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Approach to the Critical Patient
Immediate priorities
Airway and neurologic threats
Grade 3 to 4 hepatic encephalopathy
Loss of airway protection
Impending cerebral edema
If grade 3 to 4 encephalopathy, intubate for airway protection
Avoid agitation and gag stimulation
Head of bed elevation to 30 degrees
Cerebral herniation signs
Fixed dilated pupils
Brainstem herniation may contraindicate transplant
Metabolic and circulatory threats
Hypoglycemia from loss of gluconeogenesis
Glucose every 1 to 2 hours
Continuous dextrose infusion D10W or D20W
Vasodilatory shock
SBP < 90 mmHg
MAP < 65 mmHg
If fluid-refractory hypotension, norepinephrine first line
Balanced crystalloid resuscitation first
Avoid hypervolemia and hypovolemia
Etiology-directed early actions
Suspected acetaminophen toxicity
N-acetylcysteine without waiting for levels
Activated charcoal if within 4 hours of ingestion
Indeterminate etiology
Empiric NAC for grade 1 to 2 encephalopathy
Broad etiologic workup in parallel
If any ALF confirmed, contact liver transplant center early
AASLD strong recommendation
Within first few hours of presentation
Definition and recognition
Diagnostic triad
Coagulopathy with INR >= 1.5
No prior chronic liver disease
Disease course <= 26 weeks
Hepatic encephalopathy
Any grade qualifies with coagulopathy
West-Haven grading at bedside
Absence of cirrhosis
Distinguish from acute-on-chronic liver failure
No spider angiomata or splenomegaly expected
Tempo classification at triage
Hyperacute 0 to 7 days
Acetaminophen and ischemia
Highest cerebral edema risk best spontaneous survival
Acute 7 to 21 days
Viral hepatitis and drug reactions
Intermediate prognosis
Subacute > 21 days to 26 weeks
Indeterminate Wilson autoimmune
Lowest edema risk worst prognosis without transplant
Monitoring and targets
Monitoring bundle
Continuous glucose monitoring
Target euglycemia
D10W infusion to prevent hypoglycemia
Serial neurologic checks
West-Haven grade trend
Pupillary reactivity trend
Telemetry during IV NAC
QTc monitoring
Arrhythmia from electrolyte shifts
Escalation triggers
Progression to grade 3 to 4 encephalopathy
Intubation
CRRT consideration for hyperammonemia
Arterial ammonia > 200 micromol/l
55% develop intracranial hypertension
Hypertonic saline prophylaxis
Rising lactate or metabolic acidosis
pH < 7.3 as King's College trigger
Lactate > 3.0 mmol/l after resuscitation
Immediate consults
Consultation triggers
Liver transplant center referral
All ALF patients
Before full criteria met if deteriorating
Critical care and toxicology
ICU admission for all ALF
Poison control for ingestion guidance
Neurology and neurosurgery
ICP monitoring decisions
Refractory intracranial hypertension
History
Timeline and presentation
Onset and progression
Jaundice timeline
Hyperacute within 7 days
Subacute over weeks
Constitutional prodrome
Malaise and fatigue
Nausea and vomiting
Abdominal symptoms
Right upper quadrant pain
Dark urine
Encephalopathy history
Confusion or somnolence
Sleep-wake reversal
Personality change
Witnessed agitation or coma
Collateral required
Often unable to self-report
Etiologic history
Medication and ingestion review
Acetaminophen exposure
Combination products included
Sustained-release formulations
Intentional vs unintentional overdose
Time amount and co-ingestants
Suicidal ideation history
Herbal and dietary supplements
CAM products
Prescription monitoring databases
Toxin and infectious exposures
Mushroom ingestion
Amanita phalloides
Foraged wild mushrooms
Viral risk factors
Travel and sexual contacts
IV drug use tattoos transfusions
Industrial and recreational toxins
Solvent exposure
Recreational drugs
Host and contextual history
Pregnancy status
Acute fatty liver of pregnancy
HELLP syndrome
Alcohol use
Quantity and duration
Chronic use worsens outcomes
Important negatives
No prior liver disease
No known cirrhosis or decompensation
Risk factors
Drug-related risk
Acetaminophen accounts for ~50% of US ALF
Chronic supratherapeutic use
Fasting and alcohol potentiation
CYP2E1 inducers
Chronic alcohol
Certain anticonvulsants
Polypharmacy and supplements
Idiosyncratic DILI
Multiple hepatotoxins
Host susceptibility
Malnutrition and fasting
Depleted glutathione stores
Increased acetaminophen toxicity
Pregnancy third trimester
AFLP and HELLP
Rapid maternal decompensation
Ischemic or hypoxic injury
Cardiac failure
Sepsis and heat stroke
Collateral and family history
Collateral sources
Next of kin and pharmacy records
Empty pill bottles
Suicide notes
Prescription monitoring databases
Controlled substance access
Recent behavioral changes
Inherited and social context
Heritable liver disease
Wilson disease autosomal recessive
Alpha-1 antitrypsin deficiency
Psychiatric and substance history
Prior suicide attempts
Relevant to transplant candidacy
Physical Exam
Vitals and general
Hemodynamic snapshot
Blood pressure
Vasodilatory hypotension
MAP < 65 mmHg
Heart rate and respiratory rate
Sinus tachycardia hyperdynamic state
Tachypnea from respiratory alkalosis
Temperature
Fever absent in up to 30% of infected patients
Hypothermia as severe marker
General appearance
Jaundice and icterus
May be minimal in hyperacute
Scleral icterus
Excoriations
Pruritus from cholestasis
Skin findings
Neurologic exam
Encephalopathy grading
West-Haven grade 1 to 2
Asterixis present in grade 2
Mild confusion or somnolence
West-Haven grade 3 to 4
Marked confusion to coma
Airway protection threatened
Herniation screen
Pupillary reflexes
Fixed dilated pupils suggest herniation
Asymmetry as focal sign
Brainstem signs
Abnormal posturing
Loss of brainstem reflexes
Abdominal and etiologic exam
Abdominal findings
Liver size
Small shrunken liver suggests massive necrosis
Hepatomegaly suggests infiltration or Budd-Chiari
Right upper quadrant tenderness
Ascites
Splenomegaly suggests chronic disease
Chronic liver disease screen
Stigmata that should be absent in true ALF
Spider angiomata and palmar erythema
Caput medusae and gynecomastia
Dupuytren contractures
Suggest chronicity
Reconsider acute-on-chronic
Etiology-specific signs
Kayser-Fleischer rings
Slit-lamp if Wilson suspected
Young patient with hemolysis
Bleeding stigmata
Petechiae and mucosal bleeding
Easy bruising
PITFALLS
Misclassification
Acute-on-chronic liver failure mistaken for ALF
Look for stigmata of chronic disease
Splenomegaly and varices
Regenerating necrotic liver mimicking cirrhosis
Nodular appearance on imaging
Do not overcall chronicity
Missed severity
Infection without fever
Fever absent in up to 30% infected
Low threshold for cultures
Subtle early encephalopathy
Sleep-wake reversal overlooked
Serial mental status checks
Differential Diagnosis
Life threats and key categories
Must-distinguish entities
Acute-on-chronic liver failure
ICD-10 K72.10
Signs of chronic liver disease present
Sepsis with hepatic dysfunction
ICD-10 A41.9
Coagulopathy and encephalopathy mimic
Ischemic hepatitis shock liver
AST and ALT often > 5000
Rapid rise and fall after hypotension
Vascular and infiltrative
Budd-Chiari syndrome
ICD-10 I82.0
Ascites hepatomegaly abdominal pain
Malignant infiltration
Lymphoma or metastatic disease
Can present as ALF
Heat stroke
Massive rhabdomyolysis
Hepatic necrosis
Etiology-specific clues
Metabolic and autoimmune
Wilson disease
Coombs-negative hemolytic anemia
Bilirubin to ALP ratio > 2.0
Autoimmune hepatitis
Elevated ANA ASMA IgG
Largest indeterminate category
Pattern-based differentiation
Very high transaminases low bilirubin
Acetaminophen toxicity
Ischemic hepatitis
Very high bilirubin very low ALP
Wilson disease
Rapid bedside clue
Pregnancy-related
Acute fatty liver of pregnancy
HELLP syndrome
Laboratory Tests
Hepatic and coagulation
Hepatic panel
AST ALT ALP GGT
Pattern guides etiology
Magnitude and trend
Total and direct bilirubin
Hyperbilirubinemia severity
Trend over time
Albumin
Synthetic function marker
May be normal in hyperacute
Coagulation studies
PT and INR
INR >= 1.5 defines coagulopathy
Does not predict bleeding risk
aPTT and fibrinogen
Rebalanced hemostasis
Fibrinogen consumption
Factor V level
Clichy criteria input
Prognostic marker
Metabolic and perfusion
Metabolic panel
Glucose
Hypoglycemia from loss of gluconeogenesis
Monitor every 1 to 2 hours
Creatinine and electrolytes
AKI in ~50% of ALF
Creatinine > 3.4 mg equivalent as King's input
Phosphate magnesium calcium
Hypophosphatemia favorable regeneration sign
Correct electrolytes aggressively
Perfusion and gas exchange
Arterial lactate
> 3.0 mmol/l as prognostic marker
Marker of hypoperfusion
Arterial blood gas
pH < 7.3 as King's College criterion
Early respiratory alkalosis
Arterial ammonia
> 75 micromol/l risk of encephalopathy
> 200 micromol/l high risk intracranial hypertension
Etiologic workup
Toxicology
Acetaminophen level
Plot on nomogram when timed
Protein adducts identify occult toxicity
Urine drug screen and ethanol
Co-ingestants
Alcohol contribution
Viral and autoimmune serologies
Hepatitis serologies
Anti-HAV IgM HBsAg anti-HBc IgM
Anti-HCV anti-HEV IgM
Herpesvirus PCR
HSV CMV EBV PCR
HSV hepatitis treatable
Autoimmune markers
ANA ASMA anti-LKM
IgG levels
Wilson and miscellaneous
Wilson workup
Ceruloplasmin and serum copper
24-hour urine copper
Additional studies
Lipase and pregnancy test
HIV blood cultures ferritin
Key lab pearls
Interpretive clues
Very high AST and ALT with low bilirubin
Acetaminophen or ischemic hepatitis
Rapid rise and fall in ischemia
Very high bilirubin with very low ALP
Wilson disease
Bilirubin to ALP ratio > 2.0
Hypophosphatemia
Marker of hepatic regeneration
Associated with recovery
Diagnostic Tests
Scoring Systems
King's College Criteria
Acetaminophen ALF
pH < 7.3 after resuscitation
Or INR > 6.5 and creatinine > 3.4 mg equivalent and grade 3 to 4 HE
Non-acetaminophen ALF
INR > 6.5 alone
Or any 3 of age < 10 or > 40 unfavorable etiology jaundice > 7 days INR > 3.5 bilirubin elevated
Performance
Specificity 93% for acetaminophen
Sensitivity ~58% limited
MELD and adjuncts
MELD score
More sensitive than KCC 77% vs 61%
MELD >= 30.5 predicts transplant need
Viscoelastic testing
TEG or ROTEM for true bleeding risk
SCCM recommends over INR
Arterial ammonia as predictor
Independent predictor of intracranial hypertension
Threshold > 200 micromol/l
MRI
MRI role
Limited acute utility
Availability constraints
Unstable patient limitation
Problem-solving indications
MR venography for Budd-Chiari when Doppler equivocal
Characterize infiltrative disease
Neuroimaging adjunct
MRI brain not first line for edema
CT preferred acutely
CT
CT abdomen
Indications
Ultrasound inconclusive
Assess liver volume
Prognostic findings
Liver volume < 1000 cm3 poor prognosis
Regenerative failure
Contrast considerations
Renal function in AKI
Balance against contrast nephropathy
CT head non-contrast
Indications
Grade 3 to 4 encephalopathy
Altered mental status of unclear cause
Findings
Cerebral edema
Intracranial hemorrhage
Interpretation pearl
May be normal despite raised ICP
Clinical signs supersede imaging
Ultrasound
Abdominal ultrasound with Doppler
First-line imaging
Liver size and echotexture
Ascites and biliary dilation
Vascular assessment
Hepatic vein patency to exclude Budd-Chiari
Portal vein flow direction
Chronic disease screen
Nodular contour
Splenomegaly
Bedside POCUS adjuncts
Volume and cardiac assessment
IVC for fluid responsiveness limits
Gross LV function
Imaging pearl
Regenerating necrotic liver mimics cirrhosis
Do not overcall chronicity
Disposition
Level of care
ICU admission
All ALF patients require ICU
Grade 2 HE transfer to ICU
Grade 3 to 4 HE intubation
Monitoring needs
Hourly neurologic checks
Continuous glucose monitoring
Transplant center transfer
Early referral
Within first few hours
Before full criteria if deteriorating
Transfer logistics
Risk of deterioration in transit
Secure airway before transfer if borderline
Transplant listing and prognosis
UNOS Status 1a criteria
ICU-level care plus one of
Ventilator dependence
Renal replacement therapy
Coagulopathy criterion
INR >= 2 with HE onset within 8 weeks
Of initial symptoms
Prognosis counseling
Outcome thirds
One-third recover spontaneously
One-third transplant one-third die
Post-transplant survival
1-year survival 84% US
79% Europe
Etiology predicts spontaneous recovery
Acetaminophen hepatitis A pregnancy ischemic best
Indeterminate and Wilson worst
Treatment
Initial stabilization
Airway and breathing
Intubate for grade 3 to 4 HE
Airway protection
Head of bed elevation 30 degrees
Minimize stimulation
Cluster care
Avoid coughing and straining
Circulation and metabolic
Volume resuscitation
Balanced crystalloids
Avoid hypervolemia and hypovolemia
Dextrose infusion
D10W to prevent hypoglycemia
Glucose every 1 to 2 hours
If fluid-refractory hypotension, norepinephrine
First-line vasopressor
Class I supportive
N-acetylcysteine
Acetaminophen ALF IV NAC
Loading dose
150 mg/kg IV over 15 to 60 minutes
Telemetry during infusion
Second phase
50 mg/kg over 4 hours
Equals 12.5 mg/kg/h
Third phase
100 mg/kg over 16 hours
Equals 6.25 mg/kg/h
Continuation
6.25 mg/kg/h until ALT decreasing and INR < 2
Do not stop arbitrarily at 21 hours
Non-acetaminophen ALF NAC
Indication
Grade 1 to 2 encephalopathy
Improves transplant-free survival 52% vs 30%
Guideline support
ACG recommended
EASL recommended
Adjunct decontamination
Activated charcoal
1 g/kg max 50 g
If within 4 hours of acetaminophen ingestion
Etiology-specific therapy
Toxin-mediated
Mushroom Amanita poisoning
Silibinin if available
NAC and consider charcoal
Wilson disease
CRRT and consider plasma exchange
Emergent transplant evaluation
Immune and viral
Autoimmune hepatitis
Methylprednisolone 1 mg/kg
Low threshold for transjugular biopsy
HSV hepatitis
IV acyclovir
Empiric if HSV suspected
Hepatitis B reactivation
Entecavir or tenofovir
Nucleos(t)ide analogue
Cerebral edema management
Hyperammonemia and edema prophylaxis
Hypertonic saline 3%
Target Na 145 to 155 mEq/l
Prophylactic in grade 3 to 4 HE
CRRT
First-line for hyperammonemia
Used even without AKI
High-volume plasma exchange
Improved transplant-free survival in one RCT
Consider in selected patients
Acute ICP crisis
Mannitol
0.5 to 1 g/kg for acute ICP surges
Higher rebound ICP and AKI risk vs hypertonic saline
Temperature control
Avoid hyperthermia
Target normothermia
Medications to avoid
Vasopressin and terlipressin may raise ICP
Use with caution
Coagulopathy and infection
Coagulopathy management
Do not prophylactically correct INR
Hemostasis is rebalanced
Overt bleeding uncommon ~5% of deaths
Correct only for procedures or bleeding
FFP cryoprecipitate platelets
rFVIIa as needed
Viscoelastic-guided transfusion
TEG or ROTEM
Avoid volume overload from FFP
Infection management
Surveillance cultures
Blood urine sputum
Regular intervals
Empiric antimicrobials
For SIRS clinical deterioration or worsening HE
Antifungal coverage if deteriorating
Prophylaxis caveat
Routine prophylaxis not supported in well-resourced settings
Reserve for clinical triggers
Supportive and avoid-list
Supportive medications
PPI for stress ulcer prophylaxis
GI bleeding risk
Standard ICU dosing
Phosphate replacement
Correct hypophosphatemia
Supports regeneration
Medications to avoid or limit
Lactulose
May use for grade 1 to 2 HE
Discontinue grade 3 to 4 to avoid bowel distension
Lactulose and rifaximin caveat
No proven ALF benefit
Unlike chronic liver disease
Hepatotoxins and dosing
Avoid additional hepatotoxic drugs
Adjust for hepatic and renal impairment
Special Populations
Pregnancy
Pregnancy-specific etiologies
Acute fatty liver of pregnancy
Third trimester
Hypoglycemia and coagulopathy
HELLP syndrome
Hemolysis elevated LFTs low platelets
Overlaps with ALF
Definitive management
Expedited delivery
Maternal-fetal medicine and transplant center
Maternal supportive care
Best spontaneous survival category
Pregnancy-related etiology favorable
NAC safe in pregnancy
Monitoring
Fetal monitoring when viable
Maternal glucose and coagulation
Geriatric
Older adult features
Age as prognostic factor
Age > 40 worsens non-acetaminophen King's criteria
Reduced regenerative reserve
Comorbidity burden
Cardiac disease and ischemic hepatitis
Polypharmacy and DILI risk
Transplant candidacy
Age and comorbidity affect eligibility
Frailty assessment
Atypical presentation
Encephalopathy as delirium
May be attributed to dementia
Serial mental status checks
Medication dosing
Renal and hepatic adjustment
Drug accumulation risk
Pediatrics
Pediatric differences
Etiology spectrum
Metabolic and infectious causes common
Indeterminate large category
Promoting native liver survival
Aggressive medical management
CRRT for hyperammonemia
Encephalopathy grading
Age-adjusted assessment
Difficult in young children
Weight-based therapy
NAC dosing
Weight-based same protocol structure
150 mg/kg load
Dextrose support
Higher glucose infusion requirements
Frequent glucose monitoring
Transplant referral
Pediatric transplant center
Early contact
Background
Epidemiology
Incidence and burden
Rare condition
1 to 6 cases per million per year
Life-threatening emergency
Etiology distribution
Acetaminophen ~50% of US ALF
Viral autoimmune Wilson indeterminate remainder
Outcomes
One-third recover one-third transplant one-third die
AKI in ~50%
Complications frequency
Myocardial injury
Troponin elevation in 74%
OR 4.69 for death
Intracranial hypertension
55% with ammonia > 200 micromol/l
Leading cause of death
Pathophysiology
Mechanisms of injury
Massive hepatocyte necrosis
Loss of synthetic function
Coagulopathy and hypoglycemia
SIRS and multiorgan dysfunction
Hallmark of ALF
Drives cerebral edema
Hyperammonemia
Astrocyte swelling
Cerebral edema and herniation
Systemic consequences
Vasodilatory shock
Hyperdynamic circulation
Distributive physiology
Rebalanced hemostasis
Loss of pro and anticoagulant factors
INR does not reflect bleeding risk
Renal and cardiac involvement
AKI in ~50%
Subclinical myocardial injury
Therapeutic Considerations
Etiology-directed principles
NAC as cornerstone
Universal in acetaminophen ALF
Benefit in early non-acetaminophen ALF
Time-critical recognition
Rapid deterioration
Early transplant referral
Transplant as definitive therapy
When spontaneous recovery unlikely
King's and MELD guide listing
Avoiding harm
Minimize prophylactic FFP
Avoid volume overload
Obscures INR trend
Judicious antimicrobials
Trigger-based not routine
Surveillance cultures
CRRT and plasma exchange
Ammonia clearance
Bridge to transplant or recovery
Patient Discharge Instructions
copy discharge instructions
Recovery home care
Take only medicines approved by your liver team
Avoid acetaminophen and over-the-counter painkillers
Avoid alcohol completely
Keep all follow-up appointments
Hepatology within 1 to 2 weeks
Blood tests as scheduled
Mental health and substance support
Attend psychiatric follow-up if overdose
Substance use counseling if applicable
Warning signs to return to ER
Worsening yellow skin or eyes
New or deepening jaundice
Dark urine
Confusion or extreme sleepiness
Trouble waking
New disorientation
Bleeding or persistent vomiting
Vomiting blood or black stools
Cannot keep fluids down
Abdominal swelling or fever
New belly swelling
Fever or chills
Follow-up plan
Serial liver and clotting blood tests
Confirm normalization
Repeat coagulation studies
Long-term considerations
Lifelong immunosuppression if transplanted
Monitoring for rejection and cancer screening
References
Guidelines and key sources
Guideline sources
ACG Acute Liver Failure Guidelines 2023
Shingina et al American Journal of Gastroenterology
NAC and etiology-specific management
AASLD position paper on acute liver failure
Lee Stravitz Larson
Transplant referral recommendations
SCCM ICU management guidelines 2023
Nanchal et al Critical Care Medicine
Neurology and infectious disease considerations
Landmark reviews and evidence
Emergency physician review
Montrief Koyfman Long AJEM 2019
ED-focused approach
Lancet and NEJM reviews
Maiwall et al Lancet 2024
Bernal Wendon NEJM 2013
Troponin and myocardial injury data
Parekh et al Hepatology 2007
Subclinical injury and mortality
Coding standards
ICD-10 K72.00 acute hepatic failure without coma
K72.01 with coma
SNOMED CT acute liver failure disorder
SymptomDx is an educational tool for medical professionals. It does not replace clinical judgment. Verify all clinical data and drug dosages with authoritative sources.