Cystic fibrosis pathophysiology

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

Cystic fibrosis Microchapters
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Patient Information
Overview
Historical Perspective
Classification
Pathophysiology
Causes
Differentiating Cystic fibrosis from other Diseases
Epidemiology and Demographics
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Screening
Natural History, Complications and Prognosis
Diagnosis
Diagnostic Study of Choice
History and Symptoms
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Treatment
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Xyz Microchapters
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Patient Information
Overview
Historical Perspective
Classification
Pathophysiology
Causes
Differentiating Xyz from other Diseases
Epidemiology and Demographics
Risk Factors
Screening
Natural History, Complications and Prognosis
Diagnosis
Diagnostic Study of Choice
History and Symptoms
Physical Examination
Laboratory Findings
Electrocardiogram
X-ray
Echocardiography and Ultrasound
CT scan
MRI
Other Imaging Findings
Other Diagnostic Studies
Treatment
Medical Therapy
Interventions
Surgery
Primary Prevention
Secondary Prevention
Cost-Effectiveness of Therapy
Future or Investigational Therapies
Case Studies
Case #1
Cystic fibrosis pathophysiology On the Web
Most recent articles
Most cited articles
Review articles
CME Programs
Powerpoint slides
Images
American Roentgen Ray Society Images of Cystic fibrosis pathophysiology All Images X-rays Echo & Ultrasound CT Images MRI
Ongoing Trials at Clinical Trials.gov
US National Guidelines Clearinghouse
NICE Guidance
FDA on Cystic fibrosis pathophysiology
CDC on Cystic fibrosis pathophysiology
Cystic fibrosis pathophysiology in the news
Blogs on Cystic fibrosis pathophysiology
Directions to Hospitals Treating Psoriasis
Risk calculators and risk factors for Cystic fibrosis pathophysiology

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

Overview

The exact pathogenesis of [disease name] is not fully understood.

OR

It is thought that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].

OR

[Pathogen name] is usually transmitted via the [transmission route] route to the human host.

OR

Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.

OR

[Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].

OR

The progression to [disease name] usually involves the [molecular pathway].

OR

The pathophysiology of [disease/malignancy] depends on the histological subtype.

Pathophysiology

Pathogenesis

• The exact pathogenesis of [disease name] is not fully understood.

OR

• It is understood that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].
• [Pathogen name] is usually transmitted via the [transmission route] route to the human host.
• Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.
• [Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].
• The progression to [disease name] usually involves the [molecular pathway].
• The pathophysiology of [disease/malignancy] depends on the histological subtype.

Genetics

• [Disease name] is transmitted in [mode of genetic transmission] pattern.
• Genes involved in the pathogenesis of [disease name] include [gene1], [gene2], and [gene3].
• The development of [disease name] is the result of multiple genetic mutations.

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

Gross Pathology

• On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

• 
  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.