Viral

Acute liver failure is a very uncommon complication of hepatitis A infection, occurring in 0.14% to 0.35% of hospitalized patients and in 0.4% of all cases seen in the United States. The incidence of acute liver failure following hepatitis B infection is 1% to 4% of hospitalized patients. In early studies, hepatitis D coinfection or superinfection was thought to increase the risk, as it was found in 34% to 43% of patients with acute liver failure as a result of hepatitis B infection compared with 4% to 19% of less severe cases. However, the prevalence of hepatitis D appears to have decreased dramatically in recent years. Vaccination and antiviral therapy with drugs that have a rapid onset of action (e.g., lamivudine, tenofovir) should alter the observed pattern of hepatitis B–related acute liver failure (Sjögren, 2003). The risk of developing acute liver failure after exposure to hepatitis C appears to be low, although well-documented cases have been reported. Hepatitis E is common in parts of Asia and Africa but is being increasingly recognized in Western countries. The natural history of hepatitis E in India has recently been revised to show that, although pregnant females are more likely to develop acute liver failure, the outcome is independent of sex, pregnancy status, and trimester of pregnancy (Bhatia et al, 2008).

Seronegative hepatitis accounts for 14% to 32% of acute liver failure in the Western world. In the United States, a proportion of these events are considered to be related to acetaminophen (Davern et al, 2006). There is little evidence to suggest that an unrecognized viral infection is to blame because most cases are sporadic. Unidentified toxins or autoimmune processes may be the underlying mechanisms. Middle-aged females are most frequently affected, and the risk of developing acute liver failure has been calculated at 2.3% to 4.7% of hospitalized cases.

Drugs

Acetaminophen (paracetamol) overdose is the commonest cause of acute liver failure in the United Kingdom and the United States (Bernal, 2003; Lee, 2003). In the United Kingdom, excess amounts are usually taken with suicidal or parasuicidal intent; only 8% of such events were ascribed to inadvertent overdose with therapeutic use. However, in the United States, unintentional overdoses accounted for at least 48% of cases (Larson et al, 2005). Susceptibility to developing acetaminophen hepatotoxicity is increased in people with liver enzyme induction as a consequence of antiepileptic therapy, regular alcohol consumption, or malnutrition.

Drug-induced liver injury resulted in liver-related death in 3% to 4% of cases in a prospective study of 300 cases (Chalasani et al, 2008). More than 100 different agents were implicated, with 46% being associated with antimicrobials and 15% with central nervous system agents. Some of the more common offending drugs linked to acute liver failure are listed in Box 72.1. The risk of developing acute liver failure from an idiosyncratic reaction ranges from 0.001% for nonsteroidal antiinflammatory drugs (NSAIDs) to 1% for the isoniazid/rifampicin combination. Nontherapeutic drugs, such as MDMA (3,4-methylenedioxymethamphetamine; “ecstasy”) and some herbal remedies, can also cause acute liver failure. The diagnosis is made on the basis of a temporal relationship between exposure to the drug or hepatotoxin and the development of acute liver failure.

Other Etiologies

Acute liver failure associated with pregnancy tends to occur during the third trimester. Three discrete entities have been described, but considerable overlap is frequently observed. Acute fatty liver of pregnancy usually occurs in primagravids carrying a male fetus and is characterized by severe microvesicular steatosis. The syndrome is defined as the combination of hemolysis, elevated liver enzymes and low platelets (HELLP). Acute liver failure complicating preeclampsia or eclampsia typically exhibits very high serum transaminase levels and abnormal tissue perfusion patterns on CT scanning that reflect the microvascular infarction characteristic of this condition.

Wilson disease may present as acute liver failure, usually during the second decade of life. It is characterized clinically by a Coombs test negative for hemolytic anemia and demonstrable Kayser-Fleischer rings in the majority of cases. Poisoning with Amanita phalloides mushrooms is most commonly seen in central Europe, South Africa, and the West Coast in the United States. Severe diarrhea, often with vomiting, is a typical feature and commences 5 hours or more after ingestion of the mushrooms; liver failure develops 4 to 5 days later. Autoimmune chronic hepatitis may present as acute liver failure, but by then, it is usually beyond rescue with corticosteroid or other immunosuppressive therapy. Budd-Chiari syndrome (see Chapter 77) may present with acute liver failure, and the diagnosis is suggested by hepatomegaly and confirmed by the demonstration of hepatic vein thrombosis. Malignancy infiltration, especially with lymphoma, is another rare cause of acute liver failure that is typically associated with hepatomegaly. Ischemic hepatitis is being increasingly recognized as a cause of acute liver failure, especially in older patients. Other unusual causes of acute liver failure include heat stroke and sepsis.

Pediatric Causes

Children are at risk of developing some of the causes of acute liver failure discussed above, but they also are vulnerable to other unique underlying causes, especially in the category of metabolic disease. Neonatal hemochromatosis may occur within the first few weeks of life and has been treated by liver transplantation as early as 5 days of age. Acute liver failure as a result of mitochondrial disorders may be triggered by bacterial infections and are characterized by high lactate levels in blood. Other metabolic causes include tyrosinemia, galactosemia, and fructose intolerance. Young infants can develop acute liver failure with viral infections, such as adenovirus, coxsackie virus, and cytomegalovirus (see Chapter 71).

Overall Strategy

In acute liver failure, the overall strategy is a combination of intensive medical care (see Chapter 73), liver transplantation in selected patients (see Chapter 97C), and, to some degree, the use of a liver support device (Chapter 73). Management starts with identification of etiology and an initial assessment of prognosis that is then progressively updated as each individual’s clinical course evolves. Early referral to specialist centers that offer liver transplantation is recommended; monitoring is instituted, and a decision on the need for immediate liver transplantation is reviewed. Patients are then treated for the complications that may develop to the point of recovery, death, or transplantation. Although considerable variation is found among centers and countries, the outcomes in fully functional programs approximate 40% survival without transplantation, and 40% proceed to liver transplantation; a 20% mortality rate is reported without transplantation.

Patients with acute-on-chronic liver failure often require, and benefit from, intensive monitoring. This is especially appropriate when deterioration has been triggered by a specific, reversible complication, especially variceal bleeding (see Chapter 75A, Chapter 75B, Chapter 75C ). Patients with hepatorenal failure are also frequently admitted to intensive care, which is particularly appropriate in patients who are active candidates for liver transplantation. Liver support systems, particularly the Molecular Adsorbents Recirculation System (MARS; Gambro, Stockholm, Sweden), are being increasingly used in this situation.

General Measures in Liver Failure

A number of drugs have well-defined roles in specific etiologies of acute liver failure. N-acetylcysteine is established as an antedote to paracetamol hepatotoxicity when given within 16 to 24 hours of the overdose, but it has also been shown to be beneficial in reducing mortality rates and cerebral edema when begun as late as 36 hours after the overdose. In the United States, a trial of N-acetylcysteine in nonacetaminophen acute liver failure showed improved transplant-free survival of 52%, compared with 30% in patients receiving placebo, when patients were started on therapy prior to the onset of grade 3 to 4 encephalopathy (Lee et al, 2009). Penicillin, and possibly silymarin, should be added at the earliest opportunity to the standard supportive measures in patients with Amanita phalloides toxicity. Patients with Wilson disease complicated by encephalopathy do not respond to chelating therapy, but penicillamine should be considered for acute presentations not yet complicated by encephalopathy. Acute liver failure caused by autoimmune hepatitis rarely responds to immunosuppressive therapy. Patients with severe acute alcoholic hepatitis may benefit from corticosteroid therapy or treatment with pentoxifylline; however, neither of these medications is indicated in acute-on-chronic episodes of alcoholic cirrhosis in the absence of a component of alcoholic hepatitis.

Neurologic Complications

By definition, encephalopathy is present in acute liver failure and is often present in acute-on-chronic liver failure. Encephalopathy in both settings is categorized clinically on a scale from 1 to 4. Patients with grades 1 and 2 encephalopathy exhibit degrees of drowsiness or disorientation, but they can be roused and respond appropriately to verbal stimuli. Patients with chronic liver disease usually have a hepatic flap and fetor hepaticus, but these classic features of encephalopathy are absent in most patients with acute liver failure and an equivalent degree of encephalopathy. In acute liver failure, progression to grade 3 encephalopathy may be heralded by a short period of extreme agitation before the patient becomes very confused and, at best, only obeys simple commands. Grade 4 encephalopathy signifies deep coma; at best, patients are responsive to painful stimuli; most patients in this situation require intubation and supported ventilation.

Cerebral edema is common in hyperacute and acute liver failure but unusual in subacute liver failure. Clinically apparent cerebral edema has only been reported on an anecdotal basis in patients with cirrhosis (excluding Wilson disease). Emerging evidence suggests that the incidence of cerebral edema is decreasing with modern management protocols, but the precise reasons for this change have yet to be determined (Stravitz & Kramer, 2009). Nevertheless, in individual patients, cerebral edema remains an important complication that may cause death or may disqualify patients from transplantation; on that basis, treatment of cerebral edema retains its prominent role in management protocols. The clinical features of cerebral edema include systemic hypertension, “decerebrate” posturing, hyperventilation, abnormal pupillary reflexes, and, ultimately, impairment of brain stem reflexes and functions. Papilledema is rarely seen. The risk to life with cerebral edema can be from classic brain stem herniation or hypoxic brain damage.

Encephalopathy with acute-on-chronic liver failure is managed with dietary protein restriction and lactulose and phosphate enemas, usually with good effect. Treatment of triggering events is also fundamental to the management of encephalopathy, and empiric antibiotics and intravenous fluids are standard components of care (Box 72.5). With the possible exception of subacute liver failure, specific management options for encephalopathy have limited impact in acute liver failure. L-ornithine L-asparate given in a dose of 30 g/day for 3 days failed to lower ammonia levels or improve survival in acute liver failure (Acharya et al, 2009). Liver support devices can reduce ammonia and lighten encephalopathy, but no single system has demonstrated improvement in patient survival (McKenzie et al, 2008; Stradlbauer et al, 2009).

Mannitol (0.25 to 0.5 mg/kg) is the first-line treatment for surges in intracranial pressure. This process is repeated as determined by the pattern of clinical relapses, but the serum osmolarity should not be allowed to exceed 320 mOsm. Sodium thiopentone (phenobarbitone) was shown to control cerebral edema that had become unresponsive to mannitol in an uncontrolled study, but it has not been subjected to a controlled trial, nor has it been shown to improve the survival rate. Acute, but not chronic, hyperventilation was reported to be of benefit in reducing critical surges in intracranial hypertension. Nevertheless, hyperventilation to pco₂ levels below 25 mm Hg is routinely incorporated as a first-line treatment in protocols in the United States. Hypothermia, hypertonic saline infusions, and indomethacin have also been shown in small studies to be useful adjuncts in the management of intracranial hypertension (Auzinger & Wendon, 2008; Stravitz & Kramer, 2009).

In the later stages of the neurologic complications, the emphasis of management changes to the preservation of cerebral perfusion pressure, increased oxygen delivery to the brain, and manipulation of the neuronal microcirculation to promote cerebral oxygen extraction (Auzinger & Wendon, 2008; Stravitz & Kramer, 2009). The patient should be positioned with the trunk at an angle of 20 to 30 degrees to horizontal. The options for increasing the mean arterial pressure, and consequently improving cerebral perfusion pressure, are outlined in the section in this chapter dealing with hemodynamics. These adjustments are made to maintain a cerebral perfusion pressure greater than 50 mm Hg if possible. At this stage of the complication, spontaneous recovery is unlikely without liver transplantation, and hepatectomy is useful to secure transient improvement. Occult seizure activity may contribute to neurologic instability in patients with grade 4 encephalopathy. Phenytoin and diazepam are effective therapies despite the theoretic consideration that the latter may aggravate the underlying encephalopathy.

The use of intracranial pressure monitoring is controversial and has not been subjected to clinical trials (Stravitz & Kramer, 2009). Early detection of cerebral edema and a facility with the appropriate equipment to constantly monitor this complication help to optimize therapeutic interventions. Intracranial pressure monitoring allows earlier and more accurate detection of pressure changes—especially in the ventilated patient, in whom most of the clinical signs are masked—and it facilitates careful monitoring of the intracranial pressure during high-risk therapeutic interventions, such as hemodialysis and tracheal suctioning. It is also considered valuable during orthotopic liver transplantation because increases in intracranial pressure often occur during the dissection and reperfusion phases of the transplant operation. The most commonly used system places transducers on or through a small nick in the dura. The risk of intracranial hemorrhage is a deterrent, although the studies that have systematically addressed safety have favored the use of intracranial pressure monitoring, especially using fiberoptic extradural or subdural devices. Proponents argue that this has been shown to be effective and relatively safe, despite the attendant coagulopathy. Epidural transducers were associated with a low complication rate of 3.8%, but subdural and parenchymal devices had higher complication rates of 20% and 22%, respectively. Noninvasive monitoring using transcranial Doppler ultrasonography may provide an alternative way of assessing intracranial pressure and cerebral perfusion pressure in this setting (Aggarwal et al, 2008).

Infection

Immunoparesis is a feature of acute liver failure (Antonides et al, 2008); it is therefore no surprise that bacterial and fungal infections are prominent complications in all varieties of this condition (see Chapter 9, Chapter 10, Chapter 11 ). Considerable overlap is seen between the clinical features of infection and the systemic immune response syndrome (SIRS), but microbial infection can also be seen in the absence of these typical markers of sepsis. Infection is one of the most common causes of death and plays an integral role in the evolving cycle of hemodynamic instability and multisystem failure (Rolando et al, 2000). It also frequently delays or disqualifies potential candidates from emergency liver transplantation. Bacterial infection occurs in up to 80% of patients, and fungal infection occurs in 30%. Systemic fungal infection is notoriously difficult to diagnose in the setting of acute liver failure, and a high index of suspicion is required, especially in high-risk patients and in those with a very high white cell count or an arrest in the normalization of the parameters of coagulation activity during an apparent recovery phase. Risk factors for both bacterial and fungal sepsis include coexisting renal failure, cholestasis, treatment with thiopentone, and liver transplantation. Surveillance cultures are required on a regular basis (Auzinger & Wendon, 2008; Stravitz & Kramer, 2009).

Clinical trials of prophylactic antibiotics have demonstrated that systemic antibiotics reduced the incidence of culture-positive bacterial infection by half, but this strategy was associated with the emergence of highly resistant organisms in up to 10% of cases. However, this reduction in infection rates was not accompanied by a significant impact on major clinical outcomes (death, progression to transplantation) or economic considerations (length of intensive care unit and hospital stay, overall cost of antimicrobials). Small bowel decontamination was not effective in altering the pattern of infection; however, systemic antibiotics are recommended when infection is suspected, and the precise regimens used are determined by local antibiotic policy.

In chronic liver disease, infection of an apparent trivial nature is common and can be the trigger for an episode of acute-on-chronic liver failure; as a result, antibiotic therapy is a standard component of the management of this condition. Spontaneous bacterial peritonitis is a particularly important infection to consider in this setting, and the diagnosis can only be excluded with confidence if the white cell count in ascites is less than 250/mm³. Patients with a history of spontaneous bacterial peritonitis should be maintained on low-dose antibiotic prophylaxis, such as with norfloxacin 400 mg daily.

Hemodynamic Instability and Oxygen Debt

The hemodynamic changes in liver failure are very similar to those observed in SIRS. The early hemodynamic profile reflects a hyperdynamic circulation with increased cardiac output and reduced systemic peripheral vascular resistance. Profound vasodilation may cause relative hypovolemia, and invasive monitoring is used to determine appropriate fluid regimens and adequate intravascular volumes. Progressive disease leads to circulatory failure, either as a result of a falling cardiac output or an inability to maintain an adequate mean arterial pressure. Patients with acute liver failure and sepsis exhibit a different hemodynamic profile than patients in septic shock in the absence of liver disease (Tsai et al, 2008). The patients with acute liver failure had higher cardiac indexes and oxygen delivery but lower systemic vascular indexes and oxygen extraction/consumption. Circulatory failure is another important contraindication to liver transplantation and is a common mode of death in liver failure.

Hemodynamic monitoring using volumetric indices of preload is preferred over pressure-derived variables (Auzinger & Wendon, 2008). Circulatory failure is initially managed with appropriate fluid replacement in combinations of colloids, crystalline fluids, and blood products as clinically appropriate. Persistent hypotension after volume repletion indicates vasopressor agents, with a clear preference for norepinephrine as first-line therapy (Auzinger & Wendon, 2008; Stravitz & Kramer, 2009). Dopamine and vasopressin may also be used, although vasopressors may cause or aggravate an oxygen debt, but prostacyclin and N-acetylcysteine have been shown to improve these parameters in patients receiving vasopressors. Some patients with acute liver failure who develop resistance to inotropes may have a hypoadrenal profile that responds to hydrocortisone (Harry et al, 2002).

Renal Failure

Urea synthesis is impaired in acute liver failure. Consequently, serum creatinine levels are preferred for the purposes of monitoring renal function. Renal failure developed in 75% of patients with acetaminophen-related acute liver failure and in 30% of acute liver failure from other causes. Renal failure after an acetaminophen overdose is a consequence of direct renal toxicity and develops early in the course of the illness. Early renal dysfunction is also seen in Wilson disease, Amanita poisoning, and pregnancy-related syndromes. In the other etiologies, renal impairment develops relatively late and progresses from a stage of “functional” or prerenal failure (urinary sodium <10 mmol/L; urine/plasma osmolarity ratio >1.1) to acute tubular necrosis. The presence of SIRS correlated with the development of renal dysfunction in nonacetaminophen etiologies of acute liver failure but not in acetaminophen-induced disease (Leithead et al, 2009).

Hepatorenal failure is a serious complication of acute-on-chronic liver failure. Two types are recognized: type 1 is hepatorenal syndrome with a rapidly progressive decline in renal function, leading to a doubling of the initial serum creatinine to a level greater than 2.5 mg/dL, or a 50% reduction of creatinine clearance to less than 20 mL/min over a period of no longer than 2 weeks. Type 2 is hepatorenal syndrome with renal failure not fulfilling the parameters outlined above.

Hepatorenal syndrome can improve dramatically after liver transplantation, which reflects the role of vasospasm in the pathogenesis of the condition. However, true hepatorenal syndrome can progress imperceptibly to acute tubular injury that does not recover as quickly.

Optimization of intravascular filling is essential in patients with deteriorating renal function. The prophylactic use of dopamine has been common practice, but its benefits have been challenged, especially in the setting of profound vasodilation that is typical of acute liver failure. The metabolic complexity of combined liver and renal failure suggests that early intervention with hemodialysis, preempting standard indications, is prudent in the setting of acute liver failure. Continuous filtration systems are associated with less hemodynamic instability and run a lower risk of aggravating latent or established cerebral edema than does intermittent hemodialysis. Some evidence suggests that high-volume, continuous venovenous hemofiltration may reduce vasopressor requirements through modulation of proinflammatory mediators (Auzinger & Wendon, 2008). The role for renal support therapy is less well defined in acute-on-chronic liver failure, but MARS therapy may be especially useful in deeply jaundiced patients with renal dysfunction.

Metabolic Abnormalities

Hypoglycemia is common in acute liver failure and can induce reversible impairment of consciousness prior to the onset of classic encephalopathy. The signs and symptoms of hypoglycemia are often masked, and regular blood glucose monitoring is required. Metabolic acidosis is present in 30% of patients who develop acute liver failure after an acetaminophen overdose, and it is associated with a particularly high mortality rate (>90%) if the pH of arterial blood is lower than 7.30 on the second or subsequent days after the overdose. This acidosis precedes the onset of encephalopathy and is independent of renal function. In contrast, metabolic acidosis is found in 5% of patients with other etiologies of acute liver failure; it occurs later in the disease process and is also associated with a poor outcome. Increased serum lactate levels have been documented in patients with metabolic acidosis, and these correlate inversely with mean arterial pressure, systemic vascular resistance, and oxygen extraction ratios. The hyperlactatemia possibly reflects tissue hypoxia resulting from impaired oxygen extraction as a result of microvascular shunting of blood away from actively respiring tissues. In most etiologies of acute liver failure, alkalosis is the dominant acid-base abnormality and may be associated with hypokalemia. Hyponatremia may reflect sodium depletion in patients with vomiting, or it may be dilutional, resulting from excessive antidiuretic hormone secretion or intracellular sodium shifts. Hypophosphatemia is most frequently encountered in acetaminophen-induced acute liver failure when renal function is preserved.

Hyponatremia is the dominant abnormality seen in acute-on-chronic liver failure. This does not reflect sodium depletion because total body sodium levels are almost always above normal in these patients. Diuretic-induced hyponatremia may be seen in patients with ascites, and withdrawal of diuretic therapy is advised if the serum sodium level falls below 130 mEq/L. Refractory hyponatremia is managed by fluid restrictions of 800 to 1500 mL per day depending on severity. Hemofiltration may be used to correct hyponatremia in severe cases or when the serum sodium is less than 120 mEq/L immediately prior to liver transplantation This is to reduce the risk of central pontine myelinolysis associated with the rapid increase in serum sodium levels that inevitably occur.

Coagulopathy

The liver is responsible for the synthesis of most of the coagulation factors (except Factor VIII, which is produced by endothelial cells) and some of the inhibitors of coagulation and fibrinolysis. In acute liver failure, circulating levels of fibrinogen, prothrombin, and Factors V, VII, IX, and X are reduced, and the prothrombin time is widely used as an indicator of the severity of liver damage. In addition to decreased synthesis of coagulation factors by the liver, increased peripheral consumption is evident. Overt disseminated intravascular coagulation (DIC) is occasionally observed, especially in the pregnancy-related syndromes, but sensitive investigative techniques point to the presence of a low-grade process in most patients. Both quantitative and qualitative defects in platelet function are well described in acute liver failure, and platelet counts of less than 100 × 10⁹/L are seen in up to 70% of patients. Platelet aggregation is impaired, but there is an increase in platelet adhesiveness, a pattern that may be due to increased levels of circulating von Willebrand factor.

Poor correlation is reported between the laboratory and clinical manifestations of the coagulopathy of acute liver failure. This has been attributed to the fact that the decrease in the procoagulant and anticoagulant proteins is proportional (Stravitz & Kramer, 2009). The use of prophylactic repletion of coagulation has never been practiced in the United Kingdom except before significant invasive procedures. Recent data from the United States show that 92% of patients were given fresh frozen plasma at a mean of 14 units during the first week of hospitalization, even though it was acknowledged that only a minority of patients had gastrointestinal bleeding or intracranial pressure monitoring (Munoz et al, 2008). The practice of prophylactic repletion of clotting factors is also controversial because it may interfere with assessment of prognosis, especially in patients being considered for liver transplantation. The highest risk of bleeding is seen in those with an associated thrombocytopenia or a frank DIC syndrome rather than in the patients with isolated severe prolongations of prothrombin time. It has been proposed that the lack of coagulation factors does not result in a bleeding diathesis unless accompanied by an inadequate platelet scaffold on which to propagate a clot (Stravitz & Kramer, 2009). Clinical bleeding is managed by infusions of fresh frozen plasma, cryoprecipitate, and platelets as required. Limited data are available on the utility of recombinant activated Factor VII in this setting (Caldwell et al, 2004).

The severity of the abnormality of coagulation is usually less in acute-on-chronic liver failure, and thrombocytopenia in this setting is usually due to hypersplenism. Patients with protracted cholestasis may have a component to the coagulopathy that responds to parenteral vitamin K. The management of the coagulopathy follows the same principles as in acute liver failure.

Nutrition

Although the standard patient with acute liver failure is well nourished at the onset of the illness, it is important to institute nutrition support as soon as possible (see Chapter 24). The catabolic rate increases in patients with acute liver failure, and this is most apparent in those with complicating sepsis and those undergoing liver transplantation. The theoretical problems that limit nutrition options are legion: gastrointestinal ileus, desire to minimize gastrointestinal protein, difficulty maintaining isoglycemia, fluid restrictions secondary to renal failure, amino acid ratios possibly mediating encephalopathy, difficulty handling lipids, aggravation of sepsis by intravenous feeding, and so on. Despite all these considerations, adequate nutrition support can be obtained in the majority of patients. An element of enteral nutrition is desirable to help maintain the integrity of the small intestinal mucosa, which is titrated against the volume of gastric aspirates and the development of diarrhea.

Nutritional support in acute-on-chronic liver failure is equally important but subject to more constraints. Unlike acute liver failure, these patients are frequently undernourished prior to the onset of the episode of acute-on-chronic liver failure. Protein intake should not exceed 60 g/day in patients with encephalopathy. There may also be restrictions on fluid volume and the sodium content of feeds. A substantial proportion of patients will have some degree of insulin resistance that may lead to hyperglycemia with high carbohydrate intake. There is little evidence that patients with problematic esophageal varices do not tolerate the presence of nasogastric tubes for feeding purposes.