FRCA Notes

Acute Liver Failure

Acute liver failure forms part of the spectrum of hepatic disease examinable in the Final FRCA exam.

It is distinct from acute-on-chronic liver failure (see chronic liver failure).

A recent BJA Education article raises suspicion of further CRQ questions on the topic, while Deranged Physiology has a smorgasbord of pages on acute liver failure.

Resources

  • Acute liver injury is the presence of coagulopathy (INR >1.5) alone, and has a better prognosis than acute liver failure

  • Acute liver failure is defined as, in a patient with otherwise health liver, the presence of:
    • Coaguloapthy (INR >1.5) and
    • Hepatic encephalopathy

  • The overall incidence of ALI and ALF is reducing because of better vaccination for Hep. B and fewer drug-related cases
  • The definitive treatment for severe acute liver failure remains transplantation

O'Grady Classification

  • Classifies disease according to the duration between onset of jaundice to onset of encephalopathy

  • <7 days - hyperacute liver failure
    • Typically from paracetamol overdose or hepatitis (A/B)
    • May also be pregnancy- or drug-related

  • 8-28 days - acute liver failure
    • Viral hepatitis and idiosyncratic drug reactions tend to be the most common causes

  • 28 days to 12 weeks - subacute liver failure
    • Seronegative hepatitis, drugs/toxins and vascular causes


Viral Drug-induced Vascular Metabolic Neoplastic Other
Viral Paracetamol (50 - 70% of drug-induced ALF) Budd-Chiari syndrome Wilson's disease Metastases (typically colonic) Crush injury
Hepatitis B Chemotherapy Veno-occlusive disease Autoimmune hepatitis HCC Capsular haematoma
Hepatitis C Alcohol Right heart failure HLH Lymphoma Unknown (up to 20%)
Hepatitis E (Indian subcontinent) Statins Hepatic arterial ischaemia AFLP
Hepatitis A (Asia/Mediterranean) Carbamazepine
Phenytoin		 HELLP syndrome
HSV
CMV		 Anti-TB drugs
EBV
VZV		 Ecstasy
Cocaine


  • Direct hepatocyte damage (necrosis or apoptosis) leads to development of an immune-mediated response:
    • Activation of macrophages, monocytes, dendritic cells, NK-T-cells
    • Expression of toll-like receptors for both pathogen- (infection) and damage- (non-infection) associated molecular patterns a.k.a. PAMPs and DAMPs
    • Strong inflammatory response ensues locally and systemically

Respiratory

  • Unprotected airway from obtunded patient
  • Aspiration risk
  • Hypoxia from:
    • Acute lung injury ± ARDS
    • Portopulmonary shunt
    • Hepatopulmonary syndrome
    • Hepatic hydrothorax
    • Impairment of ventilation by massive ascites
    • Reversal of hypoxic pulmonary vasoconstriction by SIRS

Cardiovascular

  • There is a 'SIRS' response - the initial pro-inflammatory response can lead to MODS
  • Vasodilated shock

Neurological

  • Hepatic encephalopathy from:
    • Altered cerebral blood flow and dysregulated cerebral autoregulation
    • Circulating neurotoxins i.e. ammonia
    • Osmolar derangements e.g. hyponatraemia
  • The end result is astrocyte damage, cerebral oedema and intracranial hypertension

Renal

  • AKI and renal failure from hepatorenal syndrome

Metabolic

  • Hypercatabolic state (increased by up to 30%)
  • Reduced lactate clearance
  • Metabolic acidosis
  • Hypoglycaemia from a combination of decreased glycogen stores, impaired glycogenolysis and impaired gluconeogenesis

Haematological

  • Coagulopathy
    • Hypo-fibrinogenaemia
    • Raised PT (INR)
    • Reduced circulating pro- and anti-coagulant proteins
    • Thrombocytopaenia
  • Bone marrow suppression

  • This leads to a state of rebalanced homeostasis and a complex coagulation profile, which does not correlate well with tests such as PT or VHA
  • Patients may be hypercoagulable (35%), have normal(ish) coagulation (45%) or be hypocoagulable (20%)

Immune

  • Overall immunoparesis and predisposition to infection

  • Decreased complement synthesis
  • Defective opsonisation as the consequence of decreased complement
  • Impaired phagocytosis of encapsulated organisms due to defective opsonisation
  • Impaired chemotaxis
  • Impaired neutrophil function

History

  • Determine timing of jaundice in relation to hepatic encephalopathy
  • Drug and travel history
  • Establish whether there are symptoms of chronic liver disease

Bloods (in general)

  • FBC
    • Autoimmune hepatitis and drug reactions can cause an eosinophilia
    • Thrombocytopaenia in HELLP syndrome

  • U&E
  • Liver function tests
    • ALT | AST | ƔGT
    • ALP; may be normal and is not a sensitive indicator of liver damage
    • Albumin
    • Bilirubin; not a sensitive indicator of liver damage
    • LDH; not a sensitive indicator of liver damage

  • Amylase (5% develop pancreatitis)
  • CK
  • Serum ammonia level

  • Coagulation i.e. prothrombin time/INR

  • Uric acid (if pregnant)
  • Arterial blood gas for lactate

Identification of aetiology

  • Viral screen: Hepatitis A/B/C/D/E, HIV1&2, EBV, CMV, HSV, VZV

  • Auto-immune hepatitis: ANA and anti-smooth muscle antibodies
  • PSC/PBC: anti-mitochondrial antibodies
  • Wilson's disease: caeruloplasmin (abnormally low)
  • Paracetamol levels
  • Pregnancy test
  • Urine myoglobin

Imaging

  • TTE - is there right heart failure?
  • Ultrasound of the liver
  • Triple-phase CT of liver

Specific diseases

Disease Treatment
Parcetamol overdose NAC
Autoimmune hepatitis Steroids
Hepatitides Some evidence for lamivudine in Hepatitis B, but no evidence for antivirals in Hep. E
Wilson's disease D-Penicillamine as a copper chelating agent
Hepatic vein thrombosis Thrombolysis/anticoagulation, TIPS
Valproate overdose L-carnitine

Referral to specialist centre

  • MDT involvement should include HPB/Gastroenterology, Critical care, Tertiary centre and transplant teams
  • Referral criteria generally:
    • PT >50s
    • INR >3
    • Grade four encephalopathy
    • Lactate >3 despite resuscitation
    • pH <7.25 despite resuscitation
    • AKI with creatinine >300μmol/L
    • Bilirubin >300μmol/L

  • High-volume (15% IBW) plasma exchange increases survival in ALF for those who cannot undergo transplantation, or those who deteriorate whilst waiting for one
  • Mechanical assist devices (MARS or SPAD devices) are not routinely used
  • Liver transplantation

Respiratory

  • Early, elective intubation for Grade 3/4 encephalopathy to provide airway protection, control of agitation and allow neuroprotective ventilation
  • Standard lung-protective strategies should be used
  • VAP care bundles
  • Ventilate to low-normal PCO2 for neuroprotection against cerebral vasodilation and raised ICP

Cardiovascular

  • There is often a hyperdynamic circulation due to a profoundly reduced SVR from vasodilatory shock and raised cardiac output
  • The goal therefore is to ensure adequate tissue oxygenation with:
    1. Volume restoration, typically with balanced crystalloid
      • Albumin may be used but avoid HES as increased risk of needing RRT
      • Goal-directed fluid therapy to avoid fluid overload (and thus impair hepatic venous outflow)

    2. Vasopressor support
      • Noradrenaline first-line
      • Terlipressin is not widely used in ALF (as opposed to acute-on-chronic disease)
      • May need steroid replacement, which can reduce vasopressor requirement but increases infection risk and does not improve survival
      • A MAP >65mmHg should suffice

Neurological

  • Sedate with short-acting drugs e.g. propofol (not BZD) and short-acting opioids

  • Cerebral oedema and raised ICP is a concern, and carries a 55% mortality
  • Risk factors include young age, hyper-acute or acute liver failure, renal or cardiac dysfunction, SIRS response or ammonia >200μmol/L
  • High risk patients may benefit from ICP monitoring but there is an associated risk of haemorrhage, which may be fatal
  • Management of raised ICP is as standard

  • There may be seizures in up to 25% although prophylactic AED is not recommended

Renal

  • Replace phosphate
  • Aim high-normal sodium to minimise cerebral oedema

  • High incidence of AKI (40 - 85%)
  • Risk factors: higher age, paracetamol-induced ALF, hypotension, sepsis, SIRS

  • Early RRT may be beneficial to:
    • Provide renal support
    • Reduce degree of hyperammonaemia (may require ultrafiltration rates 60 - 90ml/kg/hr)
    • Correct sodium imbalance
    • Metabolic control
  • Continuous RRT is preferential to avoid cerebral complications from fluid shifts
  • Avoid citrate as the impaired liver cannot metabolic citrate load

Gastrointestinal

  • Hypoglycaemia is common and associated with increased mortality
    • Regularly monitor blood glucose
    • Management with high-concentration, low-volume glucose solutions (avoid excessive hypotonic solutions as can worsen cerebral oedema)

  • Ensure stress ulcer prophylaxis is prescribed
  • Drain tense ascites
  • Consider lactulose although not routinely recommended in acute liver failure (as opposed to acute-on-chronic failure)

Nutritional

  • There is a hypercatabolic state so early nutritional support is recommended
  • Daily targets are higher; 25 - 40kcal/kg/day
  • Protein requirements are unchanged; evidence base for restricting protein to reduce ammonia production is dubious
  • May need pro-kinetics ± post-pyloric feeding

Haematological

  • Consider giving vitamin K, as up to a quarter have subclinical vitamin K deficiency
  • Aim platelets >30x109/L
  • Aim fibrinogen levels >1.5g/L

Immune

  • Sepsis is the leading cause of death in ALF
    • 80% of ALF patients are bacteraemic with either gram negative enteric bacilli or gram positive cocci
    • 32% of ALF patients have fungaemia, typically Candida
  • Infections typically afflict the chest (50%), urinary tract (22%) or indwelling catheters (12%)

  • Reactivation of viral infections (CMV) can occur

  • Identification of sepsis can be challenging, as many markers may be absent (e.g. lack of CRP, normothermia)
  • Prophylactic antibiotics and antifungals are recommended

  • Outcomes are improving in general
  • Mode of death is most commonly from sepsis and MODS
  • Risk factors for poorer outcome:
    • Advanced age
    • Acute Wilson's disease
    • Either rapidly progressing or slowly progressing with delayed diagnosis

  • Predicated mortality is >90% if there is either:
    • A PT >100s, or
    • Three from:
      • PT >50s
      • Age <10yrs or >40yrs
      • Jaundice-to-encephalopathy time >7days
      • Bilirubin >300μmol/L
      • Cryptogenic aetiology