Acute liver failure including acetaminophen overdose

Abstract

Acute liver failure (ALF) is a dramatic, highly unpredictable clinical syndrome defined by the sudden onset of coagulopathy and encephalopathy. Acetaminophen overdose, the leading cause of ALF in the United States, has a 66% chance of recovery with early N-acetylcysteine treatment and supportive care. Cerebral edema and infectious complications are difficult to detect and treat in these patients and may cause irreversible brain damage and multiorgan failure. One-year survival after emergency liver transplantation is 70%, but 20% of listed patients die, highlighting the importance of early referral of patients who have ALF with a poor prognosis to a transplant center.

Figure 1

Etiologies of ALF in the United States. Amongst the 1,033 adult ALF patients enrolled in the ALFSG registry from 1998 through July 2007, acetaminophen overdose (45%) was the most common etiology followed by indeterminate ALF (15%) and idiosyncratic drug reactions (12%). Spontaneous survival at 3 weeks was greatest in subjects with acetaminophen overdose (63%) while subjects with malignancy and wilson’s disease have the lowest survival (0%) (Unpublished data courtesy of William Lee, MD, UTSW, October, 2007).

Figure 2

Metabolism of acetaminophen. Acetaminophen is metabolized by hepatic glucuronyl transferases and sulfotransferases to conjugated metabolites that are excreted in the urine. However, a small fraction can also be oxidatively metabolized to a reactive intermediate termed NAPQI (N-acetyl-p-benzoquinone imine). If excessive doses of acetaminophen are ingested (i.e. > 4 grams/day), NAPQI can covalently bind to intracellular proteins and lead to hepatocyte necrosis. In addition, if cytochrome P-450 enzyme activity is induced, the high rate of NAPQI formation may deplete intra-hepatic glutathione stores resulting in liver toxicity. Finally, depletion of glutathione stores via prolonged fasting may also increase the risk of acetaminophen hepatotoxicity but supporting evidence in humans is lacking.

Figure 3

Head CT findings in an ALF patient with cerebral edema. A 39 year old male ingested an unknown quantity of acetaminophen, zolpidem, and lamotrigine in a suicide attempt 48 hours prior to presentation. His initial acetaminophen level was 87 mcg/ml, ALT >9,000 IU/L, INR 8.9, and factor V level < 15%. He also had a severe lactic acidosis with hypotension requiring pressors and intubation. At the time of listing for liver transplantation, a head CT showed loss of the grey-white matter interface (Figure 3A) but an ICP monitor revealed an opening pressure of only 12 to 15 mm Hg. Following an uneventful liver transplantation, the patient did not wake up. A follow-up head CT (Figure 3B) showed diffuse changes of worsening cerebral edema and the patient was pronounced brain dead after the absence of intracranial blood flow on a Tc⁹⁹ albumin scan.