Cystic Fibrosis

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Ellen Rhodes, Michael A. Puente, MD

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Ellen Rhodes, Michael A. Puente, MD

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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.

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.

Genetics

CF is inherited in an autosomal recessive manner and is caused by mutations within the CFTR gene on chromosome 7. Thanks to advances in genetic sequencing, over 2,000 mutations have been identified within the CFTR gene. 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. 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. 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). 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. For a CF diagnosis, a patient must have clinical findings consistent with CF in at least one organ system or a positive newborn screen or have a sibling with CF. Additionally, a patient must have evidence of a CFTR dysfunction, including 2 mutations of the CFTR allele, a sweat chloride level >- 60 mmol/L, or an abnormal nasal potential difference (NPD). 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.

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[8], [9]. 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 [10], [11]

Patients with CF also commonly develop CFDR with prevalence increasing with age and disease progression [12]. It is estimated that 50% of patients with CF will develop CFRD making this the most common co-morbidity in individuals with CF [13], [14]. 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% [13], [15]. As life expectancy for patients with CF extends, screening for retinopathy will be increasingly important to maintain ocular health.

With the development of CFTR modulators, there have been reports of cataract formation and corneal opacity formation in patients on these treatment regimens. Cortical and posterior subcapsular cataracts were found in patients taking Ivacaftlor, a therapy aimed at gating mutations, at 84 and 96 weeks after treatment initiation [16], [17].

Other ocular findings include: -Retinal vein occlusion [9], [18], [19] -Decreased inferior-quadrant peripapillary retinal nerve fiber layer thickness [20], [21] -Decreased tear-film break-up time [20] -Reduced lens transparency [11] -Decreased contrast sensitivity [22], [23] -Oculosympathetic paresis [22]

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 specific ocular findings in individuals with CF, it is important for patients with CF to be closely monitored. Management of CF patients with ophthalmologic diagnoses is based on current practices of each diagnosis.

Xerophthalmia [24], [25] • High-dose vitamin A supplementation • Aggressive lubrication • Topical retinoic acid • Management of corneal epithelial defects or perforation if present

Retinopathy [26] • Panretinal photocoagulation (PRP) • Anti-VEGF injections

Screening • 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 [27]. With improved genetic diagnosis and understanding of disease mechanisms, ongoing research into CFTR modulators represents promising treatment options [28]. 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 [29]. Ophthalmologists will be an important part of the multidisciplinary team involved in the care of patients with CF.

References

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