Clinicopathological features of senile systemic amyloidosis: an ante- and post-mortem study

Ueda, Mitsuharu; Horibata, Yoko; Shono, Masayuki; Misumi, Yohei; Oshima, Toshinori; Su, Yu; Tasaki, Masayoshi; Shinriki, Satoru; Kawahara, Satomi; Jono, Hirofumi; Obayashi, Konen; Ogawa, Hisao; Ando, Yukio

doi:10.1038/modpathol.2011.117

Cited by 120 publications

(91 citation statements)

References 20 publications

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“…ATTRwt, previously termed SSA, is most often found in older men, with a male to female ratio of 50:1 19 20 21. Its overall clinical prevalence remains unknown.…”

Section: Introductionmentioning

confidence: 99%

The transthyretin amyloidoses: advances in therapy

Dubrey

Ackermann

Gillmore

2015

Postgraduate Medical Journal

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There are two forms of transthyretin (TTR) amyloidosis: non-hereditary and hereditary. The non-hereditary form (ATTRwt) is caused by native or wild-type TTR and was previously referred to as senile systemic amyloidosis. The hereditary form (ATTRm) is caused by variant TTR which results from a genetic mutation of TTR. The predominant effect of ATTRwt amyloidosis is on the heart, with patients having a greater left ventricular wall thickness at presentation than the devastating form which is light chain (AL) amyloidosis. ATTRm amyloidosis is broadly split into two categories: a type that predominantly affects the nervous system (often called familial amyloid polyneuropathy (FAP)) and one with a predilection for the heart (often called familial amyloid cardiomyopathy (FAC)). Approximately half of all TTR mutations known to express a clinical phenotype cause a cardiomyopathy. Since the introduction of orthotopic liver transplantation for ATTRm amyloidosis in 1991, several additional therapies have been developed. These therapies aim to provide a reduction or elimination of TTR from the plasma (through genetic approaches), stabilisation of the TTR molecule (to prevent deposition) and dissolution of the amyloid matrix. We describe the latest developments in these approaches to management, many of which are also applicable to wild-type amyloidosis.

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“…ATTRwt, previously termed SSA, is most often found in older men, with a male to female ratio of 50:1 19 20 21. Its overall clinical prevalence remains unknown.…”

Section: Introductionmentioning

confidence: 99%

The transthyretin amyloidoses: advances in therapy

Dubrey

Ackermann

Gillmore

2015

Postgraduate Medical Journal

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“…[4][5][6] The other type is senile systemic amyloidosis, which is an age-related sporadic systemic amyloidosis that is induced by wild-type transthyretin. [7][8][9] Besides full-length wild-type transthyretin, C-terminal wild-type transthyretin fragments beginning at positions 46-52 usually occur in amyloid deposits obtained from patients with senile systemic amyloidosis as well as many cases with hereditary transthyretin amyloidosis. 8,10 Lumbar spinal canal stenosis is the most common spinal disorder in elderly people.…”

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confidence: 99%

Amyloid deposits derived from transthyretin in the ligamentum flavum as related to lumbar spinal canal stenosis

et al. 2015

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Amyloidosis is a protein conformational disorder with the distinctive feature of extracellular accumulation of amyloid fibrils that come from different proteins. In the ligamentum flavum of the lumbar spine, amyloid deposits were frequently found in elderly patients with lumbar spinal canal stenosis and were at least partially formed by wild-type transthyretin. However, how amyloid deposits in the ligamentum flavum affect lumbar spinal canal stenosis has remained unclear. In this study, we analyzed clinical, pathologic, and radiologic findings of patients with lumbar spinal canal stenosis who had amyloid deposits in the ligamentum flavum. We studied 95 ligamentum flavum specimens obtained from 56 patients with lumbar spinal canal stenosis and 21 ligamentum flavum specimens obtained from 19 patients with lumbar disk herniation. We evaluated histopathologic findings and clinicoradiologic manifestations, such as thickness of the ligamentum flavum and lumbar spinal segmental instability. We found that all 95 ligamentum flavum specimens resected from patients with lumbar spinal canal stenosis had amyloid deposits, which we classified into two types, transthyretin-positive and transthyretinnegative, and that transthyretin amyloid formation in the ligamentum flavum of patients with lumbar spinal canal stenosis was an age-associated phenomenon. The amount of amyloid in the ligamentum flavum was related to clinical manifestations of lumbar spinal canal stenosis, such as thickness of the ligamentum flavum and lumbar spinal segmental instability, in the patients with lumbar spinal canal stenosis with transthyretin-positive amyloid deposits. To our knowledge, this report is the first to show clinicopathologic correlations in transthyretin amyloid deposits of the ligamentum flavum. In conclusion, transthyretin amyloid deposits in the ligamentum flavum may be related to the pathogenesis of lumbar spinal canal stenosis in elderly patients.

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“…However, recent progress in diagnosis indicates that there are many patients with hereditary ATTR amyloidosis worldwide. Furthermore, ATTRwt amyloidosis is thought to be a common ageing-related disorder, as more than 10% of people over the age of 80 have wild-type TTR deposition in postmortem studies 3 5…”

Section: Introductionmentioning

confidence: 99%

Transthyretin (ATTR) amyloidosis: clinical spectrum, molecular pathogenesis and disease-modifying treatments

Sekijima

2015

J Neurol Neurosurg Psychiatry

257

311

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Transthyretin (ATTR) amyloidosis is a life-threatening, gain-of-toxic-function disease characterised by extracellular deposition of amyloid fibrils composed of transthyretin (TTR). TTR protein destabilised by TTR gene mutation is prone to dissociate from its native tetramer to monomer, and to then misfold and aggregate into amyloid fibrils, resulting in autosomal dominant hereditary amyloidosis, including familial amyloid polyneuropathy, familial amyloid cardiomyopathy and familial leptomeningeal amyloidosis. Analogous misfolding of wild-type TTR results in senile systemic amyloidosis, now termed wild-type ATTR amyloidosis, characterised by acquired amyloid disease in the elderly. With the availability of genetic, biochemical and immunohistochemical diagnostic tests, patients with ATTR amyloidosis have been found in many nations; however, misdiagnosis is still common and considerable time is required before correct diagnosis in many cases. The current standard first-line treatment for hereditary ATTR amyloidosis is liver transplantation, which allows suppression of the main source of variant TTR. However, large numbers of patients are not suitable transplant candidates. Recently, the clinical effects of TTR tetramer stabilisers, diflunisal and tafamidis, were demonstrated in randomised clinical trials, and tafamidis has been approved for treatment of hereditary ATTR amyloidosis in European countries and in Japan. Moreover, antisense oligonucleotides and small interfering RNAs for suppression of variant and wild-type TTR synthesis are promising therapeutic approaches to ameliorate ATTR amyloidosis and are currently in phase III clinical trials. These newly developed therapies are expected to be effective for not only hereditary ATTR amyloidosis but also wild-type ATTR amyloidosis.

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Clinicopathological features of senile systemic amyloidosis: an ante- and post-mortem study

Cited by 120 publications

References 20 publications

The transthyretin amyloidoses: advances in therapy

The transthyretin amyloidoses: advances in therapy

Amyloid deposits derived from transthyretin in the ligamentum flavum as related to lumbar spinal canal stenosis

Transthyretin (ATTR) amyloidosis: clinical spectrum, molecular pathogenesis and disease-modifying treatments

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