Cystic Fibrosis-related Liver Disease Research Articles

Diagnosis, Management, and Prognosis of Cystic Fibrosis-Related Liver Disease in Children.

Cystic fibrosis (CF) is a multifaceted disorder predominantly investigated for its pulmonary manifestations, yet patients with CF also exhibit a spectrum of extrapulmonary manifestations, notably those involving the hepatobiliary system. The latter constitutes the third leading cause of morbidity and mortality in individuals with CF. Cystic fibrosis-related liver disease (CFLD), with an escalating prevalence, manifests diverse clinical presentations ranging from hepatomegaly to cirrhosis and hepatopulmonary syndrome. Consequently, early detection and appropriate management are imperative for sustaining the health and influencing the quality of life of CF patients afflicted with CFLD. This review aims to consolidate existing knowledge by providing a comprehensive overview of hepatobiliary manifestations associated with CF. It delineates the clinical hepatobiliary manifestations, diagnostic methodologies, incorporating minimally invasive markers, and therapeutic approaches, encompassing the impact of novel CFTR modulators on CFLD. Given the exigency of early diagnosis and the intricate management of CFLD, a multidisciplinary team approach is essential to optimize care and enhance the quality of life for this subset of patients. In conclusion, recognizing CF as more than solely a pulmonary ailment, the authors underscore the imperative for further clinical investigations to establish a more robust evidence base for CFLD management within the continuum of this chronic disease.

Prominent role of gut dysbiosis in the pathogenesis of cystic fibrosis-related liver disease in mice

Background & aimsCystic fibrosis-related liver disease (CFLD) is a chronic cholangiopathy that increases morbidity and mortality in patients with CF. Current treatments are unsatisfactory, and incomplete understanding of CFLD pathogenesis hampers therapeutic development. We have previously shown that mouse CF cholangiocytes respond with excessive inflammation to LPS. Thus, we investigated the role of the gut-liver axis in the pathogenesis of CFLD. MethodsWild-type (WT), whole-body CFTR knockout (CFTR-KO) and gut-corrected (CFTR-KO-GC) mice were studied. Liver changes were assessed by immunohistochemistry and single-cell transcriptomics (scRNAseq), inflammatory mediators were analyzed by proteome array, faecal microbiota by 16S rRNAseq and gut permeability by FITC-dextran assay. ResultsThe livers of CFTR-KO mice showed ductular proliferation and periportal inflammation, whereas livers of CFTR-KO-GC mice had no evident pathology. scRNAseq analysis of periportal cells showed increased presence of neutrophils, macrophages and T-cells and activation of pro-inflammatory and pathogen-mediated immune pathways in CFTR-KO livers, consistent with a response to gut-derived stimuli. CFTR-KO mice exhibited gut dysbiosis with enrichment of Enterobacteriaceae and Enterococcus spp., which was associated with increased intestinal permeability and mucosal inflammation, whereas gut dysbiosis and inflammation were absent in CFTR-KO-GC mice. Treatment with nonabsorbable antibiotics ameliorated intestinal permeability and liver inflammation in CFTR-KO mice. Faecal microbiota transfer from CFTR-KO to germ-free WT mice did not result in dysbiosis nor liver pathology, indicating that defective intestinal CFTR is required to maintain dysbiosis. ConclusionDefective CFTR in the gut sustains a pathogenic microbiota, creates an inflammatory milieu, and alters intestinal permeability. These changes are necessary for the development of cholangiopathy. Restoring CFTR in the intestine or modulating the microbiota could be a promising strategy to prevent or attenuate liver disease. Impact and implicationsSevere cystic fibrosis-related liver disease (CFLD) affects 10% of the patients and contributes to increased morbidity and mortality of CF patients. Treatment options remain limited due to a lack of understanding of the disease pathophysiology. The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mediates Cl− and HCO3− secretion in the biliary epithelium and its defective function is thought to cause cholestasis and excessive inflammatory responses in CF. However, our study in CFTR-knockout mice demonstrates that microbial dysbiosis, combined with increased intestinal permeability caused by defective CFTR in the intestinal mucosa, acts as a necessary co-factor for the development of CFLD-like liver pathology in mice. These findings uncover a major role for the gut microbiota in CFLD pathogenesis and call for further investigation and clinical validation to develop targeted therapeutic strategies acting on the gut-liver axis in CF.

Pre-emptive transjugular intrahepatic portosystemic shunt in pediatric cystic fibrosis-related liver disease and portal hypertension: prospective long-term results.

Portal hypertension (PHT) and its sequelae are the most clinically important manifestations in cystic fibrosis-related liver disease (CFLD). This paper aimed to evaluate the safety and efficacy of a pre-emptive transjugular intrahepatic portosystemic shunt (TIPS) to prevent PHT-related complications in pediatric patients with CFLD. This was a prospective single-arm study on pediatric patients with CFLD, signs of PHT, and preserved liver function who underwent a pre-emptive TIPS in a single tertiary CF center between 2007 and 2012. The long-term safety and clinical efficacy were assessed. A pre-emptive TIPS was performed on seven patients with a mean age of 9.2 years (± standard deviation: 2.2). The procedure was technically successful in all patients, with an estimated median primary patency of 10.7 years [interquartile range (IQR) 0.5-10.7)]. No variceal bleeding was observed during the median follow-up of 9 years (IQR 8.1-12.9). In two patients with advanced PHT and rapidly progressive liver disease, severe thrombocytopenia could not be stopped. Subsequent liver transplantation revealed biliary cirrhosis in both patients. In the remaining patients with early PHT and milder porto-sinusoidal vascular disease, symptomatic hypersplenism did not occur, and liver function remained stable until the end of the follow-up. Inclusion for pre-emptive TIPS was discontinued in 2013 following an episode of severe hepatic encephalopathy. TIPS is a feasible treatment with encouraging long-term primary patency to avoid variceal bleeding in selected patients with CF and PHT. However, as the progression of liver fibrosis, thrombocytopenia, and splenomegaly is inevitable, the clinical benefits due to pre-emptive placement appear to be minor.

Assessment of Progression Markers for Cirrhosis in Cystic Fibrosis Patients

Cystic Fibrosis is an autosomal dominant disease that affects the CFTR gene, which is responsible for producing a protein that regulates the transport of chloride ions across the cell membrane. This alteration results in obstruction in the body's ducts and channels, primarily affecting the pulmonary system. Additionally, other systems can be affected. Cystic Fibrosis-related liver disease is a common complication that can lead to steatosis, fibrosis, and multifocal biliary cirrhosis; however, there are no well-established diagnostic criteria yet. The present study was conducted at the Cystic Fibrosis Outpatient Clinic of the Hospital de Clínicas, Federal University of Paraná, examining 98 medical records of patients with cystic fibrosis for at least 10 years. Patients with hepatitis B, hepatitis C, alcohol consumption, or pregnancy were excluded. The objective was to determine the best predictor for the outcome of cirrhosis, and for this purpose, demographic parameters, laboratory tests, and imaging were collected. The statistical analysis was performed using SPSS® software, with quantitative variables described as mean ± standard deviation and categorical variables presented as the number of observations and percentage. ROC curves were adjusted to determine the best predictor, using the Youden index to establish the optimal cutoff point and the corresponding area under the curve to determine the model's efficacy. The study included 80 patients, and 10 of them (12.5%) were diagnosed with Cystic Fibrosis-related cirrhosis. The average age of the cirrhosis group was 21.6 years, with a predominance of males. The most accurate parameter for predisposition to cirrhosis was the APRI score, with a cutoff value of 0.27. Univariate analysis showed that gender, hepatic changes on ultrasound, splenomegaly, increased portal vein diameter, presence of vomiting, levels of alanine transaminase, aspartate transaminase, platelet count, and FIB-4 score were significantly associated with an APRI score value greater than 0.27. This study suggests the hypothesis that the APRI score is the most sensitive and specific tool for defining cirrhosis in patients with cystic fibrosis.

ESPEN-ESPGHAN-ECFS guideline on nutrition care for cystic fibrosis

Nutritional status is paramount in Cystic Fibrosis (CF) and is directly correlated with morbidity and mortality. The first ESPEN-ESPGHAN-ECFS guidelines on nutrition care for infants, children, and adults with CF were published in 2016. An update to these guidelines is presented. The study was developed by an international multidisciplinary working group in accordance with officially accepted standards. Literature since 2016 was reviewed, PICO questions were discussed and the GRADE system was utilized. Statements were discussed and submitted for on-line voting by the Working Group and by all ESPEN members. The Working Group updated the nutritional guidelines including assessment and management at all ages. Supplementation of vitamins and pancreatic enzymes remains largely the same. There are expanded chapters on pregnancy, CF-related liver disease, and CF-related diabetes, bone disease, nutritional and mineral supplements, and probiotics. There are new chapters on nutrition with highly effective modulator therapies and nutrition after organ transplantation.

Liver magnetic resonance elastography and fat fraction in pediatric patients withcystic fibrosis versus healthy children.

Liver involvement is an important cause of morbidity and mortality in patients withcystic fibrosis (CF). While liver biopsy is the gold standard for demonstrating involvement, its invasiveness prompts a search for noninvasive alternatives. To evaluate liver involvement in pediatric patients with CF(versus healthy controls) using magnetic resonance (MR) elastography/spectroscopy and to correlate the imaging findings with clinical/laboratory characteristics. This was a single-center, prospective cross-sectional study conducted between April 2020 and March 2022 in patients withCF versus healthy controls. Patients with CF were divided into two subgroups: those with CF-related liver disease and those without. MR images were acquired on a 1.5-tesla machine. Kilopascal (kPa) values were derived from processing MR elastography images. MR spectroscopy was used to measure liver fat fraction, as an indication of hepatosteatosis. Groups were compared using either the Student's t test or the Mann‒Whitney U test. The chi-square test or Fisher's exact test were used to compare qualitative variables. Fifty-one patients with CF (12 ± 3.3years, 32 boys) and 24 healthy volunteers (11.1 ± 2.4years, 15 boys) were included in the study. Median liver stiffness (P=0.003) and fat fraction (P=0.03) were higher in the CF patients than in the controls. Median liver stiffness values were higher in CF patients with CF-related liver disease than in those without CF-related liver disease (P=0.002). Liver stiffness values of CF patients with high alanine aminotransferase (ALT), high gamma-glutamyl transferase, and thrombocytopenia were found to be higher than those without (P=0.004, P<0.001, P<0.001, respectively). Only the high ALT group showed a high fat fraction (P=0.002). Patients withCF had higher liver stiffness than the control group, and patients withCF-related liver disease had higher liver stiffness than both the CF patients without CF-related liver disease and the control group. Patients withCF had a higher fat fraction than the control group. Noninvasive assessment of liver involvement using MR elastography/spectroscopy can support the diagnosis of CF-related liver disease and the follow-up of patients withCF.

Clinical and genetic risk factors for cystic fibrosis-related liver disease in Egyptian CF children: A single-center experience.

Cystic fibrosis (CF) is an autosomal recessive disease. It affects multiple organ systems, including the liver, leading to CF-related liver disease (CFLD). It was noted that CFLD in Egyptian children with CF is more common than in non-Egyptian people with CF (pwCF). This study aimed to determine the incidence of CFLD and the potential risk factors for developing CFLD in Egyptian children. The correlation between CFLD and the various genotypes prevalent in Egyptian CF children will be discussed. In addition, comparison of CFLD in Egyptian and non-Egyptian CF patients will be presented. This cross-sectional study included 50 pwCF from Ain Sham University's Pediatric Pulmonology Clinic in Children's Hospital, Cairo, Egypt. The sweat chloride test and genetic studies were done at the time of diagnosis. Additionally, all subjects underwent detailed history taking, laboratory investigations, clinical assessment, and pelvic abdominal ultrasound for evaluation of hepatic involvement. One-third of the Egyptian children with CF were found to have liver disease. The following independent risk factors for developing CFLD were identified as: male sex, severe genetic mutation (class I and II), long duration of CF disease, early onset of the CF, pancreatic insufficiency, as well as history of meconium ileus. In addition, diabetes mellitus and severe lung disease were proven to significantly increase the risk of developing CFLD. CFLD is common in Egyptian pwCF. CFLD's risk factors are similar to otherreported research from other countries in the region.

Improving detection of cystic fibrosis related liver disease using liver fibrosis assessment tools

Background & aimsCystic Fibrosis related liver disease (CFLD) is the 3rd largest cause of death in Cystic Fibrosis (CF). As advances in pulmonary therapies have increased life-expectancy, CFLD has become more prevalent. Current guidelines may underdiagnose liver fibrosis, particularly in its early stages. Newer modalities for the assessment of fibrosis may provide a more accurate assessment. FibroScan is validated in assessing fibrosis for several aetiologies including alcohol and fatty liver, the CFLD cohort have an entirely different phenotype so the cut off values are not transferrable. We appraised fibrosis assessment tools to improve diagnosis of CFLD. MethodsA prospective cohort (n = 114) of patients from the Manchester Adult Cystic Fibrosis Centre, UK were identified at annual assessment. Demographic data including co-morbidity, CFTR genotyping, biochemistry and imaging were used alongside current guidelines to group into CFLD and CF without evidence of liver disease. All patients underwent liver stiffness measurement (LSM) and assessment of serum-based fibrosis biomarker panels. A new diagnostic criterion was created and validated in a second, independent cohort. Results12 of 114 patient classified as CFLD according to the European Cystic Fibrosis Society best practice guidelines. No specific risk factors for development of CFLD were identified. Liver enzymes were elevated in patients with CFLD. Serum biomarker panels did not improve diagnostic criteria. LSM accurately predicted CFLD. A new diagnostic criterion was proposed and validated in a separate cohort, accurately predicating CFLD in 10 of 32 patients (31 %). ConclusionWe present a cohort of patients with CF assessed for the presence of liver fibrosis using blood biomarkers and LSM based platforms. We propose a new, simplified diagnostic criteria, capable of accurately predicting liver disease in patients with CF.Clinical trials number: NCT04277819

Comments and illustrations of the WFUMB CEUS liver guidelines: Cystic fibrosis associated liver disease

In this series of articles with comments and illustrations on the World Federation for Medicine and Biology (WFUMB) guidelines on contrast-enhanced ultrasound (CEUS) the topics of very rare focal liver lesions (FLL) are discussed. Improving the detection and characterization of the most common FLL are the main topics of these guidelines. The focus of this review is on the many manifestations of cystic fibrosis-related liver disease (CFLD). These include focal biliary fibrosis, liver cirrhosis, vascular manifestations with nodular regenerative hyperplasia and portal hypertension with or without cirrhosis. This article describes the diverse changes of liver involvement in cystic fibrosis and their appearance on ultrasound, duplex sonography, and contrast enhanced ultrasonography. This knowledge and the imaging should help to recognize liver manifestations in time and enable a correct interpretation of ultrasound images in CF in the corresponding clinical situation.

Evolving nutritional needs, obesity, and overweight status in cystic fibrosis.

The nutritional landscape in cystic fibrosis has shifted dramatically in the era of CFTR modulator therapy. In this review, we will critically examine the literature on overweight and obesity in CF, current nutritional care unknowns and opportunities for further investigation or adaptation in clinical care. Results of clinical trial and real-world data reflect marked improvement in nutritional status and quality of life. Clinical outcomes including CF related diabetes and CF related liver disease appear positively impacted. Secondary impacts on cardiometabolic disease have been noted, especially in association with excessive weight gain. The prior approaches to optimizing nutrition in cystic fibrosis with caloric excess can likely be safely retired for many. As modulator access expands across the lifespan, a longitudinal focus on health maintenance should be considered.

P300 The effect of Highly Effective Modulator therapy (HEMT) on liver function tests of adult patients with cystic fibrosis-related liver disease at one year: the Welsh experience

One of the important potential adverse reactions of HEMT is hepatobiliary disorders, and regular liver function monitoring is essential practice. This study aims to evaluate the effect of the triple CFTR-modulator therapy Kaftrio (elexacaftor/tezacaftor/ivacaftor) on liver function tests (LFT’s) of patients with cystic fibrosis-related liver disease (PwCFLD) one year after starting therapy.

P285 Clinical and genetic risk factors for cystic fibrosis-related liver disease in Egyptian cystic fibrosis children

Cystic fibrosis (CF) is an autosomal recessive disease affecting multiple organ systems, including the liver, leading to CF-related liver disease (CFLD). It was noted that CFLD in Egyptian children with CF is more common than in non-Egyptian people with CF (pwCF). The present study aimed to determine the incidence of CFLD and the potential risk factors for developing CFLD in Egyptian children. The correlation between CFLD and the various genotypes prevalent in Egyptian CF children and the comparison of CFLD in Egyptian and non-Egyptian pwCF was done.

P284 Assessing the potential of the FIB-4 index as a screening tool for advanced liver fibrosis in an adult cystic fibrosis population

Cystic fibrosis related liver disease (CFLD) affects a small proportion of people with CF (PWCF) but is associated with a significant increase in morbidity and mortality. The development of cystic fibrosis transmembrane conductance regulator (CFTR) modulators has led to dramatic improvements in life expectancy for PWCF. Consequently, there has been a significant emergence of liver dysfunction complicating the clinical course of the disease. The FIB-4 index has been shown to be an accurate, non invasive method for assessing liver fibrosis in non CF liver disease. We aimed to assess whether the FIB-4 index could reliably exclude significant fibrosis in an adult population of PWCF.

P288 The effects of stopping ursodeoxycholic acid in adult patients with mild cystic fibrosis-related liver disease (CFLD)

Ursodeoxycholic acid (UDCA) has been used to treat people with CFLD for years, and usually started in childhood or adolescence. This study aims to assess the effect of stopping UDCA on Liver Function Tests (LFT’s) and liver stiffness measurement (LSM) using ultrasound shear wave elastography of adult patients with CF-related liver disease (PwCFLD) under the care of the All Wales Adult CF Centre (AWACFC).

P283 Evaluation of cystic fibrosis-related liver disease in a paediatric cohort

To assess liver involvement in a cohort of pediatric patients with cystic fibrosis(CF).

Kistik Fibrozisli Çocuklarda Karaciğer Tutulumunun Shear-Wave Elastografi ile Non-invaziv Değerlendirilmesi

Objectives: Hepatobiliary complications commonly occur in cystic fibrosis with increasing prevalence due to longer life expectancies and widespread screening efforts. Shear-wave elastography is a novel noninvasive method that involves application of local mechanical compression on soft tissue using focused ultrasonography and acquiring strain images that show tissue response. We aimed to compare abdominal ultrasonography and Shear-wave elastography and also clinical and laboratory findings of children with cystic fibrosis prospectively. Methods: This study is a prospective study conducted in 13 cystic fibrosis patients followed between February 2018 and March 2019. The severity of cystic fibrosis-related liver disease was categorized according to international criteria. Elastography measurement was performed in the same session with the evaluation of the liver by abdominal ultrasonography in the patients. The liver stiffness measurements were compared with clinical data, biochemistry parameters and ultrasound findings. Results: Measurements were performed in 13 cystic fibrosis children (3 boys, 10 girls). The mean kiloPascal values of liver stiffness measurements with shear-wave elastography were 8.68 (4.1-20.2). The median liver stiffness measurement in subjects without cystic fibrosis-related liver disease was 7.79 kiloPascals (n=5); The median liver stiffness measurement in subjects with cystic fibrosis-related liver disease was 9.23 kiloPascals. Conclusion: Cystic fibrosis-related liver disease has a significantly varying disease burden, its prevalence is increasing, and its early recognition is crucial for treatment and follow-up. Although there are no clear range values determined for children in tissue stiffness measurements in Shear-wave elastography, clinical and other laboratory and imaging methods and follow-up and evaluation are important.

A82 PREVALENCE AND NON-INVASIVE SCREENING FOR CYSTIC FIBROSIS RELATED LIVER DISEASE IN A COHORT FOLLOWED AT A CYSTIC FIBROSIS REFERENCE CENTER

Abstract Background The reported prevalence of cystic fibrosis (CF) related liver disease (CFLD) varies widely based on diagnostic criteria but reaches up to 40% in some cohorts. Furthermore, its clinical impact is significant as hepatic involvement is the 3rd leading cause of mortality in CF patients and is associated with a lower life expectancy. Due to the heterogeneous clinical presentation of CFLD, clear diagnostic criteria and non-invasive assessment methods are lacking. Purpose This study aimed to measure the prevalence of CFLD in a cohort of patients followed at a tertiary CF center. Method The files of all patients followed at the CF clinic of the Centre hospitalier de l’Université de Montréal in 2021 were retrospectively reviewed. Imaging reports, histopathology, laboratory values and transient elastography results were assessed. The NIH criteria were used to define CFLD through either presence of one major criteria (abnormal imaging) or two minor criteria (persistently abnormal lab values, hepatosplenomegaly, or transient elastography ≥ 7 kPa). Result(s) 358 patients were included in our study, 56% male with a median age of 36 years. While mean liver tests were within normal limits (ALT 24 U/L, AST 26 U/L, ALP 96 U/L, GGT 29 U/L), 182 patients (51%) had at least one episode of abnormal liver function tests (LFTs), and 85 patients (24%) had persistently abnormal LFTs. CFLD was present in 42 patients (12%), with 39 patients presenting major criteria and 3 patients presenting minor criteria. In addition, 67 patients (19%) had solely hepatic steatosis. Furthermore, clinically significant portal hypertension and esophageal varices were detected in 50% of patients with CFLD who underwent upper endoscopy (n=20). Median transient elastography value was 5.4 kPa (interquartile range 4.25 kPa) in the 51 patients with exam results, and 32% had values ≥ 7 kPa. Fibroscan values correlated well with the presence of major criteria, with an area under the curve (AUROC) of 0.80 (0.68-0.92, p=0.0007), while non-invasive serological markers did not perform as well (Fib4: AUROC 0.70 (0.59-0.81) and APRI: AUROC 0.69 (0.59-0.80)). Conclusion(s) The overall prevalence of CFLD, including hepatic steatosis, was 31% in this cohort. Prompt recognition is important in clinical care in order to prevent hepatic complications from cirrhosis and portal hypertension. The use of Fibroscan seems promising for detecting CFLD. Please acknowledge all funding agencies by checking the applicable boxes below None Disclosure of Interest None Declared

Characterization of CFTR mutations in people with cystic fibrosis and severe liver disease who are not eligible for CFTR modulators

Cystic-fibrosis-related liver disease (CFLD) is a variable phenotype of CF. The severe CFLD variant with cirrhosis or portal hypertension has a poor prognosis and life expectancy.CFTR modulator therapies are now available for people with CF and eligibility for such treatment is based on their CFTR genotype. We evaluated the genetic eligibility for elexacaftor, tezacaftor, ivacaftor (ETI), and ivacaftor (IVA) monotherapy in a previously reported CF cohort of 1591 people with CF of whom 171 with severe CFLD. Based on their CFTR mutations, 13% (N=184/1420) of subjects without CFLD and 11% (N=19/171) of those with severe CFLD are not eligible for either ETI or IVA therapy.The non-eligible patients without CFLD or with severe CFLD can currently not take advantage of the potential benefits of these new treatments. Although this study cannot provide any data regarding the effect of ETI or IVA on the progression of severe CFLD, the consequences for ineligibility of patients with extreme liver phenotype may be even more significant because of their poorer disease risk profile.

Longitudinal effects of elexacaftor/tezacaftor/ivacaftor on liver tests at a large single adult cystic fibrosis centre

BackgroundElexacaftor/tezacaftor/ivacaftor (E/T/I) therapy has resulted in substantial improvements in health status for many with cystic fibrosis. Monitoring of liver tests is recommended due to observed rises in transaminases in trials and cases of hepatotoxicity. Comprehensive data in large populations of unselected individuals and those with established CF related liver disease (CFLD) is lacking. MethodsPatients prescribed E/T/I at a large, adult centre had liver tests monitored at least 3 monthly for 12 months. Changes in individual liver tests were analysed and abnormalities were compared in those with and without CFLD. Results255 of 267 eligible patients were included. Mild rises in median ALT, AST and bilirubin from baseline to 3 months (all p < 0.001) within normal limits were noted which were sustained. There were no differences in changes in liver tests between those with or without CFLD. There was a significant difference in alkaline phosphatase for those with raised levels at baseline versus those with normal baseline level (-18.5 vs +2.0 IU/L, p = 0.002). Clinically significant rises in ALT and AST occurred in 8 (3.1%) and 6 (2.4%) cases respectively, with derangements in 2 individuals attributed to therapy. ConclusionsE/T/I leads to a mild, likely clinically insignificant increase in ALT, AST and bilirubin after 3 months which is sustained but does not appear to increase further in the vast majority. Underlying CFLD should not be a barrier to treatment. Although there was a reduction in ALP when elevated at baseline, this was not unique to those with pre-existing CFLD.

Cystic fibrosis rabbits develop spontaneous hepatobiliary lesions and CF-associated liver disease (CFLD)-like phenotypes.

Cystic fibrosis (CF) is an autosomal recessive genetic disease affecting multiple organs. Approximately 30% CF patients develop CF-related liver disease (CFLD), which is the third most common cause of morbidity and mortality of CF. CFLD is progressive, and many of the severe forms eventually need liver transplantation. The mechanistic studies and therapeutic interventions to CFLD are unfortunately very limited. Utilizing the CRISPR/Cas9 technology, we recently generated CF rabbits by introducing mutations to the rabbit CF transmembrane conductance regulator (CFTR) gene. Here we report the liver phenotypes and mechanistic insights into the liver pathogenesis in these animals. CF rabbits develop spontaneous hepatobiliary lesions and abnormal biliary secretion accompanied with altered bile acid profiles. They exhibit nonalcoholic steatohepatitis (NASH)-like phenotypes, characterized by hepatic inflammation, steatosis, and fibrosis, as well as altered lipid profiles and diminished glycogen storage. Mechanistically, our data reveal that multiple stress-induced metabolic regulators involved in hepatic lipid homeostasis were up-regulated in the livers of CF-rabbits, and that endoplasmic reticulum (ER) stress response mediated through IRE1α-XBP1 axis as well as NF-κB- and JNK-mediated inflammatory responses prevail in CF rabbit livers. These findings show that CF rabbits manifest many CFLD-like phenotypes and suggest targeting hepatic ER stress and inflammatory pathways for potential CFLD treatment.