Many Drugs Harm the Liver, but Most Remain on the Market

[Guest guest]

Many Drugs Harm the Liver, but Most Remain on the

Market

By LAURIE TARKAN

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. 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. 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deaths, before it was withdrawn in March 2000.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.

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. 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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