Cystic Fibrosis (CF)


Cystic fibrosis (CF) is a rare, chronic, progressive disease characterized by the production and secretion of thick, viscous mucus. The mucus obstructs multiple organ systems, especially the digestive tract, pancreas, hepatobiliary system, and respiratory tract, and the obstruction causes various forms of organ dysfunction that are frequently diagnosed in patients with CF.1

Pancreatic Comorbidities

Exocrine Pancreatic Insufficiency

Exocrine pancreatic insufficiency is the predominant comorbidity in the digestive tract of patients with CF. Mucus plugs obstruct the pancreatic ducts, blocking the passage of sodium bicarbonate and digestive enzymes into the duodenum. In the duodenum, sodium bicarbonate from the pancreas neutralizes acid from the stomach. When the level of sodium bicarbonate in the duodenum is insufficient, a rise in the pH results in bile salt formation, contributing to gastrointestinal dysfunction. Additionally, a lack of digestive enzymes results in malabsorption and chronic diarrhea; these are due to pre-epithelial dysfunction in the gastrointestinal tract following exposure to undigested fat, proteins, and carbohydrates.1 Exocrine pancreatic insufficiency occurs in 85% to 90% of individuals with CF, and the prevalence increases with age.2

Thick mucus obstructs the pancreatic duct, preventing the secretion of pancreatic enzymes and damaging the pancreas. When the pancreas is scarred and fibrotic, insulin production decreases, and reduced secretion results in CF-related diabetes,3 which affects approximately 20% of adolescents and 40% to 50% of adults with CF.2

Hepatobiliary Comorbidities

For a diagnosis of CF-related liver disease, at least 2 of the following criteria must be present at 2 consecutive follow-up examinations within 1 year:

  • Hepatomegaly confirmed by ultrasound
  • Elevated serum levels of hepatic enzymes, including alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and gamma-glutamyltransferase
  • Other hepatic abnormalities revealed on ultrasound 

Other hepatobiliary comorbidities observed in CF include cirrhosis, ascites, portal hypertension, esophageal varices, and bleeding; these are a consequence of the production and secretion of thick bile, which causes biliary fibrosis. Multilobular hepatic cirrhosis develops in approximately 5% to 10% of patients with CF during the first 10 years of life, and in many cases, this leads to portal hypertension accompanied by complications such as variceal bleeding.1

Gastrointestinal Comorbidities

Meconium Ileus

Another condition related to exocrine pancreatic insufficiency and frequently seen in infants with CF is meconium ileus, which is an obstruction of the terminal ileum due to abnormally thick meconium.1 Along with dehydration of the intraluminal contents and increased hepatic production of glutamyl transpeptidase, exocrine pancreatic insufficiency contributes to the pathogenesis of meconium ileus because the secretion of pancreatic enzymes is reduced. These normally dilute albumin. High concentrations of albumin result in the formation of a viscid mass of meconium.4 CF-related meconium ileus occurs in 10% to 15% of neonates with CF.1,2

Constipation

Constipation occurs in 40% of individuals with CF.2 Some researchers have reported a 47% prevalence of constipation among children with CF. Independent risk factors for constipation were meconium ileus and a decrease in total fat absorption; poor fluid and fiber intake were not associated risk factors. The primary cause of constipation in CF is the altered composition of the intestinal fluid, which results from the presence of abnormal cystic fibrosis transmembrane regulator (CFTR) proteins in the gastrointestinal tract. The dysfunctional CFTR protein channels disrupt the flow of chloride and sodium, and consequently water, as water follows salt into and out of cells.5,6 Increased absorption of sodium and fluid in the gastrointestinal epithelium due to reduced CFTR-dependent chloride secretion results in dehydration of the luminal contents and constipation-related ailments.6

Intussusception

The risk for intussusception is increased in CF, although other gastrointestinal comorbidities are more common.2 Intussusception occurs in approximately 1% of patients with CF, presumably caused by a thick, congealed mass of mucus and fecal material that adheres to the mucosa and provides a lead point for intussusception.7

Distal Intestinal Obstructive Syndrome

Much like meconium ileus, distal intestinal obstruction syndrome is associated with fecal impaction in the distal portion of the intestinal tract, frequently caused by dehydration. The combination of thick, sticky mucus and fecal matter creates a large mass that either partially or completely obstructs the lumen. Obstruction may lead to symptoms such as vomiting, abdominal distention, severe abdominal pain, anorexia, constipation, and early satiety during meals.1,8 Distal intestinal obstructive syndrome occurs in 10% to 47% of individuals with CF.2

Gastroesophageal Reflux Disease

A systematic review published in 2021 revealed that anti-reflux surgery not only targets reflux but also delays lung deterioration in children with CF.9 Gastrointestinal reflux disease (GERD) correlates with accelerated lung deterioration in patients with CF—specifically, more severe lower pulmonary dysfunction and increased pulmonary exacerbations.9,10 

GERD is more likely to develop in individuals with CF because of airway hyperinflation from obstructive lung disease, chronic coughing, delaying gastric emptying, hyperalimentation to counter malabsorption, and poor dietary habits, especially consumption of a high-fat diet.10-13 

Researchers have described potential mechanisms of how GERD contributes to lung damage in CF. Both the acidic and non-acidic aspects of GERD are thought to contribute to the pathogenesis of lung disease in CF by changing the pulmonary microbiology. One possible mechanism is the aspiration of acidic stomach contents while in the supine position, which leads to a chronic cycle of inflammation, infection, and progression of lung disease. Another potential mechanism by which reflux exacerbates lung disease is the activation of afferent receptors in the esophageal mucosa by gastric acid. This triggers the output of motor neurons connected to the respiratory musculature and tracheobronchial tree, causing cough, bronchospasm, and potentially an influx of neutrophils associated with chronic respiratory inflammation.10,14 GERD occurs in up to 80% of individuals with CF.2 Approximately half of pediatric patients with CF have GERD.10 

Vitamin Deficiencies/Malnutrition

The combination of malabsorption and increased energy requirements in individuals with CF leads to malnutrition. Because improperly digested food is poorly absorbed, individuals with CF commonly have malnutrition and deficiencies of vitamins A, D, and E.1,15 

Vitamin A

Vitamin A deficiency in CF results in ocular comorbidities, such as night blindness and conjunctival xerosis.16 

Vitamin D

Vitamin D deficiency in CF may play a role in the development of bone mineralization diseases, such as osteoporosis and osteopenia.2,15 Exocrine pancreatic insufficiency, which causes fat malabsorption and alters vitamin D metabolism, and a lack of outdoor activity may contribute to vitamin D deficiency in individuals with CF.15 

Vitamin E

Vitamin E deficiency in CF results in neurological comorbidities manifesting as abnormal ocular movements, diminished reflexes, decreased vibratory and proprioceptive sense, ataxia, and muscle weakness.17

Respiratory Comorbidities

Severe Obstructive Pulmonary Disease/Bronchiectasis

Pulmonary disease is the predominant cause of morbidity and mortality in CF.18 Impaired pulmonary mucociliary clearance and chronic respiratory tract infections contribute to the development of bronchiectasis, or permanent lung tissue damage and dilation. Bronchiectasis prevents normal gas exchange and causes hypoxemia and hypoventilation. These factors predispose individuals with CF to the development of advanced lung disease, including right ventricular heart failure, pulmonary hypertension, and eventually respiratory failure.19

Chronic Respiratory Tract Infections

An accumulation of hyperviscous mucus in the lungs traps inhaled germs and pollutants. The cilia on the pulmonary epithelial surface cannot clear these efficiently, and obstructive pulmonary disease develops.18,20 Inefficient clearance of pulmonary mucus also results in chronic respiratory tract infections, especially bacterial infections caused by Pseudomonas aeruginosa, Achromobacter xylosoxidans, Stenotrophomonas maltophilia, and nontuberculous mycobacteria.20,21    

Recurrent Sinusitis/Rhinitis/Nasal Polyposis

Chronic rhinosinusitis and nasal polyposis are common comorbidities in up to 45% or more of individuals with CF.18,22,23 As in the pathogenesis of recurrent lower respiratory tract infection, hyperviscous mucus, impaired mucociliary clearance, and chronic inflammation and infection contribute to the development of chronic sinusitis.22

Pneumothorax

Pneumothorax is one of the more serious complications of CF and has adverse prognostic implications.24 Spontaneous pneumothorax occurs in approximately 3.4% of all patients with CF during their lifetime; 72.4% of cases occur after the age of 18 years. The primary risk factor for pneumothorax in patients with CF is severe obstructive pulmonary disease, indicated by a forced expiratory volume in the first second (FEV1) below 40% of the predicted value on pulmonary function testing.25

Hemoptysis

Massive hemoptysis is a commonly reported comorbidity in patients with CF, particularly older patients with severe obstructive pulmonary disease. Nearly 60% of patients whose FEV1 is below 40% of the predicted value experience an episode of massive hemoptysis, with subsequently increased morbidity and 2-year mortality.26

Pulmonary Embolism/Venous Thromboembolism

Although the risk for pulmonary embolism/venous thromboembolism in patients with CF is comparable with that in the general population (1.40% and 2.02%, respectively), pulmonary embolism/venous thromboembolism is still a potential comorbidity in persons with CF. Iatrogenic causes such as upper extremity catheterization likely contribute to most cases of venous thromboembolism (VTE) in patients with CF.27

Pulmonary Hypertension

The natural progression of obstructive pulmonary disease in CF leads to hypercapnia and pulmonary hypertension, ultimately ending in respiratory failure.18,19 In one study, pulmonary hypertension developed in approximately 57% of patients with CF before lung transplant.28

Musculoskeletal Comorbidities

Osteoporosis/Osteopenia

The prevalence of osteoporosis and osteopenia in individuals with CF appears to be decreasing. As of 2017, the prevalence of osteoporosis in these individuals was 23%, and the prevalence of osteopenia was 38%.

Several factors may contribute to the development of osteoporosis and osteopenia in CF, including vitamin D deficiency, exocrine pancreatic insufficiency leading to gastrointestinal malabsorption, altered vitamin D metabolism, and lack of exercise, especially outdoor exercise.15 

Urogenital Tract Comorbidities

Infertility 

The prevalence of infertility in males with CF is 98%.2 An increased incidence of hydrocele, undescended testicles, inguinal hernias, and absence of the vas deferens in males with CF contributes to infertility. The mutant CFTR gene responsible for CF also is suspected to alter the development of structures derived from the wolffian ducts during embryogenesis.29 

The increased viscosity of cervical mucus in females with CF can prevent fertilization. Although the fertility of many women with CF is abnormal, conception is possible.30,31 In a study conducted in 2018, 2% of women with CF reported a pregnancy, compared with 24% of women in the general population.32 

Amenorrhea, Delayed Secondary Sexual Development, and Urinary Stress Incontinence and Infections

Secondary sexual development is delayed in patients of both sexes with CF. As CF progresses, menstrual abnormalities develop in women, such as amenorrhea due to the malabsorption of important nutrients and a shift of vital energy away from the reproductive system to other critical organ systems.30,31  

Women with CF reported perceived pubertal delay (33%), urinary incontinence (16%), sexual dysfunction (16%), and yeast infections (49%).32 Frequent urinary tract infections are common in patients with CF.30

Emerging Comorbidities 

Advances in treatments for CF have prolonged the lifespan of affected individuals, so that new comorbidities have emerged, including acute and chronic kidney disease, malignancy, coronary artery disease, anxiety, and depression.2,33-36 A recent study reported a 2 to 3 times higher prevalence of depression and anxiety among persons with CF, including parent caregivers, than in the general population.37

References

  1. Haack A, Aragão GG, Novaes MRCG. Pathophysiology of cystic fibrosis and drugs used in associated digestive tract diseases. World J Gastroenterol. 2013;19(46):8552-8561. doi:10.3748/wjg.v19.i46.8552
  2. Ronan NJ, Elborn JS, Plant BJ. Current and emerging comorbidities in cystic fibrosis. La Presse Médicale. 2017;46(6, Part 2):e125-e138. doi:10.1016/j.lpm.2017.05.011 In: Cystic fibrosis comorbidities – caring for kids with cystic fibrosis. Published October 27, 2019. Accessed January 6, 2022.
  3. What Is CF-related diabetes (CFRD)? Cystic-Fibrosis.com. Accessed January 9, 2022.
  4. Sharma GD. What is the role of meconium ileus in the pathogenesis of cystic fibrosis (CF)? Medscape. Updated September 28, 2020. Accessed January 9, 2022.
  5. van der Doef HPJ, Kokke FTM, Beek FJA, Woestenenk JW, Froeling SP, Houwen RHJ. Constipation in pediatric cystic fibrosis patients: an underestimated medical condition. J Cystic Fibrosis. 2010;9(1):59-63. doi:10.1016/j.jcf.2009.11.003
  6. Reddy MM, Stutts MJ. Status of fluid and electrolyte absorption in cystic fibrosis. Cold Spring Harb Perspect Med. 2013;3(1):a009555. doi:10.1101/cshperspect.a009555 
  7. Chahine AA. What is the role of cystic fibrosis in the etiology of intussusception? Medscape. Updated December 20, 2018. Accessed January 9, 2022.
  8. Glichrist FJ, Green J, Carroll W. Interventions for treating distal intestinal obstruction syndrome (DIOS) in cystic fibrosis. Cochrane. Published December 22, 2021. Accessed January 9, 2022.
  9. Ng J, Friedmacher F, Pao C, Charlesworth P. Gastroesophageal reflux disease and need for antireflux surgery in children with cystic fibrosis: a systematic review on incidence, surgical complications, and postoperative outcomes. Eur J Pediatr Surg. 2021;31(1):106-114. doi:10.1055/s-0040-1718750
  10. Robinson NB, DiMango E. Prevalence of gastroesophageal reflux in cystic fibrosis and implications for lung disease. Ann Am Thorac Soc. 2014;11(6):964-968. doi:10.1513/AnnalsATS.201401-044FR 
  11. Pauwels A, Blondeau K, Dupont LJ, Sifrim D. Mechanisms of increased gastroesophageal reflux in patients with cystic fibrosis. Am J Gastroenterol. 2012;107(9):1346-1353. doi:10.1038/ajg.2012.213
  12. Pauwels A, Blondeau K, Mertens V, et al. Gastric emptying and different types of reflux in adult patients with cystic fibrosis. Aliment Pharmacol Ther. 2011;34(7):799-807. doi:10.1111/j.1365-2036.2011.04786.x
  13. Pauwels A, Decraene A, Blondeau K, et al. Bile acids in sputum and increased airway inflammation in patients with cystic fibrosis. Chest. 2012;141(6):1568-1574. doi:10.1378/chest.11-1573
  14. Carpagnano GE, Resta O, Ventura MT, et al. Airway inflammation in subjects with gastro-oesophageal reflux and gastro-oesophageal reflux-related asthma. J Intern Med. 2006;259(3):323-331. doi:10.1111/j.1365-2796.2005.01611.x
  15. Chesdachai S, Tangpricha V. Treatment of vitamin D deficiency in cystic fibrosis. J Steroid Biochem Mol Biol. 2016;164:36-39. doi:10.1016/j.jsbmb.2015.09.013
  16. Rayner RJ, Tyrrell JC, Hiller EJ, et al. Night blindness and conjunctival xerosis caused by vitamin A deficiency in patients with cystic fibrosis. Arch Dis Child. 1989;64(8):1151-1156. doi:10.1136/adc.64.8.1151
  17. Sitrin MD, Lieberman F, Jensen WE, Noronha A, Milburn C, Addington W. Vitamin E deficiency and neurologic disease in adults with cystic fibrosis. Ann Intern Med. 1987;107(1):51-54. doi:10.7326/0003-4819-107-1-51
  18. Ratjen F, Bell SC, Rowe SM, Goss CH, Quittner AL, Bush A. Cystic fibrosis. Nat Rev Dis Primers. 2015;1:15010. doi:10.1038/nrdp.2015.10
  19. Hayes D, Tobias JD, Mansour HM, et al. Pulmonary hypertension in cystic fibrosis with advanced lung disease. Am J Respir Crit Care Med. 2014;190(8):898-905. doi:10.1164/rccm.201407-1382OC
  20. Research into mucus. Cystic Fibrosis Foundation. Accessed January 9, 2022.
  21. Ciofu O, Hansen CR, Høiby N. Respiratory bacterial infections in cystic fibrosis. Curr Opin Pulm Med. 2013;19(3):251-258. doi:10.1097/MCP.0b013e32835f1afc
  22. Le C, McCrary HC, Chang E. Cystic fibrosis sinusitis. Adv Otorhinolaryngol. 2016;79:29-37. doi:10.1159/000444959
  23. Henriksson G, Westrin KM, Karpati F, Wikström AC, Stierna P, Hjelte L. Nasal polyps in cystic fibrosis: clinical endoscopic study with nasal lavage fluid analysis. Chest. 2002;121(1):40-47. doi:10.1378/chest.121.1.40
  24. Lord RW, Jones AM, Webb AK, Barry PJ. Pneumothorax in cystic fibrosis: beyond the guidelines. Paediatr Respir Rev. 2016;20 Suppl:30-33. doi:10.1016/j.prrv.2016.06.012
  25. Flume PA. Pulmonary complications of cystic fibrosis. Respir Care. 2009;54(5):10.
  26. Flume PA, Yankaskas JR, Ebeling M, Hulsey T, Clark LL. Massive hemoptysis in cystic fibrosis. Chest. 2005;128(2):729-738. doi:10.1378/chest.128.2.729
  27. Blower K, Seifi A, Michalek J, Keyt H. Incidence of VTE in patients with cystic fibrosis: are they high risk? – CHEST (chestnet.org) Chest. 2016;150(4 Suppl):1135A. doi:10.1016/j.chest.2016.08.1245
  28. Hayes D, Higgins RS, Kirkby S, et al. Impact of pulmonary hypertension on survival in patients with cystic fibrosis undergoing lung transplantation: an analysis of the UNOS registry. J Cyst Fibros. 2014;13(4):416-423. doi:10.1016/j.jcf.2013.12.004
  29. Holsclaw DS, Shwachman H. Increased incidence of inguinal hernia, hydrocele, and undescended testicle in males with cystic fibrosis. Pediatrics. 1971;48(3):442-445. doi:10.1542/peds.48.3.442
  30. Cystic fibrosis. statMed.org. Accessed January 9, 2022.
  31. Brunoro GVF, Wolfgramm EV, Louro ID, et al. Cystic fibrosis Δf508 mutation screening in Brazilian women with altered fertility. Mol Biol Rep. 2011;38(7):4343-4346. doi:10.1007/s11033-010-0560-x
  32. Kazmerski TM, Sawicki GS, Miller E, et al. Sexual and reproductive health behaviors and experiences reported by young women with cystic fibrosis. J Cyst Fibros. 2018;17(1):57-63. doi:10.1016/j.jcf.2017.07.017
  33. Schechter MS, Stecenko AA. Chronic kidney disease: a new morbidity of cystic fibrosis or an old morbidity of diabetes mellitus? Am J Respir Crit Care Med. 2011;184(10):1101-1102. doi:10.1164/rccm.201108-1554ED
  34. Neglia JP, FitzSimmons SC, Maisonneuve P, et al. The risk of cancer among patients with cystic fibrosis. Cystic Fibrosis and Cancer Study Group. N Engl J Med. 1995;332(8):494-499. doi:10.1056/NEJM199502233320803
  35. Skolnik K, Levy RD, Wilcox PG, Quon BS. Coronary artery disease in cystic fibrosis: an emerging concern? J Cyst Fibros. 2016;15(6):e70-e71. doi:10.1016/j.jcf.2016.09.010
  36. Baiardini I, Steinhilber G, DI Marco F, Braido F, Solidoro P. Anxiety and depression in cystic fibrosis. Minerva Med. 2015;106(5 Suppl 1):1-8. 
  37. Quittner AL, Goldbeck L, Abbott J, et al. Prevalence of depression and anxiety in patients with cystic fibrosis and parent caregivers: results of The International Depression Epidemiological Study across nine countries. Thorax. 2014;69(12):1090-1097. doi:10.1136/thoraxjnl-2014-205983

Reviewed by Debjyoti Talukdar, MD, on 1/10/2022.

READ MORE ON CF