Chapter 2 Acute liver failure
1 Acute liver failure is a syndrome of rapidly progressive hepatic dysfunction associated with a high risk of mortality.
2 The defining features of acute liver failure are hepatic encephalopathy, coagulopathy, and jaundice in patients without underlying liver disease.
3 Acetaminophen hepatotoxicity is the leading cause of acute liver failure in the United States; approximately one half of cases are unintentional.
4 Treatment strategies for acute liver failure include intensive care unit monitoring, implementation of specific therapies based on cause, and aggressive treatment of complications, including infection, renal failure, metabolic disorders, and cerebral edema.
5 The cause of acute liver failure is the strongest predictor of survival; prognostic criteria are important in identifying patients with a low probability of spontaneous recovery and potential candidacy for liver transplantation.
Definitions
Fulminant hepatic failure (FHF)
1. The earliest classification, introduced by Trey and Davidson, defined fulminant hepatic failure (FHF) by the interval from the onset of an acute hepatic illness to the development of hepatic encephalopathy:
Subfulminant hepatic failure
1. This designation refers to a prolonged course of ALF, characterized by a longer interval between the onset of illness or jaundice and the development of hepatic encephalopathy.
2. Different definitions of subfulminant hepatic failure have been introduced:
a. Late-onset hepatic failure, proposed by Gimson et al, defined by an interval from the onset of hepatic illness to the development of hepatic encephalopathy between 8 and 26 weeks
b. Subfulminant liver failure, introduced by Bernuau et al, defined by an interval from the onset of jaundice to the development of hepatic encephalopathy between 2 and 12 weeks
Epidemiology
1. The incidence of ALF in the United States is approximately 2000 cases per year; ALF accounts for 3.5 deaths per million and 31.2 hospitalizations per million.
2. Although ALF is rare, it is associated with a high mortality; ALF accounts for up to 6% of all liver-related deaths and 6% of liver transplants.
3. Outcomes of ALF have improved since 2000 in the United States, possibly because of shifting trends in etiology (Table 2.1); prospective data from the U.S. Acute Liver Failure Study Group found a rate of spontaneous recovery without liver transplantation of 45% and an overall mortality rate of 30%; approximately 25% of patients underwent liver transplantation.
TABLE 2.1 Most common causes of acute liver failure
| Cause | Frequency (%) |
|---|---|
| Acetaminophen overdose | 46 |
| Indeterminate | 14 |
| Idiosyncratic drug-induced liver injury | 11 |
| Hepatitis B | 8 |
| Autoimmune hepatitis | 6 |
| Ischemic hepatitis | 4 |
| Hepatitis A | 3 |
| Wilson disease | 2 |
| Budd–Chiari syndrome | 1 |
| Pregnancy∗ | 1 |
| Other | 5 |
∗ Pregnancy-related acute liver failure includes acute fatty liver of pregnancy and the hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome.
Adapted from Lee WM. Etiologies of acute liver failure. Semin Liver Dis 2008; 28:142–152; based on 1213 cases of acute liver failure prospectively enrolled in the U.S. Acute Liver Failure Study Group (1998–2007).
Causes
1. Based on prospective data from more than 1000 patients enrolled in the U.S. Acute Liver Failure Study Group from 1998 to 2007, acetaminophen overdose was the most common cause of ALF, followed by indeterminate cause, idiosyncratic drug-induced liver injury, acute hepatitis B, and autoimmune hepatitis (see Table 2.1); other causes of ALF are shown in Table 2.2.
2. Since 2000, the proportion of cases of ALF resulting from acetaminophen overdose in the United States has increased, whereas the percentage of cases caused by acute viral hepatitis has decreased.
TABLE 2.2 Causes of acute liver failure
| Viral hepatitis | |
| Drug-induced liver injury | |
| Toxins | |
| Metabolic disorders | |
| Vascular events | |
| Miscellaneous causes |
HELLP, hemolysis, elevated liver enzymes, and low platelets.
Adapted from Keeffe EB. Acute liver failure. In: McQuaid KR, Friedman SL, Grendell JH, eds. Current Diagnosis and Treatment in Gastroenterology, 2nd edn. New York: Lange Medical Books/McGraw-Hill; 2003:536–545.
Pathophysiology
1. Most cases of ALF are characterized by massive hepatocyte necrosis resulting in liver failure; ALF without histologic evidence of hepatocellular necrosis can also be seen, as in acute fatty liver of pregnancy and Reye’s syndrome.
2. Hepatocyte necrosis and apoptosis may coexist in the setting of ALF; hepatocyte necrosis occurs through adenosine triphosphate (ATP) depletion followed by cellular swelling and cell membrane disruption; apoptosis is a process of programmed cell death triggered by extrinsic or intrinsic mechanisms and resulting in caspase activation, degradation of genetic material, and cell shrinkage.
Clinical Features
Drug or toxin-induced ALF
1. Acetaminophen (see also Chapter 8)
a. Acetaminophen hepatotoxicity is dose related, and a massive ingestion of at least 15 to 20 g is typically required for development of ALF.
b. ALF secondary to acetaminophen hepatotoxicity frequently occurs in the setting of a suicide attempt (Table 2.3), and some individuals may be at increased risk of a severe or fatal outcome (Table 2.4).
c. Acetaminophen is predominantly metabolized in the liver by glucuronidation and sulfation; a minority of the drug is metabolized by the cytochrome P-450 system. N-acetyl-p-benzoquinone imine (NAPQI) is a toxic intermediate generated by the cytochrome P-450 pathway during acetaminophen metabolism. Clearance of NAPQI requires conjugation by glutathione; however, glutathione stores can become depleted in the setting of an overdose, thus leading to direct hepatocyte injury mediated by NAPQI.
Induction of cytochrome P-450 metabolism through long-term alcohol use or barbiturates is associated with a greater risk of acetaminophen hepatotoxicity and ALF.
Induction of cytochrome P-450 metabolism through long-term alcohol use or barbiturates is associated with a greater risk of acetaminophen hepatotoxicity and ALF.
2. Other drugs and toxins
a. Antibiotics, antifungal, and antituberculosis drugs including isoniazid, pyrazinamide, tetracyclines, nitrofurantoin, ketoconazole, and sulfa-containing agents
c. Mushroom poisoning from Amanita or Galerina species
Amatoxins are cyclic octapeptides that inhibit RNA polymerase II and lead to hepatocyte necrosis as well as renal tubular injury.
Amatoxins are cyclic octapeptides that inhibit RNA polymerase II and lead to hepatocyte necrosis as well as renal tubular injury.
d. Organic solvents that contain chlorinated hydrocarbons, in which the severity of hepatotoxicity is related to the proximity and duration of exposure
f. Illicit drugs including cocaine and methylenedioxymethamphetamine (MDMA), also known as ecstasy, that cause ALF possibly as a result of ischemic hepatic injury
TABLE 2.3 Clinical syndrome of acetaminophen overdose
| Phases of acetaminophen hepatotoxicity |
|---|
| Initial phase (0–24 hr): |
| Latent phase (24–48 hr): |
| Overt hepatocellular necrosis phase (>48 hr): |
TABLE 2.4 Risk factors for acetaminophen hepatotoxicity
| Factors associated with increased risk |
|---|
