Drug induced liver injury with analysis of alternative causes as confounding variables

Abstract

Aims: Drug-induced liver injury (DILI) is rare compared to the worldwide frequent acute or chronic liver diseases. Therefore, patients included in series of suspected DILI are at high risk of not having DILI, whereby alternative causes may confound the DILI diagnosis. The aim of this review is to evaluate published case series of DILI for alternative causes.

Methods: Relevant studies were identified using a computerized search of the Medline database for publications from 1993 through 30 October 2017. We used the following terms: drug hepatotoxicity, drug induced liver injury, hepatotoxic drugs combined with diagnosis, causality assessment and alternative causes.

Results: Alternative causes as variables confounding the DILI diagnosis emerged in 22 published DILI case series, ranging from 4 to 47%. Among 13 335 cases of suspected DILI, alternative causes were found to be more likely in 4555 patients (34.2%), suggesting that the suspected DILI was probably not DILI. Biliary diseases such as biliary obstruction, cholangitis, choledocholithiasis, primary biliary cholangitis and primary sclerosing cholangitis were among the most missed diagnoses. Alternative causes included hepatitis B, C and E, cytomegalovirus, Epstein-Barr virus, ischemic hepatitis, cardiac hepatopathy, autoimmune hepatitis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and alcoholic liver disease.

Conclusions: In more than one-third of published global DILI case series, alternative causes as published in these reports confounded the DILI diagnosis. In the future, published DILI case series should include only patients with secured DILI diagnosis, preferentially established by prospective use of scored items provided by robust diagnostic algorithms such as the updated Roussel Uclaf causality assessment method.

Keywords: Roussel Uclaf Causality Assessment Method; alternative causes; causality assessment; competing causes; drug-induced liver injury; missed diagnoses.

Figure 1

Suggestion for a flow chart of drug‐induced liver injury (DILI) case series with excluded cases

Figure 2

Checklist of differential diagnoses in cases of suspected DILI. This tabular listing is adapted and derived from a previous publication 9. Although not comprehensive, it is to be used as a guide and in connection with RUCAM 9. AAA, anti‐actin antibodies; AMA, antimitochondrial antibodies; ANA, antinuclear antibodies; ASGPR, asialo‐glycoprotein‐receptor; BMI, body mass index; CT, computed tomography; CYP, cytochrome P450; DILI, drug‐induced liver injury; PDH, pyruvate dehydrogenase; HAV, hepatitis A virus; HBc, hepatitis B core; HBV, hepatitis B virus; HCV, hepatitis C virus; HEV, hepatitis E virus; HIV; human immunodeficiency virus; LKM, liver kidney microsomes; LP, liver–pancreas antigen; LSP, liver specific protein; MRC, magnetic resonance cholangiography; MRT, magnetic resonance tomography; p‐ANCA, perinuclear antineutrophil cytoplasmatic antibodies; PCR, polymerase chain reaction; RUCAM, Roussel Uclaf Causality Assessment Method; SLA, soluble liver antigen; SMA, smooth muscle antibodies; TSH, thyroid stimulating hormone; TTG, tissue transglutaminase