Dr. Arun Aggarwal Gastroenterologist: Acute Liver Failure

The Failing Liver…..
Do we have
Rich experience…
Dr. Arun Aggarwal Gastroenterologist,
M.D.
Pediatric GI Fellow
Westchester Medical Center
Dr. Arun aggarwal Gastroenterologist

• 2 yr old male c/o
– yellowish discoloration X 1 wk
– Vomiting X 2-3 days
• No h/o fever, rash, loose stools, medication
use
• No significant past medical or family history
• O/E: liver palpable 3 cm BCM, otherwise
unremarkable.

Hb, WBC and PLT

AST, ALT and Bilirubin

Liver biopsy
• Near diffuse marked hepatocellular ballooning
degeneration.
• Scattered hepatocyte apoptosis, ~ 15-20%.
• Mild to moderate lobulitis; lymphocytes and
neutrophils.
• Hepatocytic and canalicular cholestasis, mild.
• No stainable iron identified.
• No PAS+ diastase resistant granules identified.

Definition
• Acute onset of liver disease with no known evidence of chronic liver disease.
• Biochemical and/or clinical evidence of severe liver dysfunction:

– Hepatic based coagulopathy (PT ≥ 20 or INR ≥2) that is not corrected by Vit K
and/or
– Hepatic encephalopathy (if PT is 15-19.9 or INR is 1.5-1.9)
• The lack of preexisting liver disease: implies that recovery is possible if the patient
can be supported, the cause is eliminated and the liver retains its capacity to
regenerate.
Squires et al: Acute liver failure: the first 348 patients in the pediatric acute liver failure study group. J Pediatrics 2006; 148
(5):652-8

NOMENCLATURE
Dependent on J-E Interval
 Hepatic Failure
1. Acute- onset 8-28 days
2. Hyperacute- within 1st week
3. Subacute- 29 days -12 weeks
4. Fulminant- within 2 weeks
5. Subfulminant- 2 weeks –3mos
6. Late-onset- 8-24 weeks
1-3: O’Grady JG et al. Lancet 1993
4-6: Bernuau J et al. Hepatology 1986

Epidemiology
• Frequency of ALF in all age groups is ~10 to
20,000/year (~17 cases/ 100,000 population/
year).
• Frequency in the pediatric age group is
unknown.
• ALF accounts for 10-15% of pediatric liver
transplants performed in the USA annually.

Etiology

Causes of neonatal liver failure

Etiology in Neonates
Infections Herpes virus, Echovirus, Adenovirus,
Hepatitis B virus
Inborn errors of metabolism Galactosemia, Hereditary fructose

intolerance, Tyrosinemia
Immune mediated Neonatal hemochromatosis
Ischemia and abnormal perfusion Congenital heart disease, cardiac surgery,

myocarditis, severe asphyxia
Other Hemophagocytic syndrome

Etiology in Infants
Infectious Hepatitis A virus, Hepatitis B virus, NANB
hepatitis, Herpes virus
Drugs and toxins Valproate, Isoniazid, Acetaminophen,
Amanita
Inborn errors of metabolism Hereditary fructose intolerance, others
Immune mediated Macrophage activation syndrome,
hemophagocytic syndrome
Ischemia and abnormal perfusion Congenital heart disease, cardiac surgery,
myocarditis, severe asphyxia
Other malignancy

Etiology in 2-10 years
Infectious NANB hepatitis, Hepatitis A virus,
Hepatitis B virus, Herpes virus
Drugs and toxins Valproate, Isoniazid, Acetaminophen,
Amanita
Immune mediated Autoimmune hepatitis, macrophage
activation syndrome, hemophagocytic
syndrome
Ischemia and abnormal perfusion Budd chiari syndrome, Congenital heart
disease, cardiac surgery, myocarditis,
severe asphyxia
Metabolic Wilson disease
Other Malignancy, hyperthermia

Etiology in 10-18 years
Infectious NANB hepatitis, Hepatitis A virus,
Hepatitis B virus, Herpes virus
Drugs and toxins Acetaminophen overdose, Valproate,
Isoniazid, Amanita
Immune mediated Autoimmune hepatitis, macrophage
activation syndrome, hemophagocytic
syndrome
Ischemia and abnormal perfusion Budd chiari syndrome, Congenital heart
disease, cardiac surgery, myocarditis,
severe asphyxia
Metabolic Wilson disease, fatty liver of pregnancy
Other Malignancy, hyperthermia

Pediatric ALF
Cause Age less than 3 y (%) Age greater than 3 y (%) Total (%)
Acetaminophen 2 (2) 33 (24) 35 (15)
Indeterminate 55 (60) 63 (46) 118 (52)
Metabolic 15 (27) 8 (6) 23 (10)
Autoimmune 5 (5) 9 (7) 14 (6)
Drug and toxin 1 (1) 10 (7) 11 (5)
Infectious 4 (4) 3 (2) 7 (3)
Shock 2 (2) 5 (4) 7 (3)
Other 8 (9) 6(4) 14 (16)
*Bucuvalas J et al. Clin Liver Dis 2006

Pediatric ALF
*Lee WM et al, Hepatology 2008

Infective hepatitis
• Risk of developing ALF in acute Hepatitis A is 0.1-0.4%
• Incidence of ALF owing to Hepatitis B is 1-4%
• There is a theoretical risk of developing ALF after

Hepatitis C infection.
• Risk of developing ALF after Hepatitis E infection is 0.6-

2.8% (significantly higher in pregnant)
• Hepatic dysfunction in sepsis is the result of decreased

hepatic perfusion, hypoxia and lactic acidosis.

Drugs
• Most common (90%) liver injury pattern owing to drugs is
hepatocellular necrosis, others could be cholestatic (biliary
damage), mixed or steatosis.
• Valproate can unmask underlying mitochondrial cytopathies →

detailed investigation to exclude mitochondrial hepatopathies
should be undertaken.
• Acetaminophen → hepatocyte necrosis is caused by accumulation

of the N-acetylparabenzoquine amide.
• Serum acetaminophen levels after 4 hours of ingestion are useful in

identifying high-risk patients but are not informative in patients in
whom toxicity is secondary to chronic administration.

• children with autoimmune hepatitis presenting with ALF along with
encephalopathy do not respond to any form of immunosuppression and
need urgent liver transplant.
• Galactosemia is usually associated with hypoglycemia and gram-negative

septicemia.
• Tyrosinemia presents with severe coagulopathy, mild jaundice, and rickets.
• Neonatal hemochromatosis (NH) is a disorder of iron handling of antenatal

onset with excess iron deposition in the nonreticuloendothelial system.
• NH:
– elevation of ferritin as a diagnostic test is sensitive but not specific.
– Magnetic resonance imaging of the liver or pancreas to demonstrate iron is
not usually rewarding
– Documentation of iron in salivary glands in buccal mucosa is diagnostic of NH.

Pathology and Biochemistry
• Liver cell necrosis is characteristic of ALF resulting from viral
infections, most toxic injuries, ischemic injury, and some metabolic
diseases.
• Establishing a pathological diagnosis by liver biopsy has not been

considered critical in patient management, largely because of
associated risks.
• Aminotransferase values are not predictive of outcome.
• Rapidly falling aminotransferase values signify “exhaustion” of the

hepatocyte mass and indicate imminent ALF.

• Marked jaundice often accompanies hepatic necrosis.
• Rate of increase in bilirubin often exceeds than expected

with a normal rate of production and zero clearance.
– Increased production may result from catabolism of hepatic
heme proteins or from hemolysis.
• Initially, bilirubin is in conjugated form.
• Later, majority of bilirubin may be unconjugated (indicating

loss of conjugation ability and poor prognosis since only 1%
of normal conjugation is required to maintain bilirubin
concentration).

Pathogenesis
Exposure
• Immaturity of immune function may be the key reason

for susceptibility of newborns to herpes virus.
• Severity of injury in HBV infection may be related to

the vigor of the immune response.
• Individual biochemical polymorphism may play a role

in susceptibility to certain drug induced injuries.

Pathogenesis contd..
Hepatocyte injury
• Hepatocyte necrosis is prominent in a large proportion

of patients with ALF.
• Mechanism: virus either is directly cytopathic or

induces an immune response that injures the cell.
• General cellular dysfunction is apparent in many

metabolic disorders e.g. hereditary fructose
intolerance. (cell necrosis is limited)

Regeneration
• Liver cell necrosis → regeneration
• Several growth factors are mediators of

hepatic regeneration: epidermal growth
factor, transforming growth factor α, and
human hepatocyte growth factor.

Termination (three possibilities)
• Terminal hepatic failure.
• Spontaneous recovery.
• Overall process may become muted, slowed

down by events taking place in the host → may
result in chronicity e.g. Hepatitis B infection.

Clinical manifestations and
complications

Encephalopathy
• Earliest abnormalities (stage I) may not be detectable
by clinical assessment but are apparent to family
members.
– Personality changes.
– Regression of behavior
• In brain, urea cycle enzymes are absent; hence,

ammonia is cleared by the formation of glutamine by
enzyme glutamate synthetase.
• γ-Aminobutyric acid (GABA), a principal inhibitory

neurotransmitter in the brain, is increased in ALF.

Hepatic Encephalopathy

Physical Findings

Role of ammonia in HE

Clinical stages of hepatic
encephalopathy

• Blood ammonia concentration does not correlate with the
development or degree of hepatic encephalopathy (many
centers don't rely on repeated ammonia levels to follow the
course of encephalopathy).
• Not all children with elevated ammonia have

encephalopathy.
• Ammonia is of gut origin → makes it a target for treatment.
• Increased conc or availability of endogenous

benzodiazepines contribute to HE.

Intracranial hypertension and Cerebral
edema
• Brain death associated with cerebral edema is

the most frequent cause of death in most
series of ALF.

Intracranial hypertension and Cerebral
edema
• Phase 1:
– Episodic increase in ICP either spontaneously or in response to
stimuli involved in the routine care of the patient.
– An intact Cushing reflex at this stage can maintain cerebral
perfusion by increasing mean arterial pressure.
• Phase 2: MAP does not increase with further surges in ICP,

leading to neuronal hypoxic injury.
• Phase 3: poor cerebral perfusion either owing to very high

ICP or low mean arterial pressure, leading to hypoxic brain
injury.

Factors worsening ICP
• Hypotension
• Hypoxia
• Hypoglycemia
• Sepsis
• Electrolyte disturbances (hyperkalemia)
• Gastrointestinal bleeding .

Renal failure
• Incidence of renal failure is 10–15%
• Functional renal failure (hepatorenal syndrome) usually

progresses to tubular damage as the encephalopathy
advances.
• Avid sodium retention (urinary sodium < 20 mmol/L) and

normal urine sediment may help to differentiate between
functional renal failure and tubular damage.
• The hepatorenal syndrome recovers rapidly after liver

transplant, whereas established tubular damage requires
prolonged renal replacement therapy.

Metabolic derangements
• Hypoglycemia is present in 40% of patients with ALF. This is due to increased
plasma insulin levels owing to reduced hepatic uptake and reduced
gluconeogenesis.
• Metabolic acidosis is present in about 30% of patients with acetaminophen

induced ALF and is a bad prognostic marker.
• Hypokalemia is common and is due to excessive urinary potassium loss with

inadequate replacement.
• Hyponatremia may be dilutional owing to excessive antidiuretic hormone

secretion, or it may represent a true sodium-depleted state in patients who are
vomiting.
• Hypophosphatemia is most commonly associated with acetaminophen-induced

ALF when renal function is preserved.
• Other electrolyte disturbances include hypocalcemia and hypomagnesemia.

• Hemodynamic abnormality: hyperdynamic circulation.
• Cardiac arrhythmias: usually caused by electrolyte

disturbance.
• Pulmonary complications: aspiration of gastric contents,

atelectasis, infection, intrapulmonary hemorrhage,
respiratory depression, or pulmonary edema.
• Acute pancreatitis.
• Adrenal hyporesponsiveness.

Coagulopathy
• The liver synthesizes not only the coagulation factors (except factor VIII)
but also inhibitors of coagulation and factors involved in the fibrinolytic
system.
• ALF is characterized by decreased synthesis of clotting factors (factors II, V,

VII, IX, and X), accelerated fibrinolysis, and impaired hepatic clearance of
activated clotting factors and fibrin degradation products.
• Factors V and VII have the shortest half-lives of all of the coagulation
factors and are theoretically more sensitive markers than INR of hepatic
synthetic function.
• Thrombocytopenia may develop rapidly.
• Common sites of internal hemorrhage include the gastrointestinal tract,

nasopharynx, lungs, and retroperitoneum. Intracranial hemorrhage is
uncommon.

Infections
• Patients with ALF are at increased risk of bacterial infections because of poor host
defenses.
• The additional predisposing factors are poor respiratory effort and cough reflex
and the presence of an endotracheal tube, urinary catheters, and central venous
and arterial lines.
• An active uncontrolled infection can render potential candidates disqualified for

emergency liver transplant.
• More than two thirds of bacterial infections are due to gram-positive bacteria,
usually Staphylococcus aureus, but streptococci or gram negative organisms such
as coliforms are also isolated.
• Candida is the most common fungal infections.
• Deterioration of HE after initial improvement, a markedly raised leukocyte count,

pyrexia unresponsive to antibiotics, and established renal failure are strong
indicators of fungal infection.

Prognosis
• PT is the best indicator of survival.
• Factor V concentration has been used as a prognostic marker, especially in

association with encephalopathy (Clichy criteria).
• In children, a factor V concentration of less than 25% of normal suggests a

poor outcome.
• Liver biopsy is rarely helpful in ALF and is usually contraindicated because

of the presence of coagulopathy.
• Hepatic parenchymal necrosis of more than 50% is associated with a

reduced survival.
• A small liver or, more particularly, a rapidly shrinking liver is an indictor of

a poor prognosis.

Wilson’s disease index
A score of 11 or more indicates high mortality.

Indicators of poor prognosis in
Acetaminophen induced ALF

Indicators of poor prognosis in
Nonacetaminophen etiologies of ALF

Treatment

Diagnostic tests of the causes of ALF

Investigations in infants and children
with ALF

General measures

• Should be nursed in a quiet environment with as little
stimulation as possible to minimize acute increase in
the ICP.
• Monitoring of nonventilated ALF patients should

include the following:
– Continuous oxygen saturation monitoring
– 6-hourly urine output
– 6-hourly vital signs including blood pressure, neurologic
observations, and blood glucose estimation
– 12-hourly electrolyte and coagulation studies (INR)
– Daily full blood count along with surveillance blood and
urine cultures

• patients on assisted ventilation have an arterial line for invasive
blood pressure monitoring and frequent blood sampling.
• Blood gas analysis is performed every 4 hours, and electrolytes and

PT are measured every 8 hours.
• Hypoglycemia should be avoided by use of intravenous glucose

infusion or by ensuring adequate enteral intake.
• Total fluid intake is restricted to two-thirds maintenance if there is

no evidence of dehydration, with the idea of decreasing the
possibility of development of cerebral edema.
• Prophylactic broad-spectrum antibiotics and antifungals

significantly reduce the incidence of infective episodes.
• In neonatal liver failure, intravenous acyclovir should be

commenced.
• To maintain ammonia production at a minimum,
some protein (0.8-1g/kg) should be administered
parenterally to reduce catabolism.
• Antibiotics reduce ammonia absorption by

reducing bacterial urease and proteases
responsible for ammonia production in gut.
• Lactulose acts principally as a cathartic, but also

acidifies the colonic contents (trapping NH4+)
and qualitatively alters the bacterial flora.

• Many of the complications of ALF increase the
potential for ammonia accumulation and its
neurotoxicity:
– Prevent GI hemorrhage.
– Dehydration and electrolyte and acid base
disturbances should be corrected.
– Blood glucose conc should be maintained.

Management of specific
complications

Neurologic Complications
• Ammonia-lowering measures such as dietary
protein restriction, bowel decontamination, or
lactulose are of limited or no value in rapidly
advancing encephalopathy.
• The use of branched-chain amino acids,

flumazenil, and extracorporeal circuits has
only shown transient improvement in
encephalopathy.

• The aim of ICP monitoring is to maintain cerebral
perfusion pressure (mean arterial blood pressure
– ICP) at more than 50 mm Hg.
• If the cerebral perfusion pressure falls below 50

mm Hg, the adequacy of sedation and paralysis
should be checked, along with PaCO2 levels (in
ventilated patients, PaCO2 should be kept
between 4 and 4.5 kPa).
• If the PaCO2 is more than 4.5 kPa, then

hyperventilation may be helpful.

Pathway for the management of raised
ICP

• Mannitol remains the mainstay of treatment
for increased ICP because of its property as an
osmotic diuretic.
• A rapid bolus of 0.5 g/kg as a 20% solution

over a 15-minute period is recommended, and
the dose can be repeated if the serum
osmolarity is less than 320 mOsm/L.

• Studies have shown sodium thiopental to be an effective agent in
controlling mannitol-resistant cerebral edema.
• A bolus dose of 2 to 4 mg/kg over 15 minutes is followed by a slow

intravenous infusion of between 1 and 2 mg/kg/h.
• Major concerns are hemodynamic instability and increased

incidence of infective complications following its administration.
Forbes A, Alexander GJ, O’Grady JG, et al. Thiopental infusion in the

treatment of intracranial hypertension complicating fulminant hepatic
failure. Hepatology 1989;10:306–10.

• Hypothermia (core body temperature of 32°C)
has been shown to be effective in the
management of severe intracranial
hypertension with lowering of ICP and
improvement of cerebral perfusion pressure.
Jalan R, Damink SW, Deutz NE, et al. Moderate hypothermia for uncontrolled
intracranial hypertension in acute liver failure. Lancet 1999;354:1164–8.

• Presence and maintenance of hypernatremia
(serum Na >145mmol/L) significantly
decreases ICP and improve CPP in pediatric
traumatic brain injury.
Khanna et al. Use of hypertonic saline in the treatment of severe refractory posttraumatic
ICP in pediatric traumatic brain injury. Crit Care Med 2000; 28:1144-51

• Hepatectomy with a portacaval shunt has been
shown to stabilize the patients hemodynamically
with reduction of ICP up to 48 hours followed by
successful liver transplant.
• N-Acetylcysteine has been shown to increase the

cerebral blood flow and cerebral metabolic rate,
thereby improving the microcirculatory stability.
Ytrebo et al. NAC increases CPP in pigs with fulminant hepatic failure. Crit care Med 2001;
29:1989-95.

Infections
• Bacterial and fungal infections have been documented in about 82
and 34% of patients with ALF, respectively.
• About 60% of deaths in ALF have been attributed to sepsis.
• Prophylactic intravenous antibiotics have been shown to reduce the

incidence of culture-positive bacterial infection from 61.3 to 32.1%.
• The respiratory tract is the most common site (47%), followed by

the urinary tract (23%).
• Gram positive bacteria are the most common organism isolated in

about 70% of cases, 35% of these isolates being S. aureus.

Hemodynamic instability
• Despite the presence of edema, frequently these
patients have intravascular volume depletion and need
an appropriate combination of colloids, crystalloids, or
blood products.
• In the presence of persistent hypotension despite

normal filling, pressure vasopressors such as
noradrenaline and adrenaline are inotropic agents of
choice.
• NAC has been shown to improve the parameters of

oxygen metabolism.

Care pathway for the management of
hypotension

Coagulopathy
• The possible advantage of reduced bleeding by repletion of coagulation
factors with fresh frozen plasma has not been established by clinical
studies.
• Because coagulopathy is a very good tool for assessment of prognosis and

monitoring of disease progression, correction of coagulopathy is indicated
only if the patient is already listed for transplant or prior to an invasive
procedure such as insertion of a central line or ICP monitors.
• There has been a poor correlation between the severity of prolongation of

PT and bleeding tendencies, but associated thrombocytopenia is an
important risk factor for hemorrhage; hence, the platelet count should be
maintained above 50 × 109/dL.
• The most common site of bleeding is the GI tract. Prophylactic ranitidine

or PPI have been shown to decrease the incidence of gastric bleeding.

Types of liver assist devices

Liver transplantation
• ALF accounts for 5 to 7% of all liver transplants.
• Contraindications for liver transplant are fixed and dilated

pupils, uncontrolled sepsis, and severe respiratory failure
(ARDS).
• Relative contraindications are accelerating inotropic

requirements, infection under treatment, CPP of < 40 mm
Hg for more than 2 hours, and a history of progressive or
severe neurologic problems.
• After successful transplant, cerebral edema can persist for

12 hours, and cerebral autoregulation is restored within 48
hours.

Predictors of Poor Outcome
“King’s College Criteria”
Acetaminophen: Non-Acetaminophen:
 Arterial pH < 7.30  PT > 100sec
Or, all of the following: Or, any 3 of the following:

PT > 100sec (INR>6.5) NANB/DILI
creatinine > 3.4mg/dL J-E > 7d
gr 3/4 encephalopathy age < 10 or > 40y
PT > 50sec (INR>3.5)
bilirubin >17.4mg/dL

*O’Grady JG et al. Gastroenterology 1989
Prognostic Indicators
Acute Liver Failure
Sensitivity Specificity
INR ≥4 86 73
Bilirubin ≥13.7mg/dL 85 65
Age <2 yr 93 52
WBC >9 × 106/mL 89 71
 92% (33/36) children transplanted with ALF had two

or more parameters
 Mortality associated with degree of encephalopathy:
 Grade I-II - 44%
 Grade II-IV - 78%
Dr. Arun aggarwal Gastroenterologist *Dhawan A et al, Pediatric Transplantation 2004

Future Directions
• Auxillary liver transplantation
• Hepatocyte transplantation

Disease specific therapies

Survival: ALF vs CLF

Summary
 Rare but devastating disease process
 Most pediatric cases are indeterminate;
however clues exist
 No general proven therapy to promote liver
regeneration

Dr. Arun Aggarwal Gastroenterologist: Acute Liver Failure

Caricato da

Informazioni sul documento

Titolo originale

Copyright

Formati disponibili

Condividi questo documento

Condividi o incorpora il documento

Opzioni di condivisione

Hai trovato utile questo documento?

Questo contenuto è inappropriato?

Copyright:

Formati disponibili

Dr. Arun Aggarwal Gastroenterologist: Acute Liver Failure

Caricato da

Copyright:

Formati disponibili

The Failing Liver…..

Dr. Arun aggarwal Gastroenterologist

Dr. Arun aggarwal Gastroenterologist

Dr. Arun aggarwal Gastroenterologist

Dr. Arun aggarwal Gastroenterologist

Dr. Arun aggarwal Gastroenterologist

• Biochemical and/or clinical evidence of severe liver dysfunction:

Dr. Arun aggarwal Gastroenterologist

Dr. Arun aggarwal Gastroenterologist

Dr. Arun aggarwal Gastroenterologist

Dr. Arun aggarwal Gastroenterologist

Dr. Arun aggarwal Gastroenterologist

Inborn errors of metabolism Galactosemia, Hereditary fructose

Immune mediated Neonatal hemochromatosis

Ischemia and abnormal perfusion Congenital heart disease, cardiac surgery,

Other Hemophagocytic syndrome

Dr. Arun aggarwal Gastroenterologist

Dr. Arun aggarwal Gastroenterologist

Dr. Arun aggarwal Gastroenterologist

Dr. Arun aggarwal Gastroenterologist

Indeterminate 55 (60) 63 (46) 118 (52)

Metabolic 15 (27) 8 (6) 23 (10)

Autoimmune 5 (5) 9 (7) 14 (6)

Drug and toxin 1 (1) 10 (7) 11 (5)

Infectious 4 (4) 3 (2) 7 (3)

Shock 2 (2) 5 (4) 7 (3)

Other 8 (9) 6(4) 14 (16)

*Bucuvalas J et al. Clin Liver Dis 2006

*Lee WM et al, Hepatology 2008

• Incidence of ALF owing to Hepatitis B is 1-4%

• There is a theoretical risk of developing ALF after

• Risk of developing ALF after Hepatitis E infection is 0.6-

• Hepatic dysfunction in sepsis is the result of decreased

Dr. Arun aggarwal Gastroenterologist

• Valproate can unmask underlying mitochondrial cytopathies →

• Acetaminophen → hepatocyte necrosis is caused by accumulation

• Serum acetaminophen levels after 4 hours of ingestion are useful in

Dr. Arun aggarwal Gastroenterologist

• Galactosemia is usually associated with hypoglycemia and gram-negative

• Tyrosinemia presents with severe coagulopathy, mild jaundice, and rickets.

• Neonatal hemochromatosis (NH) is a disorder of iron handling of antenatal

Dr. Arun aggarwal Gastroenterologist

• Establishing a pathological diagnosis by liver biopsy has not been

• Aminotransferase values are not predictive of outcome.

• Rapidly falling aminotransferase values signify “exhaustion” of the

Dr. Arun aggarwal Gastroenterologist

• Rate of increase in bilirubin often exceeds than expected

• Initially, bilirubin is in conjugated form.

• Later, majority of bilirubin may be unconjugated (indicating

Dr. Arun aggarwal Gastroenterologist

• Immaturity of immune function may be the key reason

• Severity of injury in HBV infection may be related to

• Individual biochemical polymorphism may play a role

Dr. Arun aggarwal Gastroenterologist

• Hepatocyte necrosis is prominent in a large proportion

• Mechanism: virus either is directly cytopathic or

• General cellular dysfunction is apparent in many

Dr. Arun aggarwal Gastroenterologist

• Liver cell necrosis → regeneration

• Several growth factors are mediators of

Dr. Arun aggarwal Gastroenterologist

• Terminal hepatic failure.

• Overall process may become muted, slowed