Transthyretin Amyloidosis: Update on the Clinical Spectrum, Pathogenesis, and Disease-Modifying Therapies

Abstract

ATTR amyloidosis is caused by systemic deposition of transthyretin (TTR) and comprises ATTRwt (wt for wild-type) amyloidosis, ATTRv (v for variant) amyloidosis, and acquired ATTR amyloidosis after domino liver transplantation. ATTRwt amyloidosis has classically been regarded as cardiomyopathy found in the elderly, whereas carpal tunnel syndrome has also become a major initial manifestation. The phenotypes of ATTRv amyloidosis are diverse and include neuropathy, cardiomyopathy, and oculoleptomeningeal involvement as the predominant features, depending on the mutation and age of onset. In addition to variant TTR, the deposition of wild-type TTR plays a significant role, even in patients with ATTRv amyloidosis. The formation of amyloid fibrils tends to occur in association with the basement membrane. The thickening or reduplication of the basement membrane surrounding endoneurial microvessels, which is similar to diabetic neuropathy, is observed in ATTRv amyloidosis, suggesting that common mechanisms, such as an accumulation of advanced glycation end products, may participate in the disease process. In addition to direct damage caused by amyloid fibrils, recent studies have suggested that the toxicity of nonfibrillar TTRs, such as TTR oligomers, participates in the process of tissue damage. Although liver transplantation has been performed for patients with ATTRv amyloidosis since 1990, late-onset patients were not eligible for this treatment. However, as the efficacy of orally administered tafamidis and diflunisal, which stabilize TTR tetramers, was suggested in the early 2010s, such late-onset patients have also become targets for disease-modifying therapies. Additionally, recent studies of small interfering RNA (patisiran) and antisense oligonucleotide (inotersen) therapies have demonstrated the efficacy of these gene-silencing agents. A strategy for monitoring patients that enables the choice of an appropriate treatment from comprehensive and long-term viewpoints should be established. As many patients with ATTR amyloidosis are aged and have heart failure, they are at increased risk of aggravation if they are infected by SARS-CoV2. The optimal interval of evaluation should also be considered, particularly in this COVID-19 era.

Keywords: Angiopathy; Cardiac amyloidosis; Electron microscopy; Microangiopathy; Pathogenesis; Pathology; Protein misfolding disease; Schwann cell; Therapy; Ultrastructure.

Fig. 1

Representative electron microscopic findings of amorphous materials forming amyloid fibrils. A cross section of a sural nerve biopsy specimen from a patient with early-onset Val30Met ATTR from an endemic area. Uranyl acetate and lead citrate stain. Amorphous electron-dense extracellular materials (asterisks) are abundant, particularly at the vicinity of a collection of collagen fibers (circular structures with a diameter of 50–70 nm). Aggregations of small dotty structures (arrows) are often observed among these amorphous materials, suggesting that nonfibrillar oligomeric intermediates are formed during the process of amyloid fibril formation. Mature amyloid fibrils are indicated by arrowheads. Scale bar 0.2 μm

Fig. 2

Amyloid fibrils formed in association with the basement membrane. A cross section of a sural nerve biopsy specimen from a patient with early-onset Val30Met ATTR from an endemic area. Uranyl acetate and lead citrate stain. Amyloid fibrils are found in association with basement membranes (arrowheads) surrounding an endoneurial microvessel. Aggregations of amyloid fibrils are indicated by arrows. Scale bar 0.5 μm

Fig. 3

Reduplication of basement membranes surrounding endoneurial microvessels. A cross section of a sural nerve biopsy specimen from a patient with late-onset Val30Met ATTR from a nonendemic area. Uranyl acetate and lead citrate stain. The reduplication of basement membranes surrounding endoneurial microvessels, which is similar to that in diabetic neuropathy patients, is frequently observed, even where amyloid deposits are not present. Scale bar 2 μm

Fig. 4

Differential characteristics of amyloid deposits between patients with conventional early-onset Val30Met ATTR amyloidosis from endemic foci (a–c) and patients with late-onset Val30Met ATTR amyloidosis from nonendemic areas (d–f). Biopsy specimens of the sural nerve (a, d) and autopsy specimens of the heart (b, c, e, f). Uranyl acetate and lead citrate staining specimens (a, d). Alkaline Congo red staining specimens (b, c, e, f). In early-onset patients from endemic foci, amyloid fibrils tend to be long and thick on electron microscopy (a). On light microscopy, amyloid deposits tend to be highly congophilic (b) and exhibit a strong apple-green birefringence (c) in early-onset patients from endemic foci. Atrophy and degeneration of myocardial cells result in the formation of amyloid rings (arrowhead). In late-onset patients from nonendemic areas, amyloid fibrils are generally short and thin on electron microscopy (d). Circular structures with a diameter of 50–70 nm are collagen fibers. On light microscopy, amyloid deposits are generally weakly congophilic (e) and exhibit a faint apple-green birefringence (f) in late-onset patients from nonendemic areas. Scale bars 0.2 μm (a, d) and 10 μm (b, d, e, f)

Fig. 5

Differential impact on neighboring tissues according the size of amyloid fibrils. Cross sections of sural nerve biopsy specimens from a patient with early-onset Val30Met ATTR with long and thick (i.e., large) amyloid fibrils (a, b) and a patient with non-Val30Met ATTR amyloidosis with short and thin (i.e., small) amyloid fibrils (c). Uranyl acetate and lead citrate stain. Large amyloid fibrils seemed to pull surrounding tissues during their maturation, resulting in distortion and atrophy of Schwann cells, particularly those associated with small-diameter nerve fibers, such as unmyelinated fibers indicated by an arrow (a). A high-powered view of the box in a is shown in b. Large myelinated fibers indicated by an asterisk are relatively preserved even though they are apposed to large amyloid fibrils. The influence of small amyloid fibrils on neighboring tissues seems to be less conspicuous than that of large amyloid fibrils (c). An asterisk indicates an axon of an unmyelinated fiber. Scale bars 2 μm (a) and 0.5 μm (b, c)