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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

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Approach to acute liver failure

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
Acute liver Failure (ALF)

  • Rare

  • Represent the most sever form of liver injury

  • Hard to treat

  • Difficult to study

Acute liver failure
Acute liver Failure

  • Fulminant hepatitis

  • Fulminant hepatic failure

  • Subfulminant liver failure

  • Subacute hepatic necrosis

  • Subacute liver failure

  • Hyperacute liver failure

Alf definition
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 definition1
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
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) vssubfulminant (2-12 wks)

Alf causes
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


U s alf study group 2002 308 patients 73 women
U.S. ALF STUDY GROUP 2002 (308 Patients, 73% Women)

Alf causes1
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
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 dili1
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.

  • OstapowiczG,et al. Ann Intern Med 2002 .

Acetaminophen hepatotoxicity
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
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 nomogram1
Rumack-Matthew Nomogram

  • The standard acetaminophen toxicity nomogrammay aid in determining the likelihood of serious liver damage

  • cannot 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
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
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
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 nac1
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
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 disease1
Wilson disease

  • Serum ceruloplasminis 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 disease2
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
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
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
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 syndrome1
Budd-Chiari Syndrome

Ischemic hepatitis and alf
Ischemic Hepatitis and ALF

  • Liver cell necrosis - massive

  • Cardiac tamponade

  • Acute heart failure

  • Pulmonary embolus

  • Hepatic artery thrombosis

Poisoning and alf
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
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 alf1
Diagnosis and Initial Evaluation ALF

  • Physical Exam:

  • Determine presence or absence

    of pre-existing liver disease

  • Hepatic tenderness

  • Hepatic decompensation

Diagnosis and initial evaluation alf2
Diagnosis and Initial Evaluation ALF


  • Family members with liver disease?

  • Recent cold sores

  • Onset of jaundice

  • Work environment- toxic agents

  • Hobbies

  • Herbal products/dietary supplements

Initial laboratory analysis
Initial Laboratory Analysis

  • Prothrombintime/INR

  • Chemistries

  • Liver enzymes

  • Arterial blood gas

  • Acetaminophen level Toxicology screen

  • Viral hepatitis serologies(anti-HAV IgM, HBsAg, anti-HBcIgM, anti-HEV, anti-HCV, HCV RNA , HSV1 IgM, VZV)

Initial laboratory analysis1
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)

Complications of acute liver failure
Complications of Acute Liver Failure:

  • CNS disturbances

    • Hepatic encephalopathy

    • Cerebral edema

  • Hemodynamic Collapse

  • Infections

  • Coagulopathy and bleeding

  • Renal failure

  • Metabolic derangements

Cerebral edema
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
Intracranial Pressure

  • CPP = MAP – ICP

    • CPP > 60mmHg

    • ICP < 20mmHg

Intracranial pressure1
Intracranial Pressure

  • CPP = MAP – ICP

    • CPP< 60mmHg

    • ICP < 20mmHg

Cerebral edema intracranial hypertension
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
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


  • 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


  • 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
Hemodynamics/Renal Failure

  • Volume replacement

  • Pressorsupport (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
Metabolic Concerns

  • Follow closely: glucose, potassium, magnesium, phosphate

  • Consider nutrition: enteral feedings if possible or total parenteral nutrition

What are the potential outcomes
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
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


Prognosis and transplantation
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
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
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<7.3Or

  • 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 criteria1
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
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
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 therapy1
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 multicenterRCT showed no survival benefit.

  • SalibaF, et al. Ann Intern Med 2013;159:522-31

Future therapy2
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 therapy3
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