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
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
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
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
Table 32–1. Classes
of CFTR Mutations that Cause CF |Favorite Table|Download (.pdf)
Table 32–1. Classes
of CFTR Mutations that Cause CF
|I||Protein production (no CFTR made)||G542X||2.4|
|621 + G–T||1.3|
|II||Processing (defect in protein trafficking leads
|III||Regulation (CFTR not
activated by ATP or cyclic AMP)||G551 D||1.6|
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