Explains acute liver failure in details, with management

1. Acute liver failure
DDr.
Ashik Majumde

2. Introduction
 Definition in children includes
Biochemical evidence of acute liver injury (usually <8 wk
duration);
No evidence of chronic liver disease;
And hepatic-based coagulopathy defined as a PT >15 sec or
INR >1.5 not corrected by vitamin K in the presence of
clinical hepatic encephalopathy, or a PT >20 sec or INR >2
regardless of the presence of clinical hepatic encephalopathy

3.  Results from massive necrosis of hepatocytes or from
severe functional impairment.
 Liver failure in the perinatal period can be associated
with prenatal liver injury and even cirrhosis
 In some cases of liver failure, particularly in the
idiopathic form of ALF, the onset of encephalopathy
occurs later, from 8-28 wk after the onset of jaundice

4. Etiology
Neonates & young infants
(A) Infections •HSV 1 & 2
•HHV 6
•Hep B
•Enterovirus
•Cocksackie virus
•Bacterial Sepsis
(B) Metabolic disease •Mitochondrial respiratory chain defects
•Tyrosinemia type 1
•Galactosemia
•Fatty acid oxidation defects
•Urea cycle defects
•Niemann Pick disease
•Woolman disease

5. Neonates & young infants
(C) Others •Neonatal hemochromatosis
•Hemophagocytic lymphohistiocytosis
•Hypocortisolism
•Maternal acetaminophen overdose
•Shock
•Indeterminate

6. Older children
(A) Infections •Hepatitis A, B, C
•HSV 1 & 2
•Ebstein Barr virus
•Parvovirus
•Cytomegalovirus
•Leptospirosis
•Dengue hemorrhagic fever
(B) Immune mediated •Autoimmune liver disease
(C) Metabolic disease •Wilson disease
•Mitochondrial respiratory chain defect
•Fatty acid oxidation defects

7. Older children
(D) Vascular disease • Acute hepatic venous outflow tract obstruction
(Budd Chiari Syndrome)
•Ischemic liver injury due to hypotension
(E) Lympho-reticular
disorders
•Hemophagocytic lymphohistiocytosis
•Acute leukemic infiltration
(F) Drug induced liver
disease
•Acetaminophen toxicity
•Rifampicin
•Pyrazinamide
•Isoniazide
•Valproate
•Others

8. Pathology
Patchy or confluent massive necrosis of hepatocytes
Multilobular or bridging necrosis can be associated
with collapse of the reticulin framework
A zonal pattern of necrosis may be observed with
certain insults
Evidence of severe hepatocyte dysfunction rather
than cell necrosis is occasionally the predominant
histologic finding

9. Pathogenesis
 Massive destruction of hepatocytes might represent both a
direct cytotoxic effect of the virus and an immune
response to the viral antigens
 Hepatotoxic metabolites from liver injury produced by
drugs such as acetaminophen and isoniazid bind
covalently to macromolecular cell constituents ; fulminant
hepatic failure can follow depletion of intracellular
substrates involved in detoxification, particularly
glutathione

10.  The pathogenesis of hepatic encephalopathy
Increased serum levels of ammonia, false
neurotransmitters, amines,
Increased γ-amino butyric acid receptor activity, or
Increased circulating levels of endogenous benzodiazepine-
like compounds
Decreased hepatic clearance of these substances
 Whatever the initial cause of hepatocyte injury, various
factors can contribute to the pathogenesis of liver
failure- impaired hepatocyte regeneration, altered
parenchymal perfusion, endotoxemia, and decreased
hepatic reticuloendothelial function

11. Summary of the role of ammonia in hepatic encephalopathy

12. It can be manifests in different ways, like
– Fulminant liver failure: without previous liver disease who
develop a rapidly progressive liver failure within 8 weeks of
onset of symptoms
– Hyperacute liver failure: acute liver failure are evident within 1
week of onset of symptoms. The survival rate is 36%
– Subacute liver failure: features of liver failure occur over 4
weeks to 6 months after onset of symptoms and is usually
associated with persistent icterus, ascites and/or encephalopathy.
The survival rate is 14 %
– Chronic liver failure: signs of liver failure such as hepatic
encephalopathy and/or clinically detectable ascites at least 6
months after onset of hepatic illness
Clinical Manifestations

13.  Fulminant hepatic failure can be the presenting feature of
liver disease or it can complicate previously known liver
disease (acute-on-chronic liver failure)
 A history of developmental delay and/or neuromuscular
dysfunction can indicate an underlying mitochondrial or
β-oxidation defect
 A child with fulminant hepatic failure has usually been
previously healthy and most often has no risk factors for
liver disease such as exposure to toxins or blood products

14.  Progressive jaundice, fetor hepaticus, fever, anorexia,
vomiting, and abdominal pain are common
 A rapid decrease in liver size without clinical
improvement is an ominous sign
 Ahemorrhagic diathesis and ascites can develop
 Hepatic encephalopathy which is initially characterized
by minor disturbances of consciousness or motor function
 Irritability, poor feeding, and a change in sleep rhythm
may be the only findings in infants; asterixis may be
demonstrable in older children

15.  Patients are often somnolent, confused, or combative on
arousal and can eventually become responsive only to
painful stimuli
 Patients can rapidly progress to deeper stages of coma in
which extensor responses and decerebrate and decorticate
posturing appear
 Respirations are usually increased early, but respiratory
failure can occur in stage IV coma
 Cerebral edema is the major cause of mortality in acute
liver failure

16. Stages of Hepatic Encephalopathy
Stages Symptoms Signs Electroencephalogram
I Periods of lethargy,
euphoria; reversal of day–
night sleeping; may be alert
Trouble drawing
figures, performing
mental tasks
Normal
II Drowsiness, inappropriate
behavior, agitation, wide
mood swings, disorientation
Asterixis, fetor
hepaticus, incontinence
Generalized slowing,
q waves
III Stupor but arousable,
confused, incoherent speech
Asterixis, hyperreflexia,
extensor reflexes,
rigidity
Markedly abnormal,
triphasic waves
IV Coma
IVa-responds to noxious
stimuli
IVb-no response
Areflexia, no asterixis,
flaccidity
Markedly abnormal
bilateral slowing,
d waves, electric-cortical
silence

17. Management of ALF
 Acute liver failure is a medical emergency
unpredictable and often fatal course
with an
 Goals in the evaluation ofALF:
To determine the etiology
To assess the severity of liver failure and the need for
liver transplant
To provide hepatic support till child recovers
spontaneously or has liver transplantation
To anticipate and prevent complications

18. •Initial evaluation ofALF
A. Biochemical tests:
 Coagulation profile: PT/INR,APTT
 LFT:AST, ALT,ALP
, GGT, TSB,
S.Protein
 Albumin
 Ammonia
 Blood gas, lactate
 Metabolic profile: Blood sugars, urea,
creatinine, sodium, potassium, calcium,
magnesium, phosphate
 Complete hemogram
Required in all
patients

19. B. Viral studies:
 Anti HA
V IgM
 Anti HEV IgM
 HBsAg,Anti-HBc IgM
 Anti HCV
 HHV-6 for neonates & infants
C. Autoimmune liver disease:
 ANA
 Anti Smooth MuscleAntibody(SMA)
 Anti Liver Kidney Microsomal antibody(LKM)
 IgM level
These markers
may be false
positive inALF
due to other
etiologies
Test for the common
hepatotropic viruses
first

20. D. Metabolic liver disease:
 Wilson’s disease:- S. ceruloplasmin
24 hr urine copper
S. copper
Slit lamp exam for KF ring
 ALF in neonate & infants:-
Lactate and pyruvate
S. amino acid profile
Urine amino acid/ organic acid
Urine succinyl acetone
Carnitine level & S. acyl carnitine profile
Ferritin, iron transferrin, TIBC

21. E. Drugs/ Toxins:- Acetaminophen level
 Liver biopsy
 Bone marrow
biopsy(Hemophagocytic
lymphohistiocytosis)
 Lip biopsy(Neonatal
hemochromatosis)
A. Imaging:- Ultrasound liver with Doppler hepatic
veins
For acute Budd
Chiari syndrome
A. Histology:-
Transjugular liver
biopsy; useful in
autoimmune liver
disease

22. Treatment
 Supportive:
Maintain normal urine output
Correct hypoglycaemia
Diet with decreased protein, high calories, high carbohydrates
and moderate fat should be given. Total parenteral nutrition may
be needed. Special formulas with high branched chain amino
acid and low in aromatic amino acids and electrolytes vitamin
supplementation should be given
Maintain a normal fluid balance. Avoid fluid overload restrict 2
mL/kg/hour. The volume can be monitored by CVP
Glucose administration to prevent hypoglycaemia

23. Administration of calcium, phosphorus, magnesium, factor
concentrate, magnesium and platelets
Gut sterilisation-using antibiotics such as
ampicillin/neomycin/rifaximin. Lactulose inhibits colonic
organisms
Exchange transfusion
Coagulopathy can be treated with parenteral vitamin K and
plasmapheresis
Platelet transfusion can be indicated in severe cases. Maintain a
platelet count of more than 50,000
Liver-assist devices
Liver transplantation

24. Flumazenil is a specific benzodiazepine antagonist which binds to
the receptor and prevents the binding of benzodiazepine to the
receptor
L-aspartate and L-ornithine stimulate the hepatic urea cycle
activity which utilises the ammonia. Also, they promote glutamine
synthesis by the skeletal muscle
Types of Liver-assist devices

25.  Specific:
Etiology Therapy
A. Wilson’s disease •D-Penicillamine
•Trientine hydrochloride
•Oral zinc acetate
•Plasmapheresis/ plasma exchange, Albumin dialysis
B. Autoimmune hepatitis •IV Methyl prednisolone(2mg/kg)
C. Budd Chiari
Syndrome
•Hepatic vein angioplasty or stenting
•TIPS
•Recanalization
D. Acute Hep B •Entecavir/ Tenofovir/ Lamivudine
•Patients may still require transplantation
E. HSV 1,2 •IV Acyclovir

26. Etiology Therapy
F. Acetaminophen toxicity •N acetyl cysteine IV(150mg/kg loading dose over
15min f/b 50mg/kg every 6-8hr for 3doses)
G. Neonatal
Hemochromatosis
•IVIG (1-3g/kg)
•Double volume exchange transfusion
•Iron chelation and antioxidant
H. Tyrosinemia type 1 •NTBC
•Low phenylamine-tyrosine diet
I. Galactosemia •Lactose-free-formula
J. Mushroom poisoning •Benzylpenicillin (1,000,000 U/kg/d) or thiotic acid (300
mg/kg/d)
K. Hemophagocytic
lymphohistiocytosis
•Corticosteroids
•Chemotherapy
•Bone marrow transplantation

27. Central nervous system
 Encephalopathy:
Nurse in quiet environment
Minimal handling
Avoid sedation in early encephalopathy
Head end elevated to 30⁰ in neutral position
Control fever, shivering, agitation
Optimize metabolic and cardiovascular parameters
Fluid 75% of requirement
Intubate for grade 3-4 encephalopathy
Avoid benzodiazepines, use propofol, fentanyl & atracurium if req

28. Central nervous system
 Raised Intracranial Pressure/Cerebral edema:
 Start 3% saline in all cases with encephalopathy
3-5ml/kg over 30-60min f/b 0.1-1ml/kg/hr
Target serum sodium 145-155 meq/L
Maintain adequate blood pressure
For acute rise in ICP: 20% mannitol 5ml/kg
Brief hyperventilation to a PaCO2 30-35mmHg
 Seizures:
Midazolam, Phenytoin, Phenobarbitone
Thiopentone may be needed for status epilepticus

30. Cardiovascular system
 Hypotension:
Maintain intravascular volume
Colloid challenge 10-20ml/kg of 20% albumin
Maintain CVP at 6-8 mmHg
Noradrenaline infusion to maintain age appropriate mean
arterial pressure and cerebral perfusion pressure (40-60
mmHg in children, 60 mmHg in adults)

31. Sepsis:
Antibiotics
Add antifungals if prolonged hospital stay
Coagulopathy and Liver Function
Routine use of FFP is not required
Platelet infusion if less than 10k/mm3 or <50k/mm3 and bleed
IV PPI to all patients
IV vitamin K daily

32. Hyperammonemia:
Lactulose 2-4 ml/kg/dose TDS or Rifaximin 10mg/kg BD
Renal replacement therapy if ammonia >150-200µg/dl till
transplantation
Protein 1-2g/kg
Nonbiologic systems, essentially a form of liver dialysis
with an albumin-containing dialysate, and biologic liver
support devices that involve perfusion of the patient’s blood
through a cartridge containing liver cell lines or porcine
hepatocytes can remove some toxins, improve serum
biochemical abnormalities

33. Electrolyte imbalance:
 Increase glucose infusion rate
 Optimize fluid
 Correct deficiencies
 Bicarbonate infusion if pH <7.25
Renal dysfunction:
 Avoid nephrotoxic drugs
 Maintain circulating volume with colloid (20% albumin) if req
 Ensure CVP 6-8 mmHg
 Consider colloid challenge if CVP is low
 Consider low dose dopamine 2-5 µg/kg/min
 Furosemide 1-2 mg/kg stat or infusion 0.5-1 mg/kg
 Renal replacement therapy

34. Orthotopic liver transplantation can be lifesaving in
patients who reach advanced stages (III, IV) of hepatic
coma.
Reduced-size allografts and living donor transplantation
have been important advances in the treatment of infants
with hepatic failure.
 Partial auxiliary orthotopic
transplantation is successful in
or heterotopic liver
a small number of
children, and in some cases it has allowed regeneration of
the native liver and eventual withdrawal of
immunosuppression.

35. Prognosis
• Children with acute hepatic failure fare better than adults.
• Prognosis varies considerably with the cause of liver failure and
stage of hepatic encephalopathy.
• Survival rates with supportive care may be as high as 90% in
acetaminophen overdose and with fulminant hepatitisA.
• By contrast, spontaneous recovery can be expected in only
approximately 40% of patients with liver failure caused by the
idiopathic form of acute liver failure or an acute onset of Wilson
disease.
• In patients who progress to stage IV coma , the prognosis is
extremely poor.
• Brainstem herniation is the most common cause of death.

36. • Age <1 yr, stage 4 encephalopathy, an INR >4, and the need for
dialysis before transplantation are associated with increased
mortality.
• A plasma ammonia concentration >200 μmol/L is associated with a
5-fold increased risk of death.
• Owing to the severity of their illness, the 6 mo post–liver
transplantation survival of approximately 75% in most studies is
significantly lower than the 90% achieved in children with chronic
liver disease.
• Patients who recover from fulminant hepatic failure with only
supportive care do not usually develop cirrhosis or chronic liver
disease.
• Aplastic anemia occurs in approximately 10% of children with the
idiopathic form of fulminant hepatic failure and is often fatal.

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