Acute liver failure (ALF) is the rapid deterioration of liver function in a patient without preexisting liver disease. The most widely accepted definition of ALF includes evidence of coagulation abnormality (international normalized ratio [INR] ≥1.5), and encephalopathy in a patient without preexisting cirrhosis and with a hepatic illness manifested by hyperbilirubinemia of less than 26 weeks’ duration. ALF is a rare condition with an incidence of one to six cases per million per year in the developed world and affecting approximately 2000 people in the United States each year.

The US Acute Liver Failure Study Group (ALFSG) was formed in 1997 as a consortium of centers aimed at capturing nationwide data on ALF. Results of 1147 patients enrolled from 1998 to 2007 found that the most common causes of ALF were acetaminophen overdose (46%), indeterminate (14%), idiosyncratic drug reactions (11%), and viral hepatitis A or B (10%).

Currently in the United States, spontaneous survival is approximately 45% without liver transplantation. The outcome of ALF, however, varies by etiology with favorable prognoses being found with acetaminophen overdose, hepatitis A, and ischemia, and poor prognoses with other drug-induced ALF, hepatitis B, and indeterminate cases.

ALF is a multisystem disorder, comprised of the acute onset of jaundice in a previously healthy person and the rapid onset of altered mental status accompanied by laboratory evidence of coagulopathy and acute hepatic injury.

A. Signs and Symptoms

Jaundice is a common physical examination finding on initial presentation, often prompting medical attention by the patient, but when minimal and the patient presents with altered mental status, the diagnosis of ALF may be delayed. The evaluation of mental status is the most critical component of the physical examination both initially and throughout the clinical course. Right upper quadrant tenderness may or may not be present. An enlarged liver may been found in early viral hepatitis, malignant infiltration, congestive heart failure, or acute Budd-Chiari syndrome. However, inability to palpate the liver or hepatic dullness to percussion may indicate diminished hepatic mass from hepatocyte loss.

Careful history taking is a critical component of the initial assessement as it may elicit the etiology of ALF. Evaluation should include a review of all possible exposures to viral infection, drugs, and toxic ingestions, as well as risk factors for underlying chronic liver disease. If the patient shows evidence of encephalopathy, history should be obtained from family members.

B. Laboratory Evaluation

Initial laboratory analysis should aim to determine the cause of ALF, the severity of presentation, and associated complications (Table 39–1).

Liver biopsy, usually done via the transjugular route due to coagulopathy, may be indicated when certain conditions such as autoimmune hepatitis, metastatic liver disease, lymphoma, or herpes simplex virus are suspected or the etiology of injury is unclear. Ongoing daily laboratory monitoring should include INR, complete metabolic panel, and complete blood count.

The initial injury in ALF results in the death of hepatocytes, leading to a systemic inflammatory response (SIRS) and multiorgan dysfunction. Significant neurologic, cardiopulmonary, and renal sequelae are associated with ALF, with cerebral edema and intracranial hypertension being the most serious of these complications. Acute renal failure complicates ALF in 30–50% of patients and can be a sign of poor prognosis though mortality is most commonly related to neurologic dysfunction and infection.

A. General Management Concerns

ALF often involves the rapid deterioration of mental status and the potential for multiorgan failure and therefore, patients should be managed in the intensive care unit. Table 39–2 outlines general treatment recommendations for intensive care management of patients with ALF according to specific potential complications. For patients not at a transplant center, the possibility of rapid progression of ALF makes early consultation with a transplant facility critical. Accordingly, plans for transfer to a transplant center should begin in patients with abnormal mentation or any indication of neurologic compromise.

Early institution of antidotes or specific therapy may prevent the need for liver transplantation and reduce the likelihood of poor outcome. N-acetylcysteine (NAC) is the antidote for acetaminophen-induced acute liver failure, but some data suggest intravenous NAC improves transplant-free survival in non–acetaminophen-induced liver failure due to its antioxidant and immunologic effects. Other measures appropriate for specific causes of ALF are described in detail later in this chapter.

B. Management of Specific Complications

1. Neurologic complications

Hepatic encephalopathy in ALF can range from minor confusion to coma and cerebral edema, and its presence, even mild severity, indicates poor prognosis. Patients should be carefully and regularly assessed to follow severity of encephalopathy as severity correlates with the occurrence of cerebral edema and intracranial hypertension (Table 39–3). The pathophysiology behind the development of encephalopathy is not completely understood but it is thought that systemic and local inflammation and circulating neurotoxins such as ammonia play a role with the risk of intracranial hypertension significantly increasing with a sustained ammonia level of over 100 μmol/L.

Goals of management in early encephalopathy (grade I/II) should revolve around minimizing severity and preventing progression. Sepsis, gastrointestinal bleeding, hypoglycemia, hypoxemia, and electrolyte abnormalities can worsen encephalopathy and should be appropriately managed. Stimulation and overhydration can cause elevations in intracranial pressure (ICP) and should be avoided. Unmanageable agitation may be treated with short-acting benzodiazepines in small doses, but may mask the severity of encephalopathy, limiting the value of neurologic evaluation. The utility of lactulose to decrease ammonia is debatable but can be considered in early stages, as long as abdominal distention is assessed for at regular intervals, and the dose of lactulose should not be so high as to result in intravascular depletion and/or diarrhea which could result in dehydration and worsening hyponatremia. A report from the ALFSG on 117 patients suggests that use of lactulose in the first 7 days after diagnosis is associated with a small increase in survival time, but with no difference in severity of encephalopathy or in overall outcome. The role of other nonabsorbable antibiotics such as neomycin and rifaximin is unclear. L-Ornithine-L-aspartate detoxifies ammonia to glutamine in muscle, but in a large randomized controlled trial, did not lower circulating ammonia levels, reduce severity of encephalopathy, or improve survival.

For patients who progress to grade III–IV encephalopathy, care should be focused on prevention of cerebral edema and intracranial hypertension. The cause of intracranial hypertension in ALF is likely multifactorial, combining cytotoxic brain edema due to an increase in cerebral blood volume and cerebral blood flow due to inflammation and toxic products of the diseased liver. Cerebral edema inside the cranial vault raises ICP and decreases cerebral perfusion assessed by cerebral perfusion pressure (CPP; defined as mean arterial pressure minus intracranial pressure).

Evidence of increased ICP includes unequal pupil size and lack of pupillary reaction to light. Patients with cerebral edema may have systemic hypertension and bradycardia (Cushing reflex), increased muscle tone followed by decerebrate rigidity and posturing, abnormal papillary reflexes (usually dilation), and finally brainstem respiratory patterns and apnea. Brain herniation from elevated ICP is the immediate cause of death in 35% of patients with ALF, and 15–20% of patients listed for transplantation die from increased ICP. Cerebral edema is rarely seen in patients with grade I–II encephalopathy but increases to 65–75% in patients with grade IV coma and is the leading cause of death in these patients.

Intubation for airway protection is generally required for patients with grade III–IV encephalopathy. In order to maintain adequate CPP, optimization of blood pressure is essential. Both arterial hypertension and hypotension can compromise CPP, and therefore the use of sedation or vasopressors, respectively, can be considered. Propofol has been suggested for sedation because it may reduce cerebral blood. Factors that increase ICP need to be avoided, including high positive end-expiratory pressure, frequent movements, neck vein compression, fever, arterial hypertension, hypoxia, coughing, sneezing, seizures, head-low position, and respiratory suctioning. The head of the bed should be elevated to 30 degrees, and electrolytes, blood gases, glucose, and neurologic status monitored frequently.

The use of ICP monitoring in patients is the most accurate method of monitoring for intracranial hypertension as clinical signs of elevated ICP are not always present, and neurologic changes such as pupillary dilation or decerebrate posturing are often present only late in the course. The risks of ICP monitoring in ALF patients include bleeding and infection, with subdural and intraparenchymal monitors demonstrating greater reliability but increased rates of complications when compared with epidural catheters. A survival benefit with the use of ICP monitoring has not been shown but the goal is to maintain ICP below 20 mm Hg and CPP above 70 mm Hg. Evidence of elevated ICP such as pupillary abnormalities, decerebrate posturing, or monitoring suggesting ICP above 20–25 mm Hg and CPP below 50–60 mm Hg, should prompt intervention.

Seizure is common in patients with ALF, although presentation is often subclinical and likely due to use of sedatives and paralytics in intubated patients. Seizures aggravate intracranial hypertension and should therefore be promptly controlled with phenytoin. Small clinical trials using prophylactic phenytoin have shown no mortality benefit and unclear impact on cerebral edema or prevention of seizures.

Mannitol, in doses of 0.5–1 g/kg, has been demonstrated to decrease cerebral edema in the short term and improve survival. The efficacy of mannitol in patients with ICP may be affected by acute renal failure and oliguria. The dose may be repeated as needed as long as serum osmolality has not exceeded 320 mOsm/L. In order to be able to use mannitol repeatedly, fluid can be taken off with hemofiltration, which by itself reduces ICP. Prophylactic administration of mannitol is not indicated.

Hypertonic saline has been studied with one randomized study suggesting that it could delay onset of intracranial hypertension in patients with high-grade encephalopathy. Although no survival benefit has been demonstrated with hypernatremia, it is currently recommended as a prophylactic measure in patients at high risk for developing cerebral edema.

Hypothermia slows whole body metabolism, therefore lowering production and cerebral uptake of ammonia. Small studies have shown a benefit with reduction of body temperature to 34°C, specifically as a bridge to liver transplantation, yet further larger multicenter trials are needed to demonstrate efficacy. Induction of hypothermia to a core body temperature of 34–35°C can be considered especially for refractory intracranial hypertension.

Hyperventilation has also been shown to cause quick reductions in ICP, but the effect is short-lived and therefore may be of therapeutic benefit only in situations of life-threatening intracranial hypertension to prevent herniation.

Barbiturate agents such as thiopental or pentobarbital may be considered when severe intracranial hypertension does not respond to other measures. However, in practice, the use of pentobarbital coma has largely been replaced with therapeutic hypothermia to decrease brain metabolism. Additionally, propofol is used more commonly given its pharmacokinetics are not altered in liver failure.