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