Acetaminophen and acute liver failure

Acetaminophen (alternative name paracetamol) is one of the most frequently used drugs and widely considered very safe in almost all clinical contexts so long as the maximum recommended dose is not exceeded. 

When taken in overdose, however, it can cause acute liver failure (ALF). In fact, acetaminophen overdose/toxicity is the most common cause of acute liver failure (ALF) in parts of the developed world, including the US and UK. 

Other less common causes of ALF include viral infection, an array of hepatotoxic drugs/toxins, and a rare inherited metabolic condition (Wilson’s disease) that is characterized by accumulation of copper in hepatocytes. Despite intensive investigation, no cause can be identified in close to 15 % of all ALF cases. 

Research conducted by the Acute Liver Failure Study Group (ALFSG) based at University of Texas in Dallas now confirms that unrecognized acetaminophen toxicity is a feature in a sizeable minority of these ALF cases of undetermined etiology. This research depended on a novel assay developed by the group that detects acetaminophen protein adducts (APA) in blood serum. 

Previous work by the group had demonstrated that serum APA concentration > 1.0 nmol/mL is a highly sensitive and specific indicator of definite acetaminophen toxicity. For this study the assay was used to test the serum of 110 patients on the ALFSG registry who were suffering ALF of undetermined etiology. 

As positive controls, the sera from a further 199 patients with known or presumed acetaminophen-induced ALF were also tested. Nearly all (94.5 %) of the positive control sera had, as expected, an APA > 1.0 nmol/mL. More significant was the finding that of the 110 sera from patients with ALF of undetermined etiology, 20 (18 %) also had APA > 1.0 nmol/L (median level for these 20 sera was 9.2 nmol/mL). 

The records of all 20 patients revealed laboratory test results (very high aminotransferase and low bilirubin concentration) that are typical of acetaminophen toxicity. It would seem that acetaminophen toxicity was at the very least a contributory cause and may have been the sole cause of the ALF in these 20 patients. 

The authors suggest that acetaminophen toxicity should be considered in all cases of ALF of undetermined etiology. Such patients might well benefit from administration of N-acetylcysteine (NAC), the antidote routinely used to treat those known to have taken an overdose of acetaminophen. A multicenter, placebo-controlled trial of the efficacy of NAC in cases of ALF of undetermined etiology is currently being conducted by the ALFSG.