It is an unsettling truth, one that people who have to take medicine would probably rather not think about: occasionally, with little or no warning, prescription and even over-the-counter drugs can cause liver damage. Cases are not common, but they can be devastating, leading to death or requiring a transplant.

"Drug-induced liver disease is probably the single leading cause of drugs' running afoul once they hit the market," said Dr. Peter K. Honig, director of the Office of Postmarketing Drug Risk Assessment at the Food and Drug Administration.

Liver failure, also called hepatotoxicity, is rare, affecting about 2,000 adults and 90 children a year in the United States. But drugs cause about 55 percent of the liver failure cases evaluated at liver transplant centers, said Dr. William M. Lee of the University of Texas Southwestern Medical Center in Dallas, who runs a group that surveys about 40 of the centers. But in addition to cases of irreversible liver failure are many more instances of less serious liver damage that are not recorded, experts say.

Liver problems and deaths have led to several drugs' being taken off the market in the last few years, and to others' having warnings added to their labels. The problems can be a tremendous drain on drug companies, which may be hit with lawsuits and forced to withdraw drugs they spent hundreds of millions of dollars to develop.

In the last year, the F.D.A. has increased its efforts to prevent the problems. It has held drug toxicity workshops for staff members who review new drug applications. It is also working with liver experts, and it held a conference in February with them and the drug industry to develop better ways to identify potentially toxic drugs and spot problems once a drug is approved. The proceedings of that conference were posted on the F.D.A.'s Web site, www.fda.gov.

The agency's actions were prompted in part by an unusually high number of drugs that were found to cause liver failure in the past few years.

Most notably, the popular diabetes drug Rezulin, approved in 1997, caused about 90 cases of liver failure, including 63 deaths, before it was withdrawn in March 2000.

A year earlier, the antibiotic Trovan was severely restricted after 14 cases of acute liver failure were reported, and the year before that, a painkiller called Duract was withdrawn after causing four deaths and necessitating eight liver transplants.

Dr. Neil Kaplowitz, director of the University of Southern California Center for Liver Diseases, said: "The problem of drugs causing injury to the liver has been recognized probably for 50 years. But the attention that has been focused on Rezulin has put the spotlight on it."

More cases are brought on by acetaminophen, the ingredient in Tylenol and many other products used for pain and fever. Each year it causes acute liver failure in nearly 800 people who take more than the recommended dose (including those who intentionally take an overdose). Most recover; in 1999, 85 died.

The F.D.A. is also looking into how to reduce the risk of liver toxicity from acetaminophen, said Dr. Robert Temple, the associate director for medical policy for the drug evaluation and research center of the F.D.A.

Children are as susceptible to liver injury as adults, although the incidence is lower in children because they take fewer medications.

The liver is particularly vulnerable to drugs because one of its functions is to break down or metabolize chemicals that are not water soluble. Most drugs fit that description.

"The liver has a machinery of enzymes that converts drugs into more water-soluble forms that can then be excreted," Dr. Kaplowitz said. But, he added, sometimes the breakdown products are toxic to liver cells.

Normally, the liver detoxifies these poisons before they can harm it. Indeed it is surprising, given the noxious chemicals that the liver is exposed to, that more drugs do not damage it.

"It's a tribute to the fact that the liver has an incredible capacity to defend itself," Dr. Kaplowitz said.

But in a few people, something goes awry. Either the liver churns out excessive toxins, or its ability to get rid of them is impaired. The toxins in turn destroy liver cells. While a majority of cases are mild to moderate, in about 10 percent of people the reaction is severe, resulting in coma, multiple organ failure and death, Dr. Kaplowitz said.

The fact that liver damage from drugs is rare and random is what makes it difficult to prevent. Acetaminophen, in fact, is the only common drug for which toxicity is predictable and therefore preventable. When taken at a high enough dose, it will cause liver toxicity in everybody. Taking more than the recommended daily dose overloads the liver and causes it to begin using an enzyme, cytochrome p450, that breaks down acetaminophen into toxins.

The maximum dose of acetaminophen for adults is 4,000 milligrams a day, or eight extra-strength tablets. Children's doses are much smaller, and vary by weight and age; a 4-year-old, for instance, should never be given more than 1,200 milligrams a day.

Adults who are chronic drinkers (having three or more drinks a day) risk liver injury if they take more than 2,000 milligrams a day. Chronic drinking raises background levels of cytochrome p450 in the liver, so that when a drinker also takes acetaminophen, more of the drug is metabolized into toxins than in nondrinkers.

The reason adults die from acetaminophen poisoning is that many perceive the drug as safe and take too much, or do not consider themselves chronic drinkers.

In children, problems occur when they are given the drug too often, or in adult doses, or for too many days, which may cause the drug to build up.

"If a child has a fever longer than 24 to 36 hours requiring 4-hour to 6-hour dosing of Tylenol, talk to your doctor to make sure the child doesn't have a more serious illness, and for help with dosing properly," said Dr. Rob Squires, an expert in pediatric hepatotoxicity at the University of Texas Southwestern Medical Center.

The American Liver Foundation believes the current warnings on acetaminophen labels do not adequately convey the risk to the liver.

With most other drugs, however, liver injury is unpredictable and therefore more difficult to prevent. A vast majority of people can take potentially harmful drugs without any problem, as was the case with the 1.5 million who took Rezulin. But a very small percentage — 1 in 10,000, or even fewer — will have a serious liver injury. Experts theorize that these people may be genetically predisposed to liver toxicity.

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The liver can also be injured by taking two or more drugs that interact poorly. The drugs may compete for the same enzyme.

"If the enzyme isn't around for the second drug, it can rise to dangerously high levels, or it can be metabolized by enzymes not normally used, and that can lead to a toxic metabolite," Dr. Lee said.

Researchers are frustrated that they cannot accurately predict which drugs will harm the liver. Clinical trials are not large enough to find such a rare reaction.

"You can't do a trial that's going to pick up a 1 in 50,000 reaction," Dr. Lee said.

So researchers look for milder reactions in the trials, like elevated liver enzymes, but experts disagree about how accurate this marker is, and sometimes drugs that raise liver enzymes get approved anyway.

"We're wrestling with the fact that liver enzyme elevations may not be completely predictive of more severe events," Dr. Honig said. "If you look at other drugs that have the ability to raise liver enzymes, some of them don't ever cause liver disease." Examples include an Alzheimer's drug, Tacrine, and even chronic use of aspirin.

The critics contend, however, that reviewers should heed these markers, however flawed. "With Rezulin, we happen to think that the signals were there, but they were ignored," said Larry D. Sasich of the Public Citizen Health Research Group in Washington.

A clearer signal of potential toxicity is elevation of enzymes along with high levels of a substance called bilirubin, a sign of liver dysfunction. The combination is thought to carry a 10 percent risk of progressing to acute liver failure. Usually drugs that cause both elevations are not approved unless the benefits far outweigh the risks.

That was the case with isoniazid, a drug that treats tuberculosis, and causes liver failure at a far greater rate than Rezulin did. "Isoniazid is such a superior drug to anything else we have, there's no rationale or compelling argument for withdrawing it," Dr. Kaplowitz said. Likewise, the F.D.A. was reluctant to remove Rezulin from the market because it helped over 1.5 million diabetics, and it was not withdrawn until two similar drugs, which did not cause liver problems, came onto the market.

"You're willing to accept a certain risk if you're weighing it against something that's fatal," said Dr. Eugene Schiff, the director of the Center for Liver Diseases at the University of Miami School of Medicine. For this reason, many drugs with the potential to cause liver trouble remain on the market with warnings and recommendations that patients be monitored with periodic liver function tests.

But even monitoring is controversial.

"There's a great debate whether monitoring of certain drugs saves lives," said Dr. Temple of the F.D.A. "We know it's burdensome, people don't like to do it, and you can go from normal to horribly abnormal in between tests."

The F.D.A., for instance, has recommended that people taking statin drugs to lower cholesterol get periodic liver function tests. The advice is based on a clinical trial that found significant enzyme elevations in about 3 percent of patients. But in daily use, these drugs have rarely been associated with liver problems.

"People have suggested that the warning is overdone in these drugs," Dr. Temple said.

Until researchers uncover better markers for drugs that can damage the liver or pinpoint who is vulnerable, many potentially useful drugs will not be approved, and a handful of others will be withdrawn.

In the meantime, some experts recommend that patients wait a year or two before taking a newly approved drug unless it has important advantages over older ones. This is enough time for cases of liver failure to emerge. The elderly and people with hepatitis or H.I.V. should be especially vigilant because they may be at greater risk.

Certain vitamins and herbs are known to cause liver injury in high doses, like vitamin A, germander, chaparral leaf, comfrey, jin bu huan, ma huang, valerian, mistletoe and pennyroyal. Cocaine and Ecstasy are also known to cause problems.

The symptoms include fatigue; fever; pain below the right rib cage; yellowing of the whites of the eyes, nail beds or skin; lethargy; and slurring of words.

"The people who really die from these drugs," Dr. Lee said, "are the faithful compliant patients who continue to take a drug even after symptoms arise."

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