Smart Sparrow 5

 Aetiology of CF is genetic mutations of the CF gene

o There are > 1800 known mutations that can cause CF and they all occur within the CF
gene
 CF gene is located on chromosome 7 (7q31.2), long arm (q) of the chromosome, region 3, band
1, sub-band .2
 In Australia, the most common CF mutation is F508del  Class II Mutation
o 1:2900 Australians have CF
o The next most common mutation in Australia is G551D
 Inheritance pattern of CF is autosomal recessive
o Heterozygous mutations do not result in disease expressions (they are carriers)
o Compound heterozygous mutations (cis/trans) may result in disease expression
o Homozygous mutations definitely result in disease expression
 Different classes of mutation result in different defections.
o Class I  Defective protein production
o Class II  Defective trafficking
o Class III  Defective regulation / activation
o Class IV  Defective function
o Class V  Reduced production
o Class VI  Defective regulation of other channels

o Class I-III are severe types. Class IV-VI are mild.

 First three classes result in complete lack of functioning CFTR.

o G551D mutation is in Class III and class VI

 The protein is synthesised and transported to the cell membrane but it is not
functional.

 Disease phenotype of each CF patient is dependent upon multiple factors including

o Specific mutation
o Whether the mutation is heterozygous, homozygous or combination of two different
heterozygous mutations (compound heterozygote)
o Non-CFTR genetic variation
o Environmental influences
Thus, not all patients will exhibit disease in all of the organs possibly affected.

 Normal CF Gene results in expression of transmembrane protein CFTR which is anchored to the
cell membrane of exocrine gland cells found on the following epitheliums
o Respiratory
o Pancreatic acinar
o Liver bile duct
o Intestinal
o Sweat gland
 Exocrine cells of the airways (Goblet cells) secrete protective mucous onto luminal surface of
epithelial cells.

 CFTR in airways
o Important channel in controlling ion transport in and out of goblet cells in the airways
o It controls balance of active transport of Cl- and Na+ ions to ensure that enough water
passively moves into the mucous to keep it fluid and hydrated.
 o Thus, in absence of functional CFTR, mucous layer lining the airways become viscous,
dehydrated, low in water content and thick and sticky due to low Cl- and sodium content
in the mucous, high concentration of these in the cells which drives water passively back
into the cells.
o This is a problem because it
 Creates favourable conditions for bacterial growth
 Causes chronic cough
 Causes inflammation and damage to the airway walls
 Traps foreign particles but is unable to remove it
 Impairs gas exchange
 And can result in bronchiectasis (permanent distention of the airways in response
to build up of viscous mucus and persistent inflammation and damage to the
epithelium)

CFTR in Pancreas
- CFTR protein is found anchored to cell membrane of the exocrine cells of the pancreas (acinar
cell which secretes digestive enzymes). These digestive enzymes are normally alkaline and are
carried into the small intestine.
- CFTR controls ion transport in and out of the acinar cells in the pancreas by controlling active
transport of Cl- ions into the digestive enzyme secretions and regulation of secretion of
 bicarbonate ions (HCO3-) through the neighbouring channels. This ensures the alkalinity.

- In the absence of functional CFTR, digestive enzymes from the pancreas become
o Viscous, dehydrated, less alkaline, low in water content and thick and sticky.
o This is because water will passively follow Cl- and Na+ ions. The lack of bicarbonate
reduces the alkalinity of the digestive enzymes.
o Viscous dehydrated secretions can block the pancreatic ducts causing
 Inflammation and damage of exocrine acinar cells
 Potential for development of type 2 diabetes
 Insufficient digestion of starch, fats and proteins
 Malabsorption of nutrients and weight loss
 Failure to neutralise acidic intestinal contents due to lack of bicarbonate ions
 CF affects many organs in the body especially lungs, pancreas and sweat glands where a build up
of thick, viscous and sticky mucus in these organs lead to respiratory problems, incomplete
digestion and increased salt loss from the sweat glands.
Generally:
o In the lungs mucus produced is thick and sticky, clogging the small air passages and
encouraging bacteria to grow.
o Ducts from pancreas to the intestine can become blocked. These ducts carry enzymes for
digestion so blockage leads to incomplete digestion  weight loss in spite of a heavy
appetite
o Sweat glands secrete sweat high in salt, depleting the body of this important substance

o
 CFTR in liver
- found anchored to cell membrane of exocrine cells which line the bile ducts and produce bile
and mucous.
- Bile travels from the liver to the gall bladder and the intestines
- It contributes to the removal of waste and digestion of fats
- Controls active transport of Cl- ions into the bile and regulation of secretion of bicarbonate ions
through neighbouring channels
- Bile is usually 97% water and needs to be fluid enough to flow through the bile duct
- Bicarbonate ions needed to ensure alkalinity
- Absence of functional CFTR leads to bile becoming viscous, dehydrated, less alkaline, low in
water content and thick and sticky.
- This can lead to
o Build up of gallstone and inflammation of gallbladder
o Failure to neutralize intestinal contents
o Insufficient digestion of fats
o Reduction in elimination of waste
o Damage in gall bladder and liver
o Lack of bile and digestive enzyme leads to impaired digestion nof fats which causes
diarrhea as they pass through the intestines (Steatorrhea) and are foul smelling
o Build up of bile and resultant damage in liver leading to fibrotic condition aka biliary
cirrhosis which begins and is most severe around the bile ducts. (bile makes liver green
coloured)

CFTR and Intestines

- CFTR anchored to cell membrane of exocrine cells of intestine (goblet cells and epithelial brush
border cells)
- Goblet cells produce mucus
- Epithelial brush border cells produce digestive enzymes
- CFTR in intestine controls
o Active transport of chloride ions into intestinal lumen
o Regulation of Na+ absorption by neighbouring channels
o Regulation of bicarbonate secretion by neighbouring channels
- Absence of functional CFTR results in same viscosity and dehydration of secretions seen in
airways, pancreas and liver and the same lack of alkalinity seen throughout the GI tract.
 o Acidity of intestinal contents can irritate the intestinal wall causing inflammation and
villous atrophy

CFTR and Sweat Glands

- CFTR found anchored to cell membrane of exocrine cells of sweat glands
- Secretory epithelial cells of sweat glands are located in the secretory coil. They secrete isotonic
substance into coil and reabsorption of NaCl along the duct produces hypotonic sweat

Treatment
- Oral administration of pancreatic enzymes to aid digestion

Prevalence of CF
1/3000 = Caucasian
1/15000 = African
1/30000 = Asian