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Current Treatment Options for Cystic Fibrosis-Related Liver Disease.

ABSTRACT: 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.

SUBMITTER: Staufer K

PROVIDER: S-EPMC7696864 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Current Treatment Options for Cystic Fibrosis-Related Liver Disease.

Staufer Katharina K

International journal of molecular sciences 20201114 22

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 ...[more]

PMID: 33202578

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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.

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Current Treatment Options for Cystic Fibrosis-Related Liver Disease.

Publications

Current Treatment Options for Cystic Fibrosis-Related Liver Disease.

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