https://orcid.org/0000-0001-5906-7670
Abstract
Purpose. Transthyretin is produced in the retina and approximately one quarter of patients with variant transthyretin amyloidosis (ATTRv) develop ocular involvement. Glaucoma is the most important ocular manifestation, leading to rapid loss of vision. The usefulness of glaucoma as a red flag for cardiac amyloidosis is unknown. Materials and Methods. On a national scale, we investigated the association between glaucoma and development of amyloidosis, compared to an age- and sex-matched population from the general population. Results. The study population included 365,496 subjects (1:1 ratio). Adjusted Cox-models showed no significant association between glaucoma and future diagnosis of amyloidosis (hazard ratio: 1.16 [0.80–1.70], p = .44). Conclusion. We conclude that while ocular involvement is a possible early manifestation of ATTRv, nationwide data suggest that glaucoma is probably not useful as a red flag for cardiac amyloidosis.
Introduction
Ocular involvement occurs in various types of amyloidosis, as part of localized or systemic disease. In patients with transthyretin amyloidosis (ATTR), hepatic synthesis of transthyretin (TTR) mainly causes neuropathy and cardiomyopathy, however, smaller amounts of TTR are also produced in the retina. While wild-type TTR does not appear no misfold and aggregate in the eye, ocular manifestations are well-described in patients with variant ATTR (ATTRv) and can be the presenting symptom [Citation1]. A large study on patients with ATTRv showed that 24.1% had ocular involvement [Citation2], but the frequency is depending on the TTR variant, Val30Met being the most commonly associated with ocular involvement [Citation3]. Ocular involvement in ATTRv can cause a variety of symptoms depending on the affected structure, and although vitreous deposits is considered a red flag for cardiac amyloidosis (CA) [Citation4], the most clinically important disorder is glaucoma, leading to rapidly progressing disease and loss of vision. Typically, medical treatment is insufficient and surgery is required. In these patients, early recognition of vitreous amyloid is important for prevention and management of secondary glaucoma [Citation5]. Considering this known association between glaucoma and ATTRv, we set out to investigate the usefulness of glaucoma as a potential red flag for CA. The hypothesis was that glaucoma is a risk marker for future development of CA, and as such might constitute an opportunity for screening.
Materials and methods
In a nationwide sample of patients ≥50 years derived from the Danish national registries, we examined the association between glaucoma and a future diagnosis of amyloidosis (International Classification of Diseases 10th revision code: E85) within the subsequent 10 years after the first prescription of an anti-glaucoma drug (Anatomical Therapeutical Chemical codes: S01E, S01A, S01EB, S01EC, S01ED, S01EE, prescribed between 2000 and 2018). Baseline was defined as the date of the first prescription of an anti-glaucoma drug. For comparison, a control group was created from the general population. The controls were assigned the same baseline date as cases, with the prerequisite that they were living in Denmark at the time. Risk-set matching was made in a 1:1 ratio by age (±1year), sex and calendar year. Study population demographics were reported at baseline. Comorbidities were evaluated via in- and outpatient diagnoses up to ten years before baseline. Pharmacotherapy was evaluated via drug prescriptions up to 180 days before baseline. See Appendix for used ICD-8, ICD-10 and ATC-codes. The study is in accordance with the Declaration of Helsinki. Ethical approval is not required for registry studies in Denmark. The study has been approved by the Danish Data Protection Agency (approval number: P-2019-348).
Statistical analysis
Baseline characteristics for study subjects with and without glaucoma were reported as medians and interquartile ranges (IQR) for continuous variables and as percentages for categorical variables. Chi-squared test and Wilcoxon-test were used to assess differences, as appropriate. Cumulative incidence functions were used to compare incidences of outcomes, incorporating competing risk of death. Hazard ratios were calculated using crude and adjusted Cox proportional hazard models. The Cox models were adjusted for sex, age group, hypertension, ischemic heart disease, heart failure, atrial fibrillation, diabetes mellitus, chronic obstructive lung disease (COPD) and chronic renal failure. The proportional hazards assumption was examined graphically using log(-log(survival function)) vs. time plots for the exposure variable, and found valid. Age did not meet linearity assumptions and was categorized. Statistical analyses were made using SAS statistical software (version 9.4, Cary, NC, USA). A two-sided p-value below .05 was considered statistically significant.
Results
The study population included 365,496 subjects, the median age was 72 years and 56% were female, see . Diagnosed amyloidosis at baseline was rare in both patients with glaucoma and in controls (0.010% vs. 0.008%, n = 19 vs. n = 15). In cases and controls without prior diagnosed amyloidosis, there was no significant difference in cumulative incidences of future diagnosis of amyloidosis (0.038% vs. 0.033%, p = 0.46). In a multivariable Cox model, adjusted for age group, sex, hypertension, diabetes mellitus, ischemic heart disease, heart failure, atrial fibrillation, chronic obstructive pulmonary disease and chronic kidney disease, there was no significant association between glaucoma and a future diagnosis of amyloidosis (hazard ratio: 1.16 [0.80–1.70], p = 0.44) [].
Figure 1. Overview of study methodology and results.
Table 1. Baseline characteristics.
Discussion
We conclude that while ocular involvement is a possible early manifestation of ATTRv, nationwide data suggest that glaucoma alone does not warrant screening for CA. Nonetheless, ophthalmologists must be aware of ocular manifestations of amyloidosis, especially in patients with established heart disease and red flags for CA, such as intolerance to beta-blocker eye drops due to bradycardia/orthostatic hypotension.
Disclosure statement
No potential conflict of interest was reported by the author(s)
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References
- Seca M, Ferreira N, Coelho T. Vitreous amyloidosis as the presenting symptom of familial amyloid polyneuropathy TTR Val30Met in a portuguese patient. Case Rep Ophthalmol. 2014;5(1):92–97.
- Reynolds MM, Veverka KK, Gertz MA, et al. Ocular manifestations of familial transthyretin amyloidosis. Am J Ophthalmol. 2017;183:156–162.
- Ando E, Ando Y, Okamura R, et al. Ocular manifestations of familial amyloidotic polyneuropathy type I: long term follow up. Br J Ophthalmol. 1997;81(4):295–298.
- Garcia-Pavia P, Rapezzi C, Adler Y, et al. Diagnosis and treatment of cardiac amyloidosis: a position statement of the ESC working group on myocardial and pericardial diseases. Eur Heart J. 2021;42(16):1554–1568.
- Kakihara S, Hirano T, Imai A, et al. Small gauge vitrectomy for vitreous amyloidosis and subsequent management of secondary glaucoma in patients with hereditary transthyretin amyloidosis. Sci Rep. 2020;10(1):5574.