Management of liver disease and portal hypertension in cystic fibrosis: a review.

INTRODUCTION: Cystic fibrosis (CF)-associated liver disease can significantly affect the quality of life and survival of people with CF. The hepatobiliary manifestations in CF are various, with focal/multilobular biliary cirrhosis more common in children and porto-sinusoidal vascular disease (PSVD) in young adults. Portal hypertensive complications, particularly bleeding from esophagogastric varices and hypersplenism are common, while liver failure is rarer and mainly linked to biliary disease. AREAS COVERED: This review explores current therapeutic options for CF-associated liver disease, presenting ongoing studies and new insights into parthenogenesis for potential future therapies. EXPERT OPINION: Monitoring for signs of portal hypertension is essential. Limited evidence supports ursodeoxycholic acid (UDCA) efficacy in halting CF liver disease progression. The effect of cystic fibrosis transmembrane conductance regulator (CFTR) modulators on liver outcomes lacks definitive data, since patients with CF-related liver disease were excluded from trials due to potential hepatotoxicity. A proposed approach involves using UDCA and modulators in early stages, along with anti-inflammatory agents, with further therapeutic strategies awaiting randomized trials. Prevention of portal hypertensive bleeding includes endoscopic sclerotherapy or ligation of esophageal varices. Nonselective beta-blockers may also prevent bleeding and could be cautiously implemented. Other non-etiological treatments require investigation.

A case of severe pulmonary exacerbation in a young patient with cystic fibrosis in the era of CFTR modulators.

The introduction of CFTR modulator drugs like Elexacaftor-Tezacaftor-Ivacaftor (ETI) has transformed the management of Cystic Fibrosis (CF), significantly improving symptoms, lung function, and quality of life, while reducing reliance on intravenous antibiotics. However, respiratory exacerbations in the CFTR modulators era remain poorly understood from both pathophysiological and clinical perspectives. We present the case of a 20-year-old Caucasian woman with CF (F508del/L1077P) who, after three years of ETI treatment, experienced a severe episode of haemoptysis, despite being almost asymptomatic in the weeks leading up to admission, requiring bronchial artery embolization. Following ETI treatment, auscultatory findings and FEV1 changes may be less significant, making the detection of respiratory exacerbation more challenging. This highlights the need for heightened vigilance in managing such cases and underscores the challenge of diagnosing and managing exacerbations in the era of modulators. Long term real-world studies are essential to comprehend the evolving course of the disease during ETI treatment.

Heterogeneity in response to Elexacaftor/Tezacaftor/Ivacaftor in people with cystic fibrosis.

BACKGROUND: Highly effective modulators of the CFTR channel have been demonstrated to dramatically impact disease progression and outcome. However, real-world data indicates that the magnitude of the clinical benefit is not equal among all patients receiving the treatment. We aimed to assess the variability in treatment response (as defined by the 6-month change in sweat chloride concentration, forced expiratory volume in one second [ppFEV1], body mass index [BMI], and CF Questionnaire-Revised [CFQ-R] respiratory domain score) and identify potential predictors in a group of patients receiving Elexacaftor-Tezacaftor-Ivacaftor (ETI) triple combination therapy. METHODS: This was a single-center, prospective cohort study enrolling adults with CF at a major center in Italy. We used linear regression models to identify a set of potential predictors (including CFTR genotype, sex, age, and baseline clinical characteristics) and estimate the variability in treatment response. RESULTS: The study included 211 patients (median age: 29 years, range: 12-58). Median changes (10-90th percentile) from baseline were: - 56 mEq/L (-76; -27) for sweat chloride concentration, +14.5 points (2.5; 32.0) for ppFEV1, +0.33 standard deviation scores (-0.13; 1.05) for BMI and +17 points (0; 39) for the CFQ-R respiratory domain score. The selected predictors explained 23 % of the variability in sweat chloride concentration changes, 18 % of the variability in ppFEV1 changes, 39 % of the variability in BMI changes, and 65 % of the variability in CFQ-R changes. CONCLUSIONS: This study highlights a high level of heterogeneity in treatment response to ETI, which can only be partially explained by the baseline characteristics of the disease.

Effects of elexacaftor / tezacaftor / ivacaftor triple combination therapy on glycaemic control and body composition in patients with cystic fibrosis-related diabetes.

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are a group of new drugs for the treatment of cystic fibrosis (CF) and elexacaftor + tezacaftor + ivacaftor (ETI) triple combination therapy has been approved as first choice therapy in the treatment of patients with at least 1 copy of F508del variation. Data on the effects of CFTR modulators on glucose metabolism are limited to small studies with conflicting results. We conducted a prospective observational study on 24 CF patients with CF-related diabetes requiring insulin therapy, with the aim to evaluate the effectiveness of ETI on glucose metabolism, glucose variability and body composition. After six months of treatment, HbA1c and coefficient of variation, measured through flash or continuous glucose monitoring, significantly decreased (median changes: -0.5, P = 0.029 and -6.3, P = 0.008, respectively), despite unchanged insulin requirements. Over the treatment period, percent of fat mass increased by a median value of 3% (p = 0.029).

Effects of prolonged proton pump inhibitor treatment on nutritional status and respiratory infection risk in cystic fibrosis: A matched cohort study.

BACKGROUND: Evidence on the effectiveness of proton pump inhibitors (PPI) as adjuvant therapy to improve maldigestion in people with cystic fibrosis (pwCF) is limited and there is increasing concern on possible side effects. METHODS: We conducted a matched cohort study based on paediatric and adult pwCF who received PPI for ≥3 months. Treated patients were matched to a group of patients who never received PPI using a nearest neighbour propensity score matching based on sex, year of birth, CFTR genotype and pancreatic insufficiency. RESULTS: The study included 160 pwCF: 80 treated and 80 untreated patients. Over a median follow-up of 2 years, no significant differences in changes in BMI z-score were detected between groups (adjusted mean difference: 0.06, 95% CI: -0.17-0.30). At baseline 25% (n = 20) of the treated patients and 22.5% (n = 18) of the untreated patients had a positive culture for P. aeruginosa (Pa). At follow-up percentages of Pa positive cultures increased to 47.5% (n = 38) in the treated group and to 26.3% (n = 21) in the untreated group (adjusted mean difference: 23.1%, 95% CI: 10.8-35.3). CONCLUSIONS: Prolonged PPI therapy should be used cautiously in pwCF since it may increase the risk of respiratory infection by Pa. In addition, such treatment does not seem to improve nutritional status.

Immunogenicity of BNT162b2 mRNA-Based Vaccine against SARS-CoV-2 in People with Cystic Fibrosis According to Disease Characteristics and Maintenance Therapies.

During the SARS-CoV-2 vaccination campaign, people with CF (pwCF) were considered a clinically vulnerable population. However, data on the immunogenicity of anti-SARS-CoV-2 vaccines in pwCF are lacking. We conducted a prospective study enrolling all patients aged > 12 and who were followed-up in our CF center and received two doses of the BNT162b2 vaccine in the period of March−October 2021. Blood samples were taken from them for the quantification of antibodies to the SARS-CoV-2 spike protein receptor binding domain immediately before receiving the first dose and 3 and 6 months after the second dose. We enrolled 143 patients (median age: 21 years, range: 13−38), 16 of whom had had a previous infection. Geometric mean antibody titer (GMT) 3 months after vaccination was 1355 U/mL (95% CI: 1165−1575) and decreased to 954 U/mL (95% CI: 819−1111) after 6 months (p < 0.0001). GMT was higher among previously infected patients as compared to those naïve to SARS-CoV-2 (6707 vs. 1119 U/mL at 3 months and 4299 vs. 796 U/mL at 6 months, p < 0.0001) with no significant differences in the rate of decline over time (p = 0.135). All pwCF mounted an antibody response after two doses of the BNT162b2 vaccine, which waned at 6 months from vaccination. Age ≥ 30 years and the use of inhaled corticosteroids were associated with a lower humoral response. Between the second and the third doses, nine episodes of vaccine breakthrough infections were observed.