Patients with hereditary transthyretin amyloidosis (hATTR) may develop ocular manifestations secondary to circulating transthyretin (TTR) or due to the local production of mutant TTR. Ocular involvement usually occurs later in the course of the disease and can be observed even after a liver transplant. In fact, some studies suggest that liver transplantation can even accelerate ocular deterioration.

The production of TTR in the eye is mainly supported by retinal pigment epithelial cells, though amyloid deposits have been identified in several ocular tissues, including the corneal endothelium, lens capsule, iris epithelium, vitreous body, conjunctiva, lacrimal glands, among others. The molecular mechanisms underlying amyloid fibrillogenesis in intraocular tissues might be different from those in extraocular tissues as the amyloid fibrils observed in the retina and in extraocular muscles exhibit biochemical differences.

Ocular manifestations in hATTR are diverse and include vitreous opacities, chronic open-angle glaucoma (COAG), abnormal conjunctival vessels, keratoconjunctivitis sicca (KCS), chorioretinal vascular changes (CRVCs), pupillary light-near dissociation, irregular pupil, optic neuropathy, and ocular adnexal amyloidosis (OAA), among others. If left untreated, these manifestations can lead to severe vision loss, with some progressing to irreversible blindness.

Hence, a complete ophthalmological examination is of utmost importance to detect ocular involvement, even if subclinical, in hATTR patients.

Possible Ocular Manifestations in hATTR

Vitreous Opacities

“Amyloid deposition in the vitreous, with floaters and a consequent progressive decrease in visual acuity, is almost pathognomonic of hereditary amyloidosis by TTR gene mutation, occurring either during the natural course of the disease or after hepatic transplantation: the greater the density of vitreous amyloid deposition, the higher the degree of visual loss, up to only light perception,” explained Angelo Maria Minnella et al in a review article published in Genes.

The incidence of vitreous opacities in hATTR varies from 5.4% to 35%, being more common and developing earlier in patients with Arg34Gly, Tyr114Cys, Thr49Ala, and Glu54Lys mutations than in those with Val30Met mutations. Indirect signs of vitreous amyloidosis (eg, pseudopodia lentis, vitreous with glass wool appearance, and perivascular amyloid deposits in the retina) may be observed in asymptomatic patients.

Read more about hATTR complications

Vitreous amyloid deposits have been described as sheet-like, film-like, band-like, cobweb-like, glass wool-like, cotton-like, and stringy fibril-like structures that are usually bilateral and asymmetrical.

In some cases, vitreous amyloidosis may be the initial sign of hATTR. Hence, it is important to assess for possible subclinical systemic manifestations of the disease in such patients.

Vitreous opacities are treated with 25-gauge pars plana vitrectomy, which aims to restore vision and prevent relapses. However, relapse may occur even several years after the procedure due to dispersion of residual vitreous deposits or ongoing intraocular production of mutated TTR.

Chronic Open-Angle Glaucoma

The release of amyloid TTR into the aqueous humor is the main cause of glaucoma in hATTR patients. Early diagnosis of COAG is essential since it is the leading cause of irreversible blindness in these patients.

The increase in intraocular pressure (IOP) caused by amyloid deposition in certain ocular tissues may develop months or years before glaucoma. Hence, long-term monitoring and follow-up of IOP in hATTR patients are important.

In contrast to glaucomatous patients, hATTR patients with COAG do not have increased levels of erythropoietin. Therefore, these patients require a more aggressive hypotonic treatment to preserve vision, as neuroprotective substances seem to be ineffective.

Abnormal Conjunctival Vessels

Alterations in conjunctival vessels (eg, segmental and fusiform dilatation of conjunctival vessels, subconjunctival hemorrhages, yellow subconjunctival deposits, and conjunctival lymphangectasia) are found in almost all patients. Since they are caused by circulating TTR, they do not progress after a liver transplant.

Keratoconjunctivitis Sicca and Corneal Neuropathy

Amyloid deposition in the corneal layers causes KCS, whereas amyloid deposition in the lacrimal gland and autonomic neuropathy contribute to neurotrophic keratopathy, with eventual corneal perforation due to eye dryness.

Corneal damage can be detected in presymptomatic stages using in vivo laser scanning corneal confocal microscopy. KCS can usually be treated using lubricant eye drops. In severe cases, when corneal perforation exists, penetrating keratoplasty can be performed, but the possibility of relapse still exists.

Accommodation Defects

Asymmetrical intraocular amyloid deposition in the anterior lens capsule may occur in patients with hATTR. This leads to early cataract or cataract progression, as well as early presbyopia. The age of onset of presbyopia was shown to be significantly lower in patients with hATTR than in control individuals and was not influenced by liver transplant.

Chorioretinal Vascular Changes

CRVCs, such as retinal and choroidal amyloid angiopathies, can be detected using fundus fluorescein angiography and indocyanine green angiography, respectively. A study in patients with the Val30Met mutation showed that choroidal amyloid angiopathy mainly affects arteries.

Hemorrhages and cotton wool spots, which are visible signs of CRVCs, are observed in about 20% of patients with hATTR, being particularly prevalent in those with the Tyr114Cys mutation. The most severe complication of retinal amyloid angiopathy is neovascularization, which, ultimately, can lead to blindness.

Read more about hATTR symptoms

Minnella et al suggest a possible association between vitreous amyloidosis and retinal angiopathy. “The appearance and rapid progression of amyloidotic retinal angiopathy after vitreous amyloidosis removal (personal unpublished data) suggest that amyloid impregnation of the small terminal vessels in the peripheral retina moves from the vitreous to the vessel lumen and may cause progressive changes to the vessel wall with subsequent obliteration,” they wrote.

Pupillary Abnormalities

Amyloid deposition at the inner pupillary margin originates peculiar pupillary indentations that are characteristic of ocular amyloidosis. Anisocoria and pupillary light-near dissociation may also be observed in some patients. Early detection of pupillary changes is essential, as they may precede the insidious onset of glaucoma by about 2 years.

Optic Neuropathy

The occurrence of optic neuropathy in hATTR patients is rare but should be suspected in cases of unexplained progressive visual loss after ruling out vitreous opacity and optic nerve damage due to glaucoma.

Ocular Adnexal Amyloidosis

Amyloid deposition can also be detected in tissues surrounding the eye, such as ocular adnexa, extraocular muscles, levator palpebrae muscle, eyelids, and the lacrimal system. Manifestations in such structures are rare and probably underdiagnosed since symptoms are vague.

An analysis of 9 autopsied eyes from hATTR patients with the Val30Met mutation revealed that most amyloid (85.7%) was localized in extraocular muscles, followed by 44.4% in the sclera. Amyloid fibrils were also detected in orbital adipose tissue.

Searching for Potential Ocular Biomarkers

In a single-center, retrospective, observational, clinical case series conducted by Minnella et al, all hATTR patients (n=9) had an abnormal electroretinogram (ERG) and showed bilateral involvement in corneal confocal microscopy and electrophysiological tests.

The authors hypothesized that these alterations “may be related to a malfunction of TTR protein leading to a perturbation of visual cycle resulting in a reduced supply of retinoids, for both rod and cone photoreceptors.”

Moreover, they found that patients with a confirmed diagnosis of primary hATTR with no visual impairment might exhibit alterations in retinal function, even if structural retinal damage is absent or minimal, together with corneal nerve abnormalities.

Therefore, Minnella et al proposed the use of corneal confocal microscopy and electroretinogram as quick, noninvasive screening methods in hATTR patients.

“Sub-epithelial nervous plexus alterations and thinning of stromal nerves, as well as ERG abnormalities might be used as specific early biomarkers for peripheral denervation, both in patients with overt disease and in carriers,” they concluded.

Reference

Minnella AM, Rissotto R, Antoniazzi E, et al. Ocular involvement in hereditary amyloidosis. Genes. 2021;12(7):955. doi:10.3390/genes12070955

Minnella AM, Rissotto R, Maceroni M, et al. Ocular involvement in hereditary transthyretin amyloidosis: a case series describing novel potential biomarkers. Genes. 2021;12(6). doi:10.3390/genes12060927