Cystic Fibrosis

From EyeWiki

All content on Eyewiki is protected by copyright law and the Terms of Service. This content may not be reproduced, copied, or put into any artificial intelligence program, including large language and generative AI models, without permission from the Academy.

Article initiated by:
Michael A. Puente, MD, Ellen Rhodes
All contributors:
Ellen Rhodes, S. Grace Prakalapakorn, MD, MPH, Michael A. Puente, MD, Amanda Ely, M.D.
Assigned editor:
Amanda Ely, M.D.
Review:
Assigned status Up to Date
 by Amanda Ely, M.D. on August 14, 2024.


Cystic Fibrosis (CF) is a genetic disorder caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. CF affects multiple organ systems including the upper and lower airways, gastrointestinal tract, reproductive tract, endocrine system, and eyes.

Disease Entity

Epidemiology

It is estimated CF affects approximately 40,000 individuals within the United States. In the United States, CF occurs in approximately 1:3200 White Americans, 1:10,000 Hispanic Americans, 1:10,500 Native Americans, 1:15,000 Black Americans, and 1:30,000 Asian Americans.[1]

Genetics

CF is inherited in an autosomal recessive manner and is caused by mutations within the CFTR gene on chromosome 7.[2] Thanks to advances in genetic sequencing, over 2,000 mutations have been identified within the CFTR gene.[3] Mutations are grouped into classes depending on what aspect of the CFTR protein is affected – protein synthesis, protein processing, gating, conduction, insufficient protein quantity, and reduced protein stability. Recently, it has been demonstrated that mutations may lead to overlap in classes.[4] Over 70% of individuals in North America and Northern Europe have a deletion of phenylalanine at position 508 (F508del), which is historically considered a protein processing mutation. Typical genetic testing for CF includes the most common mutations, so it is possible that carriers of a CFTR mutation are not picked up on screening.

Clinical Features

The CFTR protein is responsible for transport of ions including chloride, sodium, and bicarbonate across the apical surface of exocrine tissues.[5] Mutations in the CFTR gene cause abnormal ion and water transport, leading to thick and viscous secretions in affected organ systems. In the respiratory system, thick mucus and decreased mucociliary clearance leads to obstructive lung disease with bacterial colonization, chronic infection, and persistent inflammation. In the gastrointestinal system, dysfunction of the CFTR gene leads to impaired flow of bile and pancreatic secretions, leading to malabsorption and malnutrition. Disruption of digestive secretions also leads to progressive liver and pancreatic disease leading to CF related diabetes (CFRD). These gastrointestinal disturbances also lead to chronic constipation in 25% of CF patients. [6] Of note, the risk for developing cancers in patients with cystic fibrosis (CF) is known to be significantly greater than in the general population, including site-specific cancers of the esophagus, small bowel, colon, liver, biliary tract, and pancreas. An even higher risk has been found in patients who have severe CF transmembrane conductance regulator (CFTR) genotypes or who have undergone organ transplantation and are immunosuppressed.[7] CFTR acts as a tumor suppressor gene based on knockout models. Lack of CFTR expression promotes carcinogenic processes such as intestinal inflammation and deleterious gut microbiome changes. [8] Cystic fibrosis-related bone disease (CFBD), low bone mineral density, occurs across all age groups and places patients at higher risk for fracture. [9]The reproductive and endocrine systems are also commonly implicated in CF.

Diagnosis

Diagnosis of CF is based on clinical findings with biochemical or genetic confirmation. A positive CF diagnosis is made in patients who present with a positive newborn screening, have clinical features consistent with CF, or have a positive family history of CF and their sweat chloride test is >/= 60mmol/L. Additionally, these patients need to undergo CFTR genetic testing as identification of 2 CF-causing mutations helps to further define their CF risk.[10] According to the Cystic Fibrosis Foundation, over 75% of CF patients are diagnosed before the age of 2, however, some patients are diagnosed in adulthood. In 2021 newborn screening accounted for 93.8% of diagnoses in the US in infants under 6-months.[11]

Ophthalmic Manifestations

The most common ocular manifestations of CF fall within the spectrum of xerophthalmia with surface irritation and nyctalopia due to vitamin A deficiency.[12][13][14] Individuals with CF commonly have pancreatic insufficiency leading to abnormal absorption of nutrients, including the fat-soluble vitamins A, D, E and K. Studies have hypothesized that low serum vitamin A levels are linked to decreased numbers of goblet cells and ocular surface disease[15] [16] Reported anterior surface and corneal manifestations include meibomian gland disease (MGD), blepharitis, conjunctival xerosis, dry eye disease (DED), punctate keratitis (PK), filamentary keratitis (FK), xerophthalmia, and decreased endothelial cell density and central corneal thickness. [17] Careful evaluation of the aforementioned factors has been recommended in CF patients when determining their suitability for refractive surgery.[17]

Patients with CF also commonly develop CFRD (Cystic Fibrosis-Related Diabetes) with prevalence increasing with age and disease progression.[18] It is estimated that 50% of patients with CF will develop CFRD making this the most common co-morbidity in individuals with CF.[19] [20] Although CFRD is distinct from both type 1 and type 2 diabetes, microvascular damage can lead to retinopathy similar to that seen in uncontrolled diabetes. Patients with evidence of retinopathy have a longer mean duration of CFRD and insulin dependence and estimates of retinopathy range from 17- 42%.[19][21] As life expectancy for patients with CF extends, screening for retinopathy will be increasingly important to maintain ocular health.

The development of CFTR modulator therapies (HEMT), began with ivacaftor monotherapy and has since expanded to combination therapies to include, ivacaftor-lumacaftor, ivacaftor-tezacaftor, and elexacaftor-tezacaftor-ivacaftor (ETI), with more combination therapies coming down the pipeline. HEMT are small molecules designed to target the specific underlying gene defect, with the ability to modulate CFTR protein synthesis, trafficking, and functioning, ultimately restoring the CFTR channels residing on various epithelial cell surfaces. There have been reports of cataract formation and corneal opacity formation in patients on these treatment regimens, with an incidence of cataracts in the pediatric population ranging from 0.57% to 4.17%.[22] Non-congenital cataracts, cortical and subcapsular in nature, have been reported in many ivafactor combination therapies. [23]Studies point to occurrence of cataract development in patients taking ivacaftor at 84 and 96 weeks after treatment initiation.[24] [25] The ivacaftor-lumacaftor combination therapy has also been reported with cataract occurrence as early as 24 weeks post-treatment initiation. [26] These concerning findings prompted the FDA to suggest the conductance of ophthalmologic examination before and following ivacaftor monotherapy or combination modulator treatments. HEMT molecules are able pass through the placenta and into breast milk in mothers who continue on this therapy while pregnant and breast feeding.[27] More recently, case series have provided evidence of an increased incidence of developing congenital cataracts in newborns after in utero exposure to ETI. [28]

Other ocular findings reported in the setting of CF include:

  • Retinal vein occlusion[13][29] [30]
  • Decreased inferior-quadrant peripapillary retinal nerve fiber layer thickness[31] [32]
  • Reduced lens transparency[14][16]
  • Decreased contrast sensitivity[33] [34]
  • Abnormal dark adaptation[14]
  • Preganglionic oculosympathetic paresis[33]

Management

Systemic Treatment

Management of CF requires a multidisciplinary approach to target the various organ systems involved. Pulmonary disease accounts for the highest morbidity and mortality so treatments are largely focused on improving mucociliary clearance and prevention of infection.

Systemic treatments include:

  • Bronchodilators
  • Anti-inflammatory inhaled agents
  • Antibiotics
  • Mechanical Airway Clearance
  • CFTR Modulators
  • Pancreatic Enzyme Supplementation

Ophthalmic Treatment/Screening

While there are no primary ocular findings in individuals with CF, it is important for patients with CF to be closely monitored for secondary ocular disease. Management of CF patients with ophthalmologic diagnoses is based on current practices of each diagnosis.

Xerophthalmia[35] [36]

  • High-dose vitamin A supplementation
  • Aggressive lubrication
  • Topical retinoic acid
  • Management of corneal epithelial defects or perforation if present


Retinopathy[37]

  • Panretinal photocoagulation (PRP)
  • Anti-VEGF injections


Screening

  • Cataract screening before and during treatment with a CFTR modulator and for infants born to a mother on a CFTR modulator
  • Retinopathy screening
  • Visual field testing
  • RNFL analysis

Prognosis

Substantial progress has been made in the diagnosis, treatment, and pathophysiology of CF. Diagnosis of CF prior to symptom onset has demonstrated improved lung function, nutritional status, and decreased healthcare utilization, further supporting the importance of newborn screening and early intervention.[38] With improved genetic diagnosis and understanding of disease mechanisms, ongoing research into CFTR modulators represents promising treatment options.[39] As life expectancy of patients with CF continues to lengthen, it becomes of increasing importance to manage long-term complications, such as CFRD and pulmonary disease. The Cystic Fibrosis Foundation predicts that based on data from 2022, patients with CF born between 2018 and 2022 will live to 56 years.[40] Ophthalmologists will be an important part of the multidisciplinary team involved in the care of patients with CF.

References

  1. ↑ Cystic Fibrosis Foundation. About Cystic Fibrosis. https://www.cff.org/intro-cf/about-cystic-fibrosis, 2023.
  2. ↑ Kerem BS, et al., Identification of the Cystic Fibrosis Gene: Genetic Analysis. Science. 1989;245(4922):1073–1080. doi: 10.1126/science.2570460.
  3. ↑ Bell SC, et al. The future of cystic fibrosis care: a global perspective. Lancet Respir Med. 2020;8(1):65–124. doi: 10.1016/S2213-2600(19)30337-6.
  4. ↑ Veit G et al. From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations. Mol Biol Cell. 2016;27(3):424–433. doi: 10.1091/mbc.e14-04-0935.
  5. ↑ Harris A. Cystic fibrosis gene. Br Med Bull. 1992;48(4):738–753. doi: 10.1093/oxfordjournals.bmb.a072575.
  6. ↑ Saikumar P, Sadauskas M, Izhar S, Moshiree B, Patel D. Constipation and DIOS: Diagnosis, differential diagnosis, and management. Pediatr Pulmonol. 2024 Sep;59 Suppl 1:S81-S90. doi: 10.1002/ppul.27104. PMID: 39105354.
  7. ↑ Hoskins B, Wasuwanich P, Scheimann AO, Karnsakul W. Screening strategy for gastrointestinal and hepatopancreatobiliary cancers in cystic fibrosis. World J Gastrointest Oncol. 2021 Sep 15;13(9):1121-1131. doi: 10.4251/wjgo.v13.i9.1121. PMID: 34616517; PMCID: PMC8465437.
  8. ↑ Raza Z, Islam BN, Hachem CY, Cummings LC. Evolving data on risk and current screening recommendations for colorectal cancer in cystic fibrosis: Pre- and posttransplant. Pediatr Pulmonol. 2024 Sep;59 Suppl 1:S91-S97. doi: 10.1002/ppul.27060. PMID: 39105336.
  9. ↑ Williams KM, Darukhanavala A, Hicks R, Kelly A. An update on methods for assessing bone quality and health in Cystic fibrosis. J Clin Transl Endocrinol. 2021 Dec 6;27:100281. doi: 10.1016/j.jcte.2021.100281. PMID: 34984171; PMCID: PMC8693345.
  10. ↑ Farrell PM et al. Diagnosis of Cystic Fibrosis: Consensus Guidelines from the Cystic Fibrosis Foundation. J Pediatr. 2017;181:S4-S15.e1. doi: 10.1016/j.jpeds.2016.09.064.
  11. ↑ Cystic Fibrosis Foundation. 2021 Patient Registry: Annual Data Report. https://www.cff.org/sites/default/files/2021-11/Patient-Registry-Annual-Data-Report.pdf, 2021.
  12. ↑ S. Wamsley, ‘Advanced Keratomalacia With Descemetocele in an Infant With Cystic Fibrosis’, Archives of Ophthalmology, vol. 123, no. 7, p. 1012, Jul. 2005, doi: 10.1001/archopht.123.7.1012-b.
  13. ↑ 13.0 13.1 M. R. Starr, S. M. Norby, J. P. Scott, and S. J. Bakri, ‘Acute retinal vein occlusion and cystic fibrosis’, Int J Retina Vitreous, vol. 4, no. 1, p. 26, Dec. 2018, doi: 10.1186/s40942-018-0129-8.
  14. ↑ 14.0 14.1 14.2 Liberski S, Confalonieri F, Cofta S, Petrovski G, Kocięcki J. Ocular Changes in Cystic Fibrosis: A Review. Int J Mol Sci. 2024 Jun 18;25(12):6692. doi: 10.3390/ijms25126692. PMID: 38928397; PMCID: PMC11203677.
  15. ↑ D. L. Hatchell and A. Sommer, ‘Detection of Ocular Surface Abnormalities in Experimental Vitamin A Deficiency’, Archives of Ophthalmology, vol. 102, no. 9, pp. 1389–1393, Sep. 1984, doi: 10.1001/archopht.1984.01040031131040.
  16. ↑ 16.0 16.1 I. Castagna, A. M. Roszkowska, F. Famà, S. Sinicropi, and G. Ferreri, ‘The Eye in Cystic Fibrosis’, Eur J Ophthalmol, vol. 11, no. 1, pp. 9–14, Jan. 2001, doi: 10.1177/112067210101100103.
  17. ↑ 17.0 17.1 Moshirfar M, Brown AH, Sulit CA, Corbin WM, Ronquillo YC, Hoopes PC. Corneal Refractive Surgery Considerations in Patients with Cystic Fibrosis and Cystic Fibrosis Transmembrane Conductance Regulator-Related Disorders. Int Med Case Rep J. 2022 Nov 9;15:647-656. doi: 10.2147/IMCRJ.S381078. PMID: 36388243; PMCID: PMC9656410.
  18. ↑ T. A. Laguna, B. M. Nathan, and A. Moran, ‘Managing diabetes in cystic fibrosis’, Diabetes Obes Metab, vol. 12, no. 10, pp. 858–864, Oct. 2010, doi: 10.1111/j.1463-1326.2010.01250.x.
  19. ↑ 19.0 19.1 P. Kempegowda et al., ‘Retinopathy and microalbuminuria are common microvascular complications in cystic fibrosis-related diabetes’, Ther Adv Endocrinol Metab, vol. 11, p. 204201882096642, Jan. 2020, doi: 10.1177/2042018820966428.
  20. ↑ K. Konrad et al., ‘Cystic fibrosis-related diabetes compared to type 1 and type 2 diabetes in adults’, Diabetes Metab Res Rev, p. n/a-n/a, May 2013, doi: 10.1002/dmrr.2429.
  21. ↑ R. Roberts et al., ‘Retinal screening of patients with cystic fibrosis-related diabetes in Wales — A real eye opener’, Journal of Cystic Fibrosis, vol. 14, no. 2, pp. 282–284, Mar. 2015, doi: 10.1016/j.jcf.2014.07.014.
  22. ↑ Zhu Y, Li D, Reyes-Ortega F, Chinnery HR, Schneider-Futschik EK. Ocular development after highly effective modulator treatment early in life. Front Pharmacol. 2023 Sep 19;14:1265138. doi: 10.3389/fphar.2023.1265138. PMID: 37795027; PMCID: PMC10547496.
  23. ↑ FDA (2021). Trikafta (elexacaftor/tezacaftor/ivacaftor). Bethesda, Maryland: Prescribing Information, United States Food and Drug Administration.
  24. ↑ Vertex Pharmaceuticals Incorporated, ‘A Phase 3, Open-Label Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Lumacaftor in Combination With Ivacaftor in Subjects 6 Through 11 Years of Age With Cystic Fibrosis, Homozygous for the F508del-CFTR Mutation’, https://clinicaltrials.gov/ct2/show/study/NCT01897233, 2017.
  25. ↑ Vertex Pharmaceuticals Incorporated, ‘A Phase 3, Rollover Study to Evaluate the Safety and Efficacy of Long-Term Treatment With Lumacaftor in Combination With Ivacaftor in Subjects Aged 12 Years and Older With Cystic Fibrosis, Homozygous or Heterozygous for the F508del-CFTR Mutation’, https://clinicaltrials.gov/ct2/show/results/NCT01931839, 2017.
  26. ↑ Incorporated V. P. (2017a). A phase 3 rollover study of lumacaftor in combination with ivacaftor in subjects 12 Years and older with cystic fibrosis. ClinicalTrials.gov. 10.
  27. ↑ Zhu Y, Li D, Reyes-Ortega F, Chinnery HR, Schneider-Futschik EK. Ocular development after highly effective modulator treatment early in life. Front Pharmacol. 2023 Sep 19;14:1265138. doi: 10.3389/fphar.2023.1265138. PMID: 37795027; PMCID: PMC10547496.
  28. ↑ Jain R., Wolf A., Molad M., Taylor-Cousar J., Esther C. R., Shteinberg M. (2022). Congenital bilateral cataracts in newborns exposed to elexacaftor-tezacaftor-ivacaftor in utero and while breast feeding. J. Cyst. Fibros. 21, 1074–1076. 10.1016/j.jcf.2022.10.004
  29. ↑ R. J. Hiscox, C. Purslow, R. V. North, I. Ketchell, and K. S. E. Evans, ‘Branch Retinal Vein Occlusion in an Asymptomatic Adult with Cystic Fibrosis’, Optometry and Vision Science, vol. 91, no. 4, pp. S52–S54, Apr. 2014, doi: 10.1097/OPX.0000000000000186.
  30. ↑ R. Gelman, E. A. DiMango, and W. M. Schiff, ‘SEQUENTIAL BILATERAL CENTRAL RETINAL VEIN OCCLUSIONS IN A CYSTIC FIBROSIS PATIENT WITH HYPERHOMOCYSTEINEMIA AND HYPERGAMMA-GLOBULINEMIA’, Retin Cases Brief Rep, vol. 7, no. 4, pp. 362–367, 2013, doi: 10.1097/ICB.0b013e3182965271.
  31. ↑ P. Giannakouras et al., ‘Ophthalmologic manifestations of adult patients with cystic fibrosis’, Eur J Ophthalmol, vol. 32, no. 2, pp. 976–983, Mar. 2022, doi: 10.1177/11206721211008780.
  32. ↑ M. Nebbioso, S. Quattrucci, E. Leggieri, L. Spadea, and E. M. Vingolo, ‘Cystic Fibrosis and New Trends by Ophthalmological Evaluation: A Pilot Study’, Biomed Res Int, vol. 2014, pp. 1–5, 2014, doi: 10.1155/2014/580373.
  33. ↑ 33.0 33.1 R. F. Spaide, G. Diamond, R. A. D’Amico, P. F. Gaerlan, and D. S. Bisberg, ‘Ocular Findings in Cystic Fibrosis’, Am J Ophthalmol, vol. 103, no. 2, pp. 204–210, Feb. 1987, doi: 10.1016/S0002-9394(14)74228-X.
  34. ↑ J. C. Morkeberg, C. Edmund, J. U. Prause, S. Lanng, C. Koch, and K. F. Michaelsen, ‘Ocular findings in cystic fibrosis patients receiving vitamin A supplementation’, Graefe’s Archive for Clinical and Experimental Ophthalmology, vol. 233, no. 11, pp. 709–713, Nov. 1995, doi: 10.1007/BF00164674.
  35. ↑ K. E. Feroze KB, ‘Xerophthalmia’, https://www.ncbi.nlm.nih.gov/books/NBK431094/, Apr. 17, 2023.
  36. ↑ V. Y. B. M. M. A. H. M. C. A. Jeffrey M Goshe, ‘Xerophthalmia’, https://eyewiki.org/Xerophthalmia, May 17, 2022.
  37. ↑ M. D. , V. A. S. M. D. , K. T. M. (AIIMS), F. (Glasgow), H. S. R. D. O. , J. H. M. J. C. T. M. J. I. L. M. Brad H. Feldman, ‘Diabetic Retinopathy’, https://eyewiki.org/Diabetic_Retinopathy, Jul. 15, 2023.
  38. ↑ D. Borowitz et al., ‘Cystic Fibrosis Foundation Evidence-Based Guidelines for Management of Infants with Cystic Fibrosis’, J Pediatr, vol. 155, no. 6, pp. S73–S93, Dec. 2009, doi: 10.1016/j.jpeds.2009.09.001.
  39. ↑ M. Lopes-Pacheco, ‘CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine’, Front Pharmacol, vol. 10, Feb. 2020, doi: 10.3389/fphar.2019.01662.
  40. ↑ Cystic Fibrosis Foundation, ‘Understanding Changes in Life Expectancy’, https://www.cff.org/managing-cf/understanding-changes-life-expectancy, 2023.
Retrieved from "https://eyewiki.org/w/index.php?title=Cystic_Fibrosis&oldid=111156"
The Academy uses cookies to analyze performance and provide relevant personalized content to users of our website.
Learn more
Powered by MediaWiki
Powered by Canasta
Powered by Semantic MediaWiki