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Acute Fulminant Hepatic Failure
Abstract
Acute liver failure (ALF) is a clinical syndrome characterized by
sudden loss of hepatocyte function due to a large spectrum of
etiologies in previously normal individuals. In India, acute viral
hepatitis is leading cause for ALF, with hepatitis E being the
most common followed by hepatitis B. In western countries,
drug induced hepatotoxicity, mostly due to acetaminophen
(paracetamol) overdose, is the leading cause of ALF. Sepsis and
cerebral edema with encephalopathy are two most common
complication of ALF leading to death. Sepsis occurs due to altered
immunity and loss of opsonic activity in serum. Cerebral edema
is caused by alteration in permeability of blood-brain barrier.ALF
carries grave prognosis with mortality rate varying from 30 – 40%
with intensive care and liver transplantation to around 70% in
countries like India, where facilities for liver transplantation are
limited. Early identification of etiology and institution of specific
therapy, if any, can be life saving in patients with acute liver failure.
Newer advances in form of temporary liver support systems hold
a bright promise in bridging the crisis period till recovery or liver
transplantation.
Introduction
ALF is defined by occurrence of coagulopathy (INR > 1.5) and
onset of encephalopathy with in 26 weeks of acute liver insult
due to any etiology, in absence of any pre-existing liver disease.
Patients with pre-existing Wilson disease, vertically-acquired HBV,
or autoimmune hepatitis may be included in this definition in
spite of the possibility of cirrhosis, if their disease has only been
recognized for <26 weeks.1,2 In children, signs and symptoms of
encephalopathy are slow to occur and are difficult to recognize,
leading to a growing consensus for defining ALF in children in
presence of severe coagulopathy (INR > 2) alone, in addition to
standard definition1. ALF has traditionally been sub-classified on
basis of duration of disease into hyperacute/fulminant (<7 days),
acute (7-21 days) and subacute (>21 days and <26 weeks) liver
failure. But, Indian as well as western studies have failed to show
any prognostic significance of this classification and its use is no
longer recommended2,3.
Epidemiology and etiology
In India, 90 – 95 % of cases are considered to be due to viral
hepatitis.3-5 Hepatotropic viruses constitute 42% to 85% of
Premashish Kar, Rajiv Singla, Delhi
cases, while patients with clinical presentation suggestive of viral
hepatitis but without any identifiable viral marker constitute 15
to 47 % of the cases in different studies.3-5 Hepatitis E remains
the leading etiology (23 – 41% of the cases).3-5 Acute hepatitis
B infection contributes significant number of ALF cases (1127%).3-5 Acetaminophen has been implicated in very few cases
in causation of ALF in India. On the other hand, acetaminophen
is single most common etiology responsible for ALF in western
countries (30-35% in USA and 60% of cases in Europe).1 Nonacetaminophen drug toxicity is next common etiology followed
by viral hepatitis. Females constitute more than half of the cases
worldwide, irrespective of etiology of ALF. In a study by Khuroo
and Kamili, ratio of male to female was 1:1.6 with higher prevalence
of females in HEV (79.7%) than those in the non-E group (47.5%).6
Twenty-five to 30 per cent of the women patients are pregnant,
whereas the frequency of pregnancy among women in the general
population at any time in India is 3%.3,5 The prevalence of HEV in
pregnant women with ALF was 95.8% as against 41.2% in nonpregnant women (P < 0.001).6
Outcome of acute liver failure remains dismal, especially in
developing countries like India due to limited availability of intensive
care units and liver transplantations. Most of the published studies
are from tertiary care centers having good intensive care facilities
but limited or no facilities for liver transplantation.These studies
report a mortality rate of 60-70%; which would be much higher
in population overall, as not all patients with ALF have access to
ICU care. In western countries, centers with facilities for liver
transplantation report, much lesser though still unacceptably
high, mortality rate of around 30-35%. Cerebral edema and sepsis
contributes towards majority of deaths. Respiratory failure and
renal failure also contributes significantly towards mortality in
patients with ALF. Coagulopathy, if identified and corrected timely,
do not lead to death per se.
King’s college hospital criteria (Table 1) and Ph < 7.30 are two
most commonly accepted and well validated prognostic criteria
for assessing survival in patients with ALF.2 Other factors which
have been evaluated, either alone or in various combinations,
include age, duration of disease, elevated serum creatinine,
encephalopathy grade, and prothrombin time elevation, decreased
Acute Fulminant Hepatic Failure
Table 1: King’s College Hospital Criteria for poor prognosis in Acute Liver Failure
and fungal sepsis is common in ALF and endotoxemia leads to
septic shock like state.
Acetaminophen-induced disease
Arterial pH <7.3 (irrespective of the grade of encephalopathy)
or
Grade III or IV encephalopathy, and
Prothrombin time >100 seconds, and
Serum creatinine >3.4mg/dl
All other causes of fulminant hepatic failure
Prothrombin time >100 seconds (irrespective of the grade of encephalopathy)
or
Any three of the following variables (irrespective of the grade of encephalopathy)
1. Age <10 years or >40 years
2.Etiology: non-A, non-B hepatitis, halothane hepatitis, idiosyncratic
drug reactions
3. Duration of jaundice before onset of encephalopathy >7 days
4.Prothrombin time >50 seconds
5. Serum bilirrubin >18 mg/dl
Acute hepatic failure, even in absence of infection, has been
postulated to be associated with adrenal insufficiency because of
its pathophysiological similarity with septic shock. In liver disease,
low levels of high density lipoproteins (HDL) have been postulated
to be responsible for decreased synthesis of cortisol, leading to
adrenal insufficiency. Some other factors, which are common to
liver disease and sepsis, contributing to adrenal insufficiency are
increased levels of endotoxin and proinflammatory cytokines,
which suppress corticotrophin releasing hormone and
adrenocorticotrophic hormone levels; inactivation of cortisol to
cortisone; and peripheral resistance to action of cortisol.
Management
factorV level, the Acute Physiology and Chronic Health Evaluation
(APACHE) II score and Gc globulin (vitamin D binding protein,
a liver-derived component of the actin-scavenging system). In a
study by Ostapowicz et al,ALF due to acetaminophen, hepatitis A,
shock liver, or pregnancy related disease showed >50% transplant
free survival, while all other etiologies showed <25% transplantfree survival.7 Other less validated factors include alfa-fetoprotein
levels, factor VIII, adrenal insufficiency and cytokine levels.
Pathogenesis of Acute Liver Failure
Acute liver failure is characterized by massive necrosis of
hepatocytes and hence loss of synthetic and metabolic functions.
Deficiency of clotting factors synthesized by liver, factors II, V,
VII, IX, and X, account for the prolonged prothrombin time
and partial-thromboplastin time observed.8 Hypoalbuminemia
contributes towards loss of intravascular volume and interstitial
edema. Impaired metabolism leads to accumulation of toxic
substances, including benzodiazepines-like substances, leading to
hepatic encephalopathy. Impaired gluconeogenesis and impaired
hepatic uptake of insulin leads to hypoglycemia.
Impaired regulation of cytokine regulation results in systemic proinflammatory state. Levels of tumor necrosis factor, prostaglandin
E2 and thromboxane are raised in patients with ALF.9 This proinflammatory state leads to subclinical intravascular coagulation
and low grade fibrinolysis resulting in thrombocytopenia and DIC
like state. Impaired vascular permeability leads to aggravation
of hypoalbuminemia, interstial edema and increased leakage of
cytokines in tissues resulting in enhanced oxygen demand with
resultant hypoxia at tissue level.All these factors results in cerebral
edema and decrease in intracranial cerebral perfusion pressure
and hence precipitate hepatic encephalopathy.
Initial evaluation of ALF has to very extensive to confirm the
diagnosis, ascertain etiology and institution of specific therapy,
establish prognosis and referral for liver transplantation, if
indicated and available.Any patient with clinical features suggestive
of acute hepatitis should immediately undergo evaluation for
altered mental status and prothrombin time. Prolongation of
prothrombin time with INR > 1.5 and slightest evidence of altered
sensorium establishes the diagnosis ofALF and admission becomes
mandatory.As ALF progresses very rapidly, rigorous monitoring of
mental status and early admission in ICU is highly recommended.
History should include ingestion of any drug especially
acetaminophen and possible exposure viral infection. Past history
for presence of predisposing factor for chronic liver disease
should be elicited. Physical examination must include any stigmata
of chronic liver disease. Inability to palpate the liver or even to
percuss a significant area of dullness over the liver can be indicative
of decreased liver volume due to massive hepatocyte loss.
An enlarged liver may be seen early in viral hepatitis or with
malignant infiltration, congestive heart failure, or acute BuddChiari syndrome.
Initial laboratory investigations include routine blood chemistries
including Prothrombin time/INR, serum electrolytes, glucose,AST,
ALT, alkaline phosphatase, total bilirubin, albumin, renal function
tests, arterial blood gas, complete blood count, blood type and
screen, pregnancy test (females) and ammonia levels(arterial if
possible). Other investigations to ascertain etiology consist of viral
hepatitis serologies (anti-HAV IgM, HBSAg, anti-HBc IgM, anti-HEV,
anti-HCV), acetaminophen level, toxicology screen, ceruloplasmin
level and autoimmune markers (ANA, ASMA, Immunoglobulin
levels), whenever indicated according to clinical features.
Therapy for ALF consist of general supportive measures, specific
therapies for some of the etiologies, liver transplantation and
other methods of temporary liver support.
General supportive ICU care (Table 2) includes management
of raised intracranial pressure, correction of coagulopathy,
prevention and aggressive treatment of infection, pulmonary and
Altered immunity, due to impaired cytokine metabolism, results
in loss of cell mediated as well as humoral immunity. Bacterial
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Medicine Update 2010  Vol. 20
Table 2: General supportive measures for Acute Liver
Failure
Table 3 : Specific therapies for Acute Liver Failure
Acetaminophen overdose: gener- • Activated charcoal, if presentation
ates the highly reactive intermewithin 4 hours of ingestion
diate, N-para-aminoquinonimine • Oral NAC (140 mg/kg by mouth or
(NAPQI).When glutathione is
nasogastric tube diluted to 5% soludepleted, NAPQI binds to cell
tion, followed by 70 mg//kg by mouth
proteins to yield cysteine adducts.
q 4 h X 17 doses)2
• If active gastrointestinal bleeding or
worsening mental status, intravenous
NAC (loading dose is 150 mg/kg in
5% dextrose over 15 minutes; maintenance dose is 50 mg/kg given over
4 hours followed by 100 mg/kg administered over 16 hours).2
Mushroom poisoning
• Silymarin 30-40 mg/kg/day
• Penicillin G 5-7 million unit/kg/day
Autoimmune Hepatitis
Prednisolone 40-60 mg/day
Acute fatty liver of pregnancy /
Early termination of pregnancy
HELLP syndrome
Acute hepatitis B
Role of antiviral treatment (lamivudine/
adefovir) unclear
Raised Intracranial pressure • Avoid sedatives
and Hepatic Encephalopathy • Early transfer to ICU
• Brain imaging to rule out other causes of
encephalopathy
• Lactulose: no survival benefit
• Mannitol, head elevation and intubation
for encephalopathy grade III/IV
• Short acting barbiturates for refractory
raised ICP
• Role of continuous ICP monitoring +/• Phenytoin for seizures
Coagulopathy
• Intravenous vitamin K
• Fresh frozen plasma, if active bleeding or
invasive procedure
Infection
Role of prophylactic antibiotics and anti
fungal not definitive; but are usually given at
most centers
GI bleeding
Prophylactic proton pump inhibitors
Hemodynamic/ Renal dys- • Adequate fluid replacement
function
• Central venous pressure monitoring for
fluid replacement
• Ionotropic support for hypotension;
vasopressin avoided
• If dialysis required, continuous mode
should be used
Others
Avoiding hypoglycemia, dyselectrolytemia
Table 4: Indications for liver transplantation in Acute
Liver Failure
United States of
America
renal dysfunction and reversal of metabolic derangements.
For raised ICP, apart from measures listed above, hypothermia,
hyperventilation and hypertonic saline have also been used less
commonly at some centers.2 Corticosteroids have also been used
but have failed to show any evidence of benefit. If an ICP monitor is
placed, key parameters to follow are both ICP and CPP. ICP
should be maintained below 20-25 mm Hg if possible, with CPP
maintained above 50-60 mm Hg. N-acetylcysteine, the standard
antidote for acetaminophen overdose,has recently been suggested
to be beneficial in other forms of ALF, possibly through its effects
on hemodynamics in multiorgan failure and its renal protective
actions.1
• Life expectancy without transplantation of <7 days
• Onset of hepatic encephalopathy within 8 weeks of
the first symptom of liver injury
• Age ≥18 years and at least one of the following
o ventilator dependence
o receiving renal replacement therapy
o international normalized ratio >2.0
United Kingdom Poor prognosis, as indicated by King’s College Hospital
Criteria for Liver Transplantation in Acute Liver Failure
Japan
At least two of the following five criteria are satisfied at
the time of onset of ≥ Grade II hepatic encephalopathy.
1. Age ≥ 45 years.
2.Interval from the appearance of the initial symptoms
to development of hepatic encephalopathy ≥ 11 days.
3.Prothrombin time < 10% of the standardized value.
4. Serum bilirubin concentration ≥ 18.0 mg/dL.
5.Ratio of the direct to total bilirubin concentration <
0.67.
in central perfusion pressure to < 40 mmHg.10
Specific therapies have to be instituted for acetaminophen
poisoning, autoimmune hepatitis and mushroom poisoning (Table
3).
Liver transplantation has improved the outcome of ALF.
Orthotopic liver transplant has traditionally been preferred
over living donor transplantation, because of time constraints for
evaluating donors and ethical concerns.But,living donor transplant
is being increasingly used to overcome donor organ shortage.
Indications for liver transplantation vary slightly in different
countries and are summarized in Table 4. Contraindication for
liver transplantation in ALF include extrahepatic malignancy, multisystem organ failure, irreversible brain damage, refractory raised
ICP with sustained elevation of ICP > 50 mmHg and a decrease
540
Liver support systems are used in patients who have contraindication
for liver transplantation or for whom liver tissue is not available.
Liver support systems can be non-biological detoxification systems
or they can be cell based systems. Cell based systems are more
complicated and costly, but have advantage of providing metabolic
as well as detoxification support. Emerging liver support therapies
include hepatocyte transplantation and liver tissue engineering on
2-D or 3-D synthetic extracellular matrix.1
Conclusion
ALF is a rapidly progressing and life threatening medical emergency.
ALF due to Acetaminophen, shock, and hepatitis A have more
Acute Fulminant Hepatic Failure
favorable outcome than other etiologies. Key to survival is early
institution of specific therapy and liver transplantation.
prognostic factors in hepatic failure in central India. Trop. Gastroenterol.
1996; 17: 217–20.
Facilities for intensive care and liver transplantation needs to
strengthened on urgent basis to improve outcome of ALF in India.
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Ostapowicz G, Fontana RJ, Schiodt FV, et al: Results of a prospective
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