Etiology and Management of
Fulminant Hepatic Failure
Javier Vaquero, MD and Andres T. Blei, MD*
*Department of Medicine, Northwestern Feinberg Medical School and
VA Lakeside Medical Center, Searle 10-573, 303 East Chicago Avenue,
Chicago, IL 60611, USA.
Current Gastroenterology Reports 2003, 5:39–47
Current Science Inc. ISSN 1522-8037
Copyright © 2003 by Current Science Inc.
Fulminant hepatic failure (FHF) is a rare clinical syndrome
with an estimated incidence of 2000 cases per year in the
United States . For practical purposes, it is defined as the
appearance of hepatic encephalopathy in a patient with
acute deterioration of liver function and no previous his-
tory of liver disease. Viruses, drugs, toxins, and miscella-
neous conditions such as cardiovascular and metabolic
disorders are the main causes of FHF.
Orthotopic liver transplantation (OLT) is used increas-
ingly to salvage patients with FHF. Although medical man-
agement of FHF has improved, early prediction of which
patients need a liver transplant to survive is still the most
important task for the clinician. Between 10% and 30% of
patients on the waiting list for emergent OLT may recover
spontaneously. In contrast, approximately 25% of patients
in the United States die while awaiting an organ . These
facts have prompted the search for more accurate prognos-
tic criteria and for alternatives to OLT, including bioartifi-
cial liver-assist devices, auxiliary liver transplantation, and
Classifications and Definitions
Since the initial definition of FHF by Trey and Davidson
 30 years ago, several classifications have been pro-
posed. However, none of these systems has been
accepted universally, and overlap in terms and time inter-
vals among them is an obvious source of confusion
(Table 1). Hepatic encephalopathy is the hallmark of
FHF in all classifications and clearly marks the transition
from a severe condition to a deadly disease. In the differ-
ent classifications, the interval between the onset of
symptoms or jaundice and the appearance of encephal-
opathy allows grouping of patients with similar etiolo-
gies, clinical characteristics, and prognosis.
Viral hepatitis is the most common identifiable cause of
FHF worldwide, but the contribution of each etiologic
category to the total number of cases of FHF varies by
geographic region (Table 2). Thus, hepatitis B virus (HBV)
is a common cause of FHF in the Far East, and hepatitis E
virus (HEV) is relevant in India . Occurrence of FHF
within the larger number of patients with viral hepatitis,
however, is rare (0.2%–0.4% for hepatitis A, 1%–4% for
hepatitis B) .
Hepatitis A virus (HAV) is associated with a higher risk
of developing FHF if infection is acquired in older adult-
hood. Thus, vaccination is recommended for adults travel-
ing from developed countries to endemic areas. The
relevance of HAV as a cause of FHF in patients with preex-
isting chronic liver disease has been recognized recently,
and vaccination has also been suggested .
Acute HBV infection is diagnosed by detection of
IgM antibodies against hepatitis B core antigen
(HbcAg) because a substantial number of patients have
negative serum hepatitis B surface antigen (HBsAg) and
serum HBV-DNA. Low or absent levels of HBsAg and
HBV-DNA are associated with better prognosis and
lower rate of recurrence after OLT . The risk of
developing FHF after infection by precore mutants
remains controversial, with an increase reported by
some authors  but not by others . FHF follow-
ing reactivation of chronic hepatitis B has been
described mainly in male patients under diverse immu-
nosuppressant conditions; it usually has a subfulmi-
nant course and poor prognosis.
Fulminant hepatic failure (FHF) remains a rare but devastat-
ing disease. Viruses and drug-induced hepatotoxicity are
the most common causes of the syndrome, but the rele-
vance of each differs depending on the geographic area. In a
large proportion of patients no cause for FHF can be identi-
fied. Good intensive care is critical for patient survival.
Orthotopic liver transplantation (OLT) remains a definitive
therapeutic option. Prognostic indices have helped to opti-
mize patient selection and timing for performance of OLT.
However, the accuracy of these prognostic indices
decreases when they are applied to different populations,
probably because of regional differences in etiology and
peculiar native host factors. More accurate prognostic cri-
teria and new therapeutic alternatives to OLT are required.
Most studies indicate that hepatitis C virus (HCV)
infection alone does not result in FHF. However, isolated
cases of HCV-RNA in serum or tissue of patients with FHF
and negative markers for other viruses have been noted in
Western countries . Involvement of HCV in FHF is
slightly more common in the Far East . An increased
risk of FHF in patients with chronic hepatitis B and super-
infection by HCV has been suggested.
Coinfection with HBV and hepatitis D virus (HDV), or
superinfection by HDV in patients with chronic hepatitis B,
can also cause FHF. The incidence of such coinfection is
higher in studies in which intravenous drug abuse is a rele-
vant risk factor. Diagnosis of acute infection by HDV is
made by the presence of HDV antigen, anti-HDV IgM anti-
body, or HDV-RNA.
Infection by HEV is uncommon in Western countries
and is mainly diagnosed in travelers to endemic areas .
Pregnant women infected by HEV seem to have a special
propensity for developing FHF. Diagnosis is made by
detection of anti-HEV IgM antibodies.
Acetaminophen overdose accounts for more than
70% of FHF in the UK. It has also become the most com-
mon cause in the United States based on a recent series
, and its frequency is increasing in other Western
countries . Even doses considered nontoxic (< 4 g/d
in adults, < 8 mg/kg in infants) may cause hepatotoxicity
if other concurrent factors exist, such as alcohol inges-
tion, fasting, or malnutrition. Hepatotoxicity usually
develops 1 to 2 days after the overdose, with alanine ami-
notransferase levels and prothrombin time reaching their
peak around day 3. A continued increase of prothrombin
time after day 3 is associated with a 90% mortality rate.
Acetaminophen is also nephrotoxic, and renal failure
may occur in the absence of liver necrosis.
Other idiosyncratic drug reactions and toxins may
cause FHF. Isoniazid, pyrazinamide, antidepressants,
nonsteroidal anti-inflammatory drugs, and halothane
and its derivatives are most frequently implicated. Two
histologic patterns are usually distinguished, one charac-
terized by confluent necrosis (isoniazid or halothane)
and the other by hepatocyte microvesicular fatty change
(valproic acid or tetracyclines). Reemergence of tubercu-
losis in the last decade has increased the frequency of FHF
caused by isoniazid. Cotreatment with rifampin or
pyrazinamide may increase the risk. Mushroom poison-
ing is relatively common in Europe. Florid muscarinic
effects such as sweating or watery diarrhea occur early,
with FHF usually occurring 4 to 8 days after mushroom
ingestion. Other toxins (eg, carbon tetrachloride or yel-
low phosphorus) are rare causes of FHF.
Table 1. Different classifications of fulminant hepatic failure*
Trey and Davidson 
Fulminant hepatic failure: development of HE within 8 weeks of onset of symptoms
Acute liver failure (includes only patients with encephalopathy)
Subclassification depending on the interval between jaundice and HE
Hyperacute liver failure: 0 to 7 days
Acute liver failure: 8 to 28 days
Subacute liver failure: 29 to 72 days
Late-onset acute liver failure: 56 to 182 days
Acute hepatic failure: a rapidly developing impairment of liver function
Severe acute hepatic failure: prothrombin time or factor V concentration below 50% of normal with or without HE
Fulminant hepatic failure: HE within 2 weeks of onset of jaundice
Subfulminant hepatic failure: HE between 3 and 12 weeks of onset of jaundice
International Association for the Study of the Liver 
Acute liver failure (occurrence of HE within 4 weeks after onset of symptoms)
Acute liver failure—hyperacute: within 10 days
Acute liver failure—fulminant: 10 to 30 days
Acute liver failure—not otherwise specified
Subacute liver failure (development of ascites and/or HE from 5 to 24 weeks after onset of symptoms)
Subclassification by etiology
*A short interval between symptoms or jaundice and encephalopathy (most of acetaminophen-induced FHF and some of hepatitis A or B etiology) is
associated with the high risk of brain edema and greater possibility of spontaneous recovery, whereas a long interval is associated with less frequency
of brain edema, lower survival, and more common non–A-to-E cryptogenic etiology.
FHF—fulminant hepatic failure; HE—hepatic encephalopathy.
Etiology and Management of Fulminant Hepatic Failure • Vaquero and Blei
Table 2. Etiology of fulminant hepatic failure worldwide
Patients, n HBV, % HAV, % Other virus, % Acetaminophen, % Drug or toxin, % Miscellaneous, % Indeterminate, %
Detre et al. 
Detre et al. 
Dodson et al. 
Hoofnagle et al.
Schiodt et al. 
Castells et al.
Acharya et al.
* Only includes patients listed for emergent liver transplantation.
HAV—hepatitis A virus; HBV—hepatitis B virus; NR—not reported.
Miscellaneous cardiovascular, metabolic, and other
disorders account for 2% to 10% of cases of FHF. Acute
liver ischemia secondary to hypotension, arrhythmia, or
heart failure can result in hepatocyte necrosis, but the
prognosis is good if the primary condition can be cor-
rected. The prognosis is worse when other causes, such as
Budd-Chiari syndrome, veno-occlusive disease, or malig-
nancies, are responsible for the alteration of blood flow.
Sporadically, the first manifestation of Wilson’s disease is
FHF, but underlying cirrhosis is always present. Death is
the universal result without OLT. Acute fatty liver of preg-
nancy is rare, occurring in the third trimester of preg-
nancy, and responds well to fetal delivery. Other causes of
FHF are autoimmune hepatitis or Reye’s syndrome, the
latter less commonly seen in the pediatric population
once aspirin use was curtailed.
In a large group of patients (20%–50% in adults and
up to 70% in children), FHF is classified as indeterminate
despite intensive diagnostic efforts. Misdiagnosed hepatitis
B may explain some cases, given that HBV-DNA has been
found in serum and liver tissue of patients with FHF and
negative serologic markers of HBV infection . However,
this is not a common situation in other series, probably
reflecting geographic differences. Small case reports of FHF
caused by Varicella or Herpes simplex virus in pregnant
women, neonates, or immunosuppressed individuals, by
parvovirus B19 in children, or by togavirus-like particles,
explain another small proportion of cases. Although these
causes are rare, they must be ruled out because some
patients may benefit from specific therapies.
Management of Fulminant Hepatic Failure
Early referral to a transplant center is important. Patients
with slight alteration of mental state may deteriorate rap-
idly, leaving no time for alternatives. Patients should be
managed in a critical care unit for close surveillance of
Elucidation of the cause of hepatic failure allows some
patients to benefit from specific treatments and may influ-
ence posttransplant management if a transplant is per-
formed. N-acetylcysteine is used as specific antidote for
acetaminophen overdose. If it is given in the first 8 to 10
hours after overdose, it replenishes glutathione stores and
prevents the development of hepatotoxicity. The efficacy of
N-acetylcysteine declines progressively thereafter, but it
may be effective up to 72 hours after acetaminophen inges-
tion. It is used differently in Europe (intravenous, total
dose of 300 mg/kg in 20 hours) than in the United States
(oral, total dose of 1330 mg/kg in 72 hours). The poor oral
bioavailability of N-acetylcysteine explains the high doses
used in the United States. Because it is not well tolerated
orally and the intravenous formulation is not approved by
the US Food and Drug Administration (FDA), some US
practitioners have administered the oral formulation intra-
venously after adequate filtering.
In amanita intoxication, beneficial effects have been
reported with the use of penicillin G, silymarin, and forced
diuresis. Activated charcoal and cathartic agents may be
useful if they are given early after mushroom ingestion.
Hepatitis secondary to Herpesvirus may be misdiag-
nosed because of the lack of specificity of symptoms at pre-
sentation and the absence of typical mucocutaneous
lesions. If herpesvirus is suspected, treatment with acyclo-
vir or ganciclovir should be started.
As noted previously, acute fatty liver of pregnancy usu-
ally responds to fetal delivery. Urgent chemotherapy is
indicated for FHF caused by massive infiltration of the liver
by lymphoma. Acute Budd-Chiari syndrome may be ame-
nable to thrombolytic therapy or to transjugular intrahe-
patic portosystemic shunt placement.
Prevention and Management
Nutrition and metabolism
Glycemia must be controlled frequently (every 1–2 hours)
in patients with deep encephalopathy. Constant infusion
of 10% to 20% glucose is preferable to bolus administra-
tion for maintainance of euglycemia.
FHF is a catabolic state, and protein-caloric malnutri-
tion develops quickly. Thus, nutrition should be started
soon and adjusted individually to maintain an adequate
caloric intake. Enteral nutrition through a nasogastric or
nasojejunal tube is preferred to parenteral nutrition. Cor-
rection of hypomagnesemia, hypokalemia, or hypophos-
phatemia is accomplished by supplementation of these
substances. H2-receptor antagonists, proton-pump inhibi-
tors, or sucralfate are used to reduce the incidence of gas-
When evaluation of mental state is not possible, evolution
of coagulation parameters is the only way of assessing
improvement or worsening of liver function. Administra-
tion of fresh-frozen plasma does not increase survival and
may cause volume overload. Thus, correction of coagulop-
athy is not indicated unless bleeding occurs or invasive
procedures are to be performed. In those instances, 2 to 4
units of fresh-frozen plasma should be administered every
6 to 12 hours according to severity of coagulopathy and
transfusion of platelets, if the platelet count is below 50 ×
109/L. Recombinant activated factor VII offers advantages
of shorter half-life and avoidance of volume overload,
compared with fresh-frozen plasma, but reports are only
preliminary, and more studies are needed .
A high index of suspicion should be maintained concern-
ing infection in FHF. Fever and leukocytosis are absent in
Etiology and Management of Fulminant Hepatic Failure • Vaquero and Blei
up to 30% of infected patients. Infection must be suspected
in the presence of any sudden clinical or biochemical dete-
rioration, and even more so if liver function has started to
recover. Microbiologic cultures should be obtained from
different sites, and empiric antibiotics covering both gram-
negative and gram-positive bacteria should be started.
There are no generally accepted guidelines regard-
ing use of prophylactic antibiotics. Their use may be
supported by recent studies in which infection and pro-
gression to deep encephalopathy were correlated
[22••]. In the two studies that have compared prophy-
lactic antibiotics to placebo [23,24], the patients
treated with antibiotics had a lower rate of infection,
but there was no difference in survival. Both broad-
spectrum intravenous antibiotics and selective enteral
bacterial-fungal decontamination seem to be efficient
for decreasing the rate of infection. Selective enteral
decontamination, however, does not add any benefit if
the patient is already on intravenous antibiotics. Emer-
gence of meticillin-resistant Staphylococcus aureus and
vancomycin-resistant enterococci has caused great con-
cern in recent years.
Arrhythmia occurs frequently if electrolyte abnormalities
are not corrected promptly. A hyperdynamic circulation
is characteristic of FHF, with systemic and splanchnic
arterial vasodilation resulting in increased cardiac output
and decreased arterial pressure. Correction of these
abnormalities is difficult, especially in patients with
intracranial hypertension. Reposition of volume is
required to avoid or correct arterial hypotension, but
normalization of blood pressure is rarely achieved. Mon-
itoring of central venous pressure helps to guide the
amount of fluid to be infused (target, 8–12 mmHg). In
the presence of persistent hypotension or worsening
renal function, sepsis needs to be ruled out. Placement of
a pulmonary artery catheter can improve management in
these patients, though invasive procedures entail risk.
There is controversy over which volume expander is best,
but blood, colloids or albumin are usually preferred over
crystalloids. Isotonic or hypertonic, but not hypotonic,
sodium-containing solutions should be used if acute vol-
ume expansion is needed in patients at risk of brain
edema. Adrenaline or noradrenaline are the vasopressors
of choice, but caution should be exercised because they
may impair tissue oxygenation or produce an unwanted
increase of cerebral blood flow.
Intubation and mechanical ventilation are usually required
in patients with agitation or deep encephalopathy to avoid
surges of intracranial pressure and pulmonary aspiration.
Sedation must be maintained at the lowest possible level,
but some patients require additional sedation during nurs-
Frequent control of serum creatinine level, urinary output,
and urinary sodium concentrations is needed. Because of
the risk of infection, a urinary catheter should be used only
in patients with oliguria and should be removed in anuric
patients. Adequate volume repletion is essential to prevent
development of functional renal failure. Dopamine at
diuretic doses (2–4 µg/kg/h) has been used traditionally to
improve renal perfusion, but it is not efficacious. Diuretics
are not helpful and usually impair renal function. Poten-
tially nephrotoxic drugs, such as aminoglycosides, should
not be used in FHF. If dialysis is needed, continuous hemo-
filtration is preferred over intermittent hemodialysis to
avoid rapid fluid shifts that may aggravate brain edema.
Infection or any other precipitant factor must be identified
and treated. The efficacy of lactulose in FHF has not been
tested in clinical trials; it should be used with caution
because of the risk of hypernatremia and functional ileus.
Flumazenil (1 mg intravenously) may be useful if inges-
tion of benzodiazepines is suspected. Although monitor-
ing of mental state is very important for assessing
prognosis, sedation and intubation are usually required in
advanced stages of encephalopathy.
Brain edema and intracranial hypertension may develop
very quickly in patients with deep encephalopathy. An arte-
rial ammonia level higher than 200 µg/dL in stage III and
IV encephalopathy is a strong predictor of brain herniation
[25••]. Monitoring of intracranial pressure should be lim-
ited to specialized units and to patients awaiting OLT
because it has not been shown to increase survival. Intra-
cranial pressure should be maintained below 15 mm Hg,
and cerebral perfusion pressure over 50 mm Hg. Most cen-
ters prefer epidural to subdural or intraparenchymal trans-
ducers because of the lower rate of complications .
Monitoring of jugular bulb oxygen saturation with a
reversed jugular venous catheter can also guide interven-
tions to avoid intracranial hypertension. Decreased satura-
tions (< 55%) indicate cerebral ischemia, and high
saturations (< 85%) indicate either decreased metabolic
demands of the brain or cerebral hyperemia, more com-
monly the latter.
Current recommendations include maintaining the
patient’s head at a 20° angle to improve jugular venous
outflow. In episodes of intracranial hypertension, a bolus
of 0.5 to 1 g/kg of mannitol can be administered intrave-
nously and repeated until plasma osmolarity reaches 310
mOsm/L. Patients with oliguria and renal failure may
require hemodialysis to avoid hyperosmolarity. Hyperven-
tilation produces cerebral vasoconstriction and reduces
cerebral blood flow, but the effect is usually transient.
Finally, induction of barbiturate coma to decrease cerebral
metabolic activity may be useful as a last resort, but such
unwanted effects as myocardial depression or arterial
hypotension limit its use.
New therapies have been investigated. According to
recent reports, mild hypothermia reduced intracranial
pressure and cerebral blood flow and improved cere-
bral perfusion pressure both in patients with FHF [27•]
and in experimental models . Indomethacin also
reduced cerebral blood flow and prevented brain
edema in experimental models, and it has been used in
isolated cases in humans, with encouraging results
. In a recent controlled clinical trial, a prophylactic
infusion of phenytoin decreased the incidence of sub-
clinical seizure activity and appeared to prevent brain
edema . However, clinical experience with these
agents remains scarce, and their efficacy and safety
should be explored further.
Management of Liver Failure
Liver transplantation is the only measure that can radically
influence the course of FHF. However, it is an expensive
and high-risk procedure with considerable morbidity and
represents a commitment to indefinite immunosuppres-
sion. Moreover, patients transplanted for FHF have a worse
outcome than those transplanted for other causes in most
series, in part because of their poor clinical condition at the
time of the procedure.
Early identification of which patients would die if
OLT were not performed is thus a very important objec-
tive. Both the King’s College and the Clichy criteria are
used most often to identify such patients (Table 3).
However, some reports suggest that these criteria may be
suboptimal when applied to different countries [9,13].
Other prognostic parameters have been evaluated. Gc-
gammaglobulin levels are decreased in patients who do
not spontaneously survive, although these values over-
lap considerably with those of survivors. Liver volume
decreases with progression of the disease, and its mea-
surement with CT scanning may help to assess progno-
sis. Other proposed prognostic tools include the
proportion of necrosis in liver histology obtained by
transjugular venous biopsy, the amount of fresh-frozen
plasma to correct coagulopathy, or the determination of
somatosensory evoked potentials. Recently, high-serum
phosphate and blood lactate have been proposed as
markers of poor prognosis in patients with acetami-
nophen-induced FHF [33,34].
N-acetylcysteine is used in Europe to treat established FHF
of any cause, based on clinical reports from the King’s Col-
lege group. Benefits of N-acetylcysteine on survival, brain
edema, hemodynamics, oxygen delivery, and oxygen con-
sumption were found in patients with established FHF
; however, these effects were not confirmed by other
groups . Moreover, N-acetylcysteine had deleterious
effects in patients with critical illnesses other than FHF
. A randomized, controlled trial of N-acetylcysteine by
the US Acute Liver Failure Study Group in patients with
non-acetaminophen–induced FHF is currently underway
and should clarify these issues.
Preliminary reports of increased survival of patients
treated with prostaglandin-E1 in uncontrolled studies
were very encouraging, but no clear benefit supporting
the use of this agent has been found in subsequent con-
trolled trials .
Table 3. King’s College Hospital and Clichy liver transplantation criteria for fulminant hepatic failure
King’s College criteria 
FHF secondary to acetaminophen overdose
pH less than 7.30 (irrespective of encephalopathy grade), or
Hepatic encephalopathy grade III–IV, prothrombin time over 100 seconds (INR > 6.5), and serum creatinine over 300 µmol/
L (3.4 mg/dL).
FHF with other causes
Prothrombin time over 100 seconds (INR > 6.5) (irrespective of encephalopathy grade), or any three of the following
(irrespective of encephalopathy grade)
Age under 10 or over 40 years
Non-A, non-B hepatitis or drug-induced origin
Duration of jaundice before encephalopathy over 7 days
Serum bilirubin greater than 300 µmol/L (17.6 mg/dL)
Prothrombin time over 50 seconds (INR > 3.5)
Clichy criteria 
Presence of confusion or coma (stage III–IV HE)
Factor V level lower than 20% of normal in patients aged less than 30 years
Factor V level lower than 30% of normal in patients aged over 30 years
FHF—fulminant hepatic failure; HE—hepatic encephalopathy;
INR–international normalized ratio.
Etiology and Management of Fulminant Hepatic Failure • Vaquero and Blei
Artificial liver-assist devices
Several modalities of artificial liver support have shown a
benefit in FHF. Charcoal hemoperfusion consists of the
passage of plasma through columns of activated charcoal
or resins with the goal of clearing lipophilic toxins. Clin-
ical benefit was found in early reports, but randomized,
controlled trials failed to confirm such results .
High-volume plasmapheresis has been used extensively
in Copenhagen, and improvement of mental state, cor-
rection of hyperdynamic circulation, and lowering of
ammonia were reported . A few reports have also
noted beneficial hemodynamic effects and lowering of
ammonia levels with the Molecular Adsorbent Recircu-
lating System (MARS) . In this system, water-soluble
and albumin-bound toxins are cleared by dialysis of
blood against an albumin-containing dialysate. However,
no randomized clinical trials of the last two techniques
in FHF are available.
Bioartificial liver-assist devices
Several bioartificial liver-assist devices are currently under-
going clinical trials. Most of these devices use hollow-fiber
cartridges housing hepatocytes in the extraluminal space.
Blood or plasma is circulated through the hollow fibers,
allowing exchange of substances by diffusion between
plasma and hepatocytes. The cells used in these devices are
primary porcine hepatocytes (Bioartificial Liver Device
[BAL]) or human hepatoblastoma C3a line cells (Extra cor-
poreal Liver Assist Device [ELAD]).
The two systems with the most clinical experience are
the BAL (Circe Biomedical HepatAssist, Lexington, MA)
and the ELAD (Vitagen, San Diego, CA). In the ELAD,
whole blood is perfused through the hollow fibers of the
bioreactor. A controlled clinical trial of 24 patients
showed improvement in galactose elimination time,
encephalopathy, intracranial pressure, and hemodynam-
ics in the group treated with the ELAD, compared with
standard medical therapy, but no difference in survival
was noted . In the BAL system, plasma is separated
from blood and is circulated through a charcoal column
and then through the bioreactor. In several case reports,
significant improvements in blood glucose, serum
ammonia, and bilirubin levels; decrease of intracranial
pressure; increase of cerebral perfusion pressure; and
bridging to OLT were reported . An interim analysis
of the largest controlled clinical trial using a bioartificial
liver-assist device was presented at the annual meeting of
the American Association for the Study of Liver Diseases,
November 9–10, 2001 in Dallas, TX [44•]. One-hundred
and forty-seven patients with FHF and 24 with primary
graft nonfunction were randomly assigned to standard
medical treatment alone or to standard medical treat-
ment plus BAL. No significant differences were found in
the endpoint (30-day survival) between standard medi-
cal treatment and BAL (59% vs 70%, not significant),
except in patients with disease caused by acetaminophen
overdose (n=39; 37% vs 70%, P<0.05). The final results
of this trial are anxiously awaited.
The rationale behind hepatocyte transplantation is to
deliver a sufficient supply of hepatocytes to maintain liver
function until regeneration of native liver occurs or a graft
becomes available. Human hepatocytes from livers not
used for transplantation can be cryopreserved, making
them readily available if needed.
Experimental studies in models of FHF showed
engraftment and function of transplanted hepatocytes,
with increased survival. Hepatocyte transplantation has
also been performed on a few occasions in humans. Bilir
et al. [45•] reported engraftment of donor hepatocytes
in five patients with stage III and IV encephalopathy and
severe coagulopathy. In this and other reports from
small studies, improvements in encephalopathy score
and hemodynamics have been noted as well as
decreased serum ammonia and bilirubin levels [45•,46].
Pulmonary embolism of hepatocytes occurred in
patients in whom the injection was intraportal but not
in those with hepatocytes injected into the splenic artery
[45•]. Other concerns about this technique include
transplantation and acquisition of an adequate number
of hepatocytes (only 0.15–80 g have been injected com-
pared with 300 g [20% of normal liver mass required] to
replace liver function), use of immunosuppression in
FHF, and the need for a 48-hour period for engraftment
and function. Methods that reversibly immortalize
human hepatocytes are important to supply a sufficient
amount of hepatocytes for transplantation or for biore-
actors and to avoid the risks of tumorigenesis and
Auxiliary liver transplantation
Auxiliary liver transplantation involves transplantation of a
hepatic lobe from a living or cadaveric donor, leaving the
whole liver or part of the liver of the recipient in situ. In
auxiliary partial orthotopic liver transplantation (APOLT),
one hepatic lobe of the recipient is resected, and the auxil-
iary graft is placed in its original position. In heterotopic
auxiliary liver transplantation (HALT), the donor graft is
placed below the unresected liver of the recipient. A mini-
mum ratio of graft volume to recipient standard liver vol-
ume of 35% is necessary for the graft to support the
metabolic activity in FHF. In this potentially reversible con-
dition, auxiliary transplantation has the advantage of
allowing regeneration of the native liver, after which the
graft can be surgically removed or left to atrophy following
withdrawal of immunosuppression. Thus, auxiliary trans-
plantation may be especially valuable in young patients
and in those with potentially reversible causes of FHF (ie,
HAV, HBV, or drug-induced).
In studies reported in the past 3 years, 1-year survival
rates with auxiliary liver transplantation have been similar
to those for OLT [48,49]. However, incidence of portal vein
thrombosis and primary nonfunction are significantly
higher with auxiliary transplantation (more with HALT
than APOLT), reflecting the technical difficulties of these
procedures. Sixty-five percent of patients surviving auxil-
iary liver transplantation for 1 year without retransplanta-
tion were free of immunosuppression, according to a
recent report . On an intention-to-treat basis, however,
the efficacy of this procedure for full success (survival, liver
regeneration, and withdrawal of immunosuppression or
graft removal) is low, and reconsideration of the indica-
tions for this procedure may be needed in light of these
technical complications [50•].
FHF continues to be a major challenge for the clinician
because of its high mortality rate and the requirement for a
multidisciplinary approach. The geographic area in which
the patient has acquired the disease is an important con-
sideration, and efforts should be made to reach an etio-
logic diagnosis. Regional differences may influence the
application of prognostic indices as well. New prognostic
tools are needed to improve patient selection and timing
for performance of OLT. Although medical management of
liver failure has improved notably in the past decade and
more therapies targeting specific complications of the dis-
ease have been developed, only OLT radically alters the
course of the FHF. Promising experiences with artificial and
bioartificial liver-assist devices are encouraging. A reevalua-
tion of auxiliary partial liver transplantation is needed to
optimize the results with this procedure.
References and Recommended Reading
Papers of particular interest, published recently, have been
• Of importance
•• Of major importance
1. Hoofnagle JH, Carithers RL, Shapiro C, Ascher N: Fulminant
hepatic failure: summary of a workshop. Hepatology
McCashland TM, Shaw BW, Tape E: The American experience
with transplantation for acute liver failure. Semin Liver Dis
Trey C, Davidson CS: The management of fulminant hepatic
failure. Prog Liver Dis 1970, 3:282–298.
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