Tuesday, December 27, 2005

All I wanted for Christmas was...a brand-new liver!

Forbes was among the first I saw covering this rehashed story at the beginning of the month. Yet major press outlets let it lie until the dolldrums of the postholiday news dribbles grew intolerable.

Yes, it is well known that taking too much acetaminophen can damage one's liver to the point of needing a liver transplant. (Acetaminophen is sold in the US as Tylenol, and in various generic forms, but is known also as paracetamol overseas as well as by the abbreviation APAP.)

Normally, say taking 500-1000mg of acetaminophen at a time, twice a day, is totally cool. Your body can handle the small amount of highly toxic metabolite made from acetaminophen in the liver called NAPQI (if you care to read deeper, it is called N-acetyl-p-benzoquinone-imine). Dr Susan Farrell at Harvard did a nice piece on acetaminophen poisoning and Dr Judy Raucy and colleagues, formerly at the University of New Mexico, worked out the enzyme system responsible.

NAPQI is produced from acetaminophen by a liver enzyme called CYP2E1; we normally think of the liver as the place where drugs are inactivated, but many chemicals are made more dangerous when metabolized by the liver. NAPQI is one that is chemically reactive, meaning it'll bind to any major cellular constitutent it comes close to. Fortunately, the liver is home to a lot of glutathione, our major antioxidant defense. And, so, NAPQI is effectively inactivated by glutathione (often abbreviated GSH). So, your liver has the capacity for sopping up NAPQI produced by consuming up to 4 grams of acetaminophen per day. More NAPQI than that and the chemical starts attacking other parts of the liver that are necessary for life.

But there are special cases where it seems folks are taking more acetaminophen than necessary. If you take two Tylenol for a cold (1000 mg), you may also take another dose of NyQuil to get to sleep (1000-2000 mg depending on how you measure). Another dose or two during the day may add another 1000-2000 mg of acetaminophen, and now you are in the range that becomes dangerous for most people. Your liver's ability to sop up NAPQI is limited by its ability to make new glutathione.

A bigger problem is presented by people who are social drinkers, or more than normal consumers of alcohol. Remember that Judy Raucy paper I mentioned above? Well, acetaminophen is predominantly metabolized by CYP2E1. If you have more than 2-3 drinks per day, your 2E1 activity is higher than the average person's. As a result, if you take acetaminophen, you make more NAPQI than the average person who takes the exact same dose of acetaminophen. Add up all the other cold meds, and an active social drinker becomes a candidate for a liver transplant from an over-the-counter drug that has been deemed safe and effective since 1955.

Caught quickly enough (within 24-48 hours), an acetaminophen overdose can be treated with N-acetylcysteine (NAC), a building block that the body uses to make more glutathione. That buys you time but it must be given quickly.

Unfortunately in the US, it is not well known that an herbal agent, milk thistle, also has the capacity to protect against liver damage from acetaminophen. Milk thistle (Silybum marianum) is considered an invasive weed in many parts of the US and grows wild in California in particular. Let me warn you that it is NOT a cure-all and any acetaminophen overdose should be treated in the emergency room. However, many Europeans normally take milk thistle extracts whe taking acetaminophen or any other drug with the potential to be toxic to the liver. Milk thistle is even well-known enough to be recommended before Oktoberfest celebrations.

But in the emergency setting, oral milk thistle will not help you. Milk thistle components are not well-absorbed into the blood, but the liver does concentrate them about 200-fold higher than blood levels. Notably, European manufacturers make an approved, intravenous preparation of milk thistle extract for emergency treatment of poisoning by acetaminophen and the deathcap mushroom, Amanita phalloides. This preparation is not approved for use in the US, but could be used in conjunction with N-acetylcysteine preparations.

The bottom line is that all the recent concern about COX-2 inhibitors has driven consumers away from prescription pain relievers, and even ibuprofen or naproxen. As consumers turn more toward older pain relievers like acetaminophen, they should be wary of the TOTAL amount of acetaminophen being taken in various over-the-counter remedies.

For those with a healthy appetite for alcohol, acetaminophen can be that much more dangerous. Milk thistle, therefore, stands to be one of the more useful of the herbal supplements out on the US market. But even so, some products are better absorbed than others. Readers are recommended to consult objective sites like Consumerlab.com for more product-specific information since I'm not keen on being linked to one product or another.

Just let it suffice to say that among the crap I see on herbal medicine shelves, milk thistle is one that has very interesting qualities that make it worthy of further study by pharmacologists and physicians.

Something to also consider before going out New Year's Eve!


At Wed Oct 25, 03:01:00 PM EDT, Anonymous ultram said...

10/325 - Vicoprofen - Lortab- Tylenol #3- - Ativan
All Major Medications are available right here at: http://www.crdrx.com


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