Acute liver failure

Introduction

Acute liver failure (ALF) remains one of the most challenging medical emergencies. It is a rare condition in which rapid deterioration of liver function results in altered mentation and coagulopathy in previously normal individuals. The overall incidence in developed countries is between one and six cases per million people per year. The most prominent causes include viral hepatitis, drug-induced liver injury (DILI), autoimmune liver disease and shock or hypoperfusion; many cases (≈20%) have no discernible cause. ALF often affects young persons and is associated with high morbidity and mortality. In many countries, it is the most frequent indication for emergency liver transplantation. Prior to the availability of transplantation, mortality due to ALF was extremely high, often exceeding 90%; the most common causes of death were multiorgan failure, haemorrhage, infection and cerebral oedema. Currently, 1-year survival exceeds 80%. Because of its rarity, ALF has been difficult to study in depth and very few controlled therapy trials have been performed. ALF research has been limited to a handful of large units or to collaborative networks, such as the National Institutes of Health (NIH)–sponsored US Acute Liver Failure Study Group (ALFSG).

Aetiology, pathogenesis and pathology

ALF occurs when the rate of hepatocyte death exceeds the rate of hepatocyte regeneration as a result of various insults that lead to a combination of apoptosis or necrosis. Apoptosis is associated with nuclear shrinkage but without cell membrane rupture. Therefore there is no release of intracellular contents and no subsequent secondary inflammation. In contrast, necrosis is associated with ATP depletion, resulting in a swollen cell that eventually lyses with the release of intracellular contents associated with secondary inflammation. Most causes of ALF result in either apoptosis or necrosis; for example, paracetamol toxicity results in apoptosis and ischaemia results in necrosis. The clinical result of the cellular damage is a catastrophic illness that can lead rapidly to coma and death caused by multi-organ failure.

Epidemiology

There is substantial worldwide variation in the cause of ALF. It is relatively uncommon in the United Kingdom, causing fewer than 500 deaths and being responsible for less than 15% of liver transplantations per annum (<100 transplants per year). Meanwhile, ALF affects approximately 2000 people per year in the United States. There, ALF accounts for approximately 7% of all liver transplantations annually; however, it accounts for more than two-thirds of transplantations in the Far East.

Over the past half century, the relative frequency of causes of ALF has evolved, with hepatitis A and B declining in incidence and paracetamol (acetaminophen) overdose increasing in Western Europe and the United States. In parallel to paracetamol overdoses, idiosyncratic DILI is among the most common discernible causes, whereas cases of indeterminate aetiology (cause not discernible after extensive evaluation) continue to constitute a sizable patient group. The differences in aetiology between developing and developed countries are well characterized. Europe and the United States feature a high incidence of paracetamol toxicity leading to ALF, along with DILI due to prescription agents, which is less common but equally important. By contrast, South Asia and Hong Kong have a higher incidence of hepatitis viruses, specifically hepatitis E in Pakistan and hepatitis B in Hong Kong, as well as in Australia, with fewer cases of DILI observed at least in the developing world.

Prevention

Primary prevention of ALF in the West mainly involves strategies to combat increasing rates of paracetamol-induced ALF including legislation to reduce over-the-counter availability of paracetamol, printing specific warnings about overdose in the packets, use of paracetamol/methionine combination analgesics and the promotion of alternative analgesics.

Secondary prevention of ALF involves immunization strategies. Hepatitis A and B vaccination is safe and immunogenic in patients with mild to moderate chronic liver disease (CLD), although vaccination is less effective in those with decompensated liver cirrhosis or after liver transplantation.

Clinical features

History taking should include a careful review of possible exposures to viral infection and drugs or other toxins. If severe encephalopathy is present, a collateral history may be all that is available or a history may be unavailable. In this setting, limited information is available, particularly regarding possible toxin/drug ingestions.

Physical examination must include careful assessment and documentation of mental status and a search for the stigmata of CLD. Jaundice is often but not invariably seen at presentation. Right upper quadrant tenderness is variably present. Inability to palpate the liver or even to percuss a significant area of dullness over the liver can be indicative of decreased liver volume due to massive hepatocyte loss. Hepatomegaly may be seen early in viral hepatitis or with malignant infiltration, congestive heart failure or acute Budd-Chiari syndrome. History or signs of cirrhosis should be absent, as such features suggest underlying CLD, which may have different management implications.

Differential diagnosis

Common causes of ALF are hepatitis viruses or drugs ( Table 7.12.1 ). In Western countries, drug-induced ALF predominates, comprising 19% to 75% of all cases of ALF. In India, 91% to 100% of ALF cases are due to viruses, with drug-induced cases responsible for 0% to 7.4%.

The developed world is particularly subject to rare ALF due to idiosyncratic DILI because of the large quantity of drugs ingested. Idiosyncratic drug reactions account for 13% of cases of ALF in the United States and 5% of cases in the United Kingdom. Examples of causative drugs include antibiotics (amoxicillin-clavulanic acid, ciprofloxacin, doxycycline, erythromycin, isoniazid, nitrofurantoin, tetracycline, sulphonamides), antivirals (fialuridine), antidepressants (amitriptyline, nortriptyline), oral hypoglycaemic drugs (troglitazone, metformin), anticonvulsants (phenytoin, valproic acid), anaesthetics (halothane, isoflurane), statins (atorvastatin, lovastatin, simvastatin), immunosuppressants (cyclophosphamide, methotrexate, gold), non-steroidal anti-inflammatory drugs (NSAIDs), salicylates (Reye syndrome), antithyroid drugs (propylthiouracil), antiarrhythmics (amiodarone) disulfiram and flutamide. The presentation of DILI is more subacute, with lower aminotransferases and higher bilirubin levels. The likelihood of survival in this setting is less than 30% and such patients more often undergo liver transplantation.

Infectious diseases—such as falciparum malaria, typhoid fever, leptospirosis and dengue fever—may mimic ALF at presentation. Patients can present with fever, jaundice and features of encephalopathy, which should be considered in all patients presenting with ALF, particularly in patients seen in the tropics or in those who have recently travelled in the tropics. Baseline routine clinical and laboratory investigations will provide supportive evidence of an infective cause. After a definitive diagnosis has been reached, specific therapy for the infectious disease in addition to supportive therapy for ALF reduces mortality.

Clinical investigations

Initial laboratory investigation in the emergency department (ED) is aimed at evaluating both the aetiology and severity of ALF ( Table 7.12.2 ).

Other urgent investigations, mainly aimed at evaluating the aetiology of ALF following hospital admission, include viral hepatitis serologies (anti-HAV IgM, hepatitis B surface antigen [HBSAg], anti-HBc IgM, anti-HEV IgM, anti-HCV IgM), autoimmune markers (antinuclear, anti–smooth muscle antibodies, immunoglobulin levels) and ceruloplasmin level. Plasma ammonia, preferably arterial, may also be helpful. A liver biopsy, most often done via the transjugular route because of coagulopathy, may be indicated when certain conditions (e.g. autoimmune hepatitis, metastatic liver disease, lymphoma or herpes simplex hepatitis) are suspected.

Other investigations may be required as clinically indicated, for example, determination of the HIV status of patients who are candidates for liver transplantation.