Acute Liver Injury and

F a i l u re
Vincent Thawley, VMD

KEYWORDS
 Liver jury  Liver failure  Hepatic encephalopathy  Coagulopathy

KEY POINTS
 Acute liver failure is the result of a rapid loss of functional hepatic mass, such that the syn-
thetic functions of the liver are compromised.
 Treatment of acute liver injury/acute liver failure is largely supportive and directed at
ameliorating the complications that arise as a result of severe liver dysfunction.
 Although some patients may make a clinical recovery with intensive care, the prognosis
for acute liver failure is generally considered poor.

INTRODUCTION

Acute liver injury (ALI) and acute liver failure (ALF) are clinical syndromes that are
frequently life threatening, characterized by a rapid loss of hepatocyte function in a pa-
tient without pre-existing liver disease.1 Numerous definitions for ALF have been pro-
posed in the published literature, most of which involve a combination of an acute
onset of clinical signs, the presence of coagulopathy, icterus, and the development
of hepatic encephalopathy (HE).2 In people, ALF is further characterized as hyper-
acute, acute, or subacute based on the time interval between the development of
icterus and the onset of HE, because this seems to have prognostic significance.3
Similarly, in the veterinary literature, a variety of diagnostic criteria have been used
to define ALF. A recently published retrospective case series involving canine patients
defined ALF as the acute onset of clinical signs in conjunction with serum hyperbilir-
ubinemia and a prothrombin time (PT) greater than 1.5 times the upper reference
range, with or without evidence of HE.4 In contrast to ALF, ALI is generally thought
to involve an acute hepatic insult with sustained hepatic function. This article reviews
the pathophysiology and clinical approach to the ALI/ALF patient, with a particular
emphasis on the diagnostic evaluation and care in the acute setting.

The author has nothing to disclose.

Emergency and Critical Care Medicine, Department of Clinical Studies – Philadelphia, Matthew
J. Ryan Veterinary Hospital of the University of Pennsylvania, 3900 Delancey Street, Philadel-
phia, PA 19104, USA
E-mail address: [email protected]

Vet Clin Small Anim - (2016) -–-

http://dx.doi.org/10.1016/j.cvsm.2016.11.010 vetsmall.theclinics.com
0195-5616/16/ª 2016 Elsevier Inc. All rights reserved.
2 Thawley

PATHOPHYSIOLOGY

In health, the liver is responsible for a multitude of homeostatic, synthetic, and excre-
tory functions, including protein, carbohydrate, and lipid metabolism; detoxification of
metabolites and chemical compounds; immune regulation; fat digestion; albumin pro-
duction; and storage of vitamins, fats, and glycogen. Hepatic Kupffer cells are tissue
macrophages that typically reside in hepatic sinusoids but can migrate into areas of
hepatic tissue injury. These cells are highly efficient phagocytes; consequently, the
liver is a major site of blood filtration and removal of circulating microbes and microbial
antigens.5
Histologically, hepatocytes are arranged into 3 zones around the hepatic blood sup-
ply. Zone 1 contains hepatocytes that are closest to the arterial or portal inflow; cells in
this region are exposed to blood with a higher concentration of oxygen, hormones like
insulin and glucagon, and products of nutrient metabolism. Given their proximity to
vascular inflow, hepatocytes in zone 1 are susceptible to injury from directly acting
toxicants. Zone 2 contains transitional midzone hepatocytes, and zone 3 contains
the periacinar hepatocytes, which are closest to the hepatic venule and thus receive
a lower concentration of oxygen and nutrients, making them more susceptible to hyp-
oxic injury. In addition, many of the hepatic biotransformation pathways are active in
zone 3; thus, hepatocytes in this zone are more susceptible to injury caused by toxic
metabolites of the cytochrome P450 systems.5
The liver has an extensive reserve system and clinical signs or biochemical manifes-
tations of ALF often are not apparent until there has been loss of more than 70% of the
functional hepatic mass.6 However, in the setting of acute hepatocyte necrosis or he-
patic cellular or lipid infiltrates, clinical signs may progress rapidly to those consistent
with fulminant liver failure.

CAUSE

ALI/ALF may occur as a result of prolonged ischemia, toxin or toxicant exposure, idio-
syncratic or dose-dependent drug reaction, neoplasia, metabolic disorders, and infec-
tious and immune-mediated processes. In humans, ALF is considered relatively
uncommon particularly in the developed world.7 Drug-induced liver failure, most
notably a result of accidental or intentional acetaminophen overdose, is a leading
cause of human ALF in the United States, whereas there is a higher incidence of viral
hepatitis in other parts of the world.7–11 In a retrospective case series of 49 dogs with
ALF, neoplasia was the most common underlying cause (13 of 49 dogs, 27%), fol-
lowed by presumptive leptospirosis (4/49 dogs, 8%). In one dog, evidence of thrombi
within a branch of the hepatic artery and hepatic veins was found on post-mortem ex-
amination, thus ischemia-induced ALF was suspected. No definitive cause was iden-
tified in 31 dogs, but 15 of these dogs had exposure to potential hepatotoxins.4 In
addition, ALI and ALF have been documented in several reports in the veterinary liter-
ature; Table 1 summarizes the confirmed or suspected causes.4,12–43 A comprehen-
sive discussion of the various causes of ALI and ALF can be found elsewhere in the
literature.44

CLINICAL APPROACH TO THE ACUTE LIVER INJURY/ACUTE LIVER FAILURE PATIENT

Quite often the presenting clinical signs in a patient with ALI or ALF can be vague and
potentially attributable to numerous disease processes. Common chief complaints
include anorexia, lethargy, vomiting, diarrhea with or without hematochezia or melena,
weakness or other neurologic signs resulting from HE. Owners may note the presence
 Acute Liver Injury and Failure 3

Table 1
Reported inciting causes of acute liver injury/acute liver failure in dogs and cats

Toxins Drugs Infectious Other

 Aflatoxins  Acetaminophen  Infectious canine  Ischemia
 Amanita mushrooms  Oral benzodiazepines hepatitis  Hepatic lipidosis
 Blue-green algae (cats)  Feline infectious  Neoplasia
 Cycad palms  Carprofen peritonitis
 Xylitol  Lomustine  Leptospirosis
 Mitotane  Platynosum fastosum
 Phenobarbital  Salmonellosis
 Phenazopyridine  Toxoplasmosis
 Stanazol
 Sulfonamides
 Zonisamide

of icteric skin, sclera, or mucous membranes, or appreciate abdominal distention in

patients with ascites. Polydipsia and polyuria are occasionally reported.4 Because
clinical signs of liver failure are not apparent until there has been a loss of a critical
mass of functional hepatocytes, it is not uncommon for patients to have only a short
duration of clinical signs despite evidence to suggest a chronic underlying cause.
Given the variability and nonspecific nature of the clinical signs associated with ALI/
ALF, definitive diagnosis is typically contingent on integration of data from the history,
physical examination, and results of diagnostic testing.

History
In addition to an inquiry as to the nature and progression of clinical signs, additional
questions during the medical interview that may help to identify risk factors for ALI/
ALF or point toward possible underlying causes include
 Vaccination status and potential exposure to infectious disease
 Travel history, particularly to regions where leptospirosis is endemic
 Potential for exposure to recognized hepatotoxins
 Dietary history, including the introduction of new foods or treats
 Therapeutic drug history, including herbal remedies and nutritional supplements,
because many medications have been implicated in the development of ALI/ALF
in either a dose-dependent or an idiosyncratic manner

Initial Physical Examination and Stabilization

As with any sick patient, an initial primary survey is conducted at presentation to
assess for stability with a particular focus on the respiratory, cardiovascular, and
neurologic systems.
Signs of respiratory compromise can include tachypnea, orthopnea, abnormal
breathing patterns, abducted elbows and straightening of the head and neck, open-
mouth breathing, and in with patients with severe hypoxemia, cyanotic mucous mem-
branes.45 Causes of respiratory distress in the ALI/ALF patient include pleural effusion
resulting from low intravascular oncotic pressure, aspiration pneumonia, atelectasis
secondary to recumbency, and, perhaps less commonly, neurogenic pulmonary
edema, acute respiratory distress syndrome, pulmonary thromboembolism, or pulmo-
nary hemorrhage. Pulse oximetry or arterial blood gas analysis is useful in assessing
the degree of hypoxemia, and early thoracic imaging is indicated to delineate the
4 Thawley

cause for respiratory compromise. When pleural effusion is suspected, needle thora-
cocentesis is warranted, because this may be both diagnostic and therapeutic.
Assessment of the cardiovascular system involves evaluation of the mucous mem-
brane color and capillary refill time, heart rate and rhythm, and palpation of the periph-
eral pulses. Signs of circulatory shock include pale or hyperemic mucous membranes,
slow capillary refill time, tachycardia, cool extremities, decreased rectal temperature,
and either bounding, reduced, or absent peripheral pulses. In the author’s experience,
cats in circulatory shock are more commonly bradycardic than tachycardic. Shock in
the ALI/ALF patient may be the result of volume loss, for example, from reduced oral
intake coupled with vomiting, diarrhea, polyuria, hemorrhage, or ascites, from inap-
propriate vasodilation secondary to sepsis or systemic inflammation, or a combination
of the 2.46 Frequently patients with ALI are presented in a dehydrated state, but it is
imperative to differentiate dehydration from signs of circulatory shock, as the latter re-
quires immediate resuscitation.
Intravenous (IV) fluid resuscitation, aimed at restoring perfusion and improving tis-
sue oxygen delivery, is a cornerstone of therapy for circulatory shock. The shock
dose of an isotonic crystalloid solution is 15 to 25 mL/kg (dog) or 10 to 15 mL/kg
(cat), given rapidly as a bolus with subsequent patient reassessment and redosing
as needed.47 Isotonic crystalloids containing lactate should be avoided, because pa-
tients with liver dysfunction may not be able to effectively metabolize lactate to bicar-
bonate.48 For hypoproteinemic patients, a synthetic colloid like hydroxyethyl starch
may be administered in aliquots of 3 to 5 mL/kg.47 It should be noted, however, that
administration of hydroxyethyl starch solutions has been associated with the develop-
ment of impaired coagulation49 and acute kidney injury.50 Resuscitation with blood
products is generally reserved for patients with evidence of hemorrhagic shock or
for those with a documented coagulopathy and active hemorrhage, in which case
transfusing plasma may be indicated. Patients with persistent hypotension despite
adequate volume resuscitation may require vasopressor administration. The author’s
preferred vasopressor in this setting is norepinephrine, although there are insufficient
data in the published veterinary literature to suggest superiority of any one particular
vasopressor.51 Administration of supraphysiologic dosages of hydrocortisone can be
considered for patients in shock with vasopressor-refractory hypotension.52
Neurologic impairment in the ALI/ALF patient may be the result of diminished cere-
bral perfusion secondary to circulatory shock, hypoglycemia and neuroglycopenia, or
HE. Signs of HE can include lethargy, behavioral changes, obtundation, head press-
ing, circling, blindness, tremors, or seizures.53 Hypoglycemia may cause similar clin-
ical signs and so measurement of whole blood or plasma glucose is indicated. For
patients with symptomatic hypoglycemia, a 0.5- to 1-g/kg bolus of dextrose is admin-
istered IV followed by supplementation of dextrose to the intravenous fluids. Further
discussion of the management of HE is found in later discussion and in Adam G.
Gow’s article, “Hepatic Encephalopathy,” in this issue.
Following the initial patient assessment and once stabilization, as necessary, is un-
derway, a comprehensive physical examination is performed. Common findings
include icterus, abdominal pain, cranial organomegaly, and abdominal distention. Pa-
tients with a large volume of ascites may have a ballottable abdominal fluid wave.
Rectal examination may reveal hematochezia or melena. Occasionally patients may
present with fever or clinical signs referable to dysfunction of other organ systems.
Assessment of body condition and lean muscle mass may provide information as to
the chronicity of the underlying condition. Most physical examination findings, howev-
er, are not specific for acute liver dysfunction, and clinical experience suggests that a
diagnosis of ALI/ALF can rarely be made on the basis of physical examination alone.
 Acute Liver Injury and Failure 5

DIAGNOSTIC EVALUATION OF THE ACUTE LIVER INJURY/ACUTE LIVER FAILURE

PATIENT

The diagnostic evaluation of a patient with suspected ALI/ALF includes a combination

of blood testing, imaging, and potentially obtaining a sample of liver tissue via fine-
needle aspiration (FNA) or biopsy. Comprehensive discussions focusing on laboratory
evaluation of the liver, coagulation abnormalities, and liver biopsy can be found else-
where (see Yuri A. Lawrence and Jörg M. Steiner’s article, “Laboratory Evaluation of
the Liver,” and Cynthia R.L. Webster’s article, “Hemostatic Disorders Associated
with Hepatobiliary Disease,” and Jonathan A. Lidbury’s article, “Getting the Most
Out of Liver Biopsy,” in this issue).

Biochemistry Panel
Evaluation of serum hepatobiliary enzyme activities, including alanine aminotrans-
ferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and gamma-
glutamyl transpeptidase, can be used to screen for hepatobiliary disease.54 ALT is
the most liver-specific cytosolic enzyme, and the magnitude of an increase in ALT
may provide insight as to the degree of hepatocyte injury. These enzymes are pro-
duced inside the hepatocyte, and therefore, serum activities can decrease in end-
stage liver failure.54 Microcystins, produced by blue-green algae, impair hepatic
synthesis of ALT, and so activity of this enzyme may be diminished in the face of acute
hepatic necrosis due to microcystin toxicity.12
Common biochemistry findings in ALF that suggest diminished hepatic synthetic
function include decreased serum blood urea nitrogen, hypoglycemia, hypocholester-
olemia, and hypoalbuminemia.55 Hyperbilirubinemia may be prehepatic, hepatic, or
posthepatic in origin. In the setting of ALI/ALF, hyperbilirubinemia is often the result
of hepatocyte dysfunction and intrahepatic cholestasis leading to impaired uptake,
conjugation, and excretion of bilirubin.55 A concomitant reduction or normalization
of hepatic transaminase activity in the face of evidence for hepatic synthetic or excre-
tory dysfunction suggests a significant loss of hepatic functional parenchyma.54
Other common serum biochemical abnormalities include hypokalemia, hyperkale-
mia, hyponatremia, hypernatremia, hyperphosphatemia, hyperammonemia, and
elevated creatinine concentration.4 Hyperammonemia is a common finding in patients
with HE, and in both people56 and dogs,57 the degree of hyperammonemia is corre-
lated with the severity of HE.

Complete Blood Count

On a complete blood count, microcytic anemia is more commonly documented with
chronic liver disease, and regenerative anemia may suggest blood loss. Spontaneous
hemorrhage due to coagulopathy is uncommon; however, hepatic disease is a recog-
nized risk factor for gastroduodenal ulceration.58 Microcytic, hypochromic anemia is
suggestive of chronic gastrointestinal blood loss. A leukocytosis or leukopenia may
result from systemic inflammation or sepsis. Thrombocytopenia in patients with ALI/
ALF can occur as a result of impaired production due to diminished hepatic synthesis
of thrombopoietin, splenic sequestration, or consumption following hemorrhage,
thrombosis, or disseminated intravascular coagulation.59

Urinalysis
Urinalysis with sediment evaluation is warranted in any sick patient and, in the setting
of ALI/ALF, bilirubinuria is a common finding. It should be noted that bilirubinuria can
be identified in normal dogs because they have the ability to produce and conjugate
6 Thawley

bilirubin within their renal tubules; however, bilirubinuria is always a pathologic finding
in cats.60 Granular casts can be seen with concurrent acute kidney injury and may oc-
casionally be seen in patients with aflatoxicosis even in the absence of azotemia.12

Coagulation Testing
Abnormalities in tests of coagulation are common in ALF, which is not surprising
considering that increased PT (or elevated international normalized ratio [INR], which
is calculated based on the measured PT) is one of the most commonly cited criterium
for diagnosing ALF.2 Given this, patients with ALF have historically been considered at
risk for bleeding complications, although studies in human patients have found that
significant spontaneous hemorrhage is rare in ALF patients and, when it occurs is
most frequently of gastrointestinal origin as a result of portal hypertension with
bleeding varices.61,62 Indeed, some studies have found an increased risk of throm-
botic complications in patients with ALF.62 Investigation into this paradox has led to
the concept of “rebalanced hemostasis,” that is, the suggestion that the hemostatic
system is balanced between a proclivity toward hemorrhage and a tendency toward
thrombosis. This is thought to be the result of decreased hepatic synthesis of procoa-
gulant factors being balanced by decreased synthesis of anticoagulant factors,
although the presence of procoagulant platelet microparticles and altered fibrinolytic
activity may play a role.63,64 (Please also see Cynthia R.L. Webster’s article,
“Hemostatic Disorders Associated with Hepatobiliary Disease,” in this issue.)
Recent studies have evaluated the use of thromboelastography (TEG) in ALF as a
means of assessing overall hemostasis. Briefly, TEG is a whole blood viscoelastic
test of coagulation that provides information on clot kinetics, including the speed of
clot formation, clot strength, and rapidity of fibrinolysis. In a study of 51 human pa-
tients with ALI or ALF, all of whom had an elevated INR, mean and median TEG param-
eters were within the normal range for the entire study population, suggesting overall
normal hemostasis.62 In one veterinary study investigating the use of TEG in 21 dogs
with either ALI or ALF, TEG was found to be discordant with traditional tests of coag-
ulation 25% of the time, with 4/8 dogs deemed hypocoagulable based on elevated PT,
partial thromboplastin time (PTT), or both having normocoagulable TEG results.63 The
authors of this study suggested that conventional tests of coagulation might overes-
timate a tendency toward hypocoagulability, particularly early in the ALI/ALF disease
spectrum.63 As viscoelastic coagulation assays are not yet widely available, the
routine measurement of PT, PTT, platelet count, and fibrinogen is recommended for
patients with ALI or ALF; however, the data available call into question the routine
use of plasma transfusion to treat an increased PT or PTT without evidence of active
hemorrhage or intention to perform an invasive procedure that could cause bleeding.

Diagnostic Imaging
In the emergency setting, cage-side use of ultrasound can be used to quickly detect
and facilitate sampling of free abdominal, pleural, or pericardial fluid, particularly in pa-
tients that are not cardiovascularly stable.65 When available, the author recommends
the routine use of abdominal- and thoracic-focused assessment with sonography for
trauma ultrasound techniques for any patient with evidence of shock, abdominal
distention, or abdominal pain.
Abdominal radiographs may show evidence of hepatomegaly or poor organ serosal
detail, which may suggest the presence of peritoneal effusion. Thoracic radiography is
warranted in any patient with respiratory compromise to evaluate for alveolar infiltrates
or pleural effusion as well as in patients with ALI/ALF for whom underlying neoplasia is
a concern as a screening test for metastasis.
 Acute Liver Injury and Failure 7

Complete abdominal ultrasound is likely the imaging modality with the most utility in
the ALI/ALF patient, as a means of evaluating the overall size and architecture of the
liver as well as to assess for comorbidities like pancreatitis or gastrointestinal ulcera-
tion. Dogs with ALF may have variable degrees of hepatomegaly and hepatic echoge-
nicity, with the liver appearing sonographically normal in some cases.4 In one study,
ALF due to hepatic neoplasia was associated with moderate to marked hepatomegaly
seen on ultrasound, although some dogs with hepatomegaly had nonneoplastic
causes of ALF.4

Hepatic Cytology/Histopathology
Liver tissue sampling can enable a definitive histopathologic diagnosis to be made in
cases of ALI and ALF; however, in the author’s experience, this is rarely performed in
the acute setting often due to concern for hemorrhage. FNA of the liver with ultrasound
guidance can be considered, because this is relatively noninvasive and is generally
thought to be associated with a low risk of hemorrhage; however, in comparison to
a biopsy sample, a smaller number of cells are retrieved and the overall architecture
of the hepatic parenchyma cannot be evaluated. Despite these limitations, FNA may
have utility in the diagnosis of some infiltrative liver diseases, such as hepatic lipidosis
or diffuse neoplasia.4,66 Liver biopsy, performed either percutaneously with ultrasound
guidance or via laparoscopy or laparotomy, will provide larger tissue samples but
may carry an increased risk of hemorrhage. Before obtaining a biopsy, a coagulation
panel including assessment of PT, PTT, and platelet count should be performed. One
retrospective study that evaluated the incidence of complications following
ultrasound-guided percutaneous organ biopsy found that an increased incidence of
postprocedural bleeding was associated with thrombocytopenia (platelet count
<80  103/mL) in both dogs and cats, PTT greater than 1.5 times the upper limit of
the reference range in cats but not dogs, and PT above the reference range in dogs
but not cats.67 Administration of fresh frozen plasma or fresh whole blood before bi-
opsy may minimize the risk of hemorrhage in patients with mild elevations in PT/
PTT. For a more complete discussion of hepatic biopsy techniques, please see Jona-
than A. Lidbury’s article, “Getting the Most Out of Liver Biopsy,” in this issue.

MANAGEMENT OF THE ACUTE LIVER INJURY/ACUTE LIVER FAILURE PATIENT

Clinical management of the ALI/ALF patient is largely supportive in nature because

there is not a definitive therapy for most causes of acute liver dysfunction and because
liver transplantation is, to the author’s knowledge, not yet available for small animal
patients. Frequently these patients are critically ill and require aggressive care and
intensive monitoring. The discussion that follows details general guidelines on various
aspects of care for these patients.

Fluid Therapy
IV fluid therapy is an integral part of the management of the ALI/ALF patient, used to
restore and maintain perfusion, to correct dehydration, and to maintain euhydration in
patients that are not amenable to oral fluid administration. Balanced electrolyte solu-
tions are used most commonly; however, as stated previously, fluids containing
lactate as a buffer should generally be avoided.48 Although acidifying, 0.9% sodium
chloride may be considered for use in patients with HE because this fluid, compared
with other isotonic crystalloids, is less likely to decrease osmolality, which might other-
wise facilitate movement of water into the brain parenchyma.48 Careful attention to
fluid balance is essential because excessive administration of crystalloid fluids can
8 Thawley

lead to the development of interstitial edema, pleural effusion, and ascites, particularly
in patients with hypoalbuminemia and low colloid osmotic pressure, or in patients with
systemic inflammation and increased capillary permeability. Synthetic colloids could
be considered for patients with hypoalbuminemia to increase and maintain intravas-
cular colloid osmotic pressure; however, these fluids should be used cautiously in pa-
tients at risk for coagulopathy or acute kidney injury.48

Blood Products
Transfusion of whole blood or packed red blood cells is indicated in patients symp-
tomatic for moderate or severe anemia; however, it should be noted that ammonia
concentration of stored blood increases over time in both canine68 and feline69 packed
red blood cells, which may be deleterious in a patient with compromised liver function.
As previously mentioned, spontaneous hemorrhage appears to be uncommon in pa-
tients with ALF; consequently, the author only recommends the use of plasma trans-
fusions in patients with a documented coagulopathy and active hemorrhage or before
a planned invasive procedure that will likely cause bleeding.

Treatment for Hepatic Encephalopathy

HE is a common complication of ALF, likely resulting from a combination of hyperam-
monemia, excitatory neurotoxicity, oxidative stress, altered permeability of the
blood-brain barrier, inflammation, and neurosteroid-induced GABA-receptor modu-
lation within the central nervous system.70 Signs of HE may be precipitated by hypo-
kalemia, which increases renal proximal tubule ammoniagenesis,71 hyponatremia,
which is a risk factor for cerebral edema via reduced extracellular osmolarity,72
and metabolic alkalosis, which facilitates diffusion of ammonia into the central
nervous system.73 In addition, gastrointestinal hemorrhage74 and systemic inflam-
mation75 or infection may increase the risk for HE in the ALF patient. For a compre-
hensive review of the pathophysiology of HE, please see Adam G. Gow’s article,
“Hepatic Encephalopathy,” in this issue.
HE should be suspected in any patient with evidence of moderate to severe
liver dysfunction and concurrent signs of central nervous system depression or hyper-
excitability. A blood ammonia level can be measured to document the presence of
hyperammonemia, but a normal ammonia level does not rule out HE. Precipitating
factors, for example, electrolyte disturbances or hypoglycemia, should be treated
as necessary. For patients that develop seizures, the author uses levetiracetam
(20–60 mg/kg IV loading dose, then 20 mg/kg IV every 8 hours) in preference to diaz-
epam, because there is some evidence to suggest that increased levels of endoge-
nous benzodiazepine receptor ligands play a role in the pathogenesis of HE.76
For emergent stabilization of an encephalopathic crisis, a warm water cleansing
enema (10 mL/kg) may be administered to reduce the number of urease-producing
bacteria in the lower gastrointestinal tract. Following this, a lactulose retention enema
can be administered. Various doses have been reported, including 2 mL/10 kg of lac-
tulose diluted 1:1 in warm water.77 Lactulose is a nonabsorbable disaccharide that
acts as an osmotic laxative and additionally decreases the intraluminal pH of the co-
lon, limiting systemic uptake of ammonia.78 Metronidazole (7.5 mg/kg IV every
12 hours) is administered to reduce the number of intestinal urease-producing bacte-
ria. Mannitol (0.5–1 g/kg IV over 20 minutes) can be considered when intracranial
hypertension due to cerebral edema is suspected. Once the patient becomes
stable and tolerant of oral medications, lactulose can be continued at a dose of 1 to
3 mL/10 kg orally every 6 to 8 hours with the dose titrated such that the patient
 Acute Liver Injury and Failure 9

produces soft but not watery feces a few times per day. Oral antibiotic therapy, with,
for example, metronidazole, is continued.77
Antimicrobial Prophylaxis
In people with ALF, infection, most commonly originating from the respiratory or uri-
nary tracts or bloodstream, is a major cause of death and has been associated with
precipitation of HE.79,80 Prophylactic antimicrobial administration has been shown
to reduce the incidence of infection, but there was no demonstrated effect on sur-
vival.81 Current guidelines in the human literature therefore suggest considering anti-
microbial prophylaxis only in patients with vasopressor-refractory hypotension,
progression of HE, evidence for systemic inflammatory response syndrome, or
when surveillance bacterial cultures are positive.79 When considering prophylactic an-
timicrobials, empiric therapy should be broad spectrum targeting gram-positive and
gram-negative organisms and ideally narrowed based on culture/susceptibility data,
when available.
Antacid Therapy
Liver disease is a recognized risk factor for gastroduodenal ulceration, which may
ultimately result in bleeding into the gastrointestinal tract.58 Consequently, antacid
therapy is warranted for patients with ALI/ALF. The author prefers to use a proton-
pump inhibitor (pantoprazole or omeprazole, 1 mg/kg IV or orally every 12–24 hours)
because there is evidence to suggest better gastric acid suppression with this class of
antacid as compared with famotidine.82

VITAMIN K

Vitamin K deficiency may occur in patients with liver dysfunction as a result of poor
oral intake, intrahepatic or extrahepatic cholestasis, or the use of systemic antimicro-
bials, which disrupts the normal intestinal flora that synthesize vitamin K2. Vitamin K
deficiency may contribute to coagulation dysfunction, because vitamin K is necessary
for normal function of clotting factors II, VII, IX, and X.83 Therefore, empiric administra-
tion of vitamin K1 is recommended at a dose of 1 mg/kg subcutaneously once daily.
Hepatoprotectants
A variety of hepatoprotective medications have been evaluated in the treatment of liver
disease, although there is limited information in the published literature to support their
efficacy.84 Silymarin (10–20 mg/kg/day orally, divided every 8 hours),60 an extract from
the seed of the milk thistle plant Silybum marianum, may help attenuate hepatic oxida-
tive stress.85 S-adenosylmethionine (17–22 mg/kg orally every 24 hours)60 is a sub-
strate that initiates hepatic transmethylation and transsulfuration pathways, thereby
playing a role in the stabilization of hepatocyte cell membranes and generation of
glutathione, an endogenous antioxidant.24 Vitamin E (15 IU/kg/d orally) inhibits lipid
peroxidation of cell membranes and thus may reduce hepatic oxidative injury.84

NUTRITION

Early provision of nutritional support is indicated and, when tolerated, enteral feeding
is preferable to parenteral. Milk and vegetable proteins are less likely to potentiate HE
compared with animal proteins. Restricted protein diets should only be considered for
patients with HE.60
The resting energy requirement (RER) should be calculated as kilocalories per
day 5 70  body weight (kg)3/4. Aim to provide sufficient food, such that a minimum
10 Thawley

25% to 50% of the RER is provided on the first day, and slowly increase to 100% of the
RER over the next 2 to 3 days, depending on the patient’s tolerance. Antiemetics and
antacids may improve patient tolerance. Placement of a feeding tube may be consid-
ered for patients tolerant of enteral nutrition but not consuming adequate calories
voluntarily.

PROGNOSIS

The prognosis for ALI is variable depending on the inciting cause and response to ther-
apy. Unfortunately, once ALF has developed, the prognosis appears to be poor, with
one study reporting only 14% survival to discharge.4

REFERENCES

1. Lee WM. Acute liver failure. Semin Respir Crit Care Med 2012;33(1):36–45.
2. Wlodzimirow KAK. Systematic review: acute liver failure—one disease, more than
40 definitions. Aliment Pharmacol Ther 2012;35(11):1245–56.
3. O’Grady JG, Schalm SW, Williams R. Acute liver failure: redefining the syn-
dromes. Lancet 1993;342(8866):273–5.
4. Lester C, Cooper J, Peters RM, et al. Retrospective evaluation of acute liver fail-
ure in dogs (1995-2012): 49 cases. J Vet Emerg Crit Care (San Antonio) 2016;
26(4):559–67.
5. Maxie MG, editor. Jubb, Kennedy and Palmer’s pathology of domestic animals.
6th editon. St Louis (MO): Elsevier; 2016. No. 2.
6. MacKenzie R, Furnival C, O’Keane MA, et al. The effect of hepatic ischaemia on
liver function and the restoration of liver mass after 70 per cent partial hepatec-
tomy in the dog. Br J Surg 1975;62(6):431–7.
7. Bernal W, Hyyrylainen A, Gera A, et al. Lessons from look-back in acute liver
failure? A single centre experience of 3300 patients. J Hepatol 2013;59(1):74–80.
8. Adukauskiene D, Dockiene I, Naginiene R, et al. Acute liver failure in Lithuania.
Medicina (Kaunas, Lithuania) 2008;44(7):536–40.
9. Bower WA, Johns M, Margolis HS, et al. Population-based surveillance for acute
liver failure. Am J Gastroenterol 2007;102(11):2459–63.
10. Escorsell A, Mas A, de la Mata M. Acute liver failure in Spain: analysis of 267
cases. Liver Transpl 2007;13(10):1389–95.
11. Ostapowicz G, Fontana RJ, Schiodt FV, et al. Results of a prospective study of
acute liver failure at 17 tertiary care centers in the United States. Ann Intern
Med 2002;137(12):947–54.
12. Dereszynski DM, Center SA, Randolph JF, et al. Clinical and clinicopathologic
features of dogs that consumed foodborne hepatotoxic aflatoxins: 72 cases
(2005-2006). J Am Vet Med Assoc 2008;232(9):1329–37.
13. Puschner B, Wegenast C. Mushroom poisoning cases in dogs and cats: diag-
nosis and treatment of hepatotoxic, neurotoxic, gastroenterotoxic, nephrotoxic,
and muscarinic mushrooms. Vet Clin North Am Small Anim Pract 2012;42(2):
375–87, viii.
14. Tokarz D, Poppenga R, Kaae J, et al. Amanitin toxicosis in two cats with acute
hepatic and renal failure. Vet Pathol 2012;49(6):1032–5.
15. van der Merwe D, Sebbag L, Nietfeld JC, et al. Investigation of a Microcystis aer-
uginosa cyanobacterial freshwater harmful algal bloom associated with acute mi-
crocystin toxicosis in a dog. J Vet Diagn Invest 2012;24(4):679–87.
 Acute Liver Injury and Failure 11

16. Simola O, Wiberg M, Jokela J, et al. Pathologic findings and toxin identification in
cyanobacterial (Nodularia spumigena) intoxication in a dog. Vet Pathol 2012;
49(5):755–9.
17. Sebbag L, Smee N, van der Merwe D, et al. Liver failure in a dog following sus-
pected ingestion of blue-green algae (Microcystis spp.): a case report and re-
view of the toxin. J Am Anim Hosp Assoc 2013;49(5):342–6.
18. Albretsen JC, Khan SA, Richardson JA. Cycad palm toxicosis in dogs: 60 cases
(1987-1997). J Am Vet Med Assoc 1998;213(1):99–101.
19. Ferguson D, Crowe M, McLaughlin L, et al. Survival and prognostic indicators for
cycad intoxication in dogs. J Vet Intern Med 2011;25(4):831–7.
20. Dunayer EK, Gwaltney-Brant SM. Acute hepatic failure and coagulopathy associ-
ated with xylitol ingestion in eight dogs. J Am Vet Med Assoc 2006;229(7):
1113–7.
21. Schmid RD, Hovda LR. Acute hepatic failure in a dog after xylitol ingestion. J Med
Toxicol 2016;12(2):201–5.
22. DuHadway MR, Sharp CR, Meyers KE, et al. Retrospective evaluation of xylitol
ingestion in dogs: 192 cases (2007-2012). J Vet Emerg Crit Care (San Antonio)
2015;25(5):646–54.
23. Richardson JA. Management of acetaminophen and ibuprofen toxicoses in dogs
and cats. J Vet Emerg Crit Care (San Antonio) 2000;10(4):285–91.
24. Wallace KP, Center SA, Hickford FH, et al. S-adenosyl-L-methionine (SAMe) for
the treatment of acetaminophen toxicity in a dog. J Am Anim Hosp Assoc
2002;38(3):246–54.
25. Center SA, Elston TH, Rowland PH, et al. Fulminant hepatic failure associated
with oral administration of diazepam in 11 cats. J Am Vet Med Assoc 1996;
209(3):618–25.
26. Park FM. Successful treatment of hepatic failure secondary to diazepam admin-
istration in a cat. J Feline Med Surg 2012;14(2):158–60.
27. MacPhail CM, Lappin MR, Meyer DJ, et al. Hepatocellular toxicosis associated
with administration of carprofen in 21 dogs. J Am Vet Med Assoc 1998;
212(12):1895–901.
28. Skorupski KA, Hammond GM, Irish AM, et al. Prospective randomized clinical
trial assessing the efficacy of Denamarin for prevention of CCNU-induced hepat-
opathy in tumor-bearing dogs. J Vet Intern Med 2011;25(4):838–45.
29. Webb CB, Twedt DC. Acute hepatopathy associated with mitotane administration
in a dog. J Am Anim Hosp Assoc 2006;42(4):298–301.
30. Holahan ML, Littman MP, Hayes CL. Presumptive hepatotoxicity and rhabdomyol-
ysis secondary to phenazopyridine toxicity in a dog. J Vet Emerg Crit Care (San
Antonio) 2010;20(3):352–8.
31. Harkin KR, Cowan LA, Andrews GA, et al. Hepatotoxicity of stanozolol in cats.
J Am Vet Med Assoc 2000;217(5):681–4.
32. Wong VM, Marche C, Simko E. Infectious canine hepatitis associated with pred-
nisone treatment. Can Vet J 2012;53(11):1219–21.
33. Twedt DC, Diehl KJ, Lappin MR, et al. Association of hepatic necrosis with
trimethoprim sulfonamide administration in 4 dogs. J Vet Intern Med 1997;
11(1):20–3.
34. Miller ML, Center SA, Randolph JF, et al. Apparent acute idiosyncratic hepatic ne-
crosis associated with zonisamide administration in a dog. J Vet Intern Med 2011;
25(5):1156–60.
12 Thawley

35. Schwartz M, Munana KR, Olby NJ. Possible drug-induced hepatopathy in a dog
receiving zonisamide monotherapy for treatment of cryptogenic epilepsy. J Vet
Med Sci 2011;73(11):1505–8.
36. Hartmann KK. Feline infectious peritonitis. Vet Clin North Am Small Anim Pract
2005;35(1):39–79.
37. Guerra MA. Leptospirosis. J Am Vet Med Assoc 2009;234(4):472–8, 430.
38. Xavier FG, Morato GS, Righi DA, et al. Cystic liver disease related to high Platy-
nosomum fastosum infection in a domestic cat. J feline Med Surg 2007;9(1):51–5.
39. Giuliano A, Meiring T, Grant AJ, et al. Acute hepatic necrosis caused by salmo-
nella enterica serotype I 4,5,12:-:1,2 in a dog. J Clin Microbiol 2015;53(11):
3674–6.
40. Nagel SS, Williams JH, Schoeman JP. Fatal disseminated toxoplasmosis in an
immunocompetent cat. J S Afr Vet Assoc 2013;84(1):E1–6.
41. Center SA, Crawford MA, Guida L, et al. A retrospective study of 77 cats with se-
vere hepatic lipidosis: 1975-1990. J Vet Intern Med 1993;7(6):349–59.
42. Borchers A, Epstein SE, Gindiciosi B, et al. Acute enteral manganese intoxication
with hepatic failure due to ingestion of a joint supplement overdose. J Vet Diagn
Invest 2014;26(5):658–63.
43. Dayrell-Hart B, Steinberg SA, VanWinkle TJ, et al. Hepatotoxicity of phenobarbital
in dogs: 18 cases (1985-1989). J Am Vet Med Assoc 1991;199(8):1060–6.
44. Weingarten MA, Sande AA. Acute liver failure in dogs and cats. J Vet Emerg Crit
Care 2015;25(4):455–73.
45. Sigrist NE, Adamik KN, Doherr MG, et al. Evaluation of respiratory parameters at
presentation as clinical indicators of the respiratory localization in dogs and cats
with respiratory distress. J Vet Emerg Crit Care 2011;21(1):13–23.
46. O’Grady JG. Pathogenesis of acute liver failure. Trop Gastroenterol 1996;17(4):
199–201.
47. Davis H, Jensen T, Johnson A, et al. 2013 AAHA/AAFP fluid therapy guidelines for
dogs and cats. J Am Anim Hosp Assoc 2013;49(3):149–59.
48. Silverstein DC, Santoro-Beer K. Daily intravenous fluid therapy. In: Silverstein DC,
Hopper K, editors. Small animal critical care medicine. 2nd edition. St Louis
(MO): Elsevier/Saunders; 2015. p. 316–21.
49. Adamik KN, Yozova ID, Regenscheit N. Controversies in the use of hydroxyethyl
starch solutions in small animal emergency and critical care. J Vet Emerg Crit
Care 2015;25(1):20–47.
50. Hayes G, Benedicenti L, Mathews K. Retrospective cohort study on the incidence
of acute kidney injury and death following hydroxyethyl starch (HES 10% 250/0.5/
5:1) administration in dogs (2007-2010). J Vet Emerg Crit Care 2016;26(1):35–40.
51. Silverstein DC, Beer KA. Controversies regarding choice of vasopressor therapy
for management of septic shock in animals. J Vet Emerg Crit Care 2015;25(1):
48–54.
52. Peyton JLJL. Critical illness-related corticosteroid insufficiency in a dog with sep-
tic shock. J Vet Emerg Crit Care (San Antonio) 2009;19(3):262–8.
53. Lidbury JA, Ivanek R, Suchodolski JS, et al. Putative precipitating factors for he-
patic encephalopathy in dogs: 118 cases (1991-2014). J Am Vet Med Assoc
2015;247(2):176–83.
54. Alvarez L, Whittemore J. Liver enzyme elevations in dogs: physiology and path-
ophysiology. Compend Contin Educ Vet 2009;31(9):408–10, 412–3; [quiz: 414].
55. Chapman SE, Hostutler RA. A laboratory diagnostic approach to hepatobiliary
disease in small animals. Vet Clin North Am Small Anim Pract 2013;43(6):
1209–25, v.
 Acute Liver Injury and Failure 13

56. Ong JP, Aggarwal A, Krieger D, et al. Correlation between ammonia levels and
the severity of hepatic encephalopathy. Am J Med 2003;114(3):188–93.
57. Rothuizen J, van den Ingh TS. Arterial and venous ammonia concentrations in the
diagnosis of canine hepato-encephalopathy. Res Vet Sci 1982;33(1):17–21.
58. Stanton ME, Bright RM. Gastroduodenal ulceration in dogs. Retrospective study
of 43 cases and literature review. J Vet Intern Med 1989;3(4):238–44.
59. Allison MG, Shanholtz CB, Sachdeva A. Hematological issues in liver disease.
Crit Care Clin 2016;32(3):385–96.
60. Berent A. Hepatic failure. In: Silverstein DC, Hopper K, editors. Small animal crit-
ical care medicine. 2nd edition. St Louis (MO): Elsevier/Saunders; 2015.
p. 615–21.
61. Stravitz RT, Ellerbe C, Dukalski V, et al. Spontaneous bleeding complications in
acute liver failure (ALF). Hepatology 2013;58(Suppl 4):347A.
62. Stravitz RT, Lisman T, Luketic VA, et al. Minimal effects of acute liver injury/acute
liver failure on hemostasis as assessed by thromboelastography. J Hepatol 2012;
56(1):129–36.
63. Kelley D, Lester C, Shaw S, et al. Thromboelastographic evaluation of dogs with
acute liver disease. J Vet Intern Med 2015;29(4):1053–62.
64. Lisman T, Stravitz RT. Rebalanced hemostasis in patients with acute liver failure.
Semin Thromb Hemost 2015;41(5):468–73.
65. McMurray J, Boysen S, Chalhoub S. Focused assessment with sonography in
nontraumatized dogs and cats in the emergency and critical care setting. J Vet
Emerg Crit Care (San Antonio) 2016;26(1):64–73.
66. Wang KY, Panciera DL, Al-Rukibat RK, et al. Accuracy of ultrasound-guided fine-
needle aspiration of the liver and cytologic findings in dogs and cats: 97 cases
(1990-2000). J Am Vet Med Assoc 2004;224(1):75–8.
67. Bigge LA, Brown DJ, Penninck DG. Correlation between coagulation profile find-
ings and bleeding complications after ultrasound-guided biopsies: 434 cases
(1993-1996). J Am Anim Hosp Assoc 2001;37(3):228–33.
68. Waddell LS, Holt DE, Hughes D, et al. The effect of storage on ammonia concen-
tration in canine packed red blood cells. J Vet Emerg Crit Care (San Antonio)
2001;11(1):23–6.
69. Cummings KA, Abelson AL, Rozanski EA, et al. The effect of storage on
ammonia, cytokine, and chemokine concentrations in feline whole blood. J Vet
Emerg Crit Care (San Antonio) 2016;26(5):639–45.
70. Lidbury JA, Cook AK, Steiner JM. Hepatic encephalopathy in dogs and cats.
J Vet Emerg Crit Care (San Antonio) 2016;26(4):471–87.
71. Weiner ID, Wingo CS. Hypokalemia–consequences, causes, and correction.
J Am Soc Nephrol 1997;8(7):1179–88.
72. Iwasa M, Sugimoto R, Mifuji-Moroka R, et al. Factors contributing to the develop-
ment of overt encephalopathy in liver cirrhosis patients. Metab Brain Dis 2016;
31(5):1151–6.
73. Taboada J, Dimski DS. Hepatic encephalopathy: clinical signs, pathogenesis,
and treatment. Vet Clin North Am Small Anim Pract 1995;25(2):337–55.
74. Olde Damink SW, Dejong CH, Deutz NE, et al. Effects of simulated upper gastro-
intestinal hemorrhage on ammonia and related amino acids in blood and brain of
chronic portacaval-shunted rats. Metab Brain Dis 1997;12(2):121–35.
75. Tivers MS, Handel I, Gow AG, et al. Hyperammonemia and systemic inflamma-
tory response syndrome predicts presence of hepatic encephalopathy in dogs
with congenital portosystemic shunts. PLoS One 2014;9(1):e82303.
14 Thawley

76. Aronson LR, Gacad RC, Kaminsky-Russ K, et al. Endogenous benzodiazepine

activity in the peripheral and portal blood of dogs with congenital portosystemic
shunts. Vet Surg 1997;26(3):189–94.
77. Holt D. Hepatic encephalopathy. In: Silverstein DC, Hopper K, editors. Small an-
imal critical care medicine. 2nd edition. St Louis (MO): Elsevier/Saunders; 2015.
p. 458–61.
78. Kodali S, McGuire BM. Diagnosis and management of hepatic encephalopathy in
fulminant hepatic failure. Clin Liver Dis 2015;19(3):565–76.
79. Stravitz RT, Kramer AH, Davern T, et al. Intensive care of patients with acute liver
failure: recommendations of the U.S. Acute Liver Failure Study Group. Crit Care
Med 2007;35(11):2498–508.
80. Rolando N, Harvey F, Brahm J, et al. Prospective study of bacterial infection in
acute liver failure: an analysis of fifty patients. Hepatology 1990;11(1):49–53.
81. Rolando N, Gimson A, Wade J, et al. Prospective controlled trial of selective
parenteral and enteral antimicrobial regimen in fulminant liver failure. Hepatology
1993;17(2):196–201.
82. Tolbert K, Bissett S, King A, et al. Efficacy of oral famotidine and 2 omeprazole
formulations for the control of intragastric pH in dogs. J Vet Intern Med 2011;
25(1):47–54.
83. Pereira SP, Rowbotham D, Fitt S, et al. Pharmacokinetics and efficacy of oral
versus intravenous mixed-micellar phylloquinone (vitamin K1) in severe acute
liver disease. J Hepatol 2005;42(3):365–70.
84. Vandeweerd JM, Cambier C, Gustin P. Nutraceuticals for canine liver disease: as-
sessing the evidence. Vet Clin North Am Small Anim Pract 2013;43(5):1171–9.
85. Filburn CR, Kettenacker R, Griffin DW. Bioavailability of a silybin-phosphatidylcholine
complex in dogs. J Vet Pharmacol Ther 2007;30(2):132–8.