Liver Success

Then there are the "intermediate metabolizers" -- those who have one good and one bad copy of a particular gene -- say, the one for the 2D6 enzyme. Because they produce roughly half the 2D6 liver enzymes that a normal person does, explains Mrazek, they could get the same amount of a 2D6-metabolized drug into their bloodstream by taking half the normal dose. One estimate is that as many as 35 percent of Caucasians are intermediate metabolizers of 2D6.

The intermediate metabolizers are a particularly tricky group, say some experts. They might feel positive results from a drug at first, but get sick over time as it slowly builds up in their bloodstream. But because they've been on the drug for weeks or months, they might not recognize their symptoms as an adverse reaction to it.

Shirley Roberts, an African American from Orange Park, Fla., desperately wishes she'd known she was an intermediate metabolizer for both the 2D6 and the 2C19 genes. When the former parole officer suffered from severe depression in 2002, doctors first prescribed Zoloft (metabolized by the 2C19 and 2D6 enzymes, among others). The entry-level dose was okay, but when it was raised, she experienced gastrointestinal problems, hair loss, night sweats, fever and heart palpitations. She switched to Paxil (metabolized by 2D6) and then Wellbutrin (metabolized by 2D6 and three other enzymes), but bad side effects continued.

In April 2004, after nearly two years of antidepressant treatment, Roberts's doctors took her off the drugs when her blood tests showed elevated liver enzymes. Doctors first assumed she'd contracted a viral form of hepatitis, she recalls, but tests came back negative. The diagnosis: drug-induced autoimmune hepatitis, with permanent liver damage. Testing by Genelex, a DNA lab in Seattle -- at a cost of $800, paid by Roberts's insurer -- identified her enzyme problem. Roberts says she's been told her life expectancy is eight to 10 years.

So Why Not Test?

Mrazek is convinced of the value of genetic testing for enzyme problems. "Before I would put any child" on a drug metabolized by the 2D6 enzyme, he says, "I would want to know that they have at least one good copy of the 2D6 gene. . . . I've been very surprised by some very senior psychiatrists saying, 'I don't need this; I've been prescribing Prozac for years.' Young clinicians are very quick to say, 'Gee, here's a tool that can potentially prevent a tragic event.' "

But Washington psychiatrist Kelly Lynn Cozza, an assistant professor at the Uniformed Services University of the Health Sciences, regards the testing as an unnecessary expense for most patients. An alert doctor, she says, should be able to recognize drug metabolism problems clinically. For example, she can ask patients, "Have you ever had any problems taking Robitussin? Does it make you queasy or jittery or sleepy?" Since Robitussin is metabolized by 2D6, a "yes" could be a red flag.

Cozza also notes that many factors besides DNA can affect liver enzyme production, including age, weight, diet, other drugs and smoking. Brain receptors may also affect how the body reacts to different drugs.

Then there's the question of cost. Genelex will test for a problem on one gene for $250; a battery of four tests (for genes 2D6, 2C19, 2C9 and 1A2) costs $800.

Until last year, only a few labs, like Genelex and the Mayo Clinic (whose fees are similar to Genelex's), offered this genotyping. But last year Roche Diagnostics introduced a new technology, approved by the Food and Drug Administration (FDA), that allows less specialized labs to test for genetic defects on 2D6 and 2C19. Now the labs need to convince more doctors to order the tests. Pam Sherry, a spokeswoman for Roche's LabCorp, quoted a "ballpark retail" price of $1,360 -- but said insurers that have contracts with LabCorp will probably pay less.

But many policies -- including ones from Aetna, CareFirst BlueCross BlueShield and Cigna HealthCare -- won't pay at all, because the insurers consider use of the testing in clinical practice "experimental and investigational." UnitedHealthcare doesn't have a written policy on cytochrome P450 testing yet, says spokesman Steven Matthews, but the company's plans -- including M.D.-IPA and Optimum Choice -- may approve the testing on a case-by-case basis, if it's prescribed and used properly. Federal workers are guaranteed coverage for medically necessary testing, said Office of Personnel Management spokesman Michael Orenstein, because Federal Employees Health Benefit Plan contracts stipulate that FDA-approved tests may not be considered investigational.

But do you really want your health insurance plan to pay for the testing? Cozza posed an interesting question: If your insurer learned that you had a CYP defect . . . could it decide to require preapproval for every prescription any doctor writes for you?

No insurance plans are paying for routine genotyping yet. But the field of pharmacogenetics is young. "My prediction," said Mrazek, "is that, down the line, pediatricians will do this testing during a child's infancy." But first the labs know they have some convincing to do. ·

Lisa Barrett Mann has written previously for the Health section about Medicare drug benefits, autism and in vitro fertilization. Comments: health@washpost.com.