Ursodeoxycholic acid for cystic fibrosis-related liver disease

Cheng, Katharine; Ashby, Deborah; Smyth, Rosalind L

doi:10.1002/14651858.cd000222.pub4

Cited by 55 publications

(27 citation statements)

References 21 publications

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“…UDCA efficacy in CFLD remains controversial. (7) In sharp contrast with pulmonary and nutritional CF complications, where new treatments have been shown to improve survival and quality of life, no drugs have demonstrated an effect on CFLD. Although a recent Cochrane systematic review concluded that "There is currently insufficient evidence to justify routine [UDCA] use in cystic fibrosis," (7) several guidelines for CFLD patient care still recommend its use.…”

Section: Discussionmentioning

confidence: 99%

“…(7) In sharp contrast with pulmonary and nutritional CF complications, where new treatments have been shown to improve survival and quality of life, no drugs have demonstrated an effect on CFLD. Although a recent Cochrane systematic review concluded that "There is currently insufficient evidence to justify routine [UDCA] use in cystic fibrosis," (7) several guidelines for CFLD patient care still recommend its use. (8,10) High doses of UDCA treatment have even been detrimental to patients with primary sclerosing cholangitis as its biotransformation in the colon produced lithocholic acid, a secondary hydrophobic bile acid with potential toxicity.…”

Section: Discussionmentioning

confidence: 99%

“…(4) Ursodeoxycholic acid (UDCA) is prescribed in CF patients with liver disease, although there is no evidence of an effect. (7) In this study, we investigated the evolution of liver disease, its related risks factors, and the use and effect of UDCA treatment in a large cohort of patients with CF. CFLD was homogeneously defined using clinical data collected in the French CF Gene Modifier Study, in accordance with the European best-practice guidance.…”

Section: See Editorial On Page 1379mentioning

confidence: 99%

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

et al. 2018

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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. This article is protected by copyright. All rights reserved.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: See Editorial On Page 1379mentioning

confidence: 99%

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

et al. 2018

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“…In 2017, the authors concluded that, on the basis of results from 10 clinical trials, there was insufficient evidence to justify the routine use of UDCA in CFLD. (33) One study did show improved liver biochemistries in patients treated with moderate-to-high doses of UDCA, (34) and an observational study also showed a minor improvement in liver stiffness by elastography in patients treated with UDCA for 1 year. (32) It is unclear, however, whether UDCA actually improves the natural history of CFLD, even if it does appear to improve liver biochemistries.…”

Section: Ursodeoxycholic Acid Therapymentioning

confidence: 99%

“…Treatment of liver disease in CF has included ursodeoxycholic acid (UDCA), (32,33) but the mechanism by which UDCA improves liver disease is not clearly understood. Possible mechanisms include improved bile flow through calcium-dependent secretions of chloride and bicarbonate ions, along with direct anti-inflammatory effects.…”

Section: Ursodeoxycholic Acid Therapymentioning

confidence: 99%

Cystic Fibrosis–Associated Liver Disease in Lung Transplant Recipients

Mallea¹,

Bolan²,

Cortese

et al. 2019

Liver Transpl

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Cystic fibrosis (CF) is an autosomal recessive disease characterized by mutations in the gene that encodes for the cystic fibrosis transmembrane conductance regulator protein (CFTR). CFTR gene mutations manifest as epithelial cell dysfunction in the airways, biliary tract, pancreas, gut, sweat glands, paranasal sinuses, and genitourinary tract. The clinical manifestations of this dysfunction include respiratory tract infections, bronchiectasis, pancreatic insufficiency, malabsorption, intestinal obstruction, liver disease, and male infertility. The liver disease manifestations of CF can include biliary disease, multilobular cirrhosis, and portal hypertension with and without cirrhosis. Pulmonary disease is the main cause for morbidity and mortality in individuals with CF, and according to the International Society for Heart and Lung Transplantation, CF is the third most common indication for lung transplantation in adults, accounting for 16% of procedures performed. The survival after lung transplantation in individuals with CF continues to improve and is now the highest among end‐stage lung diseases requiring transplant. The survival rate at 10 years is close to 50%. Given the potential presence of liver disease in CF patients undergoing an evaluation for lung transplantation and in lung transplant recipients, it is important to understand the manifestations of liver disease in CF patients and the recommended workup and follow‐up. This review aims to discuss the current literature and provide guidance in the management of these patients.

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Modifikation der Regioselektivität einer P450‐Monooxygenase ermöglicht die Synthese von Ursodeoxycholsäure durch die 7β‐Hydroxylierung von Lithocholsäure

et al. 2020

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Wir haben die P450-Monooxygenase CYP107D1 (OleP) aus Streptomyces antibioticus für die stereo-und regioselektive 7b-Hydroxylierung von Lithocholsäure (LCS) zur Herstellung von Ursodeoxycholsäure (UDCS) durch "Protein-Engineering" angepasst. OleP wurde zuvor für die Hydroxylierung von Testosteron an der 7b-Position beschrieben, hydroxyliert jedoch LCS ausschließlich an der 6b-Position, wodurch Murideoxycholsäure (MDCS) gebildet wird. Strukturund 3DM-Analysen, sowie molekulare Modellierungen wurden verwendet, um die Aminosäurereste F84, S240 und V291 als spezifitätsbestimmend zu identifizieren. Durch einen Alaninscan wurde S240A als UDCS-produzierende Variante identifiziert. Basierend auf den identifizierten Positionen wurde eine synthetische "small but smart" Bibliothek durch die Verwendung eines farbbasierten Assays auf UDCS Produktion getestet. Hier konnte eine beinahe perfekte regio-und stereoselektive Dreifachvariante (F84Q/S240A/V291G) identifiziert werden, die UDCS in einer 10-fach hçheren Menge produziert als die S240A Variante. Der hergestellte Biokatalysator erçffnet neue Mçglichkeiten zur umweltfreundlichen Synthese von UDCS aus dem Abfallprodukt LCS. Ursodeoxycholsäure (UDCS) ist eine wertvolle Gallensäure, die häufig zur Behandlung von Cholezystitis verschrieben wird, da sie Cholesteringallensteine mit weniger Nebenwirkungen als Chenodeoxycholsäure (CDCS) auflçsen kann. [1] UDCS hat auch entzündungshemmende Eigenschaften [2] und wird in der Therapie zystischer Fibrosen [3] und Lebererkrankungen wie der primären biliären Zirrhose angewendet. [4] UDCS kommt in der Natur nur in Bärengalle [5] vor und findet Verwendung in der traditionellen Medizin, kann aber lediglich durch Gallenkatheterisierung von Zuchtbären gewonnen werden. Alternativ kann UDCS halbsynthetisch aus Chol-säure (CS) [6] oder CDCS hergestellt werden. [7, 8] Die von CS startende Syntheseroute führt zu CDCS innerhalb von 5 Schritten, einschließlich einer Wolff-Kishner-Reduktion, und bildet UDCS durch eine Epimerisierung an C7 (Schema 1 a, Schema S1). [9] Die Ausbeute dieser Syntheseroute übersteigt 30 % nicht. Um diese Limitierungen zu umgehen, wurden kürzere biokatalytische Synthesewege erschlossen, die Enzyme für die Epimerisierung von CDCS zu UDCS verwenden (Schema 1 a). [7, 10] LCS ist als Abfallprodukt der Fleischproduktion [11] reichlich und kostengünstig vorhanden, da LCS in Nutztieren wie Schafen, [12] Rindern [12] und Schweinen [13] vorkommt. Zurzeit ist kein biotechnologischer Prozess [14] bekannt, der UDCS aus LCS herstellt. Somit ist LCS als Substrat von Interesse. Bisher konnte die Produktion von UDCS aus LCS für wenige mikrobielle Organismen gezeigt werden. [15] Der Pilz Fusarium equiseti kann LCS zu einer Reihe von Produkten umsetzen; so auch zu UDCS mit einer Ausbeute von 35 %. [16] Derzeit ist kein Enzym bekannt, das LCS selektiv an der 7b-Position hydroxyliert und UDCS bildet. Der Syntheseweg zu UDCS in Mikroorganismen ist, ausgehend von LCS, unaufgeklärt. Ein Enzym zur direkten 7b-Hydroxylierung wäre ein wertvolles Werkze...

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Ursodeoxycholic acid for cystic fibrosis-related liver disease

Cited by 55 publications

References 21 publications

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

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

Cystic Fibrosis–Associated Liver Disease in Lung Transplant Recipients

Modifikation der Regioselektivität einer P450‐Monooxygenase ermöglicht die Synthese von Ursodeoxycholsäure durch die 7β‐Hydroxylierung von Lithocholsäure

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