Invited Review

Nutrition in Clinical Practice

Volume 00 Number 0
Pathophysiology of Acute Liver Failure xxxx 2019 1–10
© 2019 American Society for
Parenteral and Enteral Nutrition
DOI: 10.1002/ncp.10459
wileyonlinelibrary.com
Victor Dong, MD1 ; Rahul Nanchal, MD2 ; and Constantine J. Karvellas, MD, SM3,4

Abstract
Acute liver failure (ALF) is a rare syndrome resulting from an acute insult to the liver in patients without known underlying chronic
liver disease. It is characterized by loss of synthetic function in the form of jaundice and coagulopathy and development of hepatic
encephalopathy. Multiorgan failure (MOF) eventually develops, leading to death. Many different etiologies have been identified,
with acetaminophen (APAP) overdose and viral hepatitis being the most common causes worldwide. The pathophysiology of ALF
can be divided into cause-specific liver injury pathophysiologies and pathophysiology related to occurrence of secondary MOF. In
terms of liver injury pathophysiology, APAP toxicity is the most well known. Secondary MOF is often a result of the initial massive
proinflammatory response generating a systemic inflammatory response syndrome followed by a compensatory anti-inflammatory
response leading to immune cell dysfunction and sepsis. As the liver is a tremendously important metabolic organ involved in energy
metabolism, protein synthesis, fat metabolism, and glycemic control, multiple aspects of nutrition also need to be considered as
part of the overall pathophysiology of ALF. (Nutr Clin Pract. 2019;00:1–10)

Keywords
acute liver failure; liver diseases; nutrition support

Introduction and Definition hyper-ALF (jaundice to HE within 7 days), ALF (jaundice

Acute liver failure (ALF) is a rare syndrome characterized
by rapid deterioration of normal liver function following
an acute insult in a patient with no previously known
underlying chronic liver disease.1 Incidence is about 1–
6 cases per million in developed countries.2 It leads to
jaundice, coagulopathy, and hepatic encephalopathy (HE)
along with multiorgan failure (MOF). Clinical course varies,
depending on etiology, and ranges from spontaneous re-
covery to need for emergency liver transplantation (LT).3
Mortality is around 30%.4
Trey and Davidson’s initial definition of ALF in 1970 as
fulminant liver failure was a clinical entity that is potentially
reversible and arose from acute and severe liver injury
resulting in the appearance of HE within 8 weeks of the first
signs of symptoms in a patient without preexisting chronic
liver disease.5 However, it has become clear that this defi-
nition is too restrictive and does not encompass the entire
spectrum of patients with ALF. Currently, the definition of
ALF is a condition in which an acute hepatic insult leads
to rapid clinical deterioration, with HE occurring within
26 weeks of the first onset of symptoms of liver dysfunction
(jaundice).6 If HE occurs 26 or more weeks after the initial
onset of signs of liver disease, it is classified as chronic liver
disease.7
Within the overall cohort of ALF patients, subcate-
gories exist based on the speed of progression from initial
onset of jaundice to development of HE. These include
to HE within 1–4 weeks), and sub-ALF (jaundice to HE
within 4–26 weeks).3 Such subcategories are important
because they can inform possible etiologies of ALF and
help to predict outcome. Overall, patients with hyper-
ALF are at highest risk of cerebral edema but also have
the greatest chance of spontaneous recovery without LT,
whereas patients with sub-ALF have the lowest risk of
cerebral edema but the highest risk of mortality without
LT.8 Table 1 summarizes the clinical features and prognosis
of the different subcategories of ALF.
From the 1 Interdepartmental Division of Critical Care, University of
Toronto, Toronto, Canada; 2 Division of Pulmonary, Critical Care,
and Sleep Medicine, Medical College of Wisconsin and the Medical
Intensive Care Unit at Froedtert Hospital, Milwaukee, Wisconsin,
USA; 3 Division of Gastroenterology (Liver Unit), University of
Alberta, Edmonton, Canada; and 4 Department of Critical Care
Medicine, University of Alberta, Edmonton, Canada.
Financial disclosure: None declared.
Conflicts of interest: None declared.
This article originally appeared online on xxxx 0, 2019.
Corresponding Author:
Constantine J. Karvellas, MD, SM, Department of Critical Care
Medicine, Division of Gastroenterology (Liver Unit), University of
Alberta, 1-40 Zeidler Ledcor Building, Edmonton, Alberta T6G2X8,
Canada.
Email: dean.karvellas@ualberta.ca
2 Nutrition in Clinical Practice 00(0)

Table 1. Clinical Features and Prognosis of Acute Liver Failure Subcategories.

Clinical Course of ALF (Onset of Symptoms to Hepatic Encephalopathy)

Features of ALF Hyperacute ALF (within 7 Days) Acute ALF (8–28 days) Subacute ALF (5–26 weeks)

Etiologies Acetaminophen, hepatitis A/E, ischemia Hepatitis B Nonacetaminophen DILI

Transaminases +++ ++ +
Bilirubin + ++ +++
INR +++ ++ +
Cerebral edema Highest risk Intermediate risk Low risk
Survival without liver High Intermediate Low
transplantation

ALF, acute liver failure; DILI, drug-induced liver injury; INR, internationalized ratio; +, present, more plus signs mean higher.

Table 2. Cause, Prevalence, and Evaluation of Acute Liver Failure.

Cause Prevalencea (%) Evaluation

APAP 45 History; APAP level

HBV 7 Anti-HBc (IgM and total), HBsAg, anti-HBs, HBV DNA, anti-HDV
AIH 5 ANA, ASMA, anti-LKM, immunoglobulins
HAV 4 Anti-HAV (IgM and total)
Shock liver 4 Echocardiogram, brain natriuretic peptide
Wilson disease 3 Serum ceruloplasmin and copper; urine copper; slitlamp eye exam
BCS 2 Doppler ultrasound of liver
Malignancy 1 Contrast-enhanced CT; MRI (preferred)
AFLP/HELLP 1 Pregnancy test
HSV 0.5 Anti-HSV 1/2, HSV DNA
Other 4 Anti-HCV/HCV RNA, anti-CMV/CMV DNA, anti-EBV/EBV DNA, toxicology screen
Indeterminate 14 All of above negative
Idiosyncratic drug 13 History; all of above negative

AFLP/HELLP, acute fatty liver of pregnancy/hemolysis-elevated liver enzymes–low platelet syndrome; AIH, autoimmune hepatitis; ANA,
antinuclear antibody; Anti-HBc, anti hepatitis B core antibody; anti-HBs, anti hepatitis B surface antibody; anti-LKM, anti–liver kidney
microsomal antibody; APAP, acetaminophen; ASMA, anti–smooth muscle antibody; BCS, Budd-Chiari syndrome; CMV, cytomegalovirus; CT,
computed tomography; EBV, Epstein-Barr virus; HAV, hepatitis A virus; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV,
hepatitis C virus; HDV, hepatitis D virus; HSV, herpes simplex virus; IgM, immunoglobulin M; MRI, magnetic resonance imaging.
a Prevalence of causes are estimates based on the US Acute Liver Failure Study Group Cohort.

Epidemiology and Etiology APAP Overdose

ALF is a rare condition with approximately 2000–3000
cases per year in the United States.9 Most affected indi-
viduals are young, with a median age of 38.10 The ma-
jority of patients are female.11 Caucasians are the most
commonly affected race.10 In terms of etiology of ALF,
acetaminophen (APAP) toxicity is the most prevalent cause
in developed countries, whereas viral hepatitis accounts for
the majority of ALF cases in developing countries.4 Other
causes of ALF include non-APAP drug-induced liver injury
(DILI), ischemic hepatitis, autoimmune hepatitis (AIH),
fulminant Wilson disease (WD), pregnancy-associated in-
jury, and indeterminant etiology.12 Table 2 summarizes
the prevalence and evaluation of different etiologies of
ALF.
APAP is an intrinsic hepatotoxin with a narrow therapeutic
window and dose-dependent toxicity.13 APAP accounts for
45% of ALF cases in North America.14 About half of
APAP overdoses are intentional and attributable to suicide
attempts, whereas the other half are unintentional overdoses
in patients consuming higher than recommended daily
doses of APAP for chronic pain.15 Liver injury secondary
to APAP overdose is categorized as hyperacute and begins
within 8–12 hours of the ingestion, leading to an extreme
rise in aminotransferases that is similar in elevation to
ischemic hepatitis and higher than for other causes of
ALF.16 Metabolic acidosis and acute kidney injury due to
acute tubular necrosis can also occur in the early stages
of disease presentation.17 Patients with ALF secondary to
Dong et al
APAP toxicity have much higher rates of cerebral edema but
also higher rates of spontaneous recovery without need for
LT compared with other etiologies of ALF.18
Viral Hepatitis
Hepatotropic viruses (hepatitis A, B, D, and E) have all
been reported to cause ALF with the risk of progressing to
ALF variable depending on the certain type of virus.19 ALF
secondary to viral hepatitis can present with moderate (5–
10 times the upper limit of normal) or severe (>10 times the
upper limit of normal) elevations in transaminases.19
Hepatitis A virus (HAV) accounts for <3% of ALF cases
in developed countries and is a result of poor sanitation
and fecal-oral transmission.20 ALF secondary to hepatitis
A has a 70% spontaneous recovery rate.20 Risk factors for
progression to ALF following acute HAV infection includes
age over 40 years, history of intravenous drug use, alcoholic
liver disease, and underlying chronic hepatitis B virus (HBV)
or hepatitis C virus infection.21
HBV causes approximately 8% of cases of ALF in
developed countries with two-thirds from acute infections
and the rest from reactivation of chronic infection following
immunosuppression or chemotherapy.22 HBV transmission
occurs through sexual contact and use of needles or razors
contaminated with infected blood.19 Rates of spontaneous
recovery once ALF develops is significantly lower than for
HAV-induced ALF.19
Hepatitis D virus (HDV) requires the presence of hep-
atitis B surface antigen for replication and transmission.23
HDV is acquired in a similar fashion to HBV and
may be acquired simultaneously with HBV (coinfection)
or in a patient with underlying chronic HBV infection
(superinfection).23 The presence of HDV infection leads to
a 2-fold to 5-fold increase in the rate of ALF compared with
HBV infection alone.23
Hepatitis E virus (HEV) is endemic in parts of northern
Africa and southern Asia and rarely seen in Western coun-
tries. It is transmitted enterically via contaminated water
and food.12 Young adults and pregnant women (especially
in the third trimester) are particularly vulnerable to HEV-
induced ALF.24 Overall mortality is close to 20%.
Drug-Induced Liver Injury
Non-APAP, idiosyncratic DILI is the second most common
etiology of ALF and accounts for 10%–20% of ALF in
developed countries.14 Patients present with a subacute pat-
tern of liver failure and have higher rates of mortality with-
out LT.25 The majority of affected individuals are younger
adults and women.26 Antibiotics are responsible for 50% of
DILI-induced ALF, neuropsychoactive agents account for
10%–15% of ALF, and over-the-counter dietary and herbal
supplements are implicated in 10% of ALF cases.27 Liver
injury usually occurs within 1–2 weeks of drug exposure.26
3
Patients present with lower rises in aminotransferases but
higher bilirubin concentrations.25 Once HE develops, <25%
of patients with DILI-induced ALF have spontaneous
recovery with LT.18 Risk factors for DILI-induced ALF
include age, gender, nutrition status, concomitant drugs,
alcohol use, and certain genetic predispositions.28 Table 3
summarizes the different types of idiosyncratic reaction.
Other Etiologies
Ischemic hepatitis as a result of inadequate liver perfusion
(heart failure, hypovolemia, sepsis, hypoxia) usually leads
to a hyperacute liver injury that is most often self-limited
as long as the cause of low perfusion is reversed in a
timely fashion.4 Hepatic injury and ALF is character-
ized by a severe transaminitis that improves rapidly once
perfusion is restored.29 However, in cases of mechanical
hepatic circulatory compromise, LT may be required to treat
ALF.29
AIH usually occurs in younger female patients and
accounts for up to 6% of cases of ALF.30 AIH is often
associated with other autoimmune conditions that include
Hashimoto thyroiditis, celiac disease, and inflammatory
bowel disease.31 Patients may present with mild symptoms
responsive to corticosteroids but may also progress to
ALF with no reversibility of injury with corticosteroids.32
Overall, 10% of patients with acute AIH require LT for ALF
treatment.31
WD is an autosomal-recessive disease characterized by
copper buildup in the liver and other end organs.33 Patients
can present with neurologic symptoms, chronic liver disease,
or ALF.34 Fulminant WD represents about 3% of ALF
cases and usually occurs in young female patients within the
first 2 decades of life.12 In the setting of ALF, spontaneous
recovery is rare, and LT is required for survival.35
Pregnancy-associated liver dysfunction that can progress
to ALF includes acute fatty liver of pregnancy, preeclamp-
sia, and HELLP (hemolysis, elevated liver enzymes, low
platelets) syndrome.12 With any of these conditions, there
is significant risk of placental abruption, disseminated
intravascular coagulopathy, and death.36 ALF is often re-
versed upon delivery of the fetus.12
Pathophysiology of Acute Liver Failure
The pathophysiology of ALF can be divided into primary
liver injury specific to the etiology of ALF and secondary
MOF. In terms of the primary liver insult, APAP-induced
ALF has the best-understood mechanism. APAP in non-
toxic doses (<4 g/d) is primarily glucoronidated and sul-
fated by uridine 5’-diphospho-glucuronosyltransferase and
sulfotransferase into nontoxic compounds that are excreted
via the urine.37 The remaining APAP is converted by cy-
tochrome P450 enzymes (CYPs) into the toxic metabolite
N-acetyl-p-benzoquinone (NAPQI), which is immediately
4 Nutrition in Clinical Practice 00(0)

Table 3. Types of Idiosyncratic Drug Reactions.

Type of Reaction Effect on Cells Examples of Drugs

Hepatocellular Direct effect or production by enzyme-drug Isoniazid, trazodone, diclofenac, nefazodone,

adduct leads to cell dysfunction, membrane venlafaxine, lovastatin
dysfunction, and cytotoxic T-cell response.
Cholestasis Injury to canalicular membrane and Chlorpromazine, estrogen, erythromycin and
transporters its derivatives
Immunoallergic Enzyme-drug adducts on cell surface induce Halothane, phenytoin, sulfamethoxazole
IgE response
Granulomatous Macrophages, lymphocytes infiltrate hepatic Diltiazem, sulfa drugs, quinidine
lobule
Microvesicular fat Altered mitochondrial respiration, β-oxidation Didanosine, tetracycline, acetylsalicylic acid,
leads to lactic acidosis and triglyceride valproic acid
accumulation.
Steatohepatitis Multifactorial Amiodarone, tamoxifen
Autoimmune Cytotoxic lymphocyte response directed at Nitrofurantoin, methyldopa, lovastatin,
hepatocyte membrane components minocycline
Fibrosis Activation of stellate cells Methotrexate, excess vitamin A
Vascular collapse Causes ischemic or hypoxic injury Nicotinic acid, cocaine,
methylenedioxymethamphetamine
Oncogenesis Encourages tumor formation Oral contraceptives, androgens
Mixed Cytoplasmic and canalicular injury, direct Amoxicillin-clavulanate, carbamazepine, herbs,
damage to bile ducts cyclosporine, methimazole, troglitazone

IgE, immunoglobulin E.

conjugated to glutathione (GSH) to detoxify it.38 How-
ever, when there is an excess amount of APAP, as in
the case of overdoses, GSH is depleted by the surplus
NAPQI and results in covalent binding to hepatocellular
proteins, mitochondrial oxidative stress, and hepatocellular
necrosis.39 Toxic effects of APAP overdose are augmented
by conditions that increase NAPQI production or deplete
GSH availability. Ethanol and certain medications, includ-
ing antibiotics and antiepileptics, activate CYPs and result
in greater NAPQI generation. Fasting and malnutrition
result in reduced GSH production.38
Regarding secondary MOF, the pathophysiology ap-
pears to share many features with severe sepsis. The innate
immune response is initiated early in the disease course and
can be a reaction to pathogen-specific molecular patterns
(PAMPs) from heterotropic viruses as well as a response
to damage-associated molecular patterns (DAMPs), such
as histones, DNA, and high mobility group box-1 pro-
teins released from injured cells upon hepatocyte death
secondary to toxic etiologies.40 Many different immune cells
participate in the innate response, including monocytes,
macrophages, dendritic cells, leukocytes, and natural killer
cells. These cells recognize and respond to PAMPs and
DAMPs.40 They produce reactive oxygen species (ROS)
along with proinflammatory mediators, such as tumor
necrosis factor-α, interleukin (IL)-1β, and IL-6, which
stimulate a systemic inflammatory response.40 IL-17 and IL-
10 also play a role in the overall inflammatory response.40
ROS and cytokines subsequently lead to MOF as well
as continuing to cause liver injury. Proinflammatory cy-
tokines recruit neutrophils and promote extravasation into
the hepatic parenchyma. Once within the parenchyma,
they release ROS and proteases, which induce hepato-
cyte damage.41 Dysregulation of systemic vascular tone
leads to low systemic vascular resistance, causing hypoten-
sion and peripheral microcirculatory vasodilation results
in poor pulmonary oxygen exchange, impaired peripheral
tissue oxygen delivery, and lactic acidosis. Cerebrovascular
and renovascular tone are most affected leading to cere-
bral hyperperfusion and HE along with functional renal
failure.40
Sepsis also plays a major part in secondary MOF. A
late compensatory anti-inflammatory response syndrome
mediated by anti-inflammatory cytokines including IL-4,
IL-10, and transforming growth factor-β leads to immuno-
suppression and increased risk of infection and late sepsis.41
Monocyte dysfunction and inactivation as a result of high
circulating IL-10 levels is a major factor in development
of late sepsis. Reduced serum complement levels also oc-
cur as the liver is the predominant site of complement
synthesis, which decreases the chemoattractant ability for
neutrophils and increases the risk of infections by encap-
sulated organisms.41 Neutrophils have functional impair-
ment with decreased ROS production, reduced ability for
phagocytosis, and less complement receptor expression.42
Plasma fibronectin, a glycoprotein made in the liver that
helps Kupffer cells clear circulating microbes, is diminished
as well, leading to Kupffer cell dysfunction.43
Dong et al
Nutrition Aspects of Acute Liver Failure
The liver is a significant metabolic organ with a role in
many nutrition-related functions. It is involved in energy
metabolism, protein synthesis, fat synthesis, as well as
glycemic control.44 Overall, the liver is responsible for up
to 24% of energy expenditure.45 Normally, glucose is taken
up into hepatocytes by glucose transporter 2 membrane
transporters during the fed state. It is then phosphory-
lated via glucokinase and utilized by glycogen synthase to
form glycogen.46 During short periods of fasting, glyco-
gen is hydrolyzed in the liver by glycogen phosphorylase
to produce glucose. When fasting is prolonged, glycogen
stores are depleted and glucose synthesis has to occur via
gluconeogensis using lactate, pyruvate, glycerol, and amino
acids.46 Insulin inhibits hepatic gluconeogenesis, whereas
glucagon promotes it. The liver is the site of nonessential
amino acid production and synthesis of plasma proteins,
including albumin and coagulation factors. It is responsible
for metabolizing ammonia and amino acids. Fat metabolism
also occurs within the liver. Dietary fatty acids are taken up
by hepatocytes and converted to triacylglycerol or choles-
terol esters.46 These substances are then either stored in
hepatocytes or released into systemic circulation. Glucose
can also be converted to fatty acids in the liver depending
on availability of carbohydrates.46
In response to ALF, energy expenditure increases by up
to 30%.45 Initially, there is activation of neuroendocrine
pathways. This results in medullary sympathetic stimula-
tion, leading to increased norepinephrine and epinephrine
levels along with stimulation of the hypothalamic-pituitary
axis to release adrenocorticotropic hormone, thyroid-
stimulating hormone, and growth hormone.47 Release of
cortisol and catecholamines leads to a hypercatabolic
state.48 Proinflammatory cytokines including tumor necro-
sis factor, IL-1, and IL-6 also stimulate hypercatabolism.49
Overall, this leads to proteolysis. As proteolysis continues,
a negative nitrogen balance occurs. This results in muscle
breakdown and loss of lean body mass.49 HE also occurs
as a consequence of prolonged proteolysis. Amino acids
released from proteolysis are converted to ammonia in the
intestines. The liver is then unable to transform the ammo-
nia to urea because of failure. As a result, hyperammonemia
occurs and the ammonia enters the brain and crosses the
blood-brain barrier.44 The ammonia is then metabolized
to glutamine in astrocytes. Glutamine is quite osmotically
active and leads to an influx of extracellular fluid into the
astrocytes, resulting in swelling.44
Hypoglycemia is another significant complication
of ALF. Glycogen stores become extinguished, insulin
metabolism is impaired and leads to increased serum
insulin levels, and gluconeogenesis is reduced.49 Oral intake
is also generally diminished because of the proinflammatory
state, causing lack of appetite and anorexia. This overall
5
causes difficulties with glycemic control and persistent
hypoglycemia. Because of the rarity of ALF, there have
been minimal studies of nutrition interventions in ALF,
with the decision between enteral and parenteral nutrition
largely based on overall gastrointestinal tract functionality.
Conclusions
ALF is a rare syndrome resulting from an acute insult to
the liver in patients without known underlying chronic liver
disease. It is characterized by loss of synthetic function and
development of HE along with eventual MOF. Multiple
etiologies can be the culprit, with APAP overdose and viral
hepatitis being the most common causes worldwide. Cause-
specific pathophysiologies exist, with APAP toxicity being
the most well known. Secondary MOF is often a result
of the initial massive proinflammatory response generat-
ing a systemic inflammatory response syndrome followed
by a compensatory anti-inflammatory response leading to
immune cell dysfunction and sepsis. In addition, multiple
nutrition aspects need to be considered in the overall
pathophysiology of ALF because the liver is an important
metabolic organ that is involved in energy metabolism,
protein synthesis, fat metabolism, and glycemic control.
Statement of Authorship
V. Dong and C. J. Karvellas contributed to the conception and
design of the work; V. Dong and C. J. Karvellas contributed
to the design of the work; V. Dong and C. J. Karvellas
contributed to the acquisition and analysis of the data; V.
Dong, R. Nanchal, and C. J. Karvellas contributed to the
interpretation of the data; and V. Dong drafted the manuscript.
V. Dong, R. Nanchal, and C. J. Karvellas critically revised
the manuscript, agree to be fully accountable for ensuring the
integrity and accuracy of the work, and read and approved the
final manuscript
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