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)

Monday, October 24, 2022

10:00 AM – 12:00 PM ET

Location: Crown Ballroom

Presenting Author(s)

AB

Alfred S. Barritt, MD, MSCR

University of North Carolina
Chapel Hill, North Carolina

Alfred S. Barritt, MD, MSCR¹, Huiman Barnhart, PhD², Sean Rudnick, MD³, Paola Nicoletti, MD, PhD⁴, Herbert Bonkovsky, MD³
¹University of North Carolina, Chapel Hill, NC; ²Duke University, Durham, NC; ³Wake Forest University School of Medicine, Winston-Salem, NC; ⁴Mount Sinai, New York, NY

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.

Diagnosis	N	%	Comments
Autoimmune hepatitis	27	20.1	The most common incorrectly implicated class of medications were antibiotics (9/27) followed by HDS products (8/27). Nearly all had a liver biopsy, but findings were neither diagnostic for DILI nor classic for AIH. Other common themes included 1) prevalent systemic immune mediated disease (systemic lupus erythematous, hypothyroidism, inflammatory bowel disease, etc.) in 8/27 cases; 2) negative or relatively low antinuclear antibody titers (< 1:80) which increased on follow up; 3) a response to steroids in 14/27 with six of these having a flare in enzymes after immunosuppression titration or withdrawal.
Hepatitis C	27	20.1	Of the 24 that were acute cases, 17 were enrolled prior to 2011 and none since 2017. Most of these cases had negative HCV antibodies and were discovered to have a positive HCV viral load later in their clinical course. Three patients had prevalent detectable HCV virus which later cleared spontaneously on follow up.
Gallstones/BiliaryDisease	18	13.4	Eight cases with biliary tract malignancy. Three cases with primary sclerosing cholangitis. Normal imaging in some patients who acutely passed a stone. No differences in the presence of stones (3.3% vs. 6.7% p=0.32), or ductal dilation (3.3% vs. 2.5% p=0.89) between unlikely DILI and probable and higher DILI cases.
Hepatitis E	11	8.2	Diagnosis often delayed as test is a send-out in most centers.
Sepsis	7	5.2	Frequently in Intensive Care Unit on multiple drugs and hypotensive.
Other ( >20 diverse etiologies)	44	32.8	Etiologies included alcohol, myopathy, Epstein Barr virus, cytomegalovirus, nonalcoholic steatohepatitis, metastatic cancer, and granulomatous liver disease.

Table: Table 1: Alternative Diagnoses in 134 Unlikely DILI cases

Disclosures:

Alfred Barritt: Pfizer – DSMB. Target RWE – Advisor or Review Panel Member.

Huiman Barnhart indicated no relevant financial relationships.

Sean Rudnick: Alexion Pharma – Speakers Bureau. Alnylam Pharma – Advisory Committee/Board Member, Speakers Bureau.

Paola Nicoletti: Sema 4 – Employee.

Herbert Bonkovsky: Alnylam Pharma – Consultant, Grant/Research Support. Disc Medicine – Advisory Committee/Board Member, Consultant, Grant/Research Support. Genkyotex SA – Grant/Research Support. Gilead Sciences – Grant/Research Support. Intercept Pharma – Grant/Research Support. Mitsubishi-Tanabe, NA – Advisory Committee/Board Member, Grant/Research Support. Recordati Rare Chemicals – Advisory Committee/Board Member.

Alfred S. Barritt, MD, MSCR¹, Huiman Barnhart, PhD², Sean Rudnick, MD³, Paola Nicoletti, MD, PhD⁴, Herbert Bonkovsky, MD³. 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), ACG 2022 Annual Scientific Meeting Abstracts. Charlotte, NC: American College of Gastroenterology.