AASLD POSITION PAPER
AASLD Position Paper: The Management of
Acute Liver Failure
Julie Polson and William M. Lee
recommendations used for full Practice Guidelines
Preamble
(Table 13). These recommendations are fully endorsed
These recommendations provide a data-supported ap-
by the AASLD.
proach. They are based on the following: (1) formal re-
view and analysis of recently-published world literature
Introduction
on the topic [Medline search], (2) American College of
Physicians Manual for Assessing Health Practices and De-
Acute liver failure (ALF) is a rare condition in which
signing Practice Guidelines,1 (3) guideline policies, in-
rapid deterioration of liver function results in altered
cluding the AASLD Policy on the Development and Use
mentation and coagulopathy in previously normal indi-
of Practice Guidelines and the AGA Policy Statement on
viduals. U.S. estimates are placed at approximately 2,000
Guidelines,2 (4) the experience of the authors in the spec-
cases per year.4 The most prominent causes include drug-
ified topic.
induced liver injury, viral hepatitis, autoimmune liver dis-
Intended for use by physicians, the recommenda-
ease and shock or hypoperfusion; many cases ( 20%)
tions in this document suggest preferred approaches to
have no discernible cause.5 Acute liver failure often affects
the diagnostic, therapeutic and preventive aspects of
young persons and carries a high morbidity and mortality.
care. They are intended to be flexible, in contrast to
Prior to transplantation, most series suggested less than
standards of care, which are inflexible policies to be
15% survival. Currently, overall short-term survival with
followed in every case. Specific recommendations are
transplantation is greater than 65%.5 Because of its rarity,
based on relevant published information. This docu-
ALF has been difficult to study in depth and very few
ment has been designated as a Position Paper, since the
controlled therapy trials have been performed. As a result,
topic contains more data based on expert opinion than
standards of intensive care for this condition have not
on randomized controlled trials and thus is not consid-
been established.
ered to have the emphasis and certainty of a Practice
Guideline. Nevertheless, it serves an important pur-
pose of facilitating proper and high level patient care Definition
and we have characterized the quality of evidence
The most widely accepted definition of ALF in-
supporting each recommendation, in accordance with
cludes evidence of coagulation abnormality, usually an
the Practice Guidelines Committee of the AASLD
INR 1.5, and any degree of mental alteration (en-
cephalopathy) in a patient without preexisting cirrho-
sis and with an illness of 26 weeks duration.6 Patients
Abbreviations: ALF, acute liver failure; NAC, N-acetylcysteine; HELLP, Hemo-
with Wilson disease, vertically-acquired HBV, or auto-
lysis, Elevated Liver Enzymes, Low Platelets syndrome; ICH, intracranial hyperten-
sion; ICP, intracranial pressure; CT, computerized tomography; US ALFSG,
immune hepatitis may be included in spite of the pos-
United States Acute Liver Failure Study Group; CPP, cerebral perfusion pressure;
sibility of cirrhosis if their disease has only been
MAP, mean arterial pressure; SIRS, systemic inflammatory response syndrome; FFP,
recognized for 26 weeks. A number of other terms
fresh frozen plasma; rFVIIa, recombinant activated factor; GI, gastrointestinal; H2,
histamine-2; PPI, proton pump inhibitors; CVVHD, continuous venovenous he- have been used including fulminant hepatic failure and
modialysis; APACHE, Acute Physiology and Chronic Health Evaluation; AFP,
fulminant hepatitis or necrosis. Acute liver failure is a
alpha fetoprotein; MELD, Model for End-stage Liver Disease.
better overall term that should encompass all durations
From the Division of Digestive and Liver Diseases, University of Texas South-
up to 26 weeks. Terms used signifying length of illness
western Medical School Department, Dallas, Texas.
Received March 9, 2005; accepted March 10, 2005.
such as hyperacute ( 7 days), acute (7-21 days) and
Address reprint requests to: Julie Polson, M.D., or William M. Lee, M.D.,
subacute ( 21 days and 26 weeks) are not particu-
University of Texas, Southwestern Medical School, Division of Digestive and Liver
larly helpful since they do not have prognostic signifi-
Diseases, 5323 Harry Hines Boulevard, Dallas, TX 75390-9151. E-mail:
julie.polson@utsouthwestern.edu or william.lee@utsouthwestern.edu.
cance distinct from the cause of the illness. For
Copyright © 2005 by the American Association for the Study of Liver Diseases.
example, hyperacute cases may have a better prognosis
Published online in Wiley InterScience (www.interscience.wiley.com).
but this is because most are due to acetaminophen
DOI 10.1002/hep.20703
Potential conflict of interest: Nothing to report. toxicity.5
1179
1180 POLSON AND LEE HEPATOLOGY, May 2005
Table 1. Quality of Evidence on Which a Recommendation
bodies (anti-nuclear and anti-smooth muscle antibodies)
Is Based3
and a pregnancy test in females. Plasma ammonia, pref-
Grade Definition erably arterial,7,8 may also be helpful. A liver biopsy, most
often done via the transjugular route because of coagu-
I Randomized controlled trials
II-1 Controlled trials without randomization lopathy, may be indicated when certain conditions such
II-2 Cohort or case-control analytic studies
as autoimmune hepatitis, metastatic liver disease, lym-
II-3 Multiple time series, dramatic uncontrolled experiments
phoma, or herpes simplex hepatitis are suspected. As the
III Opinions of respected authorities, descriptive epidemiology
evaluation continues, several important decisions must be
made: whether to admit the patient to an ICU, whether to
transfer the patient to a transplant facility, and (if already
Diagnosis and Initial Evaluation
at a transplant center) whether and when to place the
patient on the list for transplantation. For patients in a
All patients with clinical or laboratory evidence of
non-transplant center, the possibility of rapid progression
moderate to severe acute hepatitis should have immediate
of ALF makes early consultation with a transplant facility
measurement of prothrombin time and careful evaluation
critical. Specific prognostic indicators may point toward
for subtle alterations in mentation. If the prothrombin
the need for transplantation. For patients with acetamin-
time is prolonged by 4-6 seconds or more (INR 1.5)
ophen-related ALF in particular, an arterial pH of 7.3
and there is any evidence of altered sensorium, the diag-
should prompt immediate consideration for transfer to a
nosis of ALF is established and hospital admission is man-
transplant center and placement on a transplant list.9
datory. Since the condition may progress rapidly, with
Patients with altered mentation should generally be
changes in consciousness occurring hour-by-hour, early
admitted to an ICU. Planning for transfer to a transplant
transfer to the intensive care unit (ICU) is preferred once
center should begin in patients with grade I or II enceph-
the diagnosis of ALF is made.
alopathy (Table 2) because they may worsen rapidly.
History taking should include careful review of possi-
Early transfer is important as the risks involved with pa-
ble exposures to viral infection and drugs or other toxins.
tient transport may increase or even preclude transfer
If severe encephalopathy is present, the history may be
once stage III or IV encephalopathy develops. Evaluation
provided entirely by the family or may be unavailable. In
for transplantation should begin as early as possible. In
this setting, limited information is available, particularly
these critically ill patients with potential for rapid deteri-
regarding possible toxin/drug ingestions. Physical exami-
nation must include careful assessment and documenta-
tion of mental status and a search for stigmata of chronic
Table 2. Initial Laboratory Analysis
liver disease. Jaundice is often but not always seen at pre-
Prothrombin time/INR
sentation. Right upper quadrant tenderness is variably
Chemistries
present. Inability to palpate the liver or even to percuss a sodium, potassium, chloride, bicarbonate, calcium, magnesium, phosphate
glucose
significant area of dullness over the liver can be indicative
AST, ALT, alkaline phosphatase, GGT, total bilirubin, albumin
of decreased liver volume due to massive hepatocyte loss.
creatinine, blood urea nitrogen
An enlarged liver may be seen early in viral hepatitis or
Arterial blood gas
Arterial lactate
with malignant infiltration, congestive heart failure, or
Complete blood count
acute Budd-Chiari syndrome. History or signs of cirrhosis
Blood type and screen
should be absent as such features suggest underlying
Acetaminophen level
chronic liver disease, which may have different manage- Toxicology screen
Viral hepatitis serologies
ment implications. Furthermore, the prognostic criteria
anti-HAV IgM, HBSAg, anti-HBc IgM, anti-HEVż, anti-HCV*
mentioned below are not applicable to patients with
Ceruloplasmin Level#
acute-on-chronic liver disease. Pregnancy test (females)
Ammonia (arterial if possible)
Initial laboratory examination must be extensive in or-
Autoimmune markers
der to evaluate both the etiology and severity of ALF
ANA, ASMA, Immunoglobulin levels
(Table 2). In addition to coagulation parameters, early
HIV status!
Amylase and lipase
testing should include routine chemistries (especially glu-
cose as hypoglycemia may be present and require correc-
*Done to recognize potential underlying infection.
#Done only if Wilson disease is a consideration (e.g., in patients less than 40
tion), arterial blood gas measurements, complete blood
years without another obvious explanation for ALF); in this case uric acid level and
counts, blood typing, acetaminophen level and screens for
bilirubin to alkaline phosphatase ratio may be helpful as well.
other drugs and toxins, viral hepatitis serologies (most
! Implications for potential liver transplantation.
prominently A and B), tests for Wilson disease, autoanti- żIf clinically indicated.
HEPATOLOGY, Vol. 41, No. 5, 2005 POLSON AND LEE 1181
oration it is necessary to make treatment plans promptly. antidote for acetaminophen poisoning, has been shown to
Social and financial considerations are unavoidably tied to be effective and safe for this purpose in numerous con-
the overall clinical assessment where transplantation is trolled trials.15-18 The standard acetaminophen toxicity
contemplated. It is important to inform the patient s fam- nomogram19 may aid in determining the likelihood of
ily or other next of kin of the potentially poor prognosis serious liver damage, but cannot be used to exclude pos-
and to include them in the decision-making process. sible toxicity due to multiple doses over time, or altered
metabolism in the alcoholic or fasting patient.20 Given
these considerations, administration of NAC is recom-
Recommendations
mended in any case of ALF in which acetaminophen over-
1. Patients with ALF should be admitted and
dose is a suspected or possible cause. NAC should be given
monitored frequently, preferably in an ICU (III).
as early as possible, but may still be of value 48 hours or
2. Contact with a transplant center and plans to
more after ingestion.21 NAC may be given orally (140
transfer appropriate patients with ALF should be ini-
mg/kg by mouth or nasogastric tube diluted to 5% solu-
tiated early in the evaluation process (III).
tion, followed by 70 mg//kg by mouthq4h 17 doses)
3. The precise etiology of ALF should be sought to
and has few side effects (occasional nausea, vomiting, rare
guide further management decisions (III).
urticaria or bronchospasm). In patients with ALF oral
administration may often be precluded (for instance, by
Determining Etiologies and Specific
active gastrointestinal bleeding or worsening mental sta-
Therapies
tus), and NAC may be administered intravenously (load-
Etiology of ALF provides one of the best indicators of
ing dose is 150 mg/kg in 5% dextrose over 15 minutes;
prognosis,5 and also dictates specific management op- maintenance dose is 50 mg/kg given over 4 hours
tions.
followed by 100 mg/kg administered over 16 hours).
Allergic reactions may be successfully treated with discon-
tinuation, antihistamines22 and epinephrine for bronch-
Acetaminophen Hepatotoxicity
spasm.
Acetaminophen hepatotoxicity is suggested by historic
evidence for excessive ingestion either as an intended sui-
Recommendations
cidal overdose or the inadvertent use of supra-therapeutic
4. For patients with known or suspected acet-
quantities of pain medications. Acetaminophen is a dose-
aminophen overdose within 4 hours of presentation,
related toxin; most ingestions leading to ALF exceed 10
give activated charcoal just prior to starting NAC (I).
gm/day. However, severe liver injury can occur rarely
5. Begin NAC promptly in all patients where the
when doses as low as 3-4 gm/day are taken.10 Very high
quantity of acetaminophen ingested, serum drug level
aminotransferases may be seen; serum levels exceeding
or rising aminotransferases indicate impending or
3,500 IU/L are highly correlated with acetaminophen
evolving liver injury (II-1).
poisoning11 and should prompt consideration of this eti-
6. NAC may be used in cases of acute liver failure
ology even when historic evidence is lacking. Because
in which acetaminophen ingestion is possible or when
acetaminophen is the leading cause of ALF (at least in the
knowledge of circumstances surrounding admission is
United States and Europe) and there is an available anti-
inadequate (III).
dote, acetaminophen levels should be drawn in all pa-
tients presenting with ALF. Low or absent
acetaminophen levels do not rule out acetaminophen poi- Mushroom Poisoning
soning since the time of ingestion may be remote or un- Mushroom Poisoning (usually Amanita phalloides)
known, especially when overdose may have been may cause ALF, and the initial history should always in-
unintentional and/or occurred over several days. If acet- clude inquiry concerning recent mushroom ingestion.
aminophen ingestion is known or suspected to have oc- There is no available blood test to confirm the presence of
curred within a few hours of presentation, activated these toxins, but this diagnosis should be suspected in
charcoal may be useful for gastrointestinal decontamina- patients with a history of severe gastrointestinal symp-
tion. While it is most effective if given within one hour of toms (nausea, vomiting, diarrhea, abdominal cramping),
ingestion,12 it may be of benefit as long as 3 to 4 hours which occur within hours to a day of ingestion. If these
after ingestion.13 Administration of activated charcoal effects are present, it may be early enough to treat patients
(standard dose 1g/kg orally, in a slurry) just prior to ad- with gastric lavage and activated charcoal via naso-gastric
ministration of N-acetylcysteine does not reduce the ef- tube. Fluid resuscitation is also important. Traditionally,
fect of N-acetylcysteine.13 N-acetylcysteine (NAC), the very low rates of survival have been reported without
1182 POLSON AND LEE HEPATOLOGY, May 2005
Table 3. Some Drugs Which May Cause Idiosyncratic Liver
transplantation,23 but more recently complete recovery
Injury Leading to ALF
has been described with supportive care and medical
treatment.24 Penicillin G and silibinin (silymarin or milk Isoniazid Isoflurane
Sufonamides Lisinopril
thistle) are the accepted antidotes despite no controlled
Phenytoin Nicotinic acid
trials proving their efficacy.23,25,26 While some reports
Statins Imipramine
have not found penicillin G to be helpful,27 enough effi- Propylthiouracil Gemtuzumab
Halothane Amphetamines/Ecstasy
cacy has been reported to warrant consideration of the
Disulfiram Labetalol
drug (given intravenously in doses of 300,000 to 1 million
Valproic acid Etoposide
units/kg/day) in patients with known or suspected mush-
Amiodarone Flutamide
Dapsone Tolcapone
room poisoning.28 Silibinin has generally been reported
Herbals* Quetiapine
to be more successful than penicillin G, although penicil-
Didanosine Nefazodone
lin G has been used more frequently in the United
Efavirenz Allopurinol
States.27,28 Silibinin/silymarin is not available as a licensed Metformin Methyldopa
Ofloxacin Ketoconazole
drug in the United States, although it is widely available in
PZA
Europe and South America. In the United States, it is
Troglitazone
commercially available as milk thistle extracts, tablets,
Diclofenac
capsules or tincture. These products usually contain
Combination agents with enhanced toxicity:
70%-80% silymarin, although there is no governmental
Trimethoprim-sulfamethoxazole
regulation of such herbal supplements; silymarin concen- Rifampin-isoniazid
Amoxicillin-clavulanate
trations may vary considerably between preparations and
*Some Herbal products/dietary supplements that have been associated with
manufacturers.29 When used for treatment of mushroom
hepatotoxicity include:
poisoning, silymarin has been given in average doses of
Kava kava Chaparral
30-40 mg/kg/day (either intravenously or orally) for an
Skullcap Germander
average duration of 3 to 4 days.26 N-acetylcysteine is often Pennyroyal Jin Bu Huan
Heliotrope Rattleweed
combined with these other therapies, but has not been
Comfrey Sunnhemp
shown to be effective in animal studies30; nevertheless,
Senecio Impila
case reports have described its use as a part of overall
Greater celandine Gum Thistle
He Shon Wu Ma Huang
management.31
LipoKinetix Bai-Fang herbs
Recommendation
7. In ALF patients with known or suspected
mushroom poisoning, consider administration of pen-
tory. There are no specific antidotes for idiosyncratic drug
icillin G and silymarin (III).
reactions; corticosteroids are not indicated unless a drug
8. Patients with acute liver failure secondary to
hypersensitivity reaction is suspected. Determination of a
mushroom poisoning should be listed for transplanta-
particular medication as the cause of ALF is a diagnosis of
tion, as this procedure is often the only lifesaving
exclusion. Other causes of ALF should still be ruled out
option (III).
even if a drug is suspected. Any presumed or possible
offending agent should be stopped immediately where
Drug Induced Hepatotoxicity
possible. Classes of drugs commonly implicated include
A variety of medications have been associated with
antibiotics, non-steroidal anti-inflammatory agents and
acute liver injury. Before implicating a particular sub- anti-convulsants (Table 3).
stance, history should include careful listing of all agents
taken, the time period involved, and the quantity in- Recommendations
gested. Drugs other than acetaminophen rarely cause 9. Obtain details (including onset of ingestion,
dose-related toxicity. Most examples of idiosyncratic drug amount and timing of last dose) concerning all pre-
hepatotoxicity occur within the first 6 months after drug scription and non-prescription drugs, herbs and di-
initiation. A potentially hepatotoxic medication that has etary supplements taken over the past year (III).
been used continually for more than 1 to 2 years is un- 10. Determine ingredients of non-prescription
likely to cause de novo liver damage. Certain herbal prep- medications whenever possible (III).
arations and other nutritional supplements have been 11. In the setting of acute liver failure due to
found to cause liver injury,32 so inquiry about such sub- possible drug hepatotoxicity, discontinue all but essen-
stances should be included in a complete medication his- tial medications (III).
HEPATOLOGY, Vol. 41, No. 5, 2005 POLSON AND LEE 1183
Viral Hepatitis Wilson disease
Hepatitis serological testing should be done for identi- Wilson disease is an uncommon cause of ALF (2%-3%
fication of acute viral infection (Table 2) even when an- of cases in the US ALFSG). Early identification is critical
other putative etiology is identified. Viral hepatitis has
because the fulminant presentation of Wilson disease is
become a relatively infrequent cause of ALF (United
considered to be uniformly fatal without transplantation.
States: 12%; hepatitis B  8%, hepatitis A  4%).5 Acute
The disease typically occurs in young patients, accompa-
hepatitis D may occasionally be diagnosed in a hepatitis B
nied by the abrupt onset of hemolytic anemia with serum
positive individual. Although controversial, hepatitis C
bilirubin levels 20 mg/dL. Due to the presence of he-
alone does not appear to cause ALF.5,33 Hepatitis E is a
molysis, the indirect-reacting bilirubin is often markedly
significant cause of liver failure in countries where it is
elevated along with the total bilirubin. Kayser-Fleischer
endemic, and tends to be more severe in pregnant
rings are present in about 50% of patients presenting with
women.33,34 This virus should be considered in anyone
ALF due to Wilson disease.40 Serum ceruloplasmin is typ-
with recent travel to an endemic area such as Russia, Pa-
ically low, but may be normal in up to 15% of cases and is
kistan, Mexico, or India. With acute viral hepatitis, as
often reduced in other forms of ALF; high serum and
with many other etiologies of ALF, care is mainly support-
urinary copper levels as well as hepatic copper measure-
ive. Of note, the nucleoside analog lamivudine (and pos-
ment may confirm the diagnosis. Very low serum alkaline
sibly adefovir), used widely in the treatment of chronic
phosphatase or uric acid levels are hints to suggest Wilson
hepatitis B, may be considered in patients with acute hep-
disease in the absence of other indicators. A high bilirubin
atitis B, although these drugs have not been subjected to a
(mg/dL) to alkaline phosphatase (IU/L) ratio ( 2.0) is a
controlled trial35 in acute disease. Acute liver failure due
reliable albeit indirect indicator of Wilson disease in this
to reactivation of hepatitis B may occur in the setting of
setting.40,41 Renal function is often impaired as the re-
chemotherapy or immunosuppression. Recent evidence
leased copper can cause renal tubular damage. Treatment
suggests that patients found to be positive for HBsAg who
to acutely lower serum copper and to limit further hemo-
are to begin such therapy should be treated prophylacti-
lysis should include albumin dialysis, continuous hemo-
cally with a nucleoside analog, and that such treatment
filtration, plasmapheresis or plasma exchange. Initiation
should be continued for 6 months after completion of
immunosuppressive therapy (please refer to the AASLD of treatment with penicillamine is not recommended in
Practice Guideline on Management of Chronic Hepatitis ALF as there is a risk of hypersensitivity to this agent;
B, Update of Recommendations36). Herpes virus infec- acute lowering of the copper is more effectively accom-
tion rarely causes ALF. Immunosuppressed patients or
plished using direct plasma copper reduction techniques,
pregnant women (usually in the third trimester) are at
especially when renal function is impaired.40 Although
increased risk, but occurrences of herpes virus ALF have
such copper lowering measures should be considered, re-
been reported in healthy individuals.33,37,38 Skin lesions
covery is infrequent without transplantation.40,42 Wilson
are present in only about 50% of cases. Liver biopsy is
disease is one of the special circumstances in which pa-
helpful in making the diagnosis. Treatment should be
tients may already have evidence of cirrhosis and still be
initiated with acyclovir for suspected or documented
considered to have a diagnosis of ALF when rapid deteri-
cases.37,38 Other viruses such as varicella zoster39 have oc-
oration occurs. Please refer to the AASLD Practice Guide-
casionally been implicated in causing hepatic failure.
line on Wilson Disease for more detailed information
regarding the diagnosis and management of patients with
Recommendations
this condition.40
12. Viral hepatitis A- and B- (and E-) related acute
liver failure must be treated with supportive care as
Recommendations
no virus-specific treatment has been proven effective
15. Diagnostic tests for Wilson disease should
(III).
include ceruloplasmin, serum and urinary copper
13. Nucleoside analogs should be given prior to
levels, total bilirubin/alkaline phosphatase ratio,
and continued for 6 months after completion of che-
slit lamp examination for Kayser-Fleischer rings,
motherapy in patients with Hepatitis B surface anti-
and hepatic copper levels when liver biopsy is fea-
gen positivity to prevent reactivation/acute flare of
sible (III).
disease (III).
16. Patients in whom Wilson disease is the likely
14. Patients with known or suspected herpes virus
or varicella zoster as the cause of acute liver failure cause of acute liver failure must be immediately
should be treated with acyclovir (III). placed on the liver transplant list (III).
1184 POLSON AND LEE HEPATOLOGY, May 2005
Autoimmune hepatitis appears to increase the risk of ALF due to herpes virus,
With autoimmune hepatitis as with Wilson disease, which should be treated with acyclovir (see section on
patients may have unrecognized preexisting chronic dis- acute viral infection).37 It is important to keep in mind
ease and yet still be considered as having ALF. Such pa- that ALF in pregnant women may also be caused by en-
tients represent the most severe form of the disease, and tities not necessarily related to the pregnant state.
would generally fall into the category of patients recom-
mended for corticosteroid therapy as outlined by the
Recommendation
AASLD Practice Guidelines for the Diagnosis and Treat-
20. For acute fatty liver of pregnancy or the
ment of Autoimmune Hepatitis (although ALF is not
HELLP syndrome, consultation with obstetrical ser-
specifically discussed in that document).43 Although some
vices and expeditious delivery are recommended (III).
patients may be responsive to steroid therapy, others re-
quire transplantation.44,45 Autoantibodies may be absent
Acute Ischemic Injury
making a definitive diagnosis difficult. Liver biopsy may
A syndrome often referred to as  shock liver occurs
be helpful if findings include presence of severe hepatic
after cardiac arrest, a period of significant hypovolemia/
necrosis accompanied by interface hepatitis, plasma cell
hypotension, or in the setting of severe congestive heart
infiltration and hepatocyte rosettes. Initiation of steroid
failure.51 Documented hypotension is not always found.
therapy may constitute a therapeutic trial for some pa-
Drug-induced hypotension or hypoperfusion may be ob-
tients (prednisone starting at 40-60 mg/day),43 although
served with long-acting niacin,52 or with cocaine,53 or
placement on the transplant list is indicated.
methamphetamine.54 Other physical findings may be
lacking, but evidence of cardiac dysfunction may be elic-
Recommendations
ited via echocardiogram.55 Aminotransferase levels will be
17. When autoimmune hepatitis is suspected as the
markedly elevated and respond rapidly to stabilization of
cause of acute liver failure, liver biopsy should be
the circulatory problem. Simultaneous onset of renal dys-
considered to establish this diagnosis (III).
function and muscle necrosis may be noted. The ability to
18. Patients with acute liver failure due to auto-
manage heart failure or other causes of ischemia success-
immune hepatitis should be treated with corticoste-
fully will determine outcome for these patients, and trans-
roids (prednisone, 40-60 mg/day) (I).
plantation is seldom indicated.
19. Patients should be placed on the list for trans-
plantation even while corticosteroids are being ad-
Recommendation
ministered (III).
21. In ALF patients with evidence of ischemic in-
jury cardiovascular support is the treatment of choice
Acute Fatty Liver of Pregnancy/HELLP (Hemolysis,
(III).
Elevated Liver Enzymes, Low Platelets) Syndrome
A small number of women near the end of pregnancy
Budd-Chiari Syndrome
will develop rapidly progressive hepatocyte failure that
The Budd-Chiari syndrome (acute hepatic vein
has been well characterized46-49 and associated with in-
thrombosis) can also present as ALF. Abdominal pain,
creased fetal or maternal mortality. A variety of presenta-
ascites and striking hepatomegaly are often present. The
tions may be seen, generally confined to the last trimester.
diagnosis should be confirmed with hepatic imaging stud-
The triad of jaundice, coagulopathy, and low platelets
ies (computed tomography, doppler ultrasonography,
may occasionally be associated with hypoglycemia. Fea-
venography, magnetic resonance venography). In the
tures of pre-eclampsia such as hypertension and protein-
presence of significant liver failure, transplantation may
uria are common. Steatosis documented by imaging
be required as opposed to venous decompression.56 As
studies supports the diagnosis. The Oil-red O staining
malignancy-associated hypercoagulability is one of the
technique best demonstrates hepatic steatosis on biopsy.
causes of Budd-Chiari syndrome, it is important to rule
Intrahepatic hemorrhage and/or hepatic rupture consti-
out underlying cancer prior to transplantation of these
tute rare emergent situations requiring rapid resuscitation
patients.
and intervention. Early recognition of these syndromes
and prompt delivery are critical in achieving good out-
comes. Recovery is typically rapid after delivery, and sup- Recommendation
portive care is the only other treatment required. Post- 22. Hepatic vein thrombosis with hepatic failure is
partum transplantation has occasionally been necessary, an indication for liver transplantation, provided un-
however.50 Pregnancy (especially in the third trimester) derlying malignancy is excluded (II-3).
HEPATOLOGY, Vol. 41, No. 5, 2005 POLSON AND LEE 1185
Malignant Infiltration of intravenous NAC versus placebo for non-acetamino-
Malignant infiltration of the liver may cause ALF. phen ALF is currently under way. Because there is no
Massive hepatic enlargement may be seen. Diagnosis proven therapy for ALF in general, management consists
should be made by imaging and biopsy, and treatment of intensive care support once treatments for specific eti-
appropriate for the underlying malignant condition is in- ologies have been initiated. While some patients with ev-
dicated. Transplantation is not an option for such pa- idence of acute liver injury but without significant
tients.57,58 Acute severe hepatic infiltration occurs with coagulopathy or encephalopathy may be monitored on a
breast cancer,59,60 small cell lung cancers,61 lymphoma58 medicine ward, any patient with altered mental status
and melanoma.62 warrants admission to an ICU as the condition may de-
teriorate quickly. Careful attention must be paid to fluid
Recommendations management, hemodynamics and metabolic parameters
23. In patients with acute liver failure who have a as well as surveillance for and treatment of infection.
previous cancer history or massive hepatomegaly, con- Maintenance of nutrition and prompt recognition and
sider underlying malignancy and obtain imaging and resuscitation of gastrointestinal bleeding are crucial as
liver biopsy to confirm or exclude the diagnosis (III). well. Coagulation parameters, complete blood counts,
metabolic panels (including glucose) and arterial blood
Indeterminate Etiology gas should be checked frequently. Serum aminotrans-
When the etiology of ALF cannot be determined after ferases and bilirubin are generally measured daily to fol-
routine evaluation, biopsy using a transjugular approach low the course of the condition, however changes in
may be helpful in diagnosing malignant infiltration, au- aminotransferase levels correlate poorly with prognosis.
toimmune hepatitis, certain viral infections and Wilson Specific Issues. See Table 4.
disease. Lack of a clear diagnosis suggests that the history
may have been inadequate regarding toxin or drug expo-
Central Nervous System
sures.
Cerebral edema and intracranial hypertension (ICH)
have long been recognized as the most serious complica-
Recommendation
tions of ALF.72 Uncal herniation may result and is uni-
24. If the etiological diagnosis remains elusive after
formly fatal. Cerebral edema may also contribute to
extensive initial evaluation, liver biopsy may be ap-
ischemic and hypoxic brain injury, which may result in
propriate to attempt to identify a specific etiology that
long-term neurological deficits in survivors.73 The patho-
might influence treatment strategy (III).
genic mechanisms leading to the development of cerebral
edema and ICH in ALF are not entirely understood. It is
Therapy: General Considerations
likely that multiple factors are involved, including os-
Background motic disturbances in the brain and heightened cerebral
While patients with ALF represent a heterogeneous blood flow due to loss of cerebrovascular autoregulation.
group, they have consistent clinical features, and share the Inflammation and/or infection, as well as factors yet un-
common disease process of acute hepatocyte loss and its identified may also contribute to the phenomenon.74 Sev-
sequelae. Despite decades of research, however, no agent eral measures have been proposed and used with varying
or therapy that is beneficial to all patients with ALF has success to tackle the problem of cerebral edema and the
been found. Systemic corticosteroids are ineffective in this associated ICH in patients with ALF. Some interventions
condition.63-65 are supported by more evidence than others; no uniform
Because most patients with ALF tend to develop some protocol has been established.
degree of circulatory dysfunction, agents that may im- Prevention/Management of Elevated Intracranial
prove hemodynamics have been of particular interest. Pressure (ICP). The occurrence of cerebral edema and
While prostacyclin and other prostaglandins have ap- ICH in ALF is related to severity of encephalopathy (Ta-
peared promising in some reports,66,67 others have not ble 5). Cerebral edema is seldom observed in patients with
supported their efficacy in ALF.68 NAC may improve grade I-II encephalopathy. The risk of edema increases to
systemic circulation parameters in patients with ALF,69 25% to 35% with progression to grade III, and 65% to
but this was not observed in all studies.70 NAC has been 75% or more in patients reaching grade IV coma.75 A
shown to improve liver blood flow and function in pa- stepwise approach to management is therefore advised.76
tients with septic shock.71 Use of NAC in all forms of ALF Grades I-II. Depending on the overall clinical pic-
cannot be justified based on current evidence. A large, ture, patients with only grade I encephalopathy may
multi-center, randomized, double-blind controlled trial sometimes be safely managed on a medicine ward with
1186 POLSON AND LEE HEPATOLOGY, May 2005
Table 4. Intensive Care of Acute Liver Failure
with cirrhosis, it has been suggested that reducing elevated
ammonia levels with enteral administration of lactulose
Cerebral Edema/Intracranial Hypertension
Grade I/II Encephalopathy
might help prevent or treat cerebral edema in ALF. A
Consider transfer to liver transplant facility and listing for transplantation
preliminary report from the United States Acute Liver
Brain CT: rule out other causes of decreased mental status; little utility to
Failure Study Group (US ALFSG), retrospectively com-
identify cerebral edema
Avoid stimulation, avoid sedation if possible
paring patients who received lactulose to a well-matched
Antibiotics: surveillance and treatment of infection required; prophylaxis
group of patients who did not, found that lactulose ther-
possibly helpful
apy was associated with a small increase in survival time,
Lactulose: possibly helpful
Grade III/IV Encephalopathy but with no difference in severity of encephalopathy or in
Continue management strategies listed above
overall outcome.78 One concern regarding the use of lac-
Intubate trachea (may require sedation)
tulose in this setting is the potential for gaseous abdomi-
Elevate head of bed
nal distension that could present technical difficulties in a
Consider placement of ICP monitoring device
Immediate treatment of seizures required; prophylaxis of unclear value
subsequent transplantation procedure.
Mannitol: use for severe elevation of ICP or first clinical signs of herniation
Grades III-IV. As patients progress to grade III or IV
Hyperventilation: effects short-lived; may use for impending herniation
encephalopathy it is advisable to intubate the trachea for
Infection
airway protection. Choice of sedation in this instance will
Surveillance for and prompt antimicrobial treatment of infection required
vary according to clinician preference: propofol is often
Antibiotic prophylaxis possibly helpful but not proven
used because it may reduce cerebral blood flow79; how-
Coagulopathy
Vitamin K: give at least one dose
ever, its effectiveness in this regard has not been shown in
FFP: give only for invasive procedures or active bleeding
controlled studies. Small doses of propofol may be ade-
Platelets: give for platelet counts 10,000/mm3 or invasive procedures
quate, given its long half-life in patients with hepatic fail-
Recombinant activated factor VII: possibly effective for invasive procedures
Prophylaxis for stress ulceration: give H2 blocker or PPI ure. Patients in advanced stages of encephalopathy require
close follow-up. Monitoring and management of hemo-
Hemodynamics/Renal Failure
Pulmonary artery catheterization
dynamic and renal parameters as well as glucose, electro-
Volume replacement
lytes and acid/base status becomes critical, and frequent
Pressor support (dopamine, epinephrine, norepinephrine) as needed to
neurological evaluation for signs of elevated intracranial
maintain adequate mean arterial pressure
Avoid nephrotoxic agents pressure should be conducted. Patients should be posi-
Continuous modes of hemodialysis if needed
tioned with head elevated at 30 degrees.80 Efforts should
NAC, prostacyclin: effectiveness unknown
be made to avoid patient stimulation. Maneuvers that
Vasopressin: not helpful in ALF; potentially harmful.
cause straining or Valsalva-like movements in particular
Metabolic Concerns
may increase ICP; it may be advisable to use endotracheal
Follow closely: glucose, potassium, magnesium, phosphate
Consider nutrition: enteral feedings if possible or total parenteral nutrition
lidocaine prior to endotracheal suctioning.
Seizures. Seizures, which may be seen as a manifesta-
tion of the process that leads to hepatic coma and ICH,
should be controlled with phenytoin. Use of any sedative
skilled nursing in a quiet environment to minimize agita-
is discouraged in light of its effects on the evaluation of
tion, although management in an ICU is preferable. Fre-
mental status. Only minimal doses of benzodiazepines
quent mental status checks should be performed with
should be used given their delayed clearance by the failing
transfer to an ICU if level of consciousness declines. With
liver. Seizure activity may acutely elevate ICP81 and may
progression to grade II encephalopathy, an ICU setting is
also cause cerebral hypoxia and thus contribute to cerebral
indicated. Head imaging with computerized tomography
(CT) is used to exclude other causes of decline in mental
status such as intracranial hemorrhage. Sedation is to be
Table 5. Grades of Encephalopathy
avoided if possible; unmanageable agitation may be
I Changes in behavior with minimal change in level of consciousness
treated with short-acting benzodiazepines in small doses.
II Gross disorientation, drowsiness, possibly asterixis, inappropriate
Lactulose. There is increasing evidence that ammonia
behavior
may play a pathogenic role in the development of cerebral
III Marked confusion, incoherent speech, sleeping most of the time but
arousable to vocal stimuli
edema/ICH; ammonia infusion has been shown to cause
IV Comatose, unresponsive to pain, decorticate or decerebrate posturing
brain edema in animal models.77 Some human studies
Note: some patients will overlap grades; clinical judgment is required. Adapted
have supported these findings, with an arterial ammonia
from Conn HO, Leevy CM, Vhlahcevic ZR, Rodgers JB, Maddrey WC, Seeff L, Levy
level 200 ug/dL being strongly associated with cerebral
LL. Comparison of lactulose and neomycin in the treatment of chronic portal-
herniation.7 Based on such evidence and on prior experi-
systemic encephalopathy. A double blind controlled trial. Gastroenterology 1977;
ence with treatment of hepatic encephalopathy in patients 72:573 583.
HEPATOLOGY, Vol. 41, No. 5, 2005 POLSON AND LEE 1187
edema. Some experts have advocated prophylactic use of surgery. There are documented studies and reports of ex-
phenytoin, especially as seizure activity may be inappar- perience which indicate ICP monitoring devices can
ent. A small randomized controlled trial of prophylactic safely provide helpful information,76,90,93 and may even
phenytoin in ALF showed no difference in overall sur- lengthen survival time,94 but there are no controlled trials
vival, but a striking diminution in cerebral edema at au- available to demonstrate an overall survival benefit. There
topsy in the treated group.82 A recent clinical trial did not is understandable concern over the risks (mainly infection
show beneficial effects on the prevention of seizures, brain and bleeding) involved in placing invasive intracranial
edema or survival.83 Further studies may clarify the value devices in critically ill, coagulopathic patients, based on
of this treatment, but it cannot be recommended as a data on 262 patients at U.S. transplant centers that ob-
prophylactic measure at this time. served a complication rate of 3.8% (1% fatal hemorrhage)
with epidural catheters. Reliability was improved but the
risk of complications increased with the use of subdural or
Intracranial Pressure Monitoring
intraparenchymal instrumentation.95 It is not known
The use of ICP monitoring devices in ALF is a subject
whether newer, smaller monitoring devices have de-
of ongoing debate. ICP monitoring is used variably across
creased the risk of complications. More aggressive correc-
the United States, with some centers not considering it
tion of coagulation parameters, perhaps with addition of
useful and others using it regularly. A survey of the initial
recombinant activated factor VII, may further reduce
14 transplant centers in the US ALFSG found ICP mon-
bleeding risk, allowing wider use of ICP monitoring de-
itoring devices were used in 13 of these sites from 1998-
vices.96 Indeed, preliminary results indicate a considerable
200084; a more recent informal review of more than 20
reduction in the prevalence of bleeding complications
sites found ICP monitors used in a little more than half
(2/58 cases with the majority being subdural monitors).97
(unpublished). Without the use of these monitoring de-
Recent data did not show improved outcomes when ICP
vices, early recognition of cerebral edema cannot reliably
monitoring devices were used.97
be made. The clinical signs of elevated ICP including
Specific Treatment of Elevated Intracranial Pres-
hypertension, bradycardia and irregular respirations
sure. If patients develop increased ICP it may be neces-
(Cushing s triad) are not uniformly present; these and
sary to perform immediate interventions beyond the
other neurological changes such as pupillary dilatation or
general strategies outlined above. If an ICP monitor is
signs of decerebration are typically evident only late in the
placed, key parameters to follow are both ICP and CPP.
course. CT of the brain does not reliably demonstrate
ICP should be maintained below 20-25 mm Hg if possi-
evidence of edema especially at early stages.85 Other
methods of monitoring (such as transcranial doppler ul- ble, with CPP maintained above 50-60 mm Hg.4,98 Evi-
dence from trauma patients with cerebral edema suggests
trasonography, near-infrared spectrophotometry, and
that maintaining CPP above 70 mm Hg may further im-
measurement of serum S-100 beta and neuronal specific
prove neurological outcomes, if this level can be
enolase) that are in various stages of evaluation have thus
far not been proven reliable in estimatingICP.86-89 A pri- achieved.99 Support of systemic blood pressure may be
required to maintain adequate CPP.
mary purpose of ICP monitoring is to detect elevations in
Mannitol. If ICH develops, either as seen on ICP
ICP and reductions in cerebral perfusion pressure (CPP;
monitoring or by obvious neurological signs (decerebrate
calculated as mean arterial pressure minus ICP) so that
posturing, pupillary abnormalities), osmotic diuresis with
interventions can be made to prevent herniation while
intravenous mannitol is effective in the short term in de-
preserving brain perfusion. The ultimate goal of such
measures is to maintain neurological integrity and pro- creasing cerebral edema.100 Mannitol has been shown in
long survival while awaiting receipt of a donor organ or controlled trials to correct episodes of elevated ICP in
recovery of sufficient functioning hepatocyte mass. ICP ALF patients; its use has also been associated with im-
monitoring is particularly important during orthotopic proved survival.101 Administration of intravenous manni-
liver transplantation, when shifts in hemodynamics can tol (in a bolus dose of 0.5-1g/kg) is therefore
cause large fluctuations in cerebral pressure parameters.90 recommended to treat ICH in ALF. The dose may be
Additionally, refractory ICH and/or decreased CPP is repeated once or twice as needed, provided serum osmo-
considered a contraindication to liver transplantation in lality has not exceeded 320 mosm/L. Volume overload is
many centers.90,91 Case reports of ALF patients demon- a risk with mannitol use in patients with renal impair-
strating spontaneous and complete recovery after pro- ment, and may necessitate use of dialysis to remove excess
longed ICH and decreased CPP may call this practice into fluid. Hyperosmolarity or hypernatremia also may result
question,92 but there is no way of knowing whether these from overzealous use. Prophylactic administration of
patients would have survived the rigors of transplantation mannitol is not indicated.
1188 POLSON AND LEE HEPATOLOGY, May 2005
Hyperventilation. Hyperventilation to reduce PaCO2
has supported a beneficial effect of hypothermia in pa-
to 25-30 mm Hg is known to quickly lower ICP via vaso- tients with ALF as well,111,112 but hypothermia has not
constriction causing decreased cerebral blood flow (CBF),
been subjected to a controlled trial. Potential deleterious
but this effect is short-lived.102 In a small series of patients effects of hypothermia include increased risk of infection,
with ALF, loss of auto-regulation of CBF appeared to be coagulation disturbance, and cardiac arrhythmias.113
restored after several minutes of hyperventilation.103 Resto-
ration of CBF auto-regulation should theoretically be bene-
Recommendations
ficial if cerebral hyperemia is contributing to cerebral edema
25. In early stages of encephalopathy, sedation
and ICH; this study did not evaluate effect on ICP or sur-
should be avoided if possible. Lactulose may be used,
vival, however. A randomized controlled trial of prophylactic
but concern has been raised about increasing bowel
continuous hyperventilation in ALF patients showed no re-
distention during the subsequent transplant procedure
duction in incidence of cerebral edema/ICH and no survival
(II-2, III).
benefit, although onset of cerebral herniation did appear de- 26. In patients progressing to grade III or IV en-
layed in the hyperventilated group.104 There has been some
cephalopathy, the head should be elevated to 30 de-
concern that cerebral vasoconstriction with hyperventilation
grees, and endotracheal intubation should be
could potentially worsen cerebral edema by causing cerebral
performed (III).
hypoxia.105 Based on available evidence, there is no role for
27. Seizure activity should be treated with phenyt-
prophylactic hyperventilation in patients with ALF. If life- oin and low-dose benzodiazepines. (III).
threatening ICH is not controlled with mannitol infusion
28. Although there is no consensus among the cen-
and other general management outlined above, hyperventi- ters and experts, intracranial pressure monitoring is
lation may be instituted temporarily in an attempt to acutely
mainly considered for patients who are listed for
lower ICP and prevent impending herniation; beyond this
transplantation (III).
acute situation it cannot be recommended as routine man- 29. In the absence of ICP monitoring, frequent
agement. evaluation for signs of intracranial hypertension are
Hypertonic Sodium Chloride. A recent controlled needed to identify early evidence of uncal herniation
trial of administration of 30% hypertonic saline to main- (III).
tain serum sodium levels of 145-155 in patients with ALF 30. In the event of intracranial hypertension, man-
and severe encephalopathy suggests that induction and nitol should be given and hyperventilation may be
maintenance of hypernatremia may be used to prevent the considered in order to temporarily reduce the ICP, but
rise in ICP values.106 Survival benefit could not be dem- prophylactic use of these interventions is not helpful
onstrated in this small trial. The role of hypertonic saline and therefore not recommended (I).
as a prophylactic measure requires confirmation in larger 31. Short-acting barbiturates may be considered
studies. for refractory intracranial hypertension (III).
Barbiturate. Barbiturate agents (thiopental or pento- 32. Corticosteroids should not be used to control
barbital) may also be considered when severe ICH does elevated ICP in patients with acute liver failure (I).
not respond to other measures; administration has been
shown to effectively decrease ICP. Significant systemic
Infection
hypotension frequently limits their use, and may necessi- All patients with ALF are at risk for acquisition of
tate additional measures to maintain adequate mean arte- bacterial114 or fungal115 infection or sepsis, which may
rial pressure (MAP).107
preclude transplantation or complicate the post-operative
Corticosteroids. Corticosteroids, which are often
course. Prophylactic antimicrobial therapy reduces the in-
used in the prevention and management of ICH caused
cidence of infection in certain groups of patients with
by brain tumors and some infections of the central ner- ALF, but no actual survival benefit has been shown,116,117
vous system, have been shown in a controlled trial to making it difficult to recommend antibiotic prophylaxis
confer no benefit in patients with ALF with respect to uniformly. Although often given, poorly absorbable anti-
controlling cerebral edema or improving survival.101 biotics for selective bowel decontamination have not been
Hypothermia. Moderate hypothermia (32-34°C) shown to impact survival either.116 Deterioration of men-
may prevent or control ICH in patients with ALF. It has tal status in hospital, particularly in patients with acet-
been shown in experimental animal models to prevent aminophen toxicity, may represent the onset of infection.
development of brain edema,108-110 possibly by prevent- If antibiotics are not given prophylactically, surveillance
ing hyperemia, altering brain ammonia or glucose metab- for infection (including chest radiography and periodic
olism, or by a combined effect. Some limited experience cultures of sputum, urine and blood for fungal and bac-
HEPATOLOGY, Vol. 41, No. 5, 2005 POLSON AND LEE 1189
terial organisms) should be undertaken, while maintain- mend more conservative levels of 15-20,000/mm3 espe-
ing a low threshold for starting appropriate anti-bacterial cially in patients with infection or sepsis,121 Experience in
or anti-fungal therapy. There are no controlled trials other conditions of thrombocytopenia suggests that val-
available to confirm whether the use of prophylactic an- ues 10,000/mm3 are generally well tolerated.122 When
timicrobials decreases the likelihood of progression of en- invasive procedures must be perfomed, platelet counts of
cephalopathy and/or development of cerebral edema in 50-70,000/mm3 are usually considered adequate.121 Pa-
ALF. Recent studies have suggested an association be- tients who develop significant bleeding with platelet levels
tween infection and/or the systemic inflammatory re- below approximately 50,000/mm3 should generally be
sponse syndrome (SIRS) and progression to deeper stages transfused with platelets provided no contraindication ex-
of encephalopathy.117,118 Given that prophylactic antibi- ists. Likewise, bleeding in the setting of a prolonged pro-
otics have been shown to reduce the risk of infection, that thrombin time (INR 1.5) warrants administration of
later stages of encephalopathy are associated with in- FFP. Recombinant activated factor VII (rFVIIa) may be
creased incidence of cerebral edema, and that fever may used in treating coagulopathy in patients with liver dis-
worsen ICH,119 it is possible that antibiotic and anti- ease. A recent small nonrandomized trial of fifteen pa-
fungal prophylaxis may decrease the risk of cerebral tients with ALF found that administration of rFVIIa in
edema and ICH. This hypothesis is yet to be proven, combination with FFP produced more effective tempo-
however. rary correction of coagulopathy and thus might be useful
in facilitating performance of invasive procedures in these
patients particularly in the setting of renal insufficiency in
Recommendations
which volume overload is a concern.96 This agent will
33. Periodic surveillance cultures should be per-
require further study and analysis of cost-benefit ratio
formed to detect bacterial and fungal infections as
(current cost for one dose is approximately $4,000) before
early as possible and prompt treatment should be
it can be broadly recommended, however.
initiated accordingly (II-2, III).
34. Prophylactic antibiotics and anti-fungals may
be considered but have not been shown to improve Recommendation
overall outcomes (II-2, III). 35. Replacement therapy for thrombocytopenia
and/or prolonged prothrombin time is recommended
only in the setting of hemorrhage or prior to invasive
Coagulopathy
procedures (III).
Clotting abnormalities are uniform in patients with
ALF as previously discussed, leaving patients at increased
risk for bleeding complications. While synthesis of coag- Gastrointestinal Bleeding
ulation factors is decreased, consumption of clotting fac- Gastrointestinal (GI) bleeding is a recognized compli-
tors and platelets also may occur, so that platelet levels are cation of ALF. A large prospective multi-center cohort
often 100,000/mm.3 In the absence of bleeding it is not study found that mechanical ventilation for more than 48
necessary to correct clotting abnormalities with fresh fro- hours and coagulopathy were the only significant risk fac-
zen plasma (FFP).120 An exception is when an invasive tors for bleeding in critically ill patients of all types.123
procedure is planned and perhaps in the setting of pro- Additional risk factors for bleeding reported in smaller
found coagulopathy (e.g., INR 7). In addition to the studies have included hepatic and renal failure, sepsis,
risks associated with transfusion of blood products, use of shock and others.124 Patients with acute liver failure are
plasma supplementation limits the value of coagulation thus at high risk for gastrointestinal hemorrhage. Hista-
parameters as a means of following the progress of ALF mine-2 receptor (H2) blocking agents such as ranitidine
patients and can also lead to volume overload which may have long been used in the prophylaxis of GI bleeding in
exacerbate ICH. Vitamin K is routinely given in a dose of critically ill patients; their efficacy has been supported in
5-10 mg subcutaneously, regardless of whether poor nu- several trials.125-128 Sucralfate has also been found to be
tritional status appears to be contributing to the coagu- effective in many studies, and there have been smaller
lopathy. randomized trials and a meta-analysis which suggested
Experts differ regarding prophylactic use of platelets in that sucralfate may be as effective in preventing gastroin-
thrombocytopenic patients or use of FFP for evidence of testinal bleeding and might be associated with lower risk
severe coagulopathy. Platelet transfusions are not gener- of nosocomial pneumonia than H2 blockers which lower
ally used until a low threshold value is observed. In the gastric pH.129,130 More recently, however, a much larger
absence of bleeding, it is safe to use a threshold platelet (1,200 patients), well-designed trial comparing ranitidine
count of 10,000/mm3, although some experts recom- to sucralfate in mechanically-ventilated patients found
1190 POLSON AND LEE HEPATOLOGY, May 2005
that ranitidine but not sucralfate decreased the risk of and vasodilatation associated with ALF will generally re-
clinically significant bleeding; the incidence of pneumo- spond to these agents, and they should be used if needed
nia was similar for the two groups.128 Limited studies of to maintain perfusion of vital organs. Agents that pro-
proton pump inhibitors (PPIs) as bleeding prophylaxis mote vasoconstriction are generally avoided unless signif-
have demonstrated their effectiveness in maintaining ele- icant systemic hypotension is present, and therefore
vated intragastric pH.131-133 Two trials found no signifi- should not be used in the setting of decreased intracranial
cant bleeding in PPI-treated patients on mechanical perfusion with normal systemic blood pressure.
ventilation,131,132 but study size may have precluded de- Acute renal failure is a frequent complication in pa-
tection of significant bleeding. H2 blockers have been tients with ALF135 and may be due to dehydration, hepa-
proven to be effective and PPIs are almost certainly effec- torenal syndrome or acute tubular necrosis.136 The
tive as well. PPIs may provide superior protection but this
frequency of renal failure may be even greater with acet-
remains to be proven. Sucralfate may be acceptable as
aminophen overdose or other toxins, where direct renal
second-line treatment.
toxicity is seen.137 Although few patients die of renal fail-
ure alone, it often contributes to mortality and may por-
tend a poorer prognosis.9,138 Every effort should be made
Recommendation
36. Patients with ALF in the ICU should receive to protect renal function by maintaining adequate hemo-
prophylaxis with H2 blocking agents or PPIs (or su- dynamics, avoiding nephrotoxic agents such as aminogly-
cralfate as a second-line agent) for acid-related gas- cosides and non-steroidal anti-inflammatory drugs, and
trointestinal bleeding associated with stress (I, III). by the prompt identification and treatment of infection.
When dialysis is needed, continuous rather than intermit-
tent modes of renal replacement therapy (e.g., continuous
Hemodynamics/Renal Failure
venovenous hemodialysis [CVVHD]) should be used, as
Hemodynamic derangements consistent with multiple
they have been shown in randomized trials to result in
organ failure occur in ALF; the underlying mechanisms
improved stability in cardiovascular and intracranial pa-
are complex and incompletely understood. Management
rameters compared with intermittent modes of hemodi-
of hemodynamic balance becomes increasingly important
alysis.139 Intravenous contrast agents are associated with
and difficult in the face of elevated ICP and/or compro-
nephrotoxicity in the setting of compromised hepatic
mised renal function. Preservation of renal function is
function, and should be used with caution. If contrast
imperative in this setting. In many ways patients with
must be administered, pretreatment with NAC may be of
ALF resemble physiologically the patient with cirrhosis
value, although this remains controversial.140-142
and hepatorenal syndrome. Intravascular volume deficits
The potential utility of prostaglandins and NAC in
may be present on admission due to decreased oral intake
improving hemodynamics and renal function was dis-
resulting from altered mental status, transudation of fluid
cussed previously; neither has sufficient evidence to be
into the extravascular space, and possibly GI blood loss.
recommended as part of the management of hemody-
Most patients will require fluid resuscitation initially.
Low systemic vascular resistance results in low blood pres- namic derangements in ALF at this time, although NAC
may have other benefits as discussed above. Evidence that
sures even in the fluid-resuscitated patient, and placement
of a pulmonary artery catheter may aid in assessing vol- terlipressin or vasopressin may be useful in patients with
ume status and guiding further management. Fluid re- cirrhosis and hepatorenal syndrome has raised the ques-
tion of whether this agent might benefit patients with
placement with colloid (such as albumin) is preferred
rather than crystalloid (such as saline); all solutions should ALF as well. A recent small study of terlipressin in patients
contain dextrose to maintain euglycemia. with ALF found that even in very small doses, the drug
While adequate fluid replacement and treatment of was associated with increased cerebral blood flow and
potential infection and sepsis may help to correct hypo- ICH.143 Such results indicate that at this time the risks
tension, inotropic or pressor support may be required in associated with vasopressin use appear to outweigh its
order to maintain mean arterial pressures of at least 50-60 benefits in patients with ALF.
mm Hg. There has been debate over which agents are best The observation that hemodynamic status as well as
used to support blood pressure in ALF and whether they ICH tends to improve after removal of the native liver
are useful at all. Alpha-adrenergic agents such as epineph- during transplantation for ALF led to a recommendation
rine and norepinephrine have been thought to potentially of hepatectomy as a  last resort means of improving se-
worsen peripheral oxygen delivery.66 On the other hand, vere circulatory dysfunction in these patients. This option
dopamine has actually been associated with increased sys- is based on uncontrolled studies and case reports, where
temic delivery of oxygen.134 In any case, the hypotension successful outcomes have occasionally been reported even
HEPATOLOGY, Vol. 41, No. 5, 2005 POLSON AND LEE 1191
with patients who remained anhepatic for more than 48 regeneration of sufficient hepatocyte mass to sustain life.
hours.144-146 Despite these reports, hepatectomy to con- As mentioned previously, the advent of transplantation
trol hemodynamics cannot be recommended. has coincided with improvement in overall survival rates
from as low as 15% in the pre-transplant era to 60%
Recommendations
presently.5 Advances in critical care and changing trends
37. Careful attention must be paid to fluid resus-
toward more benign etiologies such as acetaminophen
citation and maintenance of adequate intravascular
(having a better overall outcome) have likely helped.
volume in patients with acute liver failure (III).
Spontaneous survival rates are now around 40%,5 com-
38. If dialysis support is needed for acute renal
pared to 15% in the pre-transplant era. Post-transplant
failure, it is recommended that a continuous mode
survival rates for ALF have been reported to be as high as
rather than an intermittent mode be used (I).
80% to 90%,5,93 but accurate long-term outcome data are
39. Pulmonary artery catheterization should be
not yet available. In the largest U.S. study, only 29% of
considered in a hemodynamically unstable patient to
patients received a liver graft, while 10% of the overall
ensure that appropriate volume replacement has oc-
group (1/4 of patients listed for transplantation) died on
curred (III).
the waiting list.5 Other series have reported death rates of
40. Systemic vasopressor support with agents such
those listed for transplant as high as 40%,150,151 despite
as epinephrine, norepinephrine, or dopamine but not
the fact that ALF remains the one condition for which the
vasopressin should be used if fluid replacement fails to
most urgent (UNOS status 1) listing is reserved. Devel-
maintain MAP of 50-60 mm Hg (III, II-1).
oping effective methods of liver support or other alterna-
tives to transplantation and better prognostic scoring
Metabolic Concerns
systems remain key goals to further improve overall sur-
A number of metabolic derangements are common in
vival rates for the condition. Living-related donor liver
ALF. Alkalosis and acidosis may both occur and are best
transplantation may help address the shortage of available
managed by identifying and treating the underlying
organs, but its use has thus far been very limited probably
cause. Hypoglycemia should be managed with continu-
as a result of time constraints for evaluating donors and
ous glucose infusions, because symptoms may be ob-
ethical concerns in this setting.
scured in the presence of encephalopathy. Phosphate,
magnesium, and potassium levels are frequently low and
Recommendation
may require repeated supplementation throughout the
42. Urgent hepatic transplantation is indicated in
hospital course. Nutrition is also important. Enteral feed-
acute liver failure where prognostic indicators suggest
ings should be initiated early. Severe restrictions of pro-
a high likelihood of death (II-3).
tein should be avoided; 60 grams per day of protein is
reasonable in most cases. Branched-chain amino acids
Liver Support Systems
have not been shown to be superior to other enteral prep-
A support device to replace the acutely failing liver
arations.147 If enteral feedings are contraindicated (e.g.,
seems a reasonable but elusive goal. The ideal replacement
severe pancreatitis), parenteral nutrition is an option, al-
for the failing liver would detoxify, metabolize and syn-
though the risks of infection, particularly with fungal
thesize; in short, perform all the liver s many functions. A
pathogens, should be considered. Enteral148 and paren-
variety of systems have been tested to date, with no certain
teral nutrition149 may reduce the risk of gastrointestinal
evidence of efficacy. Sorbent systems embody only detox-
bleeding due to stress ulceration in critically ill patients.
ification and no hepatocyte replacement. Such systems,
employing charcoal or other adherent particles in a cap-
Recommendation
41. Metabolic homeostasis must be carefully main- sule or column device placed in an extracorporeal circuit,
may show loss of platelets and worsening of coagulation
tained in patients with acute liver failure. Overall
nutritional status as well as glucose, phosphate, potas- parameters across the device.152,153 Transient improve-
sium and magnesium levels should be monitored fre- ment of hepatic encephalopathy may be observed but no
improvement in hepatic function or long-term benefit has
quently, with expeditious correction of derangements
been shown. Hepatocytes, whether of human or other
(III).
mammalian origin, have been used in cartridges in extra-
Transplantation and Prognosis
corporeal circuits, either with or without sorbent col-
Transplantation umns. Few controlled trials have been published, and
Orthotopic liver transplantation remains the only de- some preliminary reports suggest no benefit to outcome,
finitive therapy for patients who are unable to achieve with or without transplantation.154 One recent multi-
1192 POLSON AND LEE HEPATOLOGY, May 2005
Table 6. Potentially Helpful Indicators* of Poor (Transplant-
center trial did report improved short-term survival for a
free) Prognosis in Patients With ALF
subgroup of patients with ALF who were treated with a
porcine hepatocyte-based bioartificial liver,155 but corrob- Etiology
Idiosyncratic drug injury
oration of these results by further studies will likely be
Acute hepatitis B (and other non-hepatitis A viral infections)
required before the true utility of this device can be estab-
Autoimmune hepatitis
lished. All such trials are difficult to perform and to con- Mushroom poisoning
Wilson disease
trol properly due to the rarity of well-characterized
Budd-Chiari syndrome
patients, the heterogeneity of etiologies, varying levels of
Indeterminate cause
disease severity and varying access to transplantation. A
Coma grade on admission
recent meta-analysis, considering all forms of devices to- III
IV
gether, demonstrated no efficacy for bio-artificial liver de-
King s College Criteria:
vices for the treatment of ALF.156 A variety of other
Acetaminophen-induced ALF:
strategies have been employed including exchange trans-
Arterial pH 7.3 (following adequate volume resuscitation) irrespective of
fusion, charcoal hemoperfusion, extracorporeal liver per-
coma grade OR
PT 100 seconds (INR 6.5) serum creatinine 300 mol/L (3.4 mg/
fusions, and intra-portal hepatocyte infusions.157-159 To
dL) in patients in grade III/IV coma
date, none can be recommended, and their use remains
Non-acetaminophen-induced ALF:
experimental. Efforts to improve hepatocyte regeneration
PT 100 seconds irrespective of coma grade OR
have likewise been futile thus far.160 When heterotopic or Any three of the following, irrespective of coma grade:
 Drug toxicity, indeterminate cause of ALF
partial replacement transplantations have been performed
 Age 10 years or 40 years!
it appears that the native liver can recover in some but not
 Jaundice to coma interval 7 days!
all situations, but this may require weeks or months to  PT 50 seconds (INR 3.5)
 Serum bilirubin 300 mol/L (17.5 mg/dL)
occur, underscoring the real challenge to liver replace-
ment devices, that is, that liver assist devices might well be
*Please note: None of these factors, with the exception of Wilson disease and
possibly mushroom poisoning, are either necessary or sufficient to indicate the
required for long periods of time.
need for immediate liver transplantation.
! These criteria, in particular, have not been found to be predictive of outcome
Recommendation
in recent analyses.5
43. Currently available liver support systems are
not recommended outside of clinical trials; their fu-
ture in the management of acute liver failure remains
subsequent studies in both acetaminophen167 and non-
unclear (I, II-1).
acetaminophen ALF165 have shown these criteria to be less
accurate than King s College Hospital criteria in predict-
Prognosis ing outcome.
See Table 6. In a recent meta-analysis, Bailey et al.168 compared
Given limited organ availability, lack of good alterna- various prognostic criteria in patients with ALF due to
tives to transplantation, and potential complications of acetaminophen, including King s College Hospital crite-
lifelong immunosuppression, accurate prognosis in ALF ria, various combinations of elevated serum creatinine,
is a paramount goal. Prognostic scoring systems, although encephalopathy, and prothrombin time elevations (both
derived from data on relatively large numbers of patients, single and serial measurements), decreased factor V levels,
still fail to achieve success, given the wide variety of etiol- the Acute Physiology and Chronic Health Evaluation
ogies that lead to this end stage syndrome. The traditional (APACHE) II scores169 and Gc globulin (vitamin D bind-
King s College Hospital criteria have been the most com- ing protein, a liver-derived component of the actin-scav-
monly utilized and most frequently tested of the numer- enging system170). The analysis found that King s College
ous proposed prognostic criteria for ALF.9 Several studies Hospital criteria and pH 7.30 alone were both fairly
evaluating these criteria have shown positive predictive specific in predicting a poor outcome. While the King s
values ranging from just below 70% to nearly 100% and College Hospital criteria were more sensitive than pH
negative predictive values ranging from 25% to alone (69% versus 57% sensitivity), use of both criteria
94%.161-165 Overall, such prognostic scores have proven was still likely to miss many patients who would ulti-
to have acceptable specificity but low sensitivity to deter- mately require transplantation. The authors also found
mine outcome. Criteria based on decreased levels of factor that an APACHE II score of 15 on admission had a
V in patients with encephalopathy predicted death in specificity of 92% (comparable to King s College Hospi-
acute viral hepatitis cases with a positive predictive value tal criteria) with a much better sensitivity of 81%, but this
of 82% and a negative predictive value of 98%,166 but measure was only examined in one limited study.169
HEPATOLOGY, Vol. 41, No. 5, 2005 POLSON AND LEE 1193
Other factors such as age and the length of time be- W. Faust, MD, Steven L. Flamm, MD, Gregory J. Gores,
MD, Elizabeth Hespenheide, MSN, ACNP, Maureen M.
tween onset of illness and onset of encephalopathy have
Jonas, MD, Michael R. Lucey, MD, David R. Nelson,
previously been proposed as important prognostic indica-
MD, F. Fred Poordad, MD, Margaret C. Shuhart, MD,
tors in ALF,9,171 these parameters did not affect outcome
in the largest U.S. multi-center study of ALF to date.5 MS, Brent A. Tetri, MD, Zobair M. Younossi, MD,
MPH, and Nizar N. Zein, MD. Disclosure Statement:
Patients presenting in grade III or IV encephalopathy
The authors have no conflicts of interest to disclose.
were less likely than those patients presenting in grade I or
II encephalopathy to survive without receiving a liver
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