March 10, 2024

CFTR Function is Impaired in a Subset of Patients with Pancreatitis Carrying Rare CFTR Variants 

Dora Angyal a 2, Karina Kleinfelder b 2, Fabiana Ciciriello c, Tessa A. Groeneweg a, Giulia De Marchi d, Nicolò de Pretis d, Laura Bernardoni d, Luca Rodella e, Francesco Tomba e, Paola De Angelis f, Cecilia Surace g, Emily Pintani h, Federico Alghisi c, Hugo R. de Jonge a 1, Paola Melotti h, Claudio Sorio b, Vincenzina Lucidi c, Marcel J.C. Bijvelds a, Luca Frulloni d

Pancreatitis, an inflammatory condition affecting the pancreatic epithelium, is a gastrointestinal disorder resulting in significant distress and is often linked to hereditary and environmental elements. Causative variants in the CFTR gene, crucial for anion and fluid excretion, are associated with increased pancreatitis risk. CF transmembrane conductance regulator (CFTR) modulators show promise in treating pancreatitis linked to CFTR dysfunction, prompting research into assessing CFTR function. 


**Keywords and Corresponding Abbreviations:**

  • – Cystic fibrosis: (CF)
    – Epithelial cells: (No standard abbreviation)
    – Organoids: (No standard abbreviation)
    – Pancreatic ducts: (No standard abbreviation)


  • – Acute pancreatitis: (AP)
    – Bubble sweat test: (BST)
    – CFTR bicarbonate conductance defect: (CFTR-BD)
    – CFTR-related disorders: (CFTR-RD)
    – Chronic pancreatitis: (CP)
    – Cystic fibrosis: (CF)
    – Elexacaftor: (ELX)
    – Elexacaftor/tezacaftor/ivacaftor: (ETI)
    – Endoscopic retrograde cholangiopancreatography: (ERCP)
    – European Cystic Fibrosis Society: (ECFS)
    – Exocrine pancreatic insufficient: (PI)
    – Exocrine pancreatic sufficient: (PS)
    – Forced expiratory volume in one second: (FEV1)
    – Gibson and Cooke sweat test: (GCST)
    – Idiopathic pancreatitis: (IP)
    – Intestinal current measurement: (ICM)
    – Intra-pancreatic activation of trypsin: (IPAT)
    – 3-isobutyl-1-methylxanthine: (IBMX)
    – Ivacaftor: (IVA)
    – Nasal potential difference: (NPD)
    – Next-generation sequencing: (NGS)
    – Recurrent acute pancreatitis: (RAP)
    – Short-circuit current: (Isc)
    – Tezacaftor: (TEZ)

Patients were selected based on criteria such as age ≥6 years and diagnosis of acute, repeated, or persistent pancreatitis. The genetic analysis involved sequencing 9 genes using the Next-Generation Sequencing. Identified variants were called utilizing the Geneyx analysis platform. CFTR function was measured using sweat tests and nasal potential difference (NPD) analysis. Electrophysiological assessments were conducted using standard procedures to determine intestinal current measurement (ICM). Statistical examination was performed to evaluate the impact of CFTR modulators on CFTR function. 


The study enrolled 32 patients with idiopathic pancreatitis and found that 38% carried cystic fibrosis (CF)-causing mutations, while 84% carried alleles with inconstant or unknown clinical outcomes. Eleven cases had variants in genes other than CFTR associated with pancreatitis. Sweat chloride levels and epithelial ion transport were assessed, with some patients showing impaired CFTR function but responding positively to CFTR modulators, suggesting potential therapeutic benefits. 


CFTR function is impaired in a subset of patients with pancreatitis carrying rare CFTR variants – ScienceDirect



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The study highlighted the challenges of diagnosing CF or CFTR-related disorders due to inconclusive sweat test results with mild CFTR mutations. Tests like NPD and ICM were found to be more consistent in individuals with the lowest function CFTR variants on both alleles. However, for other CFTR genotypes, test outcomes were often inconsistent. The study emphasized the importance of using multiple diagnostic procedures and refining CFTR dysfunction criteria in pancreatitis patients with CFTR variants. It also discussed the potential of CFTR modulators in improving CFTR function, especially in patients with pancreatitis but not CF, suggesting personalized medicine approaches for disease management. 


View additional Publications:

Variant Co-occurrence Counts by Gene in gnomAD




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