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Cystic Fibrosis Liver Disease: Outcomes and Risk Factors in a Large Cohort of French Patients.

ABSTRACT: Cystic fibrosis (CF)-related liver disease (CFLD) is a common symptom in patients with CF. However, its prevalence, risk factors, and evolution are unclear. We analyzed a large database of patients with CF to investigate the incidence of CFLD, its related risk factors, and the use and effect of ursodeoxycholic acid (UDCA) treatment. We retrospectively analyzed 3,328 CF patients with pancreatic insufficiency born after 1985 and recruited into the French CF Modifier Gene Study since 2004. We determined liver status, age at CFLD and severe CFLD onset, sex, CFTR genotype, history of meconium ileus, treatment with UDCA, and respiratory and nutritional status. The incidence of CFLD increased by approximately 1% every year, reaching 32.2% by age 25. The incidence of severe CFLD increased only after the age of 5, reaching 10% by age 30. Risk factors for CFLD and severe CFLD were male sex, CFTR F508del homozygosity, and history of meconium ileus. Increasingly precocious initiation of UDCA treatment did not change the incidence of severe CFLD. Finally, patients with severe CFLD had worse lung function and nutritional status than other CF patients. Conclusion: CFLD occurs not only during childhood but also later in the lifetime of patients with CF; male sex, CFTR F508del homozygosity, and history of meconium ileus are independent risk factors for CFLD development; earlier use of UDCA over the last 20 years has not changed the incidence of severe CFLD, leading to questions about the use of this treatment in young children given its possible adverse effects.

SUBMITTER: Boelle PY

PROVIDER: S-EPMC6519059 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Cystic Fibrosis Liver Disease: Outcomes and Risk Factors in a Large Cohort of French Patients.

Boëlle Pierre-Yves PY Debray Dominique D Guillot Loic L Clement Annick A Corvol Harriet H

Hepatology (Baltimore, Md.) 20181228 4

Cystic fibrosis (CF)-related liver disease (CFLD) is a common symptom in patients with CF. However, its prevalence, risk factors, and evolution are unclear. We analyzed a large database of patients with CF to investigate the incidence of CFLD, its related risk factors, and the use and effect of ursodeoxycholic acid (UDCA) treatment. We retrospectively analyzed 3,328 CF patients with pancreatic insufficiency born after 1985 and recruited into the French CF Modifier Gene Study since 2004. We deter ...[more]

PMID: 30058245

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Project description:BackgroundChronic liver disease (CLD) is usually asymptomatic but earlier detection is critical to permit life-saving interventions for those at risk due to high alcohol consumption and increased body mass index (BMI). The aim of this study was to estimate the association between the Enhanced Liver Fibrosis (ELF) test and liver-related events (LRE) and its performance in predicting LRE in postmenopausal women with risk factors in a nested case-control study within the United Kingdom Trial of Ovarian Cancer Screening (UKCTOCS).MethodsIn a cohort of 95,126 we performed a case-control study measuring ELF in blinded samples from 173 participants with self-reported high alcohol use and / or BMI ?25?kg/m2 comprising all 58 cases who developed LRE and 115 controls matched for age, alcohol and BMI who did not develop LRE during median follow-up of 8.5?years.ResultsUsing Cox regression at an ELF threshold of 10.51 hazard ratios (HR) for LRE were 4.88 (95% confidence interval (CI) 2.37-10.03) (unadjusted model) and 4.62 (95% CI 2.12-10.08) (adjusted for deprivation and self-reported hypertension, heart disease, hypercholesterolaemia and diabetes). At a threshold of 9.8 HR for LRE were 2.21 (95% CI 1.22-3.97) (unadjusted model) and 2.18 (95% CI 1.19-4.01) (adjusted). ELF was evaluated as a time dependent variable by generating time-dependent Cox models; HRs at an ELF threshold of 10.51 were 1.94 (95% CI 1.10-3.39) (unadjusted) and 2.05 (95% CI 1.16-3.64) (adjusted) and at a threshold of 9.8 HRs were 1.85 (95% CI 1.09-3.15) (unadjusted) and 1.80 (95% CI 1.04-3.13) (adjusted). Area under the receiver operating characteristic curve for recruitment ELF predicting LRE was 0.58 (95% CI 0.49-0.68), and for second subsequent ELF 0.61 (95% CI 0.52-0.71).ConclusionThis study demonstrates the association between ELF and CLD in postmenopausal women with risk factors for liver disease, creating the opportunity to intervene to reduce liver-related mortality and morbidity. Although larger studies are required, these results demonstrate the potential of ELF as a prognostic tool in health checks in primary care.Trial registrationThis study is nested in UKCTOCS. UKCTOCS is registered as an International Standard Randomised Controlled Trial, number ISRCTN22488978. Registered 06/04/2000.

Project description:BackgroundAbnormal biliary secretion leads to the thickening of bile and the formation of plugs within the bile ducts; the consequent obstruction and abnormal bile flow ultimately results in the development of cystic fibrosis-related liver disease. This condition peaks in adolescence with up to 20% of adolescents with cystic fibrosis developing chronic liver disease. Early changes in the liver may ultimately result in end-stage liver disease with people needing transplantation. One therapeutic option currently used is ursodeoxycholic acid. This is an update of a previous review.ObjectivesTo analyse evidence that ursodeoxycholic acid improves indices of liver function, reduces the risk of developing chronic liver disease and improves outcomes in general in cystic fibrosis.Search methodsWe searched the Cochrane CF and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. We also contacted drug companies and searched online trial registries.Date of the most recent search of the Group's trials register: 09 April 2017.Selection criteriaRandomised controlled trials of the use of ursodeoxycholic acid for at least three months compared with placebo or no additional treatment in people with cystic fibrosis.Data collection and analysisTwo authors independently assessed trial eligibility and quality. The authors used GRADE to assess the quality of the evidence.Main resultsTwelve trials have been identified, of which four trials involving 137 participants were included; data were only available from three of the trials (118 participants) since one cross-over trial did not report appropriate data. The dose of ursodeoxycholic acid ranged from 10 to 20 mg/kg/day for up to 12 months. The complex design used in two trials meant that data could only be analysed for subsets of participants. There was no significant difference in weight change, mean difference -0.90 kg (95% confidence interval -1.94 to 0.14) based on 30 participants from two trials. Improvement in biliary excretion was reported in only one trial and no significant change after treatment was shown. There were no data available for analysis for long-term outcomes such as death or need for liver transplantation.Authors' conclusionsThere are few trials assessing the effectiveness of ursodeoxycholic acid. The quality of the evidence identified ranged from low to very low. There is currently insufficient evidence to justify its routine use in cystic fibrosis.

Project description:ContextA subset (approximately 3%-5%) of patients with cystic fibrosis (CF) develops severe liver disease with portal hypertension.ObjectiveTo assess whether any of 9 polymorphisms in 5 candidate genes (alpha(1)-antitrypsin or alpha(1)-antiprotease [SERPINA1], angiotensin-converting enzyme [ACE], glutathione S-transferase [GSTP1], mannose-binding lectin 2 [MBL2], and transforming growth factor beta1 [TGFB1]) are associated with severe liver disease in patients with CF.Design, setting, and participantsTwo-stage case-control study enrolling patients with CF and severe liver disease with portal hypertension (CFLD) from 63 CF centers in the United States as well as 32 in Canada and 18 outside of North America, with the University of North Carolina at Chapel Hill as the coordinating site. In the initial study, 124 patients with CFLD (enrolled January 1999-December 2004) and 843 control patients without CFLD were studied by genotyping 9 polymorphisms in 5 genes previously studied as modifiers of liver disease in CF. In the second stage, the SERPINA1 Z allele and TGFB1 codon 10 genotype were tested in an additional 136 patients with CFLD (enrolled January 2005-February 2007) and 1088 with no CFLD.Main outcome measuresDifferences in distribution of genotypes in patients with CFLD vs patients without CFLD.ResultsThe initial study showed CFLD to be associated with the SERPINA1 Z allele (odds ratio [OR], 4.72; 95% confidence interval [CI], 2.31-9.61; P = 3.3 x 10(-6)) and with TGFB1 codon 10 CC genotype (OR, 1.53; 95% CI, 1.16-2.03; P = 2.8 x 10(-3)). In the replication study, CFLD was associated with the SERPINA1 Z allele (OR, 3.42; 95% CI, 1.54-7.59; P = 1.4 x 10(-3)) but not with TGFB1 codon 10. A combined analysis of the initial and replication studies by logistic regression showed CFLD to be associated with SERPINA1 Z allele (OR, 5.04; 95% CI, 2.88-8.83; P = 1.5 x 10(-8)).ConclusionsThe SERPINA1 Z allele is a risk factor for liver disease in CF. Patients who carry the Z allele are at greater risk (OR, approximately 5) of developing severe liver disease with portal hypertension.

Dataset Information

Cystic Fibrosis Liver Disease: Outcomes and Risk Factors in a Large Cohort of French Patients.

Publications

Cystic Fibrosis Liver Disease: Outcomes and Risk Factors in a Large Cohort of French Patients.

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