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Utah Project on Exfoliation Syndrome (UPEXS): Insight Into Systemic Diseases Associated With Exfoliation Syndrome

Wirostko, Barbara, MD*; Allingham, Rand, MD*,†,‡; Wong, Jathine, PhD§; Curtin, Karen, PhD§

doi: 10.1097/IJG.0000000000000936
Exfoliation Syndrome

The Utah Project on Exfoliation Syndrome (UPEXS) study was created to investigate the association between exfoliation syndrome (XFS) and systemic disorders or pathologies. The study utilizes the resources of the Utah Population Database, which is linked to the Utah genealogy, a compilation of large pedigrees extending back 3 to ≥11 generations, representing most families in the state. These family members medical and health records are linked to vital records and can be used effectively to identify familial clustering of disorders, like XFS, with comorbid diseases or health-related data. There is growing evidence that XFS patients have an increased risk for systemic disorders that may reflect the systemic tissue involvement of this disease. Epidemiologic studies of individuals with XFS have reported an increased risk of various pathologies that have abnormalities in extracellular matrix metabolism and repair. For this reason, the UPEXS has focused on disorders that involve the extracellular matrix in general and elastin specifically, such as pelvic organ prolapse, atrial fibrillation, inguinal hernias, and chronic obstructive pulmonary disease. In this paper we present our results from the analysis of pelvic organ prolapse, as well as, preliminary data for atrial fibrillation.

*Moran Eye Center

§Department of Medicine and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT

Duke University Medical Center, Durham, NC

Duke-National University of Singapore (Duke-NUS), Singapore

Supported in part by a grant from the Glaucoma Foundation, NY and an Unrestricted Grant from Research to Prevent Blindness Inc., New York, NY, to the Department of Ophthalmology and Visual Sciences, University of Utah. Support for data extraction and analysis was provided by John A. Moran Center for Translational Medicine and Department of Ophthalmology and Visual Sciences, University of Utah. Partial support for all data sets within the Utah Population Database was provided by the Huntsman Cancer Foundation, University of Utah and Huntsman Cancer Institute Cancer Center Support Grant, P30 CA2014 from the National Cancer Institute and by the University of Utah’s Program in Personalized Health and Center for Clinical and Translational Science, and by the Jane Banks Glaucoma Research Fund and the Joseph Cohen Research Fund of the New York Eye and Ear Infirmary of Mount Sinai.

Disclosure: The authors declare no conflict of interest.

Reprints: Barbara Wirostko, MD, Moran Eye Center, University of Utah, 65 Mario Capecchi Drive, Salt Lake City, UT 84132 (e-mail:

Received February 20, 2018

Accepted February 22, 2018

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The Utah Project on Exfoliation Syndrome (UPEXS) study was created to investigate associations between exfoliation syndrome (XFS) and systemic disorders or pathologies. To carry out this goal, the UPEXS study utilizes the broad resources of the UPDB. The UPDB ( is a unique resource (the only database of its kind in the United States and one of few in the world) that enables high-quality, health-related research to be performed from a compilation of statewide medical information, decades of state vital records, and census data on >8 million individuals residing in Utah. The UPDB is linked to the Utah genealogy, a compilation of large pedigrees extending back 3 to ≥11 generations, that represent most families in the state. These family members’ medical and health records are linked to vital records and can be used effectively to identify familial clustering of disorders, such as XFS, with comorbid diseases or health-related data. The medical record information includes comprehensive statewide medical diagnoses and data related to surgical procedures. These data include international classification of diseases (ICD)-9/10 and current procedural terminology codes from hospital discharges, ambulatory facility records, and Medicare claims data beginning in 1996. These data are linked to clinical examinations and diagnostic tests performed within the University of Utah Healthcare, a large, statewide health care system, which offers comprehensive eye services throughout the state, including the John Moran Eye Center at the University of Utah in Salt Lake City. For this project, study conduct approvals were obtained from the University of Utah Institutional Review Board and the Resource for Genetic and Epidemiologic Research (IRB 00081512).

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XFS is characterized by fibrillary material that is deposited in the anterior segment of the eye and is associated with development of exfoliation glaucoma and cataract.1–4 XFS material is found widely through the body.5,6 In addition to ocular involvement, patients with XFS have deposits of characteristic material in multiple organ systems, these include the heart, brain, lungs, and skin.6,7

There is growing evidence that XFS patients have an increased risk for systemic disorders that may reflect the systemic tissue involvement of this disease. Epidemiologic studies of individuals with XFS have reported an increased risk of abdominal aortic aneurysms, cardiovascular disease, cerebrovascular disease, and hearing loss in these patients.8–11 These diseases have been hypothesized to be related based on information provided by autopsy, epidemiologic studies, and increasing knowledge related to molecular pathways that include lysyl oxidase-like 1 (LOXL1) and elastin.5–7,12

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LOXL1 is a member of a family of 5 copper-dependent enzymes that oxidize primary amine substrates to reactive aldehydes.13 One function, among many, is the catalysis of lysine-derived cross-links in fibrillar collagens and elastin in the extracellular matrix (ECM).13 Systemic pathologies of particular interest, which relate to XFS, overlap with those that occur in the LOXL1 knockout mouse and other disorders in which dysregulation of the ECM, specifically pertaining to collagen and elastin metabolism, are known to play a role.12 For this reason, the UPEXS has focused on disorders that involve the ECM in general and elastin specifically, including pelvic organ prolapse (POP), atrial fibrillation (AFib), inguinal hernias, and chronic obstructive pulmonary disease. In this paper we present our results from the analysis of POP, as well as preliminary data for AFib.

POP, is a connective tissue disorder that affects women, particularly those who are postpartum. Prevalence estimates of symptomatic POP have been reported to range between 3% and 11%.14 About 11% to 19% of women with POP will require surgical intervention during their lifetimes.14 POP is believed to be associated with defects in elastin and connective tissue repair that are related to abnormalities in pathways for ECM tissue repair.15,16 Susceptibility to POP is believed to have a genetic component that may potentially be related to molecular pathways that include those that involve elastin and LOXL1.12,15,16 Liu et al,12 using the LOXL1 knockout mouse model, reported uterine and bladder prolapse in female knockout mice. UPEXS researchers, noting the association between LOXL1, ECM, and POP in the literature, explored the role of XFS in women with POP. These investigators reported that the risk of XFS in women with a history of POP approached 50%, a highly significant finding.17

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Study Design and Results

This study, that utilized the UPDB, applied a 2-pronged approach, which incorporated a cross-sectional analysis in Medicare patients and a retrospective cohort study in patients in the University of Utah Healthcare system of hospitals and clinics. In substudy A, a cross-sectional analysis analyzed the records of 132,772 Utah women who were Medicare recipients for ≥3 consecutive years between 1992 and 2009. In substudy B, the longitudinal risk of an incident diagnosis of XFS from January 1, 1995 to December 31, 2014 analyzed 5130 women aged between 30 and 65 years at baseline who had been diagnosed with POP compared with 15,338 age-matched female controls with no history of POP.

The results of these studies were consistent. In substudy A, the cross-sectional analysis, the mean age of the women was 82 years (age at last year of follow-up). In these Medicare beneficiaries, it was found that POP was associated with a 56% increased risk of having a diagnosis of XFS (odds ratio, 1.56; 95% confidence interval, 1.4-1.7) In substudy B, the longitudinal analysis, the incident risk of having an XFS diagnosis was 48% greater in women aged 30 to 65 years with a diagnosis of POP compared with an age-matched female control group without a diagnosis of POP over 20 years of follow-up (hazard ratio, 1.48; 95% confidence interval, 1.1-1.9). In both studies, using different approaches, the risk of being diagnosed with XFS was increased in women with POP, a common disorder of ECM.

AFib is the most common cause of sustained cardiac arrhythmia, a major cause of morbidity and, like XFS, its prevalence increases substantially after age 50.18,19 AFib results from a complex interaction between chemical and structural changes within the atrial myocardium.19 Pathologic changes include hypertrophy, dilation, and fibrosis, which ultimately lead to chaotic electrical conduction within the atria and an irregular cardiac rhythm.18,19 In a review of autopsies performed on 30 patients (age, 64±12 y) atrial fibrosis of the ECM was correlated with AFib.20 ECM volume and composition also correlate with persistence of AFib. LOX, the first of the LOX-LOXL family members identified, is upregulated in AFib and seems to contribute to structural remodeling of cardiac tissue in patients with this disease.21 Alterations of LOXL1 enzymes may alter epithelial cells and influence a fibrogenic conversion in myofibroblasts and other muscle type cells.22,23

Transforming growth factor-β1 (TGFβ1) is a potent cytokine that plays a major role in ECM remodeling, elastosis, and fibrosis. There is growing evidence that supports a role for TGFβ1 in the pathogenesis of XFS and AFib.24–27 In ocular diseases, TGFβ1 is expressed at higher levels in the aqueous humor of eyes in patients with XFS as well as in aqueous humor from patients with XFG compared with primary open angle glaucoma.24 TGFβ1 levels are also increased in the serum of patients with XFS.25 With regard to a role in cardiac diseases, TGFβ1 has been implicated as a central regulating factor in cardiac fibrogenesis, with increased serum levels of this cytokine shown to be elevated in patients with AFib.26,27 One function of TGFβ1 is to regulate the production of ECM, inhibit degradation of ECM, and induce LOX gene expression and activity, which supports the role of this protein in XFS-associated pathology.28

The potential support for a pathogenic physiological relationship between XFS and AFib was the foundation for a preliminary study to explore the hypothesis that these 2 diseases are clinically associated. We analyzed the Medicare records of a sample population of 211,768 Utah Medicare beneficiaries who were enrolled between 1992 and 2009. Patients aged 65 and above who had ≥3 consecutive years of medical records were included. We performed an unconditional logistic regression using ICD-9 codes to define XFS (365.52 and 366.11) and an outcome of AFib (427.31), after adjusting for age and sex, to calculate the hazard ratio to estimate the risk of AFib in patients with XFS compared with those without XFS. ICD-9 codes for XFS were previously validated in a chart review and found to have high sensitivity (90.7%).29

We found that the risk of patients with XFS developing AFib was 55% greater than that of patients without XFS.30 This finding, similar to that observed in the study of POP, strongly supports an association between XFS and AFib. No difference for risk based on sex was observed. We observed an unusually high prevalence for AFib (25.8%) in the UPDB population. It is possible that the ICD-9 codes, which were not validated by chart review, may lack specificity. Although these data are preliminary and under continuing analysis, we believe the findings are of interest and provide additional support for the role of XFS in systemic disorders.

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The association of XFS with systemic disorders is supported by the analysis of a robust population-based data set, the UPDB. The diagnosis of XFS, a complex inherited systemic disorder, is related to risk of XFS in women with POP. We have also observed a similar trend in a preliminary study examining the relationship of XFS with AFib. Both disorders share abnormalities in elastin and ECM metabolism. This is similar to patients with XFS, where elastin and ECM synthesis are altered or dysregulated. These data support the notion that an insult or triggering event, such as childbirth in the case of women with POP or chronic mechanical stress in AFib, is more likely to cause disease in patients with underlying genetic predisposition to XFS. These studies were conducted based on the hypothesis that connective tissue containing elastin, regulated and repaired by enzymes such as LOXL1, may be associated with XFS. These data are helping to reform our understanding of the implications of the role of XFS in systemic disorders.10,29,30 There are likely multiple genetic and environmental influences that contribute to these relationships. These include LOXL1 dysregulation that may be influenced by variants in the LOXL1 antisense gene, or environmental factors like ultraviolet light exposure.31

These studies are the first of many that will utilize this unique and robust population-based resource to continue to examine the role of XFS in nonocular systemic ECM conditions. Systemic conditions with altered ECM metabolism in addition to those discussed here, such as inguinal hernias, emphysematous lung disease, vascular diseases such as carotid artery and coronary artery diseases to name a few, may also share biological pathways with XFS. This data will continue to improve our understanding of XFS-related systemic disorders and, in so doing, will provide a unique perspective to diagnosis, management, and treatment.

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exfoliation syndrome; pelvic organ prolapse; atrial fibrillation; LOXL1; Utah Population Database (UPDB); elastin; systemic associations

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