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]

Definitions

Acute Liver Failure

Evidence 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 is defined as acute liver failure (ALF). 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, acute liver failure 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.

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

Detailed H/o & PE H/o ❑ Altered mental status ❑ Exposure to viral infections ❑ Drug and toxin intake PE ❑ Mental status ❑ Stigmata of chronic liver disease

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, Immunoglobulin levels) ❑ Ceruloplasmin level† ❑ Blood type and screen ❑ Pregnancy test (females) ❑ HIV-1, HIV-2‡

Dx: Acute liver failure (ALF) Dx criteria: 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

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

ICU Management

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

Specific Issues	Management Recommendations
Cerebral edema and intracranial hypertension	a) Intracranial pressure monitoring: 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 Hourly neurological evaluation in the absence of ICP monitors b) Prophylactic hypertonic saline: Prophylactic induction of hypernatremia with hypertonic saline to a sodium level of 145-155 mEq/L in patients with *Serum ammonia >150 μM *Grade III/IV hepatic encephalopathy *Acute renal failure *Vasopressors requirement to maintain MAP c) Intracranial hypertension treatment: *I line therapy: Mannitol bolus (0.5-1.0 gm/kg body weight) *II line therapy: Short-acting barbiturates and induction of hypothermia to a core body temperature of 34°-35°C (if refractory to mannitol) *Hyperventilate patient to PaCO2 of 25-30 mmHg (effects may be short-lived and are useful for impending herniation)
Grade I/II encephalopathy	a) Frequent neurological assessment, avoid stimulation and avoid sedation if possible (consider small doses of short-acting benzodiazepines in case of unmanageable agitation) b) Consider transfer to liver transplant facility and listing for transplantation at the earliest c) Include a stat brain CT to rule out other causes of altered mental status d) Infection surveillance and treatment required e) Antibiotic prophylaxis against infections (possibly helpful) f) Lactulose (possibly helpful and may interfere with surgical field by increasing bowel distention during liver transplantation)
Grade III/IV encephalopathy	Besides managing the patient similar to grade I/II encephalopathy a) Intubate trachea (might require sedation) *During intubation: On-depolarizing neuro-muscular blocking agents After intubation: Propofol b) Administer lidocaine during endotracheal suctioning c) Elevate head of bed to 30° d) Consider ICP monitoring with device e) Mannitol administered when severe elevation of ICP or first clinical sign of herniation noted f) Administer hypertonic saline to raise serum sodium to 145-155 mmol/L g) Hyperventilate patient (effects may be short-lived and are useful for impending herniation) h) Immediate treatment of seizures i) Monitoring and management of hemodynamic and renal parameters as well as glucose, electrolytes and acid/base status
Infection	a) 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) b) Antibiotic prophylaxis possibly helpful (not proven)
Coagulopathy	a) Vitamin K (5-10 mg subcutaneously) administered routinely (at least one dose) b) In the setting of active bleeding or before invasive procedure, consider replacement therapy for thrombocytopenia and/or prolonged prothrombin time with platelet and FFP transfusion respectively c) In case of inadequate correction of severely elevated INR and risks of volume overload, plasmapheresis or recombinant activated factor VII (rFVIIa) may be considered d) Prophylaxis for stress ulceration: *I line: H2 blocker or PPI *II line: Sucralfate
Hemodynamics and renal failure	a) Fluid resuscitation and maintenance of adequate intravascular volume (initiate hypotension treatment with intravenous normal saline) b) Systemic vasopressor support (dopamine, epinephrine, norepinephrine) as needed c) Vasopressin or terlipressin added to norepinephrine in norepinephrine-refractory cases (used cautiously in severely encephalopathic patients with intracranial hypertension) d) Goals of circulatory support: *MAP ≥75 mmHg *CPP 60-80 mmHg e) Continuous modes of hemodialysis (if needed) f) Avoid nephrotoxic agents g) Pulmonary artery catheterization is rarely necessary (it is associated with significant morbidity), instead ensure appropriate volume status with a volume challenge
Metabolic abnormalities	a) Frequently monitor and correct derangements in glucose, potassium, magnesium and phosphate b) Consider nutrition support with enteral feedings if possible or total parenteral nutrition

Etiology Specific Management

Etiology	Diagnostic Indicators	Management Recommendations
Acetaminophen toxicity	a) H/o: Acetaminophen intake (toxic dose >10 gm/day or >150 mg/kg). b) Labs: Acetaminophen in blood and urine. c) Suspected if no H/o but aminotransferase levels >3500 IU/L with low bilirubin levels, in the absence of apparent hypotension or cardiovascular collapse (because acetaminophen is the leading cause of ALF at least in the United States and Europe).	a) Activated charcoal: For patients with known or suspected acetaminophen overdose, administer activated charcoal within 4 hours of presentation and prior to starting NAC (I). b) NAC: *Promptly begin NAC in all patients where the ingested quantity of acetaminophen, serum drug level or rising aminotransferases indicate impending or evolving liver injury (II-1). *NAC may be used in cases of ALF in which acetaminophen ingestion is possible or when knowledge regarding ingestion is inadequate but elevated aminotransferases suggest acetaminophen poisoning (III).
Acute fatty liver of pregnancy/HELLP	a) H/o and PE: Jaundice and hypertension. b) Labs: Coagulopathy, thrombocytopenia, proteinuria ± hypoglycemia. c) Liver imaging or biopsy: Steatosis.	a) Early diagnosis and prompt delivery (III). b) Consider transplantation for postpartum deterioration (III).
Acute ischemic injury	a) H/o and PE: *Cardiac arrest, any period of significant hypovolemia/hypotension, or severe CHF (hypotension is not documented always). *Associated renal dysfunction & muscle necrosis. b) Labs: Elevated aminotransferase levels responding to fluid resuscitation.	Cardiovascular support is the treatment of choice (III).
Autoimmune	a) Labs: Serum autoantibodies (may be absent). b) Liver biopsy (confirms diagnosis when autoimmune hepatitis is suspected and autoantibodies are negative) (III).	a) Administer prednisolone (start with 40-60 mg/day, especially in the presence of coagulopathy and mild hepatic encephalopathy) (III). b) Consider transplantation and do not delay while awaiting response to steroid treatment (III).
Budd-Chiari	a) H/o and PE: Abdominal pain, ascites and hepatomegaly. b) Labs: Tests to identify hypercoagulability c) Liver imaging: CT, doppler USG, venography or magnetic resonance venography (confirms diagnosis).	Hepatic vein thrombosis with ALF is an indication for 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). * Include 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).	a) Discontinue all but essential medications in the setting of possible drug hepatotoxicity (III). b) NAC may be beneficial for acute liver failure induced by drugs (I).
Malignant infiltration	a) PE: Massive hepatomegaly. b) Liver imaging & biopsy: Malignant infiltration (confirms or excludes diagnosis) (III).	a) Treat the underlying malignancy accordingly. b) Supportive treatment.
Mushroom poisoning	a) H/o: Recent mushroom intake. b) Suspected if no H/o but severe GI symptoms like nausea, vomiting and diarrhea within hours or a day of ingestion.	a) Consider administration of penicillin G and N-acetylcysteine in ALF patients with known or suspected mushroom poisoning (III). b) Patients should be listed for transplantation as it is often the only lifesaving option (III).
Viral	a) PE: Toxically appearing patients with skin lesions in HSV. b) Labs: Positive hepatitis virus serology. c) Liver biopsy: HSV.	a) Supportive treatment (no virus specific treatment proven to be effective) (III). b) HBV: Nucleoside and nucleotide analogues should be considered for HBV associated ALF and for prevention of post-transplant recurrence (III). c) HSV or VZV: *Acyclovir (5-10 mg/kg every 8 hours for at least 7 days) for suspected or documented cases and transplantation may be considered (III).
Wilson's disease	a) PE: KF ring. b) Labs: Serum bilirubin >20 mg/dL, bilirubin:alkaline phosphatase >2.0, low serum ceruloplasmin, elevated serum & urine copper c) Liver biopsy: High copper levels (III).	Promptly consider for liver transplantation (III).
Intermediate etiology	Etiology undetermined after all evaluation.	a) Review drug and toxin intake H/o. b) 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 prognostic scoring systems (including the widely applied King’s College Hospital criteria-KCH Criteria) do not adequately predict outcome and determine candidacy for liver transplantation, thus not recommending the entire reliance entirely upon these guidelines.
Urgent hepatic transplantation	Urgent hepatic transplantation is indicated when prognostic indicators suggest a high likelihood of death.
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.
Liver support systems	Currently available liver support systems are not recommended outside clinical trials and their future in management of acute liver failure remains unclear

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 ICP which also allows assessment of cerebral perfusion pressure (CPP), in order to avoid hypoperfusion of the brain.
  • Correct coagulopathy that reduces bleeding risk and wider use of ICP monitors.
  • Goal in management of ICH is lowering ICP (generally to <20 mmHg) while preserving CPP (>60 mmHg) with osmotically-active agents and/or vasopressors.
  • Mannitol can be administered as needed as long as the serum osmolality is <320 mOsm/L.
• Grade III/IV encephalopathy:
  • Treat seizure activity with phenytoin and benzodiazepines with short half-lives.
• Coagulopathy:
  • In the absence of bleeding, platelet counts above 10,000/mm3 have been considered adequate.
  • For performing invasive procedures, platelet counts of 50-70,000/ mm3 have been considered adequate (thromboelastography suggests that a platelet count of 100,000/mm3 may be more appropriate).
• Nutrition:
  • Eternal feeding of protein 60 g/day is considered reasonable.

Etiology Specific Management

• Further management is based upon diagnosis of the precise etiology of ALF (III).
• Acetaminophen toxicity:
  • Administer 1g/kg PO within 1 hour after drug ingestion (may be beneficial even when administered within 3-4 hours after ingestion).
  • Plot nomogram, which helps determining the likelihood of serious liver damage (but it does not exclude possible toxicity).
  • Administer NAC at the earliest (beneficial even when administered within 48 hours after drug ingestion).
  • 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
  • Anticipate nausea and vomiting (with rapid infusion or oral NAC) and rarely urticaria or bronchospasm.
  • NAC administration is recommended even in case of non-acetaminophen acute liver failure (eg. drug-induced liver injury and hepatitis B) since it improves outcome.
• Acute fatty liver of pregnancy/HELLP:
  • Include adequate supportive care along with prompt delivery.
• Autoimmune hepatitis:
  • Consider prednisolone in patients with early stage acute liver failure and without multi-organ failure.
• 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).
• Mushroom poisoning:
  • 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).
  • Fluid resuscitation as needed.
• 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 acute liver failure.

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.
• Do not administer prophylactic mannitol.
• Do not administer mannitol if serum osmolality is >320 mOsm/L.
• Do not administer prophylactic phenytoin for seizures.
• Do not use sedatives in encephalopathy except during unimmaginable agitations during grade II hepatic encephalopathy.
• 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 acute liver failure caused by Wilson disease because of the risk of hypersensitivity to this agent.

References

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