Skip to main content

Assessment of Case Definitions for Identifying Acute Liver Injury in Large Observational Databases



Determining the aetiology of acute liver injury (ALI) may be challenging to both clinicians and researchers. Observational research is particularly useful in studying rare medical outcomes such as ALI; however, case definitions for ALI in previous observational studies lack consistency and sensitivity. ALI is a clinically important condition with various aetiologies, including drug exposure.


The aim of this study was to evaluate four distinct case definitions for ALI across a diverse set of large observational databases, providing a better understanding of ALI prevalence and natural history.

Data Sources

Seven healthcare databases: GE Healthcare, MarketScan® Lab Database, Humana Inc., Partners HealthCare System, Regenstrief Institute, SDI Health (now IMS Health, Inc.), and the National Patient Care Database of the Veterans Health Administration.


We evaluated prevalence of ALI through the application of four distinct case definitions across seven observational healthcare databases. We described how laboratory and clinical characteristics of identified case populations varied across definitions and examined the prevalence of other hepatobiliary disorders among identified ALI cases that may decrease suspicion of drug-induced liver injury (DILI) in particular.


This study demonstrated that increasing the restrictiveness of the case definition resulted in fewer cases, but greater prevalence of ALI clinical features. Considerable heterogeneity in the frequency of laboratory testing and results observed among cases meeting the most restrictive definition suggests that the clinical features, monitoring patterns and suspicion of ALI are highly variable among patients.


Creation of four distinct case definitions and application across a disparate set of observational databases resulted in significant variation in the prevalence of ALI. A greater understanding of the natural history of ALI through examination of electronic healthcare data can facilitate development of reliable and valid ALI case definitions that may enhance the ability to accurately identify associations between ALI and drug exposures. Considerable heterogeneity in laboratory values and frequency of laboratory testing among individuals meeting the criteria for ALI suggests that the evaluation of ALI is highly variable.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2


  1. Fontana RJ. Approaches to the study of drug-induced liver injury. Clin Pharmacol Ther. 2010;88(3):416–9.

    Article  CAS  PubMed  Google Scholar 

  2. Meropol SB, Chan KA, Chen Z, et al. Adverse events associated with prolonged antibiotic use. Pharmacoepidemiol Drug Saf. 2008;17(5):523–32.

    Article  PubMed  Google Scholar 

  3. Garcia-Rodriguez LA, Masso-Gonzalez EL, Wallander MA, et al. The safety of rosuvastatin in comparison with other statins in over 100,000 statin users in UK primary care. Pharmacoepidemiol Drug Saf. 2008;17(10):943–52.

    Article  CAS  PubMed  Google Scholar 

  4. Garcia Rodriguez LA, Williams R, Derby LE, et al. Acute liver injury associated with nonsteroidal anti-inflammatory drugs and the role of risk factors. Arch Intern Med. 1994;154(3):311–6.

    Article  CAS  PubMed  Google Scholar 

  5. Garcia Rodriguez LA, Duque A, Castellsague J, et al. A cohort study on the risk of acute liver injury among users of ketoconazole and other antifungal drugs. Br J Clin Pharmacol. 1999;48(6):847–52.

    Article  CAS  PubMed  Google Scholar 

  6. de Abajo FJ, Montero D, Madurga M, et al. Acute and clinically relevant drug-induced liver injury: a population based case-control study. Br J Clin Pharmacol. 2004;58(1):71–80.

    Article  PubMed  Google Scholar 

  7. Clifford GM, Logie J, Farmer RD. No risk of drug-associated liver injury with alpha1-adrenoreceptor blocking agents in men with BPH: results from an observational study using the GPRD. Pharmacoepidemiol Drug Saf. 2005;14(2):75–80.

    Article  CAS  PubMed  Google Scholar 

  8. Suissa S, Ernst P, Hudson M, et al. Newer disease-modifying antirheumatic drugs and the risk of serious hepatic adverse events in patients with rheumatoid arthritis. Am J Med. 2004;117(2):87–92.

    Article  CAS  PubMed  Google Scholar 

  9. Perez Gutthann S, Garcia Rodriguez LA. The increased risk of hospitalizations for acute liver injury in a population with exposure to multiple drugs. Epidemiology. 1993;4(6):496–501.

    Article  CAS  PubMed  Google Scholar 

  10. McAfee AT, Ming EE, Seeger JD, et al. The comparative safety of rosuvastatin: a retrospective matched cohort study in over 48,000 initiators of statin therapy. Pharmacoepidemiol Drug Saf. 2006;15(7):444–53.

    Article  CAS  PubMed  Google Scholar 

  11. Lee CH, Wang JD, Chen PC. Increased risk of hospitalization for acute hepatitis in patients with previous exposure to NSAIDs. Pharmacoepidemiol Drug Saf. 2010;19(7):708–14.

    Article  CAS  PubMed  Google Scholar 

  12. Jinjuvadia K, Kwan W, Fontana RJ. Searching for a needle in a haystack: use of ICD-9-CM codes in drug-induced liver injury. Am J Gastroenterol. 2007;102(11):2437–43.

    Article  PubMed  Google Scholar 

  13. Heaton PC, Fenwick SR, Brewer DE. Association between tetracycline or doxycycline and hepatotoxicity: a population based case-control study. J Clin Pharm Ther. 2007;32(5):483–7.

    Article  CAS  PubMed  Google Scholar 

  14. Graham DJ, Drinkard CR, Shatin D. Incidence of idiopathic acute liver failure and hospitalized liver injury in patients treated with troglitazone. Am J Gastroenterol. 2003;98(1):175–9.

    Article  CAS  PubMed  Google Scholar 

  15. Goettsch WG, Heintjes EM, Kastelein JJ, et al. Results from a rosuvastatin historical cohort study in more than 45,000 Dutch statin users, a PHARMO study. Pharmacoepidemiol Drug Saf. 2006;15(7):435–43.

    Article  CAS  PubMed  Google Scholar 

  16. Garcia-Rodriguez LA, Gonzalez-Perez A, Stang MR, et al. The safety of rosuvastatin in comparison with other statins in over 25,000 statin users in the Saskatchewan Health Databases. Pharmacoepidemiol Drug Saf. 2008;17(10):953–61.

    Article  PubMed  Google Scholar 

  17. Enger C, Gately R, Ming EE, et al. Pharmacoepidemiology safety study of fibrate and statin concomitant therapy. Am J Cardiol. 2010;106(11):1594–601.

    Article  CAS  PubMed  Google Scholar 

  18. Duh MS, Vekeman F, Korves C, et al. Risk of hepatotoxicity-related hospitalizations among patients treated with opioid/acetaminophen combination prescription pain medications. Pain Med. 2010;11(11):1718–25.

    Article  PubMed  Google Scholar 

  19. Cziraky MJ, Willey VJ, McKenney JM, et al. Statin safety: an assessment using an administrative claims database. Am J Cardiol. 2006;97(8A):61C–8C.

    Article  CAS  PubMed  Google Scholar 

  20. Chan KA, Truman A, Gurwitz JH, et al. A cohort study of the incidence of serious acute liver injury in diabetic patients treated with hypoglycemic agents. Arch Intern Med. 2003;163(6):728–34.

    Article  PubMed  Google Scholar 

  21. Carson JL, Strom BL, Duff A, et al. Acute liver disease associated with erythromycins, sulfonamides, and tetracyclines. Ann Intern Med. 1993;119(7 Pt 1):576–83.

    Article  CAS  PubMed  Google Scholar 

  22. Stang PE, Ryan PB, Racoosin JA, et al. Advancing the science for active surveillance: rationale and design for the Observational Medical Outcomes Partnership. Ann Intern Med. 2010;153(9):600–6.

    Article  PubMed  Google Scholar 

  23. Stang PE, Ryan PB, Dusetzina SB, et al. Health outcomes of interest in observational data: issues in identifying definitions in the literature. Health Outcomes Res Med. 2012;3(1):e37–44.

    Article  Google Scholar 

  24. Food and Drug Administration. Guidance for industry on drug-induced liver injury: premarketing clinical evaluation. Silver Spring: US Department of Health and Human Services; 2009. (Accessed 26 June 2011).

  25. Chalasani N, Fontana RJ, Bonkovsky HL, et al. Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology. 2008;135(6):1924–34, 1934.e1–4.

    Google Scholar 

  26. Clark JM. The epidemiology of nonalcoholic fatty liver disease in adults. J Clin Gastroenterol. 2006;40(Suppl. 1):S5–10.

    PubMed  Google Scholar 

  27. Daniels D, Grytdal S, Wasley A. Surveillance for acute viral hepatitis—United States, 2007. MMWR Surveill Summ. 2009;58(3):1–27.

    PubMed  Google Scholar 

  28. Cohen SM, Ahn J. Review article: the diagnosis and management of alcoholic hepatitis. Aliment Pharmacol Ther. 2009;30(1):3–13.

    Article  CAS  PubMed  Google Scholar 

  29. Ozer JS, Chetty R, Kenna G, et al. Recommendations to qualify biomarker candidates of drug-induced liver injury. Biomark Med. 2010;4(3):475–83.

    Article  CAS  PubMed  Google Scholar 

Download references


We would like to thank Jesse A. Berlin, ScD, of the OMOP Scientific Advisory Board and Craig Cheetham, PharmD, of Kaiser Permanente Southern California for their critical and thorough review of the manuscript.

Financial support

The OMOP is funded by the Foundation for the National Institutes of Health through generous contributions from the following: Abbott, Amgen Inc., AstraZeneca, Bayer Healthcare Pharmaceuticals, Inc., Bristol-Myers Squibb, Eli Lilly & Company, GlaxoSmithKline, Johnson & Johnson, Lundbeck, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., Pharmaceutical Research Manufacturers of America (PhRMA), Roche, Sanofi, Schering-Plough Corporation, and Takeda.

Conflict of interest

Patrick Ryan and Paul Stang are employees of Janssen Research and Development, which provides funding for the OMOP, and have received OMOP-funded travel support. They both hold stock in multiple pharmaceutical companies. Aaron Katz and Judith Racoosin have no conflicts of interest to declare that are directly relevant to the content of this study.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Aaron J. Katz.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 87 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Katz, A.J., Ryan, P.B., Racoosin, J.A. et al. Assessment of Case Definitions for Identifying Acute Liver Injury in Large Observational Databases. Drug Saf 36, 651–661 (2013).

Download citation

  • Published:

  • Issue Date:

  • DOI:


  • Index Date
  • Case Definition
  • Acute Liver Injury
  • Observational Database
  • Observational Medical Outcome Partnership