Editing Cystic fibrosis (section)

==Signs and symptoms==
[[File:Blausen 0286 CysticFibrosis.png|thumb|upright=1.3|Health problems associated with cystic fibrosis]]

Cystic fibrosis typically manifests early in life. Newborns and infants with cystic fibrosis tend to have frequent, large, greasy [[Human feces|stools]] (a result of [[malabsorption]]) and are [[Failure to thrive|underweight for their age]].<ref name = "Egan_2020">{{cite book|vauthors=Egan ME, Schechter MS, Voynow JA |chapter=Cystic Fibrosis |title=Nelson Textbook of Pediatrics |pages=2282–2297 |veditors=Kliegman RM, St Geme JW, Blum NJ, Shah SS, Tasker RC, Wilson KM |isbn=978-0-323-56890-6 |publisher=Elsevier |date=2020}}</ref>{{rp|Clinical Manifestations}} Of newborns, 15–20% have their [[small intestine]] blocked by [[meconium]], often requiring surgery to correct.<ref name = "Egan_2020" />{{rp|Clinical Manifestations}} Newborns occasionally have [[neonatal jaundice]] due to blockage of the [[bile duct]]s.<ref name = "Egan_2020" />{{rp|Clinical Manifestations}} Children with cystic fibrosis lose excessive salt in their sweat, and parents often notice salt crystallizing on the skin, or a salty taste when they kiss their child.<ref name = "Egan_2020" />{{rp|Clinical Manifestations}}

The primary cause of [[morbidity]] and death in people with cystic fibrosis is progressive lung disease, which eventually leads to [[respiratory failure]].<ref name = "Egan_2020" />{{rp|Respiratory Tract}} This typically begins as a prolonged respiratory infection that continues until treated with [[antibiotic]]s.<ref name = "Egan_2020" />{{rp|Respiratory Tract}} Chronic infection of the respiratory tract is nearly universal in people with cystic fibrosis, with ''[[Pseudomonas aeruginosa]]'', fungi, and [[mycobacteria]] all becoming increasingly common over time.<ref name=Shteinberg2021>{{cite journal | vauthors = Shteinberg M, Haq IJ, Polineni D, Davies JC | title = Cystic fibrosis | journal = Lancet | volume = 397 | issue = 10290 | pages = 2195–2211 | date = June 2021 | pmid = 34090606 | doi = 10.1016/S0140-6736(20)32542-3 | s2cid = 235327978 }}</ref> Inflammation of the upper airway results in frequent [[Rhinorrhea|runny nose]] and [[Nasal congestion|nasal obstruction]]. [[Nasal polyp]]s are common, particularly in children and teenagers.<ref name = "Egan_2020" />{{rp|Respiratory Tract}} As the disease progresses, people tend to have [[shortness of breath]], and a chronic cough that produces [[sputum]].<ref name = "Egan_2020" />{{rp|Biliary Tract}} Breathing problems make it increasingly challenging to exercise, and prolonged illness causes those affected to be underweight for their age.<ref name = "Egan_2020" />{{rp|Biliary Tract}} In late adolescence or adulthood, people begin to develop severe signs of lung disease: wheezing, [[digital clubbing]], [[cyanosis]], [[Hemoptysis|coughing up blood]], [[pulmonary heart disease]], and collapsed lung ([[atelectasis]] or [[pneumothorax]]).<ref name = "Egan_2020" />{{rp|Respiratory Tract}}

In rare cases, cystic fibrosis can manifest itself as a [[Coagulopathy|coagulation disorder]]. [[Vitamin K]] is normally absorbed from [[breast milk]], formula, and later, solid foods. This absorption is impaired in some CF patients. Young children are especially sensitive to vitamin K malabsorptive disorders because only a very small amount of vitamin K crosses the placenta, leaving the child with very low reserves and limited ability to absorb vitamin K from dietary sources after birth. Because clotting factors II, VII, IX, and X are vitamin K–dependent, low levels of vitamin K can result in coagulation problems. Consequently, when a child presents with unexplained bruising, a coagulation evaluation may be warranted to determine whether an underlying disease is present.<ref name="Reaves-2010">{{cite journal|vauthors=Reaves J, Wallace G|date=2010|title=Unexplained bruising: weighing the pros and cons of possible causes|url=https://www.pediatricsconsultantlive.com/vitamin-d-insufficiency/unexplained-bruising-weighing-pros-and-cons-possible-causes|journal=Consultant for Pediatricians|volume=9|pages=201–2|access-date=22 February 2020|archive-date=22 February 2020|archive-url=https://web.archive.org/web/20200222200803/https://www.pediatricsconsultantlive.com/vitamin-d-insufficiency/unexplained-bruising-weighing-pros-and-cons-possible-causes|url-status=dead}}</ref>

===Lungs and sinuses===
[[File:Cystic Fibrosis Respiratory Infections by Age.svg|thumb|upright=1.3|Respiratory infections in CF vary according to age.<br><br>Green = ''[[Pseudomonas aeruginosa]]''<br>Brown = ''[[Staphylococcus aureus]]''<br>Blue = ''[[Haemophilus influenzae]]''<br>Red = ''[[Burkholderia cepacia]]'' complex]]
Lung disease results from clogging of the airways due to mucus build-up, decreased [[mucociliary clearance]], and resulting [[inflammation]].<ref name="pmid20299528">{{cite journal | vauthors = Flume PA, Mogayzel PJ, Robinson KA, Rosenblatt RL, Quittell L, Marshall BC | title = Cystic fibrosis pulmonary guidelines: pulmonary complications: hemoptysis and pneumothorax | journal = American Journal of Respiratory and Critical Care Medicine | volume = 182 | issue = 3 | pages = 298–306 | date = August 2010 | pmid = 20675678 | doi = 10.1164/rccm.201002-0157OC }}</ref><ref name="kumar2007">{{cite book|title=Robbins Basic Pathology |url=https://books.google.com/books?id=-keXQ6LaXVIC |vauthors=Mitchell RS, Kumar V, Robbins SL, Abbas AK, Fausto N|publisher=Saunders/Elsevier|year=2007|isbn=978-1-4160-2973-1 |page=[https://books.google.com/books?id=-keXQ6LaXVIC&pg=PT1253 1253], [https://books.google.com/books?id=-keXQ6LaXVIC&pg=PT1254 1254] }}</ref> In later stages, changes in the architecture of the lung, such as pathology in the major airways ([[bronchiectasis]]), further exacerbate difficulties in breathing. Other signs include high [[blood pressure]] in the lung ([[pulmonary hypertension]]), [[heart failure]], difficulties getting enough [[oxygen]] to the body ([[Hypoxia (medical)|hypoxia]]), and respiratory failure requiring support with breathing masks, such as [[bilevel positive airway pressure]] machines or [[Mechanical ventilation|ventilators]].<ref name="Rowe" /> ''[[Staphylococcus aureus]]'', ''[[Haemophilus influenzae]]'', and ''[[Pseudomonas aeruginosa]]'' are the three most common organisms causing lung infections in CF patients.<ref name=kumar2007/>{{rp|1254}} In addition, opportunistic infection due to [[Burkholderia cepacia complex|''Burkholderia cepacia'' complex]] can occur, especially through transmission from patient to patient.<ref name="pmid14726455">{{cite journal | vauthors = Saiman L, Siegel J | title = Infection control in cystic fibrosis | journal = Clinical Microbiology Reviews | volume = 17 | issue = 1 | pages = 57–71 | date = January 2004 | pmid = 14726455 | pmc = 321464 | doi = 10.1128/CMR.17.1.57-71.2004 | doi-access = free }}</ref>

In addition to typical bacterial infections, people with CF more commonly develop other types of lung diseases. Among these is [[allergic bronchopulmonary aspergillosis]], in which the body's response to the common [[fungus]] ''[[Aspergillus fumigatus]]'' causes worsening of breathing problems. Another is infection with ''[[Mycobacterium avium complex|Mycobacterium avium]]'' complex, a group of bacteria related to [[tuberculosis]], which can cause lung damage and do not respond to common antibiotics.<ref name="pmid16266669">{{cite journal | vauthors = Girón RM, Domingo D, Buendía B, Antón E, Ruiz-Velasco LM, Ancochea J | title = [Nontuberculous mycobacteria in patients with cystic fibrosis] | language = es | journal = Archivos de Bronconeumologia | volume = 41 | issue = 10 | pages = 560–565 | date = October 2005 | pmid = 16266669 | doi = 10.1016/S1579-2129(06)60283-8 }}</ref>

The mucus in the [[paranasal sinus]]es is equally thick and may also cause blockage of the sinus passages, leading to infection. This may cause facial pain, fever, nasal drainage, and [[headache]]s. Individuals with CF may develop overgrowth of the nasal tissue ([[nasal polyp]]s) due to inflammation from chronic sinus infections.<ref name="pmid20209279">{{cite journal | vauthors = Franco LP, Camargos PA, Becker HM, Guimarães RE | title = Nasal endoscopic evaluation of children and adolescents with cystic fibrosis | journal = Brazilian Journal of Otorhinolaryngology | volume = 75 | issue = 6 | pages = 806–813 | date = 2009 | pmid = 20209279 | pmc = 9446041 | doi = 10.1590/S1808-86942009000600006 | doi-access = free }}</ref> Recurrent sinonasal polyps can occur in 10% to 25% of CF patients.<ref name=kumar2007/>{{rp|1254}} These polyps can block the nasal passages and increase breathing difficulties.<ref name="pmid15626248">{{cite journal | vauthors = Maldonado M, Martínez A, Alobid I, Mullol J | title = The antrochoanal polyp | journal = Rhinology | volume = 42 | issue = 4 | pages = 178–182 | date = December 2004 | pmid = 15626248 }}</ref><ref name="pmid1527348">{{cite journal | vauthors = Ramsey B, Richardson MA | title = Impact of sinusitis in cystic fibrosis | journal = The Journal of Allergy and Clinical Immunology | volume = 90 | issue = 3 Pt 2 | pages = 547–552 | date = September 1992 | pmid = 1527348 | doi = 10.1016/0091-6749(92)90183-3 | doi-access = free }}</ref>

Cardiorespiratory complications are the most common causes of death (about 80%) in patients at most CF centers in the United States.<ref name=kumar2007/>{{rp|1254}}

===Gastrointestinal===
Digestive problems are also prevalent in individuals with CF. Approximately 15%-20% of newborns diagnosed with CF experience intestinal blockage ([[meconium ileus]]), and other digestive issues may arise due to mucus accumulation in the pancreas.<ref name="pmid31353045">{{cite journal | vauthors = Padoan R, Cirilli N, Falchetti D, Cesana BM | title = Risk factors for adverse outcome in infancy in meconium ileus cystic fibrosis infants: A multicentre Italian study | journal = Journal of Cystic Fibrosis | volume = 18 | issue = 6 | pages = 863–868 | date = November 2019 | pmid = 31353045 | doi = 10.1016/j.jcf.2019.07.003 | doi-access = free }}</ref> Consequently, there is impaired insulin production, leading to cystic fibrosis-related diabetes mellitus. Moreover, enzyme transport disruption from the pancreas to the intestines results in digestive problems such as recurrent diarrhea or weight loss.<ref name="pmid16131979">{{cite journal | vauthors = Borowitz D, Durie PR, Clarke LL, Werlin SL, Taylor CJ, Semler J, De Lisle RC, Lewindon P, Lichtman SM, Sinaasappel M, Baker RD, Baker SS, Verkade HJ, Lowe ME, Stallings VA, Janghorbani M, Butler R, Heubi J | title = Gastrointestinal outcomes and confounders in cystic fibrosis | journal = Journal of Pediatric Gastroenterology and Nutrition | volume = 41 | issue = 3 | pages = 273–285 | date = September 2005 | pmid = 16131979 | doi = 10.1097/01.mpg.0000178439.64675.8d | doi-access = free }}</ref>

In cystic fibrosis, there is impaired chloride secretion due to the mutation of CFTR. This disrupts the ionic balance, causes impaired bicarbonate secretion, and alters the pH. The pancreatic enzymes that work in a specific pH range cannot act as the chyme is not neutralized by bicarbonate ions. This causes impairment of the digestion process.<ref name="Silbernagl-2015">{{Cite book | vauthors = Silbernagl S |title=Color Atlas of Physiology , Physiology |publisher=Thieme Publishing Group |year=2015 |isbn=978-3135450070 |edition=7th |publication-date=13 May 2015 |pages=260–61 |language=}}</ref>

The thick mucus seen in the lungs has a counterpart in thickened secretions from the [[pancreas]], an organ responsible for providing [[Pancreatic juice|digestive juices]] that help break down food. These secretions block the [[exocrine]] movement of the digestive enzymes into the [[duodenum]] and result in irreversible damage to the pancreas, often with painful inflammation ([[pancreatitis]]).<ref name="pmid9725922">{{cite journal | vauthors = Cohn JA, Friedman KJ, Noone PG, Knowles MR, Silverman LM, Jowell PS | title = Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis | journal = The New England Journal of Medicine | volume = 339 | issue = 10 | pages = 653–658 | date = September 1998 | pmid = 9725922 | doi = 10.1056/NEJM199809033391002 | doi-access = free }}</ref> The [[pancreatic duct]]s are totally plugged in more advanced cases, usually seen in older children or adolescents.<ref name=kumar2007/> This causes atrophy of the exocrine glands and progressive fibrosis.<ref name=kumar2007/>

In addition, protrusion of internal [[rectum|rectal]] membranes ([[rectal prolapse]]) is more common, occurring in as many as 10% of children with CF,<ref name="kumar2007" /> and it is caused by increased fecal volume, [[malnutrition]], and [[Valsalva maneuver|increased intra–abdominal pressure]] due to coughing.<ref name="pmid13578072">{{cite journal | vauthors = Kulczycki LL, Shwachman H | title = Studies in cystic fibrosis of the pancreas; occurrence of rectal prolapse | journal = The New England Journal of Medicine | volume = 259 | issue = 9 | pages = 409–412 | date = August 1958 | pmid = 13578072 | doi = 10.1056/NEJM195808282590901 }}</ref>

Individuals with CF also have difficulties absorbing the fat-soluble vitamins [[vitamin A|A]], [[vitamin D|D]], [[vitamin E|E]], and [[vitamin K|K]].<ref name="Assis2016"/>

In addition to the pancreas problems, people with CF experience more [[gastroesophageal reflux disease|heartburn]],<ref name="Assis2016"/> intestinal blockage by [[Intussusception (medical disorder)|intussusception]], and [[constipation]].<ref name="pmid1755649">{{cite journal | vauthors = Malfroot A, Dab I | title = New insights on gastro-oesophageal reflux in cystic fibrosis by longitudinal follow up | journal = Archives of Disease in Childhood | volume = 66 | issue = 11 | pages = 1339–1345 | date = November 1991 | pmid = 1755649 | pmc = 1793275 | doi = 10.1136/adc.66.11.1339 }}</ref> Older individuals with CF may develop [[distal intestinal obstruction syndrome]], which occurs when feces becomes thick with mucus ([[inspissated]]) and can cause bloating, pain, and incomplete or complete bowel obstruction.<ref name="pmid34936085">{{cite journal | vauthors = Carroll W, Green J, Gilchrist FJ | title = Interventions for preventing distal intestinal obstruction syndrome (DIOS) in cystic fibrosis | journal = The Cochrane Database of Systematic Reviews | volume = 2021 | issue = 12 | pages = CD012619 | date = December 2021 | pmid = 34936085 | pmc = 8693853 | doi = 10.1002/14651858.CD012619.pub3 }}</ref><ref name="Assis2016">{{cite journal | vauthors = Assis DN, Freedman SD | title = Gastrointestinal Disorders in Cystic Fibrosis | journal = Clinics in Chest Medicine | volume = 37 | issue = 1 | pages = 109–118 | date = March 2016 | pmid = 26857772 | doi = 10.1016/j.ccm.2015.11.004 | type = Review }}</ref>

[[Exocrine pancreatic insufficiency]] occurs in the majority (85–90%) of patients with CF.<ref name=kumar2007/>{{rp|1253}} It is mainly associated with "severe" CFTR mutations, where both alleles are completely nonfunctional (e.g. [[ΔF508]]/ΔF508).<ref name=kumar2007/>{{rp|1253}} It occurs in 10–15% of patients with one "severe" and one "mild" CFTR mutation where little CFTR activity still occurs, or where two "mild" CFTR mutations exist.<ref name=kumar2007/>{{rp|1253}} In these milder cases, a sufficient pancreatic exocrine function is still present so enzyme supplementation is not required.<ref name=kumar2007/>{{rp|1253}} Usually, no other GI complications occur in pancreas-sufficient phenotypes, and in general, such individuals usually have excellent growth and development.<ref name=kumar2007/>{{rp|1254}} Despite this, idiopathic [[chronic pancreatitis]] can occur in a subset of pancreas-sufficient individuals with CF, and is associated with recurrent abdominal pain and life-threatening complications.<ref name=kumar2007/>

Liver diseases are another common complication in CF patients. The prevalence in studies ranged from 18% at age two to 41% at age 12, with no significant increase thereafter.<ref name="pmid15582124">{{cite journal | vauthors = Lamireau T, Monnereau S, Martin S, Marcotte JE, Winnock M, Alvarez F | title = Epidemiology of liver disease in cystic fibrosis: a longitudinal study | journal = Journal of Hepatology | volume = 41 | issue = 6 | pages = 920–925 | date = December 2004 | pmid = 15582124 | doi = 10.1016/j.jhep.2004.08.006 }}</ref> Another study found that males with CF are more prone to liver diseases compared to females, and those with meconium ileus have an increased risk of liver diseases.<ref name="pmid12447862">{{cite journal | vauthors = Colombo C, Battezzati PM, Crosignani A, Morabito A, Costantini D, Padoan R, Giunta A | title = Liver disease in cystic fibrosis: A prospective study on incidence, risk factors, and outcome | journal = Hepatology | volume = 36 | issue = 6 | pages = 1374–1382 | date = December 2002 | pmid = 12447862 | doi = 10.1002/hep.1840360613 | doi-access = free }}</ref>

Thickened secretions also may cause liver problems in patients with CF. [[Bile]] secreted by the liver to aid in digestion may block the [[bile duct]]s, leading to liver damage. Impaired digestion or absorption of lipids can result in [[steatorrhea]]. Over time, this can lead to scarring and nodularity ([[cirrhosis]]). The liver fails to rid the blood of toxins and does not make important proteins, such as those responsible for [[coagulation|blood clotting]].<ref name="pmid1458306">{{cite journal | vauthors = Williams SG, Westaby D, Tanner MS, Mowat AP | title = Liver and biliary problems in cystic fibrosis | journal = British Medical Bulletin | volume = 48 | issue = 4 | pages = 877–892 | date = October 1992 | pmid = 1458306 | doi = 10.1093/oxfordjournals.bmb.a072583 }}</ref><ref name="liver">{{cite journal | vauthors = Colombo C, Russo MC, Zazzeron L, Romano G | title = Liver disease in cystic fibrosis | journal = Journal of Pediatric Gastroenterology and Nutrition | volume = 43 | issue = Suppl 1 | pages = S49–S55 | date = July 2006 | pmid = 16819402 | doi = 10.1097/01.mpg.0000226390.02355.52 | s2cid = 27836468 | doi-access = free }}</ref> Liver disease is the third-most common cause of death associated with CF.<ref name="kumar2007" />

Around 5–7% of people experience [[biliary cirrhosis|liver damage]] severe enough to cause symptoms: typically [[gallstone]]s causing [[biliary colic]].<ref name = "Egan_2020" />{{rp|Biliary Tract}}

===Endocrine===
The pancreas contains the [[islets of Langerhans]], which are responsible for making [[insulin]], a hormone that helps regulate blood [[glucose]]. Damage to the pancreas can lead to loss of the islet cells, leading to a type of diabetes unique to those with the disease.<ref name="pmid8039595">{{cite journal | vauthors = Moran A, Pyzdrowski KL, Weinreb J, Kahn BB, Smith SA, Adams KS, Seaquist ER | title = Insulin sensitivity in cystic fibrosis | journal = Diabetes | volume = 43 | issue = 8 | pages = 1020–1026 | date = August 1994 | pmid = 8039595 | doi = 10.2337/diabetes.43.8.1020 }}</ref> This [[cystic fibrosis-related diabetes]] shares characteristics of [[Diabetes mellitus type 1|type 1]] and [[Diabetes mellitus type 2|type 2]] diabetes, and is one of the principal nonpulmonary complications of CF.<ref name="Alves"/>

Vitamin D is involved in [[calcium]] and [[phosphate]] regulation. Poor uptake of vitamin D from the diet because of malabsorption can lead to the bone disease [[osteoporosis]] in which weakened bones are more susceptible to [[bone fracture|fracture]]s.<ref name="pmid10525552">{{cite journal | vauthors = Haworth CS, Selby PL, Webb AK, Dodd ME, Musson H, McL Niven R, Economou G, Horrocks AW, Freemont AJ, Mawer EB, Adams JE | title = Low bone mineral density in adults with cystic fibrosis | journal = Thorax | volume = 54 | issue = 11 | pages = 961–967 | date = November 1999 | pmid = 10525552 | pmc = 1745400 | doi = 10.1136/thx.54.11.961 }}</ref>

===Infertility===
Infertility affects both men and women. At least 97% of men with cystic fibrosis are infertile, but not sterile, and can have children with assisted reproductive techniques.<ref name="pmid11035677">{{cite journal | vauthors = McCallum TJ, Milunsky JM, Cunningham DL, Harris DH, Maher TA, Oates RD | title = Fertility in men with cystic fibrosis: an update on current surgical practices and outcomes | journal = Chest | volume = 118 | issue = 4 | pages = 1059–1062 | date = October 2000 | pmid = 11035677 | doi = 10.1378/chest.118.4.1059 }}</ref> The main cause of infertility in men with cystic fibrosis is [[congenital absence of the vas deferens]] (which normally connects the [[Testicle|testes]] to the [[ejaculatory duct]]s of the [[Human penis|penis]]), but potentially also by other mechanisms causing [[azoospermia|no sperm]], [[teratospermia|abnormally shaped sperm]], and [[oligoasthenospermia|few sperm with poor motility]].<ref name="pmid22709980">{{cite journal | vauthors = Chen H, Ruan YC, Xu WM, Chen J, Chan HC | title = Regulation of male fertility by CFTR and implications in male infertility | journal = Human Reproduction Update | volume = 18 | issue = 6 | pages = 703–713 | date = 2012 | pmid = 22709980 | doi = 10.1093/humupd/dms027 | doi-access = free }}</ref> Many men found to have congenital absence of the vas deferens during evaluation for infertility have a mild, previously undiagnosed form of CF.<ref name="pmid7968122">{{cite journal | vauthors = Augarten A, Yahav Y, Kerem BS, Halle D, Laufer J, Szeinberg A, Dor J, Mashiach S, Gazit E, Madgar I | title = Congenital bilateral absence of vas deferens in the absence of cystic fibrosis | journal = Lancet | volume = 344 | issue = 8935 | pages = 1473–1474 | date = November 1994 | pmid = 7968122 | doi = 10.1016/S0140-6736(94)90292-5 | s2cid = 28860665 }}</ref> While females with CF are generally fertile, around 20% of women with CF have fertility difficulties due to thickened cervical mucus or malnutrition. In severe cases, malnutrition disrupts [[ovulation]] and causes [[amenorrhoea|a lack of menstruation]].<ref name="pmid10893364">{{cite journal | vauthors = Gilljam M, Antoniou M, Shin J, Dupuis A, Corey M, Tullis DE | title = Pregnancy in cystic fibrosis. Fetal and maternal outcome | journal = Chest | volume = 118 | issue = 1 | pages = 85–91 | date = July 2000 | pmid = 10893364 | doi = 10.1378/chest.118.1.85 | s2cid = 32289370 }}</ref>