Acute liver failure

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Chapter 47 ACUTE LIVER FAILURE

• Acute liver failure (ALF) is defined as the rapid development of coagulopathy and mental status changes in a patient with deteriorating liver function tests with no known preexisting liver disease.

• The most common causes of ALF in the Western world include paracetamol hepatotoxicity, idiosyncratic drug toxicity and viral hepatitis.

• The clinical features of ALF result from reduced hepatocellular function and complications involving other organs, including hepatic encephalopathy, cerebral oedema and intracranial hypertension, coagulopathy and bleeding, sepsis, multiorgan failure syndrome and metabolic derangements.

• Initial evaluation is aimed at determining the underlying aetiology, assessing the severity of the illness and prognosis and identifying complications.

• Principles of management include intensive medical management with general supportive measures, aetiology-specific management when appropriate and consideration of early referral and transfer to a specialist transplant unit.

• Liver transplantation has dramatically improved outcomes for patients with ALF, with overall survival rates now greater than 60%.

DEFINITION

Acute liver failure (ALF), or fulminant hepatic failure, is defined as the rapid development of coagulopathy (INR ≥1.5) and mental status changes (encephalopathy) in a patient with rapidly deteriorating liver function tests without known preexisting liver disease. The presence of encephalopathy distinguishes ALF from severe acute hepatitis.

ALF is a broad term encompassing both fulminant hepatic failure (FHF) and subfulminant hepatic failure (or late-onset hepatic failure). FHF is generally used to describe the development of encephalopathy within 8 weeks of the onset of symptoms in a patient with a previously healthy liver. Subfulminant hepatic failure refers to patients with liver disease for up to 26 weeks prior to the development of hepatic encephalopathy. Some patients with previously unrecognised chronic liver disease decompensate and present with liver failure; although this is not technically FHF, discriminating this at the time of presentation may not be possible.

CAUSES OF ACUTE LIVER FAILURE

Acute liver failure represents a syndrome that is the final common pathway for a variety of liver insults. A cause for ALF can be established in approximately 60%–80% of cases. There is a marked worldwide variation in the relative incidence of the various underlying causes. For example, in Australia, the UK and the USA, medications (e.g. paracetamol) and idiosyncratic drug reactions are the most commonly identified aetiologies. In other parts of the world, including Asia, acute viral hepatitis is a leading cause of ALF.

Paracetamol (acetaminophen) hepatotoxicity

Paracetamol toxicity accounts for approximately 40% of cases of ALF in the UK and the US. Hepatotoxicity is dose-related; most ingestions leading to ALF exceed 10 g/day and mortality is higher with doses over 48 g. While most episodes result from deliberate acts of self-harm, a significant proportion of cases result from therapeutic use. Factors increasing susceptibility to hepatotoxicity include regular alcohol consumption, antiepileptic therapy, preexisting hepatic dysfunction and malnutrition.

Idiosyncratic drug toxicity

A variety of prescription drugs, including various antiepileptics (e.g. phenytoin, sodium valproate), non-steroidal antiinflammatory drugs (e.g. diclofenac) and antibiotics (e.g. isoniazid) have been implicated in acute liver failure (Table 47.1). Most cases occur within the first 4–6 weeks of initiating treatment, but can occur years after the drug is commenced. Certain herbal preparations and other nutritional supplements have been found to cause liver injury. In addition, a variety of illicit substances, including synthetic amphetamines, have been linked to ALF.

TABLE 47.1 Aetiologies of acute liver failure

Drug toxicity

• Paracaetamol (acetaminophen)

• Idiosyncratic drug reactions

– Ampicillin-clavulanate

– Doxycycline

– Salicylates

– Non-steroidal antiinflammatory drugs

Other causes

• Autoimmune hepatitis

• Viral hepatitis

– Hepatitis D virus

– Hepatitis B virus

– Hepatitis E virus

– Hepatitis A virus

• Wilson’s disease

• HELLP syndrome

• Acute fatty liver of pregnancy

• Ischaemic hepatitis

• Heat stroke

• Budd-Chiari syndrome

• Amanita phalloides mushroom toxin

Herbal agents

HELLP syndrome = haemolysis elevated liver enzymes low platelet syndrome.

Viral hepatitis

Hepatitis A virus and hepatitis B virus are the chief causes of ALF in India and other parts of the developing world. However, ALF is an uncommon complication of viral hepatitis, occurring in 0.2%–4% of cases depending on the underlying aetiology. The risk of developing ALF from hepatitis E approaches 20% in pregnant women. Other viral aetiologies of ALF include hepatitis D virus coinfection or superinfection (Table 47.1), Epstein-Barr virus, cytomegalovirus, herpes simplex virus and varicella zoster.

Miscellaneous

There are a number of other less common causes of ALF. Pregnancy-related liver disease may result in ALF, usually in the third trimester. A variety of presentations may be seen with thrombocytopenia and features of pre-eclampsia often present. Wilson’s disease may present as ALF, typically in young patients accompanied by the abrupt onset of haemolytic anaemia. The fulminant presentation carries a poor prognosis without transplantation. Autoimmune hepatitis, Budd-Chiari syndrome, toxins (mushroom poisoning, aflatoxins), ischaemic hepatitis and malignant infiltration of the liver are other infrequent causes of ALF (Table 47.1). A definite cause is unable to be identified in approximately 15%–40% of cases of ALF worldwide.

CLINICAL FEATURES AND MAJOR COMPLICATIONS

The clinical features of ALF result from reduced hepatocellular function and from complications involving other organs. Non-specific symptoms such as nausea, vomiting and malaise are common initially, closely followed by the onset of jaundice.

Hepatic encephalopathy and cerebral oedema

Hepatic encephalopathy is a defining characteristic of ALF. Severity is graded on a scale of 1 to 4. In stage 1, patients have subtle impairments in concentration and altered sleep patterns. Stage 2 is marked by drowsiness and confusion often accompanied by asterixis or tremor. Stage 3 is marked by increasing somnolence and incoherence, which progresses to frank coma in stage 4. Hyperreflexia, clonus and muscular rigidity may be present in the latter stages.

Progressive cerebral oedema with the development of elevated intracranial pressure (ICP) plays a major role in the pathogenesis of this condition and has long been recognised as the most serious complication of ALF. The classic signs of raised ICP include systemic hypertension, bradycardia and irregular respirations (Cushing’s triad). Intracranial hypertension can result in cerebral hypoperfusion and hypoxia leading to irreversible neurologic damage, uncal herniation and brain death. Direct intracranial pressure monitoring is commonly used in patients with ALF and severe encephalopathy.

Other complications of ALF, including hypoglycaemia, sepsis, fever, hypoxaemia and hypotension, may also contribute to neurologic abnormalities in these patients.

Coagulopathy and bleeding

Patients with ALF have a prolonged prothrombin time primarily because of decreased synthesis of clotting factors. Increased consumption of clotting factors and platelets may also occur, and platelet levels are often <100,000/mm³. Clinically significant bleeding has been reported to occur in up to 20% of patients with ALF. The most common sources include the upper gastrointestinal tract, nasopharynx and skin puncture sites.

Infection

Patients with ALF are functionally immunosuppressed. Established bacterial and fungal infections occur in about 80% and 32% of patients, respectively. The major sites of infection are the respiratory and urinary tracts, and intravascular catheters. Localising signs of infection are frequently absent and a deterioration in mental status may be the only clue. Such patients are at increased risk of worsening encephalopathy and death.

Multiorgan failure syndrome

A hyperdynamic circulation with peripheral vasodilation and central volume depletion leading to hypotension are characteristic of ALF. Respiratory failure is common in these patients and may be due to pulmonary oedema, acute respiratory distress syndrome (ARDS) or pulmonary sepsis. Renal failure complicates up to 50% of cases of ALF and may be due to dehydration, hepatorenal syndrome or acute tubular necrosis.

Metabolic abnormalities

Metabolic derangements, including alkalosis and acidosis, hypoglycaemia and electrolyte depletion (phosphate, magnesium and potassium) are common in ALF. Enteral or parenteral feeding may be necessary to maintain adequate nutritional status.

INITIAL EVALUATION AND PROGNOSIS

The initial evaluation of patients with suspected ALF should be aimed at determining the underlying aetiology, assessing the severity of the disease and the underlying prognosis and identifying complications. The outcome of ALF is related to the aetiology, the degree of encephalopathy and related complications.

History taking should address possible exposure to viral infection and drugs (including herbal medications and other nutritional supplements) or other toxins; collateral history from family members is often necessary. It is also important to ask about the date of onset of jaundice and encephalopathy. Physical examination must include careful assessment and documentation of mental status and a search for stigmata of chronic liver disease (which should be absent). Jaundice is often, but not always, present. Right upper quadrant tenderness is variably present. Liver size may be small, indicating a loss of volume due to hepatic necrosis. Hepatomegaly should raise suspicion of viral hepatitis, malignant infiltration, congestive heart failure or acute Budd-Chiari syndrome. Patients frequently present with hypotension and tachycardia, which results from the reduced systemic vascular resistance accompanying FHF.

In addition to coagulation parameters, initial laboratory examination usually includes routine chemistry (liver function, renal function, electrolytes, blood glucose), arterial blood gas measurements (acid–base status, hypoxia, lactate), full blood count, paracetamol level, viral hepatitis serology, tests for Wilson’s disease and autoimmune hepatitis and a pregnancy test in females. The serum ammonia level may be significantly elevated in patients with FHF. Liver ultrasound and Doppler may assist in determining hepatic vein flow and the presence of ascites. Any suspicion of an underlying infection should prompt a thorough search for an infective focus, including cultures of blood, sputum and urine and a chest radiograph. Cerebral computed tomography (CT) may be necessary to establish the presence of cerebral oedema. Liver biopsy is not always necessary, particularly in the context of a coagulopathy.

Determination of prognosis is important as it guides key management decisions, including the need for referral to a specialist transplant centre. However, assessment of prognosis in the individual patient is difficult and cannot be predicted by any single factor alone. The most important variables include the underlying aetiology (paracetamol toxicity, hepatitis A, ischaemic hepatitis and pregnancy-associated liver disease are associated with a more favourable outcome), the patient’s age (<10 and >40 associated with poor prognosis) and the degree of encephalopathy (spontaneous recovery less likely with stages 3 or 4 encephalopathy). In general, the best prognoses occur in the absence of complications. Cerebral oedema, renal failure, ARDS, bleeding, and sepsis reduce the probability of survival.

In patients with FHF due to hepatitis A virus, survival rates are greater than 50%. The outcome for patients with FHF as the result of other causes of viral hepatitis is much less favourable.

In patients with Wilson disease, FHF is almost uniformly fatal without liver transplantation.

Rate of development and degree of encephalopathy is a useful predictor of outcome; a short time from jaundice (usually the first unequivocal sign of liver disease recognised by the patient or family) to encephalopathy is paradoxically associated with improved survival. When this interval is less than 2 weeks, the patient has hyperacute liver failure.

MANAGEMENT

The principles of management in patients with ALF include intensive medical management with general supportive measures, preferably in an intensive care setting, aetiology-specific management (when appropriate) and early referral and transfer to a specialist liver transplant unit. Unfortunately, despite aggressive treatment, many patients die from FHF. Prior to orthotopic liver transplantation (OLT) for FHF, the mortality rate was generally greater than 80%. Approximately 6% of OLTs performed in the USA are for FHF. However, with improved intensive care, the prognosis is much better now than in the past, with some series reporting a survival rate of approximately 60%.

Aetiology-specific treatment

Identification of the underlying aetiology not only provides useful prognostic information, but may also dictate specific management options. N-acetylcysteine should be used promptly in any case of known or suspected paracetamol overdose. Other specific therapies include corticosteroids for ALF due to autoimmune hepatitis, aciclovir for herpes simplex virus- or varicella zoster-hepatitis and rapid delivery for ALF due to pregnancy-related liver disease.

General measures

For those patients with ALF in whom no aetiology-specific therapy exists, treatment is limited to general supportive measures that anticipate and manage complications, allowing the liver time to regenerate. Patients with altered mentation should generally be admitted to an intensive care unit. These patients can deteriorate rapidly and require constant monitoring; early consideration of transfer to a transplant centre is important, as worsening encephalopathy increases the risk involved with transfer and may even preclude transfer. Specific criteria have been developed to guide decisions regarding transfer to a specialist liver transplant unit. Management issues relating to the most common complications seen in patients with ALF are outlined below.

Hepatic encephalopathy

The treatment of hepatic encephalopathy (HE) associated with ALF is directed at limiting the production of ammonia and avoiding precipitating factors, such as benzodiazepines. Lactulose may be useful in patients with grade 1 or 2 encephalopathy.

Cerebral oedema/intracranial hypertension

The risk of cerebral oedema in patients with ALF increases with the severity of encephalopathy. As patients progress to grades 3 or 4 encephalopathy, tracheal intubation is usually advised for airway protection and the head should be elevated to 30 degrees. Management issues include prompt recognition and treatment of associated seizures, invasive ICP monitoring and the use of mannitol and hyperventilation to reduce elevated ICP.

Coagulopathy and bleeding

Replacement therapy for thrombocytopenia and/or prolonged prothrombin time is recommended only in the setting of haemorrhage or prior to invasive procedures.

Infection

Routine antibiotic prophylaxis in patients with ALF has not been shown to improve survival. Periodic surveillance cultures should be performed to detect bacterial and fungal infections as early as possible and a low threshold for starting appropriate antimicrobial therapy is required.

Multiorgan failure syndrome

Hypotension resulting from volume depletion should be treated with blood or colloids. Care must be taken to avoid exacerbation of cerebral oedema with aggressive fluid replacement; a central venous catheter may be useful for monitoring intravascular volume status. Vasopressor agents may be required for reduced systemic vascular resistance. Endotracheal intubation and mechanical ventilation are often required for respiratory depression due to coma or impaired gas exchange resulting from pulmonary sepsis or ARDS. Renal function should be optimised by maintaining adequate haemodynamics while avoiding nephrotoxic medications and contrast agents. Dialysis support is sometimes required, with continuous venovenous haemofiltration preferred over intermittent modalities.

Nutrition

Maintaining adequate nutrition is critical in the management of ALF. Oral or enteral feeding is preferable in patients with mild–moderate encephalopathy. Parenteral nutrition should be considered early in patients with grade 3 and 4 encephalopathy.

Liver transplantation

The advent of orthotopic liver transplantation has dramatically improved overall survival rates for patients with ALF from less than 30% in the pre-transplant era to more than 60% presently. Post-transplant survival rates for ALF have been reported to be as high as 80%–90%. In the patient with ALF being considered for transplantation (Table 47.2), the likelihood of spontaneous recovery must be balanced against the risks of surgery and longterm immunosuppression. Approximately 40%–50% of patients with ALF will undergo transplantation. Despite the urgent listing assigned to these patients, a significant proportion will die on the waiting list or develop complications precluding transplantation due to a critical ongoing shortage of donor organs. Some centres utilise artificial liver support systems, although this is still considered experimental.

TABLE 47.2 King’s College criteria for liver transplantation in acute liver failure

Paracetamol (acetaminophen) cases	Non-paracetamol (non-acetaminophen) cases
Arterial pH <7.3 or INR >6.5 and Serum creatinine >301 μmol/L and Stage 3 or 4 encephalopathy

Any three of the following;

• Age <10 or >40 years

• Duration of jaundice >7 days

• Aetiology—idiosyncratic drug reaction, non-A, non-B hepatitis, halothane hepatitis, indeterminate

• Serum bilirubin >308 μmol/L

INR = international normalised ratio.

A general approach to the management of patients with ALF is represented in Figure 47.1.

FIGURE 47.1 Management of acute liver failure.

SUMMARY

ALF is a term that encompasses both fulminant hepatic failure and subfulminant hepatic failure. It is defined as the rapid development of coagulopathy and encephalopathy in a patient with deteriorating liver function tests with no underlying liver disease. The most common causes include drug toxicity, acute viral hepatitis and pregnancy-related liver conditions. Patients may present with hepatic encephalopathy, coagulopathy, multiorgan failure and a variety of significant metabolic disturbances. Superimposed systemic infections often complicate the clinical scenario. Patients always require urgent evaluation and management, with the initial evaluation aimed at determining the underlying cause, assessing the severity of the illness and identifying complications. Such presentations necessitate intensive medical management. A high awareness of the need for early liver transplantation is warranted. Acute liver failure is associated with a high mortality rate, but with the advent of liver transplantation the overall survival rates are now greater than 60%.

FURTHER READING

Fontana RJ. Acute liver failure. In: Feldman M, editor. Sleisenger and Fordtran’s gastrointestinal and liver disease. Philadelphia: Saunders; 2006:1993-2006.

Gill RQ, Sterling RK. Acute liver failure. J Clin Gastroenterol. 2001;33:191-198.

O’Grady JG. Acute liver failure. Postgrad Med J. 2005;81:148-154.

Polsen J, Lee WM. AASLD position paper: The management of acute liver failure. Hepatology. 2005;41:1179-1197.

Sass DA, Shakil AO. Fulminant hepatic failure. Liver Transpl. 2005;11:594-605.

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