Hereditary Transthyretin Amyloidosis (hATTR)

Hereditary transthyretin (hATTR) amyloidosis is a rare hereditary systemic disease driven by mutations in the transthyretin (TTR) gene that initiate the deposition of amyloid fibrils in many organs and tissues.¹ Most often, patients display signs and symptoms of polyneuropathy; however, cardiac, renal, and ocular involvement is not uncommon.¹

Currently, various therapeutic strategies to address hATTR amyloidosis focus mainly on interfering with TTR protein production, maintaining the structural stability of TTR protein, and removing misfolded protein.^1,2 However, surgery can also be an option for these patients.

Liver Transplant

TTR protein is produced mainly in the liver; therefore, one of the first therapeutic strategies developed for controlling hATTR amyloidosis was liver transplant.¹ This approach to the disease was introduced in 1990, with the goal of preventing amyloid formation by replacing mutant TTR protein with the corresponding wild-type protein.^1,3

Many factors contribute to a successful clinical outcome following liver transplant. These include the age of the patient, the severity of disease at the time surgery is being considered, and the detected mutation in the TTR gene.¹ In a retrospective study including 1940 patients from the Familial Amyloidotic Polyneuropathy World Transplant Registry (FAPWTR), the 20-year survival rate after liver transplant was approximately 55.3%. The main cause of death in the patients included in this study were cardiovascular complications (rate of 22%).⁴ The French Reference Center Registry reported a 20-year survival rate of 38%.² 

Liver transplant does not preclude the development of a cardiac phenotype with time. It has been suggested that amyloid fibrils already formed and deposited in organs before surgery may promote the polymerization of soluble, circulating wild-type TTR protein secreted by the transplanted liver.⁵ For patients with mutant TTR protein in the leptomeninges, liver transplant may be less effective.⁶

Carpal Tunnel Release

Amyloid fibrils in hATTR amyloidosis damage and compress tissues, obstructing circulation of the blood. Carpal tunnel syndrome may result from the blockage caused by amyloid fibrils as they deposit in the flexor tenosynovium and transverse carpal ligament of the hand.^7-9 Most frequently, patients with cardiac amyloidosis present with carpal tunnel syndrome before they experience any cardiac signs or symptoms.⁹

In carpal tunnel syndrome, nerve compression and the obstruction of neural transmission cause numbness, paresthesia, and pain.⁸ Transverse carpal ligament release may be required when conservative measures such as splinting, physical therapy, and corticosteroid injections fail.⁸ Early release of the carpal tunnel is important for optimal recovery, and the outcomes of this surgery vary not only with the severity of symptoms but also with their duration before treatment.⁸

Vitrectomy

Approximately 10% of patients with hATTR amyloidosis present with ocular involvement. It has been shown that eye disease may progress after liver transplant even though TTR in plasma is unable to cross the blood-retina barrier.¹⁰ This finding can be partially explained by the local production of TTR protein; in addition to synthesis in the liver, TTR can be synthesized by the retinal pigment epithelium.^7,10 TTR can therefore be found in the corneal endothelium, lens capsule, iris epithelium, ciliary pigment epithelium, vitreous body, conjunctivae, trabecular meshwork, lacrimal glands, and retinal nerve fibers.¹⁰ Following the deposition of amyloid fibers, reported ocular manifestations include vitreous opacities and chronic open-angle glaucoma, conditions that adversely affect patients’ quality of life.^7,10

The standard treatment for vitreous opacities is surgical: a 25-gauge pars plana vitrectomy (PPV). This surgery can help restore vision and prevent relapses.¹⁰ An extensive PPV, which includes vitreous removal with indentation and shaving of the peripheral vitreous, increases the likelihood of a successful clinical outcome and decreases the likelihood of recurrence in comparison with an incomplete PPV.¹¹ Patients with vitreous remnants may undergo a second surgery consisting of extensive vitrectomy with posterior capsulectomy.¹⁰ However, after surgery, disease may still progress as a result of the local production of TTR. Other studies also report ocular effects of hATTR amyloidosis following surgery.¹⁰

References

1. Luigetti M, Romano A, Di Paolantonio A, Bisogni G, Sabatelli M. Diagnosis and treatment of hereditary transthyretin amyloidosis (hATTR) polyneuropathy: current perspectives on improving patient care. Ther Clin Risk Manag. 2020;16:109-123. doi:10.2147/TCRM.S219979

2. Adams D, Koike H, Slama M, Coelho T. Hereditary transthyretin amyloidosis: a model of medical progress for a fatal disease. Nat Rev Neurol. 2019;15(7):387-404. doi:10.1038/s41582-019-0210-4

3. Holmgren G, Steen L, Ekstedt J, et al. Biochemical effect of liver transplantation in two Swedish patients with familial amyloidotic polyneuropathy (FAP-met30). Clin Genet. 1991;40(3):242-246. doi:10.1111/j.1399-0004.1991.tb03085.x

4. Ericzon BG, Wilczek HE, Larsson M, et al. Liver transplantation for hereditary transthyretin amyloidosis: after 20 years still the best therapeutic alternative? Transplantation. 2015;99(9):1847-1854. doi:10.1097/TP.0000000000000574

5. Saelices L, Chung K, Lee JH, et al. Amyloid seeding of transthyretin by ex vivo cardiac fibrils and its inhibition. Proc Natl Acad Sci U S A. 2018;115(29):E6741–E6750. doi:10.1073/pnas.1805131115

6. Adams D, Ando Y, Beirão JM, et al. Expert consensus recommendations to improve diagnosis of ATTR amyloidosis with polyneuropathy. J Neurol. 2021;268(6):2109-2122. doi:10.1007/s00415-019-09688-0

7. Ando Y, Adams D, Benson MD, et al. Guidelines and new directions in the therapy and monitoring of ATTRv amyloidosis. Amyloid. 2022;1-13. Online ahead of print. doi:10.1080/13506129.2022.2052838.

8. Boyle RP, Sharan J, Schwartz G. Carpal tunnel syndrome in transthyretin cardiac amyloidosis: implications and protocol for diagnosis and treatment. Cureus. 2021;13(4):e14546. doi:10.7759/cureus.14546

9. Sperry BW, Reyes BA, Ikram A, et al. Tenosynovial and cardiac amyloidosis in patients undergoing carpal tunnel release. J Am Coll Cardiol. 2018;72(17):2040-2050. doi:10.1016/j.jacc.2018.07.092

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

11. Beirão NM, Matos E, Beirão I, Costa PP, Torres P. Recurrence of vitreous amyloidosis and need of surgical reintervention in Portuguese patients with familial amyloidosis ATTR V30M. Retina. 2011;31(7):1373-1377. doi:10.1097/IAE.0b013e318203c0c2

Reviewed by Harshi Dhiingra, MD, on 7/24/2022.

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Diana Diez Gaspar, PharmD, PhD

Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.