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

Background & aims: Cystic 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. Methods: A 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. Results: 12 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 %). Conclusion: We 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.

A novel free-breathing abdominal RAVE T2/T1 hybrid MRI sequence in patients with cystic fibrosis: Preliminary results.

OBJECTIVES: Patients with cystic fibrosis (CF) increasingly require imaging for the diagnosis of abdominal complications. We prospectively evaluated the image quality and signal-to-noise ratio (SNR) of a modern radial volumetric encoding (RAVE) T2/T1 hybrid sequence for abdominal magnetic resonance imaging (MRI). RAVET2/T1 is a three-dimensional radial sequence with fat saturation and blood flow suppression that acquires T2- and T1-weighted contrasts in one scan in an identical slice position during free-breathing. METHODS: Sixteen CF patients underwent axial T2 HASTE (1000 ms/93 ms TR/TE), T1 DIXON (6.8 ms/2.4 ms/4.8 ms TR/TE1/TE2), and RAVE T2/T1 hybrid sequence (1200 ms/1.7 ms/3.3 ms/4.9 ms/102 ms TR/TE1/TE2/TE3/TE4) of the upper abdomen at 1.5 Tesla. The SNR values in six different regions were assessed and compared using the Wilcoxon signed-rank test. The image quality criteria were rated on a 5-point Likert scale. RESULTS: In all regions, the SNR was significantly higher in the T2 weighted aspect of the RAVE T2/T1 hybrid sequence compared to T2 HASTE (p < 0.05) and significantly lower in the T1 weighted in-phase aspect of the RAVE T2/T1 hybrid sequence compared to the T1 DIXON sequence (p < 0.05). Qualitatively the T2 weighted aspect of the RAVE T2/T1 hybrid sequence was rated significantly higher than the T2 HASTE in 6 of 7 categories (p < 0.05) and the T1 weighted in-phase aspect of the RAVE T2/T1 hybrid sequence was rated significantly higher than the T1 DIXON in 2 of 6 categories (p < 0.05). CONCLUSIONS: The abdominal radial RAVE T2/T1 hybrid sequence provided higher image quality and SNR than the T2HASTEsequence. Together with increased robustness against motion artifacts, the RAVE T2/T1 hybrid sequence appears to be a good tool for abdominal imaging in CF patients.

Cystic fibrosis patients on cystic fibrosis transmembrane conductance regulator modulators have a reduced incidence of cirrhosis.

BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators significantly improve pulmonary function in patients with cystic fibrosis (CF) but the effect on hepatobiliary outcomes remains unknown. We hypothesized that CF patients on CFTR modulators would have a decreased incidence of cirrhosis compared to patients not on CFTR modulators or on ursodiol. AIM: To investigate the effect of CFTR modulators on the development of cirrhosis in patients with CF. METHODS: A retrospective analysis was performed using Truven MarketScan from January 2012 through December 2017 including all patients with a diagnosis of CF. Patients were excluded if they underwent a liver transplantation or if they had other etiologies of liver disease including viral hepatitis or alcohol use. Subjects were grouped by use of CFTR modulators, ursodiol, dual therapy, or no therapy. The primary outcome was development of cirrhosis. Kaplan-Meier curves estimated the incidence of cirrhosis and log-rank tests compared incidence curves between treatment groups. RESULTS: A total of 7201 patients were included, of which 955 (12.6%) used a CFTR modulator, 529 (7.0%) used ursodiol, 105 (1.4%) used combination therapy, and 5612 (74.3%) used neither therapy. The incidence of cirrhosis was 0.1% at 1 year and 0.7% at 4 years in untreated patients, 5.9% and 10.1% in the Ursodiol group, and 1.0% and 1.0% in patients who received both therapies. No patient treated with CFTR modulators alone developed cirrhosis. Patients on CFTR modulators alone had lower cirrhosis incidence than untreated patients (P = 0.05), patients on Ursodiol (P < 0.001), and patients on dual therapy (P = 0.003). The highest incidence of cirrhosis was found among patients treated with Ursodiol alone, compared to untreated patients (P < 0.001) or patients on Ursodiol and CFTR modulators (P = 0.01). CONCLUSION: CFTR modulators are associated with a reduction in the incidence of cirrhosis compared to other therapies in patients with CF.

The use of elexacaftor/tezacaftor/ivacaftor in patients with cystic fibrosis postliver transplant: A case series.

INTRODUCTION: Cystic fibrosis (CF)-related liver disease (CFLD) manifests as a wide spectrum of hepatobiliary disease and can progress to need liver transplantation. Elexacaftor/tezacaftor/ivacaftor (elx/tez/iva) is a cystic fibrosis transmembrane conductance regulator modulator that has superior efficacy compared to previously approved modulators. Use of elx/tez/iva, should be approached with caution in individuals with CFLD or following liver transplantation due to possible increases in liver function tests (LFTs) and drug-drug interactions with several immunosuppressant medications. OBJECTIVE: The purpose of this case series is to explore if the use of elx/tez/iva is safe and tolerable in patients with CF postliver transplantation. METHODS: A retrospective case series including patients prescribed elx/tez/iva following liver transplantation and an immunosuppressive regimen consisting of drug therapy metabolized by P-glycoprotein was completed. RESULTS: Ten patients at six CF centers with a median age of 22.1 years (range 14-43.4 years) and the median time from the transplant of 6.9 years (range 0.6-22 years) were included. Most patients (8, 80%) received a reduced or full dose of elx/tez/iva for a mean duration of 10.4 months (range 7-12 months). Fluctuations in LFTs occurred in all patients (10, 100%) and led to therapy discontinuation in two patients (20%). Elx/tez/iva initiation resulted in elevations in tacrolimus trough concentration in seven patients (70%). Most patients who tolerated elx/tez/iva had symptomatic and quality of life improvement, increased body mass index, and maintained or improved lung function. CONCLUSION: Initiation of elx/tez/iva in patients with CF who received liver transplantation may be safe with clinical benefits.

Non-invasive Diagnostic Tests in Cystic Fibrosis-Related Liver Disease: A Diagnostic Test Accuracy Network Meta-Analysis.

Background and Aims: Cystic fibrosis-related liver disease (CFLD) is one of the leading causes of morbidity and mortality in cystic fibrosis (CF). Several non-invasive diagnostic methods have been proposed as screening tools for CFLD. Our aim was to rank all available non-invasive modalities for diagnostic performance. Methods: A systematic search was performed in five medical databases to find studies which reported on any single or composite non-invasive diagnostic test (as an index test) compared to the Debray, the EuroCare or the Colombo criteria (as a reference standard). Ranking was carried out with a Bayesian diagnostic test accuracy network meta-analysis based on superiority indices, calculated for pooled sensitivity (Se) and specificity (Sp) with a 95% confidence interval (CI). The study was registered under CRD42020155846 in PROSPERO. Results: Fifteen studies with 15 index tests and a combination of them were included. The New criteria proposed by Koh et al. - which represent a composite diagnostic definition for CFLD including liver biochemistry, ultrasonography, transient elastography and fibrosis markers-had the best performance for detecting CFLD (Se:94%[CI:58-100], Sp:72%[CI:52-84]); while transient elastography (Se:65%[CI:56-74], Sp:88%[CI:84-91]) and a combination of it with a tissue inhibitor of metalloproteinase-4 measurement (Se:78%[CI:30-100], Sp:64%[CI:18-95%]) proved to be the second and third best options, respectively. In the imaging techniques subgroup, transient elastography (Se:66%[CI:57-72], Sp:88%[CI:85-91%]), acoustic radiation force impulse in the right lobe (Se:54%[CI:33-74], Sp:88%[CI:66-96]) and that in the left lobe (Se:55%[CI:23-81], Sp:82%[CI:50-95]) were ranked the highest. Comparing biochemical markers/fibrosis indices, the measurement of the Forns index (Se:72%[CI:25-99], Sp:63%[CI:16-94]), the aspartate aminotransferase-to-platelet ratio (Se:55%[CI:41-68], Sp:83%[CI:66-89]) and alkaline phosphatase (Se:63%[CI:18-93], Sp:64%[CI:19-95]) were ranked the highest. Conclusion: The New criteria show the best diagnostic performance. In clinical practice, transient elastography seems to be a simple, cheap and non-invasive tool, outperforming imaging, biochemical and fibrosis tests for detecting CFLD. Further studies are needed to validate our findings.

Current Treatment Options for Cystic Fibrosis-Related Liver Disease.

Cystic Fibrosis-related liver disease (CFLD) has become a leading cause of morbidity and mortality in patients with Cystic Fibrosis (CF), and affects children and adults. The understanding of the pathogenesis of CFLD is key in order to develop efficacious treatments. However, it remains complex, and has not been clarified to the last. The search for a drug might be additionally complicated due to the diverse clinical picture and lack of a unified definition of CFLD. Although ursodeoxycholic acid has been used for decades, its efficacy in CFLD is controversial, and the potential of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators and targeted gene therapy in CFLD needs to be defined in the near future. This review focuses on the current knowledge on treatment strategies for CFLD based on pathomechanistic viewpoints.

Cystic fibrosis dyslipidaemia: A cross-sectional study.

BACKGROUND: The interest in cystic fibrosis (CF) dyslipidaemia as a potential risk factor for cardiovascular disease is increasing with patients' survival. This study aimed to investigate CF dyslipidaemia, its clinical correlates and links to oxidized low-density lipoprotein (oxLDL), adiponectin, and apolipoprotein E (APOE). METHODS: This cross-sectional study assessed clinical characteristics of CF, as well as the serum lipid profile, oxLDL, adiponectin, and APOE. RESULTS: In total, 108 CF subjects were enrolled in this study, with a median age of 22 years, BMI of 20.5 kg/m2, FEV1% of 61%, of which 81% were pancreatic insufficient (PI). Healthy subjects (HS; n = 51) were in similar age. Hypocholesterolaemia occurred in 31% of CF subjects and in no HS. Hypertriglyceridaemia concerned 21% of patients (HS: 8%, p = .04), and low HDL-C 45% (HS: 6%, p < .0001). At least one of these three CF dyslipidaemia disturbances was present in 62% of CF subjects, but there were no significant differences in oxLDL, oxLDL/LDL-C ratio, adiponectin, and APOE between CF and HS groups. PI was independently associated with low total cholesterol, LDL-C, and non-high density lipoprotein cholesterol, with age and sex also modifying lipid levels. In CF (n = 42), triglycerides did not correlate with serum tumour necrosis factor α (TNF-α). CONCLUSIONS: CF dyslipidaemia is highly prevalent and heterogenous. The lipid profile weakly associates with the clinical characteristics of CF as well as oxLDL, adiponectin, and APOE. Further research is needed, especially regarding HDL function in CF, the causes of hypertriglyceridaemia, and the value of essential fatty acid supplementation for CF dyslipidaemia.

Combined liver and pancreas transplantation in two children with cystic fibrosis-First experience in Australia and New Zealand.

We report the first two pediatric patients with CF who underwent successful combined liver-pancreas transplantation in Australia and New Zealand for CF liver disease and CF-related diabetes mellitus.

Unmet needs in cystic fibrosis: the next steps in improving outcomes.

INTRODUCTION: Cystic fibrosis (CF) outcomes and survival have improved over the last century primarily due to advancements in antibiotics, nutritional, and pulmonary therapies. Reviewed here are the significant unmet needs that exist for individuals with CF. Areas covered: With the recent development of medications that address the underlying defect in the CF protein, there is hope that there will be continued improvement in CF outcomes. However, there remains a need to prevent or stop progression of CF-related complications, as the CF protein is important to several body systems. As end stage lung disease is the primary cause of mortality in CF, a need exists for advancements in pulmonary therapies to reduce time burden, identification of best practices for the treatment of pulmonary exacerbations, further development of anti-infective and anti-inflammatory therapies, and appropriately timed referral for lung transplantation at end-stage lung disease. Extra-pulmonary complications are increasingly recognized and better understanding of such problems as CF related liver disease is needed. Expert commentary: While CFTR modulators are available for the majority of CF patients, there remains a need for effective therapies to address infection, inflammation, irreversible lung disease, and extrapulmonary complications of CF.

Practical approach to the gastrointestinal manifestations of cystic fibrosis.

Cystic fibrosis (CF) is the most common, life-shortening, genetic illness affecting children in Australia and New Zealand. The genetic abnormality results in abnormal anion transport across the apical membrane of epithelial cells in a number of organs, including the lungs, gastrointestinal tract, liver and genito-urinary tract. Thus, CF is a multi-system disorder that requires a multi-disciplinary approach. Respiratory disease is the predominant cause of both morbidity and mortality in patients with CF. However, there are significant and clinically relevant gastrointestinal, liver, pancreatic and nutritional manifestations that must be detected and managed in a timely and structured manner. The aim of this review is to provide evidence-based information and clinical algorithms to guide the nutritional and gastrointestinal management of patients with CF.