Cystic fibrosis pathophysiology

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

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Overview

Pathophysiology

Gross Pathology

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

Microscopic Pathology

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  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.
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  This higher-power photomicrograph shows a cystic space (1) within an acinar lobule. Islets of Langerhans (2) are also visible.
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  This high-power photomicrograph shows more clearly these variably-sized cystic spaces within the acinar pancreas.

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  This is another high-power photomicrograph showing cystic spaces (1) within the acinar pancreas and a normal islet of Langerhans (2).
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  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).
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  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).

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  This is a higher-power photomicrograph showing the eosinophilic debris in many of the intestinal crypts (arrows).
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  This higher-power photomicrograph shows more clearly the eosinophilic debris (arrows) in the intestinal crypts.
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  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.

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  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).
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  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).
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  This low-power photomicrograph of pancreas shows increased interstitial connective tissue resulting in accentuation of the lobular pattern.

Genetics

CFTR protein - Molecular structure of the CFTR protein

The CFTR gene is found at the q31.2 locus of chromosome 7, is 230 000 base pairs long, 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 seventy percent of CF worldwide and 90 percent of cases in the United States. There are over 1,400 other mutations that can produce CF, 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

References

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