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Gastroenterology Board Review Manual
Statement of
Editorial Purpose
The Hospital Physician Gastroenterology Board
Review Manual is a study guide for fellows
and practicing physicians preparing for board
examinations in gastroenterology. Each manual
reviews a topic essential to current practice in
the subspecialty of gastroenterology.
PUBLISHING STAFF
PRESIDENT, Group PUBLISHER
Acute Liver Failure
Contributors:
Nicholas Agresti, MD
Gastroenterology Fellow, Division of Gastroenterology and
Hepatology, University of Florida, Jacksonville, FL
Christopher O’Brien, MD, AGAF, FRCMI
Chief of Clinical Hepatology and Research, Center for
Liver Diseases, Professor of Clinical Medicine, Divisions of
Liver and GI Transplantation, University of Miami School of
Medicine, Miami, FL
Bruce M. White
Senior EDITOR
Robert Litchkofski
executive vice president
Barbara T. White
executive director
of operations
Jean M. Gaul
Table of Contents
NOTE FROM THE PUBLISHER:
This publication has been developed with­
out involvement of or review by the Amer­
ican Board of Internal Medicine.
Hospital Physician Board Review Manual
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Initital Evaluation. . . . . . . . . . . . . . . . . . . . . . . . . 1
Etiology and Management . . . . . . . . . . . . . . . . . . 2
Treatment of Acute Liver Failure. . . . . . . . . . . . 10
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Board Review Questions. . . . . . . . . . . . . . . . . . . 12
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
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Acute Liver Failure
Gastroenterology Board Review Manual
Acute Liver Failure
Nicholas Agresti, MD, and Christopher O’Brien, MD, AGAF, FRCMI
Introduction
Acute liver failure (ALF) is the rapid onset of severe liver injury, hepatic encephalopathy, and coagulopathy (international normalized ratio [INR] >1.5)
in a patient without preexisting liver disease.1 The incidence of ALF in the United States is approximately
3000 cases per year, with the majority of ALF cases
caused by drug-induced liver injury (DILI) followed
by viral hepatitis.1–3 Identifying the etiology and
managing the sequelae of liver failure, such as
cerebral edema, encephalopathy, coagulopathy,
hemodynamic instability, renal failure, metabolic
disturbances, and infection, are the mainstays of
treatment.4 Prior to the advent of liver transplantation, ALF was almost universally fatal, with a 15%
survival rate. However, with liver transplantation the
1-year survival rate now ranges from 65% to 73%,
and is higher yet with a living related donor transplant.5–7 The early management of patients should
occur in the intensive care unit (ICU) with transfer to
a liver transplant center as soon as possible.
INITIAL EVALUATION
A patient with ALF will typically present with
laboratory data consistent with acute hepatitis, a
prolonged prothrombin time of 6 seconds or more,
an INR ≥1.5, and a change in mental status. A
focused history and physical examination with attention to ingestion of toxins is important so that
specific therapy can be initiated, as the natural history of ALF is impacted by its cause (Table 1).4,8 An
accurate history is critical, since certain etiologies
of ALF (ie, autoimmune hepatitis, hepatitis B, DILI,
and those of indeterminate cause) have a dismal
survival rate (<25%) without liver transplant.
The initial laboratory studies are directed to
determining the etiology and severity of the liver
disease (Table 2). Blood studies should include a
complete blood count, complete metabolic profile,
arterial blood gas analysis, coagulation profile,
blood type and screen, and diagnostic tests to rule
out specific etiologies of ALF.4
The initial physical exam should include a mental
status exam with documentation of grade of encephalopathy (Table 3) and a search for findings
consistent with preexisting, chronic liver disease,
such as bitemporal wasting, parotid gland enlargement, spider angiomata, gynecomastia, splenomegaly, and testicular atrophy. Although ascites is
typically seen in chronic liver disease, it can present in ALF with etiologies such as veno-occlusive
disease.
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Acute Liver Failure
Table 1. Etiology and Management Options in Acute Liver Failure
Table 2. Initial Laboratory Studies
Etiology
Treatment
Prothrombin time/INR
Acetaminophen
N-acetylcysteine
Herpes simplex virus
Cytomegalovirus
Pregnancy associated
Budd-Chiari syndrome
Acyclovir
Ganciclovir
Delivery
Thrombolysis, vascular shunt, treat
underlying cause, hepatic venous
angioplasty, stenting of inferior vena
cava
Decompressive vascular shunt,
thrombolysis
Inotropes
Antibiotics, vasopressor support
Liver transplantation
Penicillin, silibinin
Chemotherapy
Veno-occlusive disease
Cardiac failure
Septic shock
Wilson disease
Amanita phalloides
Lymphoma
ETIOLOGY AND MANAGEMENT
Complete metabolic profile
Blood type and screen
Complete blood count
Toxicology screen
Viral hepatitis serologies: anti-HAV IgM, HBsAg/HBcAb IgM,
anti-HCV/HCV RNA PCR, anti-HEV, HSV1 IgM, VZV
Ceruloplasmin level
Pregnancy test
Ammonia level
Autoimmune markers: ANA, ASMA, immunoglobulin levels
HIV-1, HIV-2 assays
Amylase, lipase
Arterial blood gas, arterial lactate
Acetaminophen level
Urine electrolytes
ANA = antinuclear antibody; ASMA = anti-smooth muscle antibody;
HAV = hepatitis A virus; HBsAg/HBcAb = hepatitis B surface antigen/
hepatitis B core antigen; HCV = hepatitis C virus; HEV = hepatitis
E virus; HSV1 = herpes simplex virus 1; IgM = immunoglobulin M;
PCR = polymerase chain reaction; VZV = varicella zoster virus.
ACETAMINOPHEN Toxicity
Accounting for approximately 40% of ALF cases,
ingestion of more than 10 g of acetaminophen may
cause severe liver injury and carries a high mortality
rate.4,9–12 The standard acetaminophen toxicity nomogram may be useful to determine the likelihood
of serious liver injury in a patient upon initial presentation. A low or absent level of acetaminophen does
not rule out hepatotoxicity since the time of ingestion could be unknown or the ingestion could have
occurred in multiple dosage intervals.13,14
The clinical features of acetaminophen hepatotoxicity are variable but usually occur over 12 to
72 hours and in 3 phases. The first phase (12 to
24 hours post ingestion) is characterized by nausea, vomiting, and anorexia. This is followed by a
second phase, usually lasting 24 hours, of relative
well-being, which can rapidly deteriorate to the
third phase. The third phase, occurring 24 to 48
2 Hospital Physician Board Review Manual
hours after ingestion, includes the onset of multisystem organ failure usually requiring admission
to the ICU.4
Grading Severity and Transplant Referral
The King's College Criteria provide objective
criteria to predict the risk of death after an acetaminophen overdose or other causes of ALF
(Table 4). In acetaminophen hepatotoxicity, there
are 2 important criteria for risk of death: an arterial
pH of less than 7.3, irrespective of grade of encephalopathy; or a prothrombin time greater than
100 seconds and a serum creatinine concentration
greater than 3.4 mg/dL (301 mmol/L) in patients
who have grade III or IV encephalopathy.
In other causes of ALF, liver transplantation is
indicated in patients who have either a prothrombin
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Acute Liver Failure
time greater than 100 seconds, irrespective of the
grade of encephalopathy, or any 3 of the following variables: age less than 10 or greater than 40
years, hepatitis of unknown origin, idiosyncratic
drug reactions, duration of jaundice before development of encephalopathy greater than 7 days, prothrombin time greater than 50 seconds, or serum
bilirubin greater than 18 mg/dL.
Table 3. Encephalopathy Grades
Grade of Encephalopathy
Description
I
Minimal change in consciousness,
altered mood
Inappropriate behavior, drowsy,
asterixis
Disoriented, difficult to arouse, slurred
or incoherent speech
Comatose, posturing, no response to
painful stimuli
II
III
IV
Acetaminophen Metabolic Pathways
The biochemical pathways of acetaminophen metabolism and histological changes on liver biopsy in
ALF are well known. The biochemical pathway is provided in the Figure. Acetaminophen is predominantly
conjugated into glucuronate and sulfate moieties
by phase II metabolism and excreted in the urine.
Approximately 5% is metabolized by the cytochrome
P450 pathway to the toxic metabolite NAPQI, which
is conjugated by glutathione to nontoxic cysteine and
mercapturic acid moieties. In acetaminophen toxicity,
the phase II conjugation enzymes become saturated
and a higher fraction of acetaminophen is converted
to NAPQI. The conjugation of NAPQI to glucuronide
occurs until the hepatic reserves of glutathione are
depleted, after which NAPQI accumulates and causes
damage to the hepatocytes. The NAPQI binds to
cellular proteins, inducing oxidation in thiol groups
in mitochondria leading to formation of other toxic
metabolites and overall mitochondria dysfunction.
Damage occurs primarily in areas of the liver that
are furthest away from the hepatic artery and thus
relatively poorly perfused with oxygen, termed zone
3 of the hepatic lobule. Acetaminophen overdose
is associated with zone 3 submassive (bridging) or
panacinar (massive) necrosis.11
Treatment
The basis of treatment for acetaminopheninduced liver failure focuses on early detection and
proper administration of N-acetylcysteine (NAC).
In ALF, the aminotransferase levels classically are
in the 1000s, with the aspartate aminotransferase
(AST) greater than the alanine aminotransferase
(ALT) level; these findings are helpful in differentiating acetaminophen toxicity from other causes
of ALF. Despite the severity of the presentation,
the bilirubin concentration is only (relatively) mildly
elevated in contrast to other etiologies of ALF. For
patients with known or suspected acetaminophen
overdose within 4 hours of presentation, activated
charcoal should be given just prior to the start
of NAC dosing.15 This administration of activated
charcoal does not affect the metabolism of the intravenous form of NAC.16
Oral NAC can be administered to patients with no
encephalopathy or grade 1 encephalopathy. However, patients with grade 2 and greater encephalopathy should receive intravenous NAC. Although NAC
should be given as early as possible, it still may be of
value up to 48 hours after ingestion. If the oral form is
the only option, the recommended dosing is 140 mg/kg
followed by 70 mg/kg by mouth every 4 hours for 17
doses. The intravenous form of NAC includes a loading dose of 150 mg/kg in 5% dextrose over 15 minutes; the maintenance dose is 50 mg/kg given over
4 hours followed by 100 mg/kg administered over
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Table 4. King’s College Hospital Criteria for Risk of Death in Fulminant Hepatic Failure
Acetaminophen-induced disease
All other causes of fulminant hepatic failure
Arterial pH <7.3 after adequate fluid resuscitation (independent Prothrombin time >100 sec (INR >6.5) (independent of the grade of
of the grade of encephalopathy)
encephalopathy)
OR
OR
Grade III or IV encephalopathy and
Any 3 of the following variables are present (independent of the grade of
encephalopathy):
Prothrombin time >100 sec (INR >6.5) and
1. Age <10 years or >40 years
Serum creatinine >3.4 mg/dL (300 mmol/L)
2. Etiology: non-A, non-B hepatitis, halothane hepatitis, idiosyncratic drug
reactions
3. Duration of jaundice before onset of encephalopathy >7 days
4. Prothrombin time >50 sec (INR >3.5)
5. Serum bilirubin >18 mg/dL (308 mmol/L)
16 hours, or 6 mg/kg/hr.17,18 NAC should be given in
cases of ALF in which acetaminophen ingestion is
possible or when knowledge of circumstances surrounding admission is inadequate but aminotransferases suggest acetaminophen poisoning.15
There has been controversy in the literature
regarding prolonged NAC administration for more
than 72 hours. In a randomized study, NAC administration in nonacetaminophen ALF improved
survival; this was shown during early administration in grade I and grade II encephalopathy.19 NAC
has interestingly also been shown to improve
transplant-free survival even in patients with ALF
not due to acetaminophen. This has led to the
recommendation that NAC be considered in all
patients with ALF.
DRUG-INDUCED LIVER Injury AND DRUGINDUCED ACUTE LIVER FAILURE
An important part of determining the etiology of
DILI or drug-induced acute liver failure (DILF) is a
detailed medication profile including dietary and
herbal supplements and length of therapy. DILI can
be subclinical and chronic and progress to DILF20
4 Hospital Physician Board Review Manual
and can appear solely as hepatocellular or cholestatic injury or as mixed injury.4 DILI is a diagnosis
of exclusion; usually the AST and ALT levels are
elevated 2 to 3 times the upper limit of normal.
There are over 300 medications implicated in causing DILI and DILF. In a recent prospective study that
excluded acetaminophen as a cause of ALF and
evaluated 300 patients over 3 years, a single medication was implicated in 73% of DILI cases, dietary
causes in 9%, and multiple agents in 18%.20 In this
study, DILI was characterized as mild in 27%, moderate in 19%, moderate-hospitalized in 33%, and
severe in 13%, and resulted in liver transplantation
or death in 6%.
The overall incidence of ALF secondary to drugs
is approximately 13%.7 These implicated medications may be dose-dependent, and patients will
have extrahepatic manifestations of failure such as
cerebral edema, encephalopathy, coagulopathy,
hemodynamic instability, renal failure, and metabolic disturbances.7 Many drug classes have been
implicated in DILI and DILF, and the current practice recommendations include cessation of medication, determining specific ingredients (in dietary
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Acute Liver Failure
and herbal supplements), and considering NAC
administration.15 Common medications leading to
DILI and DILF are listed in Table 5.
VIRAL HEPATITIS
The viruses that mainly affect the liver and those
associated with systemic infections that have liver
involvement vary in incidence and geographic location. These viruses include hepatitis A, hepatitis
B, hepatitis C, hepatitis D, hepatitis E, cytomegalovirus (CMV), Epstein-Barr virus, herpes simplex
virus, parvovirus B19, varicella-zoster virus, enterovirus, and adenovirus. The viruses that affect the
liver cause hepatocellular injury in 1 of 2 clinical
settings: acute viral transmission or reactivation of
latent virus in an immunosuppressed patient.
Hepatitis A and E
Hepatitis A virus (HAV) has an incubation period
of 2 to 4 weeks, is self-limited in a healthy individual, and does not have cross-reactivity with the other
hepatitis viruses.4 Approximately 5% of patients
with acute hepatitis A and E requiring admission
to a hospital will develop ALF.2 Hepatitis A and E
are transmitted via the fecal-oral route and have
a higher incidence in developing countries. One
study of an urban outbreak of hepatitis A in Tennessee (1995) that included 256 patients in 15 acute
care hospitals found that patients over 40 years
of age had a higher risk of complications, which
included death in 5 patients (2%).21 According to
the Centers for Disease Control and Prevention,
20,000 to 36,000 cases of acute HAV infections
were reported in the United States per year during
the period 1980 to 1995; the incidence declined
significantly (5683 cases in 2006) secondary to
childhood vaccination introduced in 1995.22 A similar study performed in the United States found 3.1%
of ALF cases were due to HAV infection.23
conjugation
Glucuronide
moiety
(Nontoxic)
conjugation
Sulfate
moiety
P450
(Nontoxic)
(2E1)
Acetaminophen
N-acetyl-p-benzo-quinone imine
(NAPQI) (Toxic)
NAC
Glutathione
Cysteine and mercapturic acid
conjugates (Nontoxic)
Figure. Metabolic pathways of acetaminophen. NAC = N-acetylcysteine.
A prospective evaluation which followed patients
with chronic hepatitis B and C who were seronegative for hepatitis A over a 7-year period suggested
that once a superinfection with HAV occurred, there
was an increase in ALF for patients with chronic
hepatitis C. For this reason, hepatitis A vaccination is recommended in patients with chronic
hepatitis C.24 In order to make a diagnosis of
hepatitis A, immunoglobulin M (IgM) HAV antibodies must be identified in the serum on laboratory
testing.
Hepatitis E virus (HEV) is transmitted via the
fecal-oral route and has a higher occurrence in developing countries, with a mortality of up to 54%.25
HEV is a leading cause of ALF in pregnant women
in endemic areas of India and Southeast Asia.
Various mechanisms to explain this increase in the
severity of this disease in pregnancy have been
proposed. One theory suggested that low levels of
CD4 cells and high levels of CD8 cells in addition
to high circulating steroid hormones contributed to
the increase in mortality in pregnant women compared to nonpregnant women with ALF secondary
to acute hepatitis E.26
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Table 5. Drugs Classes Associated with Drug-Induced Liver Failure
Chemotherapy
Gemcitabine, carboplatin, flutamide
Antihypertensive/antiarrhythmic
NSAIDs and analgesics
Antifungal/Antimicrobial/HAART
Captopril, enalapril, lisinopril/amiodarone
Acetaminophen, ibuprofen, diclofenac, oxaprozin
Terbinafine, ketoconazole, cotrimoxazole/ciprofloxacin, ofloxacin, trimethoprim-sulfamethoxazole,
rifampin-isoniazid, amoxicillin-clavulanate, minocycline, dapsone, lamotrigine/didanosine, efavirenz
Valproic acid, carbamazepine, phenytoin
Kava kava, he shou wu, ma huang, hydroxycut, germander
Cocaine, ecstasy
Psychiatric
Herbal and dietary supplements
Illicit drugs
Hepatitis B, C, D
The hepatitis B virus (HBV) can be reactivated
in the setting of immunosuppressive therapy, chemotherapy, abrupt discontinuation of HBV antiviral
therapy, and hepatitis D coinfection or superinfection of a patient with chronic hepatitis B. Hepatitis
B is endemic to Southeast Asia, the Middle East,
and sub-Saharan Africa. In these areas, age plays
an important role in chronicity of disease. Chronic
infection occurs in 90% of children younger than 5
years and 30% to 50% of those older than 5 but
less than 18, while 90% of infected adults will clear
the virus.27 In acute HBV infection, the nucleoside
analog lamivudine may be considered for treatment, but there have been conflicting studies of its
efficacy.12,28–39
Hepatitis B incidence is on the decline, reflecting the vaccination initiative which was started in
1982 for people in endemic areas and in 1991 for
all children.40 However, patients on active antiviral
therapy for chronic hepatitis B can develop ALF
secondary to noncompliance with their hepatitis B
medication. This situation should prompt an evaluation of the current resistance profile of their medication with reinitiation of HBV antiviral therapy as
soon as possible. It is currently recommended that
patients undergoing immunosuppressive therapy be
treated for at least 6 months after completion of im6 Hospital Physician Board Review Manual
munosuppressive therapy.41 In the setting of newly
diagnosed HIV along with acute hepatitis B, highly
active antiretroviral therapy (HAART) should target
both viruses and include a combination of lamivudine plus tenofovir or emtricitabine plus tenofovir.41
Hepatitis D virus (HDV) is a defective virus that
is dependent on HBV for assembly and secretion.
HDV superinfection of a patient with chronic hepatitis
B can lead to ALF in endemic areas of the world, although the incidence has declined.42 Travel to areas
of northern Europe, Asia, the Mediterranean, northern South America, or Africa should prompt testing
for hepatitis D.43 Patients who acquire HBV and HDV
simultaneously (co-infection) and survive to develop
chronic liver disease have a higher risk of developing
complications secondary to cirrhosis and hepatocellular carcinoma compared to monoinfected chronic
hepatitis B patients. In either case, co- or superinfection, the risk of ALF is greater than that of acute
hepatitis B monoinfection alone.44,45
Acute hepatitis C causing ALF remains controversial. However, a Taiwanese study showed that
patients with chronic hepatitis B that are subsequently exposed to hepatitis C virus (HCV) have a
higher risk of developing ALF.46 Despite this, other
authors evaluating ALF in 308 patients reported by
17 tertiary care centers within a 41-month period
found that a majority of the cases were attributed to
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acetaminophen (39%) or hepatitis A and B (12%).
This study did not report hepatitis C as a causative
agent in any patient.7
Other Viruses
Viruses such as parvovirus B19, varicella-zoster
virus, enterovirus, and adenovirus are rare causes
of ALF. Herpes virus–induced ALF usually presents in immunosuppressed or pregnant patients or
in the setting of malignancy, and skin lesions are
present in 57% of cases.47 Prompt administration
of acyclovir 5 to 10 mg/kg every 8 hours is the recommended treatment.48 CMV infection can affect
immunosuppressed patients, especially in the first
3 months following an allograft transplant; administration of ganciclovir should be considered in this
population. The major risk factors in this patient
population are medication noncompliance and
CMV-seropositive donor and CMV-seronegative
recipient.49 Lung and heart transplant patients are
at the highest risk, followed by liver transplant patients; kidney transplant patients are at lower risk.50
WILSON DISEASE
ALF secondary to Wilson disease primarily affects children or young adults without history of any
underlying liver condition. The classical hallmarks
of the disease are laboratory findings including
low ceruloplasmin, uric acid, and alkaline phosphatase, increased urinary copper, and Coombsnegative hemolytic anemia with associated renal
failure.51 Unfortunately, the diagnosis of Wilson
disease is often one of exclusion. Most frequently,
the serum ceruloplasmin can be normal or even
high. In addition, it takes days to obtain the results
of a 24-hour urinary copper test. Kayser-Fleischer
rings are present in only 50% of patients. A serum
albumin to alkaline phosphatase ratio less than
2.0 is 100% specific and sensitive to diagnose
Wilson disease.52 Chelating therapy is not effective
in the acute setting and has been shown to cause
hypersensitivity reactions.52,53 A fulminant Wilson
disease patient must be referred urgently for transplantation since survival without transplantation is
approximately zero. In addition, the removal of the
abnormal liver will cure Wilson disease.
AUTOIMMUNE HEPATITIS
Acute autoimmune hepatitis primarily affects young
females (mean age 41) who are overweight (body
mass index BMI ≥30) and do not have a preexisting
liver condition.54 The majority of patients (70%) will
have positive antinuclear and anti-smooth muscle
antibodies, representing type I autoimmune hepatitis.
Approximately 3% will be positive for the anti-liver/
kidney microsome (LKM) or anti-soluble liver antigen
(SLA) antibodies, representing type II and III autoimmune hepatitis, respectively. The remainder are
positive for anti-mitochondrial antibody, representing
a potential overlap of disease states.54 Occasionally,
these markers are negative, and if clinical suspicion
for autoimmune hepatitis is high, a liver biopsy should
be performed.53 Corticosteroids should be initiated
promptly (40–60 mg/day) and should be continued
while awaiting liver transplantation.55 Autoimmune
hepatitis, unlike Wilson disease, may recur after liver
transplantation, and these patients may have higher
rates of acute and chronic rejection compared to
patients who undergo liver transplantation for other
diseases.56,57
PREGNANCY AND ALF
Acute Fatty Liver of Pregnancy (AFLP)
AFLP is a condition which occurs in the third
trimester of pregnancy and is potentially fatal.58
The initial presentation is similar to flu-like illness
with nausea, fatigue, anorexia, and abdominal pain
which progresses to fever and jaundice.59 Patients
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with AFLP may develop altered mental status,
disseminated intravascular coagulopathy, gastrointestinal bleeding, and acute renal failure, and thus
prompt stabilization of the mother and delivery of
the fetus are required.60 Although liver biopsy is
rarely performed, a stain with oil red O is specific
to detect fat molecules.61 The characteristic pattern on liver biopsy consists of a microvesicular
fatty infiltration of the liver without any microscopic
evidence of inflammation or necrosis. Liver transplantation should be considered in patients who do
not improve post delivery.
Hemolysis, Elevated Liver enzymes, Low Platelet
(HELLP) Syndrome
HELLP is an obstetric emergency, and it can
present before or after delivery.62 The presenting
symptoms of this entity include malaise, nausea
and vomiting, and right upper quadrant pain. The
largest retrospective study to date examined 442
patients with HELLP and found a maternal mortality rate of 1.1% in patients with hypertension
and proteinuria.62 The elevations in AST and ALT
do not correlate with the severity of disease. The
mainstay of treatment includes supportive care and
prompt delivery. There are reports of complications in subsequent pregnancies, but no increase
in risk of developing HELLP syndrome a second
time.63
ACUTE ISCHEMIC INJURY
Acute ischemic injury, or “shock liver,” causes
diffuse hepatic changes which occur in the setting
of cardiac arrest, heart failure, and hypotension
and is characteristically seen in the intensive care
setting.64 Levels of lactate dehydrogenase, AST,
and ALT are markedly elevated, reaching up to 25
to 200 times the upper limit of normal, and usually
peak at the third day and return to normal between
7 and 10 days.65 The distinguishing factor of this
entity is that synthetic function is generally well
preserved and mental status changes may be related to underlying hypotension and cerebral hypoperfusion rather than hepatic encephalopathy. The
prognosis in patients with acute ischemic injury
is determined by the treatment of the underlying
cause, most notably cardiac function or systemic
infection leading to hypotension.66
BUDD-CHIARI SYNDROME
Budd-Chiari syndrome is characterized by outflow obstruction of the liver by thrombosis of one or
more of the hepatic veins or inferior vena cava.67,68
Underlying causes such as a hypercoagulable
state, malignancy, use of oral contraceptives, and
infiltrative liver diseases such as abscesses have
been reported in the literature.69–71 Patients who
develop this syndrome along with ALF can be diagnosed either on Doppler ultrasound, magnetic
resonance imaging, or computed tomography.
Unfortunately, these patients tend to have a poor
prognosis. The treatment options for acute BuddChiari include anticoagulation, thrombolysis, vascular intervention, and liver transplantation.72–75
MUSHROOM POISONING
Ingestion of amatoxin-producing mushrooms,
most commonly Amanita phalloides, can lead to
ALF in approximately 72 hours.76 The early symptoms (hours) after ingestion include abdominal
pain, nausea, vomiting, and diarrhea; activated
charcoal may be effective within this timeframe.
Progression to ALF occurs rapidly, and the administration of intravenous penicillin G and intravenous and oral silibinin are currently accepted as
antidotes.77,78 Intravenous silibinin is not available in
the United States, but an expedited application for
this drug can be approved.
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MALIGNANCY
Malignancies such as lymphoma, breast cancer,
small cell lung cancer, melanoma, myeloma, and
metastatic disease can infiltrate the liver.79–82 When
malignancy infiltrates in the liver, it rarely causes
ALF except in the setting of acute outflow obstruction such as in Budd-Chiari syndrome. Unfortunately, imaging of the liver in a patient who has a diffuse
infiltrative pattern suggestive of ALF can be nondiagnostic. Prompt biopsy to tailor chemotherapy is
the mainstay of management, and such patients are
not considered liver transplant candidates.83
TREATMENT OF ACUTE LIVER FAILURE
Management of a patient with ALF, after identifying the cause and initiating appropriate treatment,
consists of supportive care in the ICU followed by
expeditious transfer to a liver transplant center. Management of the multisystem organ failure with specific treatment tailored to addressing the changes
in the central nervous system, systemic infection,
coagulopathy, renal failure, and metabolic derangements, along with liver transplant considerations are
the basis of care.
CENTRAL NERVOUS SYSTEM
The incidence of cerebral edema is approximately
50% to 85%, with cerebral herniation as a cause of
death reported in 30% to 50% of patients.84–88 The
cause of the cerebral edema is multifactorial, with
eventual astrocyte dysfunction and increased permeability of the blood-brain barrier.89 A computed
tomography (CT) scan of the head cannot reliably
detect cerebral edema, especially early in the disease state, and a negative CT of the head does
not exclude elevated intracranial pressure (ICP).84
The grade of hepatic encephalopathy in the setting
of ALF correlates with worsening cerebral edema.
10 Hospital Physician Board Review Manual
In one study, cerebral edema was not observed
in grade I or II encephalopathy, but was found in
35% of those with grade III and 75% of those with
grade IV encephalopathy.90 Grades of encephalopathy are defined in Table 3. In addition, the serum
ammonia concentration is a very important predictor of the presence of cerebral edema (rare with
levels <100 µmol/L, but often present with levels
>150 µmol/L).91
The goal directed therapy in response to a change
in mental status secondary to cerebral edema and
increased ICP is important to minimize long-term
cognitive defects in survivors. Grade I encephalopathy patients can be managed on a quiet medical
ward with frequent neurologic exams performed.
When there is progression to grade II encephalopathy, patients should be transferred to the ICU and
sedatives avoided.15 Elevation of ICP due to frequent
movement is a major concern,92 and endotracheal
suction, tactile stimulation, and frequent patient turning should be avoided.
Progression to grade III and IV encephalopathy
warrants intubation, elevation of the head of the bed
to 30 degrees, use of short-acting sedatives such
as propofol or paralytics, and seizure precautions
as indicated. Lactulose administration is used with
caution as it may cause abdominal distention, lead
to intravascular volume depletion, and may be a
causative agent in development of toxic megacolon.
In one study, the administration of lactulose may
have increased survival time but had no impact on
overall outcomes.93 Direct monitoring of the ICP is
rarely performed since it has not been shown to
lead to an overall increase in survival.94,95 If these
devices are present to measure ICP and cerebral
perfusion pressure (CPP = mean arterial pressure
[MAP] – ICP), then the values should demonstrate
an ICP ranging from 20 to 25 mm Hg with the CPP
maintained above 50 to 60 mm Hg.96
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Acute Liver Failure
The specific treatment modalities to consider
in treating an elevated ICP that is ≥25 mm Hg
include mannitol, hyperventilation, barbiturates,
and hypothermia. Once the diagnosis of elevated
ICP is made, mannitol 0.5 to 1.0 g/kg via intravenous bolus is recommended as first-line therapy.97
Serum osmolarity should be measured every 6
hours and repeat boluses should be administered if
the serum osmolarity is less than 320 mOsm/L.97
When the ICP continues to rise despite maximal
medical therapy with mannitol, other modalities
can be considered. The use of hyperventilation
and hypertonic saline showed no survival benefit
in patients with ALF.98,99 Despite having no survival
benefit, hypertonic saline has been shown to reduce the risk of intracranial hypertension (ICH) in
a randomized, controlled study.99 Barbiturate use in
ALF has been shown to decrease ICH, but its side
effects related to decreased hepatic clearance of
the drug, such as hypotension, hypokalemia, and
prolonged neurological suppression, may worsen
the clinical condition of a septic patient.96,100 Inducing hypothermia has not been used widely in the
setting of ALF, as this may also precipitate infection
and coagulopathy.101,102
INFECTION
One of the absolute contraindications to liver
transplantation is bacterial, fungal, or viral infection.103 However, empiric antibiotic administration
has not been shown to improve outcomes or
survival in ALF.104 Practicing universal health precautions and screening for multidrug resistant
organisms should be part of the routine care for
patients with ALF. At the onset of infection based
on surveillance cultures or worsening grade of
encephalopathy with a suspected systemic inflammatory response syndrome (SIRS), antibiotics and
antifungal therapy should be initiated.105–109
COAGULOPATHY AND BLEEDING
Despite an often marked elevation of the INR, patients rarely bleed.90 The INR is an important marker for prognosis and should not be corrected unless
clinically significant bleeding ensues.109 In addition,
thrombocytopenia of a mild to moderate severity is
typically seen. Based upon experience in patients
with chronic liver disease (no studies are available
for patients in ALF), expert opinion suggests 2 units
of fresh frozen plasma should be transfused without
a specific target INR value when planning an invasive procedure. In contrast, platelet transfusions
should be given to target a platelet count greater
than 60,000/mL.110,111 It is recommended to administer either an H2 blocker or proton pump inhibitor
as prophylaxis against gastrointestinal bleeding in
the presence of coagulopathy.112–114
HEMODYNAMICS
Hypotension and renal failure are major concerns
in patients with ALF. The infusion of norepinephrine
to maintain a MAP of ≥65 mm Hg is currently recommended in patients with hypotension refractory to
isotonic volume expansion.115 Low-dose dopamine
has not shown any decrease in the incidence of renal
failure in the setting of SIRS, and epinephrine can
cause a decrease in blood flow to the mesenteric
regions and potentially decrease hepatic blood flow;
neither is a recommended treatment modality.116–118
Adrenal insufficiency occurred in approximately 62%
of patients with ALF in one study regardless of etiology.119 One should consider hydrocortisone use as it
may augment the effect of norepinephrine.120
RENAL FAILURE
Approximately 80% of patients will develop 1 of 3
types of renal failure (prerenal, functional, or acute tubular necrosis) in the setting of ALF.121 The initial laboratory data (Table 2) should include evaluation of urine
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11
Acute Liver Failure
Table 6. UNOS Transplant Requirements for Adult in Acute Liver
Failure to be Listed as Status 1A
Age >18
Life expectancy <7 days
Onset of encephalopathy within 8 weeks
Absence of preexisting liver disease
One of the following 3 criteria must be met while in the intensive
care unit:
Ventilator dependent
On hemodialysis
INR >2.0
electrolytes to determine an etiology and appropriate
therapy should be initiated. Continuous hemodialysis
rather than intermittent has been shown to improve
oxygen tissue delivery and does not increase ICP.122
METABOLIC IMBALANCE AND NUTRITION
Metabolic imbalance with concurrent acidosis
and alkalosis along with hypoglycemia, hyponatremia, hypophosphatemia, and hypomagnesemia that occur in the setting of ALF must be
corrected. In one report, hypophosphatemia correlated with higher survival rates in patients with
acetaminophen toxicity; phosphate is taken up in
the regenerating liver and used to make adenosine
triphosphate, and thus hypophosphatemia may be
a positive indicator.123 ALF is a state of negative
nitrogen balance. Administration of enteral feeds
via high caloric regimen is essential,124 with careful
attention to resulting hyperglycemia, which may
increase ICP.125
TRANSPLANT AND ARTIFICIAL SUPPORT
The selection of patients for liver transplantation
should be based on the King's College Criteria
(Table 4).126,127 The positive predictive value, sensitivity, and specificity of these criteria for a poor out12 Hospital Physician Board Review Manual
come were greater than 90% in multiple studies,
but the criteria do not predict survival.128 In a retrospective study of 177 patients with ALF,128 49%
underwent liver transplantation, 14% recovered
with medical management, and the remainder died
without liver transplantation. When placed on the
United Network for Organ Sharing (UNOS) waiting
list, patients with ALF are designated as status 1,
which is the highest priority level for liver transplant
(Table 6).129 Calculation of the MELD score, which
encompasses serum creatinine, total bilirubin, and
INR, will provide a 3-month mortality for patients
with chronic liver disease. The MELD estimate
of 3-month mortality has not been validated for
patients with ALF. The 1- and 5-year survival for
patients transplanted in a retrospective study that
evaluated over 200 patients with fulminant hepatic
failure were 73% and 63% with deceased donor
transplant and 75% with living donor transplant.4,8
Artificial support such as the molecular adsorbents
recirculation system (MARS) and bioartificial support systems are currently in clinical trials and require future studies to establish their efficacy.
CONCLUSION
ALF is a medical emergency and warrants intensive care management and transfer to a tertiary
center for evaluation for liver transplantation. Etiology of the acute insult must be determined for
more focused management. Multisystem organ
failure, cerebral edema, metabolic derangements,
infection, renal failure and hemodynamic support
are the mainstays of therapy.
BOARD REVIEW QUESTIONS
Test your knowledge of this topic.
Go to www.turner-white.com and select Gastroenterology
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