The Unsung Organ
My liver finally arrived in the mail the other day. It came all the way from China.
I’m not talking real liver, as in liver transplant. It’s just an anatomical model. But I might as well have been talking about a real liver, given the difficulty I had finding one. A model heart? No problem. An anatomically correct plastic skeleton? Easy. A scale model of a horse’s intestines? Click here. But a liver at an affordable price? For that we need to go to China.
For centuries now, the liver -- our first line of defense against toxins of every kind -- has been the subject of endless prejudice, its rightful place as the largest, and in some ways most important, internal organ having been supplanted by the heart. Part of this is romantic: It is hard to imagine giving a Valentine’s Day card with the familiar red heart replaced by a slimy brown blob.
But the main reason for the liver’s lack of a higher profile is political. Today, the American Heart Assn. and the American Cancer Society dominate every American’s view of the human body, even though it is the liver that, in the long run, determines much of the health of the heart. As Columbia University’s Dr. Howard J. Worman points out, “the American Liver Foundation can fund only about $1 million worth of research projects per year. By contrast, the average one-year budget of a single grant funded by the American Cancer Society is over $100,000.” And it funds about $100 million worth of research per year.
True, more people die from heart disease and cancer, but liver disease remains abysmally funded by any measure. It needs to hire Hill and Knowlton.
The liver once enjoyed a much more central role in humankind’s understanding of the body. Both classical and medieval medicine situated the organ at the core of health. Chinese and ayurvedic medicine still do. But beginning with the 17th century publication of William Harvey’s “Circulation of the Blood,” Western medicine has followed the heart, literally and figuratively.
Today, the liver is slowly recovering some prominence. At the Food and Drug Administration, battles over liver toxicity are flaring -- often bitterly and almost daily.
The same drug-safety expert who predicted the disaster of the diabetes medication Rezulin, which caused fatal liver failure in some patients and was ultimately taken off the market, recently spoke out passionately against re- approval of the rheumatoid arthritis drug Arava because of his concerns about liver toxicity. It was nevertheless recertified. Serzone, a popular antidepressant, is now headed for a similar showdown. In January, it was withdrawn from the European market because it caused liver toxicity in some patients, and in late April the drug was banned in Turkey. New warnings about the attention deficit disorder drug Cylert, a known liver toxin, were published in a recent Journal of the American Academy of Child and Adolescent Psychiatry.
Indeed, though alcohol abuse and hepatitis continue to be the main preventable causes of liver damage, pills are right behind them. In the case of prescription and over-the-counter drugs like acetaminophen, the liver acts as a detoxification system, using specialized enzymes and cells called hepatocytes to reduce potentially harmful drugs into harmless particles, or metabolites. This function is increasingly a concern of the nation’s leading medical epidemiologists, now confronted with a populace in which nearly one out of every two people take a prescription drug on a daily basis.
Liver toxicity is now the leading cause of drug recalls, and although full-blown drug-induced liver failure is still rare, its incidence rate is likely to increase as the population ages and we depend on more drugs to keep us healthy. Liver injury because of drugs may result from as many as one in every 50,000 prescriptions. In 2001, there were 3 billion prescriptions issued in the United States. Do the math.
Even mild liver impairment -- whether caused by toxins, alcohol, hepatitis or drugs -- can make for a much more complicated, dangerous medical life in general. Enter old age with a damaged liver and you limit your medical options in treating other diseases and conditions.
The liver also has another political problem. Its amazing metabolic success as a toxin filter -- combined with its ability to regenerate -- is also its bane as an organ competing for scarce research time and dollars. But not funding liver research increasingly seems costly and hazardous.
Preliminary signs suggest that there are more liver-toxic drugs in common use than we have yet identified, other Rezulins waiting for their spot on newspaper front pages. Recent surveys of drug-screening procedures by major drug companies have indicated that, though the use of laboratory animals usually detects and prevents the worst liver-damaging drugs from reaching the market, it doesn’t always. A 2000 FDA report noted that “in one survey where liver toxicity was the cause of project termination for seven compounds after testing in humans, [liver] toxicity in animals was demonstrated in [only] four of these compounds,” the researchers wrote. “For the remaining three compounds, liver toxicity was not observed in the animal studies.”
Translation: In these cases humans -- not animals -- became the primary guinea pigs.
Potential liver toxicity is hard to detect because people vary substantially in their reactions to different drugs and toxins. Some drugs inhibit the absorption of other drugs; others accentuate the effect of other drugs. Ethnicity and race, gender and age all figure heavily in what can be a toxic, if not deadly, metabolic brew.
The new field of pharmo-genomics, however, may someday lead to better understanding of these variables. Studying how genetic variations in an enzyme system known as cytochrome P450 affect the liver’s use of many of our most popular drugs, David Flockhart of the Indiana University School of Medicine made a major clinical advance a few years back when he issued a chart documenting which drugs interacted with which other drugs. Flockhart was also able to detail specific gene-based vulnerabilities in various ethnic populations and then link them to specific, commonly prescribed drugs. Today, many practitioners carry a pocket card with Flockhart’s findings; it has helped them avoid potential disasters.
It’s time to give our doctors -- and our beleaguered livers -- more such tools.
