By attorneys William G. Gainer and A. Leroy Toliver
Acetaminophen (APAP) is the number one cause of drug-induced acute liver failure in the United States. This statistic is now widely accepted and recognized in the medical community. APAP is found in Tylenol and over two hundred non-prescription, over-the-counter medications (OTC) available to the public. It is also a component found in a vast number of prescription medications. This presentation will focus primarily on the following, to wit:
- The mechanisms and pathophysiological explanations for how acetaminophen-induced acute liver failure occurs;
- The fact that the public is still largely unaware of the dangers posed by APAP; and
- The likelihood that its occurrence/incident rate is significantly underreported.
Background:
Acetaminophen is a simple molecule. First described in the late 1800's, acetaminophen was a by-product of a compound used to produce dyes and colors in Germany. Roughly fifty (50) years later, it was found to have analgesic (pain relieving) and antipyretic (fever reducing) properties. It was first released as a non-prescription product in the United States in approximately 1955. Today, on average, more than a hundred billion APAP containing pills are consumed each year with little or no incidence. However, as is the case with many drugs, increasing scientific research and medical evidence point to the fact that APAP also carries with it the potential for deadly side effects under certain circumstances.
The Liver:
The liver is the "engine" of the body. It is particularly vulnerable to drugs because one of its functions is to break down or metabolize chemicals that are not water soluble. The liver has a machinery of enzymes that convert drugs into more water soluble forms that can later be excreted through urine.
The Mechanisms of Injury:
APAP is metabolized through the liver through three different pathways, i.e., glucuronidation, sulfation and the cytochrome P-450 system. In every instance of APAP intake, a certain portion thereof is metabolized into a toxic by-product known as N-acetyl-p-benzoquinone (NAPQI). This toxin is produced from the metabolism of acetaminophen traveling the cytochrome P-450 pathway, more specifically known as CYP 2EI. By far, the majority of APAP is metabolized through glucuronidation and sulfation, both of which produce harmless metabolites. By analogy, you might compare those two pathways (glucuronidation and sulfation) to six-lane expressways, and the cytochrome P-450 pathway to that of a small two-lane access road. Under normal circumstances, a tripeptide known as glutathione conjugates and binds with the harmful metabolites and detoxifies them. Consequently - no harm, no foul.
What also occurs, however, with a frequency we believe is under appreciated by the medical community and certainly unrecognized by the consuming public, is that under certain circumstances too much NAPQI can be produced and too little glutathione will be available to detoxify it, resulting in significant liver damage, if not outright fulminant hepatic failure. Though the liver is known for its resiliency, once it dies, so too will the patient unless he or she receives a liver transplant within approximately 24-48 hours. Additionally, even if the patient is fortunate enough to receive a transplant in time (which is statistically unlikely), as a consequence of their near death experience they often experience extended periods of coma and concomitant episodes of hypotension. Due to repeated or sustained periods of insufficient perfusion, they will suffer significant, irreversible brain damage. So has been the case, we believe, with a number of the people we have represented.
Many commentators believe the frequent, regular use of alcohol (ethanol), when combined with APAP, "revs-up" the cytochrome P450 system producing higher quantities of the harmful metabolite/NAPQI. While this may be true, and warnings are now contained on the labels of APAP-containing products relative to dangers associated with liver damage from the use of alcohol and APAP, a growing body of evidence seems to indicate the more significant causal factor is nutrition, i.e., "fasting". Chronic alcoholics are notorious for poor nutrition and diet - often replacing food with liquid. However, retrospective studies going back over the last ten (10) years indicate a relationship between fasting, APAP, little to infrequent use of alcohol by patients, and liver damage. This includes patients who are most typically unable to eat due to nausea from the flu or flu-like symptoms, stomach virus, dental pain, and the like. Moreover, basic science studies performed and repeated over the last two plus decades add additional support to the fasting connection.
What appears to happen under these circumstances is that the "traffic" of APAP along the "expressways" of glucuronidation and sulfation slow down, and exit onto the "access road", the cytochrome P-450, CYP 2E1 pathway. Concurrent with this phenomenon is that levels of glutathione begin to become depleted, at least the glutathione available to conjugate, bind with and detoxify NAPQI. The net effect is that a patient winds up with more NAPQI, less glutathione for detoxification, and the liver's defenses are ultimately overrun and defeated. Liver death soon follows, as well as the patient's very life, unless a successful transplant is accomplished. Even if the fortuitous, successful transplant occurs, you may likely be left with a brain-damaged client who will need expensive anti-rejection drugs (that carry with them a host of potential complications, including subsequent kidney dysfunction), among other things, for the rest of their life.
Unrecognized and Underreported Danger:
Consumers are largely unaware of the potential dangers of acetaminophen use. While label warnings now exist regarding alcohol and APAP, which we feel are still inadequate to properly inform consumers of the risks involved, at least there is some warning. We are unaware of any APAP product that contains a warning associated with its use during periods of fasting - the more significant circumstance in our opinion that leads to liver damage/failure. Additionally, consumers are generally unaware of how many medications they take that contain APAP. Acetaminophen is found in a large number of prescription drugs and the average consumer can easily fall into the category of "therapeutic misadventure" as a consequence. Put another way, a patient will take their prescription medication (unaware of its APAP component), an over the counter APAP pain reliever, and unintentionally overdose. With or without alcohol, with or without fasting, it is generally accepted by the medical community that ingestion of over 10g of APAP (i.e., twenty 500mg tablets) by a patient within any twenty-four (24) hour period can destroy a person's liver.
As to the incidence of liver damage/failure from APAP that goes unreported, it is the opinion of a number of authorities on the subject that as little as ten percent (10%) of such cases are actually reported each year. Why is that? In part, because doctors and hospitals are not required to file adverse event reports involving APAP with the FDA. The only sources required to do so by law are poison control centers (of which, there are only a few regional centers in the country), and manufacturers who receive actual notice of an adverse event from a consumer or medical provider.
Additionally, our experience has been that some medical providers will presume that if a patient's APAP level is low at the time of admission (if such a blood level is, in fact, investigated), then necessarily APAP is not the cause of the patient's liver failure. What goes unnoticed, but is apparent in the medical records of the patient once we review them, are wildly elevated transaminase levels (SGOT, SGPT, AST, ALT). Massively high transaminase levels are one of the hallmarks to acetaminophen-induced liver damage. In other words, given the half-life of APAP, the patient's blood level may be low upon admission - but the damage has already been done (as evidenced by transaminase levels in the tens of thousands, which should normally be in a range below a hundred).
Much more could be said about the factors to look for when evaluating whether or not acetaminophen may have been the cause of someone's liver failure, such as the pattern of injury typically seen on liver biopsy slides, i.e., zone three centrilobular necrosis, etc. What is important to remember, however, is that consumers are unaware and medical providers are still largely uninformed of this phenomena. Consequently, if there is a history of recent or chronic acetaminophen use (via family members, friends, physicians or hospital), get the records reviewed. This is a health hazard - one which should no longer go unnoticed, nor unchallenged.
Attorneys William G. Gainer and A. Leroy Toliver
If you have been injured, give our attorneys the opportunity to meet you. Our consultations are without charge or obligation. From our office in Conyers, Toliver & Gainer represents clients in the Atlanta metro area, across Georgia, and throughout the United States. Please call (678) 374-1034.
