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Causes of acute liver failure
• Infection (hepatitis A, B, C, E, non-A non-B, cytomegalovirus, herpes simplex virus, Epstein–Barr virus, varicella) • Drugs (paracetamol (acetaminophen), isoniazid, monoamine oxidase inhibitors (MAOIs), non-steroidal anti-inflammatory drugs (NSAIDs), halothane, Ecstasy, gold, phenytoin) • Metabolic (Wilson’s disease, Reye’s syndrome)• Cardiovascular (Budd–Chiari syndrome, ischaemic hepatitis)• Miscellaneous (acute fatty liver of pregnancy, lymphoma, Acute liver failure (ALF) is an uncommon condition characterized by jaundice, coagulopathy and encephalopathy in a patient with previously normal liver function. In the USA, there are 2000 cases a year and in the UK there are 400. The main aims of treatment are the control of cerebral oedema and supportive management • plasma aspartate aminotransferase (AST) and alanine amino- of multiple organ failure until hepatic regeneration occurs. Sepsis transferase (ALT) reflecting hepatocellular damage and cerebral oedema are the main causes of death.
• prothrombin time (PT) (used as an indicator of the severity of Aetiology – in the UK, paracetamol (acetaminophen) overdose
is the most common cause (70%) of ALF, but worldwide it is viral Other common abnormalities are hypoglycaemia, hypo- natraemia, hypomagnesaemia, respiratory alkalosis and meta- Pathology – there is centrilobular necrosis of hepatocytes with
activation of macrophages and liberation of cytokines, specifically tumour necrosis factor and interleukins 1 and 6. Management
Paracetamol (acetaminophen) overdose results in the accumula-
Clinical presentation
tion of the hepatotoxic metabolite N-acetyl-p-benzoquinonimine ALF usually presents with malaise, nausea and jaundice. The which is normally inactivated by conjugation with glutathione.
interval between the onset of jaundice and the onset of enceph- N-acetylcysteine should be given as soon as possible after the alopathy depends on the aetiology and is used to classify ALF: overdose according to the standard treatment nomogram, to re- • hyperacute liver failure (7 days between onset of jaundice and plenish hepatic stores of glutathione. The management of patients who meet the clinical indicators of poor prognosis (Figure 3) should be discussed with a regional liver centre and they should • subacute liver failure (5–12 weeks).
be transferred urgently for transplant assessment. Elective intu- This classification has implications for the prognosis and inci- bation and ventilation should be considered before transfer for dence of cerebral oedema, which is more common in hyperacute patients with Grade II encephalopathy and it is mandatory for failure. As liver failure progresses, encephalopathy becomes the patients with Grade III or IV encephalopathy. The patient should characteristic feature. The grading of encephalopathy is described be transferred with full monitoring by experienced personnel.
in Figure 2. The mechanism of encephalopathy is not fully The basis of intensive care management is to provide support understood. Ammonia, false neurotransmitters and endogenous for failing organs while allowing time for hepatic regeneration. benzodiazepine ligands that enhance the effect of the inhibitory • Omeprazole or ranitidine are given as prophylaxis against transmitter γ-aminobutyric acid have been proposed as causes.
gastrointestinal bleeding. • Early enteral nutrition is recommended but there is no need Diagnosis and investigations
There is no specific diagnostic test for ALF, however specific • Hypoglycaemia is common and an infusion of 10% glucose tests to identify the cause may include: should be administered to keep the blood glucose level above • viral serology for the hepatitis viruses • plasma caeruloplasmin and 24-hour urinary copper to diag- • Agitated or aggressive patients may need ventilation to enable care to be given. Those with grade III or IV encephalopathy should • hepatic ultrasound to demonstrate hepatic vascular occlusion be electively ventilated, because of the risk of cerebral oedema.
There will be elevation of:• serum bilirubin (a level over 300 µmol/litre implies severe Grades of encephalopathy
• Grade I: altered mood, impaired concentration and Kevin E J Gunning is Director of the John Farman Intensive Care Unit,
Addenbrooke’s Hospital, Cambridge, UK. He qualified from • Grade II: drowsy, inappropriate behaviour, able to talk St Bartholomew’s Hospital, London, and after obtaining his FRCS, • Grade III: very drowsy, disorientated, agitated, aggressive trained in anaesthesia in London. His current interests include audit and • Grade IV: coma, may respond to painful stimuli 2003 The Medicine Publishing Company Ltd 2003 The Medicine Publishing Company Ltd • High levels of positive end-expiratory pressure (PEEP) should be avoided because they may increase hepatic venous pressure King’s College Hospital criteria for liver transplant-
ation in acute liver failure
• Pulmonary complications such as acute respiratory distress Paracetamol (acetaminophen) overdose
syndrome, aspiration or pneumonia occur in 50% of cases.
• Cardiac output is high (> 5.0 litre/minute) in 70% of cases, with a reduced systemic vascular resistance. Relative hypotension is therefore common and should be treated by volume loading with colloids. A pulmonary artery catheter or PiCCO should be inserted to guide therapy. Vasopressors (e.g. noradrenaline (nor- Non-paracetamol (acetaminophen)
epinephrine)) may be needed to maintain mean arterial pressure, despite adequate volume replacement.
• N-acetylcysteine may be beneficial in the management of ALF even if paracetamol (acetaminophen) is not the cause. The evidence is conflicting, but it has been shown to increase cardiac output and oxygen delivery and is given as a loading dose of • Time from jaundice to encephalopathy > 2 days 300 mg/kg followed by an infusion of 150 mg/kg/hour.
• Non-A, non-B hepatitis, halothane or drug-induced acute liver • Coagulopathy is a major feature of ALF, because the liver syn- thesizes all the coagulation factors apart from factor VIII. Sepsis, reduced protein C and antithrombin III levels contribute to low- grade disseminated intravascular coagulation (DIC). The PT is a good measure of the severity of the disease and should not be cor- a reduction in cerebral perfusion pressure. Moderate hypothermia rected unless the patient is actively bleeding. Thrombocytopenia (32–33oC) reduced ICP in one study.
should be corrected if the platelet count falls below 50 x 109/litre.
Renal failure
Infection
Renal failure occurs in 70% of patients after paracetamol (acet- Infection is common as a result of neutrophil and Küpffer cell aminophen) overdose due to its nephrotoxic effect. Sepsis and dysfunction and sepsis is the cause of death in 11% of cases. hypovolaemia also contribute to renal failure. Haemodiafiltra- Bacterial infections with Gram-positive organisms are seen in tion may be necessary to maintain fluid balance and to correct the first week and fungal infections after 2 weeks. The usual hyponatraemia, hyperkalaemia and acidosis. A lactate-free signs of infection (e.g. pyrexia, leucocytosis) may be absent and replacement fluid should be used, because the failing liver can infection surveillance must be rigorous. Prophylactic fluconazole, There has been considerable research into the developmentof an artificial liver. Trials of systems using extracorporeal Cerebral oedema
perfusion of blood through columns of hepatocytes, or dialysis Cerebral oedema develops in 80% of patients with Grade IV against an albumin-coated membrane have been undertaken, but encephalopathy and is the cause of death in about 30–50% of most studies are small and experimental.
patients with ALF. There is now evidence to suggest that it is the result of the high level of ammonia, which leads to an increase in Prognosis
the synthesis of intracellular cerebral glutamine. This increases Overall survival with medical treatment is 10–40%. The prog- osmotic pressure in astrocytes, resulting in cerebral oedema.
nosis depends on the aetiology and is best after paracetamol The patient should be nursed with a 20o head-up tilt to improve (acetaminophen) overdose and hepatitis A, and worst for non-A, cerebral perfusion pressure; there should be minimal inter- non-B hepatitis and idiosyncratic drug reactions. The time to the vention to prevent surges in ICP. Hyperventilation should be onset of encephalopathy also affects prognosis, hyperacute failure avoided and the PaCO should be maintained at 4.7–5.2 kPa.
has a 35% survival and subacute failure has a 15% survival. The Systolic hypertension and sluggish pupillary responses are outcome from transplantation for ALF is improving and is now the most reliable clinical signs of raised ICP, which should be treated with an intravenous bolus of mannitol 20%, 0.5 g/kg, which takes 20–60 minutes to act. The boluses may be re-peated provided that the serum osmolality is less than320 mOsmol/litre.
FURTHER READING
Some centres measure ICP using extradural, subdural or Carraceni P, Van Thiel D H. Acute Liver Failure. Lancet 1995; 345:
parenchymal monitors. However, the benefits must be balanced against the risk of haemorrhage, which occurs in about 15%. Gimson A. Fulminant and Late Onset Hepatic Failure. Br J Anaesth Coagulation should be corrected before the insertion of the 1996; 77: 90–8.
monitor. Cerebral perfusion pressure should be maintained above Lee W M. Acute Liver Failure. N Eng J Med 1993; 329: 1862–72.
60 mm Hg. Thiopental (thiopentone) as a 50 mg bolus or an in- Singer M, Suter P M. Acute Hepatic Failure. In: Webb A R, fusion of 50 mg/hour can be used to treat intractable intracranial Shapiro M J, eds. Oxford Textbook of Critical Care. Oxford: hypertension, but may cause a fall in systemic blood pressure and 2003 The Medicine Publishing Company Ltd 2003 The Medicine Publishing Company Ltd

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