Acute liver failure resident survival guide

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vendhan Ramanujam M.B.B.S [2]

Synonyms and keywords: Acute hepatic failure, fulminant hepatic failure, fulminant liver failure

Definitions

Acute Liver Failure

Acute liver failure is defined as the presence of coagulation abnormality (INR ≥1.5) and any degree of alteration in mental status in the absence of pre exisiting cirrhosis and any illness of <26 weeks duration. Few exceptions that are included in spite of their presentation with cirrhosis are Wilson disease, vertically-acquired HBV, and autoimmune hepatitis if they have been recognized for <26 weeks. When the above presentation duration is up to 26 weeks, ALF is the better terminology to be used when compared to terms like fulminant hepatic failure, fulminant hepatitis or necrosis, hyperacute, acute and subacute liver failure. But the original term fulminant hepatic failure, which is defined as potentially reversible severe liver injury, with onset of hepatic encephalopathy within 8 weeks of the first symptoms in the absence of pre-existing liver disease, and their subclasses remain relevant today. Fulminant hepatic failure and its subclasses or phenotypes are recognized by quantifying the interval between the onset of symptoms and the development of encephalopathy. These phenotypes and intervals can provide clues to the cause of disease, likely complications, and prognosis with supportive medical care alone. The various system that recognize fulminant hepatic failure and its subclasses or phenotypes are as follows

System	Term	Weeks From Jaundice to Encephalopathy
O’Grady System	Hyperacute Acute Subacute	Encephalopathy within 7 days of onset of jaundice Encephalopathy within an interval of 8 to 28 days from onset of jaundice Encephalopathy within 5 to 12 weeks of onset of jaundice
Bernuau System	Fulminant Subfulminant	Encephalopathy within 2 weeks of onset of jaundice Encephalopathy within an interval of 2 to 12 weeks from onset of jaundice
Japanese System	Fulminant Late-Onset Subclass: Acute Subacute	Encephalopathy within 8 weeks of onset of jaundice Encephalopathy within an interval of 8 to 24 weeks from onset of jaundice Encephalopathy within 10 days of onset of jaundice Encephalopathy within an interval of 11 to 56 days from onset of jaundice

Hepatic Encephalopathy

Based on their clinical manifestation, different grades of hepatic encephalopathy are defined as follows

Grades	Clinical Features
I	Changes in behavior, minimal changes in level of consciousness
II	Inappropriate behavior, gross disorientation, drowsiness, possibly asterixis
III	Marked confusion, incoherent speech, mostly sleeping but arousable to vocal stimuli
IV	Comatose, unresponsive to pain, decorticate or decerebrate posturing

Causes

Life Threatening Causes

Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated.

• Cocaine
• Idiosyncratic hypersensitivity reactions
• Mushroom poisoning
• Shock or hypoperfusion

Common Causes

• Autoimmune hepatitis
• Acetaminophen toxicity
• Viral hepatitis
• Shock or hypoperfusion

Management

Shown below is a diagram depicting the management of acute liver failure according to the American Association for the Study of Liver Diseases (AASLD).

Characterize the symptoms: ❑ Altered mental status and/or ❑ Fatigue/malaise and/or ❑ Pruritus and/or ❑ Abdominal distension Obtain a detailed history including: ❑ Exposure to viral infections ❑ Drug and toxin intake

Examine the patient: ❑ Mental status examination ❑ Stigmata of chronic liver disease ▸ Spider angiomata ▸ Telangiectasia ▸ Palmar erythema ▸ Dupuytren's contracture ▸ Caput medusa ▸ Hypertrophic osteoarthropathy ▸ Muehrcke's nails/Terry's nails ▸ Fetor hepaticus ❑ Jaundice ❑ Right upper quadrant tenderness ❑ Hepatomegaly ❑ Ascites ❑ Orthostatic hypotension ❑ Cushing's triad

Consider alternative diagnosis: ❑ Severe acute hepatitis ❑ HELLP syndrome of pregnancy

Initial Laboratory Analysis: ❑ Prothrombin time/INR Serum chemistries ❑ Sodium ❑ Potassium ❑ Chloride ❑ Bicarbonate ❑ Calcium ❑ Magnesium ❑ Phosphate ❑ Glucose ❑ Blood Urea Nitrogen ❑ Creatinine ❑ AST ❑ ALT ❑ Alkaline phosphatase ❑ GGT ❑ Total bilirubin ❑ Albumin ❑ Complete blood count ❑ Ammonia ❑ Arterial blood gas ❑ Arterial lactate ❑ Amylase and lipase ❑ Acetaminophen level ❑ Toxicology screen ❑ Viral hepatitis serologies ▸anti-HAV IgM ▸ HBsAg ▸ anti-HBc IgM ▸ anti-HEV ▸ anti-HCV ▸ HCV RNA ▸ HSV1 IgM ▸ VZV ❑ Autoimmune markers (ANA, ASMA, Ig levels) ❑ Ceruloplasmin level† ❑ Blood type and screen ❑ Pregnancy test (females) ❑ HIV-1, HIV-2‡

Diagnostic criteria: ❑ INR ≥1.5 ❑ Altered mental status ❑ Absence of pre exisiting cirrhosis ❑ Any illness of <26 weeks duration

Mandatory ICU admission

ICU management

Etiology specific management

Consider transplantation

^†In case of Wilson disease consideration (e.g., in patients less than 40 years without obvious explanation for ALF)
^‡Implications for potential liver transplantation

Quality of Evidence on Which a Recommendation Is Based

The quality of evidence and the based recommendations are as follows

Grade	Definition
I	Randomized controlled trials
II-1	Controlled trials without randomization
II-2	Cohort or case-control analytic studies
II-3	Multiple time series, dramatic uncontrolled experiments
III	Opinions of respected authorities, descriptive epidemiology

ICU Management

Organ System	Specific Issues	Management Recommendations
Central Nervous System	Cerebral edema and intracranial hypertension	a) Intracranial pressure monitoring: (III) ❑ ICP monitoring with monitors when patients ❑ Present with high grade hepatic encephalopathy (grade III/IV) ❑ Are in centers with expertise in ICP monitoring ❑ Are awaiting and undergoing liver transplantation ❑ Correct coagulopathy before ICP monitoring with monitors ❑ In the absence of ICP monitors ❑ Hourly neurological evaluation ❑ Monitoring of serum ammonia levels ❑ Transcranial ultrasonography b) Prophylactic hypertonic saline: (I):❑ Hypertonic saline i.v bolus (20 ml of 30% sodium chloride or 200 ml of 3% sodium chloride) for prophylactic induction of hypernatremia in patients with ❑ Serum ammonia >150 μM ❑ Grade III/IV hepatic encephalopathy ❑ Acute renal failure ❑ Vasopressors requirement to maintain MAP ❑ Maintain serum sodium level of 145-155 mEq/L c) Intracranial hypertension treatment: ❑ I line therapy: (II-2) ❑ Mannitol i.v bolus (0.5-1.0 gm/kg of body weight or 2 ml of 20% solution/kg of body weight) ❑ Administered as needed as long as serum osmolality <320 mOsm/L ❑ II line therapy: (if refractory to mannitol) (II-3) ❑ Short-acting barbiturates ❑ Hypothermia induction to a core body temperature of 34°-35°C ❑ Indomethacin i.v bolus (0.5 mg/kg) may be used when cerebral hyperemia is also present ❑ Goals of intracranial hypertension treatment ICP <20 mmHg CPP >60 mmHg ❑ Hyperventilate to PaCO2 of 25-30 mmHg (in case of impending herniation)
	Grade I/II encephalopathy	❑ Frequent neurological assessment with avoidance of stimulation and sedation ❑ Small doses of short-acting benzodiazepines in case of unmanageable agitation ❑ Stat brain CT to rule out other causes of altered mental status ❑ Consideration for transfer to a liver transplant facility and listing for transplantation at the earliest ❑ Lactulose (possibly helpful and may interfere with surgical field by increasing bowel distention during liver transplantation) (III) ❑ Infection surveillance ❑ Antibiotic prophylaxis against infections (possibly helpful) ❑ Infection treatment as required
	Grade III/IV encephalopathy	Besides managing the patient similar to grade I/II encephalopathy ❑ Intubate trachea (might require sedation) (III) ❑ Muscle relaxants for intubation During intubation: Depolarizing neuro-muscular blocking agents After intubation: Propofol ❑ Elevate head of bed to 30° ❑ Lidocaine administration during endotracheal suctioning ❑ Immediate treatment of seizures with phenytoin and benzodiazepines with short half-lives (III) ❑ ICP monitoring with devices ❑ Mannitol administration following severe elevation of ICP or first clinical sign of herniation ❑ Hypertonic saline administration to raise serum sodium to 145-155 mmol/L ❑ Hyperventilate patient in case of impending herniation ❑ Monitor and manage hemodynamic and renal parameters as well as glucose, electrolytes and acid/base status
Cardiovascular System	Hemodynamic abnormalities	❑ Fluid resuscitation and maintenance of adequate intravascular volume (initiate hypotension treatment with intravenous normal saline) (III) ❑ Systemic vasopressor support (dopamine, epinephrine, norepinephrine) as needed (II-1) ❑ Vasopressinorterlipressin added to norepinephrine in norepinephrine-refractory cases (used cautiously in severely encephalopathic patients with intracranial hypertension) (II-1) ❑ Ensure appropriate volume status with a volume challenge (pulmonary artery catheterization is rarely necessary since it is associated with significant morbidity) (III) ❑ Echocardiography for low cardiac output and right ventricular failure ❑ Goals of circulatory support: (II) MAP ≥75 mmHg CPP 60-80 mmHg
Respiratory System	Aspiration pneumonitis	❑ Neurologic observation to monitor level of consciousness ❑ Early endotracheal intubation for depressed level of consciousness
Hepatic System	Hepatic dysfunction	❑ NAC administration (acetaminophen as well as non-acetaminophen ALF)
Metabolic and Renal System	Metabolic abnormalities and renal failure	❑ Frequent monitoring and correction of derangements in glucose, potassium, magnesium and phosphate (III) ❑ Continuous modes of hemodialysis (if needed) (I)
Hematologic System	Coagulopathy	❑ Replacement therapy for thrombocytopenia and/or prolonged prothrombin time with platelet and FFP transfusion respectively in the setting of active bleeding or before invasive procedure (III) ❑ Administer at least one dose of vitamin K (5-10 mg subcutaneously) ❑ Plasmapheresis or recombinant activated factor VII (rFVIIa) in case of inadequate correction of severely elevated INR and risks of volume overload ❑ Maintenance of adequate platelet count In the absence of bleeding: >10,000/mm3 For performing invasive procedures: 50-70,000/ mm3 ❑ Prophylaxis for stress ulceration: (I) ❑ I line: H2 blocker or PPI ❑ II line: Sucralfate
Immunologic System	Infection	❑ Periodic surveillance for prompt initiation of antimicrobial treatment of infections at the earliest sign of active infection or deterioration (progression to high grade hepatic encephalopathy or elements of the SIRS) (III) ❑ Antibiotic prophylaxis (possibly helpful in patients with coagulopathy, organ failure, encephalopathy and in whom illness progression is considered likely - not proven) (III)

Etiology Specific Management

Etiology	Diagnostic Indicators	Management Recommendations
Acetaminophen toxicity	❑ H/o of acetaminophen intake (toxic dose >10 gm/day or >150 mg/kg) ❑ Acetaminophen in blood and/or urine ❑ Aminotransferase levels >3500 IU/L with low bilirubin levels, in the absence of apparent hypotension or cardiovascular collapse (suspected acetaminophen toxicity in the absence of a positive history because acetaminophen is the leading cause of ALF at least in the United States and Europe)	❑Activated charcoal: 1g/kg PO within 1 hour after drug ingestion (may be beneficial even when administered within 3-4 hours after ingestion) and prior to starting NAC (I) ❑ Nomogram (helps determining the likelihood of serious liver damage but does not exclude possible toxicity) ❑ NAC: 140 mg/kg PO or through NGT (diluted to 5% solution), then 70 mg/kg PO q4h x 17 doses or IV loading dose of 150 mg/kg in 5% dextrose over 15 minutes, then maintenance dose of 50 mg/kg IV over the next 4 hours and then 100 mg/kg IV over the following 16 hours *Promptly begin NAC (beneficial even when administered <48 hours after drug ingestion) in all patients with impending or evolving liver injury due to acetaminophen (II-1) *NAC may be used in cases of ALF due to suspected acetaminophen poisoning (III) *NAC is recommended even in case of non-acetaminophen ALF
Acute fatty liver of pregnancy/HELLP	❑ Jaundice and hypertension ❑ Coagulopathy ❑ Thrombocytopenia ❑ Proteinuria ❑ Hypoglycemia ❑ Steatosis in liver imaging or biopsy	❑ Early diagnosis and prompt delivery (III) ❑ Adequate supportive care ❑ Consider transplantation for postpartum deterioration (III)
Acute ischemic injury	❑ H/o cardiac arrest ❑ Any period of significant hypovolemia/hypotension, or severe CHF (hypotension is not documented always) ❑ Any associated renal dysfunction & muscle necrosis ❑ Elevated aminotransferase levels responding to fluid resuscitation	❑ Adequate cardiovascular support (III)
Autoimmune	❑ Positive serum autoantibodies (may be absent) ❑ Positive liver biopsy (confirms diagnosis when autoimmune hepatitis is suspected and autoantibodies are negative) (III)	❑ Prednisolone (start with 40-60 mg/day, especially in the presence of coagulopathy and mild hepatic encephalopathy) (III) ❑ Consider transplantation and do not delay while awaiting response to steroid treatment (III)
Budd-Chiari	❑ Abdominal pain ❑ Ascites ❑ Hepatomegaly ❑ Blood tests positive for hypercoagulability ❑ Positive findings during liver imaging (CT, doppler USG, venography or magnetic resonance venography) (confirms diagnosis)	❑ Liver transplantation (provided underlying malignancy is excluded) (II-3)
Drug induced	❑ H/o hepatotoxic drug intake (usually idiosyncratic hepatotoxic drug intake within first 6 months after drug initiation; continuous usage of potentially hepatotoxic drug for more than 1 to 2 years is unlikely to cause de novo liver damage) ❑ H/o inclusive of details (including onset of ingestion, amount and timing of last dose) concerning all prescription and non-prescription drugs, herbs and dietary supplements taken over the past year (III) ❑ Determine ingredients of non-prescription medications whenever possible (III)	❑ Discontinue all but essential medications in the setting of possible drug hepatotoxicity (III) ❑ NAC (may be beneficial for ALF induced by drugs) (I)
Malignant infiltration	❑ Massive hepatomegaly ❑ Malignant infiltration in liver imaging or liver biopsy (confirms or excludes diagnosis) (III)	❑ Appropriate management of underlying malignancy ❑ Supportive care
Mushroom poisoning	❑ H/o recent mushroom intake ❑ Severe GI symptoms like nausea, vomiting and diarrhea within hours or a day of ingestion (suspected mushroom poisoning in the absence of a positive history)	❑ Early gastric lavage and activated charcoal administration ❑ Penicillin G 300,000-1 million units/kg/day or Silibinin 30-40 mg/kg/day IV or PO, 3-4 days (silymarin in Europe and south America; milk thistle in north America) ❑ NAC (III) ❑ Liver transplantation (the only lifesaving option) (III) ❑ Fluid resuscitation (as needed)
Viral	❑ Toxically appearing patients with skin lesions (HSV) ❑ Positive hepatitis virus serology ❑ HSV positive liver biopsy	❑ Supportive treatment (no virus specific treatment proven to be effective) (III) ❑ Nucleoside and nucleotide analogues (for HBV associated ALF) (III) ❑ Acyclovir (5-10 mg/kg every 8 hours for at least 7 days for HSV or VZV) (III)
Wilson's disease	❑ KF ring ❑ Serum bilirubin >20 mg/dL, ❑ Bilirubin:alkaline phosphatase >2.0 ❑ Low serum ceruloplasmin ❑ Elevated serum & urine copper ❑ High copper levels in liver biopsy (III)	❑ Liver transplantation (III) ❑ Dialysis or hemofiltration or plasmapheresis or plasma exchange
Intermediate etiology	❑ Etiology undetermined after all evaluation	❑ Review drug and toxin intake H/o ❑ Transjugular biopsy (for further evaluation of possible mailgnancy, Wilson disease, autoimmune hepatitis and viral hepatitis) (III)

Transplantation

Liver Transplantation	Recommendations
Prognostic scoring systems	Currently available and widely applied prognostic scoring systems (King’s College Hospital criteria-KCH Criteria, Clichy Criteria, and Japanese Criteria) do not adequately predict outcome and determine candidacy for liver transplantation, thus not recommending the entire reliance entirely upon these guidelines (III)
Urgent hepatic transplantation	Urgent hepatic transplantation is indicated when prognostic indicators suggest a high likelihood of death (II-3)
In the setting of limited organ supply	In the setting of limited organ supply, either living donor or auxiliary liver transplantation may be considered. But its use remains controversial (II-3)
Liver support systems	Currently available liver support systems are not recommended outside clinical trials and their future in management of ALF remains unclear(II-1)

Do's

ICU Management

• Immediate hospitalization, preferably in an ICU, and frequent monitoring should be done in patients with ALF (III).
• Cerebral edema and intracranial hypertension:
  • Monitor CPP while monitoring ICP with ICP monitors in order to avoid hypoperfusion of the brain.
  • Consider indomethacin and thiopentone as rescue therapies.
• Nutrition:
  • Consider nutrition support with enteral feedings if possible or total parenteral nutrition.
  • Eternal feeding of protein 60 gm/day or 1 to 1.5 gm/kg/day is considered reasonable.

Etiology Specific Management

• Further management is based upon diagnosis of the precise etiology of ALF (III).
• Budd-Chiari:
  • Rule out malignancy, malignancy associated coagulopathy and other thrombotic disorders before transplantation.
• Malignant infiltration:
  • Look for carcinoma of breast, small cell carcinoma of lung, lymphoma and melanoma (the common causes of metastatic liver infiltration).
• Viral:
  • Hepatitis E is considered in anyone with recent travel to an endemic area (Russia, Pakistan, Mexico, or India).
  • Suspect HSV during pregnancy and in immunocompromised patients.
  • Nucleoside analogues (lamivudine) considered for acute hepatitis B.
  • Prophylactic as well as post therapy treatment with nucleotide analogues considered for reactivation of chronic or inactive hepatitis B in the setting of chemotherapy or immunosuppression.
• Wilson disease:
  • Consider copper lowering measures like dialysis or hemofiltration or plasmapheresis or plasma exchange.
• Intermediate etiology:
  • Acetaminophen, autoimmune hepatitis and malignancies are the causes that represent indeterminate ALF.

Transplantation

• Contact with transplant center and initiate plans at the earliest during evaluation to transfer appropriate patients with ALF for tranplantation (III).

Dont's

• Do not administer corticosteroids to control elevated ICP (I).
• Do not administer prophylactic mannitol (II-2).
• Do not administer mannitol if serum osmolality is >320 mOsm/L.
• Do not administer prophylactic phenytoin for seizures (III).
• Do not use sedatives in encephalopathy except during unimmaginable agitations during grade II hepatic encephalopathy.
• Do not infuse large volume of hypotonic fluids, which may result in hyponatremia and cerebral swelling.
• Do not transfuse plasma to correct INR in the absence of bleeding since it might lead to acute liver injury and volume overload.
• Do not rule out acetaminophen induced hepatotoxicity, however low or absent levels of the drug might be, since the time of ingestion may be relatively remote or unknown, especially when overdose may have been unintentional or occurred over several days.
• Do not administer penicillamine in the treatment of ALF caused by Wilson disease because of the risk of hypersensitivity to this agent.

References

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