P1933 - Drug-Induced Liver Injury From Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulators

Michelle Le, DO, Patrick Twohig, MD, MPH, Tyson Holm, MD, Marco A. Olivera-Martinez, MD, Thoetchai Peeraphatdit, MD
University of Nebraska Medical Center, Omaha, NE

Introduction: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators were approved by the FDA in 2012 for treatment of cystic fibrosis (CF)1. These medications have demonstrated improved lung function, quality of life and growth in CF patients2. In a randomized double-blind study, a minority of patients had elevations in aminotransferase levels (above 3 times the upper limit of normal), but this did not prohibit continued treatment3. There have been very limited data regarding drug-induced liver injury (DILI) attributed to CFTR modulators. We present a case series of CF patients who develop abnormal liver function tests (LFTs) while being treated with CFTR modulators. Our aim is to describe the timing, pattern of injury and outcome of these patients to increase clinician's awareness of the risk of DILI with this class of medications.

Case Description/Methods: Retrospective cohort study of patients admitted to the University of Nebraska Medical Center with ICD-9 code for CF and that were prescribed one of elexacaftor/tezacaftor/ivacaftor, tezacaftor/invacaftor, lumacaftor/invacaftor or ivacaftor. Patients were further screened for the presence of co-factors, and if a liver biopsy was performed. All cases were assessed using the adverse drug reaction probability scale4.

Four patients were included in this case series. Table 1 summarizes key information related to these cases.

Discussion: DILI is an under-diagnosed cause of abnormal LFTs in patients with CF taking CFTR modulators, where the incident can be up to 25%1. The mechanism of action is unknown, but it is thought to be due to toxic metabolites from drug metabolism through the cytochrome p450 pathway1. DILI can occur anytime after starting this class of medications and can be difficult to diagnose given a need to exclude other causes of chronic liver disease including CF liver disease (CFLD)5. Treatment includes dose reduction and drug holiday. Re-introduction of these medications can be safe in most cases1. CFTR modulators have become a cornerstone of managing CF². Clinicians should be aware of the risk of DILI from CFTR modulators along with the unique diagnostic considerations and management of liver injury in CF patients.

Age/Sex	Medication	Duration until DILI	Symptoms	AST	ALT	Alkaline phosphatase	Total bilirubin	Biopsy findings	Naranjo score4	Treatment	Outcome
26/Male	TEZ/IVA	5 months	None	99	220	220	1.0	N/a	4	Drug holiday for 1 year	AST/ALT normalized. Persistently elevated alkaline phosphatase; tolerating switch to ELX/TEZ/IVA
29/Male	TEZ/IVA	18 months	Jaundice	104	406	198	13.2	Cholestasis, bile duct proliferation	5	Indefinite drug holiday	AST/ALT normalized. Persistently elevated alkaline phosphatase. No further CFTR modulator
23/Male	ELX/TEZ/IVA	1 month	Jaundice	15	18	229	24.3	Diffuse cholestasis; Trichrome stain stage 2 fibrosis	4	Drug holiday; cholecystectomy	Improvement in total bilirubin, alkaline phosphatase and AST/ALT; CFTR currently on hold
23/Male	ELX/TEZ/IVA	7 months	None	27	48	92	2.3	N/a	6	Continued treatment	Unknown

Table: Table 1: Four cases at our institution of suspected DILI due to CFTR modulators


Disclosures:
Michelle Le indicated no relevant financial relationships.
Patrick Twohig indicated no relevant financial relationships.
Tyson Holm indicated no relevant financial relationships.
Marco Olivera-Martinez indicated no relevant financial relationships.
Thoetchai Peeraphatdit indicated no relevant financial relationships.


Michelle Le, DO, Patrick Twohig, MD, MPH, Tyson Holm, MD, Marco A. Olivera-Martinez, MD, Thoetchai Peeraphatdit, MD. P1933 - Drug-Induced Liver Injury From Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulators, ACG 2021 Annual Scientific Meeting Abstracts. Las Vegas, Nevada: American College of Gastroenterology.