HYPERACUTE DISEASE

Prevalent aetiologies in hyperacute disease include:

This group will frequently demonstrate the greatest degree of coagulopathy, encephalopathy, organ dysfunction and cerebral oedema but also carries the greatest chance of spontaneous survival.

SUBACUTE DISEASE

The aetiology is more frequently seronegative or idiopathic and drug-related, e.g. non-steroidal. Jaundice is inevitable but the transaminitis is often less pronounced than in the former group. Patients frequently present with established ascites and so may be clinically difficult to distinguish from chronic liver disease (CLD). Encephalopathy is often late and carries a lower risk of cerebral oedema and intracranial hypertension. Once they develop poor prognostic criteria the chances of effective liver regeneration and thus of spontaneous recovery are low: the prognosis is very poor without liver transplantation.

The aetiology of ALF must always be sought, not just for prognosis but for treatment options (Table 38.1).

Table 38.1 Causes of liver failure

The relative incidence of aetiologies varies across the world. Paracetamol is common in the UK, USA and Denmark, whereas hepatitis B is more common in France. A recent paper from the USA Acute Liver Failure group highlights the increasing incidence of paracetamol toxicity and also the potential role it plays as a covert agent in patients with no history of excess ingestion and non-specific symptoms that would otherwise be attributed to the seronegative group.² The rate of hepatitis B virus-induced ALF is decreasing with immunisation but is still highly prevalent and should always be considered.

A good history and review of the results of blood tests over the preceding weeks can be essential to the diagnosis. Any new drug ingestion (prescribed, recreational or over-the-counter) should be considered a potential culprit and discontinued if possible. In addition any treatments that may be detrimental to liver recovery should be avoided.

Acute viral hepatitis accounts for 40–70% of patients with ALF worldwide. Clinical characteristics are shown in Table 38.2. Acute hepatitis A (HAV) infection rarely leads to ALF (0.35% of infections), but continues to account for up to 10% of cases; morbidity increases with the age of infection. It is hoped that the rate will decrease with improving hygiene standards generally and the uptake of vaccination. It is diagnosed by the presence of the immunoglobulin (Ig) M antibody to HAV. HAV-related ALF has a relatively good prognosis, although age and comorbidity are relevant.

Table 38.2 Aetiology of acute liver failure and initial investigations

CT, computed tomography; HELLP, haemolysis (microangiopathic haemolytic anaemia), elevated liver enzymes and low platelets; HIV, human immunodeficiency virus; LDH, lactate dehydrogenase.

Acute hepatitis B (HBV) has been the cause of 25–75% of instances of ALF from viral hepatitis. The liver injury is immunologically mediated with active destruction of infected hepatocytes. Diagnosis is by the presence of the IgM antibody (HBcAb) to hepatitis B core antigen. Hepatitis B surface antigen (HbsAg) is frequently negative by the time of presentation. Hepatitis B DNA should also be assayed. ALF may also be seen with hepatitis D, as either a coinfection or suprainfection. Reactivation of hepatitis B is an increasing cause of ALF and should always be considered in a patient who has received steroids or chemotherapy. High-risk patients should be screened for sAg and HBV DNA and treated with antiviral agents if they are positive. This is a recognised problem in oncology and haematology but it is also a potential risk to patients in intensive care where steroids may be administered.

Hepatitis C (HCV) infection is commonly associated with CLD. It is detected by the presence of antibodies to HCV in serum. It rarely if ever results in ALF.

Hepatitis E (HEV), like hepatitis A, is transmitted via the faecal–oral route. It is particularly prevalent in the Indian subcontinent and Asia generally and is responsible for sporadic instances of ALF in the western world. It can be diagnosed by the detection of antibodies to HEV in serum.

Other viruses, such as herpes simplex 1 and 2, varicella-zoster virus, cytomegalovirus, Epstein–Barr virus and measles virus, may all rarely cause ALF, but may be seen especially in the immunocompromised patient. Diagnosis is by serological and polymerase chain reaction (PCR) testing. Rift Valley fever, dengue, yellow fever, lassa fever and the haemorrhagic fevers should be considered in those who are at risk.

Seronegative hepatitis (so called) is seen in patients in whom there are no identifiable viral causes nor obvious candidate drugs. Such patients may present with a prodromal illness and with acute or subacute maniifestations of the disease. Prognosis is less good than those with an identifiable virus and once they have poor prognostic criteria the chances of survival without liver transplant are exceptionally small. A subgroup may represent an acute autoimmune form of ALF, although many will not have any positive immmune markers such as elevated IgG or positive smooth-muscle or liver kidney antibodies. The pattern of markers shows an increased incidence of autoantibody positivity in seronegative cases and viral cases with elevated IgM in viral causes.^2,3

Drug-induced hepatitis is responsible for approximately 15–25% of cases of ALF. In some patients there appears to be a true hypersensitivity reaction, and symptoms develop after a sensitisation period of 1–5 weeks, recur promptly with readministration of the drug and may be accompanied by fever, rash and eosinophilia. In others the clinical pattern is less acute. Some herbal remedies are implicated as putative hepatotoxins but their role is made more difficult to assess by the variable nature of the constituent parts. Halothane hepatitis is now almost unheard of.

Paracetamol, taken intentionally or inadvertently, remains one of the commonest forms of acute hepatotoxicity. The early signs of nausea and vomiting after overdose are followed by signs of liver failure 48–72 hours after paracetamol ingestion. Treatment is with N-acetylcysteine, which increases hepatic stores of glutathione and metabolism of the toxic metabolite.

The recommended dosage schedule is 150 mg/kg in 5% dextrose over 15 minutes, followed by 50 mg/kg in 5% dextrose over 4 hours, followed by 100 mg/kg in 5% dextrose over 16 hours.

Even late administration of N-acetylcysteine (up to 36 hours after ingestion) may improve outcome. Predisposition to paracetamol-induced hepatotoxicity may occur in the following instances:

Mushroom poisoning can be seen even when only very small amounts have been ingested, e.g Amanita phalloides. The initial presentation is often with diarrhoea. Patients subsequently develop signs of hepatic necrosis at 2–3 days after ingestion. The liver injury is caused by amatoxins. Forced diuresis may be helpful as large amounts of toxin are excreted in urine, but inadvertent dehydration may result in renal failure. Thioctic acid, silibinin and penicillin have been advocated as therapy, but have not been subjected to controlled trials.

RECREATIONAL DRUGS AND ACUTE LIVER FAILURE

Ecstasy (methylenedioxymethamphetamine) may cause ALF although, given the amount of exposure to the drug, the incidence is presumably low. Proposed mechanisms of injury include immune mechanisms and/or heatstroke. Cocaine may result in an ischaemic hepatitis. Yellow phosphorus, carbon tetrachloride, chloroform, trichloroethylene and xylene (in glue sniffers) are very rare causes of ALF.

Miscellaneous causes account for a small proportion of cases of ALF but are very important to recognise.

FULMINANT WILSON’S DISEASE

The characteristic features are those of cirrhosis, seen on imaging, with concomitant problems such as thrombocytopenia which may be long-standing, Kayser–Fleischer rings on examination and frequently non-immune-mediated haemolysis.

Pregnancy-related liver failure includes HELLP (haemolysis (microangiopathic haemolytic anaemia), elevated liver enzymes and low platelets), acute fatty liver of pregnancy and liver rupture, often in association with pre-eclampsia. The prognosis of pregnancy-related ALF is usually good, although some develop severe liver injury with small-vessel disease, liver ruptures may require packing and occasionally transplantation is required (Figure 38.1).

Figure 38.1 Liver CT in pregnancy related liver disease demonstrating abnormal perfusion (a and b) with rupture, packing (a) and associated areas of infarction. Major bleeding into the liver.

Heat shock injury is now relatively rarely seen but the ischaemic hepatitides remain relatively common. They are normally associated with a congested liver that is subjected to a secondary insult – hypoxia or decreased-flow arterial inflow. This is seen with hypoxaemic respiratory failure, cardiac arrhythmias and hypotension.

Hepatic venous obstruction (Budd–Chiari syndrome) may cause ALF. There are symptoms and signs of liver of necrosis, often with capsular pain from congestion and ascites. In Asia this may be associated with anatomical anomalies of the inferior vena cava, whereas in Europe and the USA the experience is normally of thrombosis of the hepatic veins, often with an underlying procoagulant condition (Figures 38.2 and 38.3).

Figure 38.2 CT of Budd Chiari demonstrating arterio portal shunting and clot in Hepatic veins and IVC.

Figure 38.3 Budd–Chiari liver. Arrow shows liver necrosis; ischaemic/infarcted liver.

Malignancy may also present with ALF, albeit rarely. The clinical pattern normally is that of elevated biliary enzymes in addition to the transaminases. This pattern of disease may be seen in those with hepatic lymphoma, often with an elevated lactate dehydrogenase or indeed with diffuse infiltration with other malignancies.

SPECIFIC CONSIDERATIONS

N-acetylcysteine is administered for paracetamol-induced ALF, as mentioned above. Its role in non-paracetamol-induced ALF remains undefined and a US trial is at present assessing this.

Chelating agents are not of benefit in patients with established ALF secondary to Wilson’s disease but play an important role in chronic presentations. Withdrawal of such treatments, or indeed non-compliance, especially in teenagers, may precipitate ALF.

Antiviral therapy has a predominant role in preventing reactivation of hepatitis B in patients exposed to chemotherapy and steroids.

Thrombolytic therapies may be of benefit in patients with early acute Budd–Chiari syndrome, although increasingly the treatment option would be to undertake a transhepatic portosystemic shunt (TIPS) shunt, decompressing the liver with a stent passed either through the hepatic vein (if the clot is soft enough) or via the inferior vena cava and through to the portal vein. Such procedures should be undertaken in units with the facilities to transplant as there is a risk of precipitating ALF. Chemotherapy may be offered to those with lymphoma involving the liver and in these instances tissue is paramount, either of liver or from another diagnostic site.

Steroid therapy is beneficial in acute autoimmune hepatitis but its role in autoimmune ALF has been less clear. A recent publication from the Paris group suggests that steroids for those with established ALF are potentially detrimental.⁴

ENCEPHALOPATHY

This is part of the syndrome of ALF. The spectrum extends from mild confusion progressing to deep coma, cerebral oedema and raised intracranial hypertension. ALF is also associated with renal, cardiovascular and respiratory failure along with significant metabolic disarray and coagulopathy.

COAGULOPATHY

Coagulopathy is the hallmark of ALF, with prolongation predominantly of the prothrombin time and to lesser degrees the activated partial thromboplastin ratio (APTR). In a small percentage of patients the coagulopathy will respond, at least partially, to vitamin K. Intravenous vitamin K 10 mg is normally administered. Thrombocytopenia is frequent and normally consumptive in nature. Bleeding is rare, although may be seen in those with severe prolongation of APTR, low fibrinogen and severe thrombocytopenia. Coagulation or repletion of coagulation factors is necessary for clinical bleeding and prophylactically before major invasive procedures. Coagulation support is normally not given routinely so that the international normalised ratio (INR) can be monitored with regard to prognosis.

ENCEPHALOPATHY

Hepatic encephalopathy encompasses a wide spectrum of neuropsychiatric disturbances associated with both acute and chronic liver dysfunction. Importantly, encephalopathy in ALF may be complicated by cerebral oedema and progress from minor levels to deep levels of coma with great rapidity. This has to be considered when transferring patients with ALF between hospitals. Intubation and sedation prior to undertaking any transfer should be considered in any patient with progressive encephalopathy.

Encephalopathy is a clinical diagnosis, graded from 1 to 4 depending on clinical severity (Table 38.3). The development of encephalopathy is essential for the diagnosis of ALF. Patients with acute and hyperacute liver failure are at greatest risk of developing grade IV coma and cerebral oedema.

Clear aetiological factors in the development of encephalopathy remain under discussion but it is believed that there is a build-up of putative toxins, of which ammonia is thought to be most pertinent, resulting in glutamine intracerebral accumulation and the development of cerebral oedema.^5–7 In ALF there is a clear relationship between the development of higher grades of coma and arterial ammonia levels (cut-off between 150 and 200 μmol/l) renal dysfunction and aetiology.^8–10 The relationship in CLD exists but is less clear.

The development of cerebral oedema and intracranial hypertension in patients with ALF is thought to relate, amongst other things, to the speed of onset. In patients with CLD, adaptation occurs and there is improved control of intracellular osmolarity (myoinositol) so that cellular oedema is rare and of low grade.¹¹

The association between the development of encephalopathy and markers of inflammation is well demonstrated, both in regard to systemic inflammatory response syndrome (SIRS) markers and inflammatory mediators such as tumour necrosis factor.^12,13 Curiously, a similar relationship between inflammation and encephalopathy is seen in patients with CLD.¹⁴ What is not yet clear is whether treatments that modulate the inflammatory response will be of benefit. This and other avenues proposed from basic animal research may well result in several novel approaches to the treatment of cerebral oedema and possibly encephalopathy over the forthcoming years.

Cerebral blood flow shows marked variability in patients with ALF. Hyperaemia has increased prevalence in those who develop intracranial hypertension. The role of hyperventilation has not been shown to be beneficial in routine management but plays a role in the treatment of increased intracranial pressure (ICP) with associated hyperaemia.¹⁵

The clinical management of the cerebral complications of ALF has been developed pragmatically and by the extrapolation of data from the neurosurgical literature rather than from the results of large randomised controlled clinical trials. Patients whose conscious level deteriorates to grade 3/4 coma should undergo elective intubation, sedation and ventilation. Sedation may be undertaken with a variety of compounds but the standard would be to utilise an opiate and a sedative such as propofol.

Cerebral perfusion pressure of greater than 60 mmHg has been suggested as optimal. It is of note that patients with ALF often do not autoregulate to pressure and consequently increases in blood pressure may be associated with increased cerebral blood flow and potentially increased ICP, particularly if they are at a critical point on their pressure–volume curve. This promotes the use of ICP monitoring in patients requiring pressor agents.⁸ Cardiovascular failure necessitates invasive monitoring to optimise treatment and to determine the optimal therapeutic agents. The issue of noradrenaline (norepinephrine) versus vasopressin or terlipressin is difficult. In one study terlipressin resulted in a significant increase in ICP but in another there were no such detrimental effects.^14,16 It may be that the effects of terlipressin are highly individual and potentially time course-dependent, again supporting the role of ICP monitoring in these situations.

Carbon dioxide

In most patients normocapnia is ideal as the relationship between cerebral blood flow and arterial CO₂ is maintained.

The complexity of these patients defines the importance of multimodule monitoring being considered in all patients with ALF who develop grade III/V coma, and especially those who are deemed high-risk. These include those with respiratory dysfunction, of young age, hyperacute and acute presentations, renal failure, fever and other SIRS markers or any patients on vasopressors.

Arterial ammonia – both the level (levels greater than 150–200 μmol/l) and the failure of this level to fall with treatment – may help in prognostication.^8,10 The monitoring may comprise reverse jugular monitoring, middle cerebral artery Doppler measurements and ICP monitoring. ICP monitoring is more controversial as it has not been shown specifically to improve outcome (few monitoring devices in isolation have altered outcome). A recent retrospective study from the US Acute Liver Failure group showed that ICP monitoring carried a complication rate of 10%: half of the complications were serious and two-thirds possibly contributed to mortality. Monitoring did result in more treatment interventions being undertaken.¹⁷

Coagulation problems and the risk of bleeding associated with monitoring may be minimised by a combination of coagulation support at the time of placement and technical expertise. Some centres support coagulation at the time of insertion with plasma products and platelets whilst others utilise recombinant factor VII.

A standard baseline approach to the management of patients with ALF and grade III/IV coma would be as follows.

Appropriate sedation and ventilation – hypercarbia should be avoided, although in the setting of acute lung injury, lung-protective strategies should be undertaken, probably in conjunction with cerebral monitoring so as to ensure optimal manipulation of the physiological variables.

Hyponatraemia and hyperammonaemia have been shown to be detrimental, whereas a randomised controlled trial showed benefit to the patients whose serum Na was maintained between 140 and 150 mmol/l. (Bolus hypertonic saline, 30%, was used for episodes of ICP greater than 25 mmHg.)¹⁸

Cerebral perfusion pressure should be optimised using ICP monitoring to ensure that changes in mean arterial pressure do not compromise cerebral perfusion pressure.

Sustained ICP rises beyond 25 mmHg require treatment. First-line treatment remains mannitol 0.5 g/kg given as a bolus with an appropriate subsequent diuresis. It is essential that serum osmolarity is maintained at less than 320 mosmol to avoid damage to the blood–brain barrier and worsening of vasogenic oedema. Increasingly hypertonic saline may also be utilised in this setting.

Some patients remain resistant to treatment and in these cases other therapies may be considered. Hypothermia has been shown to decrease cerebral blood flow, decrease ICP and decrease cerebral ammonia uptake in one clinical study.^19,20 The role of hypothermia as an early preventive intervention in grade III/IV coma is contentious and, given the problems of hypothermia in the neurosurgical arena, the results of controlled studies are awaited. Fever should be avoided in these patients and hypothermia reserved for intracranial hypertension that is resistant to standard treatment.

Other treatment options that have been shown to be potentially beneficial are thiopental and intravenous indometacin (0.5 mg/kg).²¹ Potential monitoring and treatment algorithms, as used by this unit, are seen in Figure 38.4.

Figure 38.4 Treatment of raised intracranial pressure.

SEPSIS

Sepsis is common in ALF and both culture-positive and negative SIRS are seen in ALF patients. They are functionally immunosuppressed in terms of impaired cell-mediated immunity, complement levels and phagocytosis.²² Functional immmunoparesis can only be observed and depression of human leukocyte antigen (HLA) DR expression correlates with prognosis and severity of liver injury.^23,24 As such, scrupulous attention with regard to hand-washing and line care needs to be applied to decrease the risk of nosocomial infection. Regular culture screens are required and antimicrobials are indicated in patients with any clinical suggestion of sepsis. Prophylactic intravenous antifungals should be considered, especially in those listed for transplantation. The choice of antimicrobial agent should be driven by local resistance patterns. Antimicrobial therapy should be reviewed in the light of culture results on a daily basis.

CARDIOVASCULAR

Patients with ALF develop a hyperdynamic circulation with peripheral vasodilation and central volume depletion. Hypotension is common and may initially respond to volume repletion. Assessment of volume reponsiveness in the clinical setting may be difficult and pressure measurements are a poor indicator of volume status. Hypotension that does not respond to volume will normally require some form of invasive haemodynamic monitoring and frequently institution of vasopressor agents. Increasingly it is recognised that volume responsiveness, as in general intensive care unit patients is best determined by dynamic rather than static variables.

The requirement for pressor agents should raise the possibility of adrenal dysfunction. Patients with ALF have been demonstrated to have impaired response to adrenocorticotrophic hormone (ACTH).25 26 The response at 30 and 60 minutes in terms of cortisol should be examined following 250 μg ACTH in all patients with ALF who are requiring pressor agents. A subnormal response should result in consideration of hydrocortisone replacement therapy, normally given for a period of 10 days. Interestingly, adrenal dysfunction has similarly been reported in acute-on-chronic liver failure and steroid replacement may result in improved outcome.^26,27

Elevated troponin levels can be observed in patients with liver failure, especially those with cardiovascular failure.²⁸

RESPIRATORY

Ventilatory support is frequently required in patients with ALF, usually because of decreased conscious level rather than hypoxia, at least in the initial stages of disease.

Common respiratory complications are pleural effusions, atelectasis and intrapulmonary shunts. Acute respiratory distress syndrome (ARDS) and acute lung injury may be seen and can be precipitated by extrapulmonary sepsis or inflammation.

Ventilatory strategies are influenced by both the respiratory and the multiorgan involvement that is characteristic of ALF. Thus patients with deep levels of coma and at risk of cerebral oedema will require close attention to CO₂ levels and tailored sedation regimens. Hypercapnia may have to be tolerated in patients progressing to ARDS. This requires balancing against the cerebral needs of these patients as hypercarbia and increased cerebral blood flow will tend to increase ICP. Pleural effusions may require drainage if they are impeding ventilation. Weaning may be facilitated by undertaking tracheostomy during the recovery period of ALF.

RENAL

Renal failure is common, with an incidence as high as 50%. This is particularly the case with paracetamol-induced liver failure, where the drug may also exert a directly toxic effect on the renal tubule. The aetiology of acute renal dysfunction is frequently multifactorial, with hepatorenal failure being a rare occurrence. Acute tubular necrosis and prerenal renal failure are more common precipitants. As such, volume therapy and maintenance of intrathoracic blood volume are essential in the management of such patients, as is the avoidance of nephrotoxins. Intra-abdominal hypertension is frequent and may reduce renal perfusion pressure and contribute to renal dysfunction; the measurement of intra-abdominal pressure may be a valuable component of monitoring.

Established renal failure requires the institution of renal replacement therapy (RRT). In patients with ALF early consideration should be given to RRT to control fluid balance and acid–base disturbances and to avoid rapid changes in osmolarity. It may limit or control elevations of arterial ammonia and retard the development of cerebral complications. The haemodynamic instability and associated cerebral complications of this patient group have resulted in the application of continuous modes of RRT rather than intermittent haemodialysis. Inability of the liver to metabolise and utilise lactate or acetate buffer solutions results in the use of bicarbonate buffers. Extrapolation from data in critically ill patients with acute renal failure suggests that the optimal filtration rate is 35 ml/kg per hour.

SPECIFIC TREATMENTS

Very few specific treatments are of proven benefit. N-acetylcysteine is useful for paracetamol-related liver failure. There are specific antiviral therapies to prevent reactivation of hepatitis B in at-risk individuals.

Therapies should aim to provide an environment for liver regeneration or stability until a suitable liver is available for orthotopic transplantation. The role of extracorporeal liver support systems remains a hope for the future but at present no system has been shown to have a definitive survival benefit in a controlled trial.

CIRRHOSIS AND ACUTE-ON-CHRONIC LIVER DISEASE

This is the commonest form of liver disease presenting to the intensive care environment. The commonest precipitants are:

The cause of decompensation should be sought in all cases when it is not clinically apparent. Common causes include sepsis, dehydration, drug therapies, e.g. opiates and sedatives, hepatocellular carcinoma (HCC) and portal vein thrombosis.

Ultrasound should be undertaken in all patients, examining the hepatic veins and portal veins for patency. Signs of an HCC should be sought on ultrasound, alpha-fetoprotein and frequently axial imaging techniques. The therapies available for HCC have improved dramatically in recent years and prognosis can be good, especially with the option of cure with liver transplantation.

Sepsis should be actively sought and treated. In patients with ascites a diagnostic tap should always be undertaken for microbiological culture and cell count (a polymorphonuclear count > 250/mm³ is indicative of bacterial peritonitis).

Alcoholic hepatitis is a frequent cause of decompensation and requires aggressive treatment. The severity can be assessed using the Glasgow score or Madrey score and in high-risk patients steroid therapy may be considered.^36,37 Response to steroids over the first 7 days is associated with improved outcome.³⁸ The role of antioxidants has been examined but no benefit was seen.^39,40 Another approach has been to look at the value of enteral feeding, which was comparable with steroid treatment over a 4-week period, albeit in a small study.⁴¹ The use of pentoxifylline has been reported in a single-centre study to decrease the risk of developing hepatorenal failure and hence impacting on outcome.⁴²

ENCEPHALOPATHY

This is frequently seen in patients with cirrhosis and a systemic inflammatory response – sepsis should be sought and treated. Unlike ALF, this group does not normally develop intracranial hypertension and as such the main thrust for managing encephalopathy is determined by control of the airway and prevention of aspiration.

Therapies to alleviate encephalopathy aim to decrease ammonia levels and thus focus on bowel cleansing with agents such as lactulose. There is little evidence-based research to support any particular avenue of treatment. A recent trial examining the role of albumin dialysis in the management of encephalopathy has been recently completed.⁴³

As noted previously, the role of inflammation seems of importance in the development of encephalopathy.^44,45 The role of feeding and encephalopathy has always caused controversy. Recent guidance suggests that protein restriction is not appropriate and a study examining early versus slow introduction of protein into enteral nutrition showed no increase in encephalopathy and indeed appeared beneficial in respect of nitrogen balance.^46,47

VARICEAL HAEMORRHAGE

The management of variceal haemorrhage remains that of basic resuscitation and care of the airway. Coagulation factors require appropriate supplementation along with other blood products. The role of sepsis in variceal haemorrhage has become clearer, with sepsis being a frequent precipitant of bleeding. Cultures should be taken and all patients with variceal haemorrhage should be given antibiotics and this has been shown to decrease the risk of rebleeding.^48,49 Splanchnic vasoconstrictors, such as glypressin, are beneficial in controlling oesophageal haemorrhage but their role in gastric variceal haemorrhage per se has not been examined.^50,51 Banding ligation therapy remains the treatment of choice for oesophageal haemorrhage, with tissue adhesives being utilised in gastric varices. Failure to control variceal bleeding after two endoscopic sessions should result in consideration of TIPS insertion.^52,53 In patients in whom TIPS might be considered to be of benefit in controlling variceal bleeding, consideration needs to be given to the severity of the underlying liver disease that may in its own right make TIPS ill advised.⁵⁴

RENAL FAILURE

Hepatorenal failure is seen in cirrhosis – the rapidly progressive form is more commonly seen in the critical care environment. It should be noted that this is a diagnosis of exclusion of other causes. The evidence base for colloid therapy (to ensure adequate central volume repletion) along with splanchnic vasoconstrictor therapy (glypressin) is reasonable but more recently data suggest that constrictors such as noradrenaline may be equally applied.^51,55–57 Prevention of renal failure should also be considered with appropriate volume resuscitation in patients with sepsis and bacterial peritonitis. Ascitic drainage should be undertaken with appropriate albumin loading if large-volume drainage is undertaken or in patients at risk of central volume depletion.⁵⁸

Paracetamol-related hepatotoxicity should also be considered for transplantation if arterial lactate remains elevated following volume resuscitation (gt; 3.5 mmol/l) and serum phosphate is elevated.

It should be noted that these criteria were not developed in patients with acute Budd–Chiari syndrome, Wilson’s disease or pregnancy-related liver failure. Nor have they been or should they be applied in the setting of trauma-related liver failure. Although these criteria demonstrate that being a child (age < 10 years) is a poor prognostic feature, the decision to transplant children is not normally derived from these criteria.

In children the finding of an isolated INR > 4.5 suggests the need for transplantation, assuming that the child has not ingested paracetamol (in this setting the paracetamol criteria would be applied).

The Pittsburgh data suggest that a poor outcome is associated with a liver volume of less than 1000 ml and greater than 50% hepatocyte necrosis of biopsy. The latter may be difficult to interpret due to sampling error.

In acute Budd–Chiari syndrome the combination of encephalopathy and renal failure should lead to consideration for transplantation. Increasingly, TIPS shunts have a place in the earlier management of acute Budd–Chiari syndrome. Such an undertaking should be performed at a centre providing transplantation since a proportion of patients will decompensate with encephalopathy and severe ALF, requiring urgent transplantation.