Abstract

1. Introduction

Fuchs endothelial corneal dystrophy (FECD) is a bilateral disease of the corneal endothelium. It is characterized by a progressive and accelerated loss of corneal endothelial cells accompanied by a number of degenerative processes of the Descemet membrane (DM) [1]. This primarily includes the accumulation of an aberrant extracellular matrix (ECM) and the formation of posterior focal excrescences called guttae [1, 2]. Changes in quantity and quality of vision can eventually result due to the aforementioned DM changes as well as to the disruption of the corneal endothelial pump function, leading to corneal oedema, bullae formation, and late subepithelial fibrosis [2, 3].

While two different types of FECD exist, the late-onset form represents the most common, which is usually inherited in an autosomal dominant fashion with variable penetrance and expressivity [1, 2]. In addition, numerous ophthalmic and systemic conditions have been described to variably correlate with the presence of FECD (i e., hearing loss, cardiovascular disease, keratoconus, ocular hypertension, and macular drusen), whose expression has been eventually reported to be more common in the female gender [1, 2]. However, the evaluation of the global epidemiologic features of the disease has been rendered overtly tough, due to the vast heterogeneity in the available prevalence estimates of the disease [4–7].

Thus, the aim of this meta-analysis is to estimate the cumulative global prevalence rate of FECD in the adult population. Our analysis will use the latest publicly available data to even predict the number of actual and future FECD-affected patients worldwide.

2. Materials and Methods

This study was conducted in strict compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines supplementary (S0) [8]. Neither institutional review board approval nor informed consent were required for this study, since all the reported data were obtained from the available published literature. The review protocol was submitted, revised, accepted, and published by the International Prospective Register of Systematic Reviews (PROSPERO) (ID: CRD42021284423).

3. Results

3.1. Electronic Database Search Results

Overall, 6660 eligible papers (i e., 190 from PubMed/MedLine, 0 from Cochrane Library, and 6470 from Google Scholar) were retrieved from the preliminary search on electronic databases. Once the duplicates had been automatically removed and both titles and abstracts were screened, 20 full-text manuscripts were assessed for eligibility being considered appropriate for the present meta-analysis. Four articles were finally included in the qualitative and in the quantitative analysis, being conformed to the aforementioned eligibility criteria (Figure 1) [4–7]. The reasons justifying the exclusion of 16 studies are reported in Figure 1. The full list of the included studies and their general features are reported in Table 1.

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Figure 1

Preferred Reporting Items for Systematic Review and Meta-Analysis flowchart. Reasons for exclusion are step-by-step reported on the right.

Table 1

General features of the articles included in the qualitative and quantitative analysis.SD, standard deviation; FECD, Fuchs Endothelial Corneal Dystrophy; USA United States of America.

Author	Age (mean±SD)	FECD patients	Patients (total)	FECD (male)	Male (total)	FECD (female)	Female (total)	Country
Eghrari et al. [4]	57	32	148	9	64	23	91	USA (Tangier island)
Higa et al. [5]	59.1±14.9	124	3060	37	1513	87	1423	Japan
Zoega et al. [6]	70	71	774	24	315	47	384	Iceland
Kitagawa et al. [7]	62.1±7.6	31	465	9	205	22	260	Singapore
Kitagawa et al. [7]	64.4±8.1	11	299	2	135	9	164	Japan

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3.4. FECD Prevalence Rate

Overall, 269 patients in our sample were found to be affected by FECD (81 males; 188 females). Globally, FECD prevalence rate, as assessed by this analysis, peaked up to 7.33% (95% CI: 4.08–12.8%). The heterogeneity variance among different studies was estimated at τ²=0.463, with an I² value of 95.5% (95% CI 92.2%–97.5%). Pooled results are reported in the forest plot presented in Figure 2. Age-weighted prevalence rates are summarized in Table 2. The funnel plot generated, which shows a high asymmetry, is shown in supplementary S2. The Peter's test was not run because of the low number of studies included [13]. Results deriving from the Baujat plot and the sensitivity analysis are reported in supplementary S3 and in supplementary S4.

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Figure 2

Forest plot reassuming the pooled estimate of Fuchs Endothelial Corneal Dystrophy prevalence rate. Both fixed and random-effects models are represented. GLMM, generalized linear mixed model.

Table 2

Age-weighted prevalence rates of Fuchs endothelial corneal dystrophy.

Group	Age (years)	No. of studies	FECD prevalence (%)	95% CI (%)
1	<50	2	7.17	1.79–24.70
2	50 to 69	2	9.20	2.40–29.47
3	>70	2	10.92	4.64–23.63

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No., number; FECD, Fuchs endothelial corneal dystrophy; CI, confidence interval.

3.5. Gender and Geographical Variation

Among the included articles, 4/4 (100%) reported FECD prevalence data by gender. Prevalence rates of FECD in male and female were registered to be as high as 4.58 (95% CI: 2.37–8.66) (supplementary S5) and 9.84 (95% CI: 5.95–15.83) (supplementary S6), respectively. In the included studies, female gender appears to be more commonly affected by FECD than male. Statistically significant gender-related differences in the prevalence of FECD emerged from the analysis (OR: 2.22; 95% CI: 1.66–2.96, p=0.0016) (Figure 3).

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Figure 3

Gender-related prevalence rate of Fuchs endothelial corneal dystrophy in the adult population (>30 years old). Odds ratio is calculated and both fixed and random-effects models are represented. GLMM, generalized linear mixed model.

Meaningful differences emerged from the analysis of prevalence data differences according to geographical localization, with the American continent featuring the highest prevalence rate of FECD (supplementary S7).

4. Discussion

To the best of our knowledge, this work represents the first meta-analysis trying to ascertain the global prevalence of FECD in the adult population. Specifically, it is intended to provide comprehensive, up-to-date estimations on the current global FECD prevalence as well as to forecast projection figures of the number of FECD-affected patients in 2050.

Overall, we unfortunately found a modest number of epidemiological studies on the subject, the majority of whom were conducted in Asia. A full and representative coverage of all countries was not achieved. While this evidence substantially affects the reliability of our results, it must be also considered that our work, representing the first meta-analysis on the topic, is the only available one trying to define the effective worldwide prevalence and epidemiological burden of the disease.

Overall, we estimated the global prevalence of FECD to be as high as 7.33%, with the highest figures reported in North America, where the prevalence rate of the disease is reported to peak up to 21.62% (supplementary S7). However, this result is eventually biased by the specific setting chosen by Eghrari et al. in their study [4]. In fact, they conducted their analysis in Tangier, an island in Virginia, with a population of over 500 related individuals [4]. Hence, the overtly major prevalence of the disease in such a context might be easily explained by the highly conserved pedigree of the selected population as well as considering the genetic inheritance pattern of FECD [1, 2]. Coherently, the influence analysis shows Eghrari et al.'s study to substantially contribute to the overall heterogeneity of the proposed results, which appears to not reside when the same report is removed from the pooled analysis (supplementary S4). These data strongly suggest that external modifiable and unmodifiable external factors are mainly responsible for the vast evidenced heterogeneity. As an example, the diverse genetic background specific for different population might eventually explain the possibility of regional variation in the number of FECD-affected patients, of whom few is known due to the paucity of available large epidemiologic studies on the topic.

With a total of 4 studies and more than four thousand pooled patients, our model was sufficiently powered to detect a difference between gender- and age-groups. In fact, our finding provides substantial evidence that females have a double the risk to develop FECD than the counterpart. Furthermore, we demonstrated that the odds for FECD tended to increase by a 1.2 factor when moving from the 30–50 to the 50–70 age group. Both these data are in absolute accordance with both the available genetic and pathophysiological mechanisms responsible for FECD genesis and development [1, 2]. In fact, as reported by Liu et al. in a murine in vivo model of FECD, the greater susceptibility of females than males to the development of the disease might be at least explained by the higher levels of oestrogen DNA adducts in the former, responsible for the blockage of mitochondrial both metabolic and replicative processes [14, 15].

The number of people with FECD worldwide (>30 years) will increase from 300 million in 2020 to 415 million in 2050. This mainly results from the expected growth in the number of aged people, which is anticipated to variably affect all continents. In fact, while the United Nations probabilistic projections report only minor variations in the global amount of elderly people in Europe and in North America, the same population group is expected to increase more dramatically in Asia and in Africa because of the increased life expectancy in these regions [12]. Unfortunately, due to the modest number of studies included in this meta-analysis, we believed it was not useful to try to ascertain regional variation in the expected figures of FECD.

The strengths of our meta-analysis include a critical appraisal of study quality by the rigorously validated JBI-PCAT, strict application of inclusion and exclusion criteria and the application of a statistical significance criterium of 0.01 for a more conservative approach to the proposed results. Of note, only studies with a direct examination operated by the investigators >70% were included. Unfortunately, a reasonable coverage of all world regions was not possible, due to the spurious number of large epidemiological studies on the topic. A vast intercase heterogeneity eventually derived, which is in line with different other systematic reviews and meta-analysis of prevalence [15, 16]. Second, we excluded not-in-English publications in this review. Nevertheless, all not-in-English publications did not meet our inclusion criteria. Thus, exclusion of such publications is unlikely to result in a significant publication bias in our analysis.

Finally, in our projection of FECD numbers, the overall prevalence of the disease was assumed to remain constant over time. Nevertheless, the change of prevalence over time is difficult to quantify as it depends on changes of risk exposure and other external factors, such as public awareness of the condition, screening campaign, and diagnostic technological improvements which might in turn modify the clinical approach to the condition. As a fact, the recent implementation of deep learning algorithms has highlighted the potential of these tools in identifying early FECD cases, based on the analysis of one anterior segment-optical coherence scan without additional imaging modalities (e g., pachymetry, specular microscopy, and confocal microscopy) or other information [16]. The future adoption of such software in clinical practice might in turn determine an increase in the number of people with a diagnosis of FECD, due to the higher sensitivity of our diagnostic toolkit.

In conclusion, our study provides estimates that reflect the present and future burden of FECD globally. The findings of our analysis might be useful for the design of FECD screening, treatment, rehabilitation, and related public health strategies worldwide.

References