Acute Liver Failure

Rapidly progressive, life-threatening development of coagulopathy (INR >1.5), encephalopathy, and jaundice in a patient with a previously normal liver secondary to massive liver parenchymal injury.

Acute Liver Failure is distinct from:

  • Acute Liver Injury
    Coagulopathy and jaundice in absence of encephalopathy.
  • Acute on Chronic Liver Failure
    Acute decline in liver function in patients with chronic liver disease.

ALF is subclassified by time interval between jaundice and encephalopathy into:

Hepatic encephalopathy may complicate either acute liver failure or chronic liver disease, and is covered under Hepatic Encephalopathy.

Epidemiology and Risk Factors

Rare:

  • 400 cases annually in the UK

Pathophysiology

Pathological processes:

  • Direct hepatocyte damage
  • Immune response
    • Local
    • Systemic
      • MODS
  • Cerebral dysfunction
    • Oedema
    • Altered autoregulation

Aetiology

  • Vascular
    • Ischaemia
    • Budd-Chiari Syndrome
      Hepatic vein thrombosis, usually with an underlying procoagulant condition.
  • Infection
    • Hepatitis A
      Infection rarely leads to liver failure (<1%) and contributes to ~10% of infective cases.
    • Hepatitis B
      25-75% of viral cases. Reactivation may occur in immunosuppressed patients.
    • Hepatitis C
      Common cause of CLD but rarely causes acute failure.
    • Other viruses may cause rarely infection in the immunocompromised:
      • EBV
      • Measles
      • HSV 1/2
    • Dengue
    • Yellow fever
    • Lassa
  • Autoimmune
  • Drugs/toxins
    • Paracetamol
      50-70% of cases in the developed world. Occurs due to:
      • Depletion of hepatic glutathione
        Consumed in conjugating NAPQI, a Phase I metabolite of paracetamol.
      • NAPQI accumulation causes direct hepatocyte injury
    • Aspirin
      Reye’s syndrome.
    • Herbal
    • Halothane
    • Antituberculosis drugs
    • Alcohol
    • Ecstasy
    • Amanita phalloides
      Mushroom poisoning. Usually presents with diarrhoea, followed by hepatic necrosis at 48-72 hours.
  • Pregnancy-related
    • Acute fatty liver of pregnancy
    • Severe pre-eclampsia
    • Liver rupture
  • Hyperthermia
  • Other
    • Wilson disease
    • Haemophagocytic syndrome

Causes vary substantially with geography.

Clinical Features

History

  • Overdose
  • CNS
    • Encephalopathy
      • Confusion
      • Agitation
  • GI
    • Nausea/Vomiting
    • Diarrhoea

Examination

  • Asterixis
  • Intracranial hypertension
    • Hyperreflexia
    • Clonus
    • Hypertonicity
    • Cushing’s triad
  • Jaundice

Diagnostic Approach and DDx

Investigations

Laboratory:

  • Blood
    • Liver function testing
      Severity and pattern of injury:
      • Hepatocellular
      • Cholestatic
    • Point of care coagulation studies
      May be more accurate than standard assays.
    • Coagulation studies
      • Synthetic function
    • Lactate
      Failure of hepatic clearance.
    • Ammonia
      Neurotoxin responsible for much of hepatic encephalopathy.
      • >100μmol/L predicts the onset of encephalopathy
      • >150-200μmol/L predicts risk of herniation
      • ↑ Ammonia may reflect:
        • Hepatic metabolic dysfunction
          Degree of hepatic dysfunction typically correlates with ammonia level, though not with the degree of encephalopathy.
        • ↑↑ Protein intake
        • ↑ GI ammonia production
          Produced by gut bacteria.
        • ↓ Clearance
          Urea cycle disorder.
    • UEC
      • AKI
      • Electrolyte derangements
    • FBE
      • Anaemia
      • Thrombocytopaenia
      • Concurrent infection
    • Lipase/amylase
      • Associated pancreatitis
    • Paracetamol level
    • LDH
      Malignancy.
    • Viral screen
      Aetiology. Include:
      • Hepatitis A
      • Hepatitis B
        Core antigen indicates infection. Surface antigen often negative.
      • Hepatitis C
        Positive antibodies indicate infection.
      • Hepatitis E
        Positive antibodies indicate infection. Usually faecal-oral, though a subtype is transmissable by blood.
      • EBV
      • HSV
      • VZV
      • HIV 1/2
    • Autoimmune screen
      • ANA
        Autoimmune.
      • Anti-smooth muscle Ab
        Autoimmune.
      • Anti-mitochondrial Ab
        Primary sclerosing cholangitis.
      • Copper studies
        Wilson’s disease.
    • Blood cultures
    • Pregnancy test
  • Urine
    • Drug screen
      • Paracetamol

Imaging:

  • TTE
    • RV function
    • Transplant assessment
  • Liver ultrasound
    • Splenomegaly
    • Ascites
    • Nodularity
    • Hepatomegaly
    • Portal blood flow
    • Portal patency
  • CT
    Triple-phase liver.

Other:

  • Liver biopsy
    • Rare in acute setting due to coagulopathy
      Transjugular route safest.
    • Non-specific necrosis most common finding
    • May be useful in diagnosis of:
      • Autoimmune
      • Wilson’s disease

Management

  • Prevent cerebral oedema and treat concurrent Hepatic Encephalopathy
  • Manage vasodilatory shock
  • Treat concurrent sepsis
    Gram negative and fungal.
  • Manage coagulopathy
  • Early identification of patients for transplant
    • Significant improvement in outcomes with emergency liver transplantation
    • Early escalation to critical care and early referral to a specialist centre is essential

Resuscitation:

Specific therapy:

  • Paracetamol overdose
    • N-acetylcysteine (NAC)
      • Cornerstone of therapy as early administration results in significant reduction in mortality (to <1%), though even late administration may improve outcome
      • Dosing based on Prescott nomogram
  • Viral hepatitis
    • Antivirals
    • Hepatitis B
      • Lamivudine
        Benefit if given early.
  • Alcoholic hepatitis
  • Autoimmune hepatitis
    • Steroids
  • Mushroom poisoning
    • Forced diuresis
      ↑ Renal clearance of toxin. Avoid hypovolaemia.
  • Wilson’s disease
    • D-Penicillamine
      Chelates copper. Withdrawal of chronic treatment may precipitate failure.
  • Hepatic vein thrombosis
    • Thrombolysis
    • Clot retrieval
    • TIPS

Management of paracetamol overdose is covered under Paracetamol.

Supportive care:

Invasive intracranial pressure monitoring associated with ~10% intracranial haemorrhage rate.

  • A
    Consider securing airway if:
    • High grade (III/IV) hepatic encephalopathy
    • Need for transfer
  • B
    • Lung protective ventilation
      ARDS risk.
    • Drain pleural effusions
  • C
    • Volume resuscitation
      Can be aggressive in absence of pulmonary hypertension.
    • MAP 65-70mmHg
      Or higher if targeting CPP with concurrent hepatic encephalopathy.
      • Noradrenaline 1st line
      • Vasopressin 2nd line
    • Corticosteroids for vasopressor-refractory shock
      • Hydrocortisone 50mg IV Q6H
  • E
    • ↓ BSL
      Use high-concentration dextrose to avoid cerebral oedema/↓ Na+.
  • F
    • RRT
      • Use bicarbonate buffered solutions
        Avoid citrate!
      • CRRT strongly preferred for haemodynamic stability
      • Haemodiafiltration preferred
        Dialysis is probably more effective than filtration, but both mechanisms are effective.
      • In addition to standard indications, initiate for:
        • Hyperammonaemia (>100μmol/L)
          • Aim <60μmol/L once commenced
          • High doses (45-90mL/kg/hr) are often used to ↑ ammonia clearance
            ↑ Rate by 50% until target ammonia reached.
        • Hyperthermia
    • Avoid positive fluid balance
  • G
    • Early low-protein enteral feeding
      • May have ↑ metabolic requirements
      • Feeding may need to be interrupted if ammonia ↑
    • Hyperammonaemia
      • Lactulose
        Controversial. May ↓ hepatic encephalopathy but lead to gaseous intestinal distension.
    • PPI
    • Drain ascites
      For haemodynamic benefit.
    • Extra-corporeal hepatic support
      Broadly, ↓ encephalopathy and ↑ haemodynamic function without mortality benefit.
      • Should be regarded as experimental
      • Can be considered for severe refractory vasodilatory shock
      • Include:
        • Coupled Plasma Filtration Adsorption (CPDFA)
        • Molecular Adsorbant Recirculation System (MARS)
        • Single Pass Albumin Dialysis (SPAD)
      • Underlying mechanism is either:
        • Biological
          Using human/porcine cells.
        • Mechanical
          Molecular filtration.
  • H
    • Coagulopathy
      • Patients may be prothrombotic, anti-thrombotic, or fibrinolytic
      • Assays themselves (both coagulation profiles and point-of-care testing) may not correlate with the observed clinical effect
      • Treat if bleeding or:
        • Prior to procedures
        • INR >5
          May require continuous FFP infusion in unstable patients.
        • Fibrinogen <0.8
        • Platelets <20×109/L
      • Therapeutic options:
        • Vitamin K 10mg IV daily
          Very reasonable, probably ineffective in the majority of patients.
        • PCC
          Useful for factor replacement without volume load.
        • Fibrinogen
          Target >1.5g/L. Dysfibrinogenaemia is likely in chronic disease.
    • Individualisation of thromboprophylaxis

Disposition:

  • Liver transplant centre
    Referral if:
    • Hepatic encephalopathy
    • Ammonia >100μmol/L

Marginal and Ineffective Therapies

Anaesthetic Considerations

Complications

  • Death
    • Intracranial hypertension
      Most common mechanism in untreated disease.
    • Sepsis/multiorgan failure
  • A
    • Unprotected airway
  • B
    • ARDS
      Relatively intolerant of permissive hypercapnoea due to ↑ ICP concerns.
    • Pleural effusions
  • C
    • Distributive shock
  • D
    • Intracranial hypertension
      Usually develops rapidly with little time for adaptation.
    • Hepatic encephalopathy
  • F
    • AKI (hepatorenal syndrome)
      40-80% of cases.
      • ↑ In paracetamol toxicity (directly nephrotoxic)
  • G
    • ↓ BSL
    • Pancreatitis
    • Ascites
  • H
    • Coagulopathy
      Clinical manifestations often not in consistent with assays.
    • Bone marrow suppression
      • Thrombocytopaenia
  • I
    • Infection
      ↑ Susceptibility due to functional immunosuppression.

Prognosis

Spontaneous recovery occurs in only 40%. Factors:

  • Age
    ↑ Mortality with ↑ age.
  • Aetiology
    ↓ Mortality with pregnancy-related causes.
  • Acuity
    ↑ Mortality with ↑ acuity.

Transplantation:

  • 80% 5-year survival following liver transplant for ALF

Scoring

Eligibility for transplantation is determined using one of the prognostic scores, such as MELD or the King’s College criteria.

King’s College Criteria for Liver Transplantation
Paracetamol Toxicity Other Cause
  • pH <7.25 and
  • Lactate >3mmol/L
  • PT >100s

Or:

  • PT >100s and
  • Cr >300μmol/L and
  • Grade 3/4 encephalopathy

Or 3 of:

  • Age <10 or >40
  • Hyperacute
  • Seronegative/drug induced
  • Bilirubin >300μmol/L
  • PT >50s

The King’s criteria are the most widely used scoring system to predict liver transplant. However, there are several important caveats to use of the tool:

Estimated Survival of 20-year Old Patients Meeting Transplant Criteria

  • Development and validation occurred at a single centre in the 1970s and 1980s
    • Medical management of hepatic failure in generation and paracetamol toxicity in particular has improved significantly in the interim
    • Patients at King’s who received transplantation typically had a better prognosis than those who didn’t
      • Patients meeting criteria who were not listed had a 9% survival
      • Patients meeting criteria who were listed but did not receive a transplant had 17% survival
  • Moderate specificity
    ~90% specific for need of transplantation; ~15% of patients meeting criteria will survive without transplantation.
  • Low sensitivity
    ~60%; such that 40% of patients who do not meet criteria may still die from liver failure.
  • Patients who survive the acute liver injury and who do not receive a transplant are spared the cumulative mortality risk and quality of life impairments that come with having a liver transplant
  • Patients without cerebral oedema or haemodynamic instability tend to survive with standard ICU care
Meld Score
MELD Score Mortality
>40 71%
30-39 53%
20-29 20%
10-19 6%
<9 2%

An alternative to the King’s criteria is the MELD score, which predicts 90 day survival using:

The MELD score:

  • Is calculated by sum of logarithms
    Use an app.
  • Initially developed to predict mortality for TIPS
  • Subsequently used to prognosticate and prioritise liver transplantation
  • Bilirubin
  • INR
  • Creatinine

Key Studies

References

  1. Aziz, Riaz, Jennifer Price, and Banwari Agarwal. Management of Acute Liver Failure in Intensive Care. BJA Education 21, no. 3 (March 2021): 110–16. https://doi.org/10.1016/j.bjae.2020.11.006.
  2. Bersten, A. D., & Handy, J. M. (2018). Oh’s Intensive Care Manual. Elsevier Gezondheidszorg.
  3. Van Eldere A, Pirani T. Liver intensive care for the general intensivist. Anaesthesia. 2023;78(7):884-901.
  4. Warrillow SJ, Bellomo R. Preventing Cerebral Oedema in Acute Liver Failure: The Case for Quadruple-H Therapy. Anaesth Intensive Care. 2014;42(1):78-88.
  5. Ding GKA, Buckley NA. Evidence and consequences of spectrum bias in studies of criteria for liver transplant in paracetamol hepatotoxicity. QJM. 2008 Mar 18;101(9):723–9.