Keywords

9.1 Introduction

Acute liver failure is a rare condition, resulting from a rapid decline in hepatic function with potentially life threatening sequelae. Incidence in the UK is estimated between 1 and 8 per million population [1] accounting for approximately 400 new cases per year. Despite advances in supportive management and liver transplantation, the only curative treatment, 1-year survival is around 60 % [2, 3].

Whilst definitions of acute liver failure have been diverse and evolving [4], it remains a syndrome featuring jaundice, coagulopathy, encephalopathy and multi-organ dysfunction. The presence of hepatic encephalopathy (of any grade) is the mandatory clinical feature in establishing the diagnosis of acute liver failure (Table 9.1). Jaundice, coagulopathy and other organ dysfunction (typically but not limited to renal) may or may not be present to varying extents.

Table 9.1 Grading of severity of hepatic encephalopathy
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The differentiation between hepatic encephalopathy and other causes of altered mental state whilst difficult has to be made. Furthermore, acute liver failure must not be confused with an acute decompensation of chronic liver disease (AoCLD), which is discussed later in this chapter.

Originally the term ‘fulminant hepatic failure’ was used (as part of a surveillance study in the USA of liver damage after halothane anaesthesia) to describe ‘a severe liver injury, potentially reversible in nature and with onset of hepatic encephalopathy within 8 weeks of the first symptoms in the absence of pre-existing liver disease [5].

The observation of late-onset hepatic failure where encephalopathy appears between 8 and 26 weeks after the onset of symptoms led to the redefinition that became known as the King’s classification [6]. Here, the time interval between jaundice specifically rather than symptoms, to onset of encephalopathy defined the distinction between hyperacute, acute and subacute liver failure [6] (Table 9.2).

Table 9.2 Characteristics of subgroups of patients with acute liver failure as defined by O’Grady [6]
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Common aetiologies of acute liver failure are listed in Table 9.3 according to the time of onset of acute liver failure (Table 9.3). The significance of the King’s classification is not only in definition but also providing inference about likely outcome, aetiology and implication on management [7]. The data upon which the King’s classification is based also forms the basis of the King’s College criteria for liver transplantation, which remains in use to this day [7].

Table 9.3 Aetiology of patients with acute liver failure and interval between appearance of jaundice and development of encephalopathy
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Based on the above, another widely accepted definition of acute liver failure is that of a coagulopathy (INR > 1.5) and any degree of encephalopathy in a patient without pre-existing cirrhosis and with illness duration of <26 weeks. However, patients with vertically acquired Hepatitis B, Wilson’s disease and Autoimmune hepatitis are included despite the possibility of pre-existing cirrhosis, so long as their disease has been recognised for <26 weeks.

9.2 Initial Management

Once a diagnosis of acute liver failure is suspected or established, patients should undergo concurrent investigation and treatment with the initial aim being to identify the aetiology and institute any disease specific therapy, which may be appropriate. Depending on the initial presentation, resuscitative measures may have to be instigated simultaneously. An appreciation of factors that make for a poor prognosis also enables the early identification of patients who are likely to fail supportive medical management and require liver transplantation.

Clearly not every patient where a diagnosis of acute liver failure is made or suspected will have a metabolic derangement that would warrant intensive care unit (ICU) admission or indeed be referred to ICU. For example, patients with subacute failure may remain for long periods with low-grade encephalopathy on a medical ward.

However, it is important to bear in mind that even in the presence of hepatic regeneration patients will succumb to complications such as sepsis or multi-organ failure and will need a close level of monitoring. Furthermore, patients presenting with hyperacute or acute liver failure can rapidly progress to multi-organ failure.

As a result it is recommended that, a low threshold for admission to critical care be adopted, especially until the aetiology is established.

The main indications for ICU referral and admission are as follows [3, 8]:

  • Hyperacute or acute presentation

  • Any degree of encephalopathy

  • Renal failure

  • Metabolic derangement

The ICU clinician should anticipate the severity of presentation and likelihood of supportive and medical therapy failing despite optimal care. The most widely accepted prognostic tool in acute liver failure is the King’s College criteria.

The King’s College criteria were originally used to predict survival without liver transplantation. It is now used to refer patients to a specialist liver unit and select potential liver transplant recipients.

The King’s College criteria differ between paracetamol and non-paracetamol causes. It has a good specificity (82–92 %) but limited sensitivity (68 %). Its positive predictive value for ICU death without transplantation is 0.98 and the negative predictive value is 0.82 [7] (Tables 9.4 and 9.5).

Table 9.4 Criteria for referral to specialist liver unit following paracetamol ingestion (post resuscitation) [3]
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Table 9.5 Criteria for referral to specialist liver unit for non-paracetamol aetiologies (post resuscitation) [3]
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The use of arterial lactate is used to improve the sensitivity of the King’s Criteria in the context of paracetamol-induced liver failure [9]. Lactate concentrations of >3.5 mmol/L on admission and >3.0 mmol/L after adequate fluid resuscitation, when used in combination had similar predictive ability as the King’s criteria but identified non-surviving patients earlier. The use of the post resuscitation lactate increases the sensitivity of the King’s criteria to 91 % [9]

All patients with any degree of encephalopathy, with acute liver failure should be referred to a specialist liver unit.

It should be noted that once a decision to transfer a patient with encephalopathy has been made, then sedation and artificial ventilation should be considered for safe transfer. Specifically, good practice advocates sedation and ventilation even in grade I and II encephalopathy. These patients can deteriorate rapidly with potential for associated cardiovascular collapse.

A careful history must be taken including collateral histories from family members. Clinicians in referring hospitals often have a window of opportunity to meticulously enquire for aetiology especially regarding exposure to viral infections and drugs before the onset of encephalopathy. A common reason behind indeterminate aetiologies lies in inadequate history at the time of presentation and this can complicate further management [10], thus the taking of a thorough history in identifying the aetiology cannot be overstated.

Enquiry into recent foreign travel to endemic areas, risk factors for immunosuppression (e.g. immunosuppressant drugs, history of carcinomas and chemotherapy), high-risk sexual activity and medication history including alternative medicines should be made. Intravenous and recreational drug use particularly but not limited to cocaine and amphetamines and the ingestion of poisonous wild mushrooms, usually due to misidentification, should also be excluded.

Questioning of psychiatric history and neurological disorders especially in the context of renal tubular acidosis (especially Fanconi’s syndrome) are particularly relevant, indicating Wilson’s disease, whilst history of pregnancies, miscarriages and amenorrhea could indicate autoimmune hepatitis or HELLP syndrome. If a Budd-Chiari syndrome is diagnosed, then a search for an underlying cause should be made (to include malignancy, antiphospholipid syndrome, protein S, C and antithrombin III deficiency and factor V Leiden).

It is important to remember that even paracetamol taken within recommended daily doses have been known to cause acute liver failure, thus the potential for inadvertent overdose exists, especially in high risk groups (e.g. anorexia nervosa and alcohol abuse). Particular attention should be paid to interpreting paracetamol levels in these groups and familiarity with guideline updates is advised [11].

A thorough social history is important in lieu of any potential transplant assessment.

A history or clinical stigmata suggesting underlying chronic liver disease should be sought as this would alter management.

Imaging by computerised tomography is useful in cases where there is a history of cancer, if patency of portal vessels is queried or if Budd-Chiari syndrome is suspected. It is also indicated where intracranial hypertension and cerebral oedema is suspected, but clearly the risks in transportation in this cohort of systemically unstable patients needs to be balanced against the potential management benefits of imaging.

Initial laboratory investigations should be extensive to evaluate aetiology and severity of acute liver failure [8]. It is recommended that a full liver screen is requested on first presentation, even if it is intended for the patient to be transferred to a specialist liver unit (Box 9.1). To avoid delays, these results, once known should be communicated to the specialist liver unit to expedite the commencement of any specific aetiology-based therapy or decision for listing for transplantation.

Box 9.1. The Following Investigations Are Recommended as Part of a Complete Acute Liver Failure Aetiology Screen

Haematology

Full blood count, coagulation screen to include prothrombin time, INR, group and save

Biochemistry

Urea and electrolytes, creatinine, chloride, bicarbonate, calcium, magnesium, phosphate, glucose, liver function tests, albumin, amylase, lipase, arterial blood gas, arterial lactate, cearuloplasmin (or uric acid and bilirubin to ALP ratio) βHCG/pregnancy test (females), ammonia

Toxicology

Paracetamol and salicylate levels, toxicology screen

Virology

Anti HAV IgM, Hep BsAg, Hep Bs antibody, anti Hep Bcore IgM, anti Hep E, anti Hep C, Hep C RNA, HSV1 + 2 IgM, VZV, EBV, HIV 1 + 2

Immunology

ANA, anti SMA, ANCA, anti LKMA, immunoglobulin

  1. Adapted from Lee [8]

9.3 Causes

The aetiology and incidence of acute liver failure varies worldwide. Overall the incidence is significantly lower in the developed world when compared to developing countries where viral infections (hepatitis A, B and E) are the main aetiologies [12]. In the United States and Western Europe drug induced aetiologies, especially paracetamol predominates, followed by non A-E hepatitis where no cause is found (Table 9.6).

Table 9.6 Common causes of acute liver failure
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As previously stated, acute liver failure can be diagnosed in a previously well but undiagnosed patient with Wilson’s disease, hepatitis B or autoimmune hepatitis where compensated cirrhosis may have been present, provided the disease has been recognised for less than 26 weeks.

9.4 Clinical Features

Acute liver failure results in a systemic inflammatory response and has multi-systemic manifestations. Table 9.7 illustrates the clinical features and therapeutic options according to the organ system affected.

Table 9.7 Clinical features of acute liver failure and the resultant management issues and therapy
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9.5 General Management

There are a number of points in the general management of liver failure patients that are relevant irrespective of the underlying aetiology.

Patients with acute liver failure should be managed according to standard best practices on the intensive care unit.

Since serial evaluation of laboratory coagulation variables, like INR and PT, are important elements of prognostic evaluation, the administration of coagulation factors should be avoided except if the patient is bleeding or prior to invasive procedures [12].

Intubation of the trachea is recommended for patients with severe metabolic disturbance refractory to adequate fluid resuscitation and in patients with grade III and IV encephalopathy, typically for airway protection and carbon dioxide control. Propofol is the sedating agent of choice. Use of suxamethonium as part of a ‘rapid sequence induction’ is debatable in view of effects on intracranial pressure (ICP). Drugs with hepatic metabolism are avoided in favour of those with extra-hepatic metabolism (e.g. Atracurium – Hoffman degradation, Remifentanil – plasma esterase). The routine use of infusions of neuromuscular blockade is not recommended due to associations with neuromyopathy and ventilator associated pneumonia even in cases of raised ICP. Tracheal intubation and artificial ventilation for encephalopathy requires standard neuroprotection strategies to be employed to counter lability in ICP.

Respiratory care is based on the use of lung protective strategies with low tidal volumes, judicious use of PEEP and avoiding high peak airway pressures. Intrapulmonary shunts are uncommon in acute liver failure in contrast to chronic liver disease where the hepato-pulmonary syndrome can occur. Physiotherapy and respiratory toileting should be undertaken with caution due to the risk of bleeding and increasing ICP.

Cardiovascular effects of hypotension due to a low systemic vascular resistance in association with a high cardiac output are to be expected, often worsened by concurrent infections and hypovolaemia. Patients presenting with acute liver failure typically require fluid resuscitation to correct hypovolaemia and resulting hypoperfusion. It is not atypical to see a profound metabolic derangement fulfilling the King’s criteria upon admission to ICU to normalise with adequate resuscitation. The choice of fluid is dependent on clinical preference, with the caveat that lactate containing fluids and 5 % dextrose should be avoided. The use of 5 % dextrose in acute liver failure risks hyponatraemia, cerebral oedema and worsening intracranial hypertension [14]. The livers’ inability to efficiently clear lactate and the likelihood of a type 1 lactic acidosis precludes the use of the former.

Norepinephrine is the vasopressor of choice once intravascular volume has been restored with the aim of maintaining end organ perfusion [15]. The use of terlipressin in addition to norepinephrine has been shown to increase cerebral perfusion pressure with little effect on intracranial pressure and cerebral lactate when catecholamines alone cannot maintain adequate blood pressure [15].

In acute liver failure, high-grade encephalopathy is usually due to increasing cerebral oedema and intracranial hypertension. The incidence of intracranial hypertension is about 20–30 % in all patients with acute liver failure [16]. Table 9.8 lists risk factors associated with the development of intracranial hypertension in patients with acute liver failure.

Table 9.8 Risk factors for the development of intracranial hypertension in patients with acute liver failure
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As such, management strategies place importance on the recognition and subsequent monitoring and treatment of intracranial hypertension. Direct ICP monitoring is employed for real-time monitoring of ICP and can be combined with jugular bulb saturations (via a retrograde bulb catheter) to allow for closer monitoring.

Ammonia is implicated in the pathology of cerebral oedema and there is a close relationship between elevated arterial ammonia levels and the development of encephalopathy, with the risk of intracranial hypertension greatest when there is a sustained level of ammonia between 150 and 200 μmol per litre [12, 16, 17]. Furthermore, at serum ammonia levels of <75 μmol/L, intracranial hypertension rarely happens. Levels of >100 μmol/L is an independent risk factor for the development of high-grade encephalopathy, whilst levels >200 μmol/L predicts intracranial hypertension [18].

One hypothesis explaining the pathophysiology of cerebral oedema in acute liver failure is that high levels of serum ammonia induce a build-up of glutamine in astrocyctes (as astrocyctes contain glutamine synthetase which utilises ammonia to combine it with glutamate to produce glutamine), thus increasing osmotic potential and absorption of water. In chronic liver failure, there is time for adaptation to this increase in osmotic potential.

Cerebral blood flow varies greatly in patients with acute liver failure with the normal physiology to include ‘autoregulatory’ processes and the relationships between cerebral metabolism and flow being disturbed [19, 20]. As such, potential increases in cerebral blood flow in an already oedematous brain attenuate associated rises in intracranial pressure. It should be noted that there is no evidence for any disruption in the blood brain barrier. Because of this loss of ‘autoregulation’ the use of cerebral perfusion pressure (CPP) targets is less useful as attempts to increase CPP via mean arterial pressure (MAP) result in increases in ICP as brain volume increases. CPP is best maintained in acute liver failure by decreasing ICP and aiming for a MAP that does not result in an ICP above 25 mmHg [21].

In managing a patient with acute liver failure and possible raised ICP it is important to consider the identification of those at risk, monitoring of ICP and brain function, prophylactic therapy and overall management strategies [21].

9.5.1 ICP Monitoring

Imaging modalities like computerised tomography are able to detect cerebral oedema but are insensitive to the extent of intracranial hypertension.

There is controversy surrounding the use of direct monitoring of intracranial pressure due to the lack of evidence for improved outcomes and risk of intracranial bleeding including death.

Advocates for intracranial pressure monitoring state that medical interventions can reduce ICP and its consequences, which in turn leads to an increase in intervention rates and ICU survival [22]. However, ICP monitoring may only reduce the specific risk of cerebral death whilst the chances of death due to multi-organ failure and sepsis remain unchanged. Furthermore, an unknown ICP tends to result in indecision or occasionally overtreatment. Knowledge of ICP can be beneficial in provision of basic aspects of general care like sedation holds and trachea-bronchial toileting more confidently.

In which patients would an intracranial bolt be suitable? The following are indications for invasive ICP monitoring [12]:

  • Patients with clinical signs of a raised ICP

  • Patients with concurrent multi-organ failure [17]

  • Sustained ammonia levels of >200 μmol/L

Critically raised intracranial pressure can be managed with Mannitol 20 % at 2 mL/kg aiming to keep osmolality <320 mOsm/L). If the patient is oliguric, then the administration of Mannitol must be accompanied by renal replacement therapy where as a guide, two to three times the administered volume should be removed.

Hyponatraemia is associated with poor outcome in acute liver failure. The mechanism for hyponatraemia in acute liver failure is different to the secondary hyperaldosteronism causing hyponatraemia in chronic liver failure. There is an inverse relationship between intracranial pressure and serum sodium. The risk of developing intracranial hypertension is decreased by raising serum sodium to between 145 and 155 mmol/L with hypertonic saline [14]. Therefore the use hypertonic saline to increase serum sodium is an accepted strategy in maintaining ICP (Box 9.2).

Box 9.2. Management of Raised ICP

$$ \begin{array}{c}\mathrm{Sustainedriseof}\mathrm{I}\mathrm{C}\mathrm{P}>25\mathrm{mmHg}\left(5 \min \mathrm{ormore}\right)\\ {}\downarrow \\ {}\mathrm{Mannitol}100\;\mathrm{mlof}20\mathrm{or}0.5\mathrm{g}/\mathrm{kg}\\ {}\downarrow \\ {}\begin{array}{l}20\mathrm{mlof}30\;\mathrm{NaCLor}200\mathrm{mlof}3\;\mathrm{NaCLaiming}\mathrm{t}\mathrm{o}\mathrm{keepserum}\hfill \\ {}\mathrm{sodiumat}<150\mathrm{mmol}/\mathrm{L}\hfill \end{array}\\ {}\downarrow \\ {}\mathrm{Attempt}\mathrm{t}\mathrm{o}\mathrm{maintain}\mathrm{C}\mathrm{P}\mathrm{P}>40\mathrm{mmHgwithfluidsandvasopressor}\end{array} $$

Also consider:

  • Indomethacin 25 mg if JV sats >80 %

  • Hypothermia

  • Increase sedation with Propofol

  • Thiopentone bolus 125 mg

  • Hyperventilation (monitor Jugular bulb saturation)

Indomethacin can induce cerebral vasoconstriction and reduce ICP without impairing cerebral oxygenation and along with hypothermia, increased sedation and hyperventilation, it can be used as a method of reducing ICP.

Induced hypothermia results in a reduction in basal metabolism as well as reduced production, cerebral uptake and metabolism of ammonia. It also reduces cerebral blood flow [23]. In view of the systemic problems associated with hypothermia as well as the risk that it could impair hepatic regeneration alternative strategies should be adopted first before inducing hypothermia.

9.5.2 Renal Failure

The presence of renal failure in association with acute liver failure is a poor prognostic indicator, with the exception of when the underlying aetiology is paracetamol overdose. Renal failure is very common in paracetamol-induced liver failure and rarely leads to chronic renal impairment.

Continuous renal replacement therapy should be employed over intermittent haemodialysis once a decision for renal replacement therapy is made.

Regional citrate anticoagulation is increasingly employed in the care of critically ill patients with liver failure and in those undergoing liver transplantation due to the high risk of haemorrhage. Although rare, heparin-induced thrombocytopenia (HIT) in acute liver failure patients including those undergoing liver transplantation is potentially catastrophic for a new graft. A recent review cited the incidence to be about 2 % in patients undergoing transplantation [24]. As we know, the duration of heparin therapy is a significant risk factor in the development of HIT [25]; thus, it is understandable that heparin sparing methods of anticoagulation like regional citrate anticoagulation is desirable in patients who may require renal replacement therapy, before, during and after transplantation.

It should also be noted that in the absence of renal failure, renal replacement therapy can also be used in patients to control hyperammonaemia and temperature control in situations of raised intracranial pressure [21].

9.5.3 Immunity

A failing liver results in compromise of adaptive and innate immunity. Impaired compliment synthesis combined with macrophage (Kupffer cell), natural killer and natural killer T cell dysfunction result in an increased susceptibility to bacterial and fungal infections, reduced recruitment of circulating lymphocytes and impaired modulation of liver injury [26]. Sepsis is a major cause of mortality, and it should be noted that the usual signs of sepsis (pyrexia and leucocytosis) may not always be present. Infections early in the illness are typically gram positive commonly caused by Staphylococcus aureus, whilst gram negative infections caused by Escherichia coli are seen later. Fungal infections are nearly invariably caused by Candida albicans and are seen in about a third of cases.

Prophylactic antibiotics covering both gram positive and gram negative organisms (e.g. piperacillin with tazobactam) and antifungal (e.g. fluconazole) should be administered at admission and certainly with the advent of a deteriorating synthetic function.

9.5.4 Nutrition

Patients with acute liver failure have high energy expenditure and protein catabolism and thus have a requirement for nutritional support to avoid a negative impact on immune function. There is a paucity of data in relation to nutrition in acute liver failure and guidance here is given according to best practice.

Hypoglycaemia is seen due to loss of hepatic glycogen stores and impaired gluconeogenesis. Intravenous glucose replacement is required especially prior to the establishment of enteral feeding or if malabsorption is present [3]. Tight glycaemic control is no longer warranted but hyperglycaemia should be avoided due to its association with intracranial hypertension and poor ICP control in acute liver failure [27].

Most European liver centres favour enteral feeding via a nasoduodenal tube if possible [28]. The siting of a nasoduodenal tube should not delay the initiation of enteral feeding via a nasogastric tube if this is better facilitated. Furthermore, if enteral nutrition is poorly tolerated then parenteral nutrition should be commenced.

The recommended amount of enteral feed is based on general dosage in critical care. Glucose, lactate, triglycerides, phosphates and ammonia levels should be closely monitored [29]. Hypophosphataemia is a common sequelae in acute liver failure but also when renal replacement therapy is employed. However, it can also be indicative of increased ATP (adenosine triphosphate) utilisation when the previously failing liver undergoes regeneration [30].

Feeding should be commenced within 24 h of ICU admission aiming for 25–30 kcal per kg per day. Usually 1.0–1.5 g of enteral protein per kilogramme per day can be administered without worsening hyperammonaemia or hepatic encephalopathy. However, it is advisable to measure blood ammonia levels and lower the protein load in patients with worsening hyperammonaemia or those at risk of intracranial hypertension. The use of immunonutrition containing glutamine is contra-indicated in view of the role of glutamine in the development of cerebral oedema in acute liver failure [3, 12, 31].

9.6 Aetiology Specific Management

When appropriate, management is complimented with aetiology specific measures which are discussed below.

9.6.1 Paracetamol

Paracetamol causes toxicity in a dose dependent manner. In patients with severe paracetamol poisoning, it is accepted that the interval between drug ingestion and treatment with acetylcysteine is closely related to outcome [32].

Ingestion of doses of more than 150 mg/kg can cause toxicity but it should be noted that toxicity has been observed when doses of between 3 and 4 g per day have been taken, especially in the context of high risk groups [33]. A severe drug induced transaminitis, typically in the thousands iu/l, is seen. Its commonality, especially in the western world means that paracetamol levels should be requested in all patients presenting with acute liver failure or hepatitis [2]. It cannot be overstated that paracetamol levels must be interpreted in conjunction with a thorough history and that cases of delayed presentation since time of ingestion, unintentional overdoses and staggered ingestion are usual causes of misinterpretation.

N-acetylcysteine (NAC) is a safe and effective antidote to paracetamol poisoning and its administration is mandatory in proven and suspected cases, even up to 48 h post ingestion [34]. For cases, presenting within a few hours of ingestion, the administration of activated charcoal is most effective within 1 h [35] of ingestion but can be of benefit as long as 4 h after ingestion [36]. Furthermore, the administration of activated charcoal does not interact or reduce the effect of N-acetylcysteine [36]. In the UK, N-acetylcysteine is administered via the intravenous route as follows: loading dose of 150 mg/kg in 5 % Dextrose over 60 min (previously 15 min) and a maintenance dose of 50 mg/kg over 4 h followed by 100 mg/kg over 16 h. Some UK liver units use variations of this regimen, and early consultation with the regional liver unit is advised especially in high risk cases.

The administration of N-acetylcysteine in conjunction with its standard toxicity nomogram [37] is advised. New simplified treatment guidelines including an updated treatment nomogram have now been adopted, which eliminate the old ‘high risk’ and ‘normal risk’ treatment line (Fig. 9.1) The MHRA guidance now stipulates that all patients with a timed plasma paracetamol level on or above a single treatment line joining points of 100 mg/L at 4 h and 15 mg/L at 15 h after ingestion, should receive N-acetylcysteine. Despite this, caution needs to be exercised in cases of multiple doses ingested over time and in high risk groups (e.g. patients on enzyme inducing drugs, chronic alcohol abuse, patients with malnutrition or anorexia nervosa) [38] where the new guidelines suggest that if there is doubt over the timing of ingestion or in staggered overdose, the nomogram should not be used and N-acetylcysteine given immediately. The initial dose should now be given over 60 min to reduce the risk of dose-related adverse reactions. Furthermore, hypersensitivity is no longer a contra-indication to treatment with N-acetylcysteine [11].

Fig. 9.1
figure 1

Treatment nomogram for paracetamol overdose courtesy of the MHRA (UK). This material is printed with the permission of the Medicines and Healthcare products Regulatory Agency under delegated authority from the Controller of HMSO. Should you wish to reuse this material please contact this agency

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When to stop N-acetylcysteine therapy? This remains a controversial area and no definitive statement can be made, other than to suggest safe practice would dictate in conjunction with the patients’ clinical condition, liver biochemistry, ingestion history and regional liver unit advice if applicable. If in doubt, do seek advice.

9.6.2 Mushroom Poisoning

Amanita phalloides, also known as the death cap mushroom is a highly toxic fungus, responsible for the majority of fatal mushroom poisonings worldwide, usually due to errors in identification because of similarities in appearance to edible varieties.

There is no definitive investigation to confirm poisoning by Amanita phalloides, but questioning during the history regarding mushroom ingestion, especially if gastrointestinal symptoms are present, will usually result in the diagnosis being made.

Historically, survival rates have been poor without liver transplantation, but complete recovery has been described with supportive care and medical treatment with either Penicillin G or Silibinin [39]. Silibinin (30–40 mg/kg/day intravenously) is thought to be more successful than Penicillin G but its use may be limited by local availability. Administration of N-acetylcysteine is also recommended. Early discussion with the regional liver unit is advised as patients with acute liver failure due to mushroom poisoning are expeditiously transferred and cared for in regional centres with an emphasis on early listing for liver transplantation as the only life saving option [8].

9.6.3 Viral Hepatitis

Hepatitis A and B, hepatitis D in a hepatitis B positive individual and hepatitis E are relatively infrequent causes of acute liver failure. It is debatable if hepatitis C can cause acute liver failure. It should be noted that reactivation of chronic hepatitis B can also occur in the setting of chemotherapy or systemic immunosuppression and as such hepBsAg positive patients beginning such treatment are treated prohylactically with nucleoside analogues.

Herpes simplex and Varicella zoster virus are rare causes of acute liver failure but cases have been described even in previously healthy individuals [40, 41].

Acute liver failure due to Hepatitis A and E is treated with supportive care only as there is no virus-specific treatment. With respect to hepatitis B, nucleoside analogues are administered for acute treatment but also for prevention of post-transplant recurrence. Patients with herpes simplex or varicella zoster as the cause of acute liver failure should be treated with acyclovir and are not to be excluded from transplantation [8].

9.6.4 Wilson’s Disease

Whilst a chronic disease, it can present as an acute decompensation which is accepted as a causative presentation of acute liver failure, because when this occurs it is usually fatal without transplantation. It usually presents with a sudden onset Coombs negative haemolytic anaemia and jaundice, typically in a young patient.

Interestingly, Kayser-Fleischer rings are seen in about 50 % of patients presenting with acute liver failure due to Wilson’s disease [42]. As such, any suspected case warrants an Ophthalmology assessment, even on the intensive care unit as this can expedite specialist referral and consideration for transplantation, especially whilst other biochemistry results are pending.

Another rapid and reliable alternative to serum caeruloplasmin and urinary and serum copper analysis, is a high bilirubin (mg/dl) to alkaline phosphatase (iu/l) ratio. Typically a figure of >2.0 is accepted as a reliable indirect indicator of Wilson’s disease [42, 43].

Renal impairment is common due to copper deposition in renal tubules, which could result in renal tubular acidosis and even Fanconi’s syndrome. Renal replacement therapy is typically required not only for kidney support but also for the fact that it acutely lowers serum copper and limits further haemolysis [8].

The use of penicillamine for the treatment of Wilson’s disease in the context of acute liver failure is not recommended in contrast to chronic disease [8].

9.6.5 Autoimmune Hepatitis

Similar to Wilson’s disease, this chronic condition can present as an acute decompensation of undiagnosed liver disease, which can be considered as acute liver failure.

Whilst the use of steroids in acute liver failure per se is not recommended, in the context of autoimmune hepatitis presenting as acute liver failure, which is representative of a severe form of the disease, a trial of high dose steroids in conjunction with specialist advice can be considered. However, as the severity of the disease is such that some cases would require transplantation, referral and transfer to a specialist liver unit should not be delayed pending a response to steroid treatment [8].

9.6.6 Acute Fatty Liver of Pregnancy/HELLP (Haemolysis, Elevated Liver Enzymes, Low Platelets) Syndrome

A rare disease of pregnancy, which develops as women near term (typically last trimester), it is associated with foetal and maternal mortality.

The triad of jaundice, coagulopathy and thrombocytopenia is seen with hypoglycaemia and features of pre-eclampsia like hypertension and proteinuria. Steatosis may be seen on imaging (ultrasound scan or computed tomography).

The over-riding priority once the syndrome has been recognised is prompt delivery of the foetus and post delivery supportive care for optimal maternal and foetal outcome [8].

Whilst full recovery post delivery is usual, occasionally deterioration does occur.

9.6.7 Acute Ischaemic Liver

Usually seen after cardiac arrest, it can also occur in any situation resulting in significant hypotension or hepatic hypoperfusion. Presentation can be anything on a spectrum from a self-limiting transaminitis to established acute liver failure. It should be noted that drug-induced hypoperfusion has been described due to recreational drugs like cocaine [44] and methamphetamines [45].

A shocked liver in isolation is rare and usually concurrent renal failure occurs especially if the underlying aetiology is due to cardiac dysfunction. In cases of drug-induced hepatic dysfunction, rhabdomyolysis can also cause renal dysfunction.

Management is typically cardiovascular support and transplantation is seldom warranted or feasible.

9.6.8 Budd-Chiari Syndrome

Acute hepatic vein thrombosis can present as acute liver failure. Typically in the presence of ascites and hepatic enlargement, the diagnosis is made via suitable imaging studies (ultrasound scan, computed tomography, venography or magnetic resonance venography).

Venous decompression is attempted but if unsuccessful and in the presence of acute liver failure transplantation may be the only option, provided underlying malignancy is excluded.

If Budd-Chiari is confirmed on imaging then further investigations are needed for potential underlying causes, to include but not limited to tumour markers, protein C, protein S, Factor V Leiden and Antithrombin III.

9.6.9 Acute-on-Chronic Liver Failure

As stated earlier, acute liver failure is thankfully rare. The intensive care clinician is more likely to encounter a ‘decompensation’ of chronic liver disease, also known as acute-on-chronic liver failure. It is imperative that the intensive care clinician can recognise an acute decompensation of a cirrhotic patient as a separate entity from acute liver failure most notably because of differences in management and prognosis including the likely benefit or otherwise of supportive therapy on the ICU.

The patient with deteriorating ‘end stage’ liver disease should be appropriately identified. Such differentiations are at the behest of a good history, eliciting precipitating factors or causative aetiologies and a careful assessment of recent biochemistry and imaging. The patient with ‘end stage’ liver disease exhibits a gradual decline in clinical status and liver function without a precipitating cause. Organ support in such setting is usually futile.

Acute-on-chronic liver failure is identified when the pattern of symptoms and signs associated with acute liver failure are present on a background of chronic disease (cirrhosis) which has progressed to demonstrate stigmata of portal hypertension like ascites and variceal bleeding.

Patients with compensated cirrhosis usually decompensate due to a ‘systemic’ stress, usually sepsis or gastrointestinal haemorrhage, or due to a direct insult to the liver, like ischaemia or toxins like alcohol or drugs. Importantly, if these precipitating events are identified and appropriately treated then reversibility in the deterioration in liver function can be expected. Therefore, identifying such patients can be reassuring in the provision of continuing organ support (Table 9.9).

Table 9.9 Precipitating causes of acute-on-chronic liver failure and specific treatment
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