The administration of acetaminophen 4 g/day for 3 consecutive days to newly-abstinent chronic alcoholic subjects did not result in a change in serum ALT, AST, bilirubin, or INR. Our study had 95% power to detect a 15 IU/L change in AST or ALT, a smaller change than is typically used by common definitions of liver injury .
This study was designed to safely maximize the opportunity to detect a potential alcohol-acetaminophen interaction. Participants had been drinking alcohol for a prolonged period and abruptly discontinued alcohol intake upon presentation to the detoxification facility. This presentation reproduces the conditions commonly cited in reports of acetaminophen injury associated with therapeutic doses in the medical literature: namely, induction of CYP2E1 and concomitant depletion of glutathione [17–20].
Hepatic injury from acetaminophen is caused by the production of a reactive metabolite N-acetyl-p-benzoquinoneimine (NAPQI). Only a small percentage of acetaminophen is converted by CYP2E1 to NAPQI, which is normally detoxified by hepatic glutathione (GSH). If GSH stores are depleted, NAPQI can bind to hepatocellular components resulting in liver injury. Conditions which can increase NAPQI production, such as induction of CYP2E1 by alcohol, or conditions that decrease GSH stores, such as malnutrition, are postulated to increase the risk of acetaminophen-induced hepatic injury [5, 17, 19–24]. Human studies have demonstrated that chronic alcohol exposure can increase CYP2E1 activity, up to approximately twice baseline . Increased CYP2E1 activity begins immediately upon exposure to ethanol . Following cessation of chronic alcohol exposure, human studies have also demonstrated that CYP2E1 induction is transient, lasting at most a few days . Animal and human data suggest that different mechanisms can contribute, to different degrees and at different ethanol concentrations, to increasing CYP2E1 activity [8, 9, 26, 27].
The alcohol-induced induction of CYP2E1 wanes following alcohol abstinence with a half-life of approximately 2.5 days and CYP2E1 activity reaching normal in 3 to 8 days [12, 25, 28]. Our subjects were treated with acetaminophen in a period of probable CYP2E1 induction and potentially reduced plasma glutathione concentration, recreating the conditions postulated to allow liver injury in acetaminophen-treated patients who ingest alcohol.
As it is possible that subjects who did not develop transaminase abnormalities secondary to acetaminophen could obscure a potential detrimental effect in a small sub-group, several post-hoc analyses were performed in an attempt to identify trends that would guide further study of alcoholic patients. The analyses included the subgroup of participants that presented with an initially elevated ALT or AST, participants meeting a common definition of alcoholic hepatitis, the relationship of body mass index to change of ALT and several others. These analyses are limited by the reduction in statistical power created by the reduced number of subjects present in a subgroup analysis. However, none of the analyses identified a group that responded to acetaminophen ingestion with an increase in serum ALT or AST, bilirubin concentration or INR.
The medical literature contains few prospective studies involving administration of acetaminophen to newly-abstinent alcoholic patients. Lauterburg found that plasma glutathione concentration was decreased in eight newly-abstinent alcoholic subjects and decreased further following a single supratherapeutic dose of acetaminophen (2 g) . As shown by the increase in glutathione in both experimental groups, our results suggest that the alcoholic patient has blood concentrations of glutathione that increase when alcohol ingestion is terminated. In contrast to the Lauterburg study, our subjects group receiving acetaminophen 1 g four times daily did not develop a decrease in the plasma concentration of glutathione.
Our results differ from Watkins et al, who reported that 31% to 44% of healthy young acetaminophen treated patients experienced an ALT greater than three times the upper limit of the normal range (3 × ULN) during treatment with the acetaminophen, 4 g/day for 14 days . In contrast only 6% of our patients developed an ALT greater than 3 × ULN after 3 days of treatment and the same rate was observed in the placebo group. There are several potential explanations for this difference. First, the subject groups are considerably different: young normal subjects vs older alcoholic subjects. Alcoholic subjects repeatedly insult their liver, which might decrease the response to another stimulus. Second, although daily ALT values were not provided in the Watkins manuscript, the author stated that "Elevation of ALT to more than three times the ULN (120 U/L) was not observed prior to day 3 in any of the treatment groups." Similarly, our results indicate that the proportion of patients with an ALT greater than 3 × ULN (some patients started with ALT > ULN) decreased on day 2 and then increased slightly on days 3, 4 and 5 (Figure 2). Although the increase in ALT also occurred in the control group, we cannot exclude that the serum ALT of our patients would not have followed a course similar to those reported in Watkins. Finally, previous randomized trials established previously that the serum aminotransferase activity increases in some patients during treatment with acetaminophen, however, none of those studies determined ALT as frequently (daily) or as early in the course as Watkins . The meaning of asymptomatic increases in serum ALT is unknown. Further research with administration for longer periods in alcoholic patients is needed to answer these questions.
Previous research by our group involving administration of acetaminophen to alcoholic subjects for 2 days supports the findings of the current study [31, 32]. Therapeutic acetaminophen dosing in a total of 132 subjects showed no effect on serum ALT, AST, bilirubin or INR. Recently, Bartels et al studied the administration of acetaminophen for 4 days. He also found no difference in serum glutathione S-transferase (GST), an indicator of hepatocyte enzyme release similar to ALT and AST . Although they are few, all prospective studies in alcoholic subjects to date have failed to find liver injury associated with therapeutic doses of acetaminophen.
There are limitations to the generalizability of our results. We only studied the maximal recommended daily dose of acetaminophen (4.0 g/day), so our data should not be extrapolated to either intentional or unintentional overdoses. Larson et al reported on patients entered into the Acute Liver Failure registry . Among patients with liver injury thought to be acetaminophen-related, referred to a liver service participating in the registry and fulfilling the diagnosis of acute liver failure, 51% reported therapeutic intent and 63% reported use of an acetaminophen-opioid combination drug. Most patients ingested an overdosage of acetaminophen with a mean dosage of 7.5 g/day (range 1–78 g/day). It is crucial to distinguish between ingestion of a true therapeutic dose and ingestion of an overdose despite therapeutic intent.
Our results do not apply to all alcoholic patients. By including subjects with higher aminotransferase levels than previously studied, we were able to enroll more than 95% of alcoholic volunteers screened. However, we did not study patients with decompensated alcoholic liver disease. Our results might therefore not apply to patients with liver disease severe enough to impair hepatic synthetic function.
We evaluated a 3-day course of acetaminophen therapy. As cytochrome induction wanes substantially in the first 2 days, an alcoholic patient would be expected to be at highest risk during the first day following cessation of alcohol intake. We did not study alcoholic patients that continued to ingest alcohol concurrently with acetaminophen. However, acute ingestion of alcohol inhibits rather than increases NAPQI formation, so it is unlikely that acute alcohol consumption would increase the susceptibility of alcoholic patients to liver injury [2, 21, 24, 34]. The metabolism of acetaminophen produces a protein adduct of acetaminophen composed of a cysteine residue covalently bound to acetaminophen. In the future, this assay could allow quantitation of the amount of acetaminophen actually metabolized by a patient and allow stratification and analysis of the risk of hepatotoxicity in patients receiving acetaminophen [35, 36].
Claims of a potential acetaminophen-alcohol interaction have prompted some healthcare providers to recommend a decreased dose or complete avoidance of acetaminophen for patients who drink alcohol. If patients who drink alcohol are instructed to avoid acetaminophen altogether, they will likely use other OTC analgesics such as aspirin or other nonsteroidal anti-inflammatory medications (NSAIDs). NSAIDs and aspirin cause significant morbidity and mortality at or near the therapeutic dosage. Precise data are not available, but it is estimated that 100,000 Americans are hospitalized and 16,000 patients die each year in the United States from gastrointestinal hemorrhage, ulcers and perforations secondary to NSAIDs and aspirin [15, 20, 35, 37]. The FDA has recognized the significance of this risk and since 1998 has mandated that OTC NSAIDs such as ibuprofen and naproxen sodium carry an alcohol warning.
The alcohol warning on all common OTC analgesics advises people who consume three or more alcoholic drinks every day to consult a doctor before using these drugs. Healthcare providers are commonly faced with the question of which OTC analgesic is the safest for patients who occasionally drink alcohol as well as for those patients who are suspected or confirmed alcoholics. The answer to this question requires an assessment of the risks of each analgesic. A recent study suggested that NSAID treatment produces a tenfold increase in risk of gastrointestinal bleeding for patients within 1 week of initiating therapy . Although we did not directly compare the safety of NSAIDS to acetaminophen, we were unable to find any evidence of liver injury in "high risk" subjects ingesting acetaminophen. Acetaminophen is present in many OTC products. Inadvertent concurrent use of these products could exceed the maximum recommended dosage of 4 g/day. The relative susceptibility of alcoholic patients and other patients in doses above 4 g/day is unclear.