Acute liver failure

Question 1

are the twin cardinal
features that reflect the severity of liver injury, and both are
required to make the clinical diagnosis of ALF

Answer 1

Coagulopathy and encephalopathy

although significant
coagulopathy in the absence of definite encephalopathy has
been described as “acute liver injury

Question 2

The vast majority of patients have no evidence
of preexisting liver disease, but 2 exceptions to this requirement
have been made:

Answer 2

(1) an acute presentation of Wilson disease in
a young adult that manifests in the setting of previously asymptomatic
cirrhosis and (2) reactivation of HBV infection, either
spontaneously or as a consequence of immunosuppression or
chemotherapy.

Question 3

is an umbrella term that has replaced prior
descriptions, including fulminant hepatic failure, subfulminant
hepatitis, and late-onset hepatic failure

Answer 3

Acute liver failure

The presence of clinical
encephalopathy in the appropriate setting remains the essential
requirement for the diagnosis of ALF

time limit between the onset of either symptoms or
jaundice and the development of encephalopathy ranging from
8 weeks to 6 months

Question 4

hyperacute liver failure

Answer 4

(up to 7 days),

Patients with hyperacute
liver failure were more likely to develop cerebral edema but also
more likely to recover without LT

Question 5

acute liver failure

Answer 5

(8 to 28 days), and

Question 6

subacute liver failure

Answer 6

(4 to 24 weeks

subacute liver failure had less severe coagulopathy
and a much lower propensity to cerebral edema but had poor
outcomes with medical management alone.

Question 7

In the USA, the original definition of ALF

Answer 7

(encephalopathy and coagulopathy within 8 weeks of the illness
onset) is still widely used, especially in criteria for LT selection

Question 8

liver failure triggered
by a type of insult that causes ALF but in a patient with preexisting
liver disease and that also includes those insults specifically
associated with cirrhosis

Answer 8

acute-on-chronic liver failure

Question 9

The main identified viruses that cause ALF are

Answer 9

HAV, HBV,
HDV, and HEV.

The risk of developing ALF following these
infections has been estimated to be 0.1% to 4% of hospitalized
cases

The risk of ALF after exposure to
HCV appears to be very low, although well-documented cases
have been reported

Question 10

Three patterns of ALF are associated with drugs: doserelated,
idiosyncratic, and hypersensitivity reactions. The best
example of a drug that causes dose-related toxicity is

Answer 10

acetaminophen
for which the amount ingested is among the determinants of risk
for ALF. Idiosyncratic reactions are often referred to as DILI.

Question 11

Acetaminophen is a partially dose-dependent hepatotoxin with

mortality rates highest at doses exceeding

Answer 11

48 g.

Increased susceptibility
to acetaminophen toxicity is recognized as a consequence
of antiepileptic therapy, regular alcohol consumption, and malnutrition.

Question 12

is the substrate for glutathione repletion and is an effective antidote
to acetaminophen if administration is commenced within 16
hours of the ingestion of acetaminophen

Answer 12

N-acetylcysteine

Question 13

In the majority of cases, the diagnosis of is made when there
is a temporal relationship between exposure to the candidate drug
and the development of ALF

Answer 13

DILI

Question 14

HBV causes ALF through a number of scenarios.11 The classic

presentation, which follows primary infection, results from an

Answer 14

aggressive immune response against the virus, but is becoming
less common.

chronic hepatitis B
infection at the point of seroconversion of hepatitis B e antigen
(HBeAg) to antibody (anti-HBe). An alternative mechanism of
ALF is aggressive viral replication with high HBV DNA levels
in serum, which can occur spontaneously or after initiation of
immunosuppressive drugs (e.g., after hematopoietic stem cell or
solid organ transplantation) or chemotherapy

Question 15

Unusual viral causes of ALF include

Answer 15

HSV-1, -2, and -6,
varicella-zoster virus, EBV, CMV, parvovirus B19 and the severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

HSV is the most important to consider because
early intervention with acyclovir can be effective; associated cutaneous
lesions are seen in about 50% of cases

Question 16

ALF is an exceptionally rare complication of pregnancy.24

Answer 16

The
risk of developing ALF is highest in the first pregnancy and with a
male fetus. Three discrete syndromes have been described: acute
fatty liver of pregnancy, preeclampsia, and the HELLP syndrome,

high serum aminotransferase levels
in patients with preeclampsia, high uric acid levels in those with
acute fatty liver of pregnancy, and low platelet counts in those
with the HELLP syndrome

Question 17

Acute liver injury may occur in the setting of hyperthermia,
which may be caused by a drug reaction, often in combination
with the consequences of

Answer 17

dehydration; one of the more frequently

encountered causative agents is the recreational drug ecstasy

Question 18

An acute presentation of Wilson disease typically occurs in the

Answer 18

second decade of life and accounts for up to 25% of cases. The
diagnosis is usually suggested by unconjugated hyperbilirubinemia
as a result of the associated hemolysis

Question 19

Ratios of serum alkaline
phosphatase to total bilirubin below 4 and AST to ALT above 2.2
accurately distinguish

Answer 19

Wilson disease from other causes of ALF

Question 20

Severe
diarrhea and vomiting are characteristic early symptoms that
develop within hours after ingestion of the mushrooms; liver failure
develops 4 to 5 days later

Answer 20

Amanita phalloides

Question 21

The diagnosis of ALF is clinical and based on the presence of

Answer 21

encephalopathy in a patient with acute liver injury and coagulopathy.

The encephalopathy is usually overt and ranges from
confusion to coma; however, psychometric testing may be needed
in patients with subacute liver failure to detect subtle changes in
mental state

Altered mental function secondary to hypoglycemia
or uremia can occasionally be misinterpreted as hepatic encephalopathy.

Question 22

Standard initial laboratory investigations include a

Answer 22

CBC,
coagulation tests, liver biochemical tests, serum electrolytes and
tests of renal function, blood glucose, serum amylase, and arterial
pH or serum lactate.

Question 23

Diagnostic Testing for the Etiology of ALF

Answer 23

HAV IgM anti-HAV
HBV HBsAg, IgM anti-HBc, HBV DNA
HEV IgM anti-HEV
Acetaminophen Drug levels in blood
Autoimmune hepatitis Autoantibodies,* serum Ig levels

Idiosyncratic drug reaction Eosinophil count, liver histology
Acute fatty liver of pregnancy US, serum uric acid level, liver
histology
HELLP syndrome Platelet count
Preeclampsia or eclampsia Serum aminotransferase levels
Wilson disease Urinary copper, serum
ceruloplasmin level, serum
alkaline phosphatase/bilirubin
ratio, serum AST/ALT ratio,
slit-lamp examination for Kayser-
Fleischer rings
Budd-Chiari syndrome Imaging of hepatic veins
Hepatic malignancy Imaging of liver, liver histology
Ischemic hepatitis Serum aminotransferase levels

Question 24

Liver

enlargement in the setting of ALF is unusual, except in

Answer 24

Budd-
Chiari syndrome, and should trigger consideration of malignant
infiltration or alcohol-associated hepatitis as possible underlying
diagnoses

Question 25

The role of a liver biopsy in the diagnosis and management

of ALF is limited.

Answer 25

The characteristic findings of confluent
necrosis and parenchymal collapse are nonspecific, and in subacute
liver failure, sampling from a zone of regeneration may
be unhelpful because apparently healthy hepatic tissue is not
indicative of the likelihood of survival

Question 26

As a result, liver biopsy is not performed routinely in patients
with ALF.

Answer 26

The findings on biopsy may support specific diagnoses
such as autoimmune hepatitis (characteristic inflammation),
valproic acid toxicity (microvesicular steatosis), Wilson disease
(cirrhosis, possible interface hepatitis, hepatocyte ballooning,
steatosis), pregnancy-related syndromes (fatty infiltration
characteristic of acute fatty liver of pregnancy or fibrin microthrombi
and necrosis secondary to preeclampsia or eclampsia),
and Budd-Chiari syndrome (venous congestion, sinusoidal
dilatation). The strongest indication for a liver biopsy is to
exclude malignant infiltration or alcohol-associated hepatitis in
a patient with hepatomegaly, especially if LT is under consideration

Question 27

Other classic signs of liver failure notable for their
absence are fetor hepaticus and tremor, the hallmark features of encephalopathy secondary to chronic liver disease; rarely, they are seen in patients with subacute liver failure.

Answer 27

Ascites is characteristic
of Wilson disease and Budd-Chiari syndrome and is seen
in many patients with subacute liver failure,

Question 28

is mandatory for a diagnosis of ALF. It is classically

graded on a scale of 1 to 4.

Answer 28

Encephalopathy

Patients with grades 1 or 2
encephalopathy exhibit degrees of drowsiness or disorientation,
but they can be roused and will respond appropriately to verbal

Progression to grade 3 encephalopathy is often heralded
by a period of extreme agitation before the patient becomes confused
to the point of being able to respond only to simple commands.
Grade 4 encephalopathy signifies deep coma, with the
patient responsive at best to painful stimuli.

Question 29

The briefest period

between liver injury and the development of encephalopathy is

Answer 29

3 to 4 days, as demonstrated in patients with acetaminopheninduced
ALF

Question 30

has been a hallmark complication of ALF, major

cause of death, and threat to successful LT

Answer 30

Cerebral edema

Question 31

Patients with ALF are highly prone to infection and have been
found to have twice the risk when compared with similarly ill
patients without liver disease

Answer 31

Acute kidney injury (AKI) is common in patients with ALF, may
occur in 40% to 80% of cases and is associated with increased
mortality

Question 32

The liver is responsible for the synthesis of most of the coagulation
factors (all except

Answer 32

factor VIII, which is produced by endothelial
cells), as well as some of the inhibitors of coagulation and
fibrinolysis

Question 33

After acute liver injury, circulating

levels of

Answer 33

fibrinogen, prothrombin, and factors V, VII, IX, and X
fall and can do so rapidly because of the short half-life (measured
in hours) of some of the factors

Laboratory parameters of blood
coagulation such as the prothrombin time and the INR, as well
as levels of an individual factor (e.g., factor V), are widely used as
indicators of the severity of liver damage

Question 34

Synthesis of anticoagulant proteins (e.g., proteins C and S),
as well as antithrombin, is also decreased and often remains in physiologic balance with the levels of coagulation factors.

Answer 34

probably explains the clinical observation that patients
with severe laboratory indicators of a coagulopathy may show
little clinical evidence of bleeding

Question 35

In fact, the risk of bleeding

is much more closely linked to the

Answer 35

platelet count, and both
quantitative and qualitative defects in platelet function are well
described in ALF

Question 36

Platelet counts below

Answer 36

100,000/mm3 are seen
in up to 70% of patients, and platelet aggregation is impaired.
There is also evidence of increased platelet adhesiveness that may
be due to increased levels of circulating von Willebrand factor.

Question 37

A Coombs-negative hemolytic anemia is characteristic of

Answer 37

Wilson disease, and a Coombs-positive hemolytic anemia may be seen in ALF associated with autoimmune hepatitis.

Question 38

nonspecialist setting, the initial priorities are adequate
fluid resuscitation and protection of the airway in patients with
encephalopathy

Answer 38

rapid and appropriate fluid resuscitation in patients
with acetaminophen-related acute liver injury

Metabolic acidosis
is an indicator of severe toxicity and is linked to a poor prognosis

Question 39

Three important determinants
of outcome that are almost immediately apparent on presentation
are the

Answer 39

underlying etiology of ALF, age of the patient,
and grade of encephalopathy.

Another early indicator of a poor
prognosis is a history of jaundice for more than 7 days before the onset of encephalopathy; most “spontaneous” survivors have the hyperacute category of ALF.

Question 40

he MELD score has been validated for use in prognostication
in patients with chronic liver disease and has subsequently
been applied to patients with ALF

Answer 40

The components
of the MELD score (bilirubin, INR, serum creatinine) are
well-recognized parameters of disease severity, and in unmodified
form, the MELD score may show promise as a predictive score in
patients with nonacetaminophen etiologies

Question 41

Assessing the volume of viable hepatocytes

may have prognostic value, with a critical mass of

Answer 41

25% to

40% suggested as being associated with a good prognosis

Question 42

Encephalopathy is a consistent clinical feature of ALF

Answer 42

The main exception is in patients with subacute liver
failure, who may benefit from the standard measures used in
patients with chronic liver disease, including lactulose and nonabsorbable
oral antibiotic therapy

Question 43

The main neurologic complication amenable to therapy is

Answer 43

cerebral edema. Mannitol has been the mainstay of treatment
of increased intracranial pressure, but hypertonic saline is now
considered to be an alternative first-line therapy

These solutions
act in part by increasing serum osmolality and reducing astrocyte
swelling in the brain

A rapidly delivered bolus of 0.25 to 0.5 mg/kg is recommended
to obtain the maximal diuretic effect, which in anuric
patients is achieved by manipulating the rate of fluid removal
through hemofiltration

Question 44

Hypertonic saline has the advantage over
mannitol of also increasing blood pressure. The induction of
hypernatremia (serum sodium 145 to 155 mmol/L) by continuous
infusion of hypertonic saline solution has been shown to
reduce intracranial pressure in a randomized controlled trial and
has a prophylactic role in patients with severe encephalopathy

Answer 44

.59
Bolus therapy with hypertonic saline (200 mL of a 2.7% or 20
mL of a 30% solution) is often effective in controlling surges in
intracranial pressure.

Question 45

at the time of admission and the presence of SIRS are significant
predictors of bacteremia

Answer 45

Encephalopathy

Question 46

Most patients with ALF develop systemic vasodilatation with

reduced effective central blood volume.

Answer 46

no evidence to recommend use of one specific formulation above
others, but selection should avoid inducing or worsening hyponatremia
from dextrose solutions, hyperchloremia from saline solutions,
or elevation of the serum lactate level from lactated Ringer’s
solution. In patients who remain hypotensive despite fluid administration

Question 47

is the commonly preferred vasoconstrictor therapy, supported,
as required, by concurrent low-dose vasopressin infusion

Answer 47

Norepinephrine

In
general, epinephrine is not the first choice because it can worsen
hyperlactatemia.

patients with ALF may have a degree of
adrenal insufficiency that may contribute to hemodynamic instability.
In those patients supplemental hydrocortisone may reduce
vasopressor requirements but carries the usual risks from immunosuppression
and has not been shown to improve survival

Question 48

is not indicated in patients with hyperacute ALF,
because the pattern of renal injury is acute tubular necrosis; it
might in theory be effective for some patients with slowly evolving
renal injury in subacute ALF, but no data are available to
support this approach.

Answer 48

Terlipressin

Question 49

Routine prophylactic repletion of coagulation factors seems intuitive
but is not indicated

Answer 49

Despite often grossly abnormal laboratory
tests of coagulation, functional tests may be remarkably
normal or even indicate a prothrombotic tendency; spontaneous
bleeding is actually uncommon in patients with ALF

Question 50

An early controlled trial of fresh frozen plasma failed to
demonstrate an improvement in survival and was thought to be
detrimental in a minority of patients with a consumptive coagulopathy.

Answer 50

Administration of fresh frozen plasma interferes with the
use of coagulation studies in assessing prognosis and monitoring
disease progression and risks inducing fluid overload

Question 51

Hypoglycemia is common in patients with ALF and can be mistaken
for the onset of advanced encephalopathy

Answer 51

Metabolic acidosis is present in 30% of patients
with ALF after an acetaminophen overdose and has been associated
with a particularly high mortality rate. Fluid resuscitation
is first-line therapy, but persistence of acidosis may be an
indication to initiate hemofiltration

Hypophosphatemia is encountered
most frequently in acetaminophen-induced ALF when
renal function is preserved.

Question 52

Enteral nutrition is desirable to help maintain the integrity of the small intestinal mucosa, and, in practice, feeding is normally commenced within 24 hours of admission to an ICU, with

Answer 52

goals of 25 to 30 kcal/kg/day and a protein load of 1 to 1.2 g/kg/
day

Initial administration should be via an NG tube

Protein intake is only restricted for short periods
of time in selected patients with profound hepatic compromise
and hyperammonemia

Question 53

The most widely used

device is the

Answer 53

Molecular Adsorbents Recyling System (MARS),

which is based on an albumin dialysis circuit.