Delayed-onset drug-induced liver injury in a cystic fibrosis patient on long-term elexacaftor/ivacaftor/tezacaftor therapy: A case report and literature review

Abstract

Background:

Elexacaftor/tezacaftor/ivacaftor (ETI) is a cystic fibrosis transmembrane conductance regulator (CFTR) modulator widely used in patients with cystic fibrosis (CF), typically associated with mild, early onset liver enzyme elevations.

Methods:

We report a case of a 35-year-old man with CF who developed a marked hepatic transaminitis, with an alanine aminotransferase peaking at >1,000 IU/L after 30 months of stable ETI therapy. The patient was asymptomatic, and an extensive workup excluded viral, autoimmune, and metabolic liver disease. Various imaging modalities excluded other secondary causes, such as portal venous or arterial thromboses.

Results:

Using the Roussel Uclaf Causality Assessment Method (RUCAM), a score of 8 indicated a probable link to drug-induced liver injury (DILI), which was further supported by World Health Organization–Uppsala Monitoring Centre (WHO–UMC) causality assessment.

Conclusions:

This case highlights the potential for delayed-onset hepatotoxicity with ETI and emphasizes the need for continued liver monitoring during long-term therapy.

Lay Summary

Trikafta (elexacaftor/tezacaftor/ivacaftor) is a breakthrough treatment for people with cystic fibrosis (CF), significantly improving their lung function and overall health. While it is generally safe, mild liver enzyme changes can happen early in treatment. In this report, we describe a rare case of severe liver injury that appeared after 30 months of stable use in a patient who had no symptoms. Other causes were ruled out, and liver tests improved quickly after stopping the medication. This case shows that serious liver problems can develop even after long-term use of Trikafta. It highlights the importance of regular liver monitoring in patients on this therapy and the need for careful decision-making if such side effects occur. As Trikafta remains an essential medication for many with CF, doctors and patients must work closely to balance its benefits with any risks.

Introduction

Cystic fibrosis (CF) is a chronic, multisystem genetic disorder, primarily affecting the lungs and digestive system (1). The development of CF transmembrane conductance regulator (CFTR) modulator therapies has revolutionized the management of CF, with Trikafta or ETI (elexacaftor, tezacaftor, and ivacaftor) emerging as the most effective and widely used treatment (2). ETI improves lung function, nutritional status, and overall quality of life in patients with at least one F508del mutation (2). According to established LiverTox data, elevated hepatic transaminases occur in up to 25% of patients taking ivacaftor-based regimens (3). These elevations typically occur early in therapy and often resolve spontaneously or with dose adjustment. However, delayed-onset liver injury after long-term therapy is not well characterized in the literature. We report a case of severe drug-induced liver injury (DILI) occurring nearly 30 months after initiation of ETI therapy in a patient with CF, detected during routine outpatient follow-up.

Case Presentation

A 35-year-old man with CF (compound heterozygous for ΔF508 mutation) presented to the outpatient respiratory clinic for routine follow-up. He was clinically stable and asymptomatic. Relevant past medical history included asthma, pancreatic insufficiency, and gastroesophageal reflux disease. His home medications included Trikafta/ETI, esomeprazole, and Zenhale (mometasone/formoterol). He was a non-smoker, reported occasional marijuana use, and consumed minimal alcohol (1–2 units of ethanol per month). There was no family history of liver disease. Routine bloodwork revealed markedly elevated liver enzymes with transaminitis pattern, in comparison with normal values 3 months prior. The patient denied any recent medication changes, alcohol binges, over-the-counter supplements, systemic symptoms, or infections. The patient's liver enzymes at this presentation were noted as follows: alanine aminotransferase (ALT) 1,563 U/L, aspartate aminotransferase (AST) 846 U/L, alkaline phosphatase (ALP) 117 U/L, and gamma-glutamyl transferase (GGT) 166 U/L. Regarding synthetic function, the initial total bilirubin was 76 µmol/L, albumin 43 g/L, and international normalized ratio (INR) 1.3. An exhaustive list of secondary causes to elevated hepatic transaminases was conducted, including investigations for both common and rare causes of liver injury. (Table 1). However, other potential causes of hepatitis—such as hepatitis E virus, SARS-CoV-2, herpes simplex virus (HSV), varicella zoster virus (VZV), tissue transglutaminase immunoglobulin A (IgA), and alpha-1 antitrypsin deficiency—were not evaluated in this case, which may be relevant given the patient's young age.

Table 1:

Hepatology workup

Parameter	Result	Reference/notes
ALT	1,563 IU/L	6–45 µkat/L
AST	846 U/L	6–35 U/L
ALP	113 U/L	53–128 U/L
GGT	166 U/L	7–50 U/L
LDH	483 U/L	112–210 U/L
INR	1.3	0.88–1.12
Albumin	43 g/L	38–52 g/L
Total bilirubin (BRT)	76 µmol/L	<20 µmol/L
Direct bilirubin (DBR)	30 µmol/L	1.6–5.1 µmol/L
IgG	10.2 g/L	7–15 g/L
IgA	2.5 g/L	0.80–4 g/L
IgM	0.8 g/L	0.50–3 g/L
ANA, AMA, ASMA, LKM	Negative	Negative/Positive
Ceruloplasmin	0.18 g/L	0.16–0.45 g/L
Transferrin saturation	31.6%	20%–50%
Ferritin	338 µg/L	23.9–366 µg/L
Hepatitis A IgM/IgG	Negative	Negative/Positive
HBsAg/HBcAb	Negative	Negative/Positive
HBsAb	1,741 IU/L	Immune
Hepatitis C antibody	Negative	Negative/Positive
CMV IgG	Negative	Negative/Positive
CMV IgM	Negative	Negative/Positive
EBV IgG	Negative	Negative/Positive
EBV IgM	Negative	Negative/Positive
HIV	Negative	Negative/Positive
Respiratory virus multiplex PCR	Negative	Negative/Positive

ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; ALP = Alkaline phosphatase; GGT = Gamma-glutamyl transferase; LDH = Lactate dehydrogenase; INR = International normalized ratio; IgG = Immunoglobulin G; IgA = Immunoglobulin A; IgM = Immunoglobulin M; ANA = Anti-nuclear antibody; AMA = Antimitochondrial antibody; ASMA = Anti-smooth muscle antibody; LKM = Liver-kidney microsomal antibody; HBsAg = Hepatitis B surface antigen; HBcAb = Hepatitis B core antibody; HBsAb = Hepatitis B surface antibody; CMV = Cytomegalovirus; EBV = Epstein-Barr virus; PCR = Polymerase chain reaction

Following the discontinuation of ETI, liver enzymes began to downtrend rapidly. Two days after cessation, ALT had decreased to 710 U/L and AST to 159 U/L. By day 3, ALT was 543 U/L and AST had further declined to 73 U/L, with normalization of ALP and GGT levels (Figure 1). The INR normalized to 0.9, total bilirubin decreased to 25 µmol/L, and albumin was 38 g/L. The patient remained asymptomatic throughout hospitalization. An abdominal ultrasound revealed normal hepatic and portal vasculature with no evidence of thrombosis. On day 4, the patient was discharged with a plan for serial liver function monitoring until full normalization and for follow-up with both hepatology and respirology services. No changes to any additional medication were made at time of discharge.

Figure 1: Liver enzyme trends following ETI discontinuation.

ETI = Elexacaftor/tezacaftor/ivacaftor; ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; ALP = Alkaline phosphatase; GGT = Gamma-glutamyl transferase

Discussion

Trikafta or ETI has significantly improved the clinical management and prognosis of patients with CF who carry at least one F508del mutation (2). While generally safe and well tolerated, Trikafta is known to cause mild elevations in hepatic transaminases in a subset of patients, typically within the early phases of treatment (4,5). However, delayed-onset liver injury after long-term use remains uncommon and under-reported. In this case, the patient developed a marked hepatocellular injury nearly 30 months into stable Trikafta therapy, with no recent medication changes, infections, or other identifiable triggers.

The Roussel Uclaf Causality Assessment Method (RUCAM), which incorporates clinical, biochemical, serological, and radiological criteria, was used to quantify the likelihood of drug-induced liver injury (6). The calculated RUCAM score was 8, placing the event in the “probable” category. This was supported by the timeline, exclusion of other causes, and known hepatotoxicity of ETI. Additionally, the World Health Organization–Uppsala Monitoring Centre (WHO–UMC) (7) causality assessment system, which evaluates the overall clinical and temporal context of the adverse event, also indicated a “probable” relationship between ETI and the acute liver injury observed in this patient. Together, these assessments strengthen the conclusion that this was a case of delayed-onset drug-induced liver injury attributable to ETI. This case supports monitoring liver enzymes during long-term CFTR modulator therapy.

A previously published case report (8) described the development of mild transaminitis in a patient receiving ETI therapy approximately 5 months after initiation. In contrast, our case highlights the occurrence of significant transaminitis approximately 30 months after the initiation of ETI. While both patients remained asymptomatic, there are notable differences in the biochemical patterns. In the previously reported case, liver enzyme elevations were mild at onset and peaked following discontinuation of ETI, reaching a maximum ALT of 2,707 U/L. In contrast, our patient presented with markedly elevated transaminases—ALT exceeding 1,500 U/L and AST over 800 U/L—prior to ETI cessation, followed by a rapid decline of approximately 50% within 3 days of discontinuation.

This comparison underscores the unpredictable nature of ETI-associated liver injury. The clinical presentation can vary from early onset, mild transaminitis to delayed, severe hepatocellular injury. Furthermore, the biochemical trajectory post-discontinuation may differ, with some cases showing continued elevation and others, such as ours, demonstrating rapid improvement. These findings emphasize the importance of continued liver enzyme monitoring, even after long-term stable use of ETI, particularly in asymptomatic patients. Further, they emphasize the importance of viewing drug-induced liver injury as a spectrum of phenotypes of disease, rather than a consistent uniform pattern, to ensure early and appropriate identification of this pathology (9).

Another key takeaway is the value of a multidisciplinary approach. In our case, joint discussions between hepatology and respirology teams explored several potential management strategies, though no standardized protocol currently exists. When medications are non-essential, decision-making regarding holding to assess for DILI is reasonable; however, our case highlights an example where long-term discontinuation of therapy can have significant adverse effects on patient quality of life. Options considered included re-initiating ETI after complete normalization of liver enzymes with close biochemical monitoring; modifying the dosing schedule; or reintroducing individual components of the ETI regimen sequentially to identify the offending agent. Ultimately, decisions must be individualized, as ETI remains a cornerstone therapy in CF management, and balancing its benefits against potential hepatotoxicity is challenging. Nevertheless, multidisciplinary collaboration and vigilant follow-up remain critical to ensuring patient safety.

Funding Statement

N/A

Contributions:

Conceptualization, AF Alenzi; Writing – Original Draft, AF Alenzi, Y Sachar, A Sandhu; Writing – Review & Editing, AF Alenzi, Y Sachar, A Sandhu; Supervision, AF Alenzi, A Sandhu.

Ethics Approval:

N/A

Informed Consent:

Written informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the editor-in-chief of this journal.

Registry and the Registration No. of the Study/Trial:

N/A

Data Accessibility:

N/A

Funding:

N/A

Disclosures:

The authors have no conflicts of interest to disclose.

Peer Review:

This article has been peer reviewed.

Animal Studies:

N/A