Chapter 38. Acute Liver Failure

• Drugs, toxins, viral hepatitis, and hypoperfusion are the most common causes of acute liver failure (ALF).
• Laboratory findings may confirm the cause and severity of presentation.
• Consider acetaminophen toxicity in all patients, even without a history of toxic ingestion, particularly when serum aminotransferase levels are very high (>1000 units).
• Depending on timing of ingestion, acetaminophen levels may not be elevated even in cases of overdose.
• Rapid diagnostic and psychiatric evaluation is required at presentation.

Acute liver failure (ALF) affects approximately 2000 people in the United States each year. 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.

The U.S. 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 occurs in 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 drug-induced ALF, hepatitis B, and indeterminate cases.

The constellation of clinical findings in ALF includes jaundice in a previously healthy person, often preceded by malaise or nausea, and the rapid onset of altered mental status and coma accompanied by laboratory evidence of coagulopathy and acute hepatic injury.

Symptoms and Signs

History-taking 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 severe encephalopathy, a history should be obtained from family members.

Jaundice and right upper quadrant tenderness may or may not be present. An enlarged liver may be seen early in viral hepatitis, malignant infiltration, congestive heart failure, or acute Budd-Chiari syndrome. Alternatively, there may be decreased hepatic dullness to percussion, indicating diminished hepatic mass. The most critical part of the physical examination is the periodic assessment of mental status.

Laboratory Findings

Initial laboratory analysis should aim to determine the cause of ALF, the severity of presentation, and the need for treatment of associated complications (Table 38–1).

Liver biopsy, usually 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 virus are suspected.

Significant neurologic, cardiopulmonary, and renal sequelae are associated with ALF. Cerebral edema and intracranial hypertension are the most serious of these complications. Mortality is related to neurologic status and infection, which require careful monitoring (see next section). Acute renal failure complicates ALF in approximately 30–50% of patients and can be a sign of poor prognosis.

General Management Concerns

Because ALF often involves the rapid deterioration of mental status and the potential for multiorgan failure, patients should be managed in the intensive care unit. Table 38–2 outlines general treatment recommendations for intensive care management of patients with ALF. 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 any abnormal mentation.

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 suggests intravenous NAC improves transplant-free survival in non–acetaminophen-induced liver failure, particularly in those patients in early stage. Other measures appropriate for specific causes of ALF are described in detail later in this chapter.

Management of Common Complications

Neurologic Complications

Patients with grade I–II encephalopathy (Table 38–3) should be transferred to a liver transplant facility and listed for transplantation. Sepsis, gastrointestinal bleeding, hypoglycemia, hypoxemia and electrolyte abnormalities can worsen encephalopathy. Consider a brain-computed tomography (CT) scan to rule out other causes of decreased mental status. 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 its prognostic value. Lactulose can be considered at this stage, but abdominal distention should be assessed at regular intervals, and the dose of lactulose should be titrated to avoid intravascular depletion. 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.

For patients who progress to grade III–IV encephalopathy, intubation for airway protection is generally required. Many centers use propofol for sedation because it may reduce cerebral blood. The head of the bed should be elevated to 30 degrees, and electrolytes, blood gases, glucose, and neurologic status monitored frequently.

The cause of intracranial hypertension in ALF is probably 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).

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.

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.

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.

The use of ICP monitoring in patients with ALF is common but not universal. Clinical signs of elevated ICP are not always present, and neurologic changes such as papillary 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.

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.

Interventions may include support of systemic blood pressure to maintain adequate CPP or the use of mannitol, which 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.

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.

Other therapies are being explored but currently lack adequate supporting data to recommend use, including indomethacin, hypothermia, and hypertonic saline.

Cardiovascular Complications

Increased cardiac output and low systemic vascular resistance are characteristic of ALF. Pulmonary artery catheterization should be considered to monitor volume status. Hypotension should be treated preferentially with fluids, but systemic vasopressor support with agents such as epinephrine, norepinephrine, or dopamine should be used if fluid replacement fails to maintain mean arterial pressure of 50–60 mm Hg. Vasoconstrictive agents (especially vasopressin) should be avoided. Relative adrenal insufficiency occurs frequently in patients with ALF, and may contribute to cardiovascular collapse. Moderate doses (200–300 mg/day) of hydrocortisone have been shown to improve the vasopressor response to norepinephrine in hypotensive patients with sepsis and ALF.

Pulmonary Complications

Pulmonary edema and pulmonary infections are commonly seen in patients with ALF. Mechanical ventilation may be required. However, positive end-expiratory pressure can worsen cerebral edema and decrease hepatic blood flow.

Coagulopathy and Gastrointestinal Bleeding

Impaired hepatic synthesis of clotting factors, increased consumption of factors, low-grade fibrinolysis, and intravascular coagulation are typical of ALF. Thrombocytopenia is common and may also be dysfunctional. The prophylactic correction of INR with fresh frozen plasma is not recommended, and replacement therapy is recommended only in the setting of hemorrhage or prior to invasive procedure. Vitamin K (5–10 mg subcutaneously) should be given to treat an abnormal prothrombin time, regardless of whether there is poor nutritional status. Administration of recombinant factor VIIa has shown promise; however, this treatment approach requires further study. The use of gastrointestinal hemorrhage prophylaxis with a proton pump inhibitor is recommended.

Renal Failure

Prevention of renal failure by ensuring adequate systemic blood pressure, treating infections, and avoiding nephrotoxic agents is important. Intravascular volume deficits are often present on admission and volume replacement is required. Acute renal failure may occur due to dehydration, hepatorenal syndrome, or acute tubular necrosis. Renal failure may be even more common with acetaminophen overdose or other toxic ingestions due to direct nephrotoxicity causing acid-base disturbances and lactic acidosis. Prompt fluid resuscitation with crystalloids for low arterial pressure, or colloids in pre-hepatorenal syndrome along with midodrine and octreotide, have been suggested. If renal dysfunction, fluid balance, and metabolic derangements necessitate renal replacement, continuous therapies such as continuous venovenous or arteriovenous hemofiltration should be used as they cause less fluctuation in hemodynamics and ICP than intermittent hemodialysis.

Nutrition, Electrolytes, and Metabolic Derangements

ALF is a high catabolic state, and adequate nutrition is essential. Caloric goal for patients should be approximately 25–30 kcal/kg/d. In patients with grade I or II encephalopathy, enteral feeding should be initiated early. Parenteral nutrition should be used only if enteral feeding is contraindicated as it increases the risk of infection. Severe restriction of protein is not beneficial; 60 g/day of protein is generally reasonable. Fluid replacement with colloid (eg, albumin) is preferred rather than crystalloid (eg, saline); all solutions should contain dextrose to maintain euglycemia.

Multiple electrolyte abnormalities are common in ALF. Correction of hypokalemia is essential as hypokalemia increases renal ammonia production, potentially exacerbating encephalopathy. Hyponatremia is a poor prognostic indicator, and the desirable levels are above 125 mEq/L. Hypophosphatemia is especially common in patients with acetaminophen-induced ALF and in those with intact renal function. Hypoglycemia occurs in many patients with ALF and is often due to depletion of hepatic glycogen stores and impaired gluconeogenesis. Plasma glucose concentration should be monitored and hypertonic glucose administered as needed.

Infection

Bacterial and fungal infections are common in ALF, with one study demonstrating culture-proven infection in 80% of ALF patients. Infection remains one of the leading causes of mortality in patients with ALF. Defective cellular and humoral immunity as well as presence of indwelling catheters, coma, broad-spectrum antibiotics, and medications that suppress immunity all predispose to infection. Localizing symptoms of infection such as fever and sputum production are frequently absent, and the only clues to an underlying infectious process may be worsening of encephalopathy or renal function. There must be a low threshold for obtaining frequent cultures (blood, urine, and sputum), chest radiographs, and paracentesis. Bacteria that enter through the skin, such as streptococci and staphylococci, tend to predominate, and therefore broad spectrum antibiotics (quinolones or third-generation cephalosporin) are generally used. Fungal infections, particularly in the setting of broad-spectrum antibiotics, are also common, and disseminated fungemia is a poor prognostic sign. Aggressive surveillance is essential, as prophylactic antibiotics have shown little benefit, though empiric antibiotic administration can be considered where infection or the likelihood of impending sepsis is high.

Table 38–2 summarizes these and other strategies in the ICU management of ALF patients.

Liver Transplantation

The advent of transplantation has changed survival from as low as 15% in the pre transplant era to more than 60% today. Liver transplantation is indicated for many patients with ALF, and survival rates of 56–90% can be achieved. In addition to transplantation, better critical care and the trend toward more benign causes, such as acetaminophen, all contribute to improved survival rates. Spontaneous survival is now around 45%.

The application of transplantation among patients with ALF remains low, suggesting that the full potential of this modality may not be realized. Timely availability of an allograft is one of the major factors determining transplant outcomes. In the largest U.S. study, only 29% of patients received a liver graft, while 10% of the overall group (one fourth of patients listed for transplantation) died on the waiting list. Other series have reported death rates of those listed for transplant as high as 40%.

Current United Network for Organ Sharing (UNOS) criteria for priority (Status 1) listing are (1) onset of any degree of hepatic encephalopathy within 8 weeks of onset of acute liver injury; (2) absence of preexisting liver disease; (3) life expectancy of less than 7 days; and (4) in the intensive care unit (ICU) requiring either mechanical ventilation, renal dialysis, or with severe coagulopathy (INR 2.0).

In the ALFSG, the transplantation rate was higher in the groups with lower short-term spontaneous survival, making overall survival similar in all groups: acetaminophen, 73%; drug induced, 70%; indeterminate group, 64%; and other causes, 61%. Causes of death for the 101 patients who died within the 3-week period included cerebral edema, multiorgan failure, sepsis, cardiac arrhythmia or arrest, and respiratory failure. The median time to death after admission was 5 days.

Liver Support Systems

Clinical experience with bioartificial systems is mostly confined to small numbers of patients in uncontrolled trials. One systematic review of 12 randomized trials (with a total 483 patients) assessing artificial and bioartificial support systems for acute or acute-on-chronic liver failure as a "bridge" to transplantation showed no significant effect on mortality compared with standard medical therapy. Currently, available liver support systems are not recommended for the treatment of ALF.

Due to the scarcity of organs and the importance of the timing and decision regarding transplantation, the ability to assess prognosis in ALF is critical. The most important determinant of short-term (3 week) outcome appears to be the cause of the ALF. In the ALFSG patients with acetaminophen overdose, hepatitis A virus infection, shock liver, or pregnancy-related ALF, short-term survival without transplantation was 50% or greater. Patients with other etiologies had a survival rate of less than 25% without transplantation. Age and length of time between onset of illness and onset of encephalopathy, previously reported as prognostic, were not prognostic in the AFLSG.

The traditional King's College Hospital criteria (Table 38–4) have been the most commonly used and most frequently tested of the numerous proposed criteria for determining prognosis in ALF. Several studies evaluating these criteria have shown positive predictive values ranging from 70% to nearly 100% and negative predictive values from 25% to 94%. Fulfillment of these criteria suggests that without transplantation, the patient has a very high mortality risk. The model for end-stage liver disease (MELD) has not shown the same conclusive benefits in ALF patients.

Alternative criteria based on decreased levels of factor V in patients with encephalopathy was shown to have improved sensitivity in determining a poor prognosis in acute viral hepatitis.

Acetaminophen

The ALFSG reports a rise in the annual percentage of acetaminophen-related ALF from 28% in 1998 to 39% in 2003, with subsequent studies reporting acetaminophen overdose to account for up to 46% of all cases. These numbers may underestimate the contribution of acetaminophen to ALF. In one study using a new acetaminophen detection assay, 20% of ALF patients with indeterminate etiology were found to have acetaminophen-containing protein adducts released from dying hepatocytes, suggesting that unrecognized acetaminophen poisoning may have contributed to ALF. Acetaminophen may also contribute to ALF due to viral hepatitis, as patients may be taking acetaminophen products for relief of viral symptoms. A report from France showed ALF in acute hepatitis A patients was significantly associated with acetaminophen use.

Alcohol use, starvation, and acute illness may deplete glutathione, predisposing to liver injury from acetaminophen. In the ALFSG, participants who developed acetaminophen-induced ALF after ingesting less than 4 g acetaminophen per day before presentation more often used alcohol (65% vs 37%), more often reported unintentional overdose (74% vs 40%), and were older (median, 46 years vs 34 years) than other study participants.

Clinical Findings

Clinical signs and symptoms are dependent on the time since ingestion, which is defined into different phases. Phase 1 (first 24 hours) symptoms include anorexia, nausea/vomiting, lethargy, and diaphoresis. During phase 2 (24–72 hours), symptoms may improve, but laboratory abnormalities exist. In phase 3 (72–96 hours), nausea and vomiting can recur and be more severe. It can be accompanied by jaundice, malaise, and central nervous system symptoms. Liver test abnormalities peak during this stage. In phase 4 (4–14 days), liver damage resolves.

Acetaminophen toxicity should be considered in all patients with ALF even without a history of toxic ingestion, particularly in patients with very high aminotransferase values (ie, >1000 units/mL). Acetaminophen levels should be drawn on initial evaluation; however, keep in mind that depending on the timing of ingestion, acetaminophen levels may not be elevated even in overdose.

Treatment

If ingestion is suspected within a few hours of presentation, activated charcoal (1 g/kg orally) may be useful up to 3–4 hours after ingestion and does not reduce the effectiveness of oral N-acetylcysteine (NAC). The administration of NAC, which replenishes glutathione stores, is recommended in any patient with ALF in whom acetaminophen overdose is suspected. Although early administration enhances efficacy, some benefit has been shown even when NAC is given as late as 36 hours, and possibly even 48 hours, after ingestion. A 20-hour intravenous dosing regimen may be the therapy of choice when oral administration is not possible. No studies have shown any difference between oral and intravenous routes of administration. Allergic reactions to NAC may be treated with antihistamines and epinephrine for bronchospasm or discontinuation if necessary.

Prognosis

In the ALFSG, among 275 patients with acetaminophen-induced ALF, 65% survived, 27% died without transplantation, and 8% underwent transplantation. However, nearly one-third of those reaching the threshold of encephalopathy died. Extended acetaminophen dosing, delay in seeking medical attention, and failure to institute NAC therapy are associated with greater morbidity and mortality. Suicidal intent, a history of previous suicide attempts, or evidence of substance abuse may preclude transplant consideration. Outcomes appear to be similar between patients with suicidal intent and unintentional overdose once the patient develops ALF.

Viral Hepatitis

Hepatitis A

ALF is rare in hepatitis A (0.35%), but some studies suggest that women, the elderly, and patients with underlying liver disease may be at greater risk of morbidity and mortality with acute hepatitis A infection. Since the introduction of hepatitis A vaccines in 1995, reported cases of hepatitis A in the United States have declined by more than 85%, and with it, the incidence of hepatitis A–associated liver failure has also declined. Patients with hepatitis A infection in whom liver failure develops have a good prognosis (>60% survival), although some require liver transplantation. Recommendations for routine early childhood immunization beginning at age 12–23 months have further reduced the number of ALF cases due to hepatitis A.

Hepatitis B and D

Acute hepatitis B infection is the most common viral cause of ALF, accounting for 8% of cases in the ALFSG. Besides in the United States and United Kingdom, it is one of the most important causes of ALF. The incidence of ALF caused by hepatitis B may be underestimated, as some studies have shown evidence of hepatitis B infection by polymerase chain reaction (PCR) in patients who underwent transplantation for what was classified non-A, non-B hepatitis. Precore or pre-S mutant hepatitis B viruses cause infection but do not produce hepatitis B e antigen and may be difficult to diagnose by routine serology. Because rapid destruction of hepatocytes occurs in patients with fulminant hepatitis, some patients have no detectable hepatitis B surface antigen and lower hepatitis B virus DNA levels; however, high-titered immunoglobulin M anti–hepatitis B core antigen is required for diagnosis of acute hepatitis B.

A study in the United States comparing two separate cohorts of patients with hepatitis B–associated ALF versus chronic infection demonstrated that patients with ALF were more likely to be non-Asians and more likely to have genotype D than patients with chronic hepatitis B. In general, the care of patients with viral hepatitis B is supportive as liver transplant is the only effective treatment option. Lamivudine, entecavir, and adefovir, used to treat chronic hepatitis B, have also been used in ALF, but the data is conflicting.

Hepatitis C

The role of hepatitis C infection in ALF is controversial. Studies from Japan and India report the presence of anti-hepatitis C virus antibody or hepatitis C virus RNA among patients with ALF, but studies in France, the United States, and the United Kingdom have not shown hepatitis C to be a significant cause of ALF.

Hepatitis D

In the United States, infection with hepatitis D virus accounts for fewer than 10% of all cases of acute hepatitis related to hepatitis B virus. It has been suggested that a majority of cases of ALF in patients positive for hepatitis B are due to delta virus rather than to hepatitis B alone.

Hepatitis E

Hepatitis E occurs in epidemics in which a high incidence of ALF is seen, particularly in pregnant women. In pregnancy, the fatality rate approaches 40%. Hepatitis E has only rarely been identified in the United States but should be considered in anyone with recent travel to endemic areas such as Russia, Pakistan, Mexico, or India.

Atypical Viral Hepatitides

Adenovirus-induced ALF is rare, but multiple cases have been reported after allogeneic stem cell transplantation, liver transplantation, chemotherapy, and renal transplantation. It has an aggressive clinical course and poor prognosis.

Similarly, cytomegalovirus, Epstein-Barr virus, and herpesviruses 1, 2, and 6 are occasionally implicated as causes of ALF. ALF related to herpesvirus infection is usually associated with immunosuppressive therapy or pregnancy, although occurrences of herpes virus–induced ALF have been reported in healthy individuals. Skin lesions are present in only about 50% of cases, and liver biopsy is often helpful in establishing the diagnosis. Treatment should be initiated with acyclovir for suspected or documented cases. Varicella virus has been rarely implicated in hepatic failure and can also be treated with acyclovir.

Non–Acetaminophen Drug Toxicity

Many drugs produce idiosyncratic liver failure (Table 38–5), including halothane, sulfonamides, phenytoin, and isoniazid. In the ALFSG, 13% of ALF cases were attributed to idiosyncratic drug-induced hepatotoxicity.

Drugs most frequently associated with idiosyncratic ALF, as reported by the ALFSG, were antibiotics (especially isoniazid), nonsteroidal analgesics, antiepileptics, statins, and herbal preparations. Two drugs prominently implicated in this study, bromfenac and troglitazone, have been withdrawn by the U.S. Food and Drug Administration. Amoxicillin–clavulanate was the most common drug implicated in another registry that included 461 patients with drug-induced liver injury. The fluorinated hydrocarbons trichloroethylene and tetrachloroethane also produce ALF, often with associated renal failure, in people who sniff glue or those exposed to industrial cleaning solvents.

Clinical Findings

Identification of drug-induced ALF requires careful history taking, including all medications, over-the-counter preparations, vitamin supplements, herbal supplements, and health foods. Peripheral eosinophilia, skin rash, and fever may be seen when associated with hypersensitivity; however, many cases of drug-induced hepatotoxicity are nonallergic and idiosyncratic. Aminotransferase levels are often only moderately elevated (in contrast with acetaminophen-induced liver failure, and most other causes of ALF).

Treatment

Initial treatment of drug-induced liver disease includes supportive care, exclusion of other causes of liver injury, and withdrawal of the offending agent. Corticosteroids are not indicated unless there is evidence of a hypersensitivity reaction.

Patients with non–acetaminophen drug-induced ALF have a poor outcome overall, with only 25% recovering spontaneously, and a 60–80% mortality rate without liver transplantation. The outcome of drug-induced acute liver failure is predicted by the degree of liver dysfunction, but not by the class of drugs, drug injury pattern, age, gender, obesity, or timing of cessation of drug use. Hyman Zimmerman, in an observation known as "Hy's rule," noted that if both drug-induced hepatocellular injury and jaundice were present simultaneously without biliary obstruction (or hemolysis), a mortality rate of at least 10% could be expected.

Mushroom Poisoning

Mushroom poisoning is common in Western Europe, with 50–100 fatal cases reported yearly. Amanita phalloides is the most common species implicated. Hepatic failure is preceded by muscarinic effects such as profuse sweating, vomiting, and diarrhea. Diagnosis should be suspected in patients with a history of severe vomiting, diarrhea, and abdominal cramping within hours to a day of ingesting wild mushrooms. Gastric lavage and activated charcoal via nasogastric tube to remove stomach contents and to decrease the toxin in the enterohepatic circulation has been used although there are no definitive studies of usefulness. The cholera-type diarrhea seen most commonly as an effect of phalloidin during the first 24 hours of illness can produce a profound metabolic alkalosis requiring vigorous fluid resuscitation and electrolyte replacement. Penicillin G, in doses of 250,000–1,000,000 units/ kg/day, is used as treatment and is believed to work by displacing amanitin from plasma protein-binding sites and allowing for increased renal excretion. Sibilin (milk thistle) also has cytoprotective abilities against amatoxin. Both antidotes are used commonly despite no controlled trial demonstrating benefit. Patients should be considered for transplantation as very low rates of survival have been reported without it. Of note, encephalopathy is not always present in severe cases and should not be an absolute prerequisite for deciding on transplantation. One study of 27 cases showed that an interval between ingestion and diarrhea of less than 8 hours was a very early predictor of fatal outcome. Later on, prothrombin index and non acetaminophen and acetaminophen King's College criteria were more reliable indicators of prognosis.

Autoimmune Hepatitis

Most patients with autoimmune hepatitis exhibit clinical features of chronic hepatitis, but some present with ALF or an acute-on-chronic presentation. Diagnosis of ALF due to autoimmune hepatitis can be difficult, and other causes need to be ruled out. Autoantibodies may be absent, and liver biopsy is often needed to obtain a diagnosis. Corticosteroids should be initiated (prednisone, 40–60 mg/day), but many patients do not respond even to larger, pulsed doses of steroids. Transplantation listing should therefore be considered in all patients with this presentation.

Wilson Disease

ALF is rare in Wilson disease and appears to be more common in women. It is frequently associated with hemolytic anemia as hepatocyte necrosis results in the massive release of copper ions into the circulation. Clinical signs include jaundice, hemoglobinuria, and renal failure. Diagnosis can be difficult because ceruloplasmin, serum copper, urinary copper, and even liver biopsy with copper staining can be unreliable. As with autoimmune hepatitis, patients may have evidence of cirrhosis and still present with signs of ALF when rapid deterioration occurs. Kayser-Fleischer rings are present in 50% of patients presenting with ALF due to Wilson disease. Findings suggestive of the disease include very high bilirubin level (>20 mg/dL), markedly decreased serum albumin and cholesterol levels, decreased serum alkaline phosphatase, decreased uric acid, and a serum AST that runs higher than ALT (over 4:1) due to hemolysis. A high bilirubin (mg/dL) to alkaline phosphatase (IU/L) ratio (>2) is a reliable indicator of Wilson disease in this setting.

ALF due to Wilson disease is nearly always fatal without transplantation, making early identification and immediate listing for transplant critical. Treatment to acutely lower serum copper and limit further hemolysis should include continuous hemofiltration, plasmapheresis, or plasma exchange. Penicillamine is not recommended in ALF as there is a risk of hypersensitivity.

Malignancy & Vascular Causes

Vascular causes of ALF include portal vein thrombosis, hepatic vein thrombosis, veno-occlusive disease, and ischemic hepatitis. Ischemic liver injury produces marked aminotransferase elevations, centrilobular necrosis, and ALF often with concurrent renal failure, myocardial infarction, cardiac arrest, cardiomyopathy, congestive heart failure, hypovolemia, and pulmonary embolism. Drug-induced hypotension or hypoperfusion causing ALF can be observed with long-acting niacin, cocaine, or methamphetamine.

Budd-Chiari syndrome or acute hepatic vein thrombosis can also present as ALF and often is due to an underlying prothrombotic problem. Abdominal pain, ascites, and hepatomegaly are often present as well as lactic acidosis. The diagnosis should be confirmed by imaging. Transjugular intrahepatic portosystemic shunt, surgical decompression, portocaval shunt, or thrombolysis may be beneficial in patients with acute Budd-Chiari syndrome. Transplantation may be required in patients who do not respond to venous decompression or in whom significant liver failure has occurred. It is important to rule out underlying cancer prior to transplantation.

Malignant infiltration may cause ALF. Massive hepatic enlargement may be seen. Diagnosis should be made by imaging and biopsy, and treatment for the underlying disease is indicated. Common causes include breast cancer, small cell lung cancer, lymphoma, and melanoma. Transplantation is not an option in these patients.

Pregnancy

Viral hepatitis is the most common cause of ALF in pregnancy and accounts for 40% of jaundice. The outcome of acute fulminant hepatitis E virus infection in pregnancy is poor. Supportive care is advocated, and termination, caesarean, or discouragement of breast feeding are not indicated. Pregnancy can also increase the risk of ALF due to herpesvirus infection, which should be treated with acyclovir. Acute fatty liver of pregnancy (AFLP) occurs during the third trimester and rarely presents as ALF. It is characterized by sudden onset of jaundice and coagulopathy, altered mental status, hypoglycemia, and elevated transaminases but not to the extent seen in acute viral or drug-related hepatitis. Steatosis documented by imaging or biopsy supports the diagnosis of AFLP. Rapid delivery is the treatment, but in 40% of cases the fetus dies before delivery. Fatty liver of pregnancy can be treated with transplantation if prompt recovery does not follow delivery. Alternatively, HELLP syndrome, which involves very high aminotransferase levels, hemolysis, thrombocytopenia, hypertension, proteinuria, and preeclampsia, occurs in 0.1–0.6% of all pregnancies and in 4–12% of women with severe preeclampsia. The only definitive treatment is emergent delivery along with antepartum stabilization of hypertension and DIC, seizure prophylaxis and fetal monitoring.

Indeterminate Cause

Other rare causes of ALF include giant cell hepatitis or arteritis, amebic abscesses, disseminated tuberculosis, sepsis, heat stroke, and bone marrow transplantation. The cause of ALF is indeterminate in nearly 20% of adult patients in the United States. Indeterminate ALF carries a poor prognosis, with a spontaneous survival rate of 20% or less. Several reports have implicated a variety of viruses in indeterminate, ALF including togaviruses, paramyxoviruses, herpes simplex virus, SEN virus, and hepatitis C virus. The presence of many of these viruses has been discovered later by PCR, after results of routine serologic testing were negative.

This chapter is a revised version of the chapter by Dr. Jaya R. Agrawal and Dr. Amir A. Qamar that was in the previous edition of Current Diagnosis & Treatment: Gastroenterology, Hepatology, & Endoscopy.