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Cystic Fibrosis
Morgan Pegg

Introduction
Cystic fibrosis, or mucoviscidosis, is an autosomal recessive disorder characterized by a
mutation in the gene that codes for the CFTR (cystic fibrosis transmembrane conductance
regulator) protein. The CFTR protein is a special type of ABC (ATP binding cassette) transporter
in which a few molecules of ATP are cleaved to open the channel in which chloride ions pass
through. Although ATP is required to initially open the channel, once the channel is open,
chloride ions flow freely along their concentration gradient, and therefore, this is considered
passive transport of ions.
CFTR is found within epithelial cells of airways, pancreatic ducts, reproductive tracts, the
intestinal lumen, and the skin. Chloride ions build up within epithelial cells, altering the
concentration gradient of chloride ions so that the inside has a higher concentration than the
extracellular matrix. Chloride ions proceed to move through the CFTR transporter and flow
along this new gradient into the extracellular matrix. Sodium ions from the interstitial fluid bind
to chloride ions within the sweat gland ducts in order to form NaCl salt that draws water into the
duct. Ordinarily, sweat glands release this NaCl and water within the sweat gland coil in order to
cool the skin. This sweat from the sweat gland coil has a much higher concentration of NaCl than
the sweat actually released from the gland.

Genetics
As previously stated, cystic fibrosis is an autosomal recessive disorder affecting the gene
that codes for the CFTR protein on chromosome 7. It is a classic single gene disorder, only
affecting the gene that codes for the CFTR protein. However, it displays allelic heterogeneity, in
which different mutations at the same locus on a gene produce the same phenotype. Allelic
heterogeneity allows for the opportunity for compound heterozygotes, individuals with the two
different mutant alleles at the CFTR gene locus.
Most common mutation in cystic fibrosis is a three base pair deletion that results in a loss
of phenylalanine at the 508 codon (F508) position, causing a frameshift mutation. This specific
mutation prevents normal protein maturation, and presents with a severe phenotype. There have
also been missense and nonsense mutations found. In cystic fibrosis, the genotype does not
directly dictate the severity of the disease.

Epidemiology
The incidence rate for cystic fibrosis is between 1/2000 – 1/2500. Cystic fibrosis is
primarily found within the northern European population, but due to immigration and movement
of cultures, this is subject to change. For example, due to the founder effect, cystic fibrosis is
now common within Amish populations within the United States. The carrier frequency for this
disease is between 1/22 – 1/25. Cystic fibrosis is the most fatal disorder within Caucasian
children due to chronic malnourishment due to low levels of serum proteins, especially albumin.
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Pathophysiology/Pathology
There are six types of defects resulting from abnormal CFTR proteins. These include
complete absence of synthesis of the CFTR protein, defective protein maturation/early
degradation, abnormal protein regulation, poor chloride conductance, decreased transcription,
and quicker CFTR protein turnover. (MedScape, 2017)
Cystic fibrosis strongly affects the V/Q ratio, due to ventilation problems and obstructed
airways. This will ultimately lead to flow velocity problems, due to these blocked airways. These
are within the ‘conducting zone’ within the respiratory system, and the thick viscous mucus
causes airway obstruction and allows the growth of bacteria. Oxygen therapy is considered to fix
the affected V/Q ratio.

Clinical Manifestations
A patient with cystic fibrosis has a deficiency in the CFTR protein. Patients present with
salty skin as a newborn, which progresses to recurrent lung infections, chronic pancreatitis, and
steatorrhea later in life. Nearly all exocrine glands secrete unusually thickened mucous to
obstruct glands, ducts, and airways. Over 95% of men affected with cystic fibrosis are also
infertile because they have a condition known as congenital bilateral absence of the vas deferens
(CBAVD) in which the vas deferens is absent.
Abnormal CFTR proteins within the airway lumen makes lungs sticky and infected,
because the mutant CFTR protein does not transport chloride into the lumen of the airways, and
as a result, sodium and water in the airway luminal secretions are low. This results in viscous
mucous secretions and lungs that are more prone to bacterial infections. These infections tend to
become recurrent, and are the most common cause of mortality and/or morbidity within patients.
Within the pancreas, abnormal CFTR proteins lead to viscous acinar secretions within the
pancreatic duct lumen, which causes duct obstruction and tissue necrosis due to exocrine
pancreatic insufficiency. Eventually, the parenchyma of the pancreas is replaced by fibrotic
tissue and fat. In addition, there is a deficiency of pancreatic enzymes lipase, trypsin, and
chymotrypsin leading to poor digestion and absorption of fats. This eventually causes
steatorrhea, or excretion of fat within the stool, due to the deficiency of fat soluble vitamins in
the body. This fat malabsorption can also result in vitamin D deficiency. In addition, chronic
pancreatitis can result from cystic fibrosis.
Due to abnormal CFTR within the intestinal epithelium, there is viscous secretions in the
intestine as well. These secretions eventually lead to meconium ileus, a bowel obstruction that
occurs when the meconium (infant stool comprised of intestinal epithelial cells, amniotic fluid,
bile, water, and mucus) in the intestine becomes thicker than normal. (MedScape, 2017).
The only way that chloride ions flow back into the epithelial cells is through the CFTR
protein. In cystic fibrosis, chloride ions are not able to be salvaged due to an abnormal CFTR
protein. Because of the lack of chloride reuptake by CFTR within the skin, this leads to the
classic salty skin in cystic fibrosis. This is because the sweat has an abnormally high salty
content due to poor reabsorption of NaCl (high chloride levels within sweat).

Diagnosis/Differential Diagnosis
The primary step for diagnosis of cystic fibrosis is the sweat test. During this test,
sweating is induced and the concentration of NaCl within the sweat is measured. Abnormally
high levels of salt within the sweat are indicative of cystic fibrosis. To confirm a CFTR gene
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mutation, genetic tests such as the ASO dot blot assay are used. Tests such as this are used by
genetic counselors in order to determine potential risk for disease transmission from parent to
offspring.

Treatment
Although there are no preventative care measures, cystic fibrosis is treatable. Oral
enzyme replacement therapy is often used to treat the deficiency of pancreatic enzymes. In
addition, salt and fat-soluble vitamin supplementation to the diet is also helpful. During recurrent
respiratory bacterial infections, antibacterial drugs, bronchodilators, and anti-inflammatory drugs
are used. (MedScape, 2017).

Prevention
Unfortunately, there is no real prevention for cystic fibrosis. Potential parents are able to
receive genetic testing to determine the risk of their potential offspring for cystic fibrosis, but
aside from that, there are no preventative measures for those who possess the mutant gene.

New Developments
New research into cystic fibrosis by Ortiz et al. found seventy sequence variations within
the twenty-seven exons of the CFTR gene. Eight of the seventy variations cause cystic fibrosis.
(Ortiz et al., 2017). Research such as this seeks to determine the prevalence of the CFTR gene in
difference populations, even though Ortiz et al. focused on the prevalence within Ecuador. “One
of the most important findings of this study is the detection of the p.H609R mutation, which is
the second report of this mutation in the Ecuadorian population.” (Ortiz et al., 2017).

References
Cystic Fibrosis. (2017, December 06). Retrieved December 12, 2017, from
https://emedicine.medscape.com/article/1001602-overview#a3
Ortiz, S. C., Aguirre, S. J., Flores, S., Maldonado, C., Mejía, J., & Salinas, L. (2017). Spectrum
of CFTR gene mutations in Ecuadorian cystic fibrosis patients: the second report of the
p.H609R mutation. Molecular Genetics & Genomic Medicine,5(6), 751-757.
doi:10.1002/mgg3.337
Philadelphia, T. C. (2014, March 30). Meconium Ileus. Retrieved December 12, 2017, from
http://www.chop.edu/conditions-diseases/meconium-ileus
Raeburn, K., Dr. (2017). Basic Principles of Medicine. Lecture presented in St. George's
University. Retrieved December 12, 2017, from https://mycourses.sgu.edu/portal.