The Management of acute liver failure.pdf

AASLD POSITION PAPER

AASLD Position Paper: The Management of

Acute Liver Failure

Julie Polson and William M. Lee

Preamble

These recommendations provide a data-supported ap-

proach. They are based on the following: (1) formal re-

view and analysis of recently-published world literature

on the topic [Medline search], (2) American College of

Physicians Manual for Assessing Health Practices and De-

signing Practice Guidelines, 1 (3) guideline policies, in-

cluding the AASLD Policy on the Development and Use

of Practice Guidelines and the AGA Policy Statement on

Guidelines, 2 (4) the experience of the authors in the spec-

iﬁed 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 thus is not consid-

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

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 previously normal indi-

viduals. U.S. estimates are placed at approximately 2,000

cases per year. 4 The most prominent causes include drug-

induced liver injury, viral hepatitis, autoimmune liver dis-

ease and shock or hypoperfusion; many cases ( 20%)

have no discernible cause. 5 Acute liver failure often affects

young persons and carries a highmorbidity andmortality.

Prior to transplantation, most series suggested less than

15% survival. Currently, overall short-term survival with

transplantation is greater than 65%. 5 Because of its rarity,

ALF has been difﬁcult to study in depth and very few

controlled therapy trials have been performed. As a result,

standards of intensive care for this condition have not

been established.

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

with Wilson disease, vertically-acquired HBV, or auto-

immune hepatitis may be included in spite of the pos-

sibility of cirrhosis if their disease has only been

recognized for 26 weeks. A number of other terms

have been used including fulminant hepatic failure and

fulminant hepatitis or necrosis. Acute liver failure is a

better overall term that should encompass all durations

up to 26 weeks. Terms used signifying length of illness

such as hyperacute ( 7 days), acute (7-21 days) and

subacute ( 21 days and 26 weeks) are not particu-

larly helpful since they do not have prognostic signiﬁ-

cance distinct from the cause of the illness. For

example, hyperacute cases may have a better prognosis

but this is because most are due to acetaminophen

toxicity. 5

Abbreviations: ALF, acute liver failure; NAC, N-acetylcysteine; HELLP, Hemo-

lysis, Elevated Liver Enzymes, Low Platelets syndrome; ICH, intracranial hyperten-

sion; ICP, intracranial pressure; CT, computerized tomography; US ALFSG,

United States Acute Liver Failure Study Group; CPP, cerebral perfusion pressure;

MAP, mean arterial pressure; 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 he-

modialysis; APACHE, Acute Physiology and Chronic Health Evaluation; AFP,

alpha fetoprotein; MELD, Model for End-stage Liver Disease.

From the Division of Digestive and Liver Diseases, University of Texas South-

western Medical School Department, Dallas, Texas.

Received March 9, 2005; accepted March 10, 2005.

Address reprint requests to: Julie Polson, M.D., or William M. Lee, M.D.,

University of Texas, Southwestern Medical School, Division of Digestive and Liver

Diseases, 5323 Harry Hines Boulevard, Dallas, TX 75390-9151. E-mail:

julie.polson@utsouthwestern.edu or william.lee@utsouthwestern.edu.

Published online in Wiley InterScience (www.interscience.wiley.com).

DOI 10.1002/hep.20703

Potential conﬂict of interest: Nothing to report.

1179

Deﬁnition

The most widely accepted deﬁnition of ALF in-

cludes evidence of coagulation abnormality, usually an

INR

1180 POLSON AND LEE

HEPATOLOGY, May 2005

Table 1. Quality of Evidence on Which a Recommendation

Is Based 3

bodies (anti-nuclear and anti-smooth muscle antibodies)

and a pregnancy test in females. Plasma ammonia, pref-

erably arterial, 7,8 may also be helpful. A liver biopsy, most

often done via the transjugular route because of coagu-

lopathy, may be indicated when certain conditions such

as autoimmune hepatitis, metastatic liver disease, lym-

phoma, or herpes simplex hepatitis are suspected. As the

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

at a transplant center) whether and when to place the

patient on the list for transplantation. For patients in a

non-transplant center, the possibility of rapid progression

of ALF makes early consultation with a transplant facility

critical. Speciﬁc prognostic indicators may point toward

the need for transplantation. For patients with acetamin-

ophen-related ALF in particular, an arterial pH of 7.3

should prompt immediate consideration for transfer to a

transplant center and placement on a transplant list. 9

Patients with altered mentation should generally be

admitted to an ICU. Planning for transfer to a transplant

center should begin in patients with grade I or II enceph-

alopathy (Table 2) because they may worsen rapidly.

Early transfer is important as the risks involved with pa-

tient transport may increase or even preclude transfer

once stage III or IV encephalopathy develops. Evaluation

for transplantation should begin as early as possible. In

these critically ill patients with potential for rapid deteri-

Grade

Deﬁnition

Randomized controlled trials

II-1

Controlled trials without randomization

II-2

Cohort or case-control analytic studies

II-3

Multiple time series, dramatic uncontrolled experiments

III

Opinions of respected authorities, descriptive epidemiology

1.5)

and there is any evidence of altered sensorium, the diag-

nosis of ALF is established and hospital admission is man-

datory. Since the condition may progress rapidly, with

changes in consciousness occurring hour-by-hour, early

transfer to the intensive care unit (ICU) is preferred once

the diagnosis of ALF is made.

History taking should include careful review of possi-

ble exposures to viral infection and drugs or other toxins.

If severe encephalopathy is present, the history may be

provided entirely by the family or may be unavailable. In

this setting, limited information is available, particularly

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

liver disease. Jaundice is often but not always seen at pre-

sentation. Right upper quadrant tenderness is variably

present. Inability to palpate the liver or even to percuss a

signiﬁcant area of dullness over the liver can be indicative

of decreased liver volume due to massive hepatocyte loss.

An enlarged liver may be seen early in viral hepatitis or

with malignant inﬁltration, congestive heart failure, or

acute Budd-Chiari syndrome. History or signs of cirrhosis

should be absent as such features suggest underlying

chronic liver disease, which may have different manage-

ment implications. Furthermore, the prognostic criteria

mentioned below are not applicable to patients with

acute-on-chronic liver disease.

Initial laboratory examination must be extensive in or-

der to evaluate both the etiology and severity of ALF

(Table 2). In addition to coagulation parameters, early

testing should include routine chemistries (especially glu-

cose as hypoglycemia may be present and require correc-

tion), arterial blood gas measurements, complete blood

counts, blood typing, acetaminophen level and screens for

other drugs and toxins, viral hepatitis serologies (most

prominently A and B), tests for Wilson disease, autoanti-

Table 2. Initial Laboratory Analysis

Prothrombin time/INR

Chemistries

sodium, potassium, chloride, bicarbonate, calcium, magnesium, phosphate

glucose

AST, ALT, alkaline phosphatase, GGT, total bilirubin, albumin

creatinine, blood urea nitrogen

Arterial blood gas

Arterial lactate

Complete blood count

Blood type and screen

Acetaminophen level

Toxicology screen

Viral hepatitis serologies

anti-HAV IgM, HBSAg, anti-HBc IgM, anti-HEV§, anti-HCV*

Ceruloplasmin Level#

Pregnancy test (females)

Ammonia (arterial if possible)

Autoimmune markers

ANA, ASMA, Immunoglobulin levels

HIV status‡

Amylase and lipase

*Done to recognize potential underlying infection.

#Done only if Wilson disease is a consideration ( e.g., in patients less than 40

years without another obvious explanation for ALF); in this case uric acid level and

bilirubin to alkaline phosphatase ratio may be helpful as well.

‡Implications for potential liver transplantation.

§If clinically indicated.

Diagnosis and Initial Evaluation

All patients with clinical or laboratory evidence of

moderate to severe acute hepatitis should have immediate

measurement of prothrombin time and careful evaluation

for subtle alterations in mentation. If the prothrombin

time is prolonged by 4-6 seconds or more (INR

HEPATOLOGY, Vol. 41, No. 5, 2005

POLSON AND LEE 1181

oration it is necessary to make treatment plans promptly.

Social and ﬁnancial considerations are unavoidably tied to

the overall clinical assessment where transplantation is

contemplated. It is important to inform the patient’s fam-

ily or other next of kin of the potentially poor prognosis

and to include them in the decision-making process.

antidote for acetaminophen poisoning, has been shown to

be effective and safe for this purpose in numerous con-

trolled trials. 15-18 The standard acetaminophen toxicity

nomogram 19 may aid in determining the likelihood of

serious liver damage, but cannot be used to exclude pos-

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-

mended in any case of ALF in which acetaminophen over-

dose is a suspected or possible cause. NAC should be given

as early as possible, but may still be of value 48 hours or

more after ingestion. 21 NAC may be given orally (140

mg/kg by mouth or nasogastric tube diluted to 5% solu-

tion, followed by 70 mg//kg by mouthq4h 17 doses)

and has few side effects (occasional nausea, vomiting, rare

urticaria or bronchospasm). In patients with ALF oral

administration may often be precluded (for instance, by

active gastrointestinal bleeding or worsening mental sta-

tus), and NAC may be administered intravenously (load-

ing dose is 150 mg/kg in 5% dextrose over 15 minutes;

maintenance dose is 50 mg/kg given over 4 hours

followed by 100 mg/kg administered over 16 hours).

Allergic reactions may be successfully treated with discon-

tinuation, antihistamines 22 and epinephrine for bronch-

spasm.

Recommendations

1. Patients with ALF should be admitted and

monitored frequently, preferably in an ICU (III).

2. Contact with a transplant center and plans to

transfer appropriate patients with ALF should be ini-

tiated early in the evaluation process (III).

3. The precise etiology of ALF should be sought to

guide further management decisions (III).

Determining Etiologies and Speciﬁc

Therapies

Etiology of ALF provides one of the best indicators of

prognosis, 5

and also dictates speciﬁc management op-

Acetaminophen Hepatotoxicity

Acetaminophen hepatotoxicity is suggested by historic

evidence for excessive ingestion either as an intended sui-

cidal overdose or the inadvertent use of supra-therapeutic

quantities of pain medications. Acetaminophen is a dose-

related toxin; most ingestions leading to ALF exceed 10

gm/day. However, severe liver injury can occur rarely

when doses as low as 3-4 gm/day are taken. 10 Very high

aminotransferases may be seen; serum levels exceeding

3,500 IU/L are highly correlated with acetaminophen

poisoning 11 and should prompt consideration of this eti-

ology even when historic evidence is lacking. Because

acetaminophen is the leading cause of ALF (at least in the

United States and Europe) and there is an available anti-

dote, acetaminophen levels should be drawn in all pa-

tients presenting with ALF. Low or absent

acetaminophen levels do not rule out acetaminophen poi-

soning since the time of ingestion may be remote or un-

known, especially when overdose may have been

unintentional and/or occurred over several days. If acet-

aminophen ingestion is known or suspected to have oc-

curred within a few hours of presentation, activated

charcoal may be useful for gastrointestinal decontamina-

tion. While it is most effective if given within one hour of

ingestion, 12 it may be of beneﬁt as long as 3 to 4 hours

after ingestion. 13 Administration of activated charcoal

(standard dose 1g/kg orally, in a slurry) just prior to ad-

ministration of N-acetylcysteine does not reduce the ef-

fect of N-acetylcysteine. 13 N-acetylcysteine (NAC), the

Recommendations

4. For patients with known or suspected acet-

aminophen overdose within 4 hours of presentation,

give activated charcoal just prior to starting NAC (I).

5. Begin NAC promptly in all patients where the

quantity of acetaminophen ingested, serum drug level

or rising aminotransferases indicate impending or

evolving liver injury (II-1).

6. NAC may be used in cases of acute liver failure

in which acetaminophen ingestion is possible or when

knowledge of circumstances surrounding admission is

inadequate (III).

Mushroom Poisoning

Mushroom Poisoning (usually Amanita phalloides )

may cause ALF, and the initial history should always in-

clude inquiry concerning recent mushroom ingestion.

There is no available blood test to conﬁrm the presence of

these toxins, but this diagnosis should be suspected in

patients with a history of severe gastrointestinal symp-

toms (nausea, vomiting, diarrhea, abdominal cramping),

which occur within hours to a day of ingestion. If these

effects are present, it may be early enough to treat patients

with gastric lavage and activated charcoal via naso-gastric

tube. Fluid resuscitation is also important. Traditionally,

very low rates of survival have been reported without

tions.

1182 POLSON AND LEE

HEPATOLOGY, May 2005

transplantation, 23 but more recently complete recovery

has been described with supportive care and medical

treatment. 24 Penicillin G and silibinin (silymarin or milk

thistle) are the accepted antidotes despite no controlled

trials proving their efﬁcacy. 23,25,26 While some reports

have not found penicillin G to be helpful, 27 enough efﬁ-

cacy has been reported to warrant consideration of the

drug (given intravenously in doses of 300,000 to 1million

units/kg/day) in patients with known or suspected mush-

room poisoning. 28 Silibinin has generally been reported

to be more successful than penicillin G, although penicil-

lin G has been used more frequently in the United

States. 27,28 Silibinin/silymarin is not available as a licensed

drug in the United States, although it is widely available in

Europe and South America. In the United States, it is

commercially available as milk thistle extracts, tablets,

capsules or tincture. These products usually contain

70%-80% silymarin, although there is no governmental

regulation of such herbal supplements; silymarin concen-

trations may vary considerably between preparations and

manufacturers. 29 When used for treatment of mushroom

poisoning, silymarin has been given in average doses of

30-40 mg/kg/day (either intravenously or orally) for an

average duration of 3 to 4 days. 26 N-acetylcysteine is often

combined with these other therapies, but has not been

shown to be effective in animal studies 30 ; nevertheless,

case reports have described its use as a part of overall

management. 31

Table 3. Some Drugs Which May Cause Idiosyncratic Liver

Injury Leading to ALF

Isoniazid

Isoﬂurane

Sufonamides

Lisinopril

Phenytoin

Nicotinic acid

Statins

Imipramine

Propylthiouracil

Gemtuzumab

Halothane

Amphetamines/Ecstasy

Disulﬁram

Labetalol

Valproic acid

Etoposide

Amiodarone

Flutamide

Dapsone

Tolcapone

Herbals*

Quetiapine

Didanosine

Nefazodone

Efavirenz

Allopurinol

Metformin

Methyldopa

Oﬂoxacin

Ketoconazole

PZA

Troglitazone

Diclofenac

Combination agents with enhanced toxicity:

Trimethoprim-sulfamethoxazole

Rifampin-isoniazid

Amoxicillin-clavulanate

*Some Herbal products/dietary supplements that have been associated with

hepatotoxicity include:

Kava kava

Chaparral

Skullcap

Germander

Pennyroyal

Jin Bu Huan

Heliotrope

Rattleweed

Comfrey

Sunnhemp

Senecio

Impila

Greater celandine

Gum Thistle

He Shon Wu

Ma Huang

LipoKinetix

Bai-Fang herbs

Recommendation

7. In ALF patients with known or suspected

mushroom poisoning, consider administration of pen-

icillin G and silymarin (III).

8. Patients with acute liver failure secondary to

mushroom poisoning should be listed for transplanta-

tion, as this procedure is often the only lifesaving

option (III).

tory. There are no speciﬁc antidotes for idiosyncratic drug

reactions; corticosteroids are not indicated unless a drug

hypersensitivity reaction is suspected. Determination of a

particular medication as the cause of ALF is a diagnosis of

exclusion. Other causes of ALF should still be ruled out

even if a drug is suspected. Any presumed or possible

offending agent should be stopped immediately where

possible. Classes of drugs commonly implicated include

antibiotics, non-steroidal anti-inﬂammatory agents and

anti-convulsants (Table 3).

Drug Induced Hepatotoxicity

A variety of medications have been associated with

acute liver injury. Before implicating a particular sub-

stance, history should include careful listing of all agents

taken, the time period involved, and the quantity in-

gested. Drugs other than acetaminophen rarely cause

dose-related toxicity. Most examples of idiosyncratic drug

hepatotoxicity occur within the ﬁrst 6 months after drug

initiation. A potentially hepatotoxic medication that has

been used continually for more than 1 to 2 years is un-

likely to cause de novo liver damage. Certain herbal prep-

arations and other nutritional supplements have been

found to cause liver injury, 32 so inquiry about such sub-

stances should be included in a complete medication his-

Recommendations

9. Obtain details (including onset of ingestion,

amount and timing of last dose) concerning all pre-

scription and non-prescription drugs, herbs and di-

etary supplements taken over the past year (III).

10. Determine ingredients of non-prescription

medications whenever possible (III).

11. In the setting of acute liver failure due to

possible drug hepatotoxicity, discontinue all but essen-

tial medications (III).

HEPATOLOGY, Vol. 41, No. 5, 2005

POLSON AND LEE 1183

Viral Hepatitis

Hepatitis serological testing should be done for identi-

ﬁcation of acute viral infection (Table 2) even when an-

other putative etiology is identiﬁed. Viral hepatitis has

become a relatively infrequent cause of ALF (United

States: 12%; hepatitis B – 8%, hepatitis A – 4%). 5 Acute

hepatitis Dmay occasionally be diagnosed in a hepatitis B

positive individual. Although controversial, hepatitis C

alone does not appear to cause ALF. 5,33 Hepatitis E is a

signiﬁcant cause of liver failure in countries where it is

endemic, and tends to be more severe in pregnant

women. 33,34 This virus should be considered in anyone

with recent travel to an endemic area such as Russia, Pa-

kistan, Mexico, or India. With acute viral hepatitis, as

withmany other etiologies of ALF, care is mainly support-

ive. Of note, the nucleoside analog lamivudine (and pos-

sibly adefovir), used widely in the treatment of chronic

hepatitis B, may be considered in patients with acute hep-

atitis B, although these drugs have not been subjected to a

controlled trial 35 in acute disease. Acute liver failure due

to reactivation of hepatitis B may occur in the setting of

chemotherapy or immunosuppression. Recent evidence

suggests that patients found to be positive for HBsAg who

are to begin such therapy should be treated prophylacti-

cally with a nucleoside analog, and that such treatment

should be continued for 6 months after completion of

immunosuppressive therapy (please refer to the AASLD

Practice Guideline on Management of Chronic Hepatitis

B, Update of Recommendations 36 ). Herpes virus infec-

tion rarely causes ALF. Immunosuppressed patients or

pregnant women (usually in the third trimester) are at

increased risk, but occurrences of herpes virus ALF have

been reported in healthy individuals. 33,37,38 Skin lesions

are present in only about 50% of cases. Liver biopsy is

helpful in making the diagnosis. Treatment should be

initiated with acyclovir for suspected or documented

cases. 37,38 Other viruses such as varicella zoster 39 have oc-

casionally been implicated in causing hepatic failure.

Wilson disease

Wilson disease is an uncommon cause of ALF (2%-3%

of cases in the US ALFSG). Early identiﬁcation is critical

because the fulminant presentation of Wilson disease is

considered to be uniformly fatal without transplantation.

The disease typically occurs in young patients, accompa-

nied by the abrupt onset of hemolytic anemia with serum

bilirubin levels 20 mg/dL. Due to the presence of he-

molysis, the indirect-reacting bilirubin is often markedly

elevated along with the total bilirubin. Kayser-Fleischer

rings are present in about 50% of patients presenting with

ALF due toWilson disease. 40 Serum ceruloplasmin is typ-

ically low, but may be normal in up to 15% of cases and is

often reduced in other forms of ALF; high serum and

urinary copper levels as well as hepatic copper measure-

ment may conﬁrm the diagnosis. Very low serum alkaline

phosphatase or uric acid levels are hints to suggest Wilson

disease in the absence of other indicators. A high bilirubin

(mg/dL) to alkaline phosphatase (IU/L) ratio ( 2.0) is a

reliable albeit indirect indicator of Wilson disease in this

setting. 40,41 Renal function is often impaired as the re-

leased copper can cause renal tubular damage. Treatment

to acutely lower serum copper and to limit further hemo-

lysis should include albumin dialysis, continuous hemo-

ﬁltration, plasmapheresis or plasma exchange. Initiation

of treatment with penicillamine is not recommended in

ALF as there is a risk of hypersensitivity to this agent;

acute lowering of the copper is more effectively accom-

plished using direct plasma copper reduction techniques,

especially when renal function is impaired. 40 Although

such copper lowering measures should be considered, re-

covery is infrequent without transplantation. 40,42 Wilson

disease is one of the special circumstances in which pa-

tients may already have evidence of cirrhosis and still be

considered to have a diagnosis of ALF when rapid deteri-

oration occurs. Please refer to the AASLDPractice Guide-

line on Wilson Disease for more detailed information

regarding the diagnosis and management of patients with

this condition. 40

Recommendations

12. Viral hepatitis A- and B- (and E-) related acute

liver failure must be treated with supportive care as

no virus-speciﬁc treatment has been proven effective

(III).

13. Nucleoside analogs should be given prior to

and continued for 6 months after completion of che-

motherapy in patients with Hepatitis B surface anti-

gen positivity to prevent reactivation/acute ﬂare of

disease (III).

14. Patients with known or suspected herpes virus

or varicella zoster as the cause of acute liver failure

should be treated with acyclovir (III).

Recommendations

15. Diagnostic tests for Wilson disease should

include ceruloplasmin, serum and urinary copper

levels, total bilirubin/alkaline phosphatase ratio,

slit lamp examination for Kayser-Fleischer rings,

and hepatic copper levels when liver biopsy is fea-

sible (III).

16. Patients in whom Wilson disease is the likely

cause of acute liver failure must be immediately

placed on the liver transplant list (III).

Plik z chomika:

Inne pliki z tego folderu:

Inne foldery tego chomika: