Cystic fibrosis (CF) is a systemic autosomal recessive disease caused by mutations in the CFTR gene on chromosome 7. The CFTR protein is responsible for transporting chloride, sodium, and bicarbonate ions at the apical surface of exocrine tissues, and its dysfunction leads to the production of thick, viscous secretions. It affects multiple organs including the upper and lower respiratory tract, gastrointestinal tract, reproductive system, endocrine system, and eyes.
Over 2,000 mutations have been identified, with the F508del mutation accounting for more than 70% of patients in North America and Northern Europe. In the United States, approximately 40,000 people are affected, with incidence rates by race: 1:3,200 in Caucasians, 1:10,000 in Hispanics, 1:15,000 in Blacks, and 1:30,000 in Asians.
More than 75% of patients are diagnosed by age 2, and as of 2021 data, 93.8% of infants under 6 months are diagnosed through newborn screening. The predicted survival age for patients on ETI therapy (elexacaftor + tezacaftor + ivacaftor) has reached 72 years.
CFTR channels are expressed in the conjunctiva, cornea, and lacrimal glands, directly involved in ocular surface fluid secretion. Additionally, fat-soluble vitamin absorption disorders due to pancreatic exocrine insufficiency (in 85% of patients) cause dry eye, night blindness, and corneal opacity.
Anterior segment findings
Ocular surface dryness: Severity ranges from conjunctival dryness to corneal opacity.
Meibomian gland disease (MGD) and blepharitis: Frequently observed in CF patients.
Superficial punctate keratitis and filamentary keratitis: Reflect chronic ocular surface damage.
Decreased corneal endothelial cell density: Lower in CF patients compared to controls.
Posterior Segment Findings
CFRD-related retinopathy: Estimated frequency 17–42%. May require panretinal photocoagulation or anti-VEGF injections.
Decreased retinal nerve fiber layer (RNFL) thickness: Particularly prominent in the inferior quadrant.
Retinal vein occlusion: Cases have been reported.
HEMT-related findings
Farahbakhsh et al. (2022) reported a 2.5-year-old boy who presented with bilateral corneal opacities as the initial symptom of cystic fibrosis. Serum vitamin A level was low at 25.2 mg/dL (normal 30-60), and sweat chloride was 80 and 95 mmol/L, confirming CF. The cause was impaired absorption of fat-soluble vitamins due to pancreatic exocrine insufficiency (present in 85% of CF patients)2).
Although rare, corneal opacities due to vitamin A deficiency have been reported as the initial symptom of CF. Improvement can be achieved with pancreatic enzyme replacement therapy and high-dose vitamin A administration (single dose of 200,000 IU plus maintenance of 1,500 IU/day)2).
The cause of CF is biallelic mutations in the CFTR gene. Mutations are classified into several classes, including defects in protein synthesis, processing, gating, conduction, quantity deficiency, and reduced stability, and a single mutation may span multiple classes.
Risk factors for ophthalmic complications:
A positive newborn screening, clinical features, or family history leads to confirmation by sweat chloride test (≥60 mmol/L) and CFTR genetic testing.
The FDA recommends ophthalmologic examination before and after initiating ivacaftor-containing CFTR modulator therapy.
| Screening target | Recommended test |
|---|---|
| Children on CFTR modulator therapy | Cataract screening |
| Infant born to mother taking HEMT | Cataract screening |
| Case with CFRD | Retinopathy screening |
| All CF patients | Visual field test, RNFL analysis |
| When considering refractive surgery | MGD, corneal thickness, anterior chamber volume, dry eye evaluation |
The FDA recommends eye examinations before and after starting treatment containing ivacaftor. Non-congenital cataracts (cortical cataracts and posterior subcapsular cataracts) have been reported in 0.57–4.17% of children. Cataract screening is also necessary for infants born to mothers taking HEMT.
CF patients have a high frequency of meibomian gland disease, corneal thinning, reduced anterior chamber volume, and dry eye, so the indication for refractive surgery must be carefully evaluated. If these findings are prominent, the risk increases.
The CFTR protein is a chloride channel expressed on the apical surface of exocrine tissues, regulating the transport of chloride, sodium, and bicarbonate ions. CFTR dysfunction leads to abnormal ion and water transport, resulting in the production of concentrated, viscous secretions.
Ophthalmologically, the following mechanisms are involved:
Shah et al. (2023) reported that Sonic Hedgehog (SHH) signaling is increased in CF epithelium in airway epithelial ionocytes (cells with highest CFTR expression), leading to an increase in ionocyte number and CFTR current. It was suggested that airway basal stem cells may retain a memory of the “CF state” 1).
Shah et al. (2023) proposed a new concept called “ionocyte modulator.” They reported that pharmacologically manipulating SHH signaling to double the number of ionocytes can achieve a physiologically meaningful increase in CFTR current. This is expected as a complementary strategy for mutations that CFTR modulators cannot sufficiently rescue 1).
However, SHH activation may impair mucociliary transport by reducing ciliary beat frequency and acidifying the pH of airway surface liquid, so careful consideration is needed for therapeutic application 1).
In mouse models, calcium-sensing receptor inhibitors have been shown to increase tear volume, but clinical trials in humans are in the developmental stage.
With the extension of survival (estimated 72 years) due to ETI therapy, long-term management of ophthalmic complications in CF patients is becoming increasingly important.
