Cystic Fibrosis-associated Liver Disease Research Articles

Sotagliflozin attenuates liver-associated disorders in cystic fibrosis rabbits.

Mutations in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene lead to CF, a life-threating autosomal recessive genetic disease. While recently approved Trikafta dramatically ameliorates CF lung diseases, there is still a lack of effective medicine to treat CF-associated liver disease (CFLD). To address this medical need, we used a recently established CF rabbit model to test whether sotagliflozin, a sodium-glucose cotransporter 1 and 2 (SGLT1/2) inhibitor drug that is approved to treat diabetes, can be repurposed to treat CFLD. Sotagliflozin treatment led to systemic benefits to CF rabbits, evidenced by increased appetite and weight gain as well as prolonged lifespan. For CF liver-related phenotypes, the animals benefited from normalized blood chemistry and bile acid parameters. Furthermore, sotagliflozin alleviated nonalcoholic steatohepatitis-like phenotypes, including liver fibrosis. Intriguingly, sotagliflozin treatment markedly reduced the otherwise elevated endoplasmic reticulum stress responses in the liver and other affected organs of CF rabbits. In summary, our work demonstrates that sotagliflozin attenuates liver disorders in CF rabbits and suggests sotagliflozin as a potential drug to treat CFLD.

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.

528 Alterations in the fecal microbiota of patients with advanced cystic fibrosis–associated liver disease after 6 months of elexacaftortezacaftor-ivacaftor

528 Alterations in the fecal microbiota of patients with advanced cystic fibrosis–associated liver disease after 6 months of elexacaftortezacaftor-ivacaftor

558 Development of a gene editing strategy to treat cystic fibrosisassociated liver disease

558 Development of a gene editing strategy to treat cystic fibrosisassociated liver disease

The non-invasive evaluation of liver involvement in patients with cystic fibrosis: A prospective study.

Porto-sinusoidal vascular disease (PSVD) has been described as the prominent pathology in liver explants of patients with cystic fibrosis (CF), but data outside the transplant setting are lacking. We aimed to investigate the prevalence of portal hypertension (PH) in CF-associated liver disease (CFLD) and develop an algorithm to classify liver involvement in CF patients. This is a cross-sectional study of consecutive paediatric and adult patients in a tertiary centre between 2018 and 2019, who underwent ultrasound, liver (LSM) and spleen stiffness (SSM) measurement. CFLD was defined according to physical examination, liver tests and ultrasound findings. PSVD was likely if there were PH signs in the absence of advanced chronic liver disease (CF-ACLD, LSM <10 kPa). A historical cohort was used to validate the prognostic significance of the new definitions. Fifty (27.5%) patients met CFLD criteria. At least one sign of PH was found in 47 (26%) patients, but most (81%) had LSM <10 kPa and were likely to have PSVD; only 9 (5%) had CF-ACLD. PSVD and CFLD (LSM <10 kPa) co-existed in most (23/36) cases. In the historical cohort (n = 599 patients), likely PSVD and CFLD+PH were independently associated with a 2-fold and 3.5-fold increase in mortality compared to patients without PH, respectively. In 34 patients with SSM, values <21 and >50 kPa accurately diagnosed specific signs of PH. PSVD is the prevailing cause of PH in CF patients. We developed a new diagnostic algorithm based on clinical and elastosonography criteria to classify liver involvement in patients with CF.

Afectarea hepatică în mucoviscidoză

Among the systemic impairment in cystic fibrosis there is also hepatobiliary tract involvement, with some genetic determinants of the disease manifesting as cystic fibrosis-associated liver disease (CFLD). The pathogenesis, natural history and cyrrhogenic evolution of CFLD are discussed in relation to the multiple phenotypes of cystic fibrosis. The CFLD therapy is nonspecific, the disease progression to cirrhosis is unpredictable, and the CFTR modulators offer a still underinvestigated therapeutic alternative.

Clinical and genetic features of cystic fibrosis in Japan.

Cystic fibrosis (CF) is an autosomal recessive disease caused by pathogenic variants in CF transmembrane conductance regulator (CFTR). While CF is the most common hereditary disease in Caucasians, it is rare in East Asia. In the present study, we have examined clinical features and the spectrum of CFTR variants of CF patients in Japan. Clinical data of 132 CF patients were obtained from the national epidemiological survey since 1994 and CF registry. From 2007 to 2022, 46 patients with definite CF were analyzed for CFTR variants. All exons, their boundaries, and part of promoter region of CFTR were sequenced and the presence of large deletion and duplications were examined by multiplex ligation-dependent probe amplification. CF patients in Japan were found to have chronic sinopulmonary disease (85.6%), exocrine pancreatic insufficiency (66.7%), meconium ileus (35.6%), electrolyte imbalance (21.2%), CF-associated liver disease (14.4%), and CF-related diabetes (6.1%). The median survival age was 25.0 years. The mean BMI percentile was 30.3%ile in definite CF patients aged < 18 years whose CFTR genotypes were known. In 70 CF alleles of East Asia/Japan origin, CFTR-dele16-17a-17b was detected in 24 alleles, the other variants were novel or very rare, and no pathogenic variants were detected in 8 alleles. In 22 CF alleles of Europe origin, F508del was detected in 11 alleles. In summary, clinical phenotype of Japanese CF patients is similar to European patients, but the prognosis is worse. The spectrum of CFTR variants in Japanese CF alleles is entirely different from that in European CF alleles.

Effects of CFTR modulators on serum biomarkers of liver fibrosis in children with cystic fibrosis.

The cystic fibrosis (CF) transmembrane conductance regulator corrector/potentiator combinations lumacaftor/ivacaftor and elexacaftor/tezacaftor/ivacaftor improve sweat chloride, pulmonary function, and nutrition. Yet it is unclear whether they may also impact the progression of liver fibrosis, which is a substantial source of morbidity and mortality for patients with CF. We conducted a retrospective, single-center analysis of children and adolescents with CF treated with lumacaftor/ivacaftor and/or elexacaftor/tezacaftor/ivacaftor therapy, focusing on alterations in liver function tests and fibrosis indices using previously-established thresholds that corresponded with increased liver elastography. In pairwise comparisons of before and during treatment timepoints, we found that those with CF-associated liver involvement experienced significant decreases in gamma-glutamyl transferase, aspartate aminotransferase-to-platelet index, and gamma-glutamyl transferase-to-platelet ratio while on lumacaftor/ivacaftor. These differences were not observed in patients treated with elexacaftor/tezacaftor/ivacaftor, nor were they observed in patients without underlying CF-associated liver disease. These results provide the first evidence that lumacaftor/ivacaftor may improve liver fibrosis in children and adolescents with CF and suggest it may be beneficial in the treatment of CF-associated liver disease.

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.

The Usefulness of Combining Noninvasive Methods for Early Identification and Potential Prevention of Cystic Fibrosis-Associated Liver Disease.

Cystic fibrosis-associated liver disease is the third leading cause of morbidity and mortality in patients with cystic fibrosis (CF). Liver damage in the course of CF ranges from biochemical abnormalities to full-blown cirrhosis and may involve complicated processes like inflammation, fibrogenesis, remodeling, apoptosis, and cholestasis. Despite robust research in the field of CF, its complex pathogenesis is not fully understood. Because of the unknown pathogenesis, it is difficult to develop a highly sensitive and specific test or technology that is standardized, acceptable, and available at most pediatric institutions. The Cystic Fibrosis Foundation (CFF) recommends annual blood tests to screen for liver pathology, which often fails to identify early-onset liver disease. In this review article, wepresentthe use of different liver indices and imaging modalities that can help identify liver disease at the onset and may help in its prevention. Although the disease is commonly diagnosed in the pediatric population, due to increased life expectancy, there is increasing evidence of liver disease in adultstoo. We believe that the tools we present in this review will helpin the prevention of liver disease and thereby reduce the associated morbidity and mortality.

Cystic Fibrosis Associated Liver Disease and Bronchiectasis in Puberty. Case Report and Literature Review

Abstract Cystic fibrosis (CF) represents a multisystemic condition, due to the transmembrane conductance regulatory protein (CFTR gene), involving both gastrointestinal tract and lungs. The prevalence of CF associated liver disease is related with increased life expectancy and it is rare in childhood or puberty. Liver disease (LD) is often preceded by complications associated with pulmonary damage. We present a case of a 13 year- old girl, known with cystic fibrosis since the age of 4 months, diagnosed with cholecyst hypoplasia and cholestasis, severe malnutrition progressive extension of bronchiectasis, recurrent respiratory infections in childhood, and, later, in puberty, liver disease with third stage fibrosis (F3) revealed by Fibroscan. Hepatobiliary damage is a late consequence, which is precisely why not performing a liver biopsy, especially in infants and young children, can be justified. We highlight the value of Fibroscan, a non-invasive imaging technique capable to reveal liver fibrosis and to stage it.

Assessment of Liver Fibrosis with the Use of Elastography in Paediatric Patients with Diagnosed Cystic Fibrosis.

Background Complications of cystic fibrosis-associated liver disease (CFLD) are a leading nonpulmonary cause of death. Noninvasive tests enabling early detection of liver changes, especially in children are sought. The aim of the study was to assess the scale of liver fibrosis with the use of elastography in paediatric patients with diagnosed cystic fibrosis (CF) and its comparison with other tests (APRI and Fibrotest). Methods We examined 41 children, in the age range 2-21 years, with diagnosed CF. The analysis a included clinical picture, laboratory parameters of liver damage, and cholestasis. Aspartate aminotransferase-to-platelet ratio index (APRI) and Fibrotest were done in all patients. Liver stiffness measurements were acquired using shear-wave elastography (SWE). Results CFLD was diagnosed in 16/41 patients (39%). Abnormal elastography was observed in 19/41 patients (46.3%), and in 5/41 (12.2%), the changes were advanced (F4). Abnormal elastography was observed in 12/16 (75%) of the patients with CFLD, and in 7/25 (28%), there were no lesions observed in the liver in the course of cystic fibrosis. In all patients with F4, we observed abnormal results of the APRI and Fibrotest. In most patients with small changes in elastography, we found normal results of the APRI and Fibrotest. Conclusion Elastography seems to be a noninvasive examination useful in everyday clinical work in detecting early liver changes and monitoring of progression in paediatric patients with diagnosed cystic fibrosis, ahead of changes in laboratory tests. The cost-effectiveness of this test, the possibility of its repetition, and its availability are additional benefits.

Prevalence and Characteristics of Liver Involvement in Cystic Fibrosis Patients- An Initial Experience From India

Background: Cystic fibrosis (CF) is an uncommon autosomal recessive disorder that results due to dysfunction of epithelial chloride transport channel caused by defects in the CF trans membrane regulation (CFTR) gene. This leads to production of abnormally thick secretions that cause alterations in multiple organ systems including lungs, pancreas, liver, intestine, and reproductive tract. The liver involvement in cystic fibrosis described as Cystic fibrosis-associated liver disease (CFLD) affects about 26-45% of patients and is considered the third common cause of death after lung disease and transplantation complications respectively.

Prevalence and Characteristics of Liver Involvement in Cystic Fibrosis Patients - An Initial Experience from India

Background: Cystic fibrosis (CF) is an uncommon autosomal recessive disorder that results due to dysfunction of epithelial chloride transport channel caused by defects in the CF trans membrane regulation (CFTR) gene on chromosome 7. The dysfunction produces abnormally thick secretions that cause changes throughout multiple organ systems, such as the lungs, pancreas, liver, intestine, and reproductive tract. The liver involvement in cystic fibrosis described as Cystic fibrosis-associated liver disease (CFLD) aff ects about 26-45% of patients and is considered the third common cause of death after lung disease and transplantation complications respectively.

Gamma-glutamyl transpeptidase-to-platelet ratio as a biomarker of liver disease and hepatic fibrosis severity in paediatric Cystic Fibrosis

BackgroundCystic fibrosis (CF)-associated liver disease (CFLD) causes significant morbidity and mortality in children with CF. Diagnosis of liver disease prior to development of cirrhosis or portal hypertension (PHT) is challenging. While imaging modalities using Elastography show great promise they are still not widely available to all clinicians. This study investigated gamma-glutamyl transpeptidase-to-platelet ratio (GPR) as a non-invasive biomarker to detect liver disease and stage fibrosis severity in children with CF. Methods237 children were enroled including 76 with CFLD and 161 with CF and no detectable liver disease (CFnoLD). CFLD was diagnosed using standard clinical, biochemical and imaging practice guidelines. Hepatic fibrosis was staged on liver biopsies available from 54 children with CFLD. Serum liver biochemistry was used to calculate GPR (median, [IQR]) and receiver operating characteristics (ROC) analysis assessed utility to detect liver disease and stage fibrosis severity. ResultsGPR was significantly increased in CFLD versus CFnoLD (0.33 [0.19–0.96] vs. 0.15 [0.11–0.21], P<0.0001). GPR demonstrated good diagnostic utility for detecting CFLD with an area under the curve (AUC) of 0.81 (95% confidence Interval [CI] [0.75–0.87]; P<0.0001), with sensitivity of 74% and specificity of 73%, using a cut-off of 0.20. GPR increased with increasing hepatic fibrosis stage. GPR discriminated both moderate-advanced (F2-F4) fibrosis vs. F0-F1 (AUC=0.82; 95%CI [0.71–0.94]; P<0.0001) and advanced (F3-F4) fibrosis vs. F0-F2 (AUC=0.77; 95%CI [0.64–0.90]; P = 0.004), with a cut-off 0.32 and 0.61, respectively. An elevated GPR of >0.84 was predictive of PHT at diagnosis of CFLD (AUC=0.81; 95%CI [0.67–0.95]; P = 0.0003). ConclusionsGPR demonstrates good diagnostic utility for assessing the presence of liver disease, PHT and hepatic fibrosis severity in children with CF. These findings will aid in better identification of patients at risk for CF-related liver involvement and the potential for more targeted and timely follow-up and treatment.

Advanced but not mild liver disease is a predictor of decreased survival in children with cystic fibrosis, with far greater impact in females: A 27-year real-life cohort study

BackgroundImproved survival of children with CF has increased our need to understand the relevance of cystic fibrosis-associated liver disease (CFLD). We assessed the impact of liver disease and disease severity on the survival of children with cystic fibrosis. MethodsA real life, single center cohort study with 27 years follow up was conducted. Mild CFLD was diagnosed as children with abnormal serum liver function tests and abnormal ultrasound. Advanced CFLD was established by detection of cirrhosis or portal hypertension. A directed acyclic graph, Kaplan-Meier (KM) and Cox regression analysis were used to model survival. Results290 patients were enrolled, 48 (16.5%) had mild CFLD and 55 (19%) had advanced CFLD. Ten children with advanced CFLD and 1 with mild CFLD died. Based on the KM analysis, the mean (SE) overall survival age of all CF children was 29.1 years (0.50). The mean (SE) survival among females with advanced CFLD was 24.7 years (1.58) compared to 30.4 years (0.66) for females without advanced CFLD (p = 0.0027). Advanced CFLD was a predictor of decreased survival when adjusted for sex and diabetes (HR 2.54, 95%CI 1.05–6.15, p = 0.039). Mild CFLD was not associated with decreased survival. The effect of advanced CFLD on survival was mainly borne by females (HR = 6.37, 95%CI 1.62–25.06 vs. males, HR = 1.00, 95%CI 0.25–4.01). ConclusionAdvanced but not mild CFLD was associated with an increased risk of death when adjusted for sex and diabetes, and resulted in premature death in females with cystic fibrosis by approximately 6 years.

Cystic fibrosis associated liver disease in children.

Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CF transmembrane conductance regulator gene. CF liver disease develops in 5%-10% of patients with CF and is the third leading cause of death among patients with CF after pulmonary disease or lung transplant complications. We review the pathogenesis, clinical presentations, complications, diagnostic evaluation, effect of medical therapies especially CF transmembrane conductance regulator modulators and liver transplantation in CF associated liver disease.

Non-invasive tools for detection of liver disease in children and adolescents with cystic fibrosis.

BackgroundCystic fibrosis (CF) is a multi-organ genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene which encodes the CFTR protein. CF-associated liver disease (CFLD) is a common complication; diagnosis is based on clinical, laboratory findings and abdominal imaging. However, non-invasive diagnostic approaches are needed to early detect CFLD, its progression and severity. Recent studies demonstrate a possible role of point shear wave elastography (p-SWE) with liver stiffness measurement (LSM) as a tool for CFLD diagnosis also in children. This non-invasive technique measures liver stiffness to assess liver fibrosis and is suggested to be less operator-dependent compared to ultrasonography. Aim of our prospective observational study is to investigate the role of p-SWE with LSM for CFLD diagnosis in children and adolescents with CF and to compare this finding with aspartate aminotransferase to platelet ratio index (APRI), fibrosis index based on four factors (FIB-4) and gamma-glutamyl-transpeptidase to platelet ratio (GPR) indices.MethodsFifty-nine children with CF, who had routinely undergone abdominal imaging, were consecutively enrolled. Laboratory findings and clinical data were recorded, as abdominal ultrasound and shear wave elastography at baseline. The cases were divided into two groups based on collected data and classified as CFLD and CFnoLD (without liver disease) according to Debray criteria. APRI, FIB-4 and GPR fibrosis indices were also evaluated.ResultsTwenty-four/59 (40.7%) were defined as CFLD. LSM test is superior to the APRI (P<0.001), the FIB-4 test (P=0.001) and the GPR test for early detection of liver fibrosis. LSM had an area under receiver operating characteristic (ROC) curve =0.818 (95% CI: 0.702–0.934) compared with APRI (0.571, 95% CI: 0.421–0.722), FIB-4 (0.656, 95% CI: 0.511–0.801) and GPR (0.632, 95% CI: 0.485–0.779). At a cut-off of ≥6.2 LSM show a sensitivity of 75.0% and a specificity of 88.6%.ConclusionsLSM by transient p-SWE is a non-invasive, highly accessible, reliable, and reproducible test that can be used to assess early detection of liver fibrosis and its severity in children and adolescents with CF, limiting the use of liver biopsy. These preliminary observations point to the need of larger study population to confirm our data.

Liver disease in cystic fibrosis patients in a tertiary care center in Saudi Arabia.

BackgroundInternationally, Cystic fibrosis-associated liver disease (CFLD) is considered the third leading cause of death, following lung disease and transplantation complications.AimsTo identify the prevalence of CFLD in cystic fibrosis (CF) patients.MethodologyA retrospective chart review for all patients with CF liver disease from a tertiary care center.ResultA total of 341 CF patients were included. The mean age at the diagnosis of liver disease is 13.5 (7.6) years.The first elevated ALT was reported in 190/341 patients (56%), elevated AST in 124 patients (36%), elevated alkaline phosphatase (ALP) in 166 patients (49.1%), elevated GGT in 57 patients (23%), and elevated bilirubin in 24 patients (7%). There was an improvement of the liver enzyme values during the follow-up period, P-value = (<0.05).Ultrasound liver assessments were performed in 258/341 patients (75.7%). One hundred and twelve patients (43%) had abnormal findings. In 14 patients (5.4%), assessment exhibited advanced liver disease (liver cirrhosis and periportal fibrosis). Out of 190 patients, who were given ursodeoxycholic acid for elevated liver enzymes, 180 (94.7%) exhibited improvement. One patient underwent liver transplant at the age of 12. Four patients were submitted for liver biopsy; periportal fibrosis was observed in 4 patients (1.6%), and liver cirrhosis by ultrasound (US) in 10 patients (4%).ConclusionPatients with CF should be screened early for liver enzymes, and should undergo the US study to detect liver disease at early stages and to prevent its progression.

Factors Influencing Lung Function in Patients with Cystic Fibrosis in Western Romania.

PurposeThe aim of this cross-sectional study was to identify the major factors influencing pulmonary function in CF patients from western side of Romania.Patients and MethodsThe study enrolled 51 patients with CF between the ages of 6 and 27.8 years who were monitored at regular visits to the National Cystic Fibrosis Centre and Pius Branzeu County Hospital in Timisoara, Romania, over a period of 2 years. The relationships between lung function, as measured by forced expiratory volume in 1 s (FEV1), with patient age, sex, body mass index (BMI), pancreatic insufficiency (PI), microbial infection, CF-related diabetes (CFRD), CF-associated liver disease (CFLD), and physical activity <30 min/day, were evaluated by multivariate regression analysis.ResultsThe results showed that FEV1 was 0.32% higher for each increase in percentile of BMI (95% confidence interval: 0.034–0.619). In addition, mean FEV1 was 1.52% lower with every year rise of age. PI and female sex increased the risk of impaired lung function (FEV1 <60%). The factors most closely correlated with pulmonary function in pediatric CF patients were current age (negative) and BMI (positive).ConclusionThe findings of this study, in combination with what is known from other studies in CF, suggest that a better nutritional status and infection prophylaxis should be part of a comprehensive clinical management strategy for pediatric CF in Romania.