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Acetaminophen
no longer looks so harmless
January
28, 2006
Subject:
Acetaminophen is now the leading cause of acute liver failure. Accidental
poisonings outnumber suicide attempts.
Acetaminophen
has a reputation that it doesn't deserve. People think of it as the safe
alternative to aspirin for relieving pain, fever and inflammation. They
are wrong. Taking more than the suggested dose can cause acute liver failure.
Until
1980 the link to liver failure wasn't known. Once discovered, one might
think that the knowledge that taking too much acetaminophen can destroy
a person's liver might would generate caution and more careful use. Not
so. Between 1998 and 2003, the proportion of cases of liver failure caused
by the drug nearly doubled.
William
Lee at the University of Texas Southwestern Medical Center in Dallas and
his colleagues published data in the December, 2005 issue of Hepatology
on patients with acute liver failure. Of the 275 people with acetaminophen
poisoning, 8% received a liver transplant, 65% survived without one and
27% died.
There
was no difference in survival between 44% of cases in which people intentionally
took large doses of the drug in suicide attempts compared to the 48% who
accidentally overdosed.
Many
of the people who had accidentally poisoned themselves did so by taking
just 10 grams of the medication each day for about three days - the equivalent
of about 20 pills per day instead of the recommended eight, an overdose
that might be less serious with other drugs. Other people had mistakenly
taken two products that both contained the drug (Hepatology, 2005 Dec;42(6):1364-72).
[i]
The
toxic potential of acetaminophen on the liver can be reduced by increasing
glutathione levels. Back in 1992, research was published suggesting that
the amino acid l-glutamine, because it is converted to glutathione, could
possibly protect against acetaminophen poisoning. [ii]
As this amino acid is often used to heal ulcers and other irritations
of the gastrointestinal tract, problems often caused by anti-inflammatory
drugs, it seemed to be an ideal adjunct to take if someone requires high
dose acetaminophen.
A
more reliable way to get the liver to generate glutathione is to use the
supplement n-actyl-cysteine (NAC) and in the last few years this nutritional
supplement has replaced l-glutamine as the ‘drug' of choice in treating
acetaminophen poisoning. [iii] NAC
has a number of other valuable uses, many based on its ability to rapidly
replenish liver glutathione. It is also used for its mucolytic properties,
providing symptomatic relief in a range of conditions including cystic
fibrosis, hay fever, otitis media, and influenza.
When
taking high doses of acetaminophen it now seems more than prudent to accompany
them with one or both of these nutritional supplements. There is little
need to reserve their use for treating cases of acute liver failure. Neither
NAC or l-glutamine have serious side effects. Rather they are beneficial
for other additional reasons.
A
full list of drugs which contain acetaminophen can be found at the Liver
Foundation's website at: http://www.liverfoundation.org/db/articles/1097
Sources
of acetaminophen include:
Extra
strength Anacin
Excedrin
Percoset
Tylenol
References:
[i]
Acetaminophen-induced acute liver failure: results
of a United States
multicenter, prospective study.
Larson
AM , Polson
J , Fontana
RJ , Davern
TJ , Lalani
E , Hynan
LS , Reisch
JS , Schiodt
FV , Ostapowicz
G , Shakil
AO , Lee
WM ; Acute
Liver Failure Study Group .
Department of Internal Medicine, Division of Gastroenterology, University
of Washington Medical Center , Seattle , 98195, USA . amlarson@u.washington.edu
Severe acetaminophen hepatotoxicity frequently leads to acute liver failure
(ALF). We determined the incidence, risk factors, and outcomes of acetaminophen-induced
ALF at 22 tertiary care centers in the United States . Detailed prospective
data were gathered on 662 consecutive patients over a 6-year period fulfilling
standard criteria for ALF (coagulopathy and encephalopathy), from which
275 (42%) were determined to result from acetaminophen liver injury. The
annual percentage of acetaminophen-related ALF rose during the study from
28% in 1998 to 51% in 2003. Median dose ingested was 24 g (equivalent
to 48 extra-strength tablets). Unintentional overdoses accounted
for 131 (48%) cases , intentional (suicide attempts)
122 (44% ), and 22 (8%) were of unknown intent. In the unintentional
group, 38% took two or more acetaminophen preparations simultaneously,
and 63% used narcotic-containing compounds. Eighty-one percent of unintentional
patients reported taking acetaminophen and/or other analgesics for acute
or chronic pain syndromes. Overall, 178 subjects (65%) survived, 74 (27%)
died without transplantation, and 23 subjects (8%) underwent liver transplantation;
71% were alive at 3 weeks. Transplant-free survival rate and rate of liver
transplantation were similar between intentional and unintentional groups.
In conclusion, acetaminophen hepatotoxicity far exceeds other causes of
acute liver failure in the United States . Susceptible patients have concomitant
depression, chronic pain, alcohol or narcotic use, and/or take several
preparations simultaneously. Education of patients, physicians, and pharmacies
to limit high-risk use settings is recommended.
[ii]
Glutamine preserves liver glutathione after lethal
hepatic injury.
Hong
RW , Rounds
JD , Helton
WS , Robinson
MK , Wilmore
DW .
Department of Surgery, Brigham and Women's Hospital, Harvard Medical School
, Boston , MA 02115 .
Glutathione (GSH) is a major antioxidant that protects tissues from free
radical injury. Glutamine augments host defenses and may be important
in GSH synthesis. Acetaminophen toxicity causes hepatic GSH depletion
and hepatic necrosis. The authors hypothesized that glutamine-supplemented
nutrition would enhance liver GSH stores and diminish hepatic injury and
death after acetaminophen overdose. Wistar rats received either a standard
total parenteral nutrition (TPN) solution (STD) or an isocaloric, isonitrogenous
glutamine-supplemented solution (GLN). On the 5th day of feeding, animals
were given acetaminophen (400 mg/kg intraperitoneally) and then killed
at various time points. Standard TPN solution animals had a rapid depletion
of hepatic glutathione, whereas GLN animals were resistant to this drop
and rapidly repleted hepatic GSH stores. Glutamine-supplemented animals
maintained higher plasma glutamine concentrations, had lesser elevations
in hepatic enzymes, and sustained significantly fewer complications compared
with STD animals. The authors conclude that glutamine-supplemented nutrition
preserves hepatic glutathione, protects the liver, and improves survival
during acetaminophen toxicity. Glutamine may augment host defenses by
enhancing antioxidant protection.
PMID: 1546897 [PubMed - indexed for MEDLINE]
[iii]
[Paracetamol: therapeutic action, pathogenesis
and treatment of acute poisonings complicated by severe liver damage]
[Article in Polish]
Kolacinski
Z , Rusinski
P .
Klinika Ostrych Zatruc Instytutu Medycyny Pracy im. prof. J. Nofera w
Lodzi, ul. Sw. Teresy 8, 90-950 Lodz , skr. poczt. 199.
The biosynthesis of prostaglandins proceeds in the presence of fatty acid
cycloxygenases (COX-1, COX-2). COX-1 is responsible for the synthesis
of prostaglandins indispensable for normal homeostasis, while COX-2 regulates
local expression of pro-inflammatory prostaglandins. Paracetamol is a
selective inhibitor of COX-2 thus having an analgesic and antipyretic
potential. The drug is metabolised primarily in the liver. About 5% of
the dose transforms into N-acetylo-p-benzoquinoneimine (NAPQI), a highly
active compound. Ingestion of a single paracetamol dose higher than 8
g leads to a depletion of hepatic glutathione reserves and a loss of the
detoxifying property of the liver. As a result, hepatic necrosis develops.
The specific antidote is N-acetylcysteine (NAC). If applied within 10-15
h since the poisoning it enables complete survival. The efficacy of specific
treatment decreases after 24 h but blood paracetamol is an indication
for NAC therapy. The surviving patients with advanced paracetamol poisoning
require long-lasting conservative treatment with ornithine and phospholipids
as well as a light diet.
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