Hepatotoxicity is a mouthful to say, but its definition is simple. Hepato refers to the liver. Toxic or toxicity means poisonous or capable of causing injury or death. Substances that can damage the liver are potentially hepatotoxic.

Many substances have the potential to harm the liver. Alcohol, mushrooms, chemicals, herbs, supplements, steroids, recreational drugs, prescription and over-the-counter medications are all potentially hepatotoxic.

The general rule is that people with liver disease, such as hepatitis C virus infection (HCV), should avoid potentially hepatotoxic substances. Although medications have the potential to help us, they also may harm us. Having HCV doesn’t rule out taking drugs that could potentially damage the liver. The key is to know how to use medications safely.

Acetaminophen (Tylenol®) is a classic example. Hospitals use acetaminophen routinely for fever reduction and pain relief. Its safety record is respected. However, there are ways this safe medication can become toxic. Take too much or drink alcohol within a certain window of taking acetaminophen and the liver is threatened. Those with HCV may avoid acetaminophen because of this toxicity. Yet in most cases, acetaminophen is safe when taken correctly. Unfortunately, some medical professionals advise against acetaminophen’s use, yet liver specialists will tell you that at recommended doses, acetaminophen is safe for most people.

What causes hepatotoxicity?
Some substances are directly toxic to the liver. Amanita mushrooms and acetaminophen overdose are famous for this. However, hepatotoxicity is usually more gradual and complicated. To understand it, we need to review basic physiology.

The body treats everything as a foreign substance—be it a drug, food, or microorganism. It has to decide what to do with that substance. Basically, everything is used, neutralized and eventually eliminated. In some cases substances are stored.

This is all done utilizing various chemical processes. It is a complex system, involving every organ. Food is turned into fuel or fat. If you eat something dangerous, such as a virus or bacteria, the immune system will go into action. Medication is turned into something therapeutic unless too much or the wrong drug is taken—then it may become toxic.

When it comes to understanding hepatotoxicity, metabolism is a key concept. Metabolism occurs mostly in the liver. Metabolism is kind of a transformation process. This process occurs when substances reach the liver. The substance may be rendered inactive so it can be safely eliminated through the kidneys. Or, the substance may be turned into something active that may help fight disease. Sometimes there is too much of an active substance and it harms the liver.

A bit more technical…
Drug metabolism depends on enzymes. This enzymatic transformation occurs primarily in the liver. These enzymes are not the same as the ones for which we get regular lab tests. Rather, they are a group of proteins referred to as Cytochrome P-450 enzymes (CYPs). Certain diseases, particularly a poorly functioning liver, can interfere with drug metabolism that relies on CYPs. This means that you could get too little or too much of any of the drugs that interact with each other.

Drugs and substances that are metabolized by the same enzymes may compete with one another for metabolism. Thus, some drugs could be toxic rather than therapeutic. For example, if you take two medications that rely on the same enzymes, one drug may be metabolized while the other becomes toxic. Substances may compete so that neither will work effectively.

Some substances and diseases may speed up or delay drug metabolism. The existence of a liver disease, such as HCV, may interfere with drug metabolism, particularly if there is cirrhosis. Alcohol, grapefruit, St John’s wort and tobacco smoking can interfere with drug metabolism.

What are some of the most potentially hepatotoxic substances?
Countless substances are potentially hepatotoxic, including over a thousand drugs that can interact with any cytochrome P-450 metabolized substances. Some drugs are so clearly hepatotoxic that the Food and Drug Administration (FDA) has required their removal from the market.

The following is a partial list of common substances that may challenge the liver—particularly if taken at high doses or in combination with alcohol or other medications. Some of these may be safe if taken as directed.

acetaminophen (Tylenol®)
alcohol
amanita mushrooms
anabolic steroids
anti-fungals: fluconazole (Diflucan®) and ketonazole (Nizoral®)
anti-seizure drugs: phenytoin (Dilantin®), valproic acid or divalproex sodium (Depakote®), carbamazepine (Tegretol®)
black cohosh (Cimicifuga racemosa)
chemotherapy agents (certain ones)
comfrey (Symphytum officinale, S.asperum and S. uplandicum)
HIV drugs (certain ones)
household, garden and industrial supplies and chemicals
iron supplements
isoniazid – tuberculosis medication
kava (Piper methysticum)
methyldopa (Aldomet®) – anti-hypertension drug
methotrexate – multiple uses including cancer, psoriasis, and rheumatoid arthritis
nefazodone (Serzone®) – antidepressant
niacin (vitamin B3) in high doses
recreational drugs (some more than others)
statins – cholesterol-lowering medications such as Lipitor® and Zorcor®
vitamin A (above 5000 units daily)

Avoiding hepatotoxicity
Safe medication use starts with you and your medical provider. Tell your provider about everything you are taking. Include all dietary substances. Do this even if you fear that you will be judged. You can say, “You might not believe in herbs, but I do. I want to do this safely and here is what I take.” If your provider doesn’t know much about it or is critical, then at least you tried.

If your medical provider prescribes a medication and you don’t mention that you have liver disease or that you are on 15 other drugs or herbs, or that you drink a six-pack of beer every day, then how can your provider know what the safest medication is for you? For instance, Vicodin® has a lot of acetaminophen in it. If that is all you take and you follow directions and you don’t have cirrhosis, then it is unlikely you will have problems. However, if it turns out that every day you take 4000 mg of acetaminophen, round the clock cold capsules that include acetaminophen and you can’t live without daily vodka gimlets, then vicodin® is not the best choice.

Just because a substance has the potential to interact with another substance does not mean that you should not take it or that something bad will happen. It means the potential is there and you should talk about this with your medical provider. There may be safer ways to take certain combinations of substances, such as taking one in the morning and the other at night.

Consult with your pharmacist. Fill all your prescriptions at one place since most pharmacies keep records to help patients avoid interactions. Many pharmacies will allow you to add supplements and over-the-counter drugs to your file. Usually you can do this yourself online.

There are Internet sites that will look for potential interactions between medications and dietary supplements, such as www.drugdigest.org. Click on the Check Interactions tab and enter the information. Recommendations may be made, such as to allow 4 hours between taking calcium and thyroid medications.

Fortunately there are usually enough medications on the market that there are suitable alternatives for most medications. Occasionally, the potentially hepatotoxic drug is the best choice, so in that case, your medical provider will want to carefully monitor your liver. This usually means regular blood tests measuring your liver enzymes.

When it comes to medication safety, remember these three words—take as directed. Your medical provider may have no qualms about the safety of a drug, but if you take too much or swallow it with a shot of bourbon, you aren’t following doctor’s orders. Your provider may write the prescriptions, but following through is your responsibility.

What the Heck is Hepatotoxicity?

Drug Interactions

Nutrition and HCV

Resources
Drug Digest
www.drugdigest.org

HCSP’s Factsheet HCV and CAM: Dietary Supplements to Avoid
www.hcvadvocate.org/hepatitis/factsheets_
pdf/CAM_avoid.pdf

U.S. Food and Drug Administration
www.fda.gov/cder/info/consumer.htm