Nephrol Dial Transplant (2007) 22 [Suppl 8]: viii5–viii8
doi:10.1093/ndt/gfm650
Fulminant hepatic failure: etiology and indications
for liver transplantation
Daniel Gotthardt1, Carina Riediger1, Karl Heinz Weiss1, Jens Encke1, Peter Schemmer2,
Jan Schmidt2 and Peter Sauer1
1
Department of Internal Medicine IV, University Hospital of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg
and 2Department of Surgery, University Hospital of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
Abstract
Fulminant hepatic failure is characterized by the
development of severe liver injury with impaired
synthetic capacity and encephalopathy in patients
with previous normal liver or at least well compensated
liver disease. The etiology of fulminant hepatic failure
refers to a wide variety of causes, of which toxin-
induced or viral hepatitis are most common. In spite of
specific therapeutic options in distinctive etiologies,
orthotopic liver transplantation is the only therapy
proven to improve patient survival in the majority of
patients. The outcome is determined by the complica-
tions like severe coagulopathy, infections, renal
impairment or increased intracranial pressure. The
decision for transplantation depends on the possibility
of spontaneous hepatic recovery, which may be
estimated by several factors. The most important
variables for predicting the need of transplantation in
fulminant hepatic failure are the degree of encephalo-
pathy, patients age and the underlying cause of liver
failure.
Keywords: fulminant hepatic failure; liver
transplantation
Main Text
Overview
Fulminant hepatic failure (FHF) or acute liver failure
(ALF) is defined as the rapid development of acute
liver injury with severe impairment of the synthetic
function and hepatic encephalopathy in a patient
without obvious, previous liver disease. The time
interval of onset of symptoms like jaundice and the
Correspondence to: Daniel Gotthardt, Department of Internal
Medicine IV, University Hospital of Heidelberg,
Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
Email: Daniel_Gotthardt@med.uni-heidelberg.de
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appearance of encephalopathy led to several defini-
tions of FHF [1,2]. Although hyper acute, fulminant
and subfulminant hepatic failure may differ in their
clinical features, like the incidence of cerebral edema,
renal failure or portal hypertension, in clinical practice
the different sub-definitions were not generally
accepted [3].
FHF is not one of the major indications for
orthotopic liver transplantations (OLT), but remains
the only therapeutic option for patients, without
sufficient regeneration of hepatocytes proven to
improve survival. Before liver transplantation had
become a reasonable option survival rates of acute
liver failure were as low as 15%, but had achieved rates
of 60% up to 80% in different series in the last decade
[4]. Since the liver is capable of regenerating to a large
extent and in several cases the underlying cause of
hepatocyte injury may be removed or at least can be
controlled with supportive medical therapy, FHF in
principle may resolve in a complete recovery.
The decision for transplantation depends upon the
estimation of the probability of spontaneous recovery
and may be very difficult, weighing the advantages of
an early transplantation against the disadvantages of
an unnecessary transplantation with all consequences.
Therefore prognostic scores have been developed as
decision support systems for indication and optimal
time point of liver transplantation. Overall about 5 to
10% of annual liver transplantations are due to acute
liver failure. In the UNOS/OPTN registry, in 2004, 491
out of 5845 transplantations were due to FHF (8.4%)
[5]. In 2005 in the German registry 87 out of 1401
transplantations were reported to be associated with
FHF (6.2%) [6] (see Table 1).
Etiology of acute liver failure
Generally FHF is defined by reduced synthesis
parameters of the liver, usually INR
1.5 and reduced
detoxification resulting in any degree of encephalo-
pathy. This is accepted by the exclusion of preexisting
viii6 D. Gotthardt et al.
Table 1. Indications for Liver transplantations Table 2. Etiology of fulminant hepatic failure

UNOS/OPTN DSO OLT per Viral Hepatitis A,B,C,D,E, CMV HSV, EBV,
OLT per year (2004) year (2005) VZV, HHV 6, Parvo-virus B19,
Parainfluenza, Yellow Fever, and others
Total Percentage Total Percentage Idiosyncratic Halogenated hydrocarbons, Coumarins,
Methyldopa, Phenytoin, Carbamazepin,
Valproic acid, Rifampicin, Penicillin,
Non-cholestatic 3527 60.3 808 57.7
Sulfonamides, Chinolones, etc.
cirrhosis
Toxic Dose-dependent Acetaminophen (Paracetamol), Isoniazid,
Cholestatic liver 498 8.5 131 9.4
Tetracycline, Methotrexat, Carbon
disease/Cirrhosis
tetrachloride, Amphetamins, Amanita
FHF 491 8.4 87 6.2
phalloides-Toxin
Biliary atresia 187 3.2 30 2.1
Toxic synergistic Ethanol þ Acetaminophen, Barbiturate þ
Metabolic diseases 173 3.0 27 1.9
Acetaminophen, Isoniazid þ Rifampicin
Malignant Diseases 395 6.8 131 9.4
Metabolic M. Wilson, alpha-1-AT-deficiency,
Other 574 9.8 187 13.1
Galactosemia, Tyrosinemia, Reye-
Total 5845 100 1401 100
Syndrome, NASH
Associated with Acute fatty liver of pregnancy, HELLP-
Data from the UNOS database (2004) and data from the German
pregnancy Syndrome
registry (DSO 2005) were grouped to match classification [5,6].
Vascular Budd-Chiari-Syndrome, veno-occlusive
disease, shock, heart failure
Miscellaneous Autoimmune-hepatitis, malignant infiltra-
cirrhosis and a duration of a liver disease for less than

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26 weeks [1]. If FHF is due to autoimmune hepatitis,
Wilson’s disease, and vertically acquired HBV infec-
tion, the possibility of preexisting cirrhosis may be
neglected, if the disease has been known for less than
26 weeks [7]. FHF can result from a wide variety of
causes, but viral or toxin-induced hepatitis are the
most common (see Table 2).
Drug induced liver failure
One of the most common causes of FHF is a substance
that by itself is cytotoxic or after metabolizing is able
to trigger a cascade of cytotoxic and/or autoimmune
phenomena. The most important drug is acetamino-
phen not accounting only for the majority of drug
induced ALF, but also being the most common reason
for acute liver failure. In several cases the incidence of
acetaminophen induced FHF varies among geographic
regions, which mostly is due to the local incidence of
the different forms of viral hepatitis [4,8,9]. Mushroom
poisoning such as Amanita phalloides can cause
acute liver failure as well, which should be excluded
explicitly during initial evaluation of suspected
patients. These intoxications are often preceded by
severe gastrointestinal disease, like abdominal pain,
diarrhea and vomiting.
Viral hepatitis
Hepatitis B is probably the most common viral cause
of FHF and the incidence may be underestimated,
since precore or pre-S mutant viruses may escape by
routine serology [9]. The overall incidence varies widely
in different reports, again reflecting the overall
incidence of viral hepatitis in different geographic
regions. Since there is evidence, that new antiviral
treatment strategies against HBV may avoid fatal liver
failure, the reduced possibility of complete immune
response leading to elimination of HBV, led to an
ongoing controversy of the initiation of antiviral
tion, hyperthermia, sepsis
treatment [10]. Although hepatitis A is the most
common cause of acute viral hepatitis, a progression
to FHF is observed in rare cases. Hepatitis C virus
seems to be a cause of FHF only in a few cases. [4, 11].
Hepatitis E, which is more severe in pregnant women
and is endemic in specific areas can cause FHF, thus
travel history is important during initial presentation
[12,13]. Other viral infections leading to ALF and
requiring OLT have been described, e.g. Herpes Virus,
but are often caused by immunosuppressive treatment,
which was initiated before.
Vascular origin
The different blood supply related to the liver can be
involved in FHF. Budd-Chiari syndrome, hepatic vein
thrombosis, which is more common in females with
a medium age of 35 may lead to FHF. [14,15].
Portal vein thrombosis may be the reason for FHF,
but often is associated with cirrhosis of the liver or a
pancreatic process. Veno-occlusive disease i.e. in the
course of hematopoetic cell transplantation and
ischemic hepatitis due to reduced arterial perfusion
can also be a reason for FHF. Therefore abdominal
imaging including assessment of arterial, portal and
venous perfusion is strongly recommended
starting with ultrasound examination. In most cases
further imaging modalities like CT-scan or MRI are
required.
Wilson’s disease
A rare cause of acute liver failure is an acute
manifestation of Wilson’s disease (WD). It can occur
as FHF or as acute-on-chronic event. Together with
autoimmune hepatitis it is generally considered that
WD comply with the criteria of acute liver failure,
although in most cases a chronic disease is present,
Fulminant hepatic failure
which has not been recognized. Therefore a manifest
liver fibrosis or even cirrhosis is not considered to
be an exclusion criteria for listing as an acute
liver failure.
Rare causes of ALF
A number of metabolic related disorders other than
Wilson’s disease have been reported to be associated
with FHF including acute fatty liver of pregnancy and
Reye’s syndrome. In addition FHF has also been
reported in patients with autoimmune hepatitis,
sepsis or malignant infiltration of the liver. The
etiology of FHF can be determined in up to 80% of
cases [3], which is important since it may influence
treatment options and may help to determine the
prognosis and requirement of OLT.
Treatment options
The management of patients with FHF requires a
thorough infrastructure and understanding to deal
with the complications that may be present, including
renal failure, circulatory dysfunction, coagulopathy,
gastrointestinal bleeding, encephalopathy, cerebral
edema and metabolic disturbances like metabolic
acidosis and hypoglycemia. In the course of these
complexities, patients with FHF should be managed in
an intensive care unit and should be transferred as
soon as possible to centers with a liver transplant
program [16]. Liver transplantation remains the
main promising option of treatment of FHF.
However, depending on the etiology, specific therapies
may be used. For example, N-acetylcysteine can
significantly improve prognosis of patients with
acetaminophen intoxication [17]. Other interventions
may be helpful in other specific settings as: forced
diuresis, silibilin and activated charcoal in patients
with amanita phalloides poisoning. Due to the devel-
opment of new antiviral medication Hepatitis B virus
infection can be treated even in the acute phase [18].
Acyclovir may improve prognosis in patients with
herpes virus infection and FHF. Transjugular intrahe-
patic portosystemic stent shunt is the treatment of
choice in patients presenting with FHF due to acute
Budd-Chiari syndrome. Liver support systems that
substitute in part the functions including detoxification
and homeostasis of metabolism have been developed
and tested. The efficacy has been demonstrated in only
a small number of patients [19].
Prognostic scores and indication for orthotopic
liver transplantation
In patients with FHF, the decision to transplant
depends on the probability of spontaneous hepatic
recovery, which is variable and cannot be predicted
reliably. The most important factors for predicting
survival in FHF are the degree of encephalopathy,
the patient’s age, and the cause of FHF. As an
viii7
Table 3. King’s College Hospital criteria for liver transplantation in
fulminant hepatic failure
Acetaminophen-induced disease
 Arterial pH <7.3 (independent of the grade of encephalopathy)
OR
 Grade III or IV encephalopathy and
 Prothrombin time >100 s and
 Serum creatinine >3.4 mg/dL (301 mmol/l)
All other causes of fulminant hepatic failure
Prothrombin time >100 s (independent of the grade of
encephalopathy)
OR
Any three of the following variables (independent of the grade of
encephalopathy)
1. Age <10 years or >40 years
2. Etiology: non-A, non-B hepatitis, halothane hepatitis, idiosyn-
cratic drug reactions
3. Duration of jaundice before onset of encephalopathy >7 days
4. Prothrombin time >50 s
5. Serum bilirubin >18 mg/dl (308 mmol/l)
From [20].
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example, spontaneous recovery is more likely with
lower grades of encephalopathy [20], which is between
65 to 70 percent in patients with encephalopathy
grade I-II and is less than 20 percent in patients with
encephalopathy grade IV [20]. Patients older than 40 or
less than 10 years are less likely to show spontaneous
recovery compared to patients between these ages.
Patients with FHF due to acetaminophen intoxication,
hepatitis A, hepatitis B have a better prognosis
than those with idiosyncratic drug reactions or
Wilson’s disease [21]. Several other variables have
been used to predict the probability of recovery
but their predictive value have not been established
so far: the prothrombin time in addition with serum
bilirubin concentration and arterial pH [22], low serum
phosphate levels [23], high arterial ammonia levels [24].
Liver histology has not been shown to be reliable for
predicting recovery, and is not recommended routinely
in patients with FHF [25].
Statistical models have been developed for predict-
ing the outcome in patients with FHF [26–29].
The most commonly used scoring system are the
King’s College Hospital criteria (KCC) [20]. The model
was developed in a series of 588 patients with acute
liver failure who were managed without transplanta-
tion between 1973 and 1985 [20]. These criteria
discriminate between acetaminophen induced liver
failure and other etiologies (see Table 3). In acetami-
nophen-induced FHF, there are two important criteria
for indication to liver transplantation: an arterial
pH of less than 7.3, irrespective of grade of encephalo-
pathy; or a prothrombin time (PT) greater than
100 seconds and a serum creatinine concentration
greater than 3.4 mg/dL (301 mmol/L) in patients who
have grade III or IV encephalopathy. In other causes
of FHF, liver transplantation is indicated in patients
who have either a PT greater than 100 seconds,
irrespective of the grade of encephalopathy, or any
three of following variables: age less than 10 or greater
viii8
than 40, non-A, non-B hepatitis, idiosyncratic
drug reactions, duration of jaundice before develop-
ment of encephalopathy greater than seven days, PT
greater than 50 seconds, or serum bilirubin greater
than 18 mg/dL. The accuracy of the King’s College
Criteria has been evaluated in separate cohorts.
Although, relatively low negative predictive values
have been shown for these criteria no other scores have
been shown to be superior [30,31].
Summary
Fulminant hepatic failure is characterized by the rapid
development of severe liver injury with impaired
synthetic function and encephalopathy. Most
common, FHF is caused by toxin-induced or viral
hepatitis, but can result from a wide variety of causes.
The mainstay of therapy is orthotopic liver transplan-
tation. Therefore, patients with liver failure should be
transferred as soon as possible to a transplant center,
to ensure management of complications. The decision
for transplantation depends on the probability of
hepatic recovery, which is difficult to predict. The
most important factors, which in part are included in
the King’s College Criteria, for predicting the outcome
in FHF are the degree of encephalopathy, the patient’s
age, and the underlying cause of fulminant hepatic
failure.
Conflict of interest statement. None declared.
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