Acetaminophen Toxicity

[Guest guest]

I do not know if this has been

posted before, but I found it quite informative. It was on this

fairly comprehensive Hep C website:

http://janis7hepc.com/Symptoms.htm

Warnings for all those who have Hepatitis

Hepatitis Patients at

Risk for Accidental Acetaminophen Toxicity

By Peggy Peck, MedPage Today

Staff Writer

Reviewed by Jasmer, MD; Assistant Professor of Medicine, University of California,

San Francisco

http://www.medpagetoday.com

May 22, 2006

MedPage Today Action Points

* Explain to interested patients that a number of over-the-counter and

prescription drugs contain acetaminophen, which may put acute hepatitis

patients at risk of acetaminophen toxicity at lower doses than previously

recognized.

* This study was published as an abstract and presented in a poster at a

conference. These data and conclusions should be considered to be

preliminary as they have not yet been reviewed and published in a

peer-reviewed publication.

Review

LOS ANGELES, May 22 - Over-the-counter flu remedies such as Nyquil or

Theraflu are often used for relief of the flu-like symptoms of acute

hepatitis, a choice that may trigger acute liver failure because those

agents contain acetaminophen.

Serum samples from 72 patients with fulminant hepatitis detected evidence

of acetaminophen toxicity in 12.5% of patients, said M. Lee M.D.,

of the University of Texas Southwester Medical Center in Dallas, who reported the findings at

Digestive Disease Week sessions here today.

Dr. Lee and colleagues used a high-pressure liquid chromatography with

electrochemical detection to assess acetaminophen levels. They studied 10

patients with liver failure due to confirmed acetaminophen overdose as a

positive control group.

The average serum concentration of acetaminophen adducts was 0.45 nmol/mL

versus 5.58 nmol/mL in the control group. Nonetheless, Dr. Lee said the

evidence of acetaminophen adducts was " a second insult to the liver

cells on top of hepatitis. "

Importantly, the toxicity occurred when the patients used the

over-the-counter flu medicines at therapeutic doses. " None reported

doses that would exceed 4 g/day, " he said. That is lower than

previously reported toxic doses, he said.

Acetaminophen toxicity occurs in a dose-related fashion. Seven or eight

grams consumed over the course of three to four days can be fatal, Dr. Lee

said.

An online check of ingredients in cold and flu products found acetaminophen

listed as an ingredient in 26 OTC remedies, including Coricidin D,

Triaminic, NyQuil, DayQuil, and Dristan as well as Midol and Pamprin.

In this series, 67% of patients who had detectable acetaminophen-protein

adducts in their blood died within three weeks of hospital admission versus

27% of patients who had no evidence of acetaminophen use (P=0.017).

Liver toxicity is a well known side-effect of acetaminophen, he said,

noting that acetaminophen overdose is a leading cause of liver failure and

liver transplants " I am surprised it is still on the market, " Dr.

Lee said.

He later qualified that statement saying that but the drug is so popular,

and is sold under so many different brands-the most popular being

Tylenol-that he doubts it would ever be removed from the market.

That said, he noted that people with liver disease are frequently unaware

that they are using acetaminophen-containing compounds, which could put

them at risk for liver failure.

" Vicodin and Percocet are the two most popular prescription compounds

containing acetaminophen and these are often prescribed for pain relief in

people with liver disease, " he said. " Unbundling of both of these

drugs, which might be done at some point, would be significant in terms of

reducing accidental acetaminophen overdose. "

He said that in 2002 a FDA advisory committee recommended that labels of

over-the-counter cold and flu medicines be changed so that the front label

would list acetaminophen as an ingredient. " But that was in 2002 and

the FDA has yet to act on that recommendation. "

M. Vierling, M.D., president of the American Society for the Study of

Liver Diseases, a professor of medicine at Baylor in Houston, said the hallmarks of

acetaminophen toxicity are " a change in mental state and alteration in

clotting ability. "

Dr. Vierling called acetaminophen an " excellent drug " but added

that Dr. Lee's study suggests the need to advise patients with chronic

liver disease to avoid not only Tylenol and other acetaminophen products

but also to be cautious when selecting cold and flu medicines.

The patients were included in the National Institutes of Health Acute Liver

Failure Study (1999-2004), a national registry of acute liver failure

cases. Dr. Lee said there are roughly 2,000 cases of acute liver failure

annually and about 500 of those are fatal.

Primary source: Digestive Disease Week

Source reference:

Lee, WM et al " Acetaminophen as a co-factor in acute liver failure due

to viral hepatitis determined by measurement of acetaminophen-protein

adducts " Abstract S1002.

Acetaminophen as a co-factor in acute

liver failure due to viral hepatitis determined by measurement of

acetaminophen-protein adducts.

J. Polson1; L. P. 2; T. J. Davern3; L. Hynan4; L. Rossaro5; A. M.

Larson6; C. Pezzia1; W. M. Lee1 1. Division of Digestive and Liver

Diseases, UT Southwestern Medical Center, Dallas,

TX, USA.

2. Department of Pediatrics and Pharmacology, University

of Arkansas for Medical Sciences, Little Rock, AR,

USA. 3.

Gastroenterology, University of California at San Francisco,

San Francisco, CA, USA.

4. Center for Biostatistics and Clinical Science, UT Southwestern Medical Center,

Dallas, TX, USA.

5. Center for Transplant Medicine, University

of California at ,

Sacramento, CA, USA.

6. Hepatology, University of Washington , Seattle, WA, USA.

Background: Acetaminophen (APAP) use during the prodromal phase of acute

viral hepatitis (AVH) is often reported and may worsen liver injury. In

determining whether APAP plays a role in complicating certain cases of

severe AVH, serum APAP levels are likely less reliable than a recently

described serum assay for APAP adducts which remains positive up to 7 days

after onset of liver damage.

Methods: Sera from 72 consecutive patients with fulminant hepatitis A or B

(IgM anti-HAV or anti-HBc positive) enrolled in the US ALF Study

(1998-2004) were tested in blind fashion for APAP-protein adducts using

high-pressure liquid chromatography with electrochemical detection

(HPLC-ED). As a positive control group, 10 well-documented cases of ALF due

solely to APAP overdose were included. Outcome and other clinical data were

analyzed with Chi-square, Fisher's exact test, and Kruskall-Wallis rank

test as appropriate.

Results: 9/72 (12.5%) AVH patients had detectable APAP adducts: 5/49

(10.2%) patients with AVH B and 4/23 (17.4%) with AVH A. All 10 known

APAP-induced ALF cases had positive adducts at higher levels than those in

patients with a primary diagnosis of AVH-induced ALF (median level 5.58

nmol/mL vs 0.45 nmol/mL for AVH cases). The lower levels in AVH cases

suggest these were not intentional APAP overdoses. The admission serum ALT

and total bilirubin levels differed among the 3 groups (p<0.002), the

adducts-containing group (APAP-AVH) having values intermediate between the

pure AVH group and the pure APAP group (median values - ALT: AVH only:

1580; APAP-AVH: 2658; APAP: 5570 IU/L; total bilirubin: AVH: 19.8;

APAP-AVH: 9.7; APAP: 5.0 mg/dL). Neither admission coma grade nor degree of

coagulopathy differed significantly among the groups. 8 of 9 AVH patients

with adducts reported some APAP use in the days preceding admission; none

reported doses exceeding 4 grams per day. No history was obtainable from

the 9th patient. 4 patients received N-acetylcysteine (NAC) because they

reported APAP use; 3 were enrolled in the trial of NAC versus placebo. 67%

of AVH patients with APAP adducts died within 3 weeks of study admission as

compared to 27% of AVH patients without adducts (p=0.017).

Conclusions: HPLC-ED detects APAP adducts in more than 10% of patients with

AVH-induced ALF, implicating APAP toxicity as a cofactor during the

apparent use of therapeutic doses. Combined APAP-AVH injury is associated

with a poorer outcome. Warnings regarding use of APAP should be given to

any patient diagnosed with AVH, particularly those of moderate or greater

severity. Supported by NIH R-01 DK58369 and NIH R-03 DK067999.