Page 172 - Color Atlas Of Pathophysiology (S Silbernagl Et Al, Thieme 2000)

Cystic Fibrosis
Cystic fibrosis (CF) is a genetic syndrome in In patients with CF, CFTR does not open up
which the epithelial secretion, for example, even when cAMP concentration is high. As a
in the lungs, pancreas, liver, genital tract, in- result, especially when acinar secretion is
testine, nasal mucosa, and sweat glands are stimulated, the small pancreatic ducts con-
affected. Among Caucasians CF is the most tain a protein-rich, viscous secretion that oc-
frequent lethal (after a mean of 40 years) cludes the transporting ducts and thus leads
gene defect (1 per 2 500 births). to chronic pancreatitis with its consequences
The defect is autosomal recessive (→ A1) (e.g., malabsorption due to lack of pancreatic
and affects the epithelial transport protein enzymes and HCO 3 – in the duodenum;
CFTR (cystic fibrosis transmembrane con- → p.160).
Liver ductance regulator). CFTR in healthy people fects the intestinal epithelium so that neona-
Among other effects, abnormal CFTR af-
consists of 1480 amino acids that form 12
Stomach, Intestines, binding domains (NBD 1 , NBD 2 ), and a regula- and thus cannot, as usual, pass out of the
tal meconium becomes viscous and sticky
transmembrane domains, two nucleotide-
ileum after birth (meconium ileus).
tor domain. At the latter, CFTR is regulated by
As in the pancreas, the bile ducts may be-
a cAMP-dependent protein kinase A (→ A2;
CFTR is shown opened up frontally). CFTR is
come obstructed and neonatal jaundice may
thus be prolonged. The CFTR defect in the
probably a chloride channel that opens
struction of the vas deferens); in the female
is raised and, in addition, ATP is bound to
genital organs it causes decreased fertility.
NBD 1 (and split?). Furthermore, intact but
6 when the intracellular cAMP concentration male genital organs may cause infertility (ob-
+
not defective CFTR inhibits certain Na chan- The consequences of abnormal secretion in
nels (type ENaC). The fact that more of them the nasal mucosa are polyps and chronic in-
open in CF results in increased absorption of flammation of the nasal sinuses. In the sweat
+
Na and water, for example, at the bronchial glands the defect increases sweat secretion
epithelium, from the mucus secreted into that during fever or high ambient tempera-
the lumen, so that the latter is thickened ture can lead to hypovolemia and even circu-
(see below). latory shock. In addition, electrolyte concen-
Patients with cystic fibrosis have various tration is increased in sweat and the concen-
+
–
mutations of CFTR, but the serious forms are tration of Na is higher than that of Cl (the
most frequently caused by two defects on the reverse of normal), a fact that is used in the
NBD 1 (→ A3): either the amino acid 508, phe- diagnosis of CF (sweat test).
nylalanine (= F; mutation ∆F508), is missing, Morbidity and life-threatening complica-
or glycine (= G) in position 551 is replaced by tions of CF are mainly due to its effects on
aspartate (= D) (mutation G551 D). the bronchial epithelium. Its superficial mu-
CFTR is incorporated into the apical (lumi- cus is normally thinned by fluid secretion.
nal) cell membrane of many epithelial cells. The CTFR defect causes (in addition to in-
CFTR has an important function in the excre- creased mucus secretion) the reabsorption
tory ducts of the pancreas, in that it is in- instead of secretion of fluid. This results in a
volved in secretion of a liquid rich in NaHCO 3 . highly viscous and protein-rich layer of mu-
–
–
HCO 3 is exchanged for Cl in these cells via cus that not only hinders breathing, but also
an antiport carrier (→ A4). The opening of forms a fertile soil for infections, especially
CFTR—for example, by secretin, which in- with Pseudomonas aeruginosa and Staphylo-
creases intracellular cAMP concentration— coccus aureus. Chronic bronchitis, pneumo-
–
allows the Cl that has entered the cell to be nia, bronchiectasis, and secondary cardiovas-
recycled, so that chloride is again available cular disorders are the result.
–
for the secretion of HCO 3 , followed by Na +
and water. If the concentration of cAMP de-
162 creases, CFTR is closed and secretion dries
up.
Silbernagl/Lang, Color Atlas of Pathophysiology © 2000 Thieme
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