Fulminant Hepatic Failure

Dr. AR. Karthick

Nelson – black
Recent Advances – violet
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IP Journal - green
Definition
• Fulminant Hepatic Failure (acute liver failure) is a clinical syndrome
resulting from massive necrosis of hepatocytes or severe functional
impairment of hepatocytes. Synthetic, excretory & detoxifying
functions of the liver are severely impaired
• The currently accepted 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 prothrombin time (PT) >15 sec or
international normalized ratio (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
Definition by Pediatric Acute Liver Failure
Study Group
• No evidence of known chronic liver disease
• Hepatic based coagulopathy not corrected within 8 hours of
parenteral administration of vitamin K
• INR of 1.5-1.9 (PT 15 – 19.9sec) in the presence of Hepatic
encephalopathy
• INR of 2 (PT ≥ 20sec) in the absence of encephalopathy

• Definition different from adult – encephalopathy is not necessary & difficult

to identify in children
PALF – Definition
• The group recommended Pediatric ALF definition as
(a) evidence of liver dysfunction within 8 weeks of onset of symptoms
(neonates may have only deranged liver functions without overt symptoms)
(b) uncorrectable (6-8 hours after administration of one dose of parenteral
vitamin K) coagulopathy with International Normalized Ratio (INR) >1.5 in
patients with hepatic encephalopathy, or INR> 2.0 in patients without
encephalopathy and
(c) No evidence of chronic liver disease either at presentation or in the past
Some Definitions & Classifications
Definition by Subclassification
Trey & Davidson Coagulopathy & encephalopathy occurring within 8 weeks of onset of liver disease, in a
FHF is patient without previous liver disease
O’ Grady et al Subclassification depending on interval between jaundice & HE
1. Hyperacute liver failure: 0 – 7 days (<1 week)
2. Acute Liver failure: 8 – 28 days (1 – 4 weeks)
3. Subacute liver failure: 29 – 72 days (4 – 12 weeks)
4. Late onset acute liver failure: 56 – 182 days (8 – 16 weeks)
Bernauau et al Severe acute liver failure: PT or Factor V concentration below 50% of normal with or
without he
Subclassification:-
FHF – HE within 2 weeks of onset of jaundice
SubFHF – HE between 3 – 12 weeks of onset of jaundice
International ALF – hyperacute: within 10 days
Association for ALF – fulminant: within 10 – 30 days
the study of ALF not otherwise specified
Liver Subacute liver failure – development of ascites and/or HE from 5 – 24 weeks after onset of
symptoms
Etiology – 7 categories – IDM-AVMU
Infections Drugs Metabolic
Viral Dose dependent:- - Wilson’s Disease Autoimmune
- Viral Hepatitis (A,B,D,E) - Acetaminophen - Galactosemia
- Adenovirus - Halothane - Tyrosinemia Malignancy-induced
- EBV Idiosyncratic Reaction:-
- Hereditary fructose - Acute Leukemia
- Parvo virus B19 - Isoniazid intolerance - Hodgkin’s
- Varicella - NSAID - Neonatal - GVHD
- measles - Phenytoin hemochromatosis Vascular-induced
- Coxsackie - Valproate - Niemann-Pick disease - Asphyxia
- HSV 1, 2, 6 - Carbamazepine type C - Myocarditis
- Dengue - Antibiotics (penicillin, - Mitochondrial - Cardiomyopathy
erythromycin, tetracyclines,
quinolones, sulfonamides)
cytopathies - Budd-chiari
Bacterial - Allopurinol - Congenital disorder of - CCF
- Septicemia - Propyl thiouracil glycosylation - Heat stroke
- Enteric fever - Amiodarone - Shock
- E.coli sepsis - Ketoconazole Toxins
- Meningococcocemia - Anti-retroviral - Aflatoxins
- Weil’s disease - Amanita phalloides
Drug Combinations:-
- Cong. syphilis - INH & R Common in - Carbon tetrachloride
Protozoal - malaria - Co-trimoxazole - Iron
neonates & infants
- Amoxy-clav Undetermined
- hyperthermia
• Infections:-
• Viral hepatitis – leading cause of FHF in India
• high risk of FHF in young people with combined infections with the hepatitis B
virus (HBV ) and hepatitis D.
• Mutations in the precore and/or promoter region of HBV DNA have been
associated with fulminant and severe hepatitis.
• Drugs:-
• Dose-dependent or idiosyncratic
• Mechanisms of drug-induced liver injury – formation of reactive
intermediates, Kupffer cell activation, stellate cell activation, immune
mediated injury, disrupted cell membrane, mitochondrial dysfunction, altered
canalicular function and endothelial cell injury
• Synergistic injury from multiple drug exposure
• Paracetamol
• Dose dependent
• 95% - conjugated with sulphate & glucuronide and excreted in urine
• High dose ingestion – this pathway overwhelmed – Paracetamol now
converted to NAPQI (N-Acetyl P-BenzoQuinone Imine)  NAPQI detoxified
with glutathione – after depletion of glutathione, binds to cysteine group of of
proteins & form protein adducts
• SGPT v.high >3500 IU/L
• Very high SGPT out of proportion to jaundice – Paracetamol poisoning should
be considered
• Anticonvulsants
• Liver injury occurs within 6 weeks & always accompanied by severe rash &
eosinophilia  indicating immune mediated injury d/t neoantigens from
reactive metabolites
• Toxins
• Amanita phalloides & Amanita verna – phalloidin & amanitatoxin
• Fatal dose – 3 mushrooms (10 g)
• Hereditary tyrosinemia
• Clinical presentation varies from FHF to poor weight gain & RTA
• May present with E.coli sepsis & multiorgan failure
• DoC - Nitisinone
• Ischemic Hepatitis
• Centrilobular necrosis
• ALT may reach 5000 to 10000
• Rapid raise in ALT in absence of increasing bilirubin – distinguishes ischemic
from viral hepatitis
 CLINICAL MANIFESTATIONS AND DIAGNOSIS OF COMMON
CAUSES OF ACUTE LIVER FAILURE IN INFANTS
Neonatal hemochromatosis
• Maternal: Still births, previous sib deaths;
• Antenatal period: IUGR, oligohydramnios, placental edema.
• Presents usually few hours to sometimes weeks after birth as hypoglycemia,
coagulopathy, jaundice, anemia, ascites, anasarca, and splenomegaly with
shrunken liver.
• Diagnosis: Low to normal transaminases, hypoalbuminemia, hypofibrinogenemia,
thrombocytopenia, high serum ferritin, low serum transferrin, high transferrin
saturation (95 % to 100 %). Lip or salivary gland biopsy shows iron deposition;
MRI pancreas shows low signal intensity on T2 imaging.
• Treatment: Anti-oxidants (acetyl-cysteine and Vitamin E), high dose IVIG in
combination with exchange transfusion; liver transplantation if no response.
 CLINICAL MANIFESTATIONS AND DIAGNOSIS OF COMMON
CAUSES OF ACUTE LIVER FAILURE IN INFANTS
Herpes simplex infection
• No positive history in 60 % to 80 % of mothers.
• Suspect in a sick neonate presenting in first week of life especially if
bacterial cultures are not growing anything. Search for vesicles,
particularly on scalp.
• Diagnosis: Viral cultures form vesicles, oropharynx, conjunctiva, blood
or CSF; PCR diagnosis from blood or CSF.
• Treatment: High dose (60 mg/kg/d) acyclovir for 21 days or till PCR is
negative. Necessary to document negative CSF-PCR at end of therapy.
 CLINICAL MANIFESTATIONS AND DIAGNOSIS OF COMMON
CAUSES OF ACUTE LIVER FAILURE IN INFANTS
Mitochondrial cytopathy
• Onset in the first week of life or later, transient hypoglycemia,
neurological involvement in form of severe hypotonia, myoclonus or
psychomotor retardation.
• Diagnosis: Plasma lactate >2.5 mmol/L, molar ratio of plasma
lactate/pyruvate > 20:1, paradoxical increase in plasma ketone bodies
or lactate after meals, Urinary analysis by mass spectroscopy; Genetic
mutational analysis for respiratory chain disorders and tandem mass
spectrometry for fatty acid oxidation defects.
 CLINICAL MANIFESTATIONS AND DIAGNOSIS OF COMMON
CAUSES OF ACUTE LIVER FAILURE IN INFANTS
Type 1 tyrosinemia
• Coagulopathy with or without cholestatic jaundice,hypoglycemia,
hepatomegaly, ascites
• Diagnosis: High alpha-fetoprotein (mean level: 160,000 μg/mL vs.
84,000 μg/mL in normal term neonate), Increased urinary
succinylacetone
• Treatment:Nitisinone 1 mg/kg/d orally in two divided doses: dietary
restriction of phenylalanine and tyrosine; Liver transplantation if no
response.
 CLINICAL MANIFESTATIONS AND DIAGNOSIS OF COMMON
CAUSES OF ACUTE LIVER FAILURE IN INFANTS
Galactosemia
• Feeding intolerance, vomiting, diarrhea, jaundice, hepatomegaly,
lethargy and hypotonia after milk feeding is started; hypoglycaemia,
sepsis (particularly E.coli), cataract and developmental delay.
• Diagnosis:Urine positive for non-glucose reducing substances while
on lactose feeds; confirmation by blood Galactose-1 phosphatase
uridyl transferase enzyme assay.
• Treatment: Lactose free formula.
• FHF by autoimmune hepatitis in ~5% of cases. Positive autoimmune
marker (e.g., antinuclear antibody , anti–smooth muscle antibody ,
liver-kidney microsomal antibody , or soluble liver antigen) and
possibly an elevated serum IgG level. Liver histology – severe hepatic
necrosis with interface hepatitis & plasma cell infiltration
• Acute liver failure is a common feature of hemophagocytic
lymphohistocytosis (HLH) caused by several gene defects, infections
by mostly viruses of the herpes group, and a variety of other
conditions including organ transplantation and malignancies.
Impaired function of natural killer (NK) cells and cytotoxic T-cells (CTL)
with uncontrolled hemophagocytosis and cytokine overproduction is
characteristic for genetic and acquired forms of HLH. Biochemical
markers include elevated ferritin and triglycerides and low fibrinogen.
• An idiopathic form of FHF accounts for 40-50% of cases in children.
• Predictable liver injury can occur after exposure to carbon
tetrachloride or Amanita phalloides mushroom or after
acetaminophen overdose. Acetaminophen is the most common
etiology of acute hepatic failure in children and adolescents in the
United States and England - have reduced stores of glutathione after a
prolonged illness and a period of poor nutrition.
• Idiosyncratic damage can follow the use of drugs such as halothane,
isoniazid, or sodium valproate.
• Herbal supplements are additional causes of hepatic failure
Pathogenesis of FHF
• Factors involved in FHF
• Extent of injury to hepatocyte plasma membrane
• Organelle dysfunction
• Disturbance of hepatic circulation
• Regenerative capacity of liver
Factors involved
• Injury to hepatocyte plasma membrane
• Immune mediated attack of virus & drugs
• Loss of electrolytes, enzymes & co-enzymes
• Organelle dysfunction
• Activation of drugs to toxic metabolites by microsomal enzyme system & damage
vital macromolecules
• Disturbance of hepatic circulation
• Portosystemic shunting
• Impaired sinusoidal microcirculation
• Regenerative capacity of liver
• Regeneration will be less than degeneration
• Depends on insulin, glucagon, EGF etc
Jones classification of FHF
• Type 1 lesion
• Most common; Necrosis & loss of hepatocytes
• Seen in viral, toxic, ischemic, metabolic
• Massive confluent or multilobular necrosis at necropsy, biopsy is risky
• Sr. Bilirubin in range of 10-60mg/dl. Remaining hepatocytes take up bilirubin & conjugate but do not excrete
(energy dependent process)  results in conjugated hyperbilirubinemia
• Type 2 lesion
• Microvesicular fatty infiltration
• Damage to mitochondria, hepatocellular loss is insignificant
• Jaundice is minimal, transaminases only slightly elevated, if pt survives, histological recovery is complete
• Seen in Reye syndrome, valproate toxicity, acute fatty liver of pregnancy
• Type 3 lesion
• Swelling of hepatocytes & condensation of organelles and cytoplasmic elements
• Spotty hepatocellular necrosis & macrovesicular fatty infiltration
• Sr. Bilirubin & transaminases – moderately elevated b/w type 1 & 2
• Seen in Hereditary fructose intolerance, Type 1 tyrosinemia
Pathobiology
• Liver metabolic functions are impaired Patients develop
• Hypoglycemia coagulopathy,
• Increased lactate production hypoglycemia, acidosis
• Impaired synthesis of coagulation factors - Risk of GI bleed, seizures
• Reduced capacity to eliminate drugs, toxins & bilirubin
& myocardial dysfunction
• Bacteremia & fungaemia
• Impaired liver macrophage cell function, reduced clearance of endotoxins
• Catheters & ET tubes
• Decreased production of acute phase reactants & complements
• Multiorgan failure
• d/t microvascular injury
• Impaired clearance of inflammatory mediators & polymerization of actin (actin from damaged
hepatocytes quickly form polymers – bind to gelsolin, an actin binding protein found in monocytes
& platelets prevents polymerization, gelsolin will be depleted in FHF)
• Actin polymers is deposited at various places – myocardial dysfunction, renal dysfunction, DIC etc
• Ability to regenerate – depends on site of injury in liver
• Portal tract – has arterial blood, nutrients, contains liver progenitor cells, ductal hepatocytes
• Injury to portal zone – inhibits regenerative process
• One third to one half of patients with HBV -induced liver failure become negative for
serum hepatitis B surface antigen within a few days of presentation and often have no
detectable HBV antigen or HBV DNA in serum . These findings suggest a hyperimmune
response to the virus that underlies the massive liver necrosis.
• Formation of hepatotoxic metabolites that bind covalently to macromolecular cell
constituents is involved in the liver injury produced by drugs such as acetaminophen and
isoniazid;
• Fulminant hepatic failure can follow depletion of intracellular substrates involved in
detoxification, particularly glutathione.
• various factors can contribute to the pathogenesis of liver failure, including
• impaired hepatocyte regeneration, altered parenchymal perfusion, endotoxemia, and decreased
hepatic reticuloendothelial function.
• The pathogenesis of hepatic encephalopathy can relate to increased serum levels of
ammonia, false neurotransmitters, amines, increased γ -aminobutyric acid (GA BA )
receptor activity , or increased circulating levels of endogenous benzodiazepine-like com
pounds. Decreased hepatic clearance of these substances can produce marked central
nervous system dysfunction.
Clinical Features of FHF
• Typically – previously healthy school child, with no major medical problems
• Initial symptoms – fever, nausea, anorexia & vomiting – given treatment for
hepatitis
• Child does not improve, develops progressive lethargy, occasionally
hallucination, become desperately sick with deep jaundice & fetor
hepaticus
• Liver span decreases, bleeding from puncture site occurs
• In Viral induced FHF – jaundice is preceded by fever, myalgia, arthralgia &
nausea, thereafter jaundice worsens, liver enzymes are increased, PT
becomes prolonged
When to suspect FHF in child with suspected
hepatitis
• Persistent anorexia
• Persistent vomiting
• Deepening jaundice
• Decreasing liver span
• Relapse of initial symptoms
• Development of ascites
• Neuropsychiatric changes

A rapid decrease in liver size without clinical improvement is an ominous sign

Hepatic Encephalopathy
• 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.
• 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
Hepatic Encephalopathy
Theories of HE
• Hyperammonemia theory – direct effect on neuronal membrane
• False neurotransmitter theory – increase in Aromatic Amino acids and
decrease in branched chain amino acids – alteration in brain metabolism
• GABA – Benzodiazepine theory – increased level of neuroinhibitory
transmitter GABA
• Other theories – abnormal histamine & serotonin neurotransmission,
endogenous opioids, neurosteroids, inflammatory cytokines & potential
manganese toxicity
Factors that contribute to HE
• Hyopglycemia
• Hypoxia
• Hemorrhage
• Septicemia
• Hepatotoxic drugs
• Hypokalemia
• Reduced cerebral perfusion
• Cerebral edema
West Haven Criteria for stages of encephalopathy

DIDWA
S
L
E

SaCis

F
M H
AFI E
R
As
Stages of Hepatic Encephalopathy for infant &
children < 4 yrs
I (prodrome) II (impending coma) III (stupor) IV (coma)
Symptoms Inconsolable cry, inattention to task, not Stupor Coma
acting like self to parents Somnolence IVa – responds to
Combativeness painful stimuli
IIS
SSC IVb – no response
Signs Normal or hyper-reflexic Hyper-reflexia Areflexia, flaccidity,
Other neurological signs – difficult to test Extensor reflex decerebrate or
Rigidity decorticate
HER
posturing
EEG Difficult to test Markedly abnormal Markedly abnormal
triphasic waves bilateral slowing,
electrical cortical
silence
World Congress of Gastroenterology
• Three categories based on underlying liver dysfunction
• Type A – acute liver failure & progresses rapidly to seizures, decerebrate
rigidity, coma and frequently death
• Type B – portosystemic bypass with no intrinsic liver disease
• Type C – cirrhosis & portal hypertension
Diagnostic Workup
General Workup
General work-up
- Alanine aminotransferase,
- aspartate aminotransferase,
- gamma glutamyl transpeptidase,
- alkaline phosphatase,
- total and conjugated bilirubin,
- prothrombin time (INR), PTTK,
- hemogram,
- serum electrolytes, blood urea, creatinine,
- blood and urine cultures,
- blood group,
- chest X-ray,
- serum alphafetoprotein,
- lactate, lactate dehydrogenase,
- blood ammonia,
- arterial blood gas, and
- urine for reducing substances.
Specific Workup
Infectious
IgM anti- hepatitis A virus, IgM anti - hepatitis E
virus, hepatitis B virus surface antigen, IgM anti-
hepatitis B core antibody,
cytomegalovirus PCR, IgM varicella zoster virus,
IgM Epsteinbarr virus, HIV 1 and 2
Wilson disease
Serum ceruloplasmin, 24 hour urinary copper
estimation, KF ring. Clue to etiology: alkaline
phosphatase / bilirubin ratio <4.0,
AST/ ALT ratio > 2.2 ± evidence of Coombs
negative hemolysis
Autoimmune
Coombs test, antinuclear antibody (> 1:40), liver
kidney microsomal antibody, smooth muscle
antibody (>1:20), Immunoglobulin G levels
Hemophagocytosis
Serum triglyceride, cholesterol, ferritin and bone
marrow biopsy
Drug overdose
Acetaminophen, valproate drug levels
• Serum aminotransferase activities do not correlate well with the
severity of the illness and can actually decrease as a patient
deteriorates.
• The blood ammonia concentration is usually increased, but hepatic
coma can occur in patients with a normal blood ammonia level
Management
• Transport
• Management in ICU
• Electrolyte disturbance
• Supportive Management
• Raised ICP
• Coagulopathy
• Sepsis
• Acute Kidney Injury
• Nutrition
• Liver transplantation
Transport
• The aim of transporting - to ensure safe and timely transfer to a
higher center, preferably with liver transplant facilities.
• Any child who has grade III or IV encephalopathy - preferably be
intubated and airway secured before transport.
• A continuous monitoring of heart rate, rhythm, pulse oximetry, and
blood pressure should be available.
• Facilities for infusion of vasoactive drugs, with spare supplies should
be available during transport.
• Well secured vascular access must be assured prior to the transfer.
Management in ICU
• nursed in a quiet environment preferably in an intensive care setting.
• central venous line - to measure central venous pressure, administer fluids, medications, and blood products, and collect
blood samples.
• Volume resuscitation -if necessary. Fluids should be glucose-based with a glucose infusion rate of at least 4-6 mg/kg/min
and titrated as per requirement. Vasoactive drugs - if hypotension is unresponsive to saline.
• Medications that affect level of consciousness should be avoided (unless there is a back-up plan for ventilation) to prevent
worsening or assessment of encephalopathy. If sedation is mandatory, 1-2 mg/kg of propofol can be given.
• The group also recommends monitoring of the following clinical and biochemical parameters until the patient becomes
stable:
(a) vital signs, including blood pressure every 4 hours, more frequently in an unstable child
(b) continuous oxygen saturation monitoring
(c) neurological observations/coma grading, electrolyte, arterial blood gases, blood sugar every 12 hourly (more frequently in an
unstable child); prothrombin time should be monitored 12 hourly till patient stabilizes or decision to perform a transplant is taken
(d) daily measurements of liver span and prescription review
(e) liver function tests, blood urea, serum creatinine, calcium and phosphate at least twice weekly.
Surveillance of blood and urine cultures should be done during the course of illness.
Electrolyte disturbance
• Metabolic, electrolyte, and acid-base disturbances frequently occur in ALF.
• Hyponatremia, hypokalemia, hypocalcemia, hypophosphatemia and
hypomagnesemia are commonly observed.
• Persistent hyponatremia and hypoglycemia are poor prognostic parameters.
• Patients with ALF are at an increased risk for hypoglycemia secondary to failure of
hepatic gluconeogenesis, hyperinsulinemia, increased utilization by anerobic
metabolism and secondary bacterial infections.
• Blood sugars monitored q 2-4hrs
• Intravenous fluids should be tailored in accordance to electrolyte, sugar and renal
status of the patient.
• Hypophosphatemia, probably a reflection of liver regeneration, and early
phosphorus administration are associated with a better prognosis in acute liver
failure, whereas hyperphosphatemia predicts a failure of spontaneous recovery .
Electrolyte disturbance
• Hypokalemia
• Inadequate replacement
• Increased loss
• Secondary hyperaldosteronism
• Hyponatremia
• Total body sodium is elevated but water excretion is diminished proportionately
• Acid Base imbalance
• Respiratory alkalosis – hyperventilation in early HE
• Metabolic alkalosis – frusemide, hypokalemia
• Respiratory acidosis – resp failure, cerebral edema, obstructed ET, pneumonia
• Metabolic acidosis – accumulation of organic acids, lactic acidosis, renal failure,
citrated blood
Supportive management
• There is increasing evidence for use of N-acetyl cysteine (NAC) infusion in non-acetaminophen causes of ALF
• The group recommends routine use of NAC in the dose of 100 mg/kg/d in all cases of ALF irrespective of the
etiology.
• Though ammonia is an accepted triggering factor in cerebral edema, L-ornithine L-aspartate, lactulose and
other non-absorbable antibiotics have not been found to be beneficial.
• If lactulose is administered (preferred in grades I-II HE) care should be taken to avoid over distension of the
abdomen. There is evidence to suggest that prophylactic proton pump inhibitors are helpful in prevention of
gastrointestinal hemorrhages
• Lactulose should be given every 2-4 hr orally or by nasogastric tube in doses (10-50 m L) sufficient to cause
diarrhea. The dose is then adjusted to produce several acidic, loose bowel movements daily . Lactulose syrup
diluted with 1-3 volumes of water can also be given as a retention enema every 6 hr . Lactulose, a
nonabsorbable disaccharide, is metabolized to organic acids by colonic bacteria; it probably lowers blood
ammonia levels through decreasing microbial ammonia production and through trapping of ammonia in
acidic intestinal contents
• The group recommends prophylactic administration of proton pump inhibitors in all cases of ALF.
(omeprazole 0.5mg/kg/dose NG 1-2x/day), sucralfate 10-20mg/kg/dose NG 4-6hrly
Raised ICP
• ICP >20 mm Hg or intracerebral hypertension (ICH) - consequence of cerebral edema - the most dreaded
complications of ALF.
• The most accurate method of diagnosing ICH is by direct ICP monitoring using catheters, since the clinical
features manifest only in the late stages. ICP monitoring is associated with a 4-20% risk of local
complications and has no survival benefit, it is not routinely recommended.
• Repetitive transcranial Doppler may be used for noninvasive monitoring of ICH. CT scan or MRI may be
required o exclude other causes of raised ICP such as intracerebral hemorrhage.
• The induction of hypernatremia - decreases water influx into the brain and thereby reduce cerebral edema.
Prophylactic infusion of 3% saline to maintain sodium at 145-155 mmol/L in patients with severe
encephalopathy is associated with fewer episodes of ICH and is preferred over mannitol.
• Once obvious neurological signs develop or ICP is above 25 mm Hg for over 10 minutes, a bolus over 15
minutes of IV mannitol (0.25-1 g/kg, 20% mannitol) is recommended. This can be repeated if serum
osmolality is less than 320 mosmol/L. Urine output should be monitored and ultrafiltration may be
necessary in the setting of renal impairment.
• Hyperventilation with reduction of pCO2 to <35 mmHg decreases cerebral blood flow and may be
appropriate in the subgroup of ICH patients with cerebral hyperemia. It is not recommended routinely and
may be used temporarily in patients with impending herniation where mannitol therapy fails
• At present there is no evidence to support use of hypothermia, prophylactic phenytoin or corticosteroids in
the management of raised ICP in ALF.

Extradural monitors – Ladd transducers

Subdural monitors – Gaeltec transducers
Cerebral edema
• Clinical features
• Increased muscle tone
• Trismus
• Opisthotonus
• Decerebrate posturing
• Hyperventilation
• Pupils dilated & reacting poorly to light
Coagulopathy
• Patients with ALF develop
• platelet dysfunction,
• hypofibrinogenimia and
• vitamin K deficiency.
• Routine correction of coagulopathy and thrombocytopenia is not recommended. Prophylactic
fresh frozen plasma (FFP) is also not recommended, as it does not reduce the risk of significant
bleeding and obscures the trend of INR as a prognostic marker.
• Replacement with FFP is recommended in patients with clinically significant bleeding, while
performing invasive procedure or in situations of extreme coagulopathy with INR>7.
• FFP can be given 15-20 mL/kg every 6 hours or as a continuous infusion at 3-5mL/kg/hr
• Single dose of vitamin K 1 (5-10 mg, slowly with the rate not more than 1mg/min) is
recommended empirically in all patients with ALF.
• Cryoprecipitate in patients with significant hypofibrinogenemia (<100 mg/dL) is helpful.
• Recombinant factor VIIa is beneficial in patients with prolonged INR despite FFP, who are volume
overloaded. However, the cost of therapy is exorbitant.
• Platelet transfusion is not recommended unless a threshold platelet count of 10,000-
20,000/mm3 is reached or there is significant bleeding and platelet count <50,000/mm3. A
platelet count of 50-70,000/mm3 is usually considered adequate when an invasive procedure is to
be performed.
Coagulopathy
• All clotting factors are synthesized by liver except von Willebrand
factor.
• Coagulopathy classification
• Mild (PT < 18sec)
• Moderate (PT 18-25sec)
• Severe (PT > 25 sec)
• Thrombocytopenia – seen in 50% of FHF
• Caused d/t hypersplenism, bone marrow suppression, increased consumption
of platelets
Sepsis
• Infection - one of the major causes of death in patients with ALF.
• Most commonly isolated organisms are gram-positive cocci (Staphylococci, Streptococci)
and enteric gram-negative bacilli. Fungal infections, particularly Candida albicans, may
be present in one third of patients with ALF.
• Prophylactic parenteral and enteral antimicrobial regimens have not been shown to
improve outcome or survival in patients with ALF. Therefore, there is insufficient data to
recommend routine use of antibiotic prophylaxis in all patients with ALF.
• Empirical administration of antibiotics is recommended where infection or the likelihood
of impending sepsis is high
• surveillance cultures reveal significant isolates,
• progression of, or advanced stage (III/IV) HE,
• refractory hypotension,
• renal failure,
• presence of systemic inflammatory response syndrome components (temperature >38°C or
<36°C, white blood count >12,000 or <4,000/mm3, tachycardia).
• patients listed for liver transplantation (LT), since infection often results in delisting and
immunosuppression post- LT is imminent.
• Broad-spectrum coverage with a third-generation cephalosporin,
vancomycin/teicoplanin, and fluconazole (3-6mg/kg/day) are recommended wherever
indicated.
Infections
• Common d/t
• Neutropenia
• Impaired cell mediated & humoral immunity
• Defective opsonization
• Impaired Kupffer cell function
• Frequent venepunctures
Acute Kidney Injury
• Might be pre-renal (hypovolemia) or secondary to acute tubular necrosis.
• Blood urea is unreliable, particularly since its synthesis is impaired in hepatic dysfunction.
• Determination of the fractional excretion of sodium helps to differentiate pre-renal causes
(hypovolemia, hepatorenal syndrome) from ATN.
• Patients with prerenal AKI respond to expansion of intravascular compartment with IVF
• Standard charts should be used to modify the dose and dosing interval of drugs in accordance
with the degree of renal impairment.
• The indications for initiating renal replacement therapy include
• severe or persistent hyperkalemia (>7 mEq/L),
• uremic encephalopathy,
• fluid overload (pulmonary edema, severe hypertension),
• severe metabolic acidosis,
• hyponatremia (120 mEq/L or symptomatic) or hypernatremia.
• Peritoneal dialysis is preferred in sick and unstable patients, particularly infants. Use of single-
cuff soft or double-cuff catheters and/or an automated device decrease the risk of peritonitis.
• Hemodialysis is avoided in patients with hemodynamic instability and bleeding tendency, and in
the very young.
Renal complications
Hepatorenal syndrome ATN
Functional renal failure – m.c. cause of Renal failure in d/t hypotension, sepsis & hemorrhage
FHF

- Normal urinary sediment - Abnormal urinary sediment(granular & cellular

cast)
- Marked sodium retention – urine sodium<20mEq/L - Urine sodium > 20mEq/L
- Reduced urine output < 1ml/kg/hr - Severe oliguria <0.5ml/kg/hr
Cardiovascular complications
• Hypotension
• Reduced peripheral vascular resistance
• Arterio-venous shunting
• Bleeding etc
• In many cause – not obvious
• Relative bradycardia
• Rarely seen
• Sign of ICT
Nutrition
• Enteral feeding enriched with branched-chain amino acids (BCAA) is not
beneficial in children with ALF and encephalopathy.
• There is no role of protein restriction in children with HE.
• Energy intakes should be increased appropriately to counter the energy
catabolism and also factor-in the requirement for maintenance, growth
and physical activity.
• For reliable assessment of current nutritional status, body mass index for
age has been shown to be the most accurate.
• If there is a suspicion of a metabolic condition, then all nutrition should be
stopped for 24 hours and then restarted keeping the specific condition in
mind.
• Na restricted to 1mEq/kg/day & K to be given @ 3-6mEq/kg/day
• Fluid restriction - <75% of maintenance; Ideal maintenance fluid – 10%D
with 0.25%NS
Specific Therapy of FHF
• Paracetamol ingestion – N-acetyl cysteine
• Fulminant Hep B – lamivudine, telbivudine & entecavir
• Amanita phalloides poisoning – massive dose of benzyl penicillin
(decreases uptake of amatoxin); thioctic acid (300mg/kg/day IV
infusion)
Liver support systems
• MARS – molecular adsorbent recirculating system
• Cell free, non-biological artificial liver support system
• Using hollow fiber dialysis module – blood dialysed across albumin impregnated
polysulphone membrane (pore size of 50kD) & constant flow of albumin-rich
dialysate in extracapillary compartment
• Toxis detach from plasma albumin & binds to albumin impregnated membrane
• Extracorporeal Bio-artificial Liver support system
• Hepatocytes in plastic cartridge & semi-permeable membrane
• Problems – maintaining cell viability & numbers, membrane type & structure, cell
mass & type of hepatocyte
• Types
• HepatAssist 2000
• ELAD (Extracorporeal Liver Assist Device)
• BLSS (Bioartificial Liver Support Device)
• MELS (Modular Extracorporeal Liver System)
Liver transplantation
• LT is the only definite treatment, and has transformed the management of ALF.
• Several prognostic scoring systems have been devised to predict mortality and to identify those requiring early LT. These
include King’s College Hospital (KCH) criteria, pediatric end-stage liver disease (PELD) score, APACHE II, and Clichy
criteria.
• The KCH criteria is better performance than the Clichy criteria and is widely used. The KCH criteria have a higher specificity
than sensitivity for acetaminophen-induced ALF, while its negative predictive value for non-acetaminophen induced ALF is
low.
• Best available criteria for listing for LT
• INR >4 or factor V concentration of <25%
• Although INR and factor V concentration as prognostic markers are derived from small population studies, to date, they provide the
best available indicators predicting mortality without LT
• Acute fulminant Wilsons disease has a high mortality necessitating LT. Special prognostic score is available for children and
a score of 11 or more indicates high mortality, with 93% sensitivity and 98% specificity.
• Contraindications for pediatric LT are
1. Active uncontrollable and untreatable sepsis,
2. severe cardiopulmonary disease,
3. multi-organ failure,
4. extrahepatic malignancy,
5. mitochondrial disease,
6. active substance abuse, and
7. HE grade IV encephalopathy with severe neurological impairment.
Criteria for Liver transplantation
• O’Grady’s Criteria
• Paracetamol induced FHF
• PH < 7.3 (irrespective of grade of HE)
or
• PT > 100 sec
• Sr Creatinine > 300µmol/L (3.4mg/dl) in patients with grade 3 or 4 HE
• Non-paracetamol induced FHF
• PT > 100 sec
Or any 3 of the following (irrespective of the grade of HE)
• PT > 50 sec
• Age < 10 yrs
• Sr Bilirubin > 17.5mg%
• Aetiology – Non-A, Non-B hepatitis, idiosyncratic drug reaction
• Duration of jaundice > 7 days before onset of HE
Prognosis
• In more than 50% of children with ALF there is poor survival unless LT is offered at the appropriate time
• Spontaneous recovery can be expected only in 10-20% of patients with idiopathic forms of liver failure
• Prognostic factors predicting outcome in ALF include
• elevated serum bilirubin and prothrombin time,
• young age of the child,
• high arterial ammonia and high WBC count,
• low alanine aminotransferase, and
• presence of encephalopathy
• Increased AFP – indicates hepatocellular regeneration
• Age <1 yr, stage 4 HE, INR > 4, need for dialysis before liver transplantation – associated with increased mortality
• The outcome of ALF also varies with etiology. The prognosis is better with hepatitis A, acetaminophen
overdose and ischemia (approximately 60% spontaneous survival), and poor with drug-induced ALF (non-
acetaminophen), hepatitis B, and indeterminate cases (25% spontaneous survival).
• Pretransplant serum bilirubin concentration or the height of hepatic enzymes is not predictive of post-
transplant survival.
• Owing to the severity of their illness, the 6 mo post–liver transplantation survival of ~75% 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. A plastic anemia occurs in ~10% of children with the idiopathic form of
fulminant hepatic failure and is often fatal
Cause of Death
• Have hyporegenerative hepatocellular necrosis
• Death is most often d/t a complication of FHF or its therapy; Liver
failure per se is responsible only in a few cases
• Cerebral edema – m.c cause of death; Brainstem herniation is the
most common cause of death
• Causes of death
• Cerebral edema
• Overwhelming bacterial or fungal infection
• Respiratory failure
• Hemorrhagic diathesis
• Complications of liver transplantation