(Tylenol) and the Liver
Tse-Ling Fong, M.D.
Leslie J. Schoenfield, M.D., Ph.D.
"Is it safe for me to
Tylenol is currently the most popular painkiller in the United States.
Americans take over 8 billion pills (tablets or capsules) of Tylenol each
year. Acetaminophen is the general (generic) name for Tylenol, which is a
brand name. Although acetaminophen is contained in over 200 medications,
most of them do not have the name "Tylenol" on their labels. Moreover, just
about every patient with liver disease in my practice invariably asks: "Is
it safe for me to take Tylenol?" or "How much Tylenol can I take?" These
questions highlight the public's awareness of the potential for
acetaminophen to cause liver damage or injury.
Tylenol is a very effective pain-killing
(analgesic) and fever-reducing (anti-pyretic) agent. It is also a very safe
drug as long as the recommended dosage is not exceeded. In fact, the use of
Tylenol instead of aspirin to treat fevers in infants has greatly reduced
the occurrence of Reyes syndrome, an often fatal form of liver failure.
Ironically, however, taking too much Tylenol (an overdose) can also cause
liver failure, although by a different process (mechanism), as discussed
Do the recommended doses
of Tylenol cause any liver damage?
Some early reports did describe the occurrence of chronic liver disease that
was associated with the long-term use of Tylenol in the recommended doses.
These studies were published in the 1970s, however, and I suspect that many
of these patients may have had unrecognized chronic hepatitis C infection.
Anyway, today, the consensus is that the usual doses of Tylenol cause
significant liver damage only rarely or not at all in people with normal
Likewise, a person with liver disease does
not appear to be at an increased risk of developing additional liver injury
from taking Tylenol. This is so regardless of the cause of the liver disease
and provided the patient does not drink alcohol regularly. Thus, Tylenol is
quite safe to use in the usual dose in patients with acute (brief duration)
or chronic (long duration) hepatitis. For example, Tylenol is routinely
prescribed to treat the flu-like symptoms that can be caused by interferon
treatments for patients with chronic hepatitis. Keep in mind, however, that
all drugs, including Tylenol, should be used with caution, if at all, in
patients with severe liver disease, such as advanced cirrhosis (scarring of
the liver) or liver failure.
Why should we know that
the generic name of Tylenol is acetaminophen?
For the remainder of this discussion, I will refer to the generic name
acetaminophen, rather than to the brand name Tylenol. I decided to do this
to emphasize the need for people to read the labels of medicine bottles
carefully. As mentioned above, the labels usually will say acetaminophen
rather than Tylenol. For example, each tablespoon of the common nighttime
cold remedy, Nyquil, contains 500 milligrams (mg) of acetaminophen.
Similarly, each tablet of Vicodin, a popular, potent painkiller that
contains a narcotic, has also either 500, 650, or 750 mg of acetaminophen,
depending on the formulation.
As already mentioned, an overdose of
acetaminophen can cause liver damage. This damage occurs in a dose-related
manner. (Some other medications can cause liver injury in an unpredictable
fashion that is unrelated to the dose.) In other words, liver injury from
acetaminophen occurs only when someone takes more than a certain amount of
the drug. Likewise, the higher the dose, the greater is the likelihood of
the damage. What is more, this liver injury from an overdose of
acetaminophen is a serious matter because the damage can be severe and
result in liver failure and death. In fact, acetaminophen overdose is the
leading cause of acute (rapid onset) liver failure in the U.S. and the
Just how much
acetaminophen is safe to take?
For the average healthy adult, the recommended maximum dose of acetaminophen
over a 24 hour period is four grams (4000 mg) or eight extra-strength pills.
(Each extra-strength pill contains 500 mg and each regular strength pill
contains 325 mg.) A person who drinks more than two alcoholic beverages per
day, however, should not take more than two grams of acetaminophen over 24
hours, as discussed below. For children, the dose is based on their weight
and age, and explicit instructions are given in the package insert. If these
guidelines for adults and children are followed, acetaminophen is safe and
carries essentially no risk of liver injury.
On the other hand, a single dose of 7 to 10
grams of acetaminophen (14 to 20 extra-strength tablets) can cause liver
injury in the average healthy adult. Note that this amount is about twice
the recommended maximum dose for a 24 hour period. In children, a single
dose of 140 mg/kg (body weight) of acetaminophen can result in liver injury.
Amounts of acetaminophen, however, as low as 3 to 4 grams in a single dose
or 4 to 6 grams over 24 hours have been reported to cause severe liver
injury in some people, sometimes even resulting in death. It seems that
certain individuals, for example, those who regularly drink alcohol,
are more prone than others to developing acetaminophen-induced liver damage.
To understand this increased susceptibility in some people, it is useful to
know how acetaminophen is processed (metabolized) in the liver and how the
drug causes liver injury.
How is acetaminophen
processed (metabolized) in the body?
The liver is the primary site in the body where acetaminophen is
metabolized. In the liver, acetaminophen first undergoes sulphation (binding
to a sulphate molecule) and glucuronidation (binding to a glucuronide
molecule) before being eliminated from the body by the liver. The parent
compound, acetaminophen, and its sulphate and glucuronide compounds
(metabolites) are themselves actually not harmful. An excessive amount of
acetaminophen in the liver, however, can overwhelm (saturate) the sulphation
and glucuronidation pathways. When this happens, the acetaminophen is
processed through another pathway, the cytochrome P-450 system. From
acetaminophen, the P-450 system forms an intermediate metabolite referred to
as NAPQI, which turns out to be a toxic compound. Ordinarily, however, this
toxic metabolite is rendered harmless (detoxified) by another pathway, the
How does an overdose of
acetaminophen cause liver injury?
The answer is that liver damage from acetaminophen occurs when the
glutathione pathway is overwhelmed by too much of acetaminophen's
metabolite, NAPQI. Then, this toxic compound accumulates in the liver and
causes the damage. Furthermore, alcohol and certain medications such as
phenobarbital, phenytoin, or carbamezepine (anti-seizure medications) or
isoniazid (anti-TB drug) can significantly increase the damage. They do this
by making the cytochrome P-450 system in the liver more active. This
increased P-450 activity, as you might expect, results in an increased
formation of NAPQI from the acetaminophen. Additionally, chronic alcohol
use, as well as the fasting state or poor nutrition, can each deplete the
liver's glutathione. So, alcohol both increases the toxic compound and
decreases the detoxifying material. Accordingly, the bottom line in an
acetaminophen overdose is that when the amount of NAPQI is too much for the
available glutathione to detoxify, liver damage occurs.
Is overdose with
acetaminophen usually accidental or intentional?
In the U.S., suicide attempts account for over two thirds of
acetaminophen-related liver injury, whereas accidental overdose accounts for
only one third of the cases. In young children, accidental overdose
accounts, surprisingly, for an even lower percent of the cases. That is,
among these often-curious toddlers, accidental overdose is responsible for
less than 10% of the instances of acetaminophen toxicity. Moreover, the vast
majority of these accidental overdoses were due to unintentional overdoses
given by the caregivers of the children.
How can accidental
overdose be avoided in adults?
To avoid unintentional overdoses among adults, I offer the following
|Read the labels of the medication
bottles carefully and determine the amount or strength of acetaminophen in
each pill or spoonful. |
|Become familiar with all of the other
medications that you are taking. Remember that over 200 drugs contain
acetaminophen as one of the ingredients and that certain drugs, such as
phenobarbital, can significantly increase liver damage. |
|Before you take the medication, write
down (record) the maximum safe number of pills or spoonfuls that you can
ingest over 24 hours. Stick to that quantity and do not deviate. If,
however, you are unsure of the safe number of doses or think that you need
to take more than you should, call your doctor or pharmacist. |
|When you receive a prescription for a
new medication, ask your doctor or pharmacist whether it affects the
body's metabolism (processing) of the other medications that you are
taking, including acetaminophen. |
|If you have been drinking alcohol
regularly, do not exceed taking 2 grams of acetaminophen over 24 hours. Be
honest with yourself about the ingestion of alcohol. |
|Record the number of pills or spoonfuls
of acetaminophen and the time that you take them. |
How can overdose be
avoided in children?
The dosing of acetaminophen for children, as previously mentioned, depends
on their weight and age. To avoid overdose in children, follow the same
procedures for them as suggested above for adults. Beyond that, two adults
should independently determine the dose of acetaminophen for a child. If
there is disagreement about the recommended dose, consult a pharmacist or
physician. These precautions are not excessive when you consider that in one
experimental mock situation, only 30% of adults correctly calculated the
dose of acetaminophen for their child. If a baby-sitter is caring for a sick
child, parents should carefully write out the dose and schedule for the
administration of the drug. The fact is that each year, in children with
high fevers who were given repetitive doses of acetaminophen, deaths have
occurred due to accidental overdose and the resulting liver damage.
What happens to a person
with acetaminophen-induced liver damage?
Three clinical stages (phases) of acetaminophen-induced liver injury have
been described. During the first phase, that is, the initial 12 to 24 hours
or so after ingestion, the patient experiences nausea and vomiting. For the
next perhaps 12 to 24 hours, which is the second phase or the so-called
inactive (latent) phase, the patient feels well. In the third phase, which
begins about 48 to as late as 72 hours after the ingestion of acetaminophen,
liver blood test abnormalities begin to appear. Most notably, extremely high
(abnormal) levels of the liver blood tests, AST and ALT, are common with
this type of liver injury. The outcome (prognosis) of the liver injury can
be predicted fairly accurately on the basis of the patient's clinical exam
and blood tests. For example, at one extreme, if the patient develops severe
acid buildup in the blood, kidney failure, bleeding disorders, or coma, then
death is almost certain. Only a liver transplant can possibly save such a
What should be done if
acetaminophen toxicity is suspected?
A physician should evaluate the individual immediately. Remember that
bringing the bottles of acetaminophen and all of the person's other
medications to the emergency room is always useful. The risk that an
acetaminophen overdose will cause liver injury correlates with the blood
level of acetaminophen relative to the time the drug was taken. Physicians,
therefore, are able to estimate the patient's probability of developing
liver injury after an overdose. To make this determination, they obtain the
patient's history of acetaminophen ingestion and measure the blood level of
the drug. With this information, the doctor then can refer to a table (nomogram)
that provides an estimate of the risk of developing liver injury. The
accuracy of this estimate, however, depends on the reliability of the time
of ingestion and whether the acetaminophen was taken over a period of time
or all at once.
With suspected acetaminophen overdose, the
doctors usually will pump (gavage) the patient's stomach to remove pill
fragments. In reality, many individuals who overdose with acetaminophen in a
suicide attempt will have taken other pills in addition. Some doctors,
therefore, will consider treating the patient with activated charcoal, which
binds (and thereby inactivates) many medications. However, this treatment is
controversial because of a concern that the activated charcoal may also bind
the antidote for acetaminophen overdose.
Patients who are thought to be at a
high-risk or even only at a possible risk of developing acetaminophen liver
injury should be given the antidote, N-acetyl cystiene (Mucomyst) orally (or
intravenously in Europe). This drug works by indirectly replenishing
glutathione. The glutathione, as you recall, detoxifies the toxic metabolite
of the acetaminophen. The N-acetyl cystiene is most effective when
administered within 12 to 16 hours after the acetaminophen was taken. Most
physicians however, will administer N-acetyl cystiene even if the patient is
first seen beyond this 16 hour period. Thus, a British study showed that
patients already with liver failure who then received the N-acetyl cystiene
were more likely to survive than patients who did not receive the antidote.
Moreover, the survival occurred in these patients regardless of the time of
initial administration of N-acetyl cystiene. Finally, people who recover
from acetaminophen-induced liver damage are left, fortunately, with no
residual or ongoing (chronic) liver disease.
|Acetaminophen is a very safe drug when
taken as directed, even for people with liver disease. Nevertheless, every
drug carries risks. |
|Liver damage from acetaminophen, which
can be severe, can result either from an overdose or from regular doses
that are taken while drinking alcohol. |
|Most cases of acetaminophen-induced
liver injury are caused by an intentional or suicidal overdose.
|Unintentional or accidental overdose of
acetaminophen can usually be avoided with care and attention to the
|Physicians can estimate a patient's
probability of developing liver injury based on the timing of the overdose
and the blood level of the drug. |
|In patients with acetaminophen liver
damage, the usual clinical sequence is nausea and vomiting for the first
12-24 hours, then the patient seems well for the next 12-24 hours, after
which abnormal liver blood tests develop. |
|An antidote, N-acetyl cystiene, is
available and should be given to the patient as soon as possible,
preferably within 16 hours after the acetaminophen was taken. |