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Management of liver failure
Acute liver failure (ALF), a term that is equivalent to the now archaic “fulminant hepatic failure,” evolves after a catastrophic insult to the liver and results in the development of the dual characteristics of coagulopathy and encephalopathy within a matter of days or weeks of the liver injury. The absence of a previous diagnosis of liver disease is another requirement, with the exception of severe reactivations of hepatitis B. Patients with acute presentations of Wilson disease are also included within the definition of ALF despite having established cirrhosis at presentation. ALF should not be confused with the more recent concept of acute-on-chronic liver failure (ACLF), which occurs in patients with cirrhosis and is often precipitated by infection or gastrointestinal hemorrhage. The principles of management are similar in some respects (e.g., encephalopathy, coagulopathy) but very different in others (e.g., cerebral edema is almost exclusively observed in ALF). This chapter will be based mainly on ALF unless specified otherwise (see Chapter 74 ).
Acute liver failure is best considered as an umbrella term for a heterogenous condition that incorporates a range of clinical syndromes. The dominant factors that give rise to this heterogeneity include the underlying etiology, the age of the patient, and the duration of time during which the disease evolves. Natural history studies indicate that survival rates without liver transplantation range from 10% to 90%, with the best outcomes seen in patients with rapidly evolving pregnancy-related syndromes, severe acetaminophen hepatotoxicity, and hepatitis A. Survival rates are worse in older patients and, possibly, in very young children. The rate of progression of the disease is used to subclassify patients into groups with differing clinical problems and outcomes. There is a lack of universal agreement on terminology, but the main options in use are the terms hyperacute (encephalopathy within 7 days of the onset of jaundice), acute (encephalopathy within 8–28 days of the onset of jaundice), and subacute liver failure (encephalopathy more than 28 days of the onset of jaundice), which will be used in this chapter.
Etiology of acute liver failure
ALF remains a rare condition in the West, with probably fewer than 5 cases per million population per year. Viruses and drugs account for the majority of cases, but there is a significant variation in the patterns seen worldwide ( Table 77.1 ). In the West, there has been a trend toward more cases associated with acetaminophen and fewer from an identifiable viral infection. A number of patients have no definable cause, which is a condition referred to as acute liver failure of indeterminate etiology in this chapter, but also known as seronegative hepatitis and previously as non–A to E hepatitis . Most of the drug-induced cases are rare idiosyncratic reactions, but some, such as acetaminophen, are at least in part dose-related toxic events (see Chapters 68 and 69 ).
TABLE 77.1
Geographic Variation in the Etiology of Acute Liver Failure
| UNITED KINGDOM (%) | UNITED STATES (%) | JAPAN (%) | INDIA (%) | |
|---|---|---|---|---|
| Acetaminophen | 57 | 46 | 0 | 0 |
| Drug reactions | 11 | 11 | 7 | 4 |
| Indeterminate | 17 | 6 | 38 | 41 |
| Hepatitis A or B | 7 | 12 | 41 | 18 |
| Hepatitis E | 1 | — | 0 | 28 |
| Other causes | 7 | 25 | 14 | 9 |
Viral (see Chapter 68 )
ALF is a very uncommon complication of hepatitis A infection, occurring in 0.1% to 0.3% of hospitalized cases and in 0.4% of all cases seen in the United States. The incidence of ALF following hepatitis B was 1% to 4% of hospitalized patients. In early studies, hepatitis D coinfection or superinfection was thought to increase the risk because it was found in 30% to 40% of patients with ALF due to hepatitis B, compared with 5% to 20% of less severe cases. Vaccination and antiviral therapy have altered the observed pattern of hepatitis B–related ALF, which is now often seen in patients with previously subclinical, non-cirrhotic hepatitis B infection with a “reactivation” phenomenon following therapeutic immunosuppression, often after chemotherapy for malignancy. The risk of ALF after exposure to hepatitis C appears to be very low, but it has been described. Hepatitis E is common in parts of Asia and Africa, and the risk of ALF ranges from 0.6% to 2.8% to greater than 20% in pregnant women, and is particularly high during the third trimester. Hepatitis E is also encountered in Europe and the United States and may account for some cases that would previously have been described as indeterminate hepatitis.
Indeterminate hepatitis is a common cause of ALF in some parts of the Western world. Most cases are sporadic, and unidentified toxins or autoimmune processes may be the underlying mechanisms. Very detailed case scrutiny will identify a known etiology in some cases, but in others the cause remains obscure. Middle-aged females are most frequently affected, and the risk for ALF has been calculated at 2.3% to 4.7% of hospitalized cases.
Drugs
Acetaminophen (paracetamol) overdose and liver injury from the resultant hepatotoxicity is the most common cause of ALF in the United Kingdom and the United States. In the United Kingdom, it is usually taken with suicidal or parasuicidal intent, but in the United States, up to half of cases apparently follow therapeutic use. This is either because of unintentional overdosing or accelerated metabolism in people with liver enzyme induction as a consequence of antiepileptic therapy or regular alcohol usage. Legislation limiting the quantities of acetaminophen that can be purchased in the United Kingdom has been credited with reducing hospitalizations for ALF by about 50% by limiting the size of overdose.
The risk of developing ALF secondary to an idiosyncratic reaction ranges from 0.001% for nonsteroidal antiinflammatory drugs to 1% for the isoniazid/rifampicin combination. The diagnosis is made on the basis of a temporal relationship between exposure to the drug and the development of ALF. The more common offending drugs are listed in Box 77.1 . Most cases develop during the patient’s first exposure to the drug but some, such as halothane, occurred in sensitized individuals on the second or subsequent exposure. Nontherapeutic drugs also cause ALF, for instance, Ecstasy (methylenedioxymethamphetamine), which has been associated with a number of clinical syndromes ranging from rapidly progressive hyper-ALF associated with malignant hyperpyrexia to subacute liver failure.
BOX 77.1
HAART, Highly active antiretroviral therapy.
Note: Drugs more commonly implicated are shown in bold.
Examples of Drugs Causing of Acute Liver Failure
| MECHANISM OF LIVER INJURY | ||
|---|---|---|
| Dose-Related | Idiosyncratic | |
| Acetaminophen | Allopurinol | Monoamine oxidase inhibitors |
| Anabolic steroids a | Amiodarone | Nonsteroidal antiinflammatory drugs |
| HAART drugs | Carbamazepine | Phenytoin |
| Sulfonamides | Disulfiram | Propylthiouracil |
| Sodium valproate a | Ecstasy a | Pyrazinamide |
| Flutamide | Rifampicin | |
| Gold | Statins a | |
| Halothane | Sulfonamides | |
| HAART drugs | Terbinafine | |
| Isoniazid | Tetracycline | |
| Ketoconazole | Tricyclic antidepressants | |
| Methyldopa | ||
Both dose-related and idiosyncratic mechanisms illustrated.
Other etiologies
ALF associated with pregnancy is rare, complicating approximately 1:100,000 pregnancies, and 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 primigravidae carrying a male fetus and is characterized by severe microvesicular steatosis. The HELLP syndrome is defined as the combination of hemolysis, elevated liver enzymes, and low platelet count. ALF complicating preeclampsia or eclampsia typically exhibits very high serum aminotransferase levels and abnormal tissue perfusion patterns on computed tomography scanning, which reflect the microvascular infarction characteristic of this condition.
Wilson disease may present as ALF, usually during the second decade of life. It is characterized clinically by a Coombs-negative hemolytic anemia and demonstrable Kayser-Fleischer rings in the majority of cases. The serum ceruloplasmin levels are usually, but not invariably, low, and the serum and urinary copper levels are increased. Poisoning with Amanita phalloides (mushrooms) is most commonly seen in Central Europe, South Africa, and the west coast of the United States. Severe diarrhea, often with vomiting, is a typical feature and commences 5 or more hours after ingestion of the mushrooms, and liver failure develops 4 to 5 days later. Autoimmune chronic hepatitis may present as ALF but is usually beyond rescue with corticosteroid or other immunosuppressive therapy. Budd-Chiari syndrome may present with ALF, and the diagnosis is suggested by hepatomegaly and confirmed by the demonstration of hepatic vein thrombosis. Ischemic hepatitis resulting from hypoperfusion due to systemic shock or cardiac failure is increasingly recognized as a cause of ALF, especially in older patients. Malignancy infiltration, especially with lymphoma, may masquerade as ALF and is typically associated with hepatomegaly and again seen in older patients.
Diagnosis
The cardinal features of ALF are encephalopathy and coagulopathy. The diagnosis of encephalopathy is usually obvious on clinical evaluation and ranges from drowsiness to advanced coma. However, in subacute liver failure, clinical evidence of encephalopathy can remain subtle until the disease is advanced, and psychometric testing may be useful to establish the diagnosis and facilitate timely intervention with liver transplantation. The diagnosis of encephalopathy is supported by elevated arterial ammonia levels. Hypoglycemia should be excluded as an alternative explanation for impaired mental function.
Once a clinical diagnosis of ALF has been established, the next step is to determine the etiology. This may be obvious from the patient’s history when acetaminophen or mushroom ingestion is responsible for the liver injury. In other cases, a systematic approach is required. The appropriate investigations required in all patients are outlined in Table 77.2 , whereas those that are relevant in specific circumstances are listed in Table 77.3 . Imaging of the liver serves to assess the size and shape of the liver, which is usually small, and screen for portal hypertension. The detection of portal hypertension does not always indicate chronic liver disease because ascites and/or splenomegaly may be seen in subacute liver failure, as well as the acute presentation of Wilson disease.
TABLE 77.2
Core Investigation of Etiology of Acute Liver Failure
| ETIOLOGY | INVESTIGATION |
|---|---|
| Hepatitis A (HAV) | IgM anti-HAV |
| Hepatitis B ± D (HBV, HDV) | IgM anticore, HBV DNA (HBsAg may be negative) |
| Hepatitis E (HEV) | IgM anti-HEV |
| Acetaminophen | Drug levels in blood |
HBsAg, Hepatitis B surface antigen; IgM, immunoglobulin M.
TABLE 77.3
Extended Investigation of Etiology of Acute Liver Failure
| ETIOLOGY | INVESTIGATION |
|---|---|
| Idiosyncratic drug reactions | Eosinophil count, histology |
| Autoimmune | Autoantibodies, immunoglobulins |
| Pregnancy-related syndromes | |
| Fatty liver | Ultrasound, uric acid, histology |
| HELLP syndrome | Platelet count |
| Toxemia | Serum aminotransferases |
| Wilson disease | Urinary copper, ceruloplasmin, hemolysis screen, slit-lamp examination |
| Budd-Chiari syndrome | Ultrasound or venography |
| Malignancy | Imaging, histology, bone marrow |
| Ischemic hepatitis | Aminotransferases, echocardiography |
| Other viral Infections | IgM and nucleic acids for CMV, EBV, HSV, VZV, Parvovirus. |
CMV, Cytomegalovirus, EBV, Epstein-Barr virus, HELLP, hemolysis, elevated liver enzymes, and low platelet count; HSV, herpes simplex virus; VZV, varicella zoster virus.
Histologic assessment of liver tissue may sometimes aid the diagnosis of the cause of ALF (see Chapter 68 , 69 , and 74 ). Confluent necrosis is the most common histologic finding, and this may be zonal or panlobular. Necrosis that is zonal and coagulative or eosinophilic is more likely to be secondary to a toxic insult or ischemia. The features of necrosis and parenchymal collapse may be interspersed with evidence of regeneration, either occurring in a diffuse pattern of small areas throughout the liver or in randomly occurring larger nodules that give the “map-like” pattern that has been described in this condition. The latter pattern is most commonly seen in patients with subacute liver failure.
Histologic features may suggest specific diagnoses, including sodium valproate toxicity, malignant infiltration, Wilson disease, pregnancy-related syndromes, and Budd-Chiari syndrome. Sodium valproate toxicity is characterized by microvesicular steatosis. Screening for malignant infiltration as the cause of ALF is one of the stronger indications for performing a liver biopsy, especially when the liver is enlarged. Patients with Wilson disease presenting as ALF usually have established cirrhosis, commonly associated with interface hepatitis resembling autoimmune disease, hepatocyte ballooning, and steatosis (see Chapter 74 ). Liver histology may be useful in making a precise diagnosis within the spectrum of pregnancy-related liver diseases. The histologic features of Budd-Chiari syndrome (see Chapter 86 ) are extreme sinusoidal dilation, congestion, and coagulative necrosis.
Liver biopsy may also be of assistance in differentiating ALF from established cirrhosis and from acute alcoholic hepatitis, whether or not it is associated with cirrhosis. The former scenario can usually be distinguished on clinical grounds, but acute alcoholic hepatitis can present with clinical features very similar to subacute liver failure. A history of high alcohol consumption may not be available, but the diagnosis of acute alcoholic hepatitis is suggested by the investigational findings outlined in Box 77.2 .
BOX 77.2
Findings Suggestive of Acute Alcoholic Hepatitis
Hepatomegaly
Marked elevation of γ-glutamyl transferase
High white cell count not responding to antibiotics
Elevated immunoglobulin A level
Appearance of fatty infiltration on ultrasound
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