Selected Summary

Measurement of Serum Acetaminophen-Protein Adducts in Patients with Acute Liver Failure. Davern TJ II, James LP, Hinson JA, et al, and the Acute Liver Study Group. Gastroenterology 2006;130:687–94. Summary: The Acute Liver Failure (ALF) Study Group is a National Institutes of Health–funded study group that includes 24 sites in the United States investigating the etiology, pathogenesis, and treatment of acute liver failure. Samples and data were collected in 880 adult subjects who met predetermined criteria for ALF between 1998 and 2005. Among these adults, it would be anticipated that approximately 50% would be related to acetaminophen (APAP)–related injury. Serum was collected from 66 patients from 3 groups: 20 patients with well-characterized APAP-related ALF, 10 patients with ALF due to other well-characterized causes, and 36 patients with ALF of indeterminate cause. An additional 15 patients were studied without ALF with known APAP overdose with minimal or no biochemical liver injury. Samples were collected daily for 7 days. Serum APAP adducts were measured using a labor-intensive method of high-pressure liquid chromatography using electrochemical detection (HPLC-EC). Previous studies have demonstrated a correlation between APAP-induced liver injury and the presence of APAP adducts in liver and in serum in animal models of APAP hepatotoxicity. In all patients with known APAP-induced ALF, APAP adducts were identified in serum, which declined in parallel with serum aminotransferase levels. No APAP adducts were identified in patients with other non–APAP-related causes of ALF. Seven of 36 patients (19%) with ALF of indeterminate cause also had APAP adducts, suggesting some potential role for APAP in their ALF. Low levels of APAP adducts were found in only 2 of 15 patients with APAP overdose without evidence of significant liver injury. Detection of Acetaminophen Protein Adducts in Children With Acute Liver Failure of Indeterminate Cause. James LP, Alonso EM, Hynan LS, et al, and the Pediatric Acute Liver Failure Study Group. Pediatrics 2006;118:e676–81. Summary: The Pediatric ALF Study Group includes 21 pediatric centers in the United States, 1 in Canada, and 2 in England. Their goals are similar to those of the Adult ALF Study Group, with a focus on children 18 years of age or younger. Data and serial daily serum samples were collected on patients enrolled between February 2000 and April 2004. From this cohort a group of 151 patients with ALF of indeterminate cause were available for study. Of this group, samples were available on 64 patients (42.4%). Samples from an additional 10 patients with known APAP-induced ALF and 30 patients with ALF of other causes were assayed using the HPLC-EC method previously validated by the authors. Among patients with APAP-induced ALF, 9 of 10 had APAP adducts in serum. Eight of 64 patients (12.5%) with ALF of indeterminate cause were found to have APAP adducts. This group had higher serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and lower serum total bilirubin level than the 58 patients without APAP adducts. In 4 of 8 patients with serum APAP adducts in whom liver histology was available, centrilobular necrosis typical of APAP-induced injury was found. Among the group of patients with ALF attributed to other causes, 3 of 30 (10%) patients had serum APAP adducts present. Comment: Acetaminophen is the most widely used antipyretic and analgesic agent in the United States and Europe. It is generally considered to be a safe medication when taken as directed; however, toxicity to APAP accounts for >56,000 emergency department visits and nearly 500 deaths per year in the United States (1). APAP hepatotoxicity accounts for approximately 50% and 14% of the cases of liver failure in adults and children, respectively, when based on a typical history of ingestion, laboratory findings, and clinical course. In the pediatric population there remains a persistent problem of chronic inadvertent overdosing because of confusion by parents regarding dosing strength of preparations, use of adult preparations for children, or use of cough and cold preparations that include APAP in combination with single-ingredient APAP preparations; in addition, for the adolescent population, suicide attempts contribute to the incidence (2). The toxicity of APAP to the liver is well characterized. The principal detoxification pathways are sulfation and glucuronidation, which form conjugates that are excreted via the kidneys. With therapeutic doses, a small fraction of APAP is metabolized by the cytochrome P450 pathway (CYP 2E1) to form n-acetylparabenoquinone-imine (NAPQI), which, in the presence of glutathione, is excreted as a harmless water-soluble conjugate. If the capacity to detoxify NAPQI is overwhelmed in the presence of supratherapeutic doses of APAP or in conditions in which the CYP 2E1 pathway is induced with ethanol, isoniazid, anticonvulsants, or other agents, then NAPQI can covalently bind to intracellular proteins via cysteine residues. The NAPQI adducts have been identified in dying and dead hepatocytes in animal models of APAP-induced ALF. With cell death, these NAPQI–protein adducts (APAP adducts) may enter the serum and can be measured. During the past 15 years or longer, the laboratories of the investigators have worked to develop methods to noninvasively assess the role of the APAP adducts as a tool to define the presence of APAP-induced liver injury. The results presented in the 2 summarized articles are provocative and may offer convincing evidence that the HPLC-EC method for detecting APAP adducts may prove valuable for verifying that patients with presumed APAP-induced ALF have biochemical evidence of liver injury secondary to APAP, but more important, to define the population of patients who have APAP-induced ALF when a history of acute or chronic overdose is absent or equivocal. Based on the results of the 2 summarized articles, there may be an additional 12% to 19% of patients with ALF caused by APAP, which may increase the frequency of APAP-induced ALF to 25% in children and as high as 62% in adults. Previous studies have also suggested that some cases of ALF of indeterminate etiology in infants or children may actually be APAP-induced (3). Although this suggests that the magnitude of APAP-induced ALF may be greater than previously recognized, a note of caution is still required. There appears to be a high sensitivity (90%–100%) when using APAP adducts as an indicator of APAP toxicity; however, the specificity may not be 100%, as suggested by Davern et al. The APAP adduct assay, if it could be simplified from an analytic standpoint and therefore be made available to clinical laboratories with a reasonably rapid turnaround, could be extremely valuable in clinical decision-making regarding these patients (4). If APAP adducts were identified in patients with ALF of indeterminate etiology, then it would be appropriate to consider N-acetylcysteine (NAC) because it may be helpful when used as long as 72 hours after acute ingestion (5). It may be argued that NAC can be beneficial for all cases of ALF and should be administered to all patients (6,7); however, the results of the randomized trial of NAC in adults with ALF are not available and the trial in children is ongoing. Until these results are available, it seems injudicious to recommend routine NAC use given that anaphylaxis is observed in 3% to 16% of cases of intravenous NAC use (8,9). It is also clear that additional studies need to be performed to assess whether APAP adducts are present in serum with therapeutic dosing with APAP because it is not uncommon that adults taking therapeutic doses have increased serum ALT and AST levels (10). If it is identified that APAP adducts are found with therapeutic dosing associated with increased biochemical evidence of liver injury, a careful review of their role in determining the etiology of ALF needs to be considered. It seems unlikely that therapeutic dosing will produce serum APAP adducts because Davern et al found them in only 2 of 15 patients with potentially toxic APAP ingestions. The finding of APAP adducts in the sera of patients with ALF of indeterminate etiology does not prove that APAP caused their liver injury. It is reassuring that patients in the study of James et al had higher serum aminotransferase levels and lower total bilirubin levels and had biochemical courses like those seen in APAP-induced liver injury. The presence of APAP adducts in serum of patients with non–APAP-related known causes of liver failure clearly raises other interesting questions. In this context, does the presence of adducts suggest that APAP may have been the real cause of the ALF, or could APAP exposure in therapeutic doses aggravate a preexisting liver injury: Certainly, APAP ingestion in the presence of compromised liver function leads to altered metabolism and the propensity to exaggerate existing injury. The development and application of serum APAP adducts as a tool in the management of ALF is extremely valuable and important. It broadens our perspective regarding the affected patient population. The development of a clinical test with results provided in real time could significantly help clinicians in the management of patients with ALF.

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