Acute liver failure resident survival guide

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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: ALF, acute hepatic failure, fulminant hepatic failure, fulminant liver failure

Overview

Acute liver failure (ALF) is 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.[1][2] 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. While acetaminophen toxicity and idiosyncratic hypersensitivity reactions are the most common causes, idiosyncratic hypersensitivity reactions seem to be the most common life-threatening cause of acute liver failure. With the presentation of systemic complications and mortality close to 80%, a multidisciplinary management approach of acute liver failure in an intensive care unit that is directed towards the treatment of its etiology and complications along with a liver transplantation is mandatory.

Grades of Hepatic Encephalopathy

Based on their clinical manifestation, different grades of hepatic encephalopathy are defined as follows.[3]

Grade I

Grade I encephalopathy manifests with changes in behavior and minimal changes in level of consciousness.

Grade II

Grade II encephalopathy manifests with inappropriate behavior, gross disorientation, drowsiness, and possibly asterixis.

Grade III

Grade III encephalopathy manifests with marked confusion, incoherent speech, and mostly sleeping but arousable to vocal stimuli.

Grade IV

Grade III encephalopathy manifests with comatose, unresponsive to pain, and 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.

Common Causes

Management

Diagnostic Approach

Shown below is an algorithm depicting the diagnostic approach of acute liver failure based on the 2011 American Association for the Study of Liver Diseases (AASLD) position paper on acute liver failure.[11]


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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:

❑ 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
❑ Mental status examination
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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
Aspartate transaminase (AST)
Alanine transaminase (ALT)
Alkaline phosphatase
Gamma-glutamyl transpeptidase (GGT)
Total bilirubin
Albumin


Complete blood count (CBC)
Ammonia
Arterial blood gas (ABG)
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
HSV IgM
VZV Ig G

❑ Autoimmune markers:

Antinuclear antibodies (ANA)
Anti-SM antibody (ASMA)
Immunoglobulin levels
Ceruloplasmin level
❑ Blood type and screen
❑ Pregnancy test (females)
Human Immunodeficiency Virus (HIV-1, HIV-2)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diagnostic criteria:
INR ≥1.5
Altered mental status
❑ Absence of pre exisiting cirrhosis
❑ Any illness of <26 weeks duration
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mandatory intensive care unit (ICU) admission
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Intensive care unit 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)[12]
Implications for potential liver transplantation

Therapeutic Approach

Shown below are lists of recommendations of therapeutic approachs of acute liver failure based on the 2011 American Association for the Study of Liver Diseases (AASLD) position paper on acute liver failure.[11]

Intensive Care Unit 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)[13] 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)[13]
❑ 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[13]
❑ Goals of intracranial hypertension treatment[14]
ICP <20 mmHg
CPP >60 mmHg
❑ Hyperventilate to PaCO2 of 25-30 mmHg (in case of impending herniation)[15]
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[16][17]
During intubation: Depolarizing neuro-muscular blocking agents
After intubation: Propofol
❑ Elevate head of bed to 30°[18]
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)
Vitamin K (5-10 mg subcutaneously) (at least one dose)[19]
❑ 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[20]
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)[8]
Activated charcoal:
1g/kg PO within 1 hour after drug ingestion (may be beneficial even when administered within 3-4 hours after ingestion)[21] 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[22]
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)[23]
❑ 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,[24] Clichy Criteria,[25] and Japanese Criteria[26]) 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

Intensive Care Unit 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.[27]

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:
  • 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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  11. 11.0 11.1 Lee, WM.; Stravitz, RT.; Larson, AM. (2012). "Introduction to the revised American Association for the Study of Liver Diseases Position Paper on acute liver failure 2011.". Hepatology. 55 (3): 965–7. PMID 22213561. doi:10.1002/hep.25551.  Unknown parameter |month= ignored (help)
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  13. 13.0 13.1 13.2 Wendon, J.; Lee, W. (2008). "Encephalopathy and cerebral edema in the setting of acute liver failure: pathogenesis and management.". Neurocrit Care. 9 (1): 97–102. PMID 18688582. doi:10.1007/s12028-008-9123-6. 
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  26. Mochida, S.; Nakayama, N.; Matsui, A.; Nagoshi, S.; Fujiwara, K. (2008). "Re-evaluation of the Guideline published by the Acute Liver Failure Study Group of Japan in 1996 to determine the indications of liver transplantation in patients with fulminant hepatitis.". Hepatol Res. 38 (10): 970–9. PMID 18462374. doi:10.1111/j.1872-034X.2008.00368.x.  Unknown parameter |month= ignored (help)
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  29. Lowenthal, A.; Tur-Kaspa, R.; Brower, RG.; Almog, Y. (2003). "Acute liver failure complicating ductal breast carcinoma: two cases and literature review.". Scand J Gastroenterol. 38 (10): 1095–6. PMID 14621287.  Unknown parameter |month= ignored (help)
  30. Krauss, EA.; Ludwig, PW.; Sumner, HW. (1979). "Metastatic carcinoma presenting as fulminant hepatic failure.". Am J Gastroenterol. 72 (6): 651–4. PMID 231905.  Unknown parameter |month= ignored (help)
  31. Montero, JL.; Muntané, J.; de las Heras, S.; Ortega, R.; Fraga, E.; De la Mata, M. (2002). "Acute liver failure caused by diffuse hepatic melanoma infiltration.". J Hepatol. 37 (4): 540–1. PMID 12217611.  Unknown parameter |month= ignored (help)
  32. Rahhal, FE.; Schade, RR.; Nayak, A.; Coleman, TA. (2009). "Hepatic failure caused by plasma cell infiltration in multiple myeloma.". World J Gastroenterol. 15 (16): 2038–40. PMID 19399940.  Unknown parameter |month= ignored (help)

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