Decoding liver injury in cystic fibrosis: How to tell drug-induced liver injury from cystic fibrosis liver disease

Abstract

BACKGROUND

Cystic fibrosis liver disease (CFLD) is a significant comorbidity in individuals with cystic fibrosis (CF), marked by biliary fibrosis and progressive cholestasis. The advent of CF transmembrane conductance regulator (CFTR) modulators has revolutionized care for lung disease, but their impact on liver-specific disease and outcomes remain unclear. Additionally, the risk of comorbid cholestatic liver injury from medications and progression of CFLD complicates the diagnostic landscape.

AIM

To provide a clinical framework for differentiating CFLD and drug induced liver injury (DILI), including from CFTR modulators.

METHODS

A comprehensive literature review was conducted using PubMed, EMBASE, and Cochrane Library databases through March 2025. Studies evaluating pathogenesis, clinical features, diagnostic strategies, and management of CFLD and CFTR modulator-related DILI were included. Data were synthesized to highlight distinguishing clinical and histopathologic features and to guide evidence-based management.

RESULTS

CFLD typically presents with insidious progression, portal hypertension, and biliary cirrhosis, whereas CFTR modulator-induced DILI often manifests acutely with jaundice, elevated liver enzymes, and a temporal association with therapy initiation. Key differentiators include biochemical patterns, imaging findings, response to drug withdrawal, and, when necessary, liver histology. Management strategies range from dose modification and supportive care in DILI to ursodeoxycholic acid, nutritional optimization, and portal hypertension management in CFLD.

CONCLUSION

Early recognition and differentiation between DILI and underlying CFLD are essential for optimizing therapy, preserving liver function, and guiding long-term management in patients with CF. As CFTR modulators become the cornerstone of CF management, vigilance for hepatotoxicity is critical. A multidisciplinary approach involving hepatology and CF care teams is recommended.

Key Words: Cystic fibrosis; Liver diseases; Cystic fibrosis transmembrane conductance regulator; Drug-induced liver injury; Cholestasis

Core Tip: Cystic fibrosis (CF) liver disease is a major comorbidity in CF, complicated by progressive cholestasis and overlapping risk of drug-induced liver injury, including from CF transmembrane conductance regulator modulators. This study synthesizes literature on pathogenesis, clinical features, diagnostics, and management to aid in distinguishing advanced CF liver disease progression from drug induced liver injury. Key differentiators include biochemical profiles, imaging, treatment response, and histology. Early recognition and a multidisciplinary approach are essential to optimize therapy, preserve liver function, and balance the benefits and risks of CF transmembrane conductance regulator modulators.

INTRODUCTION

Cystic fibrosis (CF) is a multisystem genetic disorder characterized by dysfunction of the CF transmembrane conductance regulator (CFTR) protein. While pulmonary complications dominate the clinical course, liver involvement, termed as CF hepatobiliary involvement (CFHBI) and advanced CF liver disease (aCFLD) are leading cause of non-pulmonary morbidity and mortality in CF patients[1]. CFHBI is the currently preferred term for hepatobiliary involvement in CF. This can range from liver enzyme abnormalities with or without imaging changes to portal hypertensions with or without cirrhosis[2]. While the pathophysiology of CFHBI is unclear, two theories predominate: Dysfunction of the CFTR protein resulting in defective chloride transport across epithelial cells, leading to cholestasis in the liver. This leads to inflammation, chronic infections, and organ damage[3]. Alternatively defective CFTR leads to alterations in intestinal permeability combined with an altered microbiome leads to hepatic inflammation due to gut liver axis abnormalities with the same end point[4].

The introduction of CFTR modulators has transformed CF care. These drugs include ivacaftor, lumacaftor/ivacaftor, tezacaftor/ivacaftor, elexacaftor/tezacaftor/ivacaftor (ETI) and the most recent addition vanzacaftor/tezacaftor/deuterated ivacaftor (VTD). Ivacaftor and deuterated ivacafotor, are part of the potentiator class that help open the CFTR channel and increase the flux of chloride and bicarbonate across the apical cell surface. Modulators such as lumacaftor, elexacaftor, tezacaftor and vanzacaftor are part of the corrector class that help normalize the folding of the defective CFTR protein and its movement to the cell surface[5,6].

Though these drugs have enhanced treatment options, they are known to cause elevations in serum hepatic enzyme levels compared to placebo. Hepatotoxicity associated with these agents has raised new challenges in distinguishing drug induced liver injury (DILI) from underlying CFHBI, when either hepatocellular or cholestatic liver test abnormalities emerge[3]. This systematic review aims to evaluate current evidence on pathogenesis, clinical features, diagnostics, and management to aid in distinguishing CF liver disease (CFLD) progression from DILI from CFTR modulators.

MATERIALS AND METHODS

A comprehensive literature search was conducted to identify relevant studies evaluating CFHBI (often referred to as CFLD in older literature) and DILI from CFTR modulators. The search included articles from 2015 up to August 2025 across PubMed, EMBASE, and the Cochrane Library. The search strategy combined Medical Subject Headings and keywords related to CFLD, DILI, and CFTR modulators. Relevant key words such as “cystic fibrosis liver disease” or “CFTR modulators” or “drug induced liver injury” were used to find relevant sources. Additionally, the reference lists of included studies and relevant reviews were manually screened to identify any additional eligible studies. Studies were included based on the following criteria: Adult patients (≥ 18 years) with CFLD and/or CFTR modulator uses. We excluded literature related to non-human subjects, pediatric populations and articles not published in English. The authors independently screened titles and abstracts for eligibility, and articles were then retrieved for further evaluation of meeting eligibility criteria. Discrepancies were resolved through discussion by the authors to reach consensus (Figure 1).

Figure 1  PRISMA flow diagram on selection of studies.

RESULTS

A total of 59 articles were reviewed by the authors for inclusion in this systematic review. Once all the data from our literature search was collected, it was synthesized and organized into the following sections of the manuscript: Pathophysiology of liver injury in CF, DILI from CFTR modulators, differentiating CFLD and DILI in CF patients with abnormal liver function tests (LFTs), biochemical and imaging workup, diagnostic criteria and algorithms, management strategies, future directions and research needs. Furthermore, given the nature of this systematic review, the results and discussion sections were grouped together as both raw data from sources and our interpretation or summary of those results are outlined under each individual section of this paper.

DISCUSSION

Pathophysiology of liver injury in CF patients

CFLD: aCFLD may arise from inspissation of biliary secretions, ductal plugging, and periductal inflammation, leading to non-cirrhotic portal hypertension and ultimately multilobular cirrhosis. There is also a form of aCFLD that is associated with portal vasculopathy nodular regenerative hyperplasia leading to noncirrhotic portal hypertension whose pathophysiology is unclear. It is thought to potentially involve a combination of ductal epithelial injury, immune dysregulation, and gut-liver axis perturbations. At a cellular level, CFTR dysfunction impairs bile acid secretion due to defective chloride and bicarbonate secretion[7]. This leads to abnormal bile composition that is more acidic and viscous[8]. The changes to the bile composition create a favorable environment for cholestasis, which can cause periportal fibrosis from cytotoxic damage via inflammatory cells and cytokines[9]. Over time, stellate cell activation and chronic inflammation drive the transition from focal to multilobular cirrhosis, reshaping the hepatic architecture and impairing blood flow[9]. Additionally, CFTR dysfunction alters the gut microbiome, leading to inflammation and an increase in pathogenic bacteria, which, in combination with abnormalities with the ubiquitous alterations in intestinal permeability present in CF, enhances the presence of bacteria in portal circulation.

More recently, a phenotypic approach to CFHBI has been advocated[2]. This system uses liver enzyme abnormalities, imaging abnormalities, liver stiffness, presence or absence of portal hypertension with or without portal hypertension, and liver biopsy findings to classify hepatobiliary involvement. Pertinent to DILI, the prevalence of abnormal liver enzymes in CF is actually quite high. In a large study in children 95% of children had at least one abnormal liver enzyme by 18 years of age and 30% had persistently abnormal liver enzymes, typically < 3 times the upper limit of normal (ULN)[10]. The frequency of abnormal liver enzymes in persons with CF in clinical trials who were in the placebo arms of clinical drug trials demonstrated a prevalence of 2-4/100 person months[11]. This means that any evaluation for DILI is complicated by a relatively frequent rate of abnormal liver enzymes in CF that may be uncovered with the more frequent monitoring for DILI.

aCFLD typically manifests during childhood or adolescence but may be subclinical for years. Early signs of disease include mild transaminase elevations or hepatosplenomegaly, while advanced disease features cirrhosis and other sequelae of cirrhosis, like portal hypertension or variceal development[12]. Liver disease is an independent risk factor for mortality and represents one of the top 5 leading cause of death in CF, contributing to an overall 10-year cumulative mortality for cirrhotic CFLD in the CFF registry was 40%[13]. The development of cirrhosis, which occurs in about 7 percent of patients, is thought to be influenced by non-CFTR genetic variation and environmental factors[7]. There is conflicting evidence on the correlation of CFLD and sex, with some reports stating that portal hypertension specifically affects more males than females[7]. Contrarily, however, other reports suggest that there is no difference between sexes in the development of liver disease[14]. Genetic modifiers like SERPINA1 variants, particularly the Z allele, have been linked to a higher risk of liver damage in patients with CF. Carriers of these variants may show earlier or more aggressive progression of CFLD, highlighting the role of genetic modifiers in disease severity[15]. Proposed physiologic mechanisms of injury are outlined in Figure 2.

Figure 2 Mechanism of liver injury secondary to cystic fibrosis transmembrane conductance regulator modulator exposure. CFTR: Cystic fibrosis transmembrane conductance regulator; DILI: Drug induced liver injury; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; LFT: Liver function test.

DILI from CFTR modulators: CFTR modulators have transformed CF care in recent years. However, concerns have been raised in the literature about their potential for DILI[16,17]. Ivacaftor, tezacaftor, and elexacaftor are primarily metabolized in the liver through the cytochrome P450 system, mainly cytochrome P450 3A[18]. Liver injury may occur from toxic or immunogenic metabolites produced during this process, and other drugs like ketoconazole, which inhibit the cytochrome P450 system, can increase toxic effects[19]. The clinical spectrum of liver injury is variable and includes hepatocellular, cholestatic, and mixed patterns. Cases reported in literature range from asymptomatic transaminase elevations to overt hepatitis, cholestatic jaundice and acute liver failure leading to transplant[16,17,20]. The pathogenesis of DILI in this setting may involve mitochondrial toxicity, idiosyncratic immune responses, or impaired bile acid homeostasis. The risk of DILI from CFTR modulators is higher in patients with pre-existing liver disease[20], male sex, and F508del homozygosity. Younger age does not clearly increase this risk[21]. Dose and duration are linked to liver enzyme rises, with most events occurring within the first 3-6 months; therefore, close monitoring is recommended, especially early in therapy.

Differentiating DILI from CFLD in CF patients - clinical presentation and diagnostic workup

Clinical features and biomarkers: CFHBI spans a wide spectrum, from mild biochemical abnormalities and steatosis to hepatosplenomegaly, multilobular cirrhosis, and complications of portal hypertension including ascites and variceal bleeding[21]. Hepatomegaly is the most common physical examination finding in aCFLD, with splenomegaly also observed; however, the sensitivity and specificity of physical examination for detecting aCFLD are limited[22]. Many patients remain asymptomatic until advanced disease becomes clinically detectable, at which point features such as splenomegaly, ascites, and peripheral stigmata of chronic liver disease may appear[21].

Abnormalities in liver biochemistry are common in CFHBI, 53%-93% of patients demonstrating elevated aspartate aminotransferase (AST) or alanine aminotransferase levels in early adulthood and one-third showing elevated gamma-glutamyl transpeptidase (GGT) levels[10,23]. However, LFTs alone lack specificity for diagnosing or predicting a risk for development of aCFLD, as the values may be intermittently normal, even in advanced disease[21]. aCFLD usually manifests as a cholestatic or mixed biochemical pattern with elevated alkaline phosphatase (ALP) and GGT levels, whereas DILI is more likely to cause abrupt hepatocellular or mixed injury[24,25]. GGT is the most sensitive indicator, with high mean GGT levels > 35 U/L often associated with presence or risk for aCFLD with odds ratio of 39[26,27]. CFTR modulator DILI often presents acutely within weeks to months of therapy initiation, with disproportionate transaminase elevations or a mixed pattern[28]. Across clinical trials and observational studies, aminotransaminase elevations exceeding three times the ULN are observed in approximately 5%-11% of patients, with a smaller subset experiencing increases greater than five times the ULN[29-32]. Less marked increases are common; in one cohort, 75% had increases of at least 25% above baseline[32].

Biochemical and imaging workup: In CFHBI, ultrasonography may reveal heterogeneous echogenicity, nodular contour, or splenomegaly, and elastography demonstrates elevated liver stiffness (> 5.9 kPa for hepatobiliary involvement; > 8-9 kPa for advanced fibrosis)[33]. Magnetic resonance imaging with elastography offers high diagnostic accuracy and can demonstrate the patchy focal fibrosis characteristic of CFLD[34]. Signs of portal hypertension, such as varices and splenomegaly, further support the diagnosis of aCFLD. In contrast, imaging in DILI is nonspecific. Hepatomegaly, steatosis, or biliary dilation may be seen, but increased stiffness on elastography typically reflects transient inflammation and edema rather than established fibrosis[35].

Histopathology: Liver biopsy, although limited by sampling errors in CFHBI due to its patchy distribution, remains valuable in indeterminate cases[36]. A minority classified as possible or probable, emphasizing the utility of Roussel Uclaf Causality Assessment Method (RUCAM) in guiding management and minimizing unwarranted treatment discontinuation[37]. In adults, ALP may decline when elevated at baseline, GGT generally remains stable, and bilirubin may rise modestly, with approximately 9% developing new values above ULN and often isolated, likely reflecting OATP1B1/1B3 inhibition rather than intrinsic hepatotoxicity[37]. In children, ETI has been associated with reductions in AST among those with hepatic involvement, while GGT may increase slightly but remains within the normal range[38].

CFTR modulators carry strong liver safety precautions and require extra care in patients with hepatic impairment. For ETI (Trikafta), the United States Food and Drug Administration (FDA) label includes a boxed warning for serious and potentially fatal DILI, with cases of liver failure leading to transplantation and death. Use is not recommended in Child-Pugh B, and if being used, then reduced dose with close monitoring is advised. These drugs should not used in Child-Pugh C[39,40]. Patients with aCFLD may have a higher likelihood of severe outcomes if DILI occurs, and post-marketing/FDA Adverse Event Reporting System signals and label updates specifically highlight fatalities in patients with underlying hepatic impairment[41]. While case reports and small series document ETI use in aCFLD, any initiation should be individualized with heightened vigilance along with baseline and periodic LFT monitoring.

Diagnostic criteria and algorithms: Because unnecessary interruption of CFTR modulators can jeopardize clinical benefit, standardized approaches to causality assessment are recommended. The updated RUCAM provides a quantitative framework incorporating timing of exposure, biochemical profile, and competing diagnoses, with higher scores correlating with greater likelihood of DILI[17]. In ETI cohorts, most cases of elevated transaminases scored in the excluded or unlikely range, with only a minority classified as possible or probable, emphasizing the utility of RUCAM in guiding management and minimizing unwarranted treatment discontinuation[30]. Table 1 further differentiates DILI from CFTR vs progression of aCFLD.

Table 1 Comparing and contrasting characteristics of liver injury from cystic fibrosis liver disease vs cystic fibrosis transmembrane conductance regulator modulators.

	CFLD	DILI
Clinical features	Spectrum from mild biochemical changes to hepatosplenomegaly, cirrhosis, and portal hypertension (ascites, variceal bleeding). Hepatomegaly is most common; splenomegaly also observed. Often asymptomatic until advanced stages (jaundice, pruritus, ascites)	Typically presents acutely after starting CFTR modulators. Jaundice and pruritus are common, especially in cholestatic or mixed injury patterns
Biochemical patterns	Elevated AST/ALT in 53%-93% of patients; GGT elevated in approximately 1/3. Cholestatic or mixed pattern with elevated ALP and GGT. LFTs may be intermittently normal	Hepatocellular or mixed injury more common. ALT/AST elevations > 3 times ULN in 5%-11%, > 5 times ULN in a subset. Often within weeks to months of drug initiation
Imaging findings	Ultrasound: Heterogeneous echogenicity, nodular contour, splenomegaly. Elastography: Elevated liver stiffness (> 5.9-9 kPa). MRI: Patchy focal fibrosis, high diagnostic accuracy, signs of portal hypertension	Imaging findings are nonspecific: Hepatomegaly, steatosis, biliary dilation. Elastography: Stiffness usually reflects inflammation/edema, not fibrosis
Histopathology	Focal biliary fibrosis, bile duct proliferation, bridging fibrosis, and multi-lobular cirrhosis. Nodular regenerative hyperplasia with portal hypertension	Acute injury with lobular disarray, hepatocellular necrosis, cholestasis, eosinophilic infiltrates. Severe: Extensive necrosis, ductular reactions, fibrosis
Diagnostic criteria	RUCAM used to assess causality. Biochemistry and imaging support diagnosis; biopsy helpful in uncertain cases. LFTs alone are not sufficient	RUCAM scores help determine likelihood of DILI. Useful in avoiding unnecessary CFTR therapy discontinuation
Response to CFTR modulators	ALP may decline, GGT stable, bilirubin may modestly increase (adults). AST may decrease in children; GGT may slightly rise but remains normal. Underlying CFLD does not increase DILI risk	Liver enzyme changes often reflect transporter inhibition (OATP1B1/1B3), not intrinsic toxicity. Most elevations are mild or transient

CFLD: Cystic fibrosis liver disease; DILI: Drug-induced liver injury; CFTR: Cystic fibrosis transmembrane conductance regulator; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: Gamma-glutamyl transpeptidase; ALP: Alkaline phosphatase; LFT: Liver function test; MRI: Magnetic resonance imaging; RUCAM: Roussel Uclaf Causality Assessment Method; ULN: Upper limit of normal.

In adults, ALP may decline when elevated at baseline, GGT generally remains stable, and bilirubin may rise modestly, with approximately 9% developing new values above ULN and often isolated, likely reflecting OATP1B1/1B3 inhibition rather than intrinsic hepatotoxicity[30]. In children, ETI has been associated with reductions in AST among those with hepatic involvement, while GGT may increase slightly but remains within the normal range[39]. Of note, CFLD itself does not appear to increase the risk of ETI related liver enzyme changes, indicating that underlying CFLD should not preclude therapy[29].

Management strategies for cholestatic liver injury in CF

The main goals of management are to prevent progression of liver injury, optimize CF-related therapies, and maintain candidacy for advanced therapies (e.g., lung or liver transplantation).

CFLD: Ursodeoxycholic acid (UDCA) was the most used pharmacologic agent in the management of CFLD. It was thought to help protect hepatocytes from bile acid-induced injury by increasing bile flow by reducing bile viscosity and enhancing choleresis. Earlier studies suggested that long-term UDCA use stabilized or slow progression of CFLD, although recent randomized controlled trials have shown mixed efficacy and no improvement in disease progression to portal hypertension/aCFLD[12,22,41,42]. Updated guidelines recommend against the routine use of UDCA to prevent advanced liver disease in all people with CF.

Providers should not routinely prescribe UDCA to all CF patients with mild liver involvement with the sole purpose of preventing disease progression. Use of UCDA should be individualized, such as for patients who have obstruction of bile flow, or when cholestatic features are prominent. The patient’s liver disease, symptoms, risk factors, and assessment of benefits vs risks should be evaluated when deciding on treatment with UDCA.

Nutritional optimization is also central to aCFLD management, as malabsorption in these patients is exacerbated by both pancreatic insufficiency and impaired bile flow. Supplementation of fat-soluble vitamins (A, D, E, and K) is recommended. Vitamin K deficiency is particularly common in aCFLD, necessitating either high-dose oral or parenteral replacement. In addition to vitamin supplementation, optimizing caloric intake with high-energy diets and pancreatic enzyme replacement further supports growth and metabolic function[43,44].

As aCFLD progresses, portal hypertension is a frequent complication, leading to splenomegaly, hypersplenism, and esophageal varices. Thus, screening for varices and hepatocellular carcinoma is indicated in advanced disease[45]. Management strategies are extrapolated largely from non-CF populations, as robust CF-specific trials are lacking. Non-selective beta-blockers such as propranolol may be used to reduce variceal bleeding risk in patients at risk of decompensation[46]. Endoscopic variceal ligation is the preferred intervention for secondary prophylaxis after variceal bleeding, with banding favored over sclerotherapy due to lower complication rates[47]. Because of the need for screening and prophylactic management, multidisciplinary coordination with hepatology and gastroenterology teams is essential in tailoring therapy for CF patients with portal hypertension.

Liver transplantation is the definitive therapy for patients with decompensated cirrhosis, progressive portal hypertension, or hepatocellular failure in CFLD. Outcomes are generally favorable, with 5-year survival rates exceeding 70%-80%[48]. Selection criteria must carefully weigh pulmonary status, as advanced lung disease can complicate perioperative outcomes and affect transplant candidacy[49]. In select cases, combined liver-lung transplantation may be indicated[43]. Given the systemic nature of CF, transplant candidacy is best determined through multidisciplinary evaluation involving hepatology, pulmonology, nutrition, and transplant surgery.

For DILI from CFTR modulators: For suspected CFTR modulator-associated DILI, the decision to discontinue therapy hinges on the injury severity, the trajectory of laboratory values, and the clinical benefit of continuing the modulator. Most programs pause therapy when the alanine aminotransferase/AST exceed 5-8 times the ULN or bilirubin ≥ 3 times the ULN, thresholds commonly used to flag clinically significant liver injury which are reflected in product labeling for ETI (Trikafta) and VTD[16,50]. Isolated low level bilirubin elevations should not lead to therapy pause. Patients with laboratory elevations below these values have been shown to be able to continue therapy[32]. However, pharmacovigilance data from the FDA Adverse Event Reporting System demonstrate a disproportionate association of ETI with DILI, supporting a low threshold for interruption and hepatology consultation[20]. Mechanistically, idiosyncratic DILI pathways (mitochondrial dysfunction, bile-acid dysregulation, immune activation) explain why abrupt worsening can occur and why risk stratification is conservative[50].

If liver tests return to baseline and an alternative cause is not identified, cautious rechallenge can be considered given the pulmonary and nutritional benefits of CFTR modulators among these patients. DILI data suggests rechallenging does not inherently increase fatal outcomes when done selectively with strict criteria and close monitoring[27,51]. In practice, this is often done in a stepwise fashion, starting with a reduced dose accompanied by frequent LFT monitoring and a low threshold to stop if labs rebound[52]. Although much literature in CF rechallenge therapy focuses on non-hepatic adverse events (e.g., rash) successfully managed with graded re-exposure, the same approach is used for hepatic DILI[52,53].

When a positive rechallenge or recurrent LFT injury confirms ETI-related DILI, switching to a different modulator (e.g., tezacaftor/ivacaftor or ivacaftor monotherapy or VTD) may be appropriate because cross-hepatotoxicity is not universal[30]. The current standards-of-care emphasize genotype-specific alternatives and individualized risk-benefit discussions[22]. Case reports of hepatitis/necrosis with ETI underscore the importance of ETI discontinuation in severe cases, with the option for a subsequent trial of an alternative modulator with intensified monitoring[16,22].

There is no proven hepatoprotective antidote for CFTR modulator-associated DILI. Current innovation focuses on better risk detection (e.g., pharmacovigilance analytics showing ETI safety signals, exploratory biomarkers), safer re-initiation frameworks (stepwise dosing, potential therapeutic drug monitoring to individualize exposure), and mechanistic targets extrapolated from idiosyncratic DILI biology (mitochondrial injury, bile-acid homeostasis, immune pathways) that could inform future interventions. To date, these topics are still being investigated, and management remains supportive.

CFTR modulators and the gut microbiota: CFTR modulators, especially ETI, partially reverse gut dysbiosis in CF by reducing pro-inflammatory bacteria, such as Escherichia coli, Shigella, and Staphylococcus) and increasing beneficial taxa, such as Blautia and Romboutsia. These changes usually result after about 6 months and often correlate with lower fecal calprotectin levels and intestinal inflammation[54-56]. However, persistent dysbiosis remains common due to ongoing antibiotics, pancreatic insufficiency, and dietary factors, so microbiome benefits are modest, delayed, and variable across patients[57-60]. Longer follow-up and integrated large-scale studies are needed to clarify durability and clinical impact[54].

Future directions and research needs

Over the past decade, CFTR modulators have slowly become ubiquitous along with dramatic advances in CTFR science that have changed the therapeutic landscape. There is still an unmet need for comprehensive, prospective, longitudinal studies to better understand the outcomes, especially of liver disease in CF and drug related adverse events given current scarce data. While recent real world and registry data such as the French national CF cohorts suggest that CFTR modulators influence liver enzymes, they rarely lead to severe liver injury or worse outcomes. This French cohort study also showed hepatic benefit, but the results did not establish causality[61-63]. However, many existing reports are retrospective, have small sample sizes, or lack uniform definitions of CFLD vs DILI. Rigorous trials with baseline stratification (existing CFLD, genetic modifiers, and co-medications), serial monitoring of hepatic biomarkers, imaging, and when feasible, biopsy or noninvasive fibrosis assessments are essential.

There is a growing recognition of genetic and environmental risk modifiers in CF. For example, a recent case report identified heterozygous alpha1-antitrypsin deficiency (SERPINA1 Z allele) as possibly predisposing to severe DILI in a child started on ETI[15,64]. Incorporating genotyping assessment of prior liver disease, nutritional status, microbiome and bile acid metabolism could help stratify risk, guide dosage or monitoring schedules. Studies like the PREDICT-CF are studying the variations in ppFEV1 and improvement on lumacaftor/ivacaftor. Development of patient models using patient cells gives access to understanding individual transcriptomic and proteomic background and its impact on drug pharmacology, which also help with personalized therapies[65,66].

Genetic predisposition contributes to the heterogeneity of CFLD. Although the disease is largely confined to severe genotypes, no correlation has been established with specific mutations. To date, SERPINA1, encoding α-1 antitrypsin, is the only modifier gene identified[67]. The SERPINA1 Z allele increases the risk of portal hypertension and advanced liver disease, possibly through endoplasmic reticulum stress and cholangiocyte injury[34,68]. Its identification as the first genetic marker of severe CFLD highlights the potential for early risk stratification and intervention. However, because the Z allele occurs in only approximately 2.7% of patients with CF and only accounted for 3% of aCFLD subjects, which suggests additional modifier genes involvement[68,69].

Overall, the development and research on these liver-targeted therapies offers promising opportunities in the management of CF. A recent preclinical study in CF rabbit models showed that the sodium-glucose co-transporter 1/2 inhibitor sotagliflozin improves liver disease markers, bile acid profiles, and reduces fibrosis and endoplasmic reticulum stress[70]. Ongoing studies have also explored the use of prenatal CFTR modulators which showed interesting therapeutic possibilities in early case reports[71]. Other agents used in non-CFLD (e.g. anti-fibrotics, bile acid modulators, agents targeting endoplasmic reticulum stress or mitochondrial dysfunction) and even combination therapies should be explored. Additionally, therapeutic strategies combining CFTR modulators with hepatoprotective agents, or modifying modulators in patients with existing CFLD, may also improve outcomes[71,72].

Limitations

While this study provides a comprehensive synthesis of current literature on distinguishing CFLD from DILI in the context of CFTR modulator therapy, several limitations should be acknowledged. First, much of the available evidence is derived from retrospective studies, case series, and registry data, which are subject to selection bias, incomplete data capture, and lack of standardized diagnostic criteria for both CFLD and DILI. The heterogeneity in study populations, definitions of liver injury, and outcome measures further limits the generalizability of findings. Many studies included small sample sizes and short follow-up periods, restricting the ability to assess long-term outcomes and rare adverse events. Additionally, pediatric populations and non-English language studies were excluded, potentially omitting relevant data and limiting applicability to all CF patients. The evolving landscape of CFTR modulator use means that real-world experience and longitudinal data remain limited, particularly regarding the natural history of liver disease in the era of highly effective modulator therapy. Finally, the study relies on published literature up to March 2025, and emerging data or unpublished studies may not be reflected. These limitations highlight the need for prospective, multicenter studies with standardized definitions and robust phenotyping to better inform clinical practice.

CONCLUSION

The advent of CFTR modulators has significantly altered the disease trajectory for many patients with CF, yet persistent challenges in managing liver manifestations necessitate continued research. Specifically, further investigation is warranted into the mechanisms underpinning DILI in this population, as well as the identification of predictive biomarkers for early detection and risk stratification. Distinguishing DILI from underlying CFLD is critical in the care of CF patients on CFTR modulators. A thorough understanding of disease pathophysiology, clinical presentation, and diagnostic tools is essential to prevent misdiagnosis, guide safe treatment decisions, and improve long-term outcomes in this complex population. Moreover, optimizing therapeutic approaches for patients with pre-existing CFLD and those who develop DILI remain a critical area for improving long-term outcomes and quality of life. Future research should also focus on elucidating the interplay between CFTR modulators and broader metabolic pathways, particularly considering the recognized cardiovascular risks and metabolic comorbidities frequently observed in patients with metabolic-associated steatotic liver disease, a condition often co-occurring with CF. Liver transplantation remains the most effective treatment for end-stage liver disease in CF patients, highlighting the need to mitigate metabolic complications that can arise post-transplant and impact long-term survival. The evolving understanding of metabolic associated fatty liver disease and its implications for transplant recipients further underscores the importance of tailored management strategies in this complex patient population. The shifting landscape of liver transplantation, with metabolic-associated steatotic liver disease becoming a primary indication, necessitates a proactive approach to managing metabolic comorbidities in CF patients both pre- and post-transplant, specifically in a collaborative effort with hepatology and pulmonology.