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本帖最后由 风雨不动 于 2012-4-14 16:42 编辑
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AASLD: Antibiotics Top Cause of Drug-Induced Liver Failure
By John Gever, Senior Editor, MedPage Today
Published: November 04, 2009
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
BOSTON -- Antimicrobial agents are the most common cause of drug-induced liver
failure, with most cases ending in death or transplant, a researcher said here.
A prospective analysis of some 1,200 cases of acute liver failure found that
half of those caused by drugs were associated with antituberculosis,
antifungal, sulfa drugs, and other antibiotics, according to Adrian Reuben,
MBBS, of the Medical University of South Carolina in Charleston.
Herbal supplements, anticonvulsants, and statins also were relatively common
causes of drug-induced liver injury (DILI), Reuben told attendees here at the
American Association for the Study of Liver Diseases' annual meeting.
Action Points
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â– Explain to interested patients that antibiotics were the most common cause
of drug-induced liver failure in a multicenter study, with most cases ending
in death or transplant.
â– Note that this study was published as an abstract and presented at a
conference. These data and conclusions should be considered preliminary until
published in a peer-reviewed journal.
Only 27% of DILI patients in acute liver failure recovered spontaneously,
Reuben said. About 40% had successful transplants, while another 30% died
either waiting for transplant or were too ill to be wait-listed.
Overall, 66% of patients with DILI-associated liver failure survived.
Reuben said this was the first study of DILI-associated liver failure and its
outcomes to use prospectively collected data. Prior to this study, he said,
everything known about severe DILI has come from retrospective case series.
The current study involved data collected at 23 centers participating in the
Acute Liver Failure Study Group from 1998 to 2007, a total of 1,198 cases.
These centers supplied detailed information for each case on prior drug use,
presenting symptoms, laboratory findings, and outcomes.
Causality from drugs was determined on the basis of three separate expert
reviews, which were combined to assign probability of DILI for each proposed
case.
A total of 132 were ultimately identified as DILI, of which 107 were likely,
21 were probable, and four were possible. Acetaminophen reactions were
excluded.
"Likely" cases were those where the putative culprit drug was the only one
taken or was taken only with other drugs with low liver-injury potential, and
the timing of drug administration was consistent with DILI.
At the other end of the spectrum, "possible" cases involved drugs with high
DILI potential but temporal details were unknown, or there were other drugs or
comorbidities present which could also account for liver failure.
Women accounted for more than 70% of the DILI cases. About 57% of patients
were white, suggesting over-representation of blacks, Hispanics, and Asians.
Some 70% of patients had coma scores of 2 or more. Ascites was present in 25%,
Reuben said.
Deep jaundice and coagulopathy were common, but liver enzyme elevations were
relatively modest, he reported. Mean levels of alanine and aspartyl
aminotransferases were both less than 600 U/L. Alkaline phosphatase levels
averaged 165 U/L.
Predictors of spontaneous survival, versus transplant or death, included
relatively mild coma, smaller elevations in bilirubin, less extensive
coagulopathy (as measured by international normalized ratio) and lower scores
in the Model for End-Stage Liver Disease.
Serum creatinine also was much higher in patients who died, compared with
those who survived with or without transplant.
Such factors as age, gender, body mass index, blood pressure, type of drug
involved, and stoppage of the culprit drug did not appear to affect outcomes,
Reuben said.
He noted that use of N-acetyl-cysteine was common in patients who survived,
but this effect was confounded by coma grade and MELD score.
Of the 132 cases, the following drug classes were most commonly represented:
•Antituberculosis: 25
•Antibiotics: 18
•Sulfa drugs: 12
•Antifungals: 6
•Herbal and folk medicine products: 14
•Epilepsy drugs: 13
•Statins: 10
•NSAIDs: 7
•abolite agents (e.g., disulfiram): 11
Within these categories, the tuberculosis drug isoniazid and the antibiotic
agent nitrofurantoin were involved in 21 and 11 cases, respectively, according
to Reuben.
Although the liver-toxicity potential for these agents is recognized, he said
some aspects of these cases remained mysterious. For example, duration of
nitrofurantoin treatment leading up to acute liver failure ranged from one
month to three years.
Similarly, Reuben reported, the median duration of isoniazid therapy was five
months, with 30% of cases involving treatment of six to eight months.
He said the latency period between drug initiation and DILI onset was a
critical area for future research, for these and other drugs. He suggested
that statins may be a drug class for which acute toxicity after long-term use
has been overlooked.
Reuben also called for more research on the reasons underlying the
predominance of antimicrobial agents as causes of DILI.
Scott Friedman, MD, president of the AASLD and a hepatologist at Mount Sinai
School of Medicine in New York City, said the study shed important new light
on the course of DILI-associated liver failure.
"Drug-induced liver injury is a huge problem in the U.S.," he noted, adding
that it may be the single biggest reason for cancellation of drugs in
late-stage development.
The study, he said, "characterizes in much greater detail and accuracy the
features of drug-induced liver injury" than has been available in the
literature.
"We need much better genetic predictors of the risk for drug-induced liver
injury," Friedman said.
No corporate funding for the study was reported.
Reuben said he had no financial disclosures. One co-author reported
relationships with Eli Lilly, Gilead, Novartis, Schering-Plough, Bristol-Myers
Squibb, Roche, Siemens, Vertex, and Globimmune.
Friedman reported relationships with Exalenz, sanofi-aventis, Axcan, Angion,
Intercept, 7TM, Stromedix, and Celera.
Primary source: Hepatology
Source reference:
Reuben A, et al "Acute liver failure (ALF) secondary to drug induced liver
injury (DILI): Causes & consequences" Hepatology 2009; 50: 347A.
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