Cystic fibrosis pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shaghayegh Habibi, M.D.[2]

Pathophysiology

Pathogenesis

Cystic Fibrosis (CF) is an autosomal recessive, life-limiting disease resulting from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The gene is comprised of 27 exons and is situated on chromosome 7. The protein encoded by the CFTR gene is a cAMP-regulated chloride channel situated in the apical membrane of exocrine epithelial cells;1 other processes with which it is involved include regulation of the epithelial sodium channel, and bicarbonate transport. There is conflicting evidence on its role in regulating the pH of intracellular organelles and the consequences on cellular processes such as sialylation and sulfation. In patients with CF, CFTR protein function may be abnormal due to a lack of production (Class 1 mutations), failure to reach its site of action due to misfolding (Class 2; commonest Caucasian defect is Phe508Del), defects in gating (Class 3), conductance (Class 4), abnormally low channel numbers (Class 5), or decreased half-life (Class 6).

Whilst the CFTR protein is expressed in many internal organs, the major effect of such mutations is on the respiratory, gastrointestinal, and reproductive tracts, causing, in each of these sites, obstruction by thick, viscous secretions. Pulmonary disease leads to most of the morbidity associated with CF and is the cause of death in more than 90% of patients.2 The correlation of the molecular defect with this multi-system clinical picture is complex and not entirely understood. It has been shown that CF airway epithelia have abnormally high rates of sodium (and thus water) absorption, which dehydrates the airway surface liquid and impairs mucus transport. More recently, vibrating culture, which may recapitulate the in vivo setting better than the conventional static culture model, has demonstrated that these processes are well preserved until a “second hit” in the form of viral infection occurs.3 Once the airway surface becomes dehydrated, mucociliary clearance (MCC) mechanisms fail to remove any inhaled bacteria, which infect the lower airways and lead to inflammation. The CF inflammatory response is abnormal in several ways, being exaggerated,4 prolonged5 and, at least in chronic stages of infection, ineffectual.6 The presence of inflammatory cell contents such as DNA and elastase in the airway further increase mucus viscosity and contribute to tissue breakdown.

Genetics

CFTR protein - Molecular structure of the CFTR protein

The cystic fibrosis transmembrane conductance regulator (CFTR) gene is found at the q31.2 locus of chromosome 7. It is 230 000 base pairs long, comprised of 27 exons and creates a protein that is 1,480 amino acids long. The most common mutation, ΔF508 is a deletion (Δ) of three nucleotides that results in a loss of the amino acid phenylalanine (F) at the 508th (508) position on the protein.

This mutation accounts for 70% of cystic fibrosis worldwide and 90% of cases in the United States. There are over 1,400 other mutations that can produce cystic fibrosis, however. In Caucasian populations, the frequency of mutations is as follows:Template:Entête tableau charte alignement ! Mutation ! Frequency
worldwide |----- | ΔF508 | 66.0% |-Template:Ligne grise | G542X | 2.4% |----- | G551D | 1.6% |-Template:Ligne grise | N1303K | 1.3% |----- | W1282X | 1.2% |}
There are several mechanisms by which these mutations cause problems with the CFTR protein. ΔF508, for instance, creates a protein that does not fold normally and is degraded by the cell. Several mutations, which are common in the Ashkenazi Jewish population, result in proteins that are too short because production is ended prematurely. Less common mutations produce proteins that do not use energy normally, do not allow chloride to cross the membrane appropriately, or are degraded at a faster rate than normal. Mutations may also lead to fewer copies of the CFTR protein being produced.

The location of the CFTR gene on chromosome 7

Structurally, CFTR is a type of gene known as an ABC gene. Its protein possesses two ATP-hydrolyzing domains which allows the protein to use energy in the form of ATP. It also contains two domains comprised of 6 alpha helices apiece, which allow the protein to cross the cell membrane. A regulatory binding site on the protein allows activation by phosphorylation, mainly by cAMP-dependent protein kinase. The carboxyl terminal of the protein is anchored to the cytoskeleton by a PDZ domain interaction.

Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology

Gross Pathology

• 
  A gross photograph of liver and pancreas from the autopsy. The pancreas is slightly smaller than normal and it has a mucous consistency.
• 
  This section of duodenum demonstrates dilation, loss of rugae, and areas of ulceration (arrows).

Microscopic Pathology

• On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

• 
  This higher-power photomicrograph of the pancreas shows interstitial tissue and the presence of small cystic spaces (1) within the acinar lobules. These spaces are filled with an eosinophilic proteinaceous material. The islets of Langerhans (2) are unaffected.
• 
  This higher-power photomicrograph shows a cystic space (1) within an acinar lobule. Islets of Langerhans (2) are also visible.
• 
  This high-power photomicrograph shows more clearly these variably-sized cystic spaces within the acinar pancreas.

• 
  This is another high-power photomicrograph showing cystic spaces (1) within the acinar pancreas and a normal islet of Langerhans (2).
• 
  This low-power photomicrograph of intestine shows the normal layers of the intestine, including the serosa (1), the muscularis (2), the submucosa (3), and the mucosal layer (4) with its deep mucosal crypts. There is yet another cystic space within the mucosa (5).
• 
  A higher-power photomicrograph shows the bottom of the intestinal crypts and the other normal layers of the intestine. Even at this magnification, accumulations of eosinophilic debris can be seen in many of the intestinal crypts (arrows).

• 
  This is a higher-power photomicrograph showing the eosinophilic debris in many of the intestinal crypts (arrows).
• 
  This higher-power photomicrograph shows more clearly the eosinophilic debris (arrows) in the intestinal crypts.
• 
  This is a low-power photomicrograph from another section of the intestine. Saggital sections of the intestinal crypts show the crypts along their full length, extending to the mucosal surface.

• 
  A higher-power photomicrograph of intestine shows the vacuolated intestinal epithelial cells lining the crypts and necrotic debris and inspissated secretions within the crypts (arrows).
• 
  Another high-power photomicrograph of intestine shows the vacuolated intestinal epithelial cells lining the crypts and necrotic debris and inspissated secretions within the crypts (arrows).
• 
  This low-power photomicrograph of pancreas shows increased interstitial connective tissue resulting in accentuation of the lobular pattern.