Therapeutic Doses of Acetaminophen Frequently Cause Elevated Aminotransferases in Healthy Volunteers: Is it Significant?

Abstract

Watkins PB, Kaplowitz N, Slattery JT, Colonese CR, Colucci SV, Stewart PW, Harris SC (Department of Medicine, University of North Carolina, Chapel Hill). Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA 2006;296:87–93.Acetaminophen (N-acetyl-para-aminophenol [APAP]) is commonly used for its analgesic and antipyretic properties. Acetaminophen is relatively devoid of side effects at therapeutic doses, and lacks significant gastric irritant or antiplatelet effects, which have historically been associated with aspirin and other NSAIDs. Acetaminophen is available as a single agent or in combination with other medications like opioids and antihistamines. The analgesic ladder proposed by the cancer unit of the World Health Organization recommends that APAP can be combined with adjuvant analgesic or opioids to provide adequate pain relief (AHCPR Pub. No. 92-0032. Rockville, MD; 1992). This has led to the availability of numerous opioids and acetaminophen combination preparations in the United States.Although APAP has a clear safety record when used within the maximum recommended daily dose of 4 g in adults, acetaminophen-induced acute liver failure has long been recognized in the United Kingdom as a common etiology for acute hepatic failure for more than 30 years (Gut 1975;16:144–149). Prospective data obtained over a 6-year period by the United States observed that APAP overdose was the most common (42%) cause of acute liver failure (Hepatology 2005;42:1364–1372). Unintentional overdoses accounted for 48% of the cases occurring likely due to failure to comply with dosing limitation or lack of realization that APAP was part of different proprietary preparations. The majority of the unintentional cases in this study occurred when using a narcotic combination excessively for several days before the onset of liver injury, suggesting an addiction to the narcotic component. Several researchers thus have questioned the rationale of combining a highly addictive drug (opiate) with a dose-dependent hepatotoxin (acetaminophen; Hepatology 2004;40:1021–1022; Hepatology 2004;40:6–9; Hepatology 2004;40:23–26).Pooled data from 7 studies composed of 1,039 patient receiving APAP for osteoarthritis for a range of 4 weeks to 12 months was evaluated. Serum alanine aminotransferase (ALT) levels were measured at baseline and after initiating the therapy showed that low-level, transient ALT elevations usually resolve or decrease with continued therapy (Curr Med Res Opin 2006;22:2137–2148). None of the patients had ALT >3 times the upper limit of normal (ULN) while on APAP. Few cases of hepatotoxicity occurring with therapeutic doses of APAP have been reported with or without the presence of risk factors such as chronic alcohol, tobacco, opiate consumption, malnutrition, illness-induced starvation, HIV infection, and HCV infection (Clin Ther 2006;28:755–760; J Intern Med 2003;253:240–243; J Intern Med 2003;253:95–98).Watkins et al performed a randomized, parallel-group, placebo-controlled longitudinal study where 145 healthy adults were blinded to receiving 4 g of acetaminophen daily, either alone or in combination with selected opioids or placebo. They characterized the incidence and magnitude of liver test elevations and compared them with participants treated with placebo. All participants stayed in house at the research facility for the entire duration of the study, and received the same standardized, whole food meals. To our knowledge, this is the first study that systematically looked at (1) the incidence and magnitude of liver tests abnormalities during the administration of therapeutic doses of acetaminophen and (2) the role of concomitant administration of opioids in acetaminophen toxicity.Participants in the study were healthy volunteers aged 18–45 years and not on concomitant medications. All patients underwent screening physical examination and comprehensive blood work that included hepatitis B surface antigen and hepatitis C antibody. They were then randomized to receive 1 of the 5 treatment regimens and administered medication orally every 6 hours for up to 14 days. The protocol required discontinuation of treatment for any participant with ALT or aspartate aminotransferase (AST) concentrations >120 U/L (3 times the ULN). The specific treatment regimens were as follows.•Treatment 1: Percocet, 2 tablets (7.5 mg of oxycodone/500 mg of APAP) plus 2 placebo tablets;•Treatment 2: Dilaudid, 2 tablets (2 mg of hydromorphone) plus Extra Strength Tylenol, 2 caplets (500 mg of APAP);•Treatment 3: Two morphine tablets (15 mg), plus Extra Strength Tylenol, 2 caplets (500 mg of APAP);•Treatment 4: Two placebo tablets plus Extra Strength Tylenol, 2 caplets (500 mg of APAP); and•Treatment 5: Two placebo tablets plus 2 placebo tablets.Routine liver tests (bilirubin, AST, ALT, and alkaline phosphatase) and serum α-glutathione S-transferase (α-GST), a measure of hepatocellular injury, were measured daily through day 8. After day 8, chemistries were measured on alternate days or daily in participants with any liver test elevations. Monitoring for adverse events was performed during the study period, and plasma APAP concentrations were measured daily in all participants at morning trough as well as over a single 6-hour dosing interval on day 3 of therapy (48–54 hours on therapy). The participants’ APAP concentration time series was then used to estimate the area under the concentration curve (AUC at 48–54 hours) and time to peak concentration (at 48–54 hours). Adverse events were monitored during the entire study period.All treatment groups had similar baseline demographic characteristics, including body mass index. Although only 1 of 39 participant (3%) taking placebo experienced ALT >2 times ULN at any time during the study, no placebo participants experienced ALT >3 times ULN. In contrast, >19% of participants experienced ALT >5 times ULN in each of the 4 active treatment groups. It is likely that the subjects with higher baseline may have had higher ALT levels; however, a similar pattern of ALT elevations by treatment is noted when participants’ peak ALT elevations were normalized by their baseline ALT values. The incidence of ALT elevations >3 times ULN, >5 times ULN, and >8 times ULN were 38%, 23%, and 4%, respectively, in the group receiving treatment with APAP only. Meaningful differences in the magnitude and incidence of ALT elevations were not detected among the active treatment regimens. The temporal pattern of ALT elevations was similar in all the active treatment groups, including the acetaminophen-alone group. Elevation of ALT to >3 times ULN (120 U/L) was not observed before day 3 in any treatment groups. After discontinuation of dosing owing to ALT elevations to >3 times ULN, the ALT continued to increase for 0–4 days (median, 2 days) and remained >3 times ULN for a median of 6.5 days. The median of peak ALT values for the active treatments were 2.6–3.1 times higher than the placebo value. However, there were no statistically different median of peak ALT values among the active treatment groups. Peak ALT and peak α-GST values were highly correlated and suggestive of hepatocellular injury.AST elevations were generally smaller than those of ALT, but followed a similar time course. There were no abnormalities or consistent trends in total bilirubin or alkaline phosphatase and all participants with ALT elevations were asymptomatic. The relative risk of maximum ALT >3 times ULN for Hispanic Americans versus non-Hispanic was 1.9 (95% confidence interval, 1.1–3.3). Mean AUC and peak concentration of APAP across all active treatment groups were similar. Although the data was not provided in the study, the authors comment that no difference was detected in mean APAP trough levels, peak concentrations, or AUC between those participants exhibiting ALT elevation and those who did not. The APAP concentrations fell quickly when dosing was stopped and as a result, it was often not detected while ALT remained elevated.CommentThis well-conducted study makes several important observations with regard to frequency, magnitude, and temporal patterns of ALT elevations in APAP alone and APAP/opioid combination groups. It is not very clear why a 2-week duration was chosen for APAP exposure in this study. Some of their findings are not entirely novel. For example, previous osteoporosis trials evaluating the safety of APAP have shown that low-level, transient ALT elevations usually resolve or decrease with continued therapy (Curr Med Res Opin 2006;22:2137–2148). The incidence of ALT elevations >3 times ULN was 38% in the group receiving treatment with APAP only. There were no abnormalities or consistent trends in total bilirubin or alkaline phosphatase. The authors acknowledge the relatively high incidence of ALT elevations and attribute it to the high proportion of Hispanic subjects in the study. They speculate variability in APAP pharmacokinetics owing to ethnic and racial differences leading to ALT elevations. However striking the ALT elevations may be, elevations in liver enzymes without concurrently elevated serum bilirubin are generally thought to be benign. In contrast, the late Dr Hyman Zimmerman observed that elevations in transaminases in combination with jaundice signal serious liver injury and carry a significant fatality rate. AST and/or ALT >3 times the ULN or alkaline phosphatase >1.5 times the ULN in combination with an elevated bilirubin (>3 times the ULN) at any time after starting a new drug indicates serious liver injury carrying >10% mortality rate (Hy’s law). Thus, it is not likely that isolated elevations in aminotransferases observed in this study are of any clinical significance. Although the authors acknowledge that these aminotransferase elevations may have resolved with continued administration of APAP (adaptation), study protocol required discontinuation of treatment when aminotransferases increased >120 U/L (>3 times ULN). Despite wide usage of this cutoff in the drug development, there is nothing magical about it, especially when one considers wide variability in the ULN itself across various clinical laboratories. Because most subjects in this trial do not appear to be routine users of APAP, it is not clear if these data can be extrapolated to patients with chronic exposure.In this study, ALT levels >3 times the ULN were not observed before day 3 in any of the treatment groups. Upon discontinuation of APAP therapy, the ALT continued to increase for 0–4 days (median, 2 days) and remained >3 times the ULN for 1–11 days (median, 6.5 days). Of note, the APAP concentrations fell quickly when dosing was stopped, and as a result, it was often not detected while ALT remained elevated. It is for this reason that measurement of acetaminophen–protein adducts holds a promising role in the diagnostic evaluation of patients with acute liver failure of unclear etiology (Gastroenterology 2006;130:687–694). If sera are available from this study, measuring acetaminophen–protein adducts may provide an opportunity to examine if isolated ALT elevations in this setting reflect gross hepatocellular damage. Watkins PB, Kaplowitz N, Slattery JT, Colonese CR, Colucci SV, Stewart PW, Harris SC (Department of Medicine, University of North Carolina, Chapel Hill). Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA 2006;296:87–93. Acetaminophen (N-acetyl-para-aminophenol [APAP]) is commonly used for its analgesic and antipyretic properties. Acetaminophen is relatively devoid of side effects at therapeutic doses, and lacks significant gastric irritant or antiplatelet effects, which have historically been associated with aspirin and other NSAIDs. Acetaminophen is available as a single agent or in combination with other medications like opioids and antihistamines. The analgesic ladder proposed by the cancer unit of the World Health Organization recommends that APAP can be combined with adjuvant analgesic or opioids to provide adequate pain relief (AHCPR Pub. No. 92-0032. Rockville, MD; 1992). This has led to the availability of numerous opioids and acetaminophen combination preparations in the United States. Although APAP has a clear safety record when used within the maximum recommended daily dose of 4 g in adults, acetaminophen-induced acute liver failure has long been recognized in the United Kingdom as a common etiology for acute hepatic failure for more than 30 years (Gut 1975;16:144–149). Prospective data obtained over a 6-year period by the United States observed that APAP overdose was the most common (42%) cause of acute liver failure (Hepatology 2005;42:1364–1372). Unintentional overdoses accounted for 48% of the cases occurring likely due to failure to comply with dosing limitation or lack of realization that APAP was part of different proprietary preparations. The majority of the unintentional cases in this study occurred when using a narcotic combination excessively for several days before the onset of liver injury, suggesting an addiction to the narcotic component. Several researchers thus have questioned the rationale of combining a highly addictive drug (opiate) with a dose-dependent hepatotoxin (acetaminophen; Hepatology 2004;40:1021–1022; Hepatology 2004;40:6–9; Hepatology 2004;40:23–26). Pooled data from 7 studies composed of 1,039 patient receiving APAP for osteoarthritis for a range of 4 weeks to 12 months was evaluated. Serum alanine aminotransferase (ALT) levels were measured at baseline and after initiating the therapy showed that low-level, transient ALT elevations usually resolve or decrease with continued therapy (Curr Med Res Opin 2006;22:2137–2148). None of the patients had ALT >3 times the upper limit of normal (ULN) while on APAP. Few cases of hepatotoxicity occurring with therapeutic doses of APAP have been reported with or without the presence of risk factors such as chronic alcohol, tobacco, opiate consumption, malnutrition, illness-induced starvation, HIV infection, and HCV infection (Clin Ther 2006;28:755–760; J Intern Med 2003;253:240–243; J Intern Med 2003;253:95–98). Watkins et al performed a randomized, parallel-group, placebo-controlled longitudinal study where 145 healthy adults were blinded to receiving 4 g of acetaminophen daily, either alone or in combination with selected opioids or placebo. They characterized the incidence and magnitude of liver test elevations and compared them with participants treated with placebo. All participants stayed in house at the research facility for the entire duration of the study, and received the same standardized, whole food meals. To our knowledge, this is the first study that systematically looked at (1) the incidence and magnitude of liver tests abnormalities during the administration of therapeutic doses of acetaminophen and (2) the role of concomitant administration of opioids in acetaminophen toxicity. Participants in the study were healthy volunteers aged 18–45 years and not on concomitant medications. All patients underwent screening physical examination and comprehensive blood work that included hepatitis B surface antigen and hepatitis C antibody. They were then randomized to receive 1 of the 5 treatment regimens and administered medication orally every 6 hours for up to 14 days. The protocol required discontinuation of treatment for any participant with ALT or aspartate aminotransferase (AST) concentrations >120 U/L (3 times the ULN). The specific treatment regimens were as follows.•Treatment 1: Percocet, 2 tablets (7.5 mg of oxycodone/500 mg of APAP) plus 2 placebo tablets;•Treatment 2: Dilaudid, 2 tablets (2 mg of hydromorphone) plus Extra Strength Tylenol, 2 caplets (500 mg of APAP);•Treatment 3: Two morphine tablets (15 mg), plus Extra Strength Tylenol, 2 caplets (500 mg of APAP);•Treatment 4: Two placebo tablets plus Extra Strength Tylenol, 2 caplets (500 mg of APAP); and•Treatment 5: Two placebo tablets plus 2 placebo tablets. Routine liver tests (bilirubin, AST, ALT, and alkaline phosphatase) and serum α-glutathione S-transferase (α-GST), a measure of hepatocellular injury, were measured daily through day 8. After day 8, chemistries were measured on alternate days or daily in participants with any liver test elevations. Monitoring for adverse events was performed during the study period, and plasma APAP concentrations were measured daily in all participants at morning trough as well as over a single 6-hour dosing interval on day 3 of therapy (48–54 hours on therapy). The participants’ APAP concentration time series was then used to estimate the area under the concentration curve (AUC at 48–54 hours) and time to peak concentration (at 48–54 hours). Adverse events were monitored during the entire study period. All treatment groups had similar baseline demographic characteristics, including body mass index. Although only 1 of 39 participant (3%) taking placebo experienced ALT >2 times ULN at any time during the study, no placebo participants experienced ALT >3 times ULN. In contrast, >19% of participants experienced ALT >5 times ULN in each of the 4 active treatment groups. It is likely that the subjects with higher baseline may have had higher ALT levels; however, a similar pattern of ALT elevations by treatment is noted when participants’ peak ALT elevations were normalized by their baseline ALT values. The incidence of ALT elevations >3 times ULN, >5 times ULN, and >8 times ULN were 38%, 23%, and 4%, respectively, in the group receiving treatment with APAP only. Meaningful differences in the magnitude and incidence of ALT elevations were not detected among the active treatment regimens. The temporal pattern of ALT elevations was similar in all the active treatment groups, including the acetaminophen-alone group. Elevation of ALT to >3 times ULN (120 U/L) was not observed before day 3 in any treatment groups. After discontinuation of dosing owing to ALT elevations to >3 times ULN, the ALT continued to increase for 0–4 days (median, 2 days) and remained >3 times ULN for a median of 6.5 days. The median of peak ALT values for the active treatments were 2.6–3.1 times higher than the placebo value. However, there were no statistically different median of peak ALT values among the active treatment groups. Peak ALT and peak α-GST values were highly correlated and suggestive of hepatocellular injury. AST elevations were generally smaller than those of ALT, but followed a similar time course. There were no abnormalities or consistent trends in total bilirubin or alkaline phosphatase and all participants with ALT elevations were asymptomatic. The relative risk of maximum ALT >3 times ULN for Hispanic Americans versus non-Hispanic was 1.9 (95% confidence interval, 1.1–3.3). Mean AUC and peak concentration of APAP across all active treatment groups were similar. Although the data was not provided in the study, the authors comment that no difference was detected in mean APAP trough levels, peak concentrations, or AUC between those participants exhibiting ALT elevation and those who did not. The APAP concentrations fell quickly when dosing was stopped and as a result, it was often not detected while ALT remained elevated. CommentThis well-conducted study makes several important observations with regard to frequency, magnitude, and temporal patterns of ALT elevations in APAP alone and APAP/opioid combination groups. It is not very clear why a 2-week duration was chosen for APAP exposure in this study. Some of their findings are not entirely novel. For example, previous osteoporosis trials evaluating the safety of APAP have shown that low-level, transient ALT elevations usually resolve or decrease with continued therapy (Curr Med Res Opin 2006;22:2137–2148). The incidence of ALT elevations >3 times ULN was 38% in the group receiving treatment with APAP only. There were no abnormalities or consistent trends in total bilirubin or alkaline phosphatase. The authors acknowledge the relatively high incidence of ALT elevations and attribute it to the high proportion of Hispanic subjects in the study. They speculate variability in APAP pharmacokinetics owing to ethnic and racial differences leading to ALT elevations. However striking the ALT elevations may be, elevations in liver enzymes without concurrently elevated serum bilirubin are generally thought to be benign. In contrast, the late Dr Hyman Zimmerman observed that elevations in transaminases in combination with jaundice signal serious liver injury and carry a significant fatality rate. AST and/or ALT >3 times the ULN or alkaline phosphatase >1.5 times the ULN in combination with an elevated bilirubin (>3 times the ULN) at any time after starting a new drug indicates serious liver injury carrying >10% mortality rate (Hy’s law). Thus, it is not likely that isolated elevations in aminotransferases observed in this study are of any clinical significance. Although the authors acknowledge that these aminotransferase elevations may have resolved with continued administration of APAP (adaptation), study protocol required discontinuation of treatment when aminotransferases increased >120 U/L (>3 times ULN). Despite wide usage of this cutoff in the drug development, there is nothing magical about it, especially when one considers wide variability in the ULN itself across various clinical laboratories. Because most subjects in this trial do not appear to be routine users of APAP, it is not clear if these data can be extrapolated to patients with chronic exposure.In this study, ALT levels >3 times the ULN were not observed before day 3 in any of the treatment groups. Upon discontinuation of APAP therapy, the ALT continued to increase for 0–4 days (median, 2 days) and remained >3 times the ULN for 1–11 days (median, 6.5 days). Of note, the APAP concentrations fell quickly when dosing was stopped, and as a result, it was often not detected while ALT remained elevated. It is for this reason that measurement of acetaminophen–protein adducts holds a promising role in the diagnostic evaluation of patients with acute liver failure of unclear etiology (Gastroenterology 2006;130:687–694). If sera are available from this study, measuring acetaminophen–protein adducts may provide an opportunity to examine if isolated ALT elevations in this setting reflect gross hepatocellular damage. This well-conducted study makes several important observations with regard to frequency, magnitude, and temporal patterns of ALT elevations in APAP alone and APAP/opioid combination groups. It is not very clear why a 2-week duration was chosen for APAP exposure in this study. Some of their findings are not entirely novel. For example, previous osteoporosis trials evaluating the safety of APAP have shown that low-level, transient ALT elevations usually resolve or decrease with continued therapy (Curr Med Res Opin 2006;22:2137–2148). The incidence of ALT elevations >3 times ULN was 38% in the group receiving treatment with APAP only. There were no abnormalities or consistent trends in total bilirubin or alkaline phosphatase. The authors acknowledge the relatively high incidence of ALT elevations and attribute it to the high proportion of Hispanic subjects in the study. They speculate variability in APAP pharmacokinetics owing to ethnic and racial differences leading to ALT elevations. However striking the ALT elevations may be, elevations in liver enzymes without concurrently elevated serum bilirubin are generally thought to be benign. In contrast, the late Dr Hyman Zimmerman observed that elevations in transaminases in combination with jaundice signal serious liver injury and carry a significant fatality rate. AST and/or ALT >3 times the ULN or alkaline phosphatase >1.5 times the ULN in combination with an elevated bilirubin (>3 times the ULN) at any time after starting a new drug indicates serious liver injury carrying >10% mortality rate (Hy’s law). Thus, it is not likely that isolated elevations in aminotransferases observed in this study are of any clinical significance. Although the authors acknowledge that these aminotransferase elevations may have resolved with continued administration of APAP (adaptation), study protocol required discontinuation of treatment when aminotransferases increased >120 U/L (>3 times ULN). Despite wide usage of this cutoff in the drug development, there is nothing magical about it, especially when one considers wide variability in the ULN itself across various clinical laboratories. Because most subjects in this trial do not appear to be routine users of APAP, it is not clear if these data can be extrapolated to patients with chronic exposure. In this study, ALT levels >3 times the ULN were not observed before day 3 in any of the treatment groups. Upon discontinuation of APAP therapy, the ALT continued to increase for 0–4 days (median, 2 days) and remained >3 times the ULN for 1–11 days (median, 6.5 days). Of note, the APAP concentrations fell quickly when dosing was stopped, and as a result, it was often not detected while ALT remained elevated. It is for this reason that measurement of acetaminophen–protein adducts holds a promising role in the diagnostic evaluation of patients with acute liver failure of unclear etiology (Gastroenterology 2006;130:687–694). If sera are available from this study, measuring acetaminophen–protein adducts may provide an opportunity to examine if isolated ALT elevations in this setting reflect gross hepatocellular damage.