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Pancreatic insufficiency (PI) is a term used to define patients who have lost a significant amount (usually >95%) of pancreatic exocrine function and therefore their ability to digest and assimilate nutrients normally.1 Cystic fibrosis (CF) is by far the most common form of PI in children and the focus of this chapter.

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CF is the most common life-threatening autosomal recessive disease in the United States. The prevalence is higher in populations of northern European descent (~1 in 2500 births) compared to people from Hispanic (1 in 4000–10,000), African American (1 in 15,000–20,000), or Asian (1:30,000) ethnic backgrounds. The carrier rate is estimated to be around 3.5% for Caucasians; heterozygotes show no clinically relevant phenotypes.2

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CF is caused by a mutation in the gene that encodes CF transmembrane conductance regulator (CFTR) protein. CFTR is expressed in many epithelial cells (sweat duct, airway, pancreatic duct, intestine, biliary tree, and vas deferens) and functions as an apical membrane anion channel, mainly involved in chloride and bicarbonate secretion.3–5 It is proposed that the lack of CFTR leads to acidic, dehydrated, and protein-rich secretions, which then plug the lumen and cause the destruction of the organ.4 Pulmonary involvement causes the most significant morbidity and mortality in patients with CF. With substantial improvement in the medical care of CF patients, the projected life expectancy has now increased to ~37 years of age.6

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Although >1500 CFTR mutations have been identified, the functional importance is known only for a small number of mutations. CFTR mutations can be classified into six types of defects (class I–VI mutations) (Table 32–1)2: absence of protein synthesis (class I); defective protein maturation and premature degradation (class II); disordered regulation (class III); defective chloride (Cl) conductance or channel gating (class IV); a reduced number of CFTR transcripts due to a promoter or splicing abnormality (class V); and accelerated turnover from the cell surface (class VI) (Figure 32–1).4,7,8CFTR function is virtually absent with class I–III and VI mutations while class IV and V mutations allow some residual CFTR function.6 Pancreatic function appears to correlate well with the gene mutations at the CFTR locus. Exocrine pancreatic dysfunction is seen almost exclusively in association with class I–III and VI mutations.7 Patients with at least one mutation belonging to class IV or V generally present with symptoms in late childhood or adulthood.

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Table 32–1. Classes of CFTR Mutations that Cause CF

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