Cystic fibrosis-related liver disease: Clinical presentations, diagnostic and monitoring approaches in the era of CFTR modulator therapies

Dana, Jérémy; Debray, Dominique; Beaufrère, Aurélie; Hillaire, Sophie; Fabrè, Monique; Reinhold, Caroline; Baumert, Thomas F.; Berteloot, Laureline; Vilgrain, Valérie

doi:10.1016/j.jhep.2021.09.042

Cited by 63 publications

(76 citation statements)

References 151 publications

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“…The disease is asymptomatic in the early stages. Blood parameters have poor predicting accuracy, although abnormal liver enzyme levels such as ALT and AST are often presented in CF patients ( 58 ). Liver ultrasound is a key examination in the diagnosis of CFLD, which aids the physicians to evaluate the liver, gallbladder, biliary tree, and importantly, the signs of portal hypertension, which often occurs in late stage CFLD ( 58 ).…”

Section: Discussionmentioning

confidence: 99%

“…Blood parameters have poor predicting accuracy, although abnormal liver enzyme levels such as ALT and AST are often presented in CF patients ( 58 ). Liver ultrasound is a key examination in the diagnosis of CFLD, which aids the physicians to evaluate the liver, gallbladder, biliary tree, and importantly, the signs of portal hypertension, which often occurs in late stage CFLD ( 58 ). The main histological presentation of CFLD is focal biliary fibrosis, with the primary hypothesis being that the loss of CFTR in the cholangiocytes leads to increased viscosity of the bile, reduced bile flow, and biliary obstruction, and ultimately peribiliary inflammation and fibrosis ( 58 ).…”

Section: Discussionmentioning

confidence: 99%

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Cystic fibrosis rabbits develop spontaneous hepatobiliary lesions and CF-associated liver disease (CFLD)-like phenotypes

Hou

Song

et al. 2022

PNAS Nexus

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Cystic fibrosis (CF) is an autosomal recessive genetic disease affecting multiple organs. Approximately 30% CF patients develop CF-related liver disease (CFLD), which is the third most common cause of morbidity and mortality of CF. CFLD is progressive, and many of the severe forms eventually need liver transplantation. The mechanistic studies and therapeutic interventions to CFLD are unfortunately very limited. Utilizing the CRISPR/Cas9 technology, we recently generated CF rabbits by introducing mutations to the rabbit cystic fibrosis transmembrane conductance regulator (CFTR) gene. Here we report the liver phenotypes and mechanistic insights into the liver pathogenesis in these animals. CF rabbits develop spontaneous hepatobiliary lesions and abnormal biliary secretion accompanied with altered bile acid profiles. They exhibit non-alcoholic steatohepatitis (NASH)-like phenotypes, characterized by hepatic inflammation, steatosis, and fibrosis, as well as altered lipid profiles and diminished glycogen storage. Mechanistically, our data reveal that multiple stress-induced metabolic regulators involved in hepatic lipid homeostasis were up-regulated in the livers of CF-rabbits, and that endoplasmic reticulum (ER) stress response mediated through IRE1α-XBP1 axis as well as NF-κB- and JNK-mediated inflammatory responses prevail in CF rabbit livers. These findings show that CF rabbits manifest many CFLD-like phenotypes and suggest targeting hepatic ER stress and inflammatory pathways for potential CFLD treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cystic fibrosis rabbits develop spontaneous hepatobiliary lesions and CF-associated liver disease (CFLD)-like phenotypes

Hou

Song

et al. 2022

PNAS Nexus

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“…Non-cirrhotic portal hypertension secondary to obliterative portal venopathy and/or nodular regenerative hyperplasia is a common presentation in adult CFLD patients. Obliterative portal venopathy, septal and perisinusoidal fibrosis, vascular changes and sinusoidal dilatation are the most typical histological abnormalities in these cases [31 ▪▪ ]. Liver biopsy in CFLD should be considered when porto-sinusoidal vascular disease and nodular regenerative hyperplasia are suspected, and should ideally be done via transjugular access, so hepatic venous pressure gradient can be measured in the same procedure [31 ▪▪ ].…”

Section: Cystic Fibrosis Related Liver Diseasementioning

confidence: 99%

Histological evaluation in biliary diseases

Saffioti

Motta

Quaglia

2023

Current Opinion in Gastroenterology

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Purpose of reviewThis review focuses on recent developments of histopathology in the most common biliary disorders affecting adults. The reader is referred to other sources for the specialized topics on paediatric populations and post liver transplantation.Recent findingsFibrosis stage at diagnosis is an independent predictor of liver transplant-free survival in patients with primary biliary cholangitis. Immunohistochemistry might have an important role in predicting response to treatment. New histological scoring systems with excellent correlation with long-term clinical outcomes are being developed in primary sclerosing cholangitis (PSC). Quantification of fibrosis with collagen proportionate area can improve risk stratification and could be particularly useful to assess treatment response in PSC.Gene sequencing on cytology and intrabiliary biopsy may improve risk stratification for cholangiocarcinoma. Genetic variants of ATP8B1, ABCB11 and ABCB4 are relatively common in adults with cholestatic liver disease. New causes of cholestatic liver injury have recently been described.SummaryHistology is often not necessary for the diagnosis of biliary disease, but can provide important information that may assist the clinician in patients’ management. Histopathology remains crucial to confirm a diagnosis of cholangiocarcinoma, and to identify the pattern of biliary injury in immune-mediated cholangiopathies and rarer pathological entities.

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“…The table below shows representative compounds tested for CFTR modulation and the biological data obtained from testing representative examples. For EC 50 : “+++” means <500 nM; “++” means 500 nM–1 μM; and “+” means >1 μM. …”

Section: Important Compound Classesmentioning

confidence: 99%

Novel Macrocyclic 1,3,4-Oxadiazoles as CFTR Modulators for Treating Cystic Fibrosis

Sabnis¹

2022

ACS Med. Chem. Lett.

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Assignee Company. Vertex Pharmaceuticals Incorporated, USA Disease Area. Cystic fibrosis Biological Target. CFTR Summary. Cystic fibrosis (CF) is a recessive genetic disease that affects approximately 83 000 children and adults worldwide. Despite progress in the treatment of CF, there is no cure. In patients with CF, mutations in cystic fibrosis transmembrane conductance regulator (CFTR), endogenously expressed in respiratory epithelia, lead to reduced apical anion secretion, causing an imbalance in ion and fluid transport. The resulting decrease in anion transport contributes to increased mucus accumulation in the lungs and accompanying microbial infections that ultimately cause death in CF patients. In addition to respiratory disease, CF patients typically suffer from gastrointestinal problems and pancreatic insufficiency that, if left untreated, result in death. In addition, the majority of males with CF are infertile, and fertility is reduced among females with CF.Sequence analysis of the CFTR gene has revealed a variety of disease-causing mutations. To date, more than 2000 mutations in the CF gene have been identified. Currently, the CFTR2 database contains information on only 322 of these

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Cystic fibrosis-related liver disease: Clinical presentations, diagnostic and monitoring approaches in the era of CFTR modulator therapies

Cited by 63 publications

References 151 publications

Cystic fibrosis rabbits develop spontaneous hepatobiliary lesions and CF-associated liver disease (CFLD)-like phenotypes

Cystic fibrosis rabbits develop spontaneous hepatobiliary lesions and CF-associated liver disease (CFLD)-like phenotypes

Histological evaluation in biliary diseases

Novel Macrocyclic 1,3,4-Oxadiazoles as CFTR Modulators for Treating Cystic Fibrosis

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