Transaminase Elevations in Patients Receiving Bovine or Porcine Heparin

Dukes, George E.; Sanders, Steven W.; Russo, John; Swenson, Elise; Burnakis, Thomas G.; Saffle, Jeffrey R.; Warden, Glenn D.

doi:10.7326/0003-4819-100-5-646

Cited by 60 publications

(29 citation statements)

References 10 publications

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“…The search dates were from 1975 to December 2014, which covers the time since the first published case reports of anticoagulant-related DILI [6, 8, 19]. The literature searches were based on the following search engines: MEDLINE/Pubmed, Livertox, and Google Scholar.…”

Section: Methodsmentioning

confidence: 99%

Enoxaparin-Induced Liver Injury: Case Report and Review of the Literature and FDA Adverse Event Reporting System (FAERS)

Hahn

Morales

Lewis

2015

Drug Saf - Case Rep

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Anticoagulants are a well known cause of drug-induced liver injury (DILI). We recently encountered a 45-year-old male who developed DILI during treatment with enoxaparin, a low-molecular-weight heparin (LMWH), for dural venous thrombosis. The man received enoxaparin 80 mg subcutaneously, twice daily. After 4 days, the patient was asymptomatic but he developed liver aminotransferase elevations: AST 340 U/L and ALT 579 U/L. Investigation revealed an R ratio of 19.9 by day 5 and a Roussel Uclaf Causality Assessment Method score of 10, giving a high probable likelihood that enoxaparin was the cause of hepatic injury. Enoxaparin was discontinued on day 7, and 1 week later AST and ALT had decreased to 61 and 273 U/L, respectively. This case prompted a literature search and a review of the FDA Adverse Event Reporting System (FAERS) database for the range of hepatic adverse events (HAEs) associated with this class. A MEDLINE/PubMed search was conducted using DILI terms and cross-referenced with the anticoagulant classes. A Freedom of Information Act (FOIA) request was also made to identify adverse events (AEs) associated with enoxaparin in FAERS. Case type, severity of outcome, and demographic information were analyzed. Five publications have reported DILI with enoxaparin. Trial data found elevations in ALT >3 times the upper limit of normal (ULN) for unfractionated heparins (UFH) and LMWH in 8 and 4–13 % of subjects, respectively. However, liver injury in all cases was mild, self-limited, and asymptomatic. Our FOIA request yielded 8336 adverse events related to enoxaparin over a 14-year period (Jan 2000–Sept 2014). Specific HAEs were found in 4 % of reports, but all were described with other serious adverse events. The reported outcomes of hospitalization (75 %), death (17 %), and life-threatening medical events (5 %) were likely due to other related serious adverse events such as hemorrhage (28 %) and thrombocytopenia (11 %). We conclude that LMWH-related liver injury is uncommon and reversible. The mechanism of liver injury is not known, although an idiosyncratic effect is postulated. Although the FAERS database lists hepatic injury in 4 % of all enoxaparin-related AEs, it appears that serious outcomes are related to non-hepatic events.

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Section: Methodsmentioning

confidence: 99%

Enoxaparin-Induced Liver Injury: Case Report and Review of the Literature and FDA Adverse Event Reporting System (FAERS)

Hahn

Morales

Lewis

2015

Drug Saf - Case Rep

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“…A small percentage of the patients treated with tacrine in these trials developed ALT >20× ULN, which completely resolved despite continued treatment with the drug . The phenomenon of asymptomatic aminotransferase elevation is called adaptation and has been reported for other pharmaceutical compounds as well, including heparins and cholestyramine …”

Section: Traditional Biomarkers Of Dilimentioning

confidence: 97%

“…15 The phenomenon of asymptomatic aminotransferase elevation is called adaptation and has been reported for other pharmaceutical compounds as well, including heparins and cholestyramine. [16][17][18][19] Although it is a somewhat common phenomenon, the observation of frequent or high ALT elevations in individuals treated with a drug that have not been observed in participants treated with a placebo can have a significant impact on the development of promising drug candidates that do not fulfill an important and unmet clinical need. This is because, similar to safe drugs, many drugs with serious DILI liabilities, including isoniazid and troglitazone, also show a propensity to induce minor and asymptomatic ALT elevations in a substantial proportion of treated patients which resolve despite continued treatment.…”

Section: Hepatocellular Injury Biomarkersmentioning

confidence: 99%

Serum biomarkers of drug‐induced liver injury: Current status and future directions

Church

Watkins

2018

J of Digest Diseases

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Drug‐induced liver injury (DILI), which is caused by drugs and herbal or dietary supplements, remains a serious concern for drug developers, regulators, and clinicians; however, serum biomarkers utilized to detect and monitor DILI have not changed in decades and have limitations. Data‐driven mathematical modeling that incorporates the release and clearance kinetics of traditional biomarkers has improved their use in the prediction of liver safety liabilities for new drug candidates. Several newer biomarkers have shown promise in terms of liver specificity, predicting the outcome of DILI events, and providing insight into its underlying mechanisms. For these new biomarkers to be qualified for regulatory acceptance, it will require their assessment in large numbers of patients who are receiving a wide range of compounds and who develop a broad spectrum of liver injuries. The ongoing and evolving international biomarker consortia should play a major role in this effort, which is likely to transform the assessment of liver safety in clinical trials and in the clinic.

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“…A number of studies have reported the elevation of the liver enzymes alanine aminotransferase and aspartate aminotransferase with UH and LMWH treatment (Monreal et al, 1989;Carlson et al, 2001), with an incidence estimated at approximately 15% (Arora and Goldhaber, 2006). The mechanism for this effect has not been identified, but the enzyme levels return to normal after treatment has finished or, in some cases, during therapy (Dukes et al, 1984).…”

Section: F Adverse Reactionsmentioning

confidence: 99%