RESEARCH - Acetaminophen: most common cause of acute liver failure in US

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Acetaminophen: Most common cause of acute liver failure in US

Rheumawire

Dec 12, 2005

Zosia Chustecka

Seattle, WA- Acetaminophen/paracetamol, the most widely used analgesic in

the US, has become the most common cause of acute liver failure (ALF), US

researchers report in the December 2005 issue of Hepatology [1].

" We were surprised that the incidence of acetaminophen ALF has risen in the

US over the years, " says lead researcher Dr Anne Larson (University of

Washington Medical Center, Seattle). " This was rather alarming, particularly

since half the cases were accidental (unintentional), " she tells rheumawire.

The researchers belong to the Acute Liver Failure Study Group, set up in

1997 by Dr Lee (University of Texas Southwestern Medical Center,

Dallas), the senior author on the current paper. " The percentage of all ALF

cases in our registry that were due to acetaminophen has nearly doubled in

six years, " they report.

Before the 1980s, there was no mention of acetaminophen as a cause of ALF,

they comment. A US retrospective study from 1994 to 1996 found a 20%

incidence of acetaminophen toxicity leading to ALF. Now, their own study

found an increase in the annual percentage of acetaminophen-related ALF from

28% in 1998 to 51% in 2003.

Half of cases were accidental overdose

" One of the most alarming findings in our study was that unintentional

acetaminophen overdose accounted for half of the cases, " the researchers

comment. This is a much higher rate than has been reported from other

countries: the rate of unintentional overdose has been estimated at 31% in

Australia, and nonsuicidal overdoses are only rarely reported in the UK and

in Europe, they note.

The team found that of 275 cases of ALF resulting from acetaminophen liver

injury, unintentional overdoses accounted for 131 cases (48%), intentional

overdose (ie, suicide attempts) for 122 cases (42%), and the remaining 22

cases (8%) were of unknown intent. The clinical picture and outcomes were

similar for the intentional and unintentional overdoses, with a mortality

rate of 29% and liver transplantation in 7% and 9% of cases, respectively.

Although the serum levels of acetaminophen were lower in the cases due to

unintentional overdose, these patients were more likely to have severe

hepatic encephalopathy on admission, perhaps because they had waited longer

before seeking medical care (median of four days after symptom onset vs one

day for the intentional group).

In many of the cases of unintentional overdose with acetaminophen, there

appeared to be multiple factors at play, the researchers comment. This group

was more likely to be taking several different products containing

acetaminophen (38%), and they were more likely to be using prescription

products containing a combination of acetaminophen with narcotics (63%). The

most popular of these was Vicodin (acetaminophen with hydrocodone, Abbott

Laboratories). Another issue was that individuals were taking more tablets

than the maximum of 4 g daily recommended on product package inserts; the

mean daily dose in this group was 7.5 g (1.0-7.8 g).

" Patients with chronic pain appear to be particularly susceptible to this

problem, " Larson et al comment. Most of the cases in the

unintentional-overdose group reported taking the products specifically for

pain (79%). The most common causes of chronic pain that were mentioned were

chronic back pain and headache, but fibromyalgia, rheumatologic pain, and

orthopedic pain all featured as reasons that individuals were using

acetaminophen products.

" Many claimed to have ingested modest amounts of acetaminophen over weeks or

months, " the researchers comment " Why, then, the sudden onset of severe

liver injury? Our data suggest that there is a narrow therapeutic margin and

that consistent use of as little as 7.5 mg/day may be hazardous. " The

researchers also note that some of the cases resulted after less than seven

days of ingestion, which suggests " that there is no chronic form of injury,

but rather a threshold of safety that may be breached with devastating

results. "

More than half used OTC products

More than half of all the ALF cases in this study (147 subjects, 53%) were

using over-the-counter acetaminophen products. The researchers note that a

third of patients who were using narcotics also took an OTC acetaminophen

product, which points to a lack of awareness of the hazards of using OTC

products in combination with prescription drugs.

Unintentional overdose is now the leading form of acetaminophen

hepatotoxicity in US ALF subjects, the researchers point out, although they

add that suicidal ingestion remains important as well. " Efforts to limit OTC

package size and to restrict the prescription of narcotic-acetaminophen

combinations (or to separate the narcotic from acetaminophen) may be

necessary to reduce the incidence of this increasingly recognized but

preventable cause of ALF in the US. "

Restrictions on OTC package sizes of acetaminophen are already in place in

the UK, and they have reduced the problem, comments Dr O'Grady

(Institute of Liver Studies, King's College Hospital, London, UK) in an

accompanying editorial [2]. The UK introduced a maximum 16-g pack size for

OTC acetaminophen in 1998, and in the four years following that change in

legislation, there was a 30% reduction in the number of patients with severe

acetaminophen-induced acute liver failure admitted to specialist liver units

and liver transplant centers [3]. Even more severe restrictions operate in

France (where the maximum packet size is 8 g), and this measure is highly

effective in minimizing severe acetaminophen hepatotoxicity, he adds.

In contrast, OTC acetaminophen products are freely available in the US and

are sold in large packs in supermarkets and other stores. " People can buy

megabottles of it, " says Larson, adding that " it's advertised as completely

safe. " In addition, acetaminophen is contained in many different products,

such as cold remedies, flu remedies, headache tablets, etc. " As a group, the

Acute Liver Failure Study Group believes that there should be some

restrictions on acetaminophen in the US similar to what has been done in the

UK. " In addition to restrictions on pack sizes in the UK, there is also

widespread use of blister packs.

" The most alarming part of our findings was the unintentional poisoning, "

Larson tells rheumawire. " This is a completely preventable problem with

proper education (of physicians, pharmacists, and consumers) and medication

packaging. "

" The most important message we have is EDUCATION! " she says. Patients should

always be informed what is in the preparations they're being given (eg, told

that Vicodin contains acetaminophen), and they should be strongly counseled

against polypharmacy. Patients must be taught to read labels and not to

combine products, she adds.

Sources

1. Larson A, Polson J, Fontana RJ, et al.

Acetaminophen-induced acute liver failure: results of a United States

multicenter, prospective study. Hepatology 2005; 42:1364-1372.

2. O'Grady JG. Broadening the view of acetaminophen

hepatotoxicity. Hepatology 2005; 42:1252-1254.

3. Hawton K, Simkin S, Deeks J, et al. UK legislation on

analgesic packs: before and after study of long-term effect on poisonings.

BMJ 2004; 329:1076.

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Mayo Clinic in Rochester

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s Hopkins Medicine

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