B0538 - When Is Suspected Drug Induced Liver Injury (DILI) Not DILI? An Analysis of Unlikely Cases from the U.S. Drug Induced Liver Injury Network (DILIN)

Introduction: The diagnosis of drug induced liver injury (DILI) is difficult as it is largely a clinical diagnosis of exclusion. To aid in diagnostic decision making, we reviewed cases enrolled in DILIN with an initial diagnosis of DILI that were ultimately adjudicated as unlikely with alternative etiologies accounting for the abnormal liver tests.

Methods: The DILIN is an ongoing NIH observational trial in which hepatologists enrolled patients from 2004 to the present with a high suspicion of DILI. Cases were adjudicated by a panel of experts through a structured process and scored from 1 (definite DILI) to 5 (unlikely DILI). Cases that were scored at least probable DILI (1-3) were compared to unlikely DILI (5). Unlikely cases were further reviewed for salient features and trends over time.

Results: From 9/04 to 12/21, 1916 cases were adjudicated; 134 (7%) were unlikely DILI. There were no demographic features to distinguish at least probable cases from unlikely cases. Unlikely cases more often had renal disease (18% vs 9%, p=0.005), HIV (7% vs 2% p< 0.001), hepatitis C (HCV) (12% vs 3% p< 0.001), and hepatitis B (5% vs 1 % p< 0.001). Unlikely DILI vs. true DILI was higher for brief latency between drug use and liver injury (< 1 week 9% vs 5%) or very long latency ( >24 weeks 28% vs 16%) p=0.002 overall. The most common alternative diagnoses for unlikely cases were autoimmune hepatitis (AIH) (20%) and HCV (20%) (Table 1). Among white patients, carriage frequency of two copies of HLA-DQA1*03:01 was greater among those with AIH (13%) compared to DILI (3%) and population controls (1%). Patients with unlikely DILI had greater all-cause (16% vs 7%, p< 0.001) and liver related mortality (10% vs 3%, p< 0.001). Unlikely DILI cases died within six months at a higher rate (14% vs 6%, p=0.004). Transplant rates, hospitalization, and duration of illness were similar.

Discussion: DILI is difficult to diagnose, even among experienced hepatologists. Demographic factors are not helpful in the initial diagnosis. Very short or very long latency between suspect drug and initial liver injury decreases likelihood of true DILI. HCV PCR testing is critical in presumed DILI. Genetic testing in white patients with AIH vs. DILI may be useful. Longitudinal follow up of patients with DILI is essential to refine the diagnosis, treat an alternative disease, and potentially absolve a medication presumed to have caused DILI.