Antibiotics Top Cause of Drug-Induced Liver Failure

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AASLD: Antibiotics Top Cause of Drug-Induced Liver Failure

By 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 Earn CME/CE credit

for reading medical news

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 Reuben, MBBS, of the

Medical University of South Carolina in ton.

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

--------------------------------------------------------------------------------

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.

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

2009; 50: 347A

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AASLD: Antibiotics Top Cause of Drug-Induced Liver Failure

By 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 Earn CME/CE credit

for reading medical news

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 Reuben, MBBS, of the

Medical University of South Carolina in ton.

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

--------------------------------------------------------------------------------

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.

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

2009; 50: 347A