AACN Advanced Critical Care
Volume 27, Number 4, pp. 420-429
Acute Liver Failure
Ami Grek, MSN, ACNP
Lisa Arasi, DNP, ACNP
ABSTRACT
Acute liver failure, also known as fulminant
hepatic failure, is a rare life-threatening
disease that has a high mortality rate and
affects many organ systems. Causes of
acute liver failure varyit can be attributed
to drugs, viruses, and other uncommon
sources. Complications of liver failure can
include encephalopathy, cerebral edema,
sepsis, renal failure, gastrointestinal bleeding,
A cute liver failure (ALF), also known as
fulminant hepatic failure, is a rare life-
threatening disease with a high mortality rate.
Clinical manifestations include rapid hepatic
injury, derangements in coagulopathy, hepatic
encephalopathy (HE), and in some instances,
multisystem organ failure occurring in a patient
with no history of liver disease. A liver biopsy
often shows massive hepatic necrosis and var-
ious degrees of inflammation.1 It is important
to recognize that ALF differs from acute-on-
chronic liver failure in that patients with chronic
liver failure have underlying cirrhosis and typi-
cally decompensate because of an acute injury.
In most cases, prognosis and treatment differ
between the 2 diseases; therefore, it is essential
to differentiate between ALF and acute-on-
chronic liver failure.2 The purpose of this article
is to define ALF, describe its manifestations by
organ system, and discuss current treatment
practices and organ support.
OGrady3 divides ALF into 3 types according
to the onset of encephalopathy: (1) hyperacute,
(2) acute, and (3) subacute. The onset of
encephalopathy is within 7 days of symptom
onset in hyperacute ALF, within 8 to 28 days
in acute ALF, and in more than 28 days in
subacute ALF.3 Fortunately, advances in critical
care medicine and emergent liver transplant
have led to an improvement in mortality rates
420
2016 AACN
and respiratory failure. Fortunately, with
advances in critical care medicine and
emergent liver transplant, mortality rates
have decreased in the past decade. This
article reviews acute liver failure, its mani-
festations in different organ systems, and
its treatment.
Keywords: acute liver failure, liver transplant,
hepatic failure
(Figure 1).4,5 Survival depends on a number
of factors, including the cause of disease, the
patients age, the degree of encephalopathy,
the degree of liver necrosis, and the patients
other comorbid conditions. A number of tools
are available to estimate prognosis in these
patients, including Kings College criteria, the
Model for End-Stage Liver Disease (MELD),
and the Clichy criteria.6-8 Kings College criteria
(Table 1) differ between acetaminophen-induced
and nonacetaminophen-induced liver injury
and include the degree of acidemia, coagu-
lopathy, renal dysfunction, and encephalopathy
in patients with ALF. In nonacetaminophen-
induced injury, age, serum level of bilirubin,
and time of jaundice presentation are impor-
tant predictors of mortality. MELD score
calculation involves international normalized
ratio (INR) and serum levels of bilirubin and
creatinine. The higher the MELD score, the
higher the likelihood of death. The Clichy
Ami Grek is Nurse Practitioner, Department of Critical Care
Medicine, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL
32224 (grek.ami@mayo.edu).
Lisa Arasi is Nurse Practitioner, General Surgery, Mayo Clinic,
Jacksonville, Florida.
The authors declare no conflicts of interest.
DOI: http://dx.doi.org/10.4037/aacnacc2016324
 VO L U ME 27 N U MB ER 4 OCTOBE R-D E CE M BE R 2016 ACUTE LIVER FAILURE

100

80 77

74
61
62
60
Survival, %

51
56
55
47
40 44
38

20 25 25

0
0 1 2 3 4 5 6 7 8 9 10
Years

Before December 1984 (24) January 1985 to December 1989 (482)

January 1990 to December 1994 (1259) January 1995 to December 1999 (1537)
January 2000 to December 2004 (1713) January 2005 to December 2008 (1158)

Figure 1: Survival after liver transplant for acute liver failure by date of surgery in Europe, from 1984 to
2008. Reprinted from The Lancet, 376(9736), Bernal W, Auzinger G, Dhawan A, Wendon J, Acute Liver
Failure, pp. 190-201, Copyright (2010), with permission from Elsevier.

criteria use factor V assay, degree of enceph-

Table 1: Kings College Criteria for Liver alopathy, serial _-fetoprotein levels and plasma
Transplant groupspecific component protein (Gc glob-
Acetaminophen-Induced Other Causes ulin) levels.6 The Kings College criteria and the
MELD score are the most widely used today.
pH < 7.3 or International normalized
ratio > 6.5 or
International normalized
Causes of ALF
ratio > 6.5 with Meet 3 criteria below Drugs
Creatinine level > 3.4 Liver injury related to drugs can be divided
mg/dL and Age < 10 y or > 40 y into 2 separate categories. The first category is
Grade 3-4 Cause is not hepatitis A, related to the medication itself, dose, or con-
encephalopathy hepatitis B, or drug comitant use of multiple hepatotoxic medica-
reaction tions. The second category is host-related injury,
Duration of jaundice which takes into account the patients age, sex,
before encephalopathy alcohol intake, or concomitant infections.9
> 7 days In the United States and United Kingdom,
International normalized drug-induced ALF is the most common type
ratio > 3.5 of ALF, with acetaminophen being the most
Serum level of bilirubin
common offender.10 Unfortunately, with the
> 17.5 mg/dL introduction of combination drugs, uninten-
tional overdose of acetaminophen is becoming
more common, and in 1 study,11 it was the
Conversion factors: To convert creatinine to micromoles per liter,
multiply by 88.4; to convert bilirubin to micromoles per liter, multiply cause in 48% of the patients with ALF. A vari-
by 17.104. ety of medications and herbal supplements have

421
G R E K A ND A R AS I W W W .AACN ACCON LIN E .ORG

Other drugs:
Propylthiouracil (19)
Disulfiram (9)
Halothane (8) Antituberculosis:
Herbal (6) Isoniazid (48)
Amitriptyline (2) Isoniazid plus another
Nefazodone (2) antituberculosis drug (2)
Methotrexate (5)
Troglitazone (4)
Methyldopa (5)
Mercaptopurine or azathioprine (3)
Antiepileptics:
Fialuridine (3)
Phenytoin (20)
Single cases
Valproate (20)
Carbamazepine (3)
Nonsteroidal Single case: Felbamate
anti-inflammatories:
Diclofenac (3) Statins: Antibiotics :
Bromfenac (2) Atorvastatin (3) Nitrofurantoin (12)
Ibuprofen (2) Cerivastatin (2) Ketoconazole (8)
Single cases: Simvastatin (2) Amoxicillin and clavulanate (5)
Etodolac Single cases: Trimethoprim-sulfamethoxazole (2)
Naproxen Pravastatin Minocycline (2)
Indometacin Ezetimibe Single cases:
Fluvastatin Terbinafine
Ciprofloxacin
Telithromycin
Levofloxacin
Itraconazole
Moxifloxacin

Figure 2: Nonacetaminophen-based drugs causing acute liver failure in patients requiring emergent liver trans-
plant in the United States, from 1987 to 2006. Reprinted from The Lancet, 376(9736), Bernal W, Auzinger G,
Dhawan A, Wendon J, Acute Liver Failure, pp. 190-201, Copyright (2010), with permission from Elsevier.

been implicated in ALF (Figure 2). Gathering
a thorough medical history is key to identify-
ing drug-induced injury, specifically, one must
determine the symptom onset, underlying liver
disease, alcohol intake, and use of other pre-
scription or over-the-counter medications.9
Typically, stopping the offending agent will
result in improvement of liver enzyme levels;
however, admission to the hospital for closer
monitoring is necessary in severe cases.
Viruses
Virus-associated ALF represents 12%
of the ALF population in the United States,
although less than 1% of acute viral infec-
tions result in hepatic failure.12 Hepatitis A
and B viruses are the most common viruses
identified in ALF patients referred for liver
transplant in the United States. The incidence
of hepatitis B has decreased in the past few
decades because of vaccination, whereas the
incidence of hepatitis A is unchanged. ALF
induced by hepatitis B virus may be a result
of an acute infection or reactivation of the virus
in a patient with chronic hepatitis B. Diagnosis
of an acute infection with hepatitis B virus is
confirmed by the detection of immunoglobulin
M antibodies against hepatitis B core antigen.
In developing nations, hepatitis A and E are
responsible for the majority of ALF cases and
are a result of an acute viral infection.13 Hep-
atitis C is rarely the culprit in ALF patients but
has been seen when a concomitant infection is
present.12 Typically hepatitis C results in chronic
liver disease, and most studies indicate that it
does not cause ALF. Cytomegalovirus, Epstein-
Barr virus, human herpesvirus-6, herpes sim-
plex virus, and varicella-zoster virus have
all been implicated in ALF as well, but cases
remain minimal.
Miscellaneous
Other less common causes of ALF include
Wilson disease, which results in copper accu-
mulation in the liver due to an inherited copper
transport disorder,14 hepatic veno-occlusive

422
VO L U ME 27 N U MB ER 4 OCTOBE R-D E CE M BE R 2016
disease or Budd Chiari syndrome, ischemic
liver injury due to cardiopulmonary disease
processes, and invasive neoplastic disease.13
ALF has been seen in pregnancy, usually during
the third trimester or early postpartum, with
an incidence of 5 per 100 000 women.15 Table 2
summarizes the different causes of ALF.
Manifestations by System
Gastrointestinal/Hepatic
Determining the cause of ALF is imperative
in order to direct treatment and prognostica-
tion. Gathering a thorough medical history
from the patient and the patients family may
help uncover the offending agent or cause.
Liver function tests, coagulation profiles, and
a renal profile will give valuable information
regarding liver failure and differential diag-
noses. Serum viral studies, a drug screen,
acetaminophen levels, and urine copper level
should also be included in the workup. A liver
biopsy will show the degree of liver necrosis
and is useful in determining whether liver
transplant is necessary; pathology studies
will help narrow down the differential diag-
nosis as to the cause of ALF.
Abdominal ultrasound or computed tomog-
raphy scans are important to assess blood flow
to the liver and will further define causes of
ALF. Abdominal ultrasound with duplex imag-
ing is useful in ALF workup and will assist
with narrowing down differential diagnoses.
If Budd-Chiari syndrome is present, occlu-
sion of hepatic veins may be visualized on
ultrasound. If ascites is present, it may be
possible to determine how long the problem
has been going on. Ascites typically takes
time to develop, so fewer incidences will
occur if the cause of the ALF is truly acute,
as in an acetaminophen overdose.
Treatment. Intravenous administration of
N-acetylcysteine should be initiated in patients
with suspected acetaminophen overdose or
those with severe or evolving elevation of
transaminase levels of unknown origin.16
N-acetylcysteine has anti-inflammatory
properties as well as vasodilatory effects
that help improve blood flow to vital organs.17
It is a glutathione precursor thought to pre-
vent toxic effects by limiting the formulation
and accumulation of N-acetyl-p-benzoquinone
imine, and it acts as a glutathione substi-
tute, which enhances nontoxic sulfate conju-
gation.17 The role of N-acetylcysteine in
423
ACUTE LIVER FAILURE
Table 2: Causes of Acute Liver Failure
Viruses Drugs Other Causes
Hepatitis Acetaminophen Budd-Chiari
A, B, C, D, E syndrome
Amanita
Epstein-Barr phalloides Wilson disease
Cytomegalovirus Halothane Cardiac-related
hepatic ischemia
Herpesvirus Sulfonamides
1, 2, 6 Phenytoin Fatty liver of
pregnancy
Carbon
tetrachloride
Isoniazid
acetaminophen-induced ALF is well established,
and researchers in some studies report it is
also useful in nonacetaminophen-induced
injury.17 N-acetylcysteine can be given intra-
venously or orally and is typically started
with a bolus dose of 140 mg/kg followed
by a maintenance dose of 70 mg/kg, for which
the duration differs between oral and intrave-
nous administration.
Owing to disturbances in gluconeogenesis,
hypoglycemia may occur and requires frequent
monitoring of blood glucose level, and in some
cases, intravenous infusion of dextrose. Alter-
ations in coagulopathy pose a greater risk for
bleeding, often manifesting as gastrointestinal
bleeding. Portal hypertension may occur in
patients with ALF, but bleeding gastric or
esophageal varices are unlikely.18 Urgent inter-
vention with esophagogastroduodenoscopy
may be necessary, as well as replacement of
clotting factors. Gastric acid suppression with
H2 blockers or proton pump inhibitors may
help decrease the risk of gastric bleeding in
patients with ALF.18
If ascites is present, draining and sampling
the fluid to rule out spontaneous bacterial
peritonitis is imperative. If the abdomen is
tense, paracentesis would be warranted to
drain as much ascitic fluid as possible; how-
ever, close monitoring of intake, output, and
blood pressure along with replacement of
losses with hyperoncotic albumin (25%)
should occur for plasma volume expansion.
Typically 6 to 8 g/L of ascitic fluid is removed
and replaced with albumin to avoid intravas-
cular depletion after paracentesis. Removal
of more than 5 L of ascites fluid without
administration of plasma volume expanders
may result in renal impairment.19
G R E K A ND A R AS I
Table 3: West Haven Criteria for Hepatic Encephalopathy
Stage Consciousness Intellect and Behavior
0 Normal Normal
1 Mild lack of Shortened attention span
awareness
2 Lethargic Disoriented; inappropriate behavior Obvious asterixis; slurred speech
3 Somnolent but Gross disorientation; bizarre
arousable behavior
4 Coma Coma
Neurological
A key assessment finding that defines ALF
is the onset of HE, a reversible disturbance
in consciousness related to liver dysfunction
that can range in severity from mild person-
ality changes and confusion (grade 1) to
coma (grade 4) with increased intracranial
pressure (ICP). ALF has a high morbidity
and mortality rate as it is; however, severe
encephalopathy often is associated with a
very poor prognosis.20
Hepatic encephalopathy develops as a
result of the livers inability to clear ammonia
and is a complex process that results in ammo-
nia and other toxins crossing the blood-brain
barrier, causing various neurological changes.21
The pathophysiology in ALF is not completely
understood; however, it is postulated that
widespread inflammation occurring as a result
of the liver injury contributes to the develop-
ment of HE through alteration of cerebral
endothelial permeability to neurotoxins and
altered cerebral blood flow.13 Cerebral hyper-
emia, or the increase of blood flow to the
brain due to elevated serum levels of ammonia,
also occurs and contributes to the risk of cer-
ebral edema developing. Ammonia is thought
to increase cellular osmolarity through cere-
bral metabolism to glutamine, which induces
changes in neurotransmitter synthesis and release
that affect mitochondrial function, which results
in altered cerebral function and swelling.22
Early identification of HE is key. Frequent
neurological assessments are a must to catch
subtle changes in mental status that could
precipitate rather quickly to coma, cerebral
edema, brain herniation, and even death.
Nurses must understand that, although ele-
vated ammonia levels are often a poor prog-
nostic factor for the development of HE, levels
do not always correlate with the severity of
424
W W W .AACN ACCON LIN E .ORG
Neurological Findings
Normal findings; if impaired psychomotor test-
ing, consider minimal hepatic encephalopathy
Impaired addition or subtraction
Mild asterixis or tremor
Muscular rigidity and clonus; hyperreflexia
Decerebrate posturing
HE (ie, low ammonia levels can be present
in patients with severe HE or coma). Some
of the most widely used criteria for determin-
ing level of HE are the West Haven criteria.22
Stage 1 is defined as minimal HE, where
minimal changes in memory, coordination,
and intellect may be present. This stage can
progress to stage 5, defined as coma with or
without response to painful stimuli (Table 3).
Evaluating for the presence of asterixis (flap-
ping tremor of the hand when the arms and
wrist are extended) is important in addition to
assessing for ankle clonus (series of abnormal
reflex movements of the foot induced by sud-
den dorsiflexion) and monitoring upper and
lower extremity reflexes because hyperreflexia
correlates with worsening HE.
Kumar et al23 performed a prospective obser-
vational study on 295 consecutive patients
admitted with ALF. Ammonia levels were meas-
ured daily for 5 days. Lower rates of survival
were found in patients who had persistent
elevated ammonia levels (> 122 mol/L) dur-
ing days 1 through 3. Overall survival was
significantly lower (23% vs 72%, P < .001)
in those patients with ammonia levels greater
than 122 mol/L compared with those with
a decreasing ammonia level. Cerebral edema
(71% vs 37% P < .001), risk of infection
(67% vs 28%), and seizures (41% vs 7.7%)
also had significantly higher incidences in
patients with elevated ammonia levels.
Treatment. Interventions aimed at decreas-
ing ammonia levels as quickly as possible,
such as frequent lactulose administration or
antibiotic administration with rifaximin,
should be used. If mental status is depressed
so that the patient cannot take medication
orally, then medication given per rectum or
nasogastric tube is recommended if not
contraindicated.
VO L U ME 27 N U MB ER 4 OCTOBE R-D E CE M BE R 2016
Efforts should also be aimed at control-
ling cerebral hyperemia because autoregula-
tion of cerebral blood flow is compromised.
The blood-brain barrier is compromised in
patients with ALF, and increased levels of nitric
oxide and hyponatremia are only some of
the many pathophysiologic influences on the
development of increased cerebral blood flow.
Acidosis, volume overload, and hypercarbia
are identified as risk factors for increased
incidence of elevated ICP.20
Early or elective intubation is required for
airway protection (to decrease the risk of
aspiration) once the patient progresses to later
stages of HE. If cerebral edema is not present,
then a low dose of sedatives should be used
in order to continue to monitor the patients
mental status. Use of short-acting analgesics
such as fentanyl or sedatives such as propofol
is recommended over use of benzodiazepines
because clearance may be poor.20 Benzodiaz-
epines that are primarily metabolized via the
hepatic cytochrome Pmediated oxidation may
have prolonged duration of effect in patients
with liver dysfunction and can exacerbate HE.
If increased ICP is suspected, placement
of an invasive ICP monitoring device may be
needed, although the risk of bleeding in a most
likely coagulopathic patient is present. The
incidence of intracranial hemorrhage has been
reported as 2% to 10%; however, additional
studies have not reported improvement in sur-
vival to warrant the risk.20 If an ICP monitor
is placed, maintaining a cerebral perfusion pres-
sure of at least 60 mm Hg is desirable. Tran-
scranial Doppler ultrasound is often used as
a noninvasive way to assess ICP. Well-known
interventions to aid in prophylactically decreas-
ing ICP include maintaining head-of-bed ele-
vation at 30 with the patients neck in neutral
position and use of hypertonic saline or man-
nitol. If the patient is intubated and sedated,
using hypothermia as a way to decrease ICP
may also be helpful. Lowering a patients
body temperature to between 32C and 35C
leads to decreases in ICP and cerebral blood
flow and an increase in cerebral perfusion
pressure. Risks of decreasing a patients body
temperature include increasing infection rate,
bleeding potential, and arrhythmias.24 A ret-
rospective review was performed on patients
with grade 3 or 4 HE in which 97 received
therapeutic hypothermia. Survival in younger
patients (< 25 years old) was improved when
therapeutic hypothermia was used; however,
ACUTE LIVER FAILURE
it seemed to be worsened for elderly patients
(> 64 years old; odds ratio, 0.167; 95% CI,
0.028-0.999).24 Therapeutic hypothermia was
not associated with higher incidence of bleed-
ing or infections.
Cardiovascular/Renal
Systemic vasodilatation with associated
hypotension is a common hemodynamic
finding in patients with ALF. Systemic vascu-
lar resistance is usually low, and peripheral
vasodilatation is thought to be due to effects
of cytokines and circulating endotoxin caus-
ing proinflammatory effects.25 Patients with
ALF often have a history of nausea or vom-
iting and poor oral intake leading to hypo-
volemia, which is a contributing factor to
hypotension. However, infection and sepsis
may also be causes, and if present, they carry
with them a higher risk of encephalopathy and
mortality rate.13 ALF may lead to a systemic
inflammatory response syndrome, resulting
in widespread peripheral vasodilatation due
to the initial liver injury and subsequent
cytokine release.5
Lactic acidosis may also be present in ALF
presentation due to decreased clearance by
the liver or by increased production causing
acid/base disturbances that also lead to hypo-
tension. In normal liver function, uptake of
lactate occurs as a result of gluconeogenesis;
however, in liver injury, the uptake of lactate is
decreased and the release of lactate is increased
as a result of accelerated glycolysis and reduc-
tion in hepatic gluconeogenesis.26
Renal failure is often present in about 50%
of patients with ALF as a result of poor per-
fusion, liver dysfunction, and multisystem organ
failure. Failure of the kidneys may contribute
to fluid status, hemodynamic complications,
and disturbances in acid and base balances.
The hemodynamic profile of a patient with
ALF typically reveals a low mean arterial pres-
sure, low systemic vascular resistance, and high
cardiac output.20 Extremities are often warm
to the touch due to vasodilatation. Lower
extremity edema or anasarca (generalized
edema) may be present as a result of the third
spacing that occurs. If renal failure ensues, it
may be difficult to accurately determine the
patients actual fluid status; therefore, invasive
monitoring is often required, such as measure-
ment of central venous pressure and possible
use of a Swan-Ganz catheter to assess filling
pressures and cardiac output in order to guide
425
G R E K A ND A R AS I
treatment accurately. Echocardiography is
helpful to ensure adequate function of the
right ventricle and to assess cardiac filling.
Myocardial dysfunction may occur as a result
of systemic stress rather than myocardial
injury, and troponin levels may be elevated.20
Excessive release of catecholamines, which
causes stress-induced cardiomyopathy, has
been described in patients with ALF.27
Treatment. If hemodynamic compromise is
present, efforts should be aimed at improving
perfusion and oxygen delivery with aggressive
fluid resuscitation and vasopressors if needed.
Norepinephrine is the first choice for a vaso-
pressor, followed by a vasopressin infusion if
maximal doses of norepinephrine are being
reached. The goal for mean arterial pressure
should be 65 mm Hg or greater to ensure
organ perfusion; however, if increased ICP is
of concern, a goal of more than 80 mm Hg
for mean arterial pressure is recommended
to assist in ensuring adequate cerebral perfu-
sion pressure.20 If relative adrenal insufficiency
is suspected (found in about 60% of patients
with ALF), the addition of stress-dose steroids
may be helpful in patients with refractory
hypotension who are not responsive to pres-
sors. Steroids remain controversial and improve
hemodynamic stability; however, no improve-
ment in mortality was reported.28 Concern
for further immunosuppression and increased
risk of infection is present with this interven-
tion. A low threshold for starting continuous
renal replacement therapy should be considered
if renal failure develops. Continuous renal
replacement therapy will assist in maintain-
ing acid and base status, electrolytes, and fluid
balance in this often tenuous situation. Use
of intermittent hemodialysis may lead to rapid
fluid shifts that could compromise hemody-
namics significantly and lead to increases
in ICP.20
Respiratory
Patients with ALF and subsequent HE are
at risk for aspiration if not monitored closely,
and intubation for airway protection may be
needed once grade 3 HE is present. Patients
will be at risk for development of acute lung
injury (ALI) as a result of generalized inflam-
mation, which can lead to acute respiratory
distress syndrome. The current incidence of
ALI in patients with ALF is around 20%.20
Chest radiographs may reveal acute develop-
ment of diffuse bilateral pulmonary infiltrates
426
W W W .AACN ACCON LIN E .ORG
in the setting of a pulmonary wedge pressure
of 18 mm Hg or less without evidence of left
atrial hypertension.29 A ratio of Pao2 to frac-
tion of inspired oxygen that is less than 300
defines ALI and limits confusion between
severe pulmonary edema and ALI.29
Worsening gas exchange leading to meta-
bolic and respiratory acidosis can hasten
the progression of encephalopathy to grade
3. In addition to refractory hypoxemia, an
increase in pulmonary dead space can make
ventilation difficult; increasing Pco2 should
be avoided because this will contribute to
cerebral vasodilatation and increased ICP.18
Pulmonary edema and pleural effusions may
also develop from hypoalbuminemia.
Treatment. For patients who require intuba-
tion and have ALI develop, ventilation at low
tidal volume improves survival rates and can
be used in patients with ALF.30 Tidal volumes
should be aimed at 6 mL/kg of predicted body
weight. Minute ventilation should be adjusted
to allow for slight hypoventilation to aid in
possible increased ICP.20 Slight hyperventilation
with Pco2 levels just below normal range may
assist in reinstating autoregulation of cerebral
blood flow. Although fluid resuscitation must
be aggressive initially to treat hypotension and
improve perfusion, careful fluid administration
should continue in patients with ALF who have
lung involvement in an effort to decrease ven-
tilator support.5
Nutrition
Nutrition supplementation should be initi-
ated early because of increased catabolism and
high energy states in ALF.13 If caloric require-
ments are not met orally, then enteral feeding
is initiated. Branch-chain amino acid supple-
ments may be beneficial in reducing the effects
of HE.21 Protein recommendations are 1.0
to 1.5 g/kg with daily monitoring of ammonia
levels.13 Protein restriction in order to minimize
HE is no longer recommended unless ammo-
nia levels remain greater than 150 mol/L
for 1 or 2 consecutive days because of the
high catabolic state of ALF. Typically, calorie
requirements are 20 to 25 kcal/kg.
Hematology
Patients with ALF have an elevated INR;
this factor is required for the diagnosis of
ALF. Thrombocytopenia is often noted as
well and is a poor prognostic factor because it
has been associated with an increase in
VO L U ME 27 N U MB ER 4 OCTOBE R-D E CE M BE R 2016
multisystem organ failure and mortality. Pro-
longed bleeding times are to be expected in
ALF because the liver is responsible for pro-
duction of proteins and factors needed for
clotting and fibrinolysis. Despite these pro-
longed bleeding times, the risk of significant
bleeding in ALF remains minimal, occurring
in only approximately 5% of patients.20
Quick decisions to give a blood transfusion
because of prolonged prothrombin time and
INR should be avoided if active bleeding is
not present. An imbalance in procoagulants
and anticoagulants is present in ALF and not
appropriately represented in laboratory values.
Unwarranted transfusions of blood products
such as fresh frozen plasma may put the patient
at risk for volume overload, pulmonary edema,
lung injury, and increased ICP. Before invasive
procedures (placement of central catheters or
ICP monitors) are performed, use of thrombo-
elastography is ideal for assessing the coag-
ulation profile of a patient with ALF.20
Transfusion goals before procedures or for
bleeding are platelet counts greater than
50 000/L and an INR less than 2.0. The
dose of fresh frozen plasma can be calcu-
lated as 12 to 15 mL/kg.
Frequent monitoring of coagulopathy with
thromboelastography and INR is recommended
in order to recognize rapid liver decompensa-
tion. Thromboelastography has been studied
in the cardiothoracic and liver transplant pop-
ulation and can be used as a tool to assist with
determining specific blood product types to
transfuse in coagulopathic patients. Throm-
boelastography provides a graphic represen-
tation of clot formation and lysis and reports
laboratory values that coincide with specific
factor deficits in patients. Therefore, rather than
relying primarily on the INR to determine
whether to administer fresh frozen plasma,
thromboelastography can provide valuable
information on whether to transfuse fresh
frozen plasma, platelets, or cryoprecipitate.31
Infectious Disease
Patients with ALF are susceptible to having
infection develop as a result of liver necrosis
and inflammation that occurs with the liver
injury. Kupffer cell function is decreased in
addition to severe complement deficiency.
Leukocytosis is typically present as a result
of the inflammatory response. Bacteremias
and fungemias are associated with ALF, and the
incidence varies, with bacteremias occurring
427
ACUTE LIVER FAILURE
in 22% to 80% and fungemia in approximately
30%.32 Given the similarities of the hemody-
namic presentation of patients with ALF and
patients with septic shock, it is difficult to
determine if infection is actually the cause of
the systemic inflammatory response syndrome.24
The Acute Liver Failure Study Group per-
formed a retrospective analysis of more than
1500 patients to determine whether prophy-
laxis with antibiotics had an effect on the
occurrence of bloodstream infections in patients
with ALF, in addition to the effects of blood-
stream infections on 21-day mortality after
the development of ALF. Bloodstream infections
affected 21-day survival negatively; however,
prophylaxis with antimicrobial agents did
not seem to influence the incidence of blood-
stream infection development.24
Routine prophylactic administration of
antibiotics is not recommended in the most
recent guidelines of the American Association
for the Study of Liver Disease; however, addi-
tion of broad-spectrum antibiotics is most likely
warranted if other organ system dysfunction
is noted upon admission, HE is progressing,
hypotension is significant and requiring pres-
sor support, and patients are being considered
for liver transplant.24
Treatment With Extracorporeal Supportive
Devices. Even with advances in liver transplant,
donor organ availability does not match the
number of patients needing a transplant. Given
the dilemma of organ mismatch, a number of
liver support devices are now available. Often,
these devices are used as a bridge to liver trans-
plant or to recovery. These therapies are based
on 2 different concepts: non-cell-based (artifi-
cial) and bioartificial. Bioartificial devices use
whole-organ perfusion systems to replace
detoxification and synthetic function through
the use of hepatocytes obtained from porcine
or human organs.13,33 Because studies associ-
ated with bioartificial support systems did
not demonstrate a clinical benefit and intro-
duced logistical and safety concerns associated
with the use of porcine and human models,
research focus in the past decade has been
primarily on artificial support devices.33
The 2 artificial support systems most recently
studied are the Molecular Adsorbents Recir-
culating System (Gambro) and Prometheus
(Fresenius), both of which are based on remov-
ing harmful toxins from the blood by using
dialysis with albumin.33 This process allows
smaller albumin-bound and water-soluble
G R E K A ND A R AS I
toxins, which are responsible for the multiple
organ dysfunctions seen in hepatic failure, to
be removed from the bloodstream.
Further research is needed to determine
whether extracorporeal support devices are
beneficial in patients with ALF. Previous
studies on artificial support systems showed
improvements in biomarkers seen in ALF
such as elevated bilirubin levels, HE, and
jaundice; however, these improvements are
short-lived, and there was no clear benefit
to long-term survival.33
Treatment With Liver Transplant. Liver
transplant is the definitive treatment in patients
with ALF who do not go on to improve with
supportive therapy. The probability of spon-
taneous recovery and the use of various pre-
dictor models discussed earlier help with the
decision whether to proceed with liver trans-
plant. Before advances in liver transplant and
ALF support, survival rates for ALF were as
low as 15%, but they have improved to
60% to 80% in the past decade with or
without liver transplant.34 Because of the high
mortality associated with ALF, patients deemed
transplant candidates are listed as status 1 in
the United Network for Organ Sharing, which
designates them as the first recipients when
an organ becomes available. Unfortunately,
organ shortages challenge clinicians to deter-
mine a patients need for transplant with the
likelihood of a good outcome. Prognostic tools
such as the Kings College criteria and the
MELD score, in addition to ongoing clinical
evaluations, are helpful in determining the
right candidates.7
Survival rates following transplant for ALF
have been reported to be as high as 61% after
1 year and 55% at 5 years, with 1 US center
reporting survival rates as high as 93%.7
Reuben et al35 published a large study exam-
ining ALF survival during a 15-year period
and reported improved posttransplant survival
toward the later years of the study as well as
improved survival without liver transplant.
Conclusion
ALF is a rare life-threatening disease in
which early identification and treatment are
imperative for patients survival. If not caught
early, ALF can progress to multisystem organ
failure and death. Aggressive supportive care
and developments in critical care can reduce
mortality and improve transplant-free survival.
428
W W W .AACN ACCON LIN E .ORG
ACKNOWLEDGMENTS
A special thanks to Dr Canabal, Dr Moreno-
Franco, and Dr Kramer for all their teaching
and support.
REFERENCES
1. Lefkowitch JH. The pathology of acute liver failure.
Adv Anat Pathol. 2016;23(3):144-158.
2. Olson JC, Kamath PS. Acute-on-chronic liver failure:
concept, natural history, and prognosis. Curr Opin Crit
Care. 2011;17(2):165-169.
3. OGrady JG. Acute liver failure. Postgrad Med J. 2005;
81(953):148-154.
4. Bernal W, Auzinger G, Dhawan A, Wendon J. Acute
liver failure. Lancet. 2010;376(9736):190-201.
5. Kramer DJ, Canabal JM, Arasi LC. Application of inten-
sive care medicine principles in the management of the
acute liver failure patient. Liver Transpl. 2008;14(suppl 2):
S85-S89.
6. Renner EL. How to decide when to list a patient with acute
liver failure for liver transplantation? Clichy or Kings
College criteria, or something else? J Hepatol. 2007;
46(4):554-557.
7. OGrady J. Liver transplantation for acute liver failure.
Best Pract Res Clin Gastroenterol. 2012;26(1):27-33.
8. Saab S, Wang V, Ibrahim AB, et al. MELD score predicts
1-year patient survival post-orthotopic liver transplan-
tation. Liver Transpl. 2003;9(5):473-476.
9. Mohankumar N, Ranjan P, Kumari A. Drug-induced liver
injury: diagnosing (and treating) it early. J Fam Pract.
2015;64(10):634-644.
10. Castaldo ET, Chari RS. Liver transplantation for acute
hepatic failure. HPB (Oxford). 2006;8(1):29-34.
11. Larson AM, Polson J, Fontana RJ, et al. Acetaminophen-
induced acute liver failure: results of a United States
multicenter, prospective study. Hepatology. 2005;42(6):
1364-1372.
12. Schiodt FV, Davern TJ, Shakil AO, McGuire B, Samuel
G, Lee WM. Viral hepatitis-related acute liver failure.
Am J Gastroenterol. 2003;98(2):448-453.
13. Bernal W, Wendon J. Acute liver failure. N Engl J Med.
2013;369(26):2525-2534.
14. Seo JK. [Wilson disease: an update]. Korean J Hepatol.
2006;12(3):333-363.
15. Pandey CK, Karna ST, Pandey VK, Tandon M. Acute liver
failure in pregnancy: challenges and management.
Indian J Anaesth. 2015;59(3):144-149.
16. Polson J, Lee WM. AASLD position paper: the manage-
ment of acute liver failure. Hepatology. 2005;41(5):
1179-1197.
17. Mumtaz K, Azam Z, Hamid S, et al. Role of N-acetylcysteine
in adults with non-acetaminophen-induced acute liver
failure in a center without the facility of liver transplan-
tation. Hepatol Int. 2009;3(4):563-570.
18. Stravitz RT, Kramer DJ. Management of acute liver failure.
Nat Rev Gastroenterol Hepatol. 2009;6(9):542-553.
19. Grabau CM, Crago SF, Hoff LK, et al. Performance stan-
dards for therapeutic abdominal paracentesis. Hepatol-
ogy. 2004;40:484-488.
20. Kandiah PA, Olson JC, Subramanian RM. Emerging strat-
egies for the treatment of patients with acute hepatic
failure. Curr Opin Crit Care. 2016;22(2):142-151.
21. Chaney A, Werner KT, Kipple T. Primary care manage-
ment of hepatic encephalopathy: a common cirrhosis
complication. J Nurse Pract. 2015;11(3):300-306.
22. Atterbury CE, Maddrey WC, Conn HO. Neomycin-sorbitol
and lactulose in the treatment of acute portal-systemic
encephalopathy: a controlled, double-blind clinical trial.
Am J Dig Dis. 1978;23(5):398-406.
23. Kumar R, Shalimar, Sharma H, et al. Persistent hyper-
ammonemia is associated with complications and poor
VO L U ME 27 N U MB ER 4 OCTOBE R-D E CE M BE R 2016
outcomes in patients with acute liver failure. Clin Gas-
troenterol Hepatol. 2012;10(8):925-931.
24. Karvellas CJ, Todd Stravitz R, Battenhouse H, Lee WM,
Schilsky ML. Therapeutic hypothermia in acute liver
failure: a multicenter retrospective cohort analysis.
Liver Transpl. 2015;21(1):4-12.
25. Fink M, Abraham E, Vincent J, Kochanek P. Textbook of
Critical Care. 5th ed. Philadelphia, PA: Elsevier; 2005.
26. Jeppesen JB, Mortensen C, Bendtsen F, Moller S. Lactate
metabolism in chronic liver disease. Scand J Clin Lab
Invest. 2013;73(4):293-299.
27. Jophlin L, Koch D. Takotsubo cardiomyopathy following
acute liver failure. Hepatology. 2015;61(4):1430-1431.
28. Rinaldi L, Ferrari E, Marietta M, et al. Effectiveness of
sepsis bundle application in cirrhotic patients with sep-
tic shock: a single-center experience. J Crit Care. 2013;
28(2):152-157.
29. Johnson ER, Matthay MA. Acute lung injury: epidemi-
ology, pathogenesis, and treatment. J Aerosol Med
Pulm Drug Deliv. 2010;23(4):243-252.
429
ACUTE LIVER FAILURE
30. Ventilation with lower tidal volumes as compared with
traditional tidal volumes for acute lung injury and the
acute respiratory distress syndrome: the Acute Respira-
tory Distress Syndrome Network. N Engl J Med. 2000;
342(18):1301-1308.
31. Salooja N, Perry D. Thrombelastography. Blood Coagul
Fibrinolysis. 2001;12:327-337.
32. Lee WM. Recent developments in acute liver failure.
Best Pract Res Clin Gastroenterol. 2012;26(1):3-16.
33. Nevens F, Laleman W. Artificial liver support devices
as treatment option for liver failure. Best Pract Res Clin
Gastroenterol. 2012;26(1):17-26.
34. Gotthardt D, Riediger C, Weiss KH, et al. Fulminant
hepatic failure: etiology and indications for liver trans-
plantation. Nephrol Dial Transplant. 2007;22(suppl 8):
viii5-viii8.
35. Reuben A, Tillman H, Fontana RJ, et al. Outcomes in
adults with acute liver failure between 1998 and 2013:
an observational cohort study. Ann Intern Med. 2016;
164(11):724-732.