Cystic fibrosis is an autosomal recessive genetic disease* that is due to mutations that reduce or eliminate function of the protein CFTR. As you have learned, the movement of Cl- ions through the CFTR channel (located on the apical membrane) is the rate-limiting and regulated step for fluid secretion by many epithelia.
*In an autosomal recessive disease, the disease is expressed when both copies of the gene are mutant.
Although most people think of cystic fibrosis as a lung disorder, it affects secretion in the GI tract and thus causes digestive system pathologies. In the intestines, the lack of fluid secretion can cause intestinal blockage. For instance, some infants with cystic fibrosis present with meconium ileus, which is the failure to pass meconium (meconium refers to the first tarry stool produced by newborns).
Another important location for CFTR-dependent secretion is the pancreas. In the pancreas,
clusters of cells called acinar cells secrete inactive digestive
enzyme precursors known as zymogens. Duct cells are
epithelial cells that form small pancreatic ducts and line the
larger ducts. Duct cells secrete bicarbonate ions and
fluid. This secretion by duct cells is necessary to ensure
that the zymogens are carried out of the pancreas and into the
small intestine before being activated. In patients
with a defective CFTR protein, the lack of secretion by pancreatic
duct cells can lead to chronic
pancreatitis, when inappropriate zymogen activation
inside the pancreas leads to digestion of cellular components and
subsequent inflammation, damage, and loss of pancreatic
tissue. Chronic pancreatitis can affect individuals that are
heterozygous for a CFTR mutation. (Heterozygotes have one
normal CFTR allele, but have reduced CFTR function).
The most common digestive system pathology affecting patients with cystic fibrosis is pancreatic insufficiency, meaning there is inadequate production of digestive enzymes. This occurs because blocked ducts and tissue damage in the pancreas will prevent release of adequate amounts of digestive enzymes into the small intestine. If severe enough, pancreatic insufficiency causes malnourishment--for instance in an infant, it might cause a failure to thrive. Roughly 85% of newborns with cystic fibrosis have pancreatic insufficiency at birth or will develop it within the first year of life.
Finally, because chronic pancreatitis causes generalized tissue
damage in the pancreas, there may also be damage to endocrine
tissue in the pancreas. When cystic
fibrosis-associated pancreatitis damages the beta cells in
the pancreatic islets of Langerhans, this causes insulin
deficiency and diabetes mellitus.
CFTR-related diabetes mellitus is treated with insulin
replacement.
In the lungs, the defect in CFTR changes the environment in the airways so that they are much more prone to infection by pathogens. One important factor is that a lack of fluid secretion causes insufficient hydration of mucus. As a result, the mucus becomes very thick. Normally mucus is moved up out of the lungs by the beating of cilia present on the surface of airway epithelial cells. The thick mucus is not easily cleared, and is conducive to bacterial and fungal growth. This causes cycles of infection, inflammation, and tissue damage in the upper airways, which leads to further problems in clearing the mucus. However, the situation in the lungs is complex, and other changes caused by CFTR dysfunction may be contributing to pathology in the lungs.
More than 2000 different genetic mutations in the gene for CFTR
have been identified. Biochemical and DNA testing is used to
screen newborns to identify patients so that appropriate treatment
can begin at an early age. One of the tests that is used to
diagnose cystic fibrosis is the sweat-chloride test*. It is
described in the "Running Problem" on page 151 of the textbook (OPTIONAL:
Work through the running problem on pages 122, 131, 138, 151, 152,
and 159 of the textbook).
*Interestingly, the epithelial cells in the sweat ducts
are involved in the reabsorption of Cl-
ions. The fluid secreted by the sweat glands is isotonic
with the extracellular fluid, but as it flows through the sweat
ducts, Na+ and Cl- ions are reabsorbed, so
that the resulting sweat has a lower salt content. When
CFTR is defective in cystic fibrosis, the chloride content of
sweat is abnormally high.
The lung problems in cystic fibrosis have traditionally been treated with antibiotics to prevent infection and various therapies to hydrate and remove the thick mucus. An important innovation has been the development of inhaled antibiotics. Pancreatic insuffiency is treated with pancreatic enzyme replacement therapy.
The CFTR gene was identified in 1989. When early trials of
gene therapy were unsuccessful, a program was launched to identify
small molecule drugs that could modulate the function of defective
CFTR proteins (CFTR modulators). Two general types of drugs
have been developed. CFTR
potentiators are drugs that improve CFTR function
by increasing the amount of time that the channel stays
open. Many CFTR mutations (such as the F508 deletion that
affects two-thirds of all patients) affect protein trafficking of
the mutant CFTR so that it doesn't get expressed on the apical
plasma membrane. CFTR correctors
are drugs designed to correct for this protein trafficking
defect. The newest cystic fibrosis treatment, Trikafta
(elexacaftor-tezacaftor-ivacaftor; approved in October 2019) is a
combination of two CFTR correctors and one CFTR potentiator.
Treatment with Trikafta should be able to effectively improve lung
function in about 90% of patients with cystic fibrosis.