Approach to Acute liver Failure
Bader Alenezi, MD
Chairman of Internal Medicine
Jahra Hospital
Consultant Gastroenterolgy & Hepatology
Definition Acute Liver failure
common causes of ALF
Acetaminophen toxicity
Diagnosis and Initial Evaluation ALF
Manage complications of ALF
Identify prognostic criteria
Future therapy in ALF
Acute liver Failure (ALF)
Represent the most sever form of liver injury
Hard to treat
Difficult to study
Acute liver Failure
Fulminant hepatitis
Fulminant hepatic failure
Subfulminant liver failure
Subacute hepatic necrosis
Subacute liver failure
Hyperacute liver failure
ALF: Definition
• The original term “fulminant hepatic failure”
• “a severe liver injury, potentially reversible in
nature and with onset of hepatic
encephalopathy within 8 weeks of the first
symptoms in the absence of pre-existing liver
Trey C , Davidson CS. The management of fulminant hepatic failure. Prog Liver Dis
ALF: Definition
• The most widely accepted definition of ALF:
• Coagulation abnormality, usually an INR >1.5,
and any degree of mental alteration
(encephalopathy) without preexisting
cirrhosis and with an illness of <26 weeks
AASLD Position Paper: The Management of Acute Liver Failure: Update 2011
William M. Lee, MD, Anne M. Larson, MD, and R. Todd Stravitz, MD
Defining Acute Liver Failure
• INR > 1.5
• Altered mental status
• Illness of < 26 weeks duration
• Hyperacute < 7 days
• Acute 7-21 days
• Subacute > 21 days and < 26 weeks
• Fulminant (2 wks) vs subfulminant (2-12 wks)
ALF: Causes
Acetaminophen 39%
Indeterminite 17%
Idiosynchratic drug rxns 13%
Viral hepatitis 12%
Autoimmune 4-5%
Wilson’s Disease 2-3%
Mushroom Poisoning
Herbal Medications
– Bud-Chiarri
– Ischemic
– Hepatic Vein Thrombosis
• Reye’s Syndrome
• Fatty Liver of Pregnancy
(308 Patients, 73% Women)
ALF: Causes
• ALF in developed world << developing world
• developing world viral infections (hepatitis A,
B, and E) are the predominant causes.
• Western world drug-induced liver injury is the
most common cause of acute liver failure
• Globally, hepatitis A and E infections are probably
responsible for the majority of cases of ALF
• ALF may occur after hepatitis B infection, Asian
and Mediterranean countries.
• Reactivation of HBV without established chronic
liver disease treatment-induced
immunosuppression during or after therapy for
• Antiviral prophylaxis before the initiation of
chemotherapy, immunotherapy, or glucocorticoid
therapy are effective in prevention
ALF CAUSES: Other Viruses
rare viral causes of acute liver failure :
Herpes simplex virus
Epstein–Barr virus
Ichai P, Samuel D. Etiology and prog- nosis of fulminant hepatitis in adults. Liver Transpl
2008;14:Suppl 2:S67-S79.
Drug-Induced Liver Injury (DILI)
Drug-Induced Liver Injury (DILI)
• DILI is responsible for approximately 50% of cases of ALF in United
• Can be dose- dependent and predictable, as exemplified by
acetaminophen-induced hepatotoxicity
• Or may be idiosyncratic, unpredictable, and independent of dose
• idiosyncratic drug hepatotoxicity usually within the first 6 months
after drug initiation.
• A potentially hepatotoxic medication used continually 1 to 2 years
is unlikely to cause de novo liver damage.
• Certain herbal preparations, weight loss agents and other
nutritional supplements  need complete medication history.
Ostapowicz G,et al. Ann Intern Med 2002 .
Acetaminophen Hepatotoxicity
• Dose-related
• Dose leading to ALF exceed 10 gm/day (>150
• Doses as low as 3-4 gm/day rarely causes ALF
• Very high aminotransferase levels
• Serum levels exceeding 3,500 IU/L are highly
correlated with acetaminophen poisoning
• low or absent levels do not rule out
hepatotoxicity (remote ingestion or over several
Rumack-Matthew Nomogram
• Used to interpret plasma acetaminophen
values to assess hepatotoxicity risk after a
single, acute ingestion
• Nomogram tracking begins 4 hours after
ingestion (time when acetaminophen
absorption is likely to be complete) and ends
24 hours after ingestion
• About 60% of patients with values above the
"probable" line develop hepatotoxicity
Rumack-Matthew Nomogram
• The standard acetaminophen toxicity nomogram
may aid in determining the likelihood of serious
liver damage
• can not be used if:
• 1- multiple doses over time
• 2- when the time of ingestion is unknown
• 3- When altered metabolism occurs such as in the
alcoholic or fasting patient
Larson AM. Acetaminophen hepatotoxicity. Clin Liver Dis. 2007;11: 525-48.
Lee WM. Drug-Induced Hepatotoxicity. N Engl J Med 2003;349: 474-485.
Treatment of Acetaminophen
• Activated charcoal for gastrointestinal
decontamination best if given within 1hr of
ingestion may be of benefit as long as 3 to 4
hours after ingestion.
• Administration of activated charcoal (standard
dose 1 gm/kg orally) just prior to administration
of N-acetylcysteine does not reduce the effect of
Sato RL,et al Efficacy of superactivated charcoal administration late (3 hours) after acetaminophen
overdose. Am J Emerg Med 2003;21:189-191.
Treatment: N-acetylcysteine (NAC)
• N-acetylcysteine (NAC), the antidote for
acetaminophen poisoning effective and
• NAC should be given as early as possible
• NAC is nearly 100% hepato protective when it
is given within 8 hours
• but may still be of value 48 hours or more
after ingestion
N-acetylcysteine (NAC)
• NAC orally (140 mg/kg by mouth or nasogastric
tube diluted to 5% solution, followed by 70
mg/kg by mouth q 4 h x 17 doses)
• Oral administration has largely been replaced by
intravenous administration (loading dose is 150
mg/kg in 5% dextrose over 15 minutes;
maintenance dose is 50 mg/kg given over 4 hours
followed by 100 mg/kg administered over 16
hours or 6 mg/kg/hr)
N-acetylcysteine (NAC)
• Use of the IV formulation of NAC is preferred in
the following situations:
• Altered mental status
• GI bleeding and/or obstruction
• A history of caustic ingestion
• Potential fetal acetaminophen toxicity in a
pregnant woman
• Inability to tolerate oral NAC because of emesis
refractory to proper use of antiemetics
Wilson disease
• uncommon cause of ALF (2% to 3% of cases in the
• Early identification is critical because the
fulminant presentation of Wilson disease is
considered to be uniformly fatal without
• young patients with Coombs negative hemolytic
anemia with serum bilirubin levels >20 mg/dL
• Kayser-Fleischer rings are present in about 50% of
Wilson disease
• Serum ceruloplasmin is typically low, but may be
normal in up to 15% of cases and is reduced in
~50% of other forms of ALF.
• High plasma and urinary copper levels as well as
hepatic copper measurement will confirm the
• Very low serum alkaline phosphatase or uric acid
• A high bilirubin to alkaline phosphatase ratio
(>2.0) is a rapid, reliable indicator of Wilson
Wilson disease
• Rx:
• penicillamine is not recommended in ALF due
to risk of hypersensitivity
• recovery is very rare absent transplantation.
• Patients must be promptly considered for liver
• (AASLD recommendation 2011)
Autoimmune Hepatitis
• unrecognized preexisting chronic disease and yet
still be considered as having ALF.
• AIH patients that develop ALF represent the most
severe form of the disease.
• Autoantibodies absent (up to 30% of cases)
• Liver biopsy should be considered if autoimmune
hepatitis is suspected and autoantibodies are
• Recommended to receive corticosteroid therapy
ALF in Pregnancy
• Acute Fatty Liver of Pregnancy/HELLP (Hemolysis,
Elevated Liver Enzymes, Low Platelets) Syndrome
• Near the end of pregnancy will develop rapidly
progressive hepatocyte failure.
• Increased fetal or maternal mortality.
• Triad of jaundice, coagulopathy, and low platelets
• Hypoglycemia and Features of pre-eclampsia are
• Transplantation may need to be considered if hepatic
failure does not resolve quickly following delivery
Budd-Chiari Syndrome
• Acute hepatic vein thrombosis
• Abdominal pain, ascites and striking
• Diagnosis confirmed with hepatic imaging studies
(computed tomography, Doppler
ultrasonography, venography, magnetic
resonance venography)
• Prognosis is poor
• Liver transplantation is indicated, provided
underlying malignancy is excluded
Budd-Chiari Syndrome
Ischemic Hepatitis and ALF
• Liver cell necrosis - massive
Cardiac tamponade
Acute heart failure
Pulmonary embolus
Hepatic artery thrombosis
Poisoning and ALF
• Amanita mushrooms (amanatoxins)
• - LD = 50 gms (3 mushrooms)
• - Toxins not destroyed by cooking
• - Rapid onset of HE in 4-8 days
following severe emesis and diarrhea
• Solvents - chlorinated hydrocarbons
• Herbal remedies
• Yellow phosphorus
Diagnosis and Initial Evaluation ALF
• In all patients with clinical or laboratory of
acute hepatitis PT and careful evaluation for
subtle alterations in mentation should done
• If PT is prolonged by ~4-6 seconds or more
(INR >1.5) and there is any evidence of altered
sensorium, the diagnosis of ALF is established
and hospital admission is mandatory.
• Transfer to intensive care unit (ICU) and
contact with a transplant center if indicated
Diagnosis and Initial Evaluation ALF
• Physical Exam:
• Determine presence or absence
of pre-existing liver disease
• Hepatic tenderness
• Hepatic decompensation
Diagnosis and Initial Evaluation ALF
Family members with liver disease?
Recent cold sores
Onset of jaundice
Work environment- toxic agents
Herbal products/dietary supplements
Initial Laboratory Analysis
Prothrombin time/INR
Liver enzymes
Arterial blood gas
Acetaminophen level Toxicology screen
Viral hepatitis serologies (anti-HAV IgM,
HBsAg, anti-HBc IgM, anti-HEV, anti-HCV, HCV
Initial Laboratory Analysis
• Ceruloplasmin level
• Pregnancy test (females) Ammonia (arterial if
• Autoimmune Markers (ANA, ASMA,
Immunoglobulin levels )
• Liver Biopsy reserved for diagnostic dilemma
(Transjugular approach)
Liver biopsy in ALF
Complications of Acute Liver Failure:
• CNS disturbances
– Hepatic encephalopathy
– Cerebral edema
• Hemodynamic Collapse
• Infections
• Coagulopathy and bleeding
• Renal failure
• Metabolic derangements
Cerebral Edema
• There is increasing evidence that ammonia plays an
important role in the pathogenesis of cerebral edema/ ICH
• arterial ammonia level >200 ug/dL  cerebral herniation;
rarely if <75 ug/dL
• Degree of encephalopathy correlates w/ cerebral edema
– Grade I-II: rare
– Grade III: 25-35% risk risk
– Grade IV: 65-75% risk
• Uncal herniation
• Compromises cerebral blood flow  hypoxic brain injury
Intracranial Pressure
CPP > 60mmHg
ICP < 20mmHg
Intracranial Pressure
CPP< 60mmHg
ICP < 20mmHg
Cerebral Edema/Intracranial
• Grade I/II Encephalopathy Consider transfer to
liver transplant facility and listing for
• Brain CT: rule out other
• Avoid stimulation; avoid sedation if possible
Antibiotics: surveillance and treatment of
infection required; prophylaxis possibly
• Lactulose, possibly helpful
Grade III/IV Encephalopathy
Intubate trachea
Elevate head of bed
Consider placement of ICP monitoring device
Immediate treatment of seizures required; prophylaxis
of unclear value
• Mannitol: use for severe elevation of ICP or first
clinical signs of herniation
• Hypertonic saline to raise serum sodium to 145-155
• Hyperventilation: effects short-lived; may use for
impending herniation
• Surveillance for and prompt antimicrobial
treatment of infection required
• Antibiotic prophylaxis possibly helpful but not
• Prophylactic antibiotics and antifungals have
not been shown to improve overall outcomes
in ALF
• Vitamin K: give at least one dose
• FFP: give only for invasive procedures or active
• Platelets: give only for invasive procedures or
active bleeding
• Recombinant activated factor VII: possibly
effective for invasive procedures
• Prophylaxis for stress ulceration: give H2
blocker or PPI
Hemodynamics/Renal Failure
• Volume replacement
• Pressor support (dopamine, epinephrine,
norepinephrine) as needed to maintain
adequate mean arterial pressure
• Avoid nephrotoxic agents
• Continuous modes of hemodialysis if needed
• Vasopressin recommended in hypotension
refractory to volume resuscitation and
Metabolic Concerns
• Follow closely: glucose, potassium,
magnesium, phosphate
• Consider nutrition: enteral feedings if possible
or total parenteral nutrition
What are the potential outcomes?
• 1. Recovery because of a successful
– NAC for acetaminophen toxicity
– Antivirals for acute hepatitis B
• 2. Spontaneous recovery with supportive care
• 3. Death
• 4. Rescue by liver transplant
Predicting Outcomes in Acute Lifer
• Most important predictive factors:
– Degree of encephalopathy
• Suggested laboratory markers:
Factor V
Serum Phosphate
VII/V ratio > 30
Gc globulin
• Clinical algorithms:
– King’s College Criteria
Prognosis and Transplantation
• overall mortality has improved to between 3040%
• Transplant free-survival was >50% in
acetaminophen, hepatitis A, shock liver, or
pregnancy-related disease.
• other etiologies showed <25% transplant-free
Poor Prognosis in Patients With ALF
• Idiosyncratic drug injury
• Acute hepatitis B (and other non-hepatitis A
viral infections)
• Autoimmune hepatitis
• Mushroompoisoning
• Wilson disease
• Budd-Chiari syndrome
• Indeterminate cause
King’s College Criteria
• Acetaminophen-Induced ALF:
• Strongly consider OLT listing if:
• arterial lactate >3.5 mmol/L after early fluid
• List for OLT if: pH<7.3 Or
• arterial lactate >3.0 mmol/L after adequate fluid
• List for OLT if all 3 occur within a 24-hour period:
• 1- presence of grade 3 or 4 hepatic encephalopathy
• 2- INR >6.5
• 3- Creatinine >3.4 mg/dL
King’s College Criteria
• Non-acetaminophen:
• INR > 6.5 OR
• Any 3 of the following 5:
Age < 10 or > 40
Serum bilirubin > 18
Jaundice to encephalopathy interval > 7 days
INR > 3.5
Unfavorable Etiology
• Non-A, non-B hepatitis, halothane, idiosyncratic drug
reaction, Wilson’s
AASLD Recommendation
• Currently available prognostic scoring systems
do not adequately predict outcome and
determine candidacy for liver transplantation.
Reliance entirely upon these guidelines is thus
not recommended.(III)
AASLD Position Paper: The Management of Acute Liver Failure: Update 2011
William M. Lee, MD, Anne M. Larson, MD, and R. Todd Stravitz, MD
Liver Transplantation
• Urgent hepatic transplantation is indicated in
acute liver failure where prognostic indicators
sug- gest a high likelihood of death (II-3).
• Living donor or auxiliary liver transplantation
may be considered in the setting of limited
organ supply, but its use remains controversial
AASLD Position Paper: The Management of Acute Liver Failure: Update 2011
William M. Lee, MD, Anne M. Larson, MD, and R. Todd Stravitz, MD
Future therapy
Future therapy
• extracorporeal liver-assist devices:
• Nonbiologic dialysis-based systems for
systemic detoxification
• Bioartificial devices that incorporate hepatic
cells of porcine or human origin to replace
both detoxification and synthetic functions.
• A multicenter RCT showed no survival benefit.
Saliba F, et al. Ann Intern Med 2013;159:522-31
Future therapy
• Liver Support Systems:
• Currently available liver support systems are
not recommended outside of clinical trials;
their future in the management of acute liver
failure remains unclear
Future therapy
• Hepatocyte transplantation
• Intraportal & intraperitoneal infusion of isolated
human hepatocytes
• Some success in neonates and children with
inborn errors of metabolism
• Limited experience in pediatric acute liver failure
• Remains experimental.
Hughes RD,et al Current status of hepatocyte transplantation. Transplantation 2012;93:342-7.
• Management of ALF is real challenge for the
treating team
• ALF should be treated in ICU
• Treatments for specific etiologies
• Consideration of transplantation should be
under-taken urgently

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