Acute Liver Failure

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CLINICAL OVERVIEW
Acute Liver Failure

Copyright © 2022 by Elsevier, Inc. All rights reserved.
Released January 1, 2022.
Basic Information
Definition
Acute liver failure (ALF) is defined as the rapid progression of liver dysfunction
resulting in coagulopathy and altered mentation in patients without previously known
liver disease. Practically, it is described as the constellation of acute severe hepatic
injury (<26 wk); synthetic liver dysfunction, specifically coagulopathy (international
normalized ratio [INR] >1.5); and any degree of mental alteration (encephalopathy) in a
patient without preexisting cirrhosis and in the absence of acute alcoholic hepatitis.
ALF can also be diagnosed in patients with preexisting liver disease, such as Wilson
disease, vertically acquired hepatitis B, and autoimmune hepatitis (despite the
possibility of cirrhosis in these patients), provided that diagnosis of these conditions
was made within the preceding 26 wk. Box 1 summarizes classifications of acute liver
failure.
BOX 1
Classifications of Acute Liver Failure
From Vincent JL et al: Textbook of critical care, ed 7, Philadelphia, 2017, Elsevier.
https://www.clinicalkey.com/#!/content/clinical_overview/76-s2.0-B9780323755702000230#hl0000881 Page 1 of 29
HE, Hepatic encephalopathy.
Trey and Davidson

Fulminant hepatic failure: Development of HE within 8 wk of onset of symptoms
British Classification
Acute liver failure (includes only patients with encephalopathy)
Subclassification Depending on the Interval

between the Onset of Jaundice and HE
• Hyperacute liver failure: 0-7 days
• Acute liver failure: 8-28 days
• Subacute liver failure: 29-72 days
• Late-onset acute liver failure: 56-182 days
French Classification
Acute hepatic failure: A rapidly developing impairment of liver function
Severe acute hepatic failure: Prothrombin time or factor V concentration below

50% of normal with or without HE
Subclassification
• Fulminant hepatic failure: HE within 2 wk of onset of jaundice
• Subfulminant hepatic failure: HE between 3 and 12 wk of onset of jaundice
International Association for the Study of Acute

Liver Failure
Acute liver failure (occurrence of HE within 4 wk after onset of symptoms)
Subclassification
• Acute liver failure—hyperacute: Within 10 days
• Acute liver failure—fulminant: 10-30 days
• Acute liver failure—not otherwise specified
• Subacute liver failure (development of ascites and/or HE from 5 to 24 wk after

onset of symptoms)
“Acutely decompensated cirrhosis” refers to the development of ascites,

encephalopathy, gastrointestinal hemorrhage, or any combination of these disorders in
patients with cirrhosis. 1
1Sarin SK, Choudhury A, Sharma MK et al: Acute-on-chronic liver failure: consensus

recommendations of the Asian Pacific association for the study of the liver (APASL): an
update, Hepatol Int 13:353-90, 2019.
“Acute-on-chronic liver failure” is a syndrome characterized by the following 3 major

features:
1. It occurs in the context of intense systemic inflammation
2. Frequently develops in close temporal relationship with pro-inflammatory

precipitating events (e.g., infections or alcoholic hepatitis)
3. Is associated with single- or multiple-organ failure 2
2Arroyo V, Moreau R, Jalan R: Acute-on-chronic liver failure, N Engl Med 382:2137-

45, 2020.
Synonyms
Fulminant hepatic failure
Fulminant hepatitis
Fulminant hepatic necrosis
Acute hepatic necrosis
Acute and subacute necrosis of liver
ALF
ICD-10CM CODES
K72 Hepatic failure, not elsewhere classified
K72.0 Acute and subacute hepatic failure
K72.00 Acute and subacute hepatic failure without coma
K72.01 Acute and subacute hepatic failure with coma
Epidemiology & Demographics
Incidence
Affects approximately 2000 people/yr in U.S. and 1 to 8 people per million population
in the U.K.
Predominant Sex & Age

Seen more often in women (90% of cases), often affects younger people.
Risk Factors
• Intentional or inadvertent drug overdose
• Risk factors for viral hepatitis:
1. Intravenous drug use
2. Occupational exposure to blood or body fluids
3. Blood transfusions
4. Hemodialysis
5. Intranasal cocaine use
6. Imprisonment
7. Travel to endemic hepatitis areas
• Previous alcohol use
• Hepatotoxic medications
• Critical illness
Etiology
• Common causes in the Western world:
1. Acetaminophen toxicity (46%)
2. Indeterminate (14%)
3. Idiosyncratic drug reaction (12%)
4. Viral hepatitis (A, B) (10%)
Other, more rare causes include alcoholic hepatitis, autoimmune hepatitis, Wilson
disease, ischemic hepatopathy, Budd-Chiari syndrome, acute fatty liver of pregnancy,
venoocclusive disease, toxin ingestion (e.g., mushroom poisoning [Amanita phalloides]),
sepsis, infiltrative malignancy (breast cancer, lymphoma, myeloma, melanoma, small
cell lung cancer), and other viruses (adenovirus, hepatitis E, HSV). Box 2 summarizes
possible etiologies of liver failure.
BOX 2
Etiologic Classification of Acute Liver Failure
CCl4, Carbon tetrachloride.
Acetaminophen Toxicity
Idiosyncratic Drug Injury
Infrequent Agents
Isoniazid
Valproate
Halothane
Phenytoin
Sulfonamide
Propylthiouracil
Amiodarone
Disulfiram
Dapsone
Bromfenac
Troglitazone
Zidovudine
Lamivudine
Lamotrigine
Gatifloxacin
Methotrexate
Miscellaneous Agents
Ecstasy
Cocaine
Phencyclidine
Rare Agents
Carbamazepine
Ofloxacin
Ketoconazole
Lisinopril
Nicotinic acid
Labetalol
Etoposide
Imipramine
Interferon alfa
Flutamide
Tolcapone
Nefazodone
Oral contraceptives
Combination Agents with Enhanced Hepatotoxicity

Alcohol-acetaminophen
Trimethoprim-sulfamethoxazole
Rifampicin-isoniazid
Amoxicillin-clavulanic acid
Viral Hepatitides
Hepatitis A, B, C, D, E, G
Human herpesvirus
Cytomegalovirus
Epstein-Barr virus
Herpes simplex virus
Varicella zoster virus
Paramyxovirus
Parvovirus B19
Adenovirus
Togavirus
Parvovirus
SEN virus
TT virus
Yellow fever virus
Toxins
CCl4
Amanita phalloides
Yellow phosphorus
Herbal products
Vascular
Ischemic
Venoocclusive disease
Budd-Chiari syndrome
Malignant infiltration
Non-Hodgkin lymphoma
Miscellaneous
Wilson disease
Autoimmune hepatitis
Acute fatty liver of pregnancy
Reye syndrome
Clinician Presentation & Physical Findings
• Clinical Presentation Initial symptoms of ALF are mostly nonspecific and depend
on the etiology of liver injury. They include fatigue, lethargy, anorexia, and
nausea/vomiting. Pruritus, jaundice, and right upper quadrant abdominal pain and
distention may be present. Symptoms may also be more serious and consist of severe
hypotension, sepsis, and hepatic encephalopathy.
• Physical examination Findings include, by definition, abnormal neurologic

findings of encephalopathy (see Table 1). Other findings may include jaundice,
asterixis, hepatomegaly, decreased hepatic mass on percussion, and ascites.
Multisystem organ failure can ensue. In rare cases, as the hepatic encephalopathy
progresses, cerebral edema and increased intracranial pressure can occur, with
abnormal pupillary exam findings, hypertension, bradycardia, respiratory depression
(Cushing triad), and loss of brain stem reflexes. Seizures secondary to increased
intracranial pressure and hypoxia can occur. Vesicular skin lesions are suggestive of
herpes simplex virus (HSV).
TABLE 1
Grades of Encephalopathy
Grade Description
I Changes in behavior with minimal change in level of consciousness (mild confusion,

slurred speech, disordered sleep)
II Gross disorientation, drowsiness, possibly asterixis, inappropriate behavior
III Marked confusion (stupor), incoherent speech, sleeping most of the time but rousable to
vocal stimuli
IV Comatose, unresponsiveness to pain, decorticate or decerebrate posturing
• Family history of unexplained liver disease/cirrhosis should prompt slit lamp ocular
examination for the identification of Kayser-Fleischer rings (copper rings around the
iris seen in Wilson disease).
Laboratory Findings
• Coagulopathy is characteristic of patients with ALF, given decreased synthesis of

clotting factors II, V, VII, IX and X by the liver. Patients with ALF typically have a
prolonged prothrombin time (INR >1.5), elevated transaminases, and elevated
bilirubin, and may have a low platelet count (<150,000).
• Other possible laboratory findings can include an elevated BUN/creatinine (studies

show 30%to 50% also have acute kidney injury) and hypoglycemia (impairment of
gluconeogenesis). Electrolyte disturbances, hyponatremia, hypophosphatemia,
hypomagnesemia, hypokalemia, metabolic acidosis or respiratory alkalosis, elevated
LDH, and elevated ammonia.
Diagnosis
Differential Diagnosis
• Severe acute hepatitis, also known as acute liver injury (including alcoholic hepatitis):
Jaundice and coagulopathy without encephalopathy
• Acute on chronic liver failure (in patients with liver disease duration >26 wk)
• Cirrhosis (includes decompensated cirrhosis)
• Hepatocellular carcinoma
Workup (Box 3)
• Fig. 1 describes an algorithm for evaluation of acute liver failure.
FIG. 1
Initial management of a patient presenting with liver failure. HDU, High-

dependency unit; ICU, intensive care unit; INR, international normalized ratio; NAC,
N-acetylcysteine.
From Parrillo JE, Dellinger RP: Critical care medicine, principles of diagnosis and
management in the adult, ed 5, Philadelphia, 2019, Elsevier.
BOX 3
Investigations in Fulminant Hepatic Failure
From Fuhrman BP, Zimmerman JJ: Fuhrman and Zimmerman’s pediatric critical
care, ed 4, Philadelphia, 2011, Mosby.
CMV, Cytomegalovirus; CT, computed tomography; EBV, Epstein-Barr virus; HSV,

herpes simplex virus; PT, prothrombin time; PTT, partial thromboplastin time.
Baseline essential investigations
Biochemistry
• Bilirubin, transaminases
• Alkaline phosphatase
• Albumin
• Urea and electrolytes
• Creatinine
• Calcium, phosphate
• Ammonia
• Acid-base, lactate
• Glucose
Hematology
• Full blood count, platelets
• PT, PTT
• Factors V or VII
• Blood group cross-match
Septic screen
Omitting lumbar puncture
• Radiology
• Chest radiograph
• Abdominal ultrasound
• Head CT scan or MRI
Neurophysiology
• Electroencephalogram
Diagnostic investigations
Serum
• Acetaminophen levels
• Cu, ceruloplasmin (>3 yr)
• Autoantibodies
• Immunoglobulins
• Amino acids
• Lactate
• Pyruvate
• Hepatitis A, B, C, E
• EBV, CMV, HSV viral loads
• Other viruses
Urine
• Toxic metabolites
• Amino acids, succinylacetone
• Organic acids
• Reducing sugars
• Clinical history is critical, but in the case of patients with severe encephalopathy, the
history may be limited, and efforts should be made to obtain information from the
patient’s family. Important history components include medication use (6-mo
history of prescriptions, over-the-counter medications, herbal supplements), alcohol
use, recreational drug use, prior symptoms of jaundice, onset of symptoms, history
of depression and prior suicide attempts, recent travel to endemic areas of viral
hepatitis, sexual exposures, previous blood transfusions, family history of liver
failure/disease, history of malignancy, or hypercoagulable state.
• Physical examination should include assessing for stigmata of chronic liver disease,
as their presence has different diagnostic and management implications, and mental
status. Grading of hepatic encephalopathy should be performed (Table 1). Perform an
asterixis maneuver, consider psychometric tests (i.e., number connection test) to
detect subtle degree of encephalopathy.
• Laboratory evaluation should be targeted to assess the severity of ALF, as well as its
etiology. Early testing includes complete blood count, liver function tests (LFTs)
including prothrombin time and INR, bilirubin, chemistry panel (sodium,
potassium, chloride, bicarbonate, BUN, creatinine, glucose, magnesium, phosphate,
calcium), arterial blood gas, arterial lactate, blood type and screen, acetaminophen
level, ethanol level, toxicology screen, viral hepatitis serologies (hepatitis A IgM,
hepatitis B surface antigen, anti-hepatitis B core IgM, anti-hepatitis C antibody [IgM
and IgG]), hepatitis C viral load (HCV RNA), anti-hepatitis E IgM and IgG, HSV-1
IgM and HSV PCR, EBV DNA PCR, CMV DNAPCR, anti-hepatitis D IgM and IgG,
hepatitis D viral load (HDV RNA), ceruloplasmin level (as well as serum copper and
24-hr urine copper if high suspicion), pregnancy test, arterial ammonia level,
autoimmune markers (ANA, ASMA, anti-LKM-1, total IgG levels), HIV-1, HIV-2,
amylase, lipase. Imaging studies include abdominal ultrasound with Doppler to
evaluate for Budd-Chiari syndrome, portal hypertension, hepatic congestion, and
hepatic steatosis. Cirrhosis cannot be diagnosed in the setting of ALF, as the liver
may appear nodular in ALF due to massive necrosis; consider cross-sectional
imaging of the liver (triphasic CT, MRCP, or MRI with gadolinium). CT or MRI of
the head should be considered to ensure no other causes for altered mental status.
• Prompt liver biopsy (via transjugular approach to decrease risk of bleeding) should
be performed in cases in which:
1. The etiology is unknown after the initial workup; or
2. Etiology is thought to be secondary to autoimmune hepatitis, malignancy, or

HSV.
Complications
Complications or progression of liver failure may result in cerebral edema due to
increased intracranial pressure (in up to 40% of patients). Hypoglycemia and lactic
acidosis are common complications of ALF, as well as acute kidney injury and
pancreatitis (particularly in acetaminophen-induced ALF). Upper gastrointestinal
hemorrhage is uncommon (in 1.5% of patients). Infections do occur from impaired
leukocyte function (in nearly 80% patients), High-output cardiac failure can occur, as
well acute respiratory distress syndrome. Hypotension occurs due to decreased oral
intake as well as extravasation of fluid into extravascular space.
Treatment (Boxes 4 and 5)

Broadly, the treatment of acute liver failure should include:
• Identification of the etiology of liver injury, if possible, and specific treatment
• Symptomatic and supportive management and transfer to an ICU if necessary
• Early involvement of a liver specialist and transfer to a transplant center when

required
BOX 4
Management of Fulminant Hepatic Failure
From Fuhrman BP, Zimmerman JJ: Fuhrman and Zimmerman’s pediatric critical care,
ed 4, Philadelphia, 2011, Mosby.
BP, Blood pressure; CVP, central venous pressure; FFP, fresh frozen plasma; PN,
parenteral nutrition; PT, prothrombin time; PTT, partial thromboplastin time.
No sedation except for procedures
Minimal handling
Enteric precautions until infection ruled out
Monitor:
• Heart and respiratory rate
• Arterial BP, CVP
• Core/toe temperature
• Neurologic observations
• Gastric pH (>5.0)
• Blood glucose (>4 mmol/L)
• Acid-base
• Electrolytes
• PT, PTT
Fluid balance
• 75% maintenance
• Dextrose 10%-50% (provide 6-10 mg/kg/min)
• Sodium (0.5-1 mmol/L)
• Potassium (2-4 mmol/L)
Maintain circulating volume with colloid/FFP
Coagulation support only if required
Drugs:
• Vitamin K
• H2 antagonist
• Antacids
• Lactulose
• N-acetylcysteine for acetaminophen toxicity
• Broad-spectrum antibiotics
• Antifungals
Nutrition
• Enteral feeding (1-2 g protein/kg/day)
• PN if ventilated
BOX 5
Hepatic Replacement Therapeutic Options Available to Patients with Fulminant

Hepatic Failure
From Vincent JL, et al: Textbook of critical care, ed 6, Philadelphia, 2011, Saunders.
Liver Transplantation
• Cadaveric transplantation
• Whole liver
• Reduced-size liver
• Split liver
• Auxiliary partial liver
• Orthotopic position
• Heterotopic position
• Auxiliary whole liver
• Living-related transplantation
• Left lateral segment
• Left lobe
• Extended left lobe
• Right lobe
Artificial Liver Assist Devices

• Non–cell-based systems
• Charcoal hemoperfusion
• High-volume plasmapheresis
• Continuous high-frequency hemodiafiltration
• Molecular adsorbent recirculating system (MARS)
• Cell-based systems (bioartificial liver assist devices)
• Primary porcine hepatocytes
• Human hepatoblastoma cells
• Extracorporeal liver assist device (ELAD)
Hepatocyte Transplantation
Nonpharmacologic Therapy
• Initial treatment should focus on the patient’s mental status and managing
encephalopathy.
1. Grade I encephalopathy may be managed on a medical ward (neuro vital signs

q4h).
2. Grade II, III, and IV encephalopathy should be managed in ICU (with elevated
head of the bed to 30 degrees). Grade III and IV encephalopathy require
intubation and mechanical ventilation.
3. Decreased stimulation is important (avoiding sedatives; dimly lit, quiet room;

no audible monitor alarms).
• A liver specialist should be notified urgently, and arrangements should be made for
imminent transfer to a transplant center. Early transport is important, as the patient
transport risks increase or even preclude transfer in later stages of encephalopathy.
• Nutritional support should be initiated early. A daily intake goal of 60 g of protein

(or amino acids 0.8 to 1.2 g/kg/day) is recommended to prevent catabolism of protein
stores. Enteral feeding should be initiated in patients with grade III or IV
encephalopathy.
• Fluid support should be initiated if patient is not tolerating oral intake, or signs of
hypoperfusion are present. Crystalloid solutions (normal saline in hypotensive
patients, ½ normal saline + 75 mEq/L NaCO3 in acidotic patients, normal saline +
dextrose in hypoglycemic patients) can be used.
Pharmacologic Treatment
• If encephalopathy progresses and cerebral edema develops leading to increased ICP,
intravenous mannitol is recommended to reduce cerebral edema transiently.
Prophylactic hyperventilation is not recommended in patients with ALF.
Phenytoin can be used to manage seizures. In patients not responding to phenytoin,

• short-acting benzodiazepines may be used.
• Sedative medications should also be avoided, as they are not cleared well and may
mask signs of worsening encephalopathy or cerebral edema.
• Lactulose is not routinely recommended for encephalopathy treatment; neomycin

should be avoided due to concerns of nephrotoxicity.
• Broad-spectrum antibiotics should be started immediately if infection is suspected.

Sources usually include respiratory, urinary, and blood; there is no evidence for
empiric antibiotic treatment. Antifungals should be initiated if no initial
improvement with antibiotics occurs.
• In the case of persistent hypotension, norepinephrine is the initial vasopressor of

choice; vasopressin can be added as a second pressor to maintain MAP >75 mm Hg.
Persistent hypotension despite fluid resuscitation and pressor support should
prompt concern for adrenal insufficiency.
• Patients should receive stress ulcer prophylaxis, given the risk of gastrointestinal
bleeding.
• Routine correction of thrombocytopenia or INR correction are not recommended in

the absence of bleeding. However, in the setting of clinical bleeding or the need for a
procedure with a high bleeding risk, plasma or clotting factors are recommended.
Vitamin K should be given routinely since in patients with ALF vitamin K deficiency
is common.
• Part of the pharmacologic treatment will be specific to the suspected etiology of ALF.
• If acetaminophen is the known or suspected cause, an IV acetylcysteine protocol

should be initiated. N-acetylcysteine is not harmful and dramatically alters the
course in acetaminophen toxicity, so there should be a low threshold to start,
particularly in young patients or those with no known cause of ALF.
• The 20-hr protocol is:
1. Initial loading dose of 150 mg/kg IV given over 60 min followed by;
2. 12.5 mg/kg IV/hr over 4 hr followed by;
3. 6.25 mg/kg IV/hr for 16 hr.
• A repeat acetaminophen level and ALT should be checked at hr 18 of NAC treatment.

If either the acetaminophen level or the ALT is elevated, the 16-hr portion of
treatment (6.25 mg/kg) should be extended and another ALT, INR, or acetaminophen
level should be checked every 12 hr. The acetylcysteine can be stopped once the
acetaminophen level is undetectable, INR <2, or ALT is shown to be either normal or
decreasing. Additional information on acetaminophen overdose is available in the
topic “Acetaminophen Poisoning.”
• N-acetylcysteine therapy outside of acetaminophen poisoning has been investigated

and may be beneficial; however, its routine use is not currently recommended by
practice guidelines and is center specific.
• Liver support systems:
1. Liver support systems have been trialed either to support the patient until the
liver recovers or as a bridge to liver transplantation.
2. High-volume plasma exchange can improve hepatic encephalopathy and

transplant-free survival in a patient ineligible for liver transplantation, but no
survival benefit has been shown for a patient undergoing liver transplantation
with plasma exchange compared with supportive therapy alone.
3. The molecular absorbents recirculating system (MARS) is an artificial

extracorporeal hepatic support system that allows albumin-bound toxins to be
removed. But this, too, has failed to show a survival benefit in patients with ALF.
4. Bioartificial support systems in the form of hepatocytes (human or other

mammalian origin) have also been used in cartridges as part of extracorporeal
systems. These have not shown any benefit, with or without transplantation.
Monitoring
• In patients with high-grade HE awaiting transplant, intracranial pressure (ICP)
monitoring is recommended in centers with expertise in ICP monitoring.
• Neurologic examination every 1 to 4 hr is recommended in the absence of ICP

monitoring.
• Patients with suspected acetaminophen toxicity should have LFTs monitored every
12 hr. Otherwise, LFTs can be monitored daily.
• Chemistry panels and PT/INR should be monitored every 8 to 12 hr. Correction of

coagulopathy should be avoided because it can interfere with assessment of liver
function. In the setting of life-threatening bleeding, fresh frozen plasma (FFP) and
recombinant factor VIIa can be considered.
• Point-of-care glucose should be checked every 4 hr initially to evaluate for

hypoglycemia. If hypoglycemia is detected, dextrose should be added to crystalloid
solution.
• Because of the increased risk of infection, daily urine, sputum, and blood cultures, as
well as chest radiographs, should be checked even in the absence of signs or
symptoms of infection.
Prognosis
• Overall mortality from ALF is 30% to 40% and has improved significantly over the
last 20 yr.
• Transplant-free survival in ALF in the setting of acetaminophen, hepatitis A, shock

liver, and pregnancy-related disease is >50%; for all other causes of ALF, transplant-
free survival is <25%.
• Higher-grade hepatic encephalopathy and renal dysfunction in nonacetaminophen

ALF predict worse survival.
• Multiple models have been developed to predict spontaneous recovery in ALF

patients (King’s College criteria, Clichy criteria, MELD score, APACHE II score).
• The King’s College criteria form the basis of the model most commonly used for
prognostication (Table 2).
TABLE 2
King’s College Hospital Criteria for Liver Transplantation in Acute Liver Failure
Acetaminophen-Induced Acute Non–Acetaminophen-Induced Acute Liver Failure

Liver Failure
Arterial pH <7.3 (irrespective of grade Prothrombin time >100 sec (irrespective of grade of
of encephalopathy) encephalopathy OR Any of three of the following variables
OR Grade III or IV encephalopathy (irrespective of grade of encephalopathy):
and Prothrombin time >100 sec and
Serum creatinine >3.4 mg/dl 1. Age <10 yr or >40 yr
2. Etiology: Non-A hepatitis, non-B hepatitis, halothane

hepatitis, idiosyncratic drug reactions
3. Duration of jaundice before onset of encephalopathy

>7 days
4. Prothrombin time >50 sec
5. Serum bilirubin >18 mg/dl
Sec, Seconds.
• Transplantation:
1. Patients with ALF are given the highest priority for liver transplantation.
ALFaccounts for only 10% of the U.S. liver transplants.
2. Contraindications to listing include medical history of irreversible brain injury,

psychiatric illness severe enough to affect patients’ survival or likelihood of
compliance with medications, active sepsis, severe medical comorbidities
including malignancy, increasing dependence on ventilator/inotropic support,
acute substance abuse, previous episodes of self-harm (>5 episodes), refractory
mental illness, and inadequate family support.
3. For patients with alcoholic liver disease, many centers require a 6-mo
abstinence period, but several transplant centers in North America and Europe
have transplanted selected patients with alcoholic hepatitis who were unlikely to
survive 6 mo.
4. Mortality on the waiting list is 25%; 1-yr and 5-yr survival after transplantation
is 73% and 67%, respectively.
5. Various prognostic criteria used for liver transplantation in patients with

fulminant hepatic failure are summarized in Box E6.
BOX E6
Various Prognostic Criteria Used for Liver Transplantation in Patients with Fulminant
Hepatic Failure
King’s College Criteria
Acetaminophen Overdose
• Arterial pH <7.3 (irrespective of grade of encephalopathy)
or
• PT >100 sec (INR >6.5) and
• Serum creatinine >3.4 mg/dl (>300 μmol/L) and
• Patients with grade III and IV hepatic encephalopathy
Non–Acetaminophen-Induced Liver Injury

Acute form (delayed jaundice-encephalopathy <7 days):
• PT >100 sec (INR >6.5) (irrespective of grade of encephalopathy) or any three of

the following variables:
• Aged <10 or >40 yr
• Non-A, non-B hepatitis, halothane hepatitis, idiosyncratic drug reactions
• Subacute form: Delayed encephalopathy >7 days
• Serum bilirubin 17.4 mg/dl (300 μmol/L)
• PT >50 sec
Clichy Criteria
• Grade III or IV encephalopathy
and
• Factor V <20% in patients <30 yr
or
• Factor V <30% in patients >30 yr
Serum Gc Globulin Levels

Decreasing Gc levels due to dying hepatocytes
Serum α-Fetoprotein Levels

Serial increase from day 1 to day 3 has been correlated with survival
Liver Biopsy
70% necrosis is discriminant of 90% mortality
Pearls & Considerations

• ALF is defined as severe hepatic injury (as evidenced by elevated liver enzymes) with
INR >1.5 and hepatic encephalopathy occurring <26 wk before presentation in a
patient with no prior history of liver disease.
• Close to half of ALF is caused by drug ingestion, usually acetaminophen.
• Given the potential rapidity of deterioration, referral must be made as soon as

possible to a liver transplant center.
• There should be a low threshold to start N-acetylcysteine.
• Coagulopathy should not be corrected unless life-threatening bleeding occurs or it is

recommended by the liver transplant hepatologist.
Suggested Readings
American Association for the Study of Liver Diseases: AASLD Position Paper: the management of
acute liver failure: update 2011. Available at. www.aasld.org/sites/default/files/2019-
06/AcuteLiverFailureUpdate201journalformat1.pdf (http://www.aasld.org/sites/default/files/2019-
06/AcuteLiverFailureUpdate201journalformat1.pdf ).
Flamm S.L., et al.: American Gastroenterological Association Institute Guidelines for the diagnosis
and management of acute liver failure. Gastroenterology 2017; 152 (3): pp. 644-647.
Herrine S.K., et al.: American Gastroenterological Association Institute Technical Review on initial
testing and management of acute liver disease. Gastroenterology:648-664.e5, 2017; 152 (3):
Hu J., et al.: Efficacy and safety of acetylcysteine in “non-acetaminophen” acute liver failure: a
meta-analysis of prospective clinical trials. Clin Res Hepatol Gastroenterol 2015; 39 (5): pp. 594-
599.
Im G.Y., et al.: Liver transplantation for alcoholic hepatitis. J Hepatol 2019; 70 (2): pp. 328-334.
Lee W.M., et al.: Acute liver failure: summary of a workshop. Hepatology 2008; 47 (4): pp. 1401-
1415.
Lee W.M., et al.: Intravenous N-acetylcysteine improves transplant-free survival in early stage non-
acetaminophen acute liver failure. Gastroenterology 2009; 137 (3): pp. 856-864.
Nabi T., et al.: Role of N-acetylcysteine treatment in non-acetaminophen-induced acute liver

failure: a prospective study. Saudi J Gastroenterol 2017; 23 (3): pp. 169-175.
Ostapowicz G., 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): pp. 947-954.
Reuben A.: Outcomes in adults with acute liver failure between 1998 and 2013, an observational
cohort study. Ann Intern Med 2016; 164: pp. 724-732.
Copyright © 2021 Elsevier, Inc. All rights reserved.

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Acute Liver Failure - ClinicalKey 12/10/2021, 18:29

All Types Type your search Search

Released January 1, 2022.

Classifications of Acute Liver Failure

From Vincent JL et al: Textbook of critical care, ed 7, Philadelphia, 2017, Elsevier.

HE, Hepatic encephalopathy.

Trey and Davidson

Subclassification Depending on the Interval

• Acute liver failure: 8-28 days

• Subacute liver failure: 29-72 days

• Late-onset acute liver failure: 56-182 days

Severe acute hepatic failure: Prothrombin time or factor V concentration below

• Subfulminant hepatic failure: HE between 3 and 12 wk of onset of jaundice

International Association for the Study of Acute

• Acute liver failure—fulminant: 10-30 days

• Acute liver failure—not otherwise specified

• Subacute liver failure (development of ascites and/or HE from 5 to 24 wk after

“Acutely decompensated cirrhosis” refers to the development of ascites,

1Sarin SK, Choudhury A, Sharma MK et al: Acute-on-chronic liver failure: consensus

“Acute-on-chronic liver failure” is a syndrome characterized by the following 3 major

1. It occurs in the context of intense systemic inflammation

2. Frequently develops in close temporal relationship with pro-inflammatory

3. Is associated with single- or multiple-organ failure 2

2Arroyo V, Moreau R, Jalan R: Acute-on-chronic liver failure, N Engl Med 382:2137-

Fulminant hepatic necrosis

Acute hepatic necrosis

Acute and subacute necrosis of liver

K72 Hepatic failure, not elsewhere classified

K72.0 Acute and subacute hepatic failure

K72.00 Acute and subacute hepatic failure without coma

K72.01 Acute and subacute hepatic failure with coma

Epidemiology & Demographics

Predominant Sex & Age

• Risk factors for viral hepatitis:

1. Intravenous drug use

2. Occupational exposure to blood or body fluids

5. Intranasal cocaine use

7. Travel to endemic hepatitis areas

• Previous alcohol use

1. Acetaminophen toxicity (46%)

3. Idiosyncratic drug reaction (12%)

4. Viral hepatitis (A, B) (10%)

Etiologic Classification of Acute Liver Failure

From Vincent JL et al: Textbook of critical care, ed 7, Philadelphia, 2017, Elsevier.

CCl4, Carbon tetrachloride.

Idiosyncratic Drug Injury

Combination Agents with Enhanced Hepatotoxicity

Herpes simplex virus

Varicella zoster virus

Yellow fever virus

Acute fatty liver of pregnancy

Clinician Presentation & Physical Findings

• Physical examination Findings include, by definition, abnormal neurologic

I Changes in behavior with minimal change in level of consciousness (mild confusion,

II Gross disorientation, drowsiness, possibly asterixis, inappropriate behavior

IV Comatose, unresponsiveness to pain, decorticate or decerebrate posturing

• Coagulopathy is characteristic of patients with ALF, given decreased synthesis of

• Other possible laboratory findings can include an elevated BUN/creatinine (studies

• Cirrhosis (includes decompensated cirrhosis)

Initial management of a patient presenting with liver failure. HDU, High-

Investigations in Fulminant Hepatic Failure

CMV, Cytomegalovirus; CT, computed tomography; EBV, Epstein-Barr virus; HSV,

Baseline essential investigations