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__NOTOC__
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{{CMG}} {{AE}}
{{Cystic fibrosis}}
{{Cystic fibrosis}}


{{CMG}}; {{AE}} {{SHH}}
==Overview==
==Overview==
Cystic fibrosis is an [[autosomal recessive]] disease that caused by [[Mutation|mutations]] in the [[CFTR (gene)|cystic fibrosis transmembrane conductance regulator (CFTR) gene]]. [[Point mutation|Substitution of a single amino acid]] is the most common type of [[CFTR (gene)|CFTR gene]] [[mutation]]. [[CFTR (gene)|CFTR gene]] functions as a [[chloride channel]] (pumps [[chloride]] from the [[intracellular]] space to the [[extracellular]] space) found on the surface of the [[Epithelium|epithelial cells]]. The genetic [[Mutation|mutations]] result in defective transport of [[chloride]], and secondarily [[sodium]] and eventually abnormal viscous [[Mucoid plaque|mucoid]] secretions mostly in [[lungs]] (results in [[airway]] surface liquid depletion, decreased [[Mucociliary clearance|mucociliary transport]], [[inflammation]] and [[infection]]) and [[Gastrointestinal tract|GI tract]] (results in reduced volume of [[Pancreas|pancreatic]] secretion, [[Pancreas|pancreatic]] tissue destruction and [[fibrosis]], [[malnutrition]] and poor growth). [[Infertility]] due to [[atresia]]/absent [[Vas deferens|vasa deferentia]] and abnormal/absent [[Seminal vesicle|seminal vesicles]] is the associated condition of cystic fibrosis.
==Pathophysiology==
==Pathophysiology==


===Gross Pathology===
===Pathogenesis===
* Cystic fibrosis (CF) is an [[autosomal recessive]] disease that caused by [[Mutation|mutations]] in the [[CFTR (gene)|cystic fibrosis transmembrane conductance regulator (CFTR) gene]].<ref>National Center for Biotechnology Information (US). Genes and Disease [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 1998-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK22183/</ref><ref name="pmid18506640">{{cite journal |vauthors=Voter KZ, Ren CL |title=Diagnosis of cystic fibrosis |journal=Clin Rev Allergy Immunol |volume=35 |issue=3 |pages=100–6 |year=2008 |pmid=18506640 |doi=10.1007/s12016-008-8078-x |url=}}</ref><ref name="pmid19393104">{{cite journal |vauthors=Ratjen FA |title=Cystic fibrosis: pathogenesis and future treatment strategies |journal=Respir Care |volume=54 |issue=5 |pages=595–605 |year=2009 |pmid=19393104 |doi= |url=}}</ref>
* [[CFTR (gene)|CFTR gene]] functions as a [[chloride channel]] (pumps [[chloride]] from the [[intracellular]] space to the [[extracellular]] space) found on the surface of the [[Epithelium|epithelial cells]], that line multiple organs especially [[Lung|lungs]] and [[Gastrointestinal tract|GI tract]].
* The genetic [[Mutation|mutations]] result in defective transport of [[chloride]], and secondarily [[sodium]], by [[Epithelium|epithelial cells]], and eventually abnormal viscous mucoid secretions mostly in [[Lung|lungs]] and [[Gastrointestinal tract|GI tract]].
* Other organs containing [[Epithelium|epithelia]] such as the [[Sweat gland|sweat glands]], [[Bile duct|biliary duct]], the male [[Reproductive system|reproductive]] tract, and the [[intestine]] are also affected.
* Two mechanisms which cause airway-surface-liquid depletion are as follow:
{{familytree/start |summary=Lack of CFTR normal activity}}
{{familytree | | | | A02 | |A02=Lack of [[CFTR]] normal activity}}
{{familytree | | |,|-|^|-|.| | | }}
{{familytree | | B01 | | B02 |B01=Less [[chloride]] secretion|B02=More [[sodium]] absorption}}
{{familytree | | |!| | | |!| | | | }}
{{familytree | | C01 | | C02 | | |C01=Less water transport into the [[epithelial]] surface layer|C02=Excessive [[sodium]] and water absorption through the [[epithelial]] channel}}
{{familytree/end}}
 
===Lung involvement in cystic fibrosis===
* In patients with cystic fibrosis abnormal [[chloride]] conductance of [[Epithelium|epithelial cells]] results in [[airway]] surface liquid depletion and decreased [[Mucociliary clearance|mucociliary transport]] ([[airway]] surface liquid is essential to support ciliary function).
* The consequence of cystic fibrosis is a vicious circle of [[inflammation]], [[tissue]] damage and [[infection]].<ref name="pmid19393104">{{cite journal |vauthors=Ratjen FA |title=Cystic fibrosis: pathogenesis and future treatment strategies |journal=Respir Care |volume=54 |issue=5 |pages=595–605 |year=2009 |pmid=19393104 |doi= |url=}}</ref>
* Also, exaggerated, generalized, and prolonged inflammatory response of lungs to [[Bacteria|bacterial]] and [[Virus|viral]] pathogen is observed.
* The inflammatory response is characterized by [[Neutrophil|neutrophilic]] dominated airway [[inflammation]] which is present even in clinically stable patients and in young [[Infant|infants]] diagnosed by neonatal [[Screening (medicine)|screening]].<ref name="pmid19393104">{{cite journal |vauthors=Ratjen FA |title=Cystic fibrosis: pathogenesis and future treatment strategies |journal=Respir Care |volume=54 |issue=5 |pages=595–605 |year=2009 |pmid=19393104 |doi= |url=}}</ref><ref name="pmid25404111">{{cite journal |vauthors=Cutting GR |title=Cystic fibrosis genetics: from molecular understanding to clinical application |journal=Nat. Rev. Genet. |volume=16 |issue=1 |pages=45–56 |year=2015 |pmid=25404111 |pmc=4364438 |doi=10.1038/nrg3849 |url=}}</ref>
* Breakdown of accumulated [[Neutrophil|neutrophils]] in the infected [[Lung|lungs]] of patients with cystic fibrosis leads to the release of large amounts of [[DNA]].
* Accumulated [[DNA]] causes high viscosity of the infected [[sputum]], followed by decreased ciliary transport and function.<ref name="pmid22093951">{{cite journal |vauthors=Konstan MW, Ratjen F |title=Effect of dornase alfa on inflammation and lung function: potential role in the early treatment of cystic fibrosis |journal=J. Cyst. Fibros. |volume=11 |issue=2 |pages=78–83 |year=2012 |pmid=22093951 |pmc=4090757 |doi=10.1016/j.jcf.2011.10.003 |url=}}</ref>
 
===Gastrointestinal tract involvement in cystic fibrosis===
 
==== Pancreatic disease: ====
* In cystic fibrosis, approximately 90% of patients present with [[Exocrine gland|exocrine]] [[pancreatic insufficiency]].
* [[Pancreas|Pancreatic]] disease results from a reduced volume of [[Pancreas|pancreatic]] secretion with low concentrations of [[bicarbonate]], followed by retained and prematurely activated digestive [[Zymogen|proenzymes]] in [[Pancreatic duct|pancreatic ducts]], resulting in tissue destruction and [[fibrosis]].<ref name="pmid12606185">{{cite journal |vauthors=Ratjen F, Döring G |title=Cystic fibrosis |journal=Lancet |volume=361 |issue=9358 |pages=681–9 |year=2003 |pmid=12606185 |doi=10.1016/S0140-6736(03)12567-6 |url=}}</ref>
* Abnormally viscous secretions in the [[Duct (anatomy)|ducts]] of the [[pancreas]], followed by loss of [[Pancreas|pancreatic]] [[Exocrine gland|exocrine]] function results in [[malnutrition]] and [[Delayed milestone|poor growth]].<ref name="pmid25404111" />
 
==== Biliary disease: ====
* One third of patients with cystic fibrosis have abnormal results on [[liver function tests]].
* Fatty infiltration is reported in up to 70% of older patients and in nearly 10% of these progresses to biliary [[cirrhosis]].
* [[Histology|Histological]] evaluation shows [[Duct (anatomy)|duct]] dilatation and intraluminal concretions.
* Bile-duct [[epithelium]] becomes [[Hyperplasia|hyperplastic]] with periductal [[inflammation]] and [[fibrosis]].
* Up to one third of patients with cystic fibrosis, a small and poorly functioning [[gallbladder]] is detected.<ref name="pmid12606185">{{cite journal |vauthors=Ratjen F, Döring G |title=Cystic fibrosis |journal=Lancet |volume=361 |issue=9358 |pages=681–9 |year=2003 |pmid=12606185 |doi=10.1016/S0140-6736(03)12567-6 |url=}}</ref>
 
==Genetics==
Cystic fibrosis is caused by [[Mutation|mutations]] in the [[CFTR (gene)|CF transmembrane conductance regulator (CFTR) gene]]. This [[gene]] codes for a [[chloride]] transporter regulated by [[Cyclic adenosine monophosphate|cyclic AMP]] ([[Cyclic adenosine monophosphate|cAMP]])-dependent [[phosphorylation]]. There are almost 2,000 variants of [[CFTR (gene)|CFTR gene]] [[Mutation|mutations]]:<ref name="pmid25404111">{{cite journal |vauthors=Cutting GR |title=Cystic fibrosis genetics: from molecular understanding to clinical application |journal=Nat. Rev. Genet. |volume=16 |issue=1 |pages=45–56 |year=2015 |pmid=25404111 |pmc=4364438 |doi=10.1038/nrg3849 |url=}}</ref>
* [[Point mutation|Substitution of a single amino acid]] (40%)
* Alter RNA processing including [[Nonsense mutation|nonsense]], [[Frameshift mutation|frameshift]] and missplicing (36%)
* Large rearrangements of [[Cystic fibrosis transmembrane conductance regulator|CFTR]] (3%)
* [[Promoter|Promoter regions]] (1%)
* Neutral variants (14%)
* The effect of the remaining 6% is unclear.
*Children who [[Inherited|inherit]] one [[Mutation|mutated]] [[CFTR (gene)|CFTR gene]] and one normal [[CFTR (gene)|CFTR gene]] are "CF [[Carrier|carriers]]". CF [[Carrier|carriers]] usually have no symptoms of cystic fibrosis but they can pass the [[Mutation|mutated]] [[CFTR (gene)|CFTR gene]] to their children.<ref name="urlCystic Fibrosis - National Library of Medicine - PubMed Health">{{cite web |url=https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063023/ |title=Cystic Fibrosis - National Library of Medicine - PubMed Health |format= |work= |accessdate=}}</ref>
 
[[Image:CFTR.jpg|thumb|left|350px|'''CFTR protein -''' Molecular structure of the CFTR protein Source: Wikimedia Commons<ref name="urlFile:CFTR.jpg - Wikimedia Commons">{{cite web |url=https://commons.wikimedia.org/wiki/File:CFTR.jpg |title=File:CFTR.jpg - Wikimedia Commons |format= |work= |accessdate=}}</ref>]]
 
<br style="clear:left" />
 
In Caucasian populations, the frequency of [[Mutation|mutations]] is as follows:<ref name="table">''Prevalence of ΔF508, G551D, G542X, R553X mutations among cystic fibrosis patients in the North of Brazil.'' Brazilian Journal of Medical and Biological Research 2005; 38:11–15. PMID 15665983</ref>{{entête tableau charte alignement|left}}<noinclude></noinclude>
! Mutation
! Frequency<br />worldwide
|-----
| ΔF508
| 66.0%
|-
| G542X
| 2.4%
|-----
| G551D
| 1.6%
|-
| N1303K
| 1.3%
|-----
| W1282X
| 1.2%
|}
<br style="clear:left" />
 
==Associated Conditions==
* In cystic fibrosis, 98% of men are [[Infertility|infertile]]. The causes of [[aspermia]] include:<ref name="pmid126061852">{{cite journal |vauthors=Ratjen F, Döring G |title=Cystic fibrosis |journal=Lancet |volume=361 |issue=9358 |pages=681–9 |year=2003 |pmid=12606185 |doi=10.1016/S0140-6736(03)12567-6 |url=}}</ref>
** [[Atresia]] or absent [[Vas deferens|vasa deferentia]]
** Abnormal or absent [[Seminal vesicle|seminal vesicles]]
 
==Gross Pathology==
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==Microscopic Pathology==
 
===Microscopic Pathology===
 
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===Genetics===
[[Image:CFTR.jpg|thumb|left|350px|'''CFTR protein -''' Molecular structure of the CFTR protein]]
The [[CFTR (gene)|CFTR gene]] is found at the q31.2 [[locus (genetics)|locus]] of [[chromosome 7]], is 230 000 [[base pair]]s long, and creates a protein that is 1,480 [[amino acid]]s 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:<ref name="table">''Prevalence of ΔF508, G551D, G542X, R553X mutations among cystic fibrosis patients in the North of Brazil.'' Brazilian Journal of Medical and Biological Research 2005; 38:11–15. PMID 15665983</ref>{{entête tableau charte alignement|left}}<noinclude></noinclude>
! Mutation
! Frequency<br/>worldwide
|-----
| ΔF508
| 66.0%
|-{{ligne grise}}
| G542X
| 2.4%
|-----
| G551D
| 1.6%
|-{{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 [[Protein folding|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 [[Translation (genetics)|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.
[[Image:Mucoviscidose.PNG|thumb|left|50px|The location of the CFTR gene on chromosome 7]]
Structurally, CFTR is a type of gene known as an [[ATP-binding cassette transporter genes|ABC gene]]. Its protein possesses two [[ATP hydrolysis|ATP-hydrolyzing]] [[Structural domain|domains]] which allows the protein to use [[energy]] in the form of [[Adenosine triphosphate|ATP]]. It also contains two domains comprised of 6 [[Alpha helix|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 [[C-terminal end|carboxyl terminal]] of the protein is anchored to the [[cytoskeleton]] by a [[PDZ (biology)|PDZ]] domain interaction.<ref>Short DB, Trotter KW, Reczek D, Kreda SM, Bretscher A, Boucher RC, Stutts MJ, Milgram SL. ''An apical PDZ protein anchors the cystic fibrosis transmembrane conductance regulator to the cytoskeleton.'' J Biol Chem. 1998 Jul 31;273(31):19797-801. PMID 9677412</ref>
[http://www.peir.net Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology]


==References==
==References==
{{Reflist|2}}
{{Reflist|2}}


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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]

Overview

Cystic fibrosis is an autosomal recessive disease that caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Substitution of a single amino acid is the most common type of CFTR gene mutation. CFTR gene functions as a chloride channel (pumps chloride from the intracellular space to the extracellular space) found on the surface of the epithelial cells. The genetic mutations result in defective transport of chloride, and secondarily sodium and eventually abnormal viscous mucoid secretions mostly in lungs (results in airway surface liquid depletion, decreased mucociliary transport, inflammation and infection) and GI tract (results in reduced volume of pancreatic secretion, pancreatic tissue destruction and fibrosis, malnutrition and poor growth). Infertility due to atresia/absent vasa deferentia and abnormal/absent seminal vesicles is the associated condition of cystic fibrosis.

Pathophysiology

Pathogenesis

 
 
 
Lack of CFTR normal activity
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Less chloride secretion
 
More sodium absorption
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Less water transport into the epithelial surface layer
 
Excessive sodium and water absorption through the epithelial channel
 
 

Lung involvement in cystic fibrosis

  • In patients with cystic fibrosis abnormal chloride conductance of epithelial cells results in airway surface liquid depletion and decreased mucociliary transport (airway surface liquid is essential to support ciliary function).
  • The consequence of cystic fibrosis is a vicious circle of inflammation, tissue damage and infection.[3]
  • Also, exaggerated, generalized, and prolonged inflammatory response of lungs to bacterial and viral pathogen is observed.
  • The inflammatory response is characterized by neutrophilic dominated airway inflammation which is present even in clinically stable patients and in young infants diagnosed by neonatal screening.[3][4]
  • Breakdown of accumulated neutrophils in the infected lungs of patients with cystic fibrosis leads to the release of large amounts of DNA.
  • Accumulated DNA causes high viscosity of the infected sputum, followed by decreased ciliary transport and function.[5]

Gastrointestinal tract involvement in cystic fibrosis

Pancreatic disease:

Biliary disease:

Genetics

Cystic fibrosis is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. This gene codes for a chloride transporter regulated by cyclic AMP (cAMP)-dependent phosphorylation. There are almost 2,000 variants of CFTR gene mutations:[4]

CFTR protein - Molecular structure of the CFTR protein Source: Wikimedia Commons[8]


In Caucasian populations, the frequency of mutations is as follows:[9]Template:Entête tableau charte alignement ! Mutation ! Frequency
worldwide |----- | ΔF508 | 66.0% |- | G542X | 2.4% |----- | G551D | 1.6% |- | N1303K | 1.3% |----- | W1282X | 1.2% |}

Associated Conditions

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.
    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).
    This section of duodenum demonstrates dilation, loss of rugae, and areas of ulceration (arrows).

Microscopic Pathology

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

References

  1. ↑ National Center for Biotechnology Information (US). Genes and Disease [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 1998-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK22183/
  2. ↑ Voter KZ, Ren CL (2008). "Diagnosis of cystic fibrosis". Clin Rev Allergy Immunol. 35 (3): 100–6. doi:10.1007/s12016-008-8078-x. PMID 18506640.
  3. ↑ 3.0 3.1 3.2 Ratjen FA (2009). "Cystic fibrosis: pathogenesis and future treatment strategies". Respir Care. 54 (5): 595–605. PMID 19393104.
  4. ↑ 4.0 4.1 4.2 Cutting GR (2015). "Cystic fibrosis genetics: from molecular understanding to clinical application". Nat. Rev. Genet. 16 (1): 45–56. doi:10.1038/nrg3849. PMC 4364438. PMID 25404111.
  5. ↑ Konstan MW, Ratjen F (2012). "Effect of dornase alfa on inflammation and lung function: potential role in the early treatment of cystic fibrosis". J. Cyst. Fibros. 11 (2): 78–83. doi:10.1016/j.jcf.2011.10.003. PMC 4090757. PMID 22093951.
  6. ↑ 6.0 6.1 Ratjen F, Döring G (2003). "Cystic fibrosis". Lancet. 361 (9358): 681–9. doi:10.1016/S0140-6736(03)12567-6. PMID 12606185.
  7. ↑ "Cystic Fibrosis - National Library of Medicine - PubMed Health".
  8. ↑ "File:CFTR.jpg - Wikimedia Commons". External link in |title= (help)
  9. ↑ Prevalence of ΔF508, G551D, G542X, R553X mutations among cystic fibrosis patients in the North of Brazil. Brazilian Journal of Medical and Biological Research 2005; 38:11–15. PMID 15665983
  10. ↑ Ratjen F, Döring G (2003). "Cystic fibrosis". Lancet. 361 (9358): 681–9. doi:10.1016/S0140-6736(03)12567-6. PMID 12606185.


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