Avoiding acetaminophen-related liver injury

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Avoiding acetaminophen-related liver injury

Misuse of an otherwise safe painkiller can cause acute liver failure.

It never occurred to Tara Ryan (not her real name) that she could take too much over-the-counter pain medication. She just wanted to relieve the intense back pain from a muscle she pulled while sailing one Friday afternoon. Over the next three days, she took a lot of acetaminophen — judging from the amount left in the bottle, more than twice the recommended maximum. Tara became seriously ill and died Tuesday on the way to the hospital. She never knew that her liver had failed.

The vast majority of people who use acetaminophen — the best-known brand is Tylenol — do so safely. But each year overdoses account for more than 56,000 emergency room visits, 2,600 hospitalizations, and an estimated 458 deaths due to acute liver failure. And according to a study from the U.S. Acute Liver Failure Study Group, the number of acetaminophen-related liver failures appears to be rising.

When an overdose is discovered in time, an antidote — N-acetylcysteine (Mucomyst, Acetadote) — can prevent liver damage. Intentional overdoses are usually caught that way. But accidental overdoses tend to accumulate over several days, as in Tara’s case, so they often go unrecognized until liver failure is well under way — and irreversible.

Acetaminophen labels caution users not to exceed the maximum recommended dose and warn regular alcohol users about the potential for liver damage. But some experts believe that greater efforts are needed, in particular, because there are so many acetaminophen-containing products, some of them in new, higher-strength formulations. Moreover, the name Tylenol is closely associated with safety — it’s used in hospitals and by pregnant women — so some people mistakenly assume it’s okay to take in almost any amount.

The study

Researchers at the University of Washington Medical Center in Seattle reviewed data collected at 22 medical centers participating in the U.S. Acute Liver Failure Study Group. They found that between 1998 and 2003, the percentage of acute liver failure cases attributed to acetaminophen nearly doubled, rising from 28% to 51% (see graphic).

Percentage of acute liver failure cases due to acetaminophen overdose In a major study of acute liver failure (ALF), the proportion of cases attributed to acetaminophen almost doubled between 1998 and 2003. Source: Adapted from “Acetaminophen-Induced Acute Liver Failure: Results of a United States Multicenter, Prospective Study,” in Hepatology 2005; 42:1364–1372.

In about half the cases, the overdose was unintentional. Exact doses were hard to ascertain, but the researchers concluded that continual use of as little as 7.5 grams (7,500 milligrams) per day could be dangerous.

Compared to those who overdosed intentionally, study subjects who did so accidentally were more likely to have been taking two or more acetaminophen-containing medications or a narcotic-acetaminophen combination, usually for pain. They were also more likely to have suffered severe hepatic encephalopathy — the mental confusion and disorientation characteristic of later-stage acute liver failure.

Overall, 71% of patients survived the overdoses, although 8% required a liver transplant. Results were published in the December 2005 issue of Hepatology.

How does the liver get into trouble?

Acetaminophen itself isn’t toxic. But when the liver breaks down acetaminophen, it produces a toxic by-product, N-acetyl-p-benzoquinone imine (NAPQI). Normally, NAPQI is neutralized and ushered out of the body by a substance called glutathione. But excess acetaminophen can overwhelm glutathione stores, allowing NAPQI to build up and damage the liver. Alcohol can deplete glutathione, which is one reason why it shouldn’t be mixed with acetaminophen. Glutathione levels are also reduced by certain genetic defects, inadequate nutrition, and some medical conditions or medications.

What now?

Acetaminophen is safe when taken as directed. Problems occur mainly when people underestimate its toxicity or take more than they realize. Here are some tips for avoiding trouble:

Read labels. For healthy adults, the maximum recommended intake is 4 grams — 4,000 milligrams (mg) — per day. That’s the amount in 12 regular-strength (325-mg) Tylenol tablets or eight extra-strength (500-mg) ones. Some newer products, such as Tylenol 8 Hour, Tylenol Arthritis Pain, and Tylenol Cold and Flu, contain even more milligrams per tablet or dose. So read the labels carefully. Acetaminophen also goes by the brand names APAP and Panadol.

Use caution with combinations. Acetaminophen is found in many over-the-counter combination medicines such as Alka-Seltzer Plus, Benadryl Allergy and Sinus Headache, Excedrin, Vanquish, NyQuil Multi-Symptom Cold and Flu, and TheraFlu Flu and Sore Throat.

Certain prescription painkillers, such as Darvocet, Endocet, Percocet, and Vicodin, also contain it. Check the labels of all your medications to make sure you’re not exceeding the maximum recommended intake per day (4,000 mg) — and don’t combine prescription with over-the-counter painkillers before consulting your clinician or pharmacist.

Alternate painkillers. If the recommended doses of acetaminophen don’t control your pain or fever, talk to your clinician about alternating acetaminophen with a nonsteroidal anti-inflammatory drug, such as ibuprofen or aspirin. This approach might relieve your pain, and you’d be taking less acetaminophen per day. Your clinician can help determine the best dosing schedule for your particular situation.

Be careful about alcohol. The labels warn against using acetaminophen if you take three or more alcoholic drinks each day. But don’t assume you’re safe if you drink less than that. Women don’t metabolize alcohol as well as men, and they’re more susceptible to liver damage. Until we know more about women’s unique risks, it’s probably safer to avoid alcohol entirely while taking acetaminophen. If you have a history of alcohol abuse, talk to your clinician before using acetaminophen.

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Last updated:	August 21, 2006