Cystic fibrosis (CF) results from the defective functioning of cystic fibrosis transmembrane conductance regulator (CFTR), an epithelial membrane protein which acts as a chloride ion channel.1 Previous reports suggest ocular complications in CF are widespread, ranging from abnormal tear volume and composition2–5 to impaired dark adaptation,6,7 yet few reports discuss the retinal changes associated with CF. Ocular abnormalities in CF have commonly been attributed to secondary disease characteristics, including vitamin A deficiency.7 However, CFTR has been localized to the corneal8,9 and conjunctival9 epithelium, the corneal endothelium,8,10 and the retinal pigment epithelium.11,12 It is therefore possible that some ocular abnormalities in CF may be primary manifestations of the genetic defect.
Retinal vein occlusion (RVO) is the second most common sight-threatening vascular disease after diabetic retinopathy, with over 50% of cases presenting in persons over 65 years of age.13 While the exact pathogenesis of RVO remains unclear, the primary mechanism is considered to be a multifactorial process involving a combination of hemodynamic changes, degenerative changes of the vessel wall, and blood hypercoagulability.14 Identified risk factors include systemic atherosclerotic vascular disease, hypertension, diabetes mellitus, dyslipidemia, high body mass index, and smoking.15 The pathogenesis of BRVO in younger persons is poorly understood. The association with cardiovascular disease is less common and it is suggested that thrombophilic disorders may play a greater role.16
A 35-year-old male patient with CF presented for an ocular examination. He had been diagnosed with CF (ΔF508 homozygous) at 9 months of age, presenting with failure to thrive, and had exocrine pancreatic insufficiency. He had a liver transplant at the age of 20 and normal glucose tolerance at presentation. His forced expiratory volume (FEV1) was 1.09 L (31% predicted) and his blood pressure was normal. Medications at the time of examination included pancreatic enzyme replacement therapy; the fat-soluble vitamins A, D, E, and K; calcium supplements; and a bisphosphonate for osteoporosis. Inhaled steroid and bronchodilators, nebulized mucolytics DNAse, and hypertonic saline were also being taken, along with prophylactic antibiotics including nebulized ceftazidime and oral azithromycin and flucloxacillin. All medications have no known reported association with increased risk of BRVO.
At the time of examination, he had no visual concerns. Visual acuity was normal, measured at −0.06 LogMAR (ETDRS; Prevision Vision, La Salle, IL, USA) for right and left eyes. Intraocular pressure was also normal, at 11 mm Hg and 10 mm Hg for right and left eyes, respectively. Fundus photography showed a left superior temporal branch retinal vein occlusion (Fig. 1), with retinal hemorrhage spanning approximately 2 disc diameters. Dilated fundus examination revealed no further pathology in either eye, and optical coherence tomography showed no macular edema. The patient was monitored to ensure no secondary complications arose. Subsequent exploratory blood tests are shown in Table 1.
To our knowledge, this is the first time a branch retinal vein occlusion has been reported in CF. Retinal vascular abnormalities have previously been reported in CF patients, with retinal vein tortuosity and engorgement and retinal hemorrhages noted only in those patients with moderate to severe pulmonary disease, and often showing resolution with improvement of respiratory function.17 Similar retinal vascular findings have been reported in patients with chronic pulmonary insufficiency and carbon dioxide retention from other causes.18
CF patients may be at increased risk of RVO for numerous reasons. Approximately 50% of CF patients over 30 years of age suffer from diabetes, a known risk factor for RVO.15 Increased incidence of vascular thrombosis has been described in CF patients fitted with totally implantable venous access devices,19 with the insertion site significantly influencing the incidence of thrombosis. Oxidative stress, which is exacerbated in CF during times of pulmonary infection, has also been implicated in the development of thrombosis. Oxidative stress may be a constant local feature at epithelial surfaces in CF because CFTR is not only a chloride channel but also a channel for the antioxidant glutathione.20 CF patients show an increase in circulating activated platelets and platelet-leukocyte complexes.21 Previous data have shown that platelet activation and hypercoagulability inducing thrombus formation may be important factors in the development of RVO.20
While the exact mechanism resulting in thrombosis in RVO is not fully understood, thrombophilic risk factors such as antithrombin deficiency, protein C and S deficiency, and hyperhomocysteinemia have been associated with thromboembolism.20 An acquired prothrombotic condition is often present in CF secondary to protein C and S deficiency because of poor vitamin K absorption (protein S is a vitamin K–dependent cofactor which forms a complex with activated protein C) and some degree of liver failure.22
It is reasonable to speculate that the most likely cause of BRVO in this case was elevated fibrinogen levels resulting in an increased risk of thrombosis.23,24 Fibrinogen is an acute phase reactant; its concentration rises in inflammatory conditions, explaining why fibrinogen levels may be raised in CF and why retinal changes may be noted at times of pulmonary exacerbation.
This finding leads us to suggest that it may be appropriate to advise regular, annual ocular screening for patients with CF. Given the risk of significant visual loss associated with RVO, CF patients should receive education on what action to take should they encounter visual problems. Practitioners should also be aware of the possible link between BRVO and CF.
The authors have no financial or proprietary interest in any material or methods mentioned.
Received September 5, 2013; accepted November 12, 2013.
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