Approach to Acute liver Failure

Bader Alenezi, MD
Chairman of Internal Medicine
Jahra Hospital
Consultant Gastroenterolgy & Hepatology
 Outlines
• 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)
• Rare
• 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
disease,”
• Trey C , Davidson CS. The management of fulminant hepatic failure. Prog Liver Dis
1970;3:282-98
 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
duration.

• 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%
– HBV > HAV > HEV, HSV
• Autoimmune 4-5%
• Wilson’s Disease 2-3%
• Mushroom Poisoning
• Herbal Medications
• Vascular
– Bud-Chiarri
– Ischemic
– Hepatic Vein Thrombosis
• Reye’s Syndrome
• Fatty Liver of Pregnancy
• HELLP
 U.S. ALF STUDY GROUP 2002
(308 Patients, 73% Women)
40
35
30
25
20
15
10
5
0
ACM HBV HAV Indet Other
 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
 ALF CAUSES: Viruses
• 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
cancer
• 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
• CMV
• Epstein–Barr virus
• Parvoviruses

• 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
States
• 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
mg/kg)
• 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
days)
 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
Hepatotoxicity
• 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
N-acetylcysteine.

• 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
U.S.
• Early identification is critical because the
fulminant presentation of Wilson disease is
considered to be uniformly fatal without
transplantation
• young patients with Coombs negative hemolytic
anemia with serum bilirubin levels >20 mg/dL
• Kayser-Fleischer rings are present in about 50% of
patients
 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
diagnosis.
• Very low serum alkaline phosphatase or uric acid
levels
• A high bilirubin to alkaline phosphatase ratio
(>2.0) is a rapid, reliable indicator of Wilson
disease
 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
transplantation
• (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
negative
• 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
common
• 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
hepatomegaly
• 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
• HISTORY:
• Family members with liver disease?
• Recent cold sores
• Onset of jaundice
• Work environment- toxic agents
• Hobbies
• Herbal products/dietary supplements
 Initial Laboratory Analysis
• Prothrombin time/INR
• Chemistries
• Liver enzymes
• Arterial blood gas
• Acetaminophen level Toxicology screen
• Viral hepatitis serologies (anti-HAV IgM,
HBsAg, anti-HBc IgM, anti-HEV, anti-HCV, HCV
RNA , HSV1 IgM, VZV)
 Initial Laboratory Analysis
• Ceruloplasmin level
• Pregnancy test (females) Ammonia (arterial if
possible)
• 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 = MAP – ICP

CPP > 60mmHg
ICP < 20mmHg
Intracranial Pressure

CPP = MAP – ICP

CPP< 60mmHg
ICP < 20mmHg
 Cerebral Edema/Intracranial
Hypertension
• Grade I/II Encephalopathy Consider transfer to
liver transplant facility and listing for
transplantation
• Brain CT: rule out other
• Avoid stimulation; avoid sedation if possible
Antibiotics: surveillance and treatment of
infection required; prophylaxis possibly
helpful
• 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
mmol/L
• Hyperventilation: effects short-lived; may use for
impending herniation
 Infection
• Surveillance for and prompt antimicrobial
treatment of infection required

• Antibiotic prophylaxis possibly helpful but not

proven
• Prophylactic antibiotics and antifungals have
not been shown to improve overall outcomes
in ALF
 Coagulopathy
• Vitamin K: give at least one dose
• FFP: give only for invasive procedures or active
bleeding
• 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
norepinephrine
 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
intervention
– 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
Failure
• Most important predictive factors:
– Degree of encephalopathy

• Suggested laboratory markers:

– Factor V
– AFP
– Serum Phosphate
– VII/V ratio > 30
– Gc globulin

• Clinical algorithms:
– King’s College Criteria
– APACHE II
 Prognosis and Transplantation
• overall mortality has improved to between 30-
40%
• Transplant free-survival was >50% in
acetaminophen, hepatitis A, shock liver, or
pregnancy-related disease.
• other etiologies showed <25% transplant-free
survival.
 Poor Prognosis in Patients With ALF
(Etiology)
• 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
resuscitation
• List for OLT if: pH<7.3 Or
• arterial lactate >3.0 mmol/L after adequate fluid
resuscitation
• 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.

 Summary
• 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