AASLD POSITION PAPER
Introduction to the Revised American Association
for the Study of Liver Diseases Position Paper
on Acute Liver Failure 2011
William M. Lee, R. Todd Stravitz, and Anne M. Larson
The full text of the position paper is available at: www.aasld.org/
practiceguidelines/Documents/AcuteLiverFailureUpdate2011.pdf.
Preamble
The present version of the American Association for
the Study of Liver Diseases (AASLD) Position Paper
represents a thorough overhaul from the previous
version of 2005. In addition to two new additional
authors, the revision includes updated expert opinion
regarding (1) etiologies and diagnosis, (2) therapies
and intensive care management, and (3) prognosis and
transplantation. Because acute liver failure (ALF) is an
orphan disease, large clinical trials are impossible and
much of its management is based on clinical experi-
ence only. Nonetheless, there are certain issues that
continue to recur in this setting as well as growing
consensus (amidst innovation) regarding how to
maximize the ALF patient’s chance of recovery. The
changes in ALF management are not global in nature,
but are more consistent with incremental experience
and improvements in diagnosis and intensive care unit
management.
Introduction
The diagnosis of ALF hinges on identifying that the
patient has an acute insult and is encephalopathic.
Imaging in recent years has suggested ‘‘cirrhosis,’’ but
this is often an overcall by radiology, because a regener-
ating massively necrotic liver will give the same nodular
profile as cirrhosis.1 It is vital to promptly get viral hep-
atitis serologies, including A-E as well as autoimmune
serologies, because these often seem to be neglected at
the initial presentation. Fulminant Wilson’s disease can
be diagnosed most effectively not by waiting for copper
levels (too slow to obtain) or by obtaining ceruloplas-
min levels (low in half of all ALF patients, regardless of
etiology), but by simply looking for the more readily
available bilirubin level (very high) and alkaline phos-
phatase (ALP; very low), such that the bilirubin/ALP ra-
tio exceeds 2.0.2 The availability of an assay that meas-
ures acetaminophen adducts has been used for several
years as a research tool and has improved our clinical
recognition of acetaminophen cases when the diagnosis
is obscured by patient denial or encephalopathy.3 Any
patient with very high aminotransferases and low biliru-
bin on admission with ALF very likely has acetamino-
phen overdose, with the one possible exception being
those patients who enter with ischemic injury. Obtain-
ing autoantibodies should be routine and a low thresh-
old for biopsy in patients with indeterminate ALF
should be standard, given that autoimmune hepatitis
may be the largest category of indeterminate, after
unrecognized acetaminophen poisoning.4
Advances in Management of ALF
The medical management of ALF has not been
extensively studied and remains poorly defined. In the
absence of evidence-based clinical trials, experts from
23 centers in the United States have proposed detailed
management guidelines by consensus.5 Since the last
AASLD Position Paper, several noteworthy advances
have been made in assessing the risk of developing,
and managing, specific complications of ALF.
All AASLD Practice Guidelines are updated annually. If you are viewing a
Practice Guideline that is more than 12 months old, please visit www.aasld.org
for an update in the material.
Abbreviations: AASLD, the American Association for the Study of Liver
Diseases; ALF, acute liver failure; ALP, alkaline phosphatase; CPP, cerebral
perfusion pressure; ICH, intracranial hypertension; ICP, intracranial pressure;
INR, international normalized ratio; MAP, mean arterial pressure; MELD,
model for end-stage liver disease.
From the University of Texas Southwestern Medical Center, Dallas, TX.
Received December 2, 2011; accepted December 2, 2011.
Address reprint requests to: William Lee, M.D., University of Texas
Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX
75390. E-mail: william.lee@utsouthwestern.edu; fax: 214-648-8955.
Copyright VC 2011 by the American Association for the Study of Liver
Diseases.
View this online at wileyonlinelibrary.com.
DOI 10.1002/hep.25551
Potential conflicts of interest: Dr. Lee received grants from Gilead,
Genentech, and Bristol-Myers Squibb. Dr. Larson received royalties from
UpToDate.
965
A detailed analysis of serum ammonia in patients
with ALF identified a concentration of 75 lM as an
important threshold below which patients rarely de-
velop intracranial hypertension (ICH).6 Conversely, ar-
terial ammonia levels of >100 lM on admission rep-
resent an independent risk factor for the development
of high-grade hepatic encephalopathy, and a level of
>200 lM predicts ICH. The risk of developing ICH
is decreased by raising the serum sodium to 145-155
mEq/L with hypertonic saline.7 Once established, how-
ever, the medical treatment of ICH must bridge
patients to liver transplantation, because no treatment
permanently reverses cerebral edema. In cases of ICH
refractory to osmotic agents (e.g., mannitol and hyper-
tonic saline), therapeutic hypothermia (cooling to a
core temperature of 32�C-34�C) has been shown to
bridge patients to transplantation,8 but is associated
with a theoretical risk of impairing liver regeneration.
To optimize neurological recovery after ALF, mean
arterial pressure (MAP) and cerebral perfusion pressure
(CPP) must be raised to avoid cerebral underperfusion
and anoxia. In hypotensive patients with ALF, intravas-
cular volume should be repleted first with normal sa-
line, and vasopressors should be administered subse-
quently to titrate the MAP to >75 mmHg and CPP
to 60-80 mmHg. Vasopressin, or its analog, terlipres-
sin, is often added to norepinephrine in critically ill
patients who remain hypotensive on norepinephrine,
but was reported to increase intracranial pressure
(ICP) in patients with ALF.9 More recent data suggest,
however, that vasopressin and analogs increase cerebral
perfusion without increasing ICP and may be used
safely as an adjunct to norepinephrine.10
It is generally accepted that patients with ALF have
a bleeding diathesis based upon elevation of the inter-
national normalized ratio (INR). Concern about the
safety of inserting ICP monitors and other invasive
devices has prompted the use of recombinant factor
VIIa,11 although the practice has been associated with
thrombotic complications in patients with ALF.12
However, a recent study has suggested that global
hemostasis assessed by thromboelastography usually
remains normal, suggesting that the perceived bleeding
risk based upon INR may be overstated.13
Prognosis and Transplantation
To date, it often remains difficult to predict which
ALF patients will ultimately require transplantation.
Newer models, including the model for end-stage liver
disease (MELD) score, have not improved our accu-
racy. In fact, the discriminative power of the MELD
was not found to be superior to that of the INR or
the King’s College Hospital criteria.14 In addition,
equating transplantation with death, in many models,
inflates the positive predictive value of a particular sys-
tem. The King’s College Criteria remain the most clin-
ically useful, with a sensitivity of 68%-69% and a
specificity of 82%-92%.15 However, reliance entirely
upon any set of guidelines cannot be recommended.
Despite great early interest in liver support systems,
the field has had little forward movement since our last
publication. Both artificial (i.e., sorbent-based) and bio-
artificial (i.e., cell-based) systems have been tested.
There has been no good evidence that any artificial sup-
port system reliably reduces mortality in the setting of
ALF.16,17 Thus, the currently available liver support sys-
tems cannot be recommended outside of clinical trials.
Liver transplantation remains the only definitive
treatment for patients who fail to demonstrate recovery.
The 1-year survival after cadaveric liver transplant for
ALF is less than that observed in patients transplanted
for chronic liver failure.18 However, after the first year,
this trend had reversed and ALF patients have a better
long-term survival. The use of live donor liver trans-
plantation and auxiliary liver transplant remain contro-
versial.19 Urgent cadaveric liver transplantation remains
the standard of care in the setting of ALF.
Developing effective methods of liver support or
other alternatives to transplantation and better prog-
nostic scoring systems remain key goals to further
improve overall survival rates and avoid unnecessary
transplants.
References
1. Poff JA, Coakley FV, Qayyum A, Yeh BM, Browne LW, Merriman RB,
et al. Frequency and histopathologic basis of hepatic surface nodularity
in patients with fulminant hepatic failure. Radiology 2008;249:
518-523.
2. Korman JD, Volenberg I, Balko J, Webster J, Schiodt FV, Squires RH,
Jr., et al. Screening for Wilson disease in acute liver failure: a compari-
son of currently available diagnostic tests. HEPATOLOGY 2008;48:
1167-1174.
3. Khandelwal N, James LP, Sanders C, Larson AM, Lee WM; and the
Acute Liver Failure Study Group. Unrecognized acetaminophen toxicity
as a cause of indeterminate acute liver failure. HEPATOLOGY 2011;53:
567-576.
4. Stravitz RT, Lefkowitch JH, Fontana RJ, Gershwin ME, Leung PSC,
Sterling RK, et al. Autoimmune acute liver failure: proposed clinical
and histological criteria. HEPATOLOGY 2011;53:517-526.
5. Stravitz RT, Kramer AH, Davern T, Shaikh AOS, Caldwell SH, Mehta
RL, et al. Intensive care of patients with acute liver failure: recommen-
dations of the Acute Liver Failure Study Group. Crit Care Med 2007;
35:2498-2508.
6. Bernal W, Hall C, Karvellas CJ, Auzinger G, Sizer E, Wendon J. Arte-
rial ammonia and clinical risk factors for encephalopathy and intracra-
nial hypertension in acute liver failure. HEPATOLOGY 2007;46:
1844-1852.
966 LEE, STRAVITZ, AND LARSON HEPATOLOGY, March 2012
7. Murphy N, Auzinger G, Bernal W, Wendon J. The effect of hypertonic
sodium chloride on intracranial pressure in patients with acute liver
failure. HEPATOLOGY 2002;39:464-470.
8. Jalan R, Olde Damink SW, Deutz NE, Hayes PC, Lee A. Moderate
hypothermia in patients with acute liver failure and uncontrolled intra-
cranial hypertension. Gastroenterology 2004;127:1338-1346.
9. Shawcross DL, Davies NA, Mookerjee RP, Hayes PC, Williams R, Lee
A, et al. Worsening of cerebral hyperemia by the administration of ter-
lipressin in acute liver failure with severe encephalopathy. HEPATOLOGY
2004;39:471-475.
10. Eefsen M, Dethloff T, Frederiksen HJ, Hauerberg J, Hansen BA,
Larsen FS. Comparison of terlipressin and noradrenalin on cerebral
perfusion, intracranial pressure, and cerebral extracellular concentrations
of lactate and pyruvate in patients with acute liver failure in need of
inotropic support. J Hepatol 2007;47:381-386.
11. Shami VM, Caldwell SH, Hespenheide EE, Arseneau KO, Bickston SJ,
Macik BG. Recombinant activated factor VII for coagulopathy in ful-
minant hepatic failure compared with conventional therapy. Liver
Transpl 2003;9:138-143.
12. Pavese P, Bonadona A, Beaubien J, Labrecque P, Pernod G, Letoublon
C, Barnoud D. FVIIa corrects the coagulopathy of fulminant hepatic
failure but may be associated with thrombosis: a report of four cases.
Can J Anesth 2005;52:26-29.
13. Stravitz RT, Lisman T, Luketic VA, Sterling RK, Puri P, Fuchs M,
et al. Minimal effects of acute liver injury/acute liver failure on
hemostasis as assessed by thromboelastography. J Hepatol 2011;56:
129-136.
14. Schmidt LE, Larsen FS. MELD score as a predictor of liver failure and
death in patients with acetaminophen-induced liver injury. HEPATOLOGY
2007;45:789-796.
15. McPhail MJ, Wendon JA, Bernal W. Meta-analysis of performance
of King’s College Hospital Criteria in prediction of outcome in
nonparacetamol-induced acute liver failure. J Hepatol 2010;53:
492-499.
16. McKenzie TJ, Lillegard JB, Nyberg SL. Artificial and bioartificial liver
support. Semin Liver Dis 2008;28:210-217.
17. Kjaergard LL, Liu J, Als-Nielsen B, Gluud C. Artificial and bioartificial
support systems for acute and acute-on-chronic liver failure: a system-
atic review. JAMA 2003;289:217-222.
18. Freeman RB, Jr., Steffick DE, Guidinger MK, Farmer DG, Berg CL,
Merion RM. Liver and intestine transplantation in the United States,
1997-2006. Am J Transplant 2008;8:958-976.
19. Campsen J, Blei AT, Emond JC, Everhart JE, Freise CE, Lok AS, et al.
Outcomes of living donor liver transplantation for acute liver failure:
the adult-to-adult living donor liver transplantation cohort study. Liver
Transpl 2008;14:1273-1280.
HEPATOLOGY, Vol. 55, No. 3, 2012 LEE, STRAVITZ, AND LARSON 967
AASLD Position Paper
Corrections to the AASLD Position Paper: The Management of Acute Liver Failure: Update 2011 William
M. Lee, MD,1 Anne M. Larson, MD,2 and R. Todd Stravitz, MD3
* Corresponding author: William M. Lee
From the 1University of Texas, Southwestern Medical Center at Dallas, 5959 Harry Hines Boulevard, HP4.420E,
Dallas, TX 75390-8887;2Director, Swedish Liver Center, Swedish Health Systems, 1101 Madison Street #200,
Seattle WA 98104-1321; 3Virginia Commonwealth University, Section of Hepatology, PO Box 980341, 1200 East
Broad Street, Richmond, VA 23298
The electronic version of this article can be found online at:
http://www.aasld.org/practiceguidelines/Documents/AcuteLiverFailureUpdate2011.pdf
Published November 5, 2011 at www.aasld.org
Copyright © 2011 by the American Association for the Study of Liver Diseases
Correction December 2, 2011
Upon publication of the AASLD Position Paper on the Management of Acute Liver Failure: Update 2011, we
noticed that the end of paragraph three on page 14 was omitted. The complete paragraph can be found below.
In patients who do not respond to a volume challenge and norepinephrine, vasopressin and its analogues may
potentiate the effects of norepinephrine and allow a decrease in its infusion rate, which in turn may avoid intense
vasoconstriction in peripheral tissues which can lead to ischemia. However, the use of vasopressin/terlipressin was
discouraged by a study reporting cerebral vasodilation and increased ICH in severely encephalopathic patients.1 A
more recent study, however, has shown that terlipressin increased CPP and cerebral perfusion without increasing
ICP, and concluded that vasopressin and analogues might be useful with norepinephrine to ensure adequate brain
perfusion.2 In the US where terlipressin is not yet available, the addition of vasopressin should be considered in
hypotensive patients requiring escalating doses of norepinephrine, but should be administered with caution in
patients with ICH. Finally, persistence of hypotension despite volume repletion and vasopressors should prompt a
trial of hydrocortisone.3, 4
References
1. Shawcross DL, Davies NA, Mookerjee RP, Hayes PC, Williams R, Lee A, et al. Worsening of cerebral
hyperemia by the administration of terlipressin in acute liver failure with severe encephalopathy. Hepatology
2004;39:471-475.
2. Eefsen M, Dethloff T, Frederiksen HJ, Hauerberg J, Hansen BA, Larsen FS. Comparison of terlipressin and
noradrenalin on cerebral perfusion, intracranial pressure and cerebral extracellular concentrations of lactate and
pyruvate in patients with acute liver failure in need of inotropic support. J Hepatol 2007;47:381-6.
3. Harry R, Auzinger G, Wendon J. The effects of supraphysiological doses of corticosteroids in hypotensive liver
failure. Liver Internat 2003;23:71-7.
4. Harry R, Auzinger G, Wendon J. The clinical importance of adrenal insufficiency in acute hepatic dysfunction.
Hepatology 2002;36:395-402.
POSITION PAPER
AASLD Position Paper: The Management of
Acute Liver Failure: Update 2011
William M. Lee, MD,1 Anne M. Larson, MD,2 and R. Todd Stravitz, MD3
Preamble
These recommendations provide a data-supported
approach. They are based on the following: 1) Formal
review and analysis of recently-published world litera-
ture on the topic [Medline search]; 2) American Col-
lege of Physicians Manual for Assessing Health Prac-
tices and Designing Practice Guidelines;1 3) guideline
policies, including the AASLD Policy on the Develop-
ment and Use of Practice Guidelines and the AGA
Policy Statement on Guidelines;2; and 4) the experi-
ence of the authors in the specified topic.
Intended for use by physicians, the recommenda-
tions in this document suggest preferred approaches to
the diagnostic, therapeutic and preventive aspects of
care. They are intended to be flexible, in contrast to
standards of care, which are inflexible policies to be
followed in every case. Specific recommendations are
based on relevant published information. This docu-
ment has been designated as a Position Paper, since
the topic contains more data based on expert opinion
than on randomized controlled trials and is thus not
considered to have the emphasis and certainty of a
Practice Guideline. Nevertheless, it serves an important
purpose of facilitating proper and high level patient
care and we have characterized the quality of evidence
supporting each recommendation, in accordance with
the Practice Guidelines Committee of the AASLD
recommendations used for full Practice Guidelines
(Table 1)3 These recommendations are fully endorsed
by the AASLD.
Introduction
Acute liver failure (ALF) is a rare condition in
which rapid deterioration of liver function results in
altered mentation and coagulopathy in individuals
without known pre-existing liver disease. U.S. esti-
mates are placed at approximately 2,000 cases per
year.4,5 A recent estimate from the United Kingdom
was 1-8 per million population.6 The most promi-
nent causes include drug-induced liver injury, viral
hepatitis, autoimmune liver disease and shock or hy-
poperfusion; many cases (�15%) have no discernible
cause.7 Acute liver failure often affects young persons
and carries a high morbidity and mortality. Prior to
transplantation, most series suggested less than 15%
survival. Currently, overall short-term survival (one
year) including those undergoing transplantation is
greater than 65%.7 Because of its rarity, ALF has
been difficult to study in depth and very few con-
trolled therapy trials have been performed. As a
result, standards of intensive care for this condition
have not been established although a recent guideline
provides some general directions.8
Definition
The most widely accepted definition of ALF
includes evidence of coagulation abnormality, usually
an International Normalized Ratio (INR) �1.5, and
any degree of mental alteration (encephalopathy) in a
patient without preexisting cirrhosis and with an illness
of <26 weeks’ duration.9 Patients with Wilson disease,
vertically-acquired hepatitis B virus (HBV), or autoim-
mune hepatitis may be included in spite of the possi-
bility of cirrhosis if their disease has only been recog-
nized for <26 weeks. A number of other terms have
Abbreviations: ALF, acute liver failure; NAC, N-acetylcysteine; HELLP,
Hemolysis, Elevated Liver Enzymes, Low Platelets syndrome; gm/day, grams
per day; gm/kg, grams per kilogram; ICH, intracranial hypertension; ICP,
intracranial pressure; INR, international normalized ratio; CT, computerized
tomography; US ALFSG, United States Acute Liver Failure Study Group;
CPP, cerebral perfusion pressure; MAP, mean arterial pressure; mg/dL,
milligrams per deciliter, SIRS, systemic inflammatory response syndrome; FFP,
fresh frozen plasma; rFVIIa, recombinant activated factor; GI,
gastrointestinal; H2, histamine-2; PPI, proton pump inhibitors; CVVHD,
continuous venovenous hemodialysis; AFP, alpha fetoprotein; MELD, Model
for End-stage Liver Disease; mg/kg, milligrams per kilogram; IU/L,
international units per liter;
From the 1University of Texas, Southwestern Medical Cente
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