Which Patients with Cystic Fibrosis are at Greatest Risk for Pancreatitis?

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) cause well-known lung defects, but in the January issue of Gastroenterology, Chee Y. Ooi et al. describe specific CFTR genotypes that increase risk for pancreatitis.

Most patients with cystic fibrosis that carry mutations that severely disrupt CFTR function have a pancreatic insufficient (PI) phenotype. However, patients who carry a mutation on at least 1 allele that confers some residual ion channel function usually have sufficient exocrine pancreatic function to maintain normal nutrient digestion, without the use of pancreatic enzyme supplements.  Nonetheless, the prevalence of pancreatitis is high in these patients (22.4%)—it is a challenge to determine which of these patients are at greatest risk for pancreatitis.

Ooi et al. studied 277 patients with cystic fibrosis who did not have major pancreatic defects, although some had pancreatitis, and who had CFTR mutations on both alleles. The authors were able to predict and classify the functional severity of CFTR mutations based on a pancreatic insufficiency prevalence (PIP) score. Paradoxically, Ooi et al. found that genotypes associated with otherwise mild phenotypic effects have the greater risk for causing pancreatitis, compared with genotypes associated with moderate to severe disease phenotypes.  People with cystic fibrosis that have more residual CFTR function are therefore at greater risk for pancreatitis (see below figure).

Development of pancreatitis depends on the opposing factors of severity of ductal obstruction and degree of pancreatic acinar reserve.

The authors propose that patients with enough functional CFTR for the pancreas to function have an increased risk of pancreatitis, because sufficient pancreatic acinar tissue is present for obstructive ductal lesions to cause disease.

Pancreatitis is a strong risk factor for progressive decline in exocrine pancreatic function in people with cystic fibrosis. The findings of Ooi et al. provide insight into the complex pathogenesis of pancreatitis, and indicate the importance of monitoring exocrine pancreatic function and pancreatic sufficiency in these patients.

More Information on Cystic Fibrosis:

Read the article online:
Ooi CY, Dorfman R, Cipolli M, et al. Type of CFTR mutation determines risk of pancreatitis in patients with cystic fibrosis. Gastroenterology 2011;140:153–161.

2 Comments

  1. Avatar
    Keith C.Y. Ooi January 29, 2011

    Kristine – Many thanks for blogging and showing interests in our work.

    The study was able to identify novel findings due to the difference in subject selection and study methodology between our study cohort and other published studies in this area. While other studies have ascertained subjects based on a prior diagnosis of pancreatitis (+/- compared with a variably selected control group), the study cohort was identified by the fact that they all had confirmed pancreatic sufficient CF disease. The study only included patients who were identified to carry 2 CFTR mutations further refining our focus on CFTR.

    The study demonstrated that CF patients developing pancreatitis were more likely to carry mild than severe CFTR genotypes. Furthermore, there appeared to be a gradation of risk of developing pancreatitis according to severity of each allele carried: highest risk seen in CF patients who carried 2 mild mutations (mild/mild) followed by those who carried 1 mild mutation (mild/severe), compared with those who carried functionally severe mutations on both alleles. Thus, this is the first systematic study to date demonstrating an association between higher risks of pancreatitis with different degrees of genotype mildness. Since we performed extensive instead of limited CFTR genotyping, we found that pancreatitis was associated with functional mild CFTR mutations and not necessarily limited to specific mutations. Not every patient with mild genotypes developed pancreatitis, confirming that other modifier factors (genetic and/or environmental) are involved in the development of pancreatitis even in a monogenic disease such as CF.

    As demonstrated by the Figure, the study can be translatable to the majority of patients with so-called idiopathic pancreatitis who are identified to carry 1-2 CFTR mutations and who do not necessarily fulfil the diagnostic criteria of CF. In these individuals, we hypothesise that non-CFTR factors “tip the balance” into developing pancreatitis.

    Dr Keith C.Y. Ooi

  2. Avatar
    Kristine Novak February 16, 2011

    Thanks for the information Keith!

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