
Wilson disease mortality rate is 80-90% .

62. Prognosis
The prothrombin time is the best indicator of
survival.
73% of children with an< INR 4 surviving versus only
4 of 24 (16.6%) with an> INR 4.
This is now the widely accepted criteria.
 Bhaduri BR, Mieli-Vergani G. Fulminant hepatic failure:pediatric aspects.
Semin Liver Dis 1996;16:349-355.

63. Poor prognosis is seen in :
 age less than 1 year
 stage 4 encephalopathy
 INR more than 4
 Need of dialysis before transplantation