Real-world data confirm elexacftor/tezacaftor/ivacaftor modulators halves sweat chloride concentration in eligible people with cystic fibrosis.

Sweat chloride concentration, a diagnostic feature in cystic fibrosis (CF), reflects CF transmembrane conductance regulator (CFTR) activity. CFTR modulator therapies, especially elexacaftor/tezacaftor/ivacaftor (ETI), has improved CF outcomes. We report nationwide, real-world data on sweat chloride concentration in people with CF (pwCF) with and without modulator therapies. All Danish pwCF with a minimum of one F508del allele were included. Sweat chloride measurements were stratified by genotype and modulator treatment. Differences were assessed using mixed-effects models. We included 977 sweat chloride measurements from 430 pwCF, 71% of which were F508del homozygous. Heterozygous and homozygous ETI-treated pwCF had an estimated mean sweat chloride concentration of 43 mmol/L (95% confidence interval: 39; 48) and 43 mmol/L (39; 47), respectively-48% and 59% lower than those without treatment. High variation in concentrations remained regardless of treatment status. Despite ETI treatment, 27% heterozygous and 23% homozygous pwCF had elevated concentrations (≥60 mmol/L). These real-world data confirm a substantial decrease in sweat chloride concentration during modulator treatment, especially ETI, where mean concentrations halved. However, large variation remained, including persistently high concentrations. These findings emphasize the potential of sweat chloride concentration as a treatment response biomarker and the need to explore its heterogeneity and relationship with clinical outcomes.

TMEM16 proteins: Ca2+­activated chloride channels and phospholipid scramblases as potential drug targets (Review).

TMEM16 proteins, which function as Ca2+­activated Cl­ channels are involved in regulating a wide variety of cellular pathways and functions. The modulators of Cl­ channels can be used for the molecule­based treatment of respiratory diseases, cystic fibrosis, tumors, cancer, osteoporosis and coronavirus disease 2019. The TMEM16 proteins link Ca2+ signaling, cellular electrical activity and lipid transport. Thus, deciphering these complex regulatory mechanisms may enable a more comprehensive understanding of the physiological functions of the TMEM16 proteins and assist in ascertaining the applicability of these proteins as potential pharmacological targets for the treatment of a range of diseases. The present review examined the structures, functions and characteristics of the different types of TMEM16 proteins, their association with the pathogenesis of various diseases and the applicability of TMEM16 modulator­based treatment methods.

Silence of the lungs: comparing measures of slow and non-communicating lung units from pulmonary function tests with computed tomography.

Multiple breath washout (MBW) has successfully assessed the silent lung zone particularly in cystic fibrosis lung disease, however, it is limited to the communicating lung only. There are a number of different pulmonary function methods that can assess what is commonly referred to as trapped air, with varying approaches and sensitivity. Twenty-five people with cystic fibrosis (pwCF) underwent MBW, spirometry, body plethysmography, and spirometry-controlled computed tomography (spiro-CT) on the same day. PwCF also performed extensions to MBW that evaluate air trapping, including our novel extension (MBWShX), which reveals the extent of under-ventilated lung units (UVLU). Additionally, we used 2 previously established 5-breath methods that provide a volume of trapped gas (VTG). We used trapped air % from spiro-CT as the gold standard for comparison. UVLU derived from MBWShX showed the best agreement with trapped air %, both in terms of correlation (RS 0.89, P<0.0001) and sensitivity (79%). Bland-Altman analysis demonstrated a significant underestimation of the VTG by both 5-breath methods (-249ml [95%CI -10796; 580ml] and -203ml [95%CI -997;591ml], respectively). Parameters from both spirometry and body plethysmography were sub-optimal at assessing this pathophysiology. The parameters from MBWShX demonstrated the best relationship with spiro-CT and had the best sensitivity compared to the other pulmonary function methods assessed in this study. MBWShX shows promise to assess and monitor this critical pathophysiological feature, which has been shown to be a driver of lung disease progression in pwCF.

Burkholderia cenocepacia ST-250 in cystic fibrosis patients in Switzerland: Genomic investigation of transmission routes.

This report describes the characterization of Burkholderia cenocepacia isolates belonging to sequence type (ST)-250, detected in eight patients with cystic fibrosis (CF) in Switzerland. We retrospectively analyzed 18 isolates of B. cenocepacia ST-250 isolated between 2003 and 2015 by whole-genome sequencing and evaluated clinical and epidemiological data. Single nucleotide polymorphism analysis of the B.°cenocepacia ST-250 lineage showed that the isolates from all patients cluster tightly, suggesting that this cluster has a recent common ancestor. Epidemiological investigations showed that six out of eight patients acquired B.°cenocepacia ST-250 in the years 2001-2006, where participation in CF summer camps was common. Two patients were siblings. Genomic relatedness of the B. cenocepacia ST-250 isolates supported transmission by close contact, however, a common source or nosocomial routes cannot be excluded. With respect to the fatal outcome in six patients, our study shows the importance of infection control measurements in CF patients with B.°cenocepacia.

Robust identification of environmental exposures and community characteristics predictive of rapid lung disease progression.

Environmental exposures and community characteristics have been linked to accelerated lung function decline in people with cystic fibrosis (CF), but geomarkers, the measurements of these exposures, have not been comprehensively evaluated in a single study. To determine which geomarkers have the greatest predictive potential for lung function decline and pulmonary exacerbation (PEx), a retrospective longitudinal cohort study was performed using novel Bayesian joint covariate selection methods, which were compared with respect to PEx predictive accuracy. Non-stationary Gaussian linear mixed effects models were fitted to data from 151 CF patients aged 6-20 receiving care at a CF Center in the midwestern US (2007-2017). The outcome was forced expiratory volume in 1 s of percent predicted (FEV1pp). Target functions were used to predict PEx from established criteria. Covariates included 11 routinely collected clinical/demographic characteristics and 45 geomarkers comprising 8 categories. Unique covariate selections via four Bayesian penalized regression models (elastic-net, adaptive lasso, ridge, and lasso) were evaluated at both 95 % and 90 % credible intervals (CIs). Resultant models included one to 6 geomarkers (air temperature, percentage of tertiary roads outside urban areas, percentage of impervious nonroad outside urban areas, fine atmospheric particulate matter, fraction achieving high school graduation, and motor vehicle theft) representing weather, impervious descriptor, air pollution, socioeconomic status, and crime categories. Adaptive lasso had the lowest information criteria. For PEx predictive accuracy, covariate selection from the 95 % CI elastic-net had the highest area under the receiver-operating characteristic curve (mean ±â€¯standard deviation; 0.780 ±â€¯0.026) along with the 95 % CI ridge and lasso methods (0.780 ±â€¯0.027). The 95 % CI elastic-net had the highest sensitivity (0.773 ±â€¯0.083) while the 95 % CI adaptive lasso had the highest specificity (0.691 ±â€¯0.087), suggesting the need for different geomarker sets depending on monitoring goals. Surveillance of certain geomarkers embedded in prediction algorithms can be used in real-time warning systems for PEx onset.

Phase-resolved MRI for measurement of pulmonary perfusion and ventilation defects in comparison with dynamic contrast-enhanced MRI and 129Xe MRI.

INTRODUCTION: This meta-analysis aims to evaluate the agreement and correlation between phase-resolved functional lung MRI (PREFUL MRI) and dynamic contrast-enhanced (DCE) MRI in evaluating perfusion defect percentage (QDP), as well as the agreement between PREFUL MRI and 129Xe MRI in assessing ventilation defect percentage (VDP). METHOD: A systematic search was conducted in the Medline, Embase and Cochrane Library databases to identify relevant studies comparing QDP and VDP measured by DCE MRI and 129Xe MRI compared with PREFUL MRI. Meta-analytical techniques were applied to calculate the pooled weighted bias, limits of agreement (LOA) and correlation coefficient. The publication bias was assessed using Egger's regression test, while heterogeneity was assessed using Cochran's Q test and Higgins I2 statistic. RESULTS: A total of 399 subjects from 10 studies were enrolled. The mean difference and LOA were -2.31% (-8.01% to 3.40%) for QDP and 0.34% (-4.94% to 5.62%) for VDP. The pooled correlations (95% CI) were 0.65 (0.55 to 0.73) for QDP and 0.72 (0.61 to 0.80) for VDP. Furthermore, both QDP and VDP showed a negative correlation with forced expiratory volume in 1 s (FEV1). The pooled correlation between QDP and FEV1 was -0.51 (-0.74 to -0.18), as well as between VDP and FEV1 was -0.60 (-0.73 to -0.44). CONCLUSIONS: PREFUL MRI is a promising imaging for the assessment of lung function, as it demonstrates satisfactory deviations and LOA when compared with DEC MRI and 129Xe MRI. PROSPERO REGISTRATION NUMBER: CRD42023430847.

Cystic fibrosis dermatitis arthritis syndrome: A series of four cases.

Dermatologic manifestations of cystic fibrosis (CF) include nutrient deficiency dermatoses, vasculitis, transient reactive papulotranslucent acrokeratodema, digital clubbing, and increased rates of atopy and drug reactions. Few cases of a characteristic eruption in patients with episodic arthritis of CF have been described with prior reports primarily occurring outside of the dermatology literature. We report four cases consistent with this presentation to add to the literature and propose a new and unifying name to recognize this entity as cystic fibrosis dermatitis arthritis syndrome (CF-DAS). Clinical suspicion should remain high in young female patients with cystic fibrosis presenting with episodic joint pain and rash, independent of pulmonary exacerbations.

PM2.5 Exposure Inhibits Transepithelial Anion Short-circuit Current by Downregulating P2Y2 Receptor/CFTR Pathway.

Fine particulate matter (PM2.5) can damage airway epithelial barriers. The anion transport system plays a crucial role in airway epithelial barriers. However, the detrimental effect and mechanism of PM2.5 on the anion transport system are still unclear. In this study, airway epithelial cells and ovalbumin (OVA)-induced asthmatic mice were used. In transwell model, the adenosine triphosphate (ATP)-induced transepithelial anion short-circuit current (Isc) and airway surface liquid (ASL) significantly decreased after PM2.5 exposure. In addition, PM2.5 exposure decreased the expression levels of P2Y2R, CFTR and cytoplasmic free-calcium, but ATP can increase the expressions of these proteins. PM2.5 exposure increased the levels of Th2-related cytokines of bronchoalveolar lavage fluid, lung inflammation, collagen deposition and hyperplasisa of goblet cells. Interestingly, the administration of ATP showed an inhibitory effect on lung inflammation induced by PM2.5. Together, our study reveals that PM2.5 impairs the ATP-induced transepithelial anion Isc through downregulating P2Y2R/CFTR pathway, and this process may participate in aggravating airway hyperresponsiveness and airway inflammation. These findings may provide important insights on PM2.5-mediated airway epithelial injury.

The impact of elexacaftor/tezacaftor/ivacaftor on cystic fibrosis health-related quality of life and decision-making about daily treatment regimens: a mixed methods exploratory study.

Background: Elexacaftor/tezacaftor/ivacaftor (ETI) has reduced many symptoms of cystic fibrosis (CF). Objectives: We sought to identify the impact of ETI on both symptoms and treatment decisions among adults with CF. Design: Participants were enrolled in a cross-sectional study. Surveys were sent via a RedCap link. Semistructured interviews were administered remotely via Microsoft Teams. Interviews were audio recorded and professionally transcribed. Methods: We assessed Cystic Fibrosis Questionnaire-Revised (CFQ-R) subscales for physical, respiratory, emotion, and treatment, and analyzed semistructured interviews covering CF treatment regimens and daily living. Quantitative and qualitative results were analyzed separately and via a mixed-methods convergence coding matrix. Results: Twenty-four adults with CF taking ETI were included. CFQ-R subscale scores (mean scores/standard deviation) were physical (82.1/22.8), respiratory (83.7/11.2), emotion (65.3/14.2), and treatment (57.5/20.1). Three themes about decision-making for non-ETI-treatments emerged: (1) How I'm feeling, (2) Not noticing a difference, and (3) Uncertainty about long-term impact of modifying treatment regimens, and we found participants weighed each of these factors in their treatment decisions. Key findings from mixed-methods analysis show that among individuals experiencing higher CFQ-R scores for physical and respiratory compared to emotion and treatment, there were statements indicating that while those participants were experiencing better physical health, many continued their burdensome treatment regimens. Conclusion: With little long-term data on the impact of reducing non-ETI treatments, participants weighed how they were feeling, treatment efficacy beliefs, and risk tolerance when making treatment decisions.

The impact of Trikafta on CF health, health-related quality of life, and treatment adherence People with cystic fibrosis may be experiencing many health benefits from taking Trikafta, leading some people to cut back on or stop their other non-Trikafta treatments. We explored the impact of Trikafta on CF health, health-related quality of life, and treatment adherence for people with CF currently taking Trikafta. We compared health-related quality of life subscales from the CF Questionnaire-Revised questionnaire focused on physical symptoms, respiratory symptoms, treatment burden, and emotional well-being to assess whether people with CF were experiencing improved physical and respiratory health compared to emotional health and feelings of treatment burden. We found that many people were feeling better physically, but were still experiencing poor mental health and high treatment burden. We then looked at results from open-ended interviews to see if our qualitative data could explain the differences in the health-related quality of life scores. We found that while people were feeling better physically, many people were still continuing with the pre-Trikafta treatment regimens which may explain why physical health and respiratory health scores were higher than emotional well-being and treatment burden scores. At this time, we believe that more research is needed to guide treatment decisions related to cutting back or stopping burdensome treatment regimens.

Identification of 6,9-dihydro-5H-pyrrolo[3,2-h]quinazolines as a new class of F508del-CFTR correctors for the treatment of cystic fibrosis.

Although substantial advances have been obtained in the pharmacological treatment of cystic fibrosis (CF) with the approval of Kaftrio, a combination of two correctors (VX-661, VX-445) and one potentiator (VX-770), new modulators are still needed to rescue F508del and other CFTR mutants with trafficking defects. We have previously identified PP compounds based on a tricyclic core as correctors with high efficacy in the rescue of F508del-CFTR on native epithelial cells of CF patients, particularly in combination with class 1 correctors (VX-809, VX-661). Compound PP028 was found as a lead candidate for the high rescue of F508del-CFTR and used for mechanistic insight indicating that PP028 behaves as a class 3 corrector, similarly to VX-445. From the exploration of the chemical space around the hit structure, based on iterative cycles of chemical synthesis and functional testing, the class of 6,9-dihydro-5H-pyrrolo [3,2-h]quinazolines with corrector activity was discovered. Within a series of 38 analogues, two derivatives emerged as promising candidates and used for further insight to assess the mechanism of action. Both compounds, decorated with a benzensulfonylamino group at the pyrimidine moiety, were able to generate a dose-dependent increase in CFTR function, particularly in the presence of VX-809. Half-effective concentrations (EC50) were in the single digit micromolar range and decreased in the presence of VX-809 thus indicating a synergistic interaction with class 1 correctors. Synergy was also observed with corr-4a (class 2 corrector) but not with VX-445 and PP028 (class 3 correctors) indicating that the new compounds behave as class 3 correctors. These results suggest that tricyclic pyrrolo-quinazolines interact with CFTR at a site different from that of VX-809 and represent a novel class of CFTR correctors suitable for combinatorial pharmacological treatments for the basic defect in CF.

Stellate cells are in utero markers of pancreatic disease in cystic fibrosis.

BACKGROUND: Pancreatic fibrosis is an early diagnostic feature of the common inherited disorder cystic fibrosis (CF). Many people with CF (pwCF) are pancreatic insufficient from birth and the replacement of acinar tissue with cystic lesions and fibrosis is a progressive phenotype that may later lead to diabetes. Little is known about the initiating events in the fibrotic process though it may be a sequela of inflammation in the pancreatic ducts resulting from loss of CFTR impairing normal fluid secretion. Here we use a sheep model of CF (CFTR-/-) to examine the evolution of pancreatic disease through gestation. METHODS: Fetal pancreas was collected at six time points from 50-days of gestation through to term, which is equivalent to ~ 13 weeks to term in human. RNA was extracted from tissue for bulk RNA-seq and single cells were prepared from 80-day, 120-day and term samples for scRNA-seq. Data were validated by immunochemistry. RESULTS: Transcriptomic evidence from bulk RNA-seq showed alterations in the CFTR-/- pancreas by 65-days of gestation, which are accompanied by marked pathological changes by 80-days of gestation. These include a fibrotic response, confirmed by immunostaining for COL1A1, αSMA and SPARC, together with acinar loss. Moreover, using scRNA-seq we identify a unique cell population that is significantly overrepresented in the CFTR-/- animals at 80- and 120-days gestation, as are stellate cells at term. CONCLUSION: The transcriptomic changes and cellular imbalance that we observe likely have pivotal roles in the evolution of CF pancreatic disease and may provide therapeutic opportunities to delay or prevent pancreatic destruction in CF.

[Assessment of the risk of hearing loss in children with cystic fibrosis]. / Otsenka riska patologii slukha pri mukovistsidoze u detei.

BACKGROUND: Cystic fibrosis (CF) is a severe hereditary disease with a multisystem lesion. Manifestations of CF include severe infectious purulent lesions of all parts of the respiratory tract, including purulent rhinosinusitis with nasal polyps. The involvement of the sinonasal region and the need for systemic use of ototoxic drugs (primarily aminoglycosides to treat resistant bacterial infection) potentially create a risk of both conductive and sensorineural hearing loss (SNHL). The available data on the epidemiology of hearing disorders in CF is contradictory. Currently, genetic determinants of the development of aminoglycoside SNHL have been identified. MATERIAL AND METHODS: For 136 CF patients (75 girls, 61 boys) aged 3 to 17 (9.4±3.9) years were performed audiological examination: tympanometry, transient-evoked otoacoustic emission and the pure tone threshold audiometry (standard frequency range) (n=126). History of systemic therapy with aminoglycosides was evaluated for each patient. Sequencing of c.35delG mutations in the GJB2 gene (nuclear DNA) and A1555G in the 12S rRNA gene (mitochondrial DNA) was performed in 215 patients with cystic fibrosis (the group partially overlaps with the audiological group), and as a control - 106 children with bronchial asthma and 103 healthy children, their age ranged from 3 to 17 (8.8±3.8) years. RESULTS: Audiological examination of CF children reveled a prevalence of conductive hearing loss comparable to the general population (2.4%). The frequency of SNHL was 1.6%, wich exceeds that of non-CF children. A genetic study revealed one case of heterozygous carriage of the c.35delG mutation in the GJB2 gene in a patient with bronchial asthma. In the group of patients with CF (n=215), mutations in the connexin 26 gene were not detected. No A1555G mutation was detected either in the group of patients with CF or in the control groups. CONCLUSIONS: Children with CF are at risk for the development of sensorineural, but not conductive hearing loss. Routine total screening for A1555G and c.35delG mutations probably seems not to be recommended.

Mucociliary Clearance is Impaired in Small Airways of Cystic Fibrosis Pigs.

Cystic fibrosis is a genetic disorder characterized by recurrent airway infections, inflammation, impaired mucociliary clearance and progressive decline in lung function. The disease may start in the small airways; however, this is difficult to prove due to limited accessibility of the small airways with the current single photon mucociliary clearance assay. Here, we developed a dynamic positron emission tomography assay with high spatial and temporal resolution. We tested that mucociliary clearance is abnormal in the small airways of newborn cystic fibrosis pigs. Clearance of [68Ga] tagged macro-aggregated albumin from small airways started immediately after delivery and continued for the duration of the study. Initial clearance was fast but slowed down few minutes after delivery. Cystic fibrosis pig small airways cleared significantly less than non-CF pig small airways (non-CF 25.1±3.1% vs. CF 14.6±0.1%). Stimulation of the cystic fibrosis airways with the purinergic secretagogue UTP further impaired clearance (non-CF with UTP 20.9±0.3% vs. CF with UTP 13.0±1.8%). None of the cystic fibrosis pig treated with UTP (N = 6) cleared more than 20% of the delivered dose. These data indicate that mucociliary clearance in the small airways is fast and can easily be missed if the assay is not sensitive enough. The data also indicate that mucociliary clearance is impaired in the small airways of cystic fibrosis pigs. This defect is exacerbated by stimulation of mucus secretions with purinergic agonists.

Increased Activity of Epithelial Cdc42 Rho GTPase and Tight Junction Permeability in the Cftr Knockout Intestine.

Increased intestinal permeability is a manifestation of cystic fibrosis (CF) in people with CF (pwCF) and in CF mouse models. CF transmembrane conductance regulator knockout (Cftr KO) mouse intestine exhibits increased proliferation and Wnt/ß-catenin signaling relative to wild-type mice (WT). Since the Rho GTPase Cdc42 plays a central role in intestinal epithelial proliferation and tight junction remodeling, we hypothesized that Cdc42 may be altered in the Cftr KO crypts. Immunofluorescence showed distinct tight junction localization of Cdc42 in Cftr KO fresh crypts and enteroids, the latter indicating an epithelial-autonomous feature. Quantitative PCR and immunoblots revealed similar expression of Cdc42 in the Cftr KO crypts/enteroids relative to WT, whereas pull-down assays showed increased GTP-bound (active) Cdc42 in proportion to total Cdc42 in Cftr KO enteroids. Cdc42 activity in the Cftr KO and WT enteroids could be reduced by inhibition of the Wnt transducer Disheveled 2. Using a dye permeability assay, Cftr KO enteroids exhibited increased paracellular permeability to 3kD dextran relative to WT. In Cftr KO relative to WT enteroids, leak permeability and Cdc42 tight junction localization were reduced to a greater extent by inhibition of Wnt/ß-catenin signaling with Endo-IWR1. Increased proliferation or inhibition of Cdc42 activity with ML141 had no effect on WT enteroid permeability. In contrast, inhibition of Cdc42 with ML141 increased permeability to both 3kD dextran and tight-junction impermeant 500 kD dextran in Cftr KO enteroids. These data suggest that increased constitutive Cdc42 activity may alter the stability of paracellular permeability in Cftr KO crypt epithelium.

Improving growth in infants with CF.

Cystic fibrosis (CF) results in chronic pulmonary infections, inflammation, pancreatic insufficiency, and multiple gastrointestinal manifestations. Malnutrition and poor growth are hallmarks of CF, and strongly associated with poor outcomes. Through newborn screening, many infants can be diagnosed within a few days of life, which allows for early initiation of nutritional counseling and close clinical follow-up. Obstacles to growth for infants with CF start in utero, as newborns with CF can have a lower birth weight than the general population. Improving infant growth has been linked to improved clinical outcomes and survival. It remains a top priority and challenge for caregivers and healthcare teams. An interdisciplinary approach, including registered dietitian and social work support, is essential to optimize health for infants with CF. Remaining barriers to normalcy include deficits in linear growth, lack of accurate nutrition biomarkers, persistence of inequities related to social determinant of health, particularly in the global CF community.

Evolving data on risk and current screening recommendations for colorectal cancer in cystic fibrosis: Pre- and posttransplant.

Advances in treatment for cystic fibrosis (CF), including cystic fibrosis transmembrane conductor regulator (CFTR) modulators, have ushered in an era where patients with CF have much longer life expectancies. This shift in life expectancy demands increased attention to diseases of aging in patients with CF. A notable complication of CF is early-onset colorectal cancer (CRC), which is especially prevalent in patients with severe mutations and after transplant. CFTR acts as a tumor suppressor gene based on knockout models. Lack of CFTR expression promotes carcinogenic processes such as intestinal inflammation and deleterious gut microbiome changes. The consensus Cystic Fibrosis Foundation recommendations advocate treating this population as a high-risk group, using a colonoscopy-only screening strategy starting at age 40 in patients without transplant and at age 30 after transplant. Screening should be considered every 5 years if negative and every 3 years or sooner for patients with adenomatous polyps. Future research will determine the role of noninvasive CRC screening tools in this population, as well as the effects of CFTR modulators on the risk of developing CRC.

Nutritional status in the era of highly effective CFTR modulators.

Advances in cystic fibrosis (CF) diagnostics and therapeutics have led to improved health and longevity, including increased body weight and decreased malnutrition in people with CF. Highly effective CFTR modulator therapies (HEMT) are associated with increased weight through a variety of mechanisms, accelerating trends of overweight and obesity in the CF population. Higher body mass index (BMI) is associated with improved pulmonary function in CF, yet the incremental improvement at overweight and obese BMIs is not clear. Improvements in pulmonary health with increasing BMI are largely driven by increases in fat-free mass (FFM), and impact of HEMT on FFM is uncertain. While trends toward higher weight and BMI are generally seen as favorable in CF, the increased prevalence of overweight and obesity has raised concern for potential risk of traditional age- and obesity-related comorbidities. Such comorbidities, including impaired glucose tolerance, hypertension, cardiac disease, hyperlipidemia, fatty liver, colon cancer, and obstructive sleep apnea, may occur on top of pre-existing CF-related comorbidities. CF nutrition recommendations are evolving in the post-modulator era to more individualized approaches, in contrast to prior blanket high-fat, high-calorie prescriptions for all. Ultimately, it will be essential to redefine goals for optimal weight and nutritional status to allow for holistic health and aging in people with CF.

Pathophysiology of Cystic Fibrosis Liver Disease.

Hepatobiliary complications of Cystic Fibrosis (CF) constitute a significant burden for persons with CF of all ages, with advanced CF liver disease in particular representing a leading cause of mortality. The causes of the heterogeneity of clinical manifestations, ranging from steatosis to focal biliary cholestasis and biliary strictures, are poorly understood and likely reflect a variety of environmental and disease-modifying factors in the setting of underlying CFTR mutations. This review summarizes the current understanding of the pathophysiology of hepatobiliary manifestations of CF, and discusses emerging disease models and therapeutic approaches that hold promise to impact this important yet incompletely addressed aspect of CF care.

Early detection of hepatobiliary involvement in cystic fibrosis: Biomarkers, radiologic methods, and genetic influences.

Cystic fibrosis-related hepatobiliary involvement (CFHBI) is a term used to describe a spectrum of hepatobiliary involvement ranging from a transient elevation of transaminase levels to advanced cystic fibrosis-associated liver disease (aCFLD). While CFHBI is common among people with cystic fibrosis (PwCF), aCFLD is rare impacting only approximately 5%-10% of the CF population. After respiratory/cardiorespiratory issues and transplant-related complications, aCFLD is now the 4th leading cause of mortality among PwCF. Additionally, aCFLD is an independent predictor of all-cause mortality and is associated with significant morbidity. Despite this recognition, our ability to predict those patients at greatest risk for aCFLD, identify early aCFLD, and monitor the incremental progression of CFHBI is lacking. Here, we review the strengths and weaknesses of the common biomarkers and imaging modalities used in the evaluation and monitoring of CFHBI, as well as the current understanding of genetic modifiers related to aCFLD.