C0536 - Characteristics of Liver Injury Due to Azole Antifungal Drugs in the United States: Results From the Drug Induced Liver Injury Network (DILIN) Prospective Study

Monday, October 24, 2022

3:00 PM – 5:00 PM ET

Location: Crown Ballroom

Has Audio

Presenting Author(s)

Jiayi Ma, MD

Indiana University School of Medicine
Indianapolis, IN

Jiayi Ma, MD¹, Jawad Ahmad, MD², Victor Navarro, MD³, Jiezhun Gu, PhD⁴, Marwan Ghabril, MD¹
¹Indiana University School of Medicine, Indianapolis, IN; ²Icahn School of Medicine at Mount Sinai, New York, NY; ³Einstein Healthcare Network, Jefferson Health System, Philadelphia, PA; ⁴Duke University, Durham, NC

Introduction: The azole antifungal (AA) class of drugs is a rare cause of drug induced liver injury (DILI). AA-DILI most often presents with transient elevations in liver enzymes but has not been well studied or compared to DILI from other agents. The aim of this study is to describe the clinical features and outcomes of patients with AA-DILI in a large prospective registry.

Methods: The DILIN Prospective Study enrolls participants with suspected DILI and determines causality and severity by committee consensus. Between 9/2004 and 6/2021, a total of 1726 participants with high confidence (causality score: definite, highly likely, probable) DILI were enrolled. The clinical course and outcomes of 15 consecutive patients with high confidence AA-DILI were reviewed and compared with DILI due to other agents.

Results: The implicated agents among the 15 cases of AA-DILI were voriconazole (6), fluconazole (5), and ketoconazole (4). The median age was 47 with 53% females, 71% White, and 21% African American. The median (IQR) latency was 37 days (14,93) and the median ALT at DILI onset was 320 (200,906), alkaline phosphatase 176 (146,361), and total bilirubin 1.2 (.7,3). The most common symptoms were nausea 47%, rash 40%, and abdominal pain 33%. The pattern of liver injury included 47% hepatocellular, 40% mixed, and 13% cholestatic. 4 cases met Hy’s Law. 1 patient was treated with steroids while 2 died from non-liver related causes. No patients received liver transplantation or developed chronic DILI.

Compared to liver injury due to all other agents (n=1711), there were no significant differences in age, sex, or race. Comorbidities were similar except for malignancy which was present in 33% of AA-DILI compared to 11% of other DILI cases. While there was no difference in latency, AA-DILI cases had significantly shorter time from earliest sign to drug stop, likely due to patients starting azoles inpatient or having close follow-up. Clinically, AA-DILI cases had significantly lower total bilirubin at DILI onset and was less likely to present with jaundice. The pattern of liver injury and number of patients treated with steroids did not differ significantly. Rates of all death and liver transplant did not differ. During follow up, AA-DILI had significantly lower peak total bilirubin and significantly shorter time to recovery of ALT and AST compared to other agents.

Discussion: AA-DILI is characterized by hepatocellular or mixed injury without jaundice. The course of AA-DILI appears to be relatively benign.

Characteristic	Azole Cases n=15	Other Agents n=1711	p value
Age (years, median, IQR)	46.8 (34.3, 66.3)	51.8 (37.2, 62.7)	0.972
Female	53%	58%	0.710
Caucasian	71%	78%	0.558
Days from primary drug start to DILI onset/latency (median (IQR))	37 (14, 93)	46 (22, 104)	0.256
Days from earliest sign/symptom to primary drug stop (median (IQR))	1 (1,1)	6 (1, 16)	0.029
Jaundice at DILI onset	20%	63%	< 0.001
Treated with prednisone or corticosteroids	7%	23%	0.214
Total bilirubin at DILI onset (mg/dl, median, IQR)	1.2 (0.7, 3)	4.6 (1.3, 9.1)	0.013
Pattern of liver injury (Cholestatic/Mixed/Hepatocellular)	13%/40%/47%	23%/22%/55%	0.288
Peak total bilirubin (from DILI onset to 6 months) (mg/dl) (median ((IQR))	1.9 (0.9, 4.5)	9.1 (2.3, 19.4)	0.007
ALT (days from peak to below upper limit of normal) (IU/mL)	34	64	0.009
AST (days from peak to below upper limit of normal) (IU/mL)	28	57	0.005
All death	13%	6.4%	0.254
All liver transplant	0%	3.5%	>0.999
Chronic DILI	0%	16.9%	0.236

Table: Selected characteristics of patients with DILI due to azoles versus other agents

Disclosures:

Jiayi Ma indicated no relevant financial relationships.

Jawad Ahmad indicated no relevant financial relationships.

Victor Navarro indicated no relevant financial relationships.

Jiezhun Gu indicated no relevant financial relationships.

Marwan Ghabril indicated no relevant financial relationships.

Jiayi Ma, MD¹, Jawad Ahmad, MD², Victor Navarro, MD³, Jiezhun Gu, PhD⁴, Marwan Ghabril, MD¹. C0536 - Characteristics of Liver Injury Due to Azole Antifungal Drugs in the United States: Results From the Drug Induced Liver Injury Network (DILIN) Prospective Study, ACG 2022 Annual Scientific Meeting Abstracts. Charlotte, NC: American College of Gastroenterology.