1. 
   

   How is acute liver failure (ALF) defined and diagnosed, and how does it differ from acutely decompensated cirrhosis?

   
   
2. 
   

   Which causes of decompensated chronic liver failure can also be classified as “acute” failure with respect to transplant candidacy?

   
   
3. 
   

   How should clinicians acutely evaluate, triage, and manage ALF patients, including initial diagnostic testing follow-up testing?

   
   
4. 
   

   What clinical and laboratory parameters should be frequently monitored?

   
   
5. 
   

   What complications of ALF lead to high mortality, and how are they managed?

   
   
6. 
   

   How is intracranial hypertension and cerebral edema managed medically?

   
   
7. 
   

   What prognostic measures best identify ALF patients who will require liver transplant in order to survive?

   
   
8. 
   

   What evidence-based interventions improve outcomes in patients with acute liver failure? Are they etiology specific?

Definition

Acute liver failure (ALF) is a rare clinical syndrome that is defined by coagulopathy and encephalopathy that occurs over a span of less than 6 months in a patient without preexisting liver disease. Based on the time to encephalopathy from the onset of jaundice, three types of ALF have been described: hyperacute (0–7 days), acute (8–28 days), and subacute (29 days–12 weeks).

Patients with subacute liver failure often pose a clinical challenge, as they may show signs suggesting chronic liver disease, such as ascites or prolonged encephalopathy. Also, patients with subacute liver failure (eg, drug induced) may follow a variable and unpredictable course, often leading to heightened anxiety for the patient, family, and medical providers.

As an exception to the definition of ALF, patients with Wilson disease, reactivation/superinfection of chronic hepatitis B, or autoimmune hepatitis may be considered to have ALF despite the presence of underlying chronic liver disease.

Epidemiology

Approximately 2000 cases of ALF occur each year in the United States. ALF can affect people of all ages and is associated with high morbidity and mortality. Multiorgan failure (MOF) is the most common cause of death (> 50% of cases), with infection and intracranial hypertension responsible for most of the remaining deaths. With recent improvements in care, spontaneous recovery and overall survival now exceed 40% and 65%, respectively. Over the past 25 years in the United States, overall mortality from ALF has decreased from more than 80% to 33%.

ALF involves massive hepatocellular necrosis and liver dysfunction. A resulting cytokine storm leads to oxidative stress and a systemic inflammatory response syndrome. HIV medications, Wilson disease, and acute fatty liver of pregnancy may uniquely cause severe mitochondrial dysfunction with resulting lactic acidosis. Ultimately, multiorgan dysfunction occurs.

Intracranial hypertension (ICH) and cerebral edema may result from both elevated ammonia levels, which causes direct astrocyte toxicity, and loss of cerebral blood flow autoregulation. Loss of cerebral autoregulation in ALF leads to ICH, and intracranial contents are rapidly damaged by both hydrostatic and osmolar shifts. Noncardiogenic pulmonary edema (acute respiratory distress syndrome, ARDS) and renal failure may result from cytokine-induced damage and hemodynamic derangements. Cardiovascular collapse can be seen with a severe depression of systemic vascular resistance, another process that is driven by cytokines and derangements in vasoactive substances. Loss of the normal synthetic function of the liver also leads to both a coagulopathy and prothrombotic state. Metabolism of medications and other physiologic mechanisms, such as biliary excretion, are also disrupted in the setting of ALF.

Acute liver failure differs from acute on chronic liver failure. Although there are some examples of overlap (eg, Wilson disease, autoimmune hepatitis, acute on chronic hepatitis B), the pathophysiology of the two clinical syndromes differ with respect to physiologic adaptation. For instance, patients with ALF are at risk for elevated intracranial pressure (ICP) because neuronal adaptation does not have time to occur as the ammonia levels rapidly rise.

In the setting of possible ALF, clinicians must exclude chronic liver disease. Only a few chronic hepatic conditions may present with true ALF: (1) Wilson disease, (2) autoimmune hepatitis, and (3) acute on chronic viral hepatitis B.

A nodular appearing liver on imaging studies can be misleading, as an irregular contour may represent regenerative nodules interspersed with areas of acute injury and necrosis. Similar to acute alcoholic hepatitis, acute portal hypertension and ascites may also be seen with ALF. Finally, sepsis with disseminated intravascular coagulation in a patient who has cirrhosis can also mimic ALF, as such a patient can present with altered mental status, coagulopathy, and jaundice.

Causes of ALF

In the United States, acetaminophen toxicity is the number one cause of ALF (39%). Approximately 20% to 25% of these patients undergo orthotopic liver transplantation. Whereas most cases of acetaminophen-induced ALF involve ingestions exceeding 10 g/day, severe liver injury can occur with doses as low as 3 to 4 g/day, as is seen with therapeutic misadventure. Therapeutic misadventure, referring to therapeutic doses of acetaminophen in the setting of alcohol, malnutrition, or cytochrome p450-inducing medications, occurs in nearly half of acetaminophen toxicity cases (Table 158-1).

In addition to acetaminophen, multiple other causes can lead to ALF, and in the United States approximately 20% of ALF cases have no discernible cause (Table 158-2). Non-acetaminophen drug or toxin-induced liver injury accounts for 13% of cases (Table 158-3). Toxins may include Amanita phalloides (mushrooms), sea anemone sting, or carbon tetrachloride. Acute hepatitis A and B account for 4% and 7% of ALF cases, respectively. The remainder of cases may be due to other viruses (herpes simplex virus [HSV], Epstein-Barr virus [EBV], cytomegalovirus [CMV]), Wilson disease, Budd-Chiari syndrome, sinusoidal obstruction syndrome, acute fatty liver of pregnancy, autoimmune hepatitis, malignant infiltration, or ischemia.

Presentation

A patient can present at any point along the disease severity spectrum. Multiorgan failure may rapidly ensue and manifest with abrupt clinical decompensation. Some patients, such as those who recently ingested an acetaminophen overdose, or those with subacute liver failure, may initially present asymptomatically, despite having markedly abnormal blood work. Nonspecific symptoms may include nausea, vomiting, abdominal pain, fever, malaise, fatigue, arthralgias, itching, bleeding, headache, and diarrhea. Nonspecific clinical signs may include abdominal pain, altered mental status, jaundice, or ascites.

History

A detailed history, including a careful review of possible exposure to viruses, drugs, or toxins, may help uncover a possible cause of liver failure. Clinicians must question about over the counter medications, alternative therapies, herbs, and supplements (Table 158-3). If the patient is encephalopathic, a collateral history from friends or family is important, as identifying a cause can be paramount in the management of ALF.

Acetaminophen toxicity may involve intentional overdose or may involve high doses over an extended period of time. For example, a patient who takes over the counter acetaminophen in addition to prescribed acetaminophen-containing pain medications may exceed a critical daily dose that leads to severe liver injury. Alcoholics and malnourished patients are at greater risk for acetaminophen-induced liver injury.

Most idiosyncratic drug-induced liver injuries are not dose-related and tend to occur within the first 6 months of drug initiation (Table 158-3).

A history of IV drug abuse may indicate risk for infections such as acute hepatitis B and D. Travel to endemic regions (eg, Russia, Pakistan, India, Mexico) may place a patient at risk for acute hepatitis E infection. Immunosuppressed patients and women in their 3rd trimester of pregnancy are at increased risk for herpes simplex infection. A history of preeclampsia in a pregnant woman increases the risk of acute fatty liver of pregnancy, which also occurs in the 3rd trimester. Previous or coexisting autoimmune diseases (thyroiditis, insulin dependent diabetes, lupus, vitiligo, etc) may indicate an increased risk for autoimmune hepatitis. Cardiac disease (congestive heart failure, myocardial infarction, arrhythmia) or hemodynamic instability may lead to “shock liver” from hypoperfusion. Documented hypotension is not always found with ischemic liver injury. A history of malignancy or hypercoagulable state may raise concern for malignant infiltration or Budd-Chiari syndrome (hepatic vein thrombosis), which often presents with acute abdominal pain, ascites, and striking hepatomegaly. Finally, a history of chemotherapy may place a patient at risk for sinusoidal obstruction syndrome, formerly known as veno-occlusive disease, which can present in a similar manner as Budd-Chiari syndrome (Table 158-4).

Physical Examination

With ALF, the most important step in the physical examination is assessing mental status and performing frequent neurological examinations. Clinicians must also examine closely for any signs of chronic liver disease including spider angiomata, telangiectasias, Terry nails (fingernails and/or toenail appear white with a characteristic “ground glass” appearance, with no lunula), palmar erythema, asterixis, splenomegaly, caput medusa, collateral venous patterns, and gynecomastia. Whereas ascites and varices are classically seen with chronic liver disease, these signs of portal hypertension can be seen with acute liver disease as well (eg, alcoholic hepatitis, venous thrombosis, pre-sinusoidal portal hypertension).

In patients suspected of Wilson disease, a slit lamp examination of the eye should be performed to assess for the presence of Kayser-Fleischer rings. In patients with ICH from cerebral edema, Cushing triad—hypertension, bradycardia, irregular respirations—may or may not be present. Pupillary dilation or signs of decerebrate posturing typically occur late in the course of ALF and indicate a grave prognosis.

Laboratory

When ordering laboratory testing for patients admitted with ALF, a standard protocol can facilitate a thorough evaluation, since the initial lab survey is often extensive. Even if a diagnosis seems clear, evaluating for concomitant diseases such as viral hepatitis or human immunodeficiency virus is important in a patient who may require a liver transplant. Frequent hepatic function testing often necessitates indwelling vascular access (central venous catheter or arterial catheter) for serial blood draws and other clinical management (Table 158-5). No consensus guidelines recommend specific laboratory testing in the setting of probable ALF; however, laboratory testing is necessary in anticipation of possible liver transplantation (Table 158-5).

Upon presentation, very high transaminase levels (AST and ALT levels > 1000 U/L) may limit the differential to a few possible etiologies: acute viral infection, acetaminophen-induced injury, shock liver, or autoimmune hepatitis. AST and ALT levels exceeding 3500 U/L are highly correlated with acetaminophen poisoning. Whereas transaminase levels may be helpful initially, they do not add much information once the diagnosis of ALF is established. Transaminase levels that appear to be normalizing may indicate an obliterated liver, especially if associated with hypoglycemia and an unabated rise in the international normalized ratio (INR). Alternatively, normalizing liver enzymes may also indicate improving hepatic injury facilitated by removal of a toxic exposure, natural history of a virus, or a treatment response (eg, autoimmune hepatitis, herpes simplex, hepatitis B). A bilirubin level on presentation carries prognostic significance, especially with drug-induced liver injury (Hy’s law, a prognostic indicator that suggests that drug-induced liver injury leading to jaundice, without hepatic transplantation, has a case fatality rate of 10–50%). Initial INR and creatinine also provide prognostic information.

Imaging

Ordering a multitude of imaging tests that require patient transport and movement may present unnecessary risk for a critically ill patient with ALF. Nevertheless, imaging—when safe to perform—can provide diagnostic information to direct management. All patients with ALF should undergo an abdominal ultrasound with Doppler to assess for signs of chronic liver disease, and to assess the hepatic vasculature (hepatic veins, portal vein, hepatic artery). Computed tomography (CT) scan of the abdomen without contrast is preferred if the patient’s body habitus (eg, obesity, ascites, bowel distension) precludes an adequate ultrasound examination. Avoidance of IV contrast is important since many patients with ALF are at risk for developing acute kidney injury. MRI of the abdomen with IV gadolinium is an alternative imaging modality that is center specific and depends on radiologic expertise.

In a patient with worsening mental status, a noncontrast brain CT will help evaluate for intracranial hemorrhage or cerebral edema. Cerebral edema, while prognostically ominous if seen on CT, may indicate the need for placement of an ICP monitor. In a patient with suspected brain damage, transcranial Doppler ultrasounds or continuous electroencephalograms (EEGs) may provide prognostic information. To assess heart function and valves, a transthoracic echocardiogram may be necessary, especially if a patient is a possible liver transplant candidate. Plain films, such as chest x-rays and abdominal radiographs, may also be ordered as clinically indicated but are generally performed at the patient bedside (portable machine) to avoid unnecessary patient transport.

Liver Biopsy

When specific diseases such as autoimmune hepatitis, Wilson disease, HSV hepatitis, or lymphoma are suspected, a liver biopsy may be useful in assisting with diagnosis. A liver biopsy may also help determine the extent of necrosis and regeneration in cases of subacute liver failure. For the majority of ALF cases, a liver biopsy is not necessary and may even lead to complications such as hemorrhage or infection. In cases of severe ALF, a biopsy will most likely show extensive necrosis and “ghosts” of hepatocytes.