Acute Liver Failure


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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. United States estimates are placed at approximately 2000 cases per year. The most prominent causes include drug-induced liver injury, viral hepatitis, autoimmune liver disease and shock or hypoperfusion; many case (≈20%) have no discernible causes.

Acute liver failure often affects young persons and carries a high morbidity and mortality. Prior to transplantation, most series suggested less than 15% survival. Currently, overall short-term survival with transplantation is greater than 65%. Because of its rarity, ALF has been difficult to study in depth and very few controlled therapeutic trials have been performed. As a result, standards of intensive care for this condition have not been established.

1.  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 subsequent secondary inflammation. In contrast, necrosis is associated with ATP depletion, resulting in a swollen cell that eventually lyses, with the release of intracellular content 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 multiorgan failure.

2.  Epidemiology

There is significant worldwide variation in the cause of ALF. It is relatively uncommon in the UK, causing fewer than 500 deaths and being responsible for less than 15% of liver transplantations per annum (fewer than 100 transplants per year). Meanwhile, in the USA ALF affects approximately 2000 people per year. Although it accounts for fewer than 10% of all liver transplantations in the United States, it accounts for more than two-thirds of transplantations in the Far East.

Paracetamol poisoning is the commonest cause of ALF in the UK and USA, causing up to 70% of cases in the United Kingdom and 51% of cases in the United States. Up to 10% of patients with paracetamol self-poisoning develop severe liver damage, but less than 2% go on to develop ALF, the worst outcomes being in patients with concurrent alcohol use.

Other major causes of ALF in the United States include idiosyncratic drug reactions (13%), secondary to hepatitis C (HCV; 4%). Seventeen per cent of ALF cases in the United States are of determinate cause. A small number of cases in the United States result from miscellaneous causes such as Wilson’s disease, cardiogenic, pregnancy related, auto-immune disease and Budd-Chiari syndrome.

In the United Kingdom, approximately 5% of cases are caused by non-paracetamol drugs such as anti-tuberculous therapy, anticonvulsants, sterioids, NSAIDs, herbal remedies and recreational drugs (for example Ecstasy and cocaine). Less than 0.05% of cases of acute hepatitis A and B lead to ALF, with these viruses contributing less than 5% of the ALF cases.

Seronegative (no-A-E) hepatitis, a diagnosis of exclusion, is the commonest presumed viral cause in the United Kingdom and other western countries, but contributes less than 10% of all ALF cases. In the UK, unusual viral causes include herpes simplex, Epstein-Barr, cytomegalovirus, and varicella zoster. Small numbers of ALF cases in the United Kingdom result from miscellaneous causes such as pregnancy, Wilson’s disease, Budd-Chiari syndrome, autoimmune hepatitis, ischaemic hepatitis and malignant infiltration.

Although ALF is most commonly drug-induced in the west, in the developing world and the Far East it is most often caused by viral hepatitis. Particularly common causes are exacerbations of chronic HBV, which is endemic in many countries, including Hong Kong, and hepatitis E in India. Flares of chronic HBV may be spontaneous, represent a secondary response to increased levels of replicating wild-type or mutant virus, occur after immunosuppressive and cytotoxic therapy, or occur following superinfection with other hepatotrophic viruses such as hepatitis D and HCV.

3.   Prevention

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

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

4.   Clinical Features

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

Physical examination must include careful assessment and documentation of mental status and a search for 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 reduced liver volume due to massive hepatocyte loss.

Hepatomegaly may be seen early in viral hepatitis or with malignant infiltration, congestive heart failure or acute Buddi-Chiari syndrome. History or signs of cirrhosis should be absent, as such features suggest underlying CLD, which may have different management implications.

5.   Differential Diagnosis

Common causes of ALF are hepatitis viruses or drugs (Table X1). In western countries, drug-induced ALF predominates, comprising 19–75% of all cases. In India 91–100% of cases are due to viruses, with drug-induced cases responsible for 0–7.4%.

Table X1 | Differential Diagnosis of ALF
VirursesHepatitis A and B viruses (typical viruses causing viral hepatitis)
Hepatitis C virus (rare)
Hepatitis D virus
Hepatitis E virus (often in pregnant women in endemic areas)
Haemorrhagic fever viruses
Herpes simplex virus
Epstein-Barr virus
DrugsParacetamol hepatotoxicity
Idiosyncratic hypersensitivity reactions (e.g. isoniazid, statins, halothane)
Illicit drugs (e.g. ecstasy, cocaine)
Alternative medicines (e.g. chaparral and Terucrium polium)
ToxinsMushroom poisoning (usually Amanita phalloides)
Bacillus cereus toxin
Cyanobacteria toxin
Organic solvents (e.g. carbon tetrachloride)
Yellow phosphorus
VasculopathyIschaemic hepatitis
Hepatic vein thrombosis (Budd-Chiari syndrome)
Hepatic veno-occlusive disease
Portal vein thrombosis
Hepatic arterial thrombosis
MetabolicAcute fatty liver of pregnancy/HELLP (haemolysis, elevated liver enzymes, low platelets) syndrome
α1-Antitrypsin deficiency
Fructose intolerance
Lecithin-cholesterol acyltransferase deficiency
Reye’s syndrome
Wilson’s disease
AutoimmuneAutoimmune hepatitis
MalignancyPrimary liver malignancy (hepatocellular carcinoma or cholangiocarcinoma)
Secondary (e.g. extensive hepatic metastases or infiltration of adenocarcinoma)
MiscellaneousAdult-onset Still’s disease
Primary graft non-function (in liver transplant recipients)
Indeterminate aetiology (≈20% of ALF cases)

Idiosyncratic drug reactions account for 13% of cases of ALF in the United States and 5% of cases in the UK. Examples of causative drugs include:

  • antibiotics (amoxicillin-clavulant 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),
  • NSAIDs,
  • salicylates (Reye’s syndrome),
  • anti-thyroid drugs (propylthiouracil),
  • anti-arrhythmics (amiodarone)
  • disulfiram and
  • flutamide.

Infectious diseases such as falciparum malaria, typhoid fever, leptospirosis and dengue fever may mimic ALF at presentation. They can present with fever, jaundice and features of encephalopathy, and should be considered in all patients presenting with ALF, particularly in the tropics, or in patients who have recently travelled in the tropics.

Baseline routine clinical and laboratory investigations will provide supportive evidence of an infective cause. After reaching a definitive diagnosis, specific therapy for the infectious disease in addition to supportive therapy for ALF reduces mortality.

Table X2 | Emergency Department Investigations for ALF
HaematologyFull blood count
Prothrombin time/INR
Blood type and screen
BiochemistryLiver function tests
Urea & electrolytes
Arterial blood gas
Arterial ammonia
ToxicologyParacetamol level
Toxicology screen
UrinalysishCG (females)
Imaging studiesChest radiography
Liver ultrasonography

6.   Clinical Investigations

Initial laboratory investigation in the emergency department (ED) is aimed at evaluating both the aetiology and severity of ALF (Table X2). Other urgent investigations, mainly aimed at evaluating the aetiology of ALF following hospital admission, include viral hepatitis serologies (anti-HAV IgM, HBSAg, anti-HBc IgM, anti-HEV IgM, anti-HCV IgM), autoimmune markers (anti-nucear, 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 such as autoimmune hepatitis, metastatic liver disease, lymphoma, or herpes simplex hepatitis are suspected.

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

Table X3 | Grades of Hepatic Encephalopathy
Grade 1Drowsy but coherent, mood change
Grade 2Drowsy, confused at times, inappropriate behavior
Grade 3Very drowsy and stuporose but rousable; alternatively restless, screaming
Grade 4Comatose, barely rousable

7.  Criteria for Diagnosis

The most widely accepted definition of ALF includes impairment of liver function with evidence of coagulation abnormality (usually an international standardized ratio of prothrombin (INR) ≥1.5) and any degree of mental alteration (encephalopathy; Table X3) in a patient without existing cirrhosis and with an illness of less than 26 weeks’ duration. Patients with Wilson’s disease, vertically acquired HBV, or autoimmune hepatitis may be included in spite of the possibility of cirrhosis if their disease has only been recognized for less than 26 weeks.

A number of other terms have been used, including fulminant hepatic failure and fulminant hepatitis or necrosis. It is intuitively logical that acute liver failure is a better overall term that should encompass all durations up to 26 weeks.

Terms signifying duration of illness, such as hyperacute (<7 days), acute (7–21 days) and subacute (>21 days and <26 weeks), are not particularly helpful as they do not have prognostic significance distinct from the cause of the illness.

8.   Treatment

The most important step in the treatment of ALF is to identify the cause, as the prognosis depends on this. Death in ALF is predominantly related to sepsis, multiorgan failure and intracranial hypertension.

The circulatory disturbances in ALF, which contribute to the often-associated renal failure, are characterized by a generalized vasodilatation that results in increased cardiac output and reduced systemic vascular resistance and mean arterial pressure.

Emergency liver transplantation is the only proven therapeutic intervention for ALF. Whereas treatments for specific aetiologies are also initiated, emergency management requires intensive care support because deterioration can be rapid. Careful attention must be paid to fluid management, haemodynamics and metabolic parameters, as well as surveillance for and treatment of infection.

Maintenance of nutrition and prompt recognition and resuscitation of gastrointestinal bleeding are crucial as well. Coagulation parameters, complete blood counts, metabolic panels (including glucose) and arterial blood gas should be checked frequently. Liver function tests (LFTs) are generally measured daily to follow the course of the condition; however, changes in aminotransferase levels correlate poorly with prognosis.

8.1    General Measures

Fundamental to the management of patients with ALF is the provision of good intensive care support. Aggressive monitoring is required to detect respiratory and haemodynamic complications, neurological changes, infections and gastrointestinal haemorrhage. Airway protection and endotracheal intubation may be required, because as patients become comatose their ability to protect their airway from aspiration is reduced.

Central venous access and invasive and non-invasive arterial blood pressure monitoring are useful for monitoring vascular status. Swan-Ganz pulmonary artery pressure monitoring may provide helpful information about cardiac output. All patients should have a urinary catheter placed to monitor output. Volume resuscitation should ideally be with colloids and titrated to a pulmonary wedge pressure of 12–14 mmHg. Intravenous dopamine may be required to encourage renal perfusion, and noradrenaline (norepinephrine) may be required for systemic hypotension.

Metabolic derangements such as hypoglycaemia should be sought and treated aggressively. Hypokalaemia is common and should be managed with intravenous supplements. Intravenous phosphate and magnesium supplements may also be required. Platelets may be required if the count falls below 20 000/mL. H2-receptor blockers are given for prophylaxis against gastrointestinal bleeding. Nasogastric tube insertion for stomach decompression may be required in comatose patients. Dialysis may be required for deteriorating renal function and worsening acidosis.

Maintaining adequate cerebral perfusion is paramount, and the patient should be nursed in a quiet environment with 10o head-up tilt. Intracranial pressure monitoring may be helpful in some patients for directing therapy to prevent brainstem herniation.

Withdrawal of dietary protein is commonly recommended to treat acute hepatic encephalopathy, although the traditional use of lactulose for enteral decontamination is now more controversial. Instead, other agents such as metronidazole and neomycin have been recommended to treat acute hepatic encephalopathy. Systemic antimicrobial therapy with or without enteral decontamination reduces the infection rate in patients with acute liver failure.

8.2    Specific Measures

8.2.1    N-acetylcysteine (NAC)

Several clinical trials support the use of NAC in ALF. In late-presenting paracetamol overdose, mortality and progression to grade III–IV encephalopathy is reduced in those receiving NAC.

8.2.2    Penicillin G and Silibinin

Penicillin G and silibinin (silymarin or milk thistle) are accepted antidotes for mushroom poisoning (usually Amanita phalloides), despite no controlled trials proving their efficacy. Although some reports have not found penicillin G to be helpful, enough efficacy has been reported to warrant consideration of the drug (given intravenously in doses of 300 000–1 million units/kg/day) in patients with known or suspected mushroom poisoning. Silibinin has generally been reported to be more successful than penicillin G, although the latter has been used more frequently. Silibinin/silymarin is not available as a licensed drug in the United States, although it is widely available in Europe and South America. When used for the treatment of mushroom poisoning, silymarin has been given in average doses of 30–40 mg/kg/day either intravenously or orally, for an average of 3–4 days.

8.2.3    Drug-induced Hepatotoxicity

There are no specific antidotes for idiosyncratic drug reactions; corticosteroids are not indicated unless a drug hypersensitivity reaction is suspected. Current recommendations are:

  1. obtain details (including onset of ingestion, amount and timing of last dose) concerning all prescription and non-prescription drugs, herbs and dietary supplement taken over the past year;
  2. determine the ingredients of non-prescription medications whenever possible;
  3. in the setting of ALF due to possible drug hepatoxicity, discontinue all but essential medications.

8.2.4    Lamivudine and Nucleoside Analogues

ALF due to reactivation of hepatitis B may occur in the setting of chemotherapy or immunosuppression. The nucleoside analogue lamivudine (and possibly adefovir), used widely in the treatment of chronic hepatitis B, may be considered in patients with acute hepatitis B, although these drugs have not been subjected to controlled trials in acute disease. It is currently recommended that nucleoside analogues be given prior to and continued for 6 months after completion of chemotherapy in patients with hepatitis B surface antigen positivity to prevent reactivation/acute flare of disease.

8.2.5    Aciclovir

Although herpes virus infection rarely causes ALF, immunosuppresed patients or pregnant women (usually in the third trimester) are at increased risk. In addition, the occurrence of herpes virus ALF has been reported in previously healthy individuals. Meanwhile, other viruses such as varicella zoster have occasionally been implicated in causing hepatic failure. Patients with known or suspected herpes virus or varicella zoster as the cause of ALF should be treated with aciclovir.

8.2.6    Corticosteroids

Patients with autoimmune hepatitis may have unrecognized pre-existing chronic disease and yet still be considered as having ALF, if their illness is of less than 26 weeks’ duration. Such patients represent the most severe form of the disease, and would generally fall into the category of patients recommended for corticosteroid therapy (prednisone, 40–60 mg/day). Initiation of steroid therapy may constitute a therapeutic trial for some patients , and placement on the transplant list is indicated as although some patients with ALF due to autoimmune hepatitis respond to steroid therapy, others require transplantation.

8.2.7    Cardiovascular Support

In patients with evidence of ischaemic injury cardiovascular support is the treatment of choice. In such patients the ability to manage heart failure or other causes of ischaemia (for example, significant hypovolaemia) will determine outcome.

8.2.8    Liver Transplantation

Orthotopic liver transplantation (OLT) remains the only definitive therapy for patients who are unable to achieve regeneration of sufficient hepatocyte mass to sustain life. Urgent liver transplantation is indicated where prognostic indicators suggest a high likelihood of death. Post-transplant survival rates for ALF have been reported to be as high as 80–90%, but accurate long-term outcome data are not yet available.

Patients with ALF secondary to the following causes should be listed for transplantation: mushroom poisoning, Wilson’s disease, autoimmune hepatitis and hepatic vein thrombosis (provided underlying malignancy is excluded). In such patients, initial laboratory investigations should include determination of their HIV status, because this has implications for potential liver transplantation.

Early liaison with a liver transplantation unit is mandatory, and any contraindications to transplantation should be identified with collateral histories through the family, friends and primary care physicians, if necessary. Planning should begin in patients with grade I or II encephalopathy (see Table X3 ) because they may worsen rapidly. Early transfer is important as the risks involved with patient transport may increase or even preclude transfer once stage III and IV encephalopathy develops.

Table X4 | ‘Bridging Options’ for ALF
Auxiliary transplantHeterotopic auxiliary liver transplantation (HALT)
Auxiliary partial orthotopic liver transplantation (APOLT)
Liver support devicesBioartificial liver (BAL) devices
Demetriou’s Hepatassist BAL
Amsterdam Medical Center BAL
Extracorporeal liver assist device (MELS)
Bioartificial liver support system (BLSS)
Non-biological liver devices
Molecular adsorbents
Recirculating system (MARS)
Prometheus system
Plasmapheresis and high-volume plasmapheresis
Hepatocyte transplantationCryopreserved human hepatocytes via: intraportal hepatocyte
Splenic artery infusion
Innovative/experimental techniquesTotal emergency hepatectomy
Portal vein arterializations
Auxiliary liver organ formation by implantation of spleenencapsulated hepatocytes

8.2.8    ‘Bridging Options’

The aim of bridging devices is to provide adequate liver function and maintain the patient well enough until native liver function recovers or until a graft is found. In one study, only 29% of patients listed for transplantation received a liver graft, and 10% of the overall group (one-quarter of patients listed for transplantation) died on the waiting list.

Other series have reported death rates as high as 40% of those listed for the transplantation, despite most organ donor allocation systems prioritizing ALF.

The many and divers function of the liver (metabolic, immunological and physiological) make the task of developing bridging devices a major challenge: the effects of the ‘toxic liver’ itself also require consideration. Bridging devices can be classified into four categories:

  1. auxiliary transplant;
  2. liver support devices (biological and non-biological);
  3. hepatocyte transplantation;
  4. innovative/experimental techniques (see Table X4 Opens in new window).

The current data regarding the efficacy, cost effectiveness and safety of liver support devices, both biological and non-biological (artificial) are conflicting and less promising in ALF. Currently available liver support systems are therefore not recommended outside clinical trials; their future in the management of ALF remains unclear.

9.   Prognosis

The prognosis of ALF is variable and depends on the cause. Outcomes are much better for patients who have ALF associated with paracetamol, pregnancy or hepatitis A than those who have seronegative hepatitis, non-A non-B viral hepatitis, idiosyncratic drug reactions or Wilson’s disease. Hepatitis B has an intermediate outcome.

The age of the patient and the rate of disease progression also determine outcome. Generally, patients with slow disease progression tend to do worse than those with a rapid downhill course to encephalopathy. Other factors associated with a poor prognosis include the presence of a metabolic acidosis and, in cases of paracetamol toxicity, a continuing rise in the prothrombin time at days 3–4, which may rise to 180 seconds.

Given that the only proven beneficial therapeutic intervention in advanced ALF is transplantation, the timing of transplantation and selection of patients is crucial.

Although scoring systems have been proposed, the variety of causes of ALF tends to limit their accuracy. Validating selection criteria is difficult because of poor methodology in several reported series. Furthermore, ALF is rare; therefore, most case series involve small numbers and span long periods of time, during which important supportive medical therapies may have evolved that could affect prognosis.

Two main prognostic scoring systems are currently in use: the Clichy and the King’s College (London) criteria. Both include different demographic, clinical and biochemical variables to identify a group most likely to require transplantation.

Other prognostic criteria have been proposed, including severity of SIRS, α-fetoprotein (AFP) levels; ratios of factor VIII and factor V, liver histology, CT scanning of the liver, cytokine levels, serum phosphate levels and adrenal insufficiency. The model for Endstage Liver Disease (MELD) score, now widely used to predict mortality among patients with chronic liver disease who are under consideration for liver transplantation, has been reported by some studies to have similar or better predictive value than the more established scores.

    Adapted from: Textbook of Adult Emergency Medicine E-Book. Authored By Peter Cameron, George Jelinek, Anne-Maree Kelly, Lindsay Murray, Anthony F. T. Brown. Further Readings as cited include:
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