DOCTOR'S VIEW ARCHIVEMedical Author: Tse-Ling Fong, MD
Medical Editor: Leslie J. Schoenfield, MD, PhD
Medical Reviewing Editor: Dennis Lee, MD
Dietary supplements, which are also referred to as health supplements, include herbal products, vitamins, minerals, and any product that is not being marketed as a food or drug (medication). People take dietary supplements with the idea of maintaining or improving their health. Recently, however, my colleagues and I reported in a medical journal a series of seven patients who were referred to us with severe liver injury. They developed the liver damage after taking a health supplement called Lipokinetix® to lose weight. This supplement is a mixture of chemicals that includes an extract from a particular tea. It is said to reduce weight by working to mimic exercise and increase metabolism.
How and why can dietary supplements damage the liver? Within three months of starting Lipokinetix, these seven patients developed symptoms of acute hepatitis, including tiredness, loss of appetite, and abdominal pain. They sought medical attention and their blood tests revealed severe liver damage. One of the patients actually developed acute (rapid) liver failure and almost required a liver transplant to save her life. After being in a coma for three days, she miraculously recovered and was able to leave the hospital. Indeed, in all seven patients, the symptoms disappeared and the liver tests returned to normal within several months after discontinuing Lipokinetix. That said, I have since been informed of another individual who took this same supplement, developed acute liver failure, and did require a liver transplant. She is doing well now. However, so that her body can continue to accept the new (foreign) liver, she will be taking powerful anti-rejection medications for the rest of her life.
But that's not all! Numerous instances have been reported in the medical literature of dietary supplements, especially herbal products, causing liver damage. These supplements include kava (which has received much recent coverage in the press), Jin Bu Huan, germander, chaparral, shark cartilage, and mistletoe, to name a few. Dietary supplements can cause liver injury in a number of different ways. In some instances, for example with kava, liver injury is dose-related. That is, the higher the dose, the more often liver damage occurs. In many instances, however, liver injury is an unpredictable peculiarity in an individual (an idiosyncratic reaction).
It is well known that people often take combinations of herbal and/or other dietary supplements. In this circumstance, if a person develops severe liver injury, identifying which supplement is the specific culprit is very difficult. What's more, as the dietary supplement market becomes more competitive, the manufacturers of supplements are mixing and matching their products and doing so in proportions that have never before been tried. A case in point is the above-mentioned Lipokinetix, which contains among its ingredients an ephedrine-like stimulant, a type of thyroid hormone, and the tea extract.
The main problem is that the Food and Drug Administration (FDA) does not regulate the manufacturing process for dietary supplements, as it does for conventional drugs. You see, the FDA cannot consider a dietary supplement to be a food or a drug. Thus, the purity of dietary supplements is determined and reported to the public by the manufacturer only. Moreover, the dosage of these supplements is determined by the manufacturer and is often without scientific support or data that is published in peer reviewed scientific journals. Furthermore, the FDA requires no pre-marketing animal or clinical testing of dietary supplements, as it does for conventional drugs. Additionally, physicians report adverse events only voluntarily when they happen to encounter them.
Therefore, as long as the manufacturer does not make an outrageous claim about their product, and does not market the product as a food or a drug, these supplements end up on the store shelves without much, if any, scrutiny by the FDA. It turns out that designating a health product as a dietary supplement is a loophole created by the 1994 Dietary Supplements Health and Education Act. (The term "dietary supplement" implies an addition to the diet of something that is already present in the food we eat.) This loophole enables the producers of dietary supplements to avoid FDA regulation of the manufacturing of these products. Well, this situation regarding the rather loose regulation of dietary supplements makes me nervous. I am concerned, especially when considering that conventional drugs (medications) are subjected to a fairly rigorous review process.
What is the review process for conventional drugs? For a drug to be released on the market in the U.S., it must go through many steps, including extensive testing in animals and three phases of clinical testing in people. In the first phase, the drug is given to healthy subjects to determine the potential for adverse effects (toxicity). In doing this, different doses of the drug are tested to ensure that even a dose that is several times greater than the intended dose is safe in humans.
In the second phase, the drug is given to patients who actually have the condition that the drug is intended to treat. This phase usually involves up to fifty to one hundred patients. Once again, several different doses are tried to determine the effectiveness and toxicity of the various doses. The goal is to find the dose that achieves maximal efficacy with minimal (tolerable) side effects (toxicity).
The third phase usually involves a randomized controlled trial (RCT). In an RCT, each of usually two groups of several hundred patients with the specific condition is randomly assigned to receive one of two treatments. One treatment is the drug that is being evaluated and the other (the control) treatment is either a placebo (an inactive, so-called sugar pill) or the standard (effective) treatment for the specific condition. RCTs are usually carried out in a double blind (masked) fashion. This means that neither the patients nor the physicians caring for and evaluating them know which treatments the individual patients are receiving until the study is completed. A drug safety monitoring board consisting of independent experts that are unrelated to the manufacturer and researchers is usually appointed to oversee the study.
The FDA also reviews the data gathered at each phase to ensure safety before approving the next phase of testing. Then, at the end of phase three, all of the clinical data about the drug are submitted to the FDA for their review. In addition, before the drug can be approved, the FDA brings in an independent panel of experts to review all of the data and materials. Finally, after the drug has received FDA approval and can be prescribed, physicians are obliged to report any instances of possible adverse drug reactions to the FDA sponsored MedWatch program. This last type of monitoring is referred to as post-marketing surveillance.
Ironically, consumers, physicians, and the pharmaceutical industry have sometimes criticized this rigorous evaluation process for drugs. These critics claim that the process causes unnecessary delays in the release of potentially life-saving cures. I feel, however, that these procedures are necessary to safeguard the health of the public. Indeed, despite this demanding process, we still occasionally hear of previously unrecognized, terrible adverse reactions to drugs that already have been approved by the FDA. The diabetic drug, troglitazone (Rezulin), comes to mind.
Troglitazone was considered a novel medication for the treatment of adult onset diabetes. It was not until after the drug had received FDA approval and was in wide use that it became apparent that troglitazone could cause severe liver injury and death. (This tragic story actually came to light through the persistence of an investigative reporter at the LA Times.) The drug has since been removed from the market, but it reminds us that we must be vigilant when taking any medication or supplement.
Back to the dietary health supplements. More research, including clinical studies, is needed on the effectiveness and safety of dietary supplements. As a matter of fact, I am not aware of published data in peer-reviewed medical journals from Phase 1 or Phase 2 studies on these supplements. Nor do I know of randomized controlled trials that have been conducted on dietary supplements to show safety, let alone effectiveness.
On the other hand, it is important to recognize that few manufacturers of health supplements have the resources (money) to carry out valid RCTs because these trials are extremely expensive to run. Moreover, at present, no federal funding for the FDA is available to actively study and monitor the adverse events associated with these supplements. Nevertheless, more regulation of dietary supplements is needed and should be instituted. In this regard, a White House Commission on Complementary and Alternative Medicine (CAM) recently released its somewhat controversial report after two years of study. The good news is that the report called for more funding for valid scientific research on the benefits and hazards of CAM, including dietary supplements.
As a final note, I would like to caution our readers. A drug is a drug, whether it is a medication or a dietary supplement. Moreover, any drug can interact with another drug and result in a serious adverse event. For example ginkgo biloba, which is an herbal product touted to improve memory, can react with ibuprofen (Motrin) to cause severe internal bleeding. Don't go by what is said in an advertisement about a drug or dietary supplement. Rather, look critically at the data about the product. When you see your physicians, let them know about all drugs you are taking, including supplements. In your interest, they should know this. In fact, I have learned to ask, not just once but several times, whether my patients are taking any dietary supplements, especially herbal products. If you don't feel well, stop the supplement immediately and consult a physician. Don't withhold information from your physician about your supplements.