Tylenol and Liver Function

Summarized by Robert W. Griffith, MD
August 28, 2006

Summary

Taking 4 grams of acetaminophen, the active component of Tylenol, is linked to an increase in a liver enzyme usually associated with liver damage.

Introduction

Ever since the non-steroidal anti-inflammatory drugs (NSAIDS), especially the COX-2 inhibitors like Vioxx®, were found to be linked to increased coronary artery disorders, people have turned to Tylenol®, Excedrin®, and other acetaminophen-containing pain killers. Tylenol has been subtlety promoted as a safer over-the-counter alternative to aspirin (stomach irritation) or NSAIDS (cardiac risk).

It's always been known that high does of acetaminophen can cause liver toxicity. But a new study, reported in the Journal of the American Medical Association has found that repeated daily doses of 4 grams causes raised liver enzymes, which are normally seen with liver damage.

The reason for this study is interesting. A new combination of a prescription product containing hydrocodone and acetaminophen was associated with a high rate of increased levels of serum alanine aminotransferase, or ALT. (This enzyme is also called serum glutamate pyruvate transaminase, or SGPT.) Concern that the hydrocodone might increase susceptibility to acetaminophen liver toxicity led the researchers to do this study with acetaminophen alone. Here's a summary.

What was done

One hundred and forty-five healthy volunteers were randomly assigned to take one of three acetaminophen/hydrocodone combinations, or acetaminophen alone, or placebo. (The combinations were Percocet®, Dilaudin®, and a combination of 2 morphine tablets and 2 Tylenol tablets.) There were 26 to 39 volunteers per group. The acetaminophen dose was 4 grams in all 4 treated groups - this is the maximum recommended dose. The planned treatment duration was 14 days.

Serum liver enzyme levels were measured daily for the first 8 days, and then on alternate days. The tests included bilirubin level, aspartate aminotransferase (AST), ALT, and serum alpha glutathione S-transferase. Any patient with ALT or AST levels above 120 U/L was to be discontinued from the treatment.

What was found

The average age of participants was 34; 78% of them were men; 13% were African American, 57% were Hispanic American, and 30% were White American.

The upper normal limit of serum ALT is 40 units/liter (U/L). None of the 39 placebo patients reached a level more than 3 times greater than the upper limit of normal, i.e. more than 120 U/L, at any of their blood tests. However, in the 4 treatment groups taking acetaminophen there were 41 cases out of 106 volunteers (39%) where the ALT exceeded 120 U/L. Over 15% of them had levels more than 5 times the upper limit of normal.

The time course of the elevations of ALT showed increases after day 3, and continued increases for 2-4 days after stopping the treatment. The highest levels reached were around 15 times the upper limit of normal.

AST and alpha-glutathione S-transferase increases were seen, but were in general smaller than the ALT increases. Bilirubin levels were unchanged.

Attempts were made to identify possible co-factors in the increase in ALT with acetaminophen. The only one that emerged was connected with race: the relative risk of having an ALT more than 3 times the upper limit of normal with acetaminophen was twice as great in Hispanic as in non-Hispanic Americans.

What the results mean

This study shows that acetaminophen, taken at the top recommended dose, may cause an increase in ALT levels; unexpectedly, taking opioids did not influence the outcome.

How important, clinically, are these findings? The size of the increase, together with the accompanying AST and alpha-glutathione S-transferase elevations, means that the liver is the source of the raised enzyme. Were it not for the presence of acetaminophen in the blood, the finding would indicate damage to the liver. So does this mean that Tylenol is liver-toxic at its top dose level?

Experience provides no clear answer to this. There are few approved drugs known to cause ALT increases to the extent found here with acetaminophen. On the other hand, the drug has a remarkably good safety record when taken in this dose for prolonged periods. Its only when it's given at much higher doses, or to someone with a diseased liver, that serious liver toxicity is seen. The authors of the study, therefore, suspect that the changes they've seen in this study would probably disappear with continued therapy; i.e. the liver can 'adapt' to the continued presence of acetaminophen in the blood.

What are the practical consequences of this new finding? It certainly provides a field of research for future studies, to see whether continued use of the pain killer at the 4 gram dose can, in fact, result in a gradual decline in the raised ALT levels. Second, if any patient, especially a Hispanic, presents with elevated liver enzymes without an obvious explanation they should be questioned closely about acetaminophen intake. And third, everyone should be aware that all medications, even over-the-counter drugs with a known safety profile, may have hidden effects apart from the desired beneficial ones.

Source

• Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily. A randomized controlled trial. PB. Watkins , N. Kaplowitz , JT. Slattery ,  et al. , JAMA, 2006, vol. 296, pp. 87--93

Related Links
Alcohol-Acetaminophen Syndrome
Wikipedia: Acetaminophen/Paracetamol
Acetaminophen: Watch Dosage in Children