Cardiac amyloidosis is a manifestation of one of several systemic diseases known as the amyloidoses.1,2 This uncommon disease is probably underdiagnosed, and even when a diagnosis of amyloidosis of the heart is made, the fact that there are several types of amyloid, each with its unique features and treatment, is often unrecognized. This can lead to errors in management and in the information conveyed to the patient. The purpose of this review is to familiarize the reader with the clinical features of amyloidosis and to address the approach to the patient with this disease, focusing on the various types of amyloidosis, their prognosis and treatment.

The common feature of this group of diseases is the extracellular deposition of a proteinaceous material that, when stained with Congo red, demonstrates apple-green birefringence under polarized light and that has a distinct color when stained with sulfated Alcian blue (Figure 1). Viewed with electron microscopy, the amyloid deposits are seen to be composed of a β-sheet fibrillar material (Figure 2). These nonbranching fibrils have a diameter3 of 7.5 to 10 nm and are the result of protein misfolding.4,5 Cardiac involvement in amyloidosis may be the predominant feature or may be found on investigation of a patient presenting with another major organ involvement. The presence of cardiac amyloidosis and its relative predominance varies with the type of amyloidosis. Thus, senile systemic amyloidosis and some forms of transthyretin amyloidosis invariably affect the heart, whereas cardiac involvement ranges from absent to severe in amyloidosis derived from a light-chain precursor (AL amyloidosis). Secondary amyloidosis almost never affects the heart in any clinically significant manner.6 The specific composition of the fibrils differs in the different types of amyloid7 and are outlined in the Table. Both on the basis of common usage and for …

Diagnosis and Management of the Cardiac Amyloidoses

Transthyretin Amyloid Cardiomyopathy: JACC State-of-the-Art Review

The systemic amyloidoses are a family of diseases induced by misfolded or misassembled proteins. Extracellular deposition of these proteins as soluble or insoluble cross β-sheets disrupts vital organ function.1 More than 27 different precursor proteins have the propensity to form amyloid fibrils.2 The particular precursor protein that misfolds to form amyloid fibrils defines the amyloid type and predicts the patient's clinical course. Several types of amyloid can infiltrate the heart, resulting in progressive diastolic and systolic dysfunction, congestive heart failure, and death. Treatment of cardiac amyloidosis is dictated by the amyloid type and degree of involvement. Consequently, early recognition and accurate classification are essential.3

The diagnosis of amyloidosis requires histological identification of amyloid deposits. Congo Red staining renders amyloid deposits salmon pink by light microscopy, with a characteristic apple green birefringence under polarized light conditions (Figure 1). Additional immunohistochemical staining for precursor proteins identifies the type of amyloidosis (Figure 2).4 Ultimately, immunogold electron microscopy and mass spectrometry confer the greatest sensitivity and specificity for amyloid typing.5,6



Figure 1. 
Congo Red staining of myocardial tissue from a patient with amyloid cardiomyopathy. A , Light microscopy; B , polarized light microscopy, 400× magnification.





Figure 2. 
Transthyretin amyloid cardiomyopathy by immunohistochemical staining. Endomyocardial biopsy samples were stained with antibodies to ( A ) kappa light chain, ( B ) lambda light-chain, ( C ) serum amyloid A, and ( D ) transthyretin amyloid. Bright-light micrographs at 400× magnification.



Two types of amyloid commonly infiltrate the heart: (1) Immunoglobulin light-chain (AL or primary systemic) amyloid and (2) transthyretin (TTR) amyloid. Transthyretin-related amyloidoses, in turn, encompass 2 forms of disease: Familial disease arising from misfolding of a mutated or variant TTR (familial amyloid cardiomyopathy or familial amyloidotic polyneuropathy [FAP]) and a sporadic, nongenetic disease caused by misaggregation of wild-type transthyretin (senile systemic amyloidosis [SSA]). Cardiac amyloidosis can also be …

/pdf/transthyretin-ttr-cardiac-amyloidosis-2d6v126inv.pdf

Transthyretin (TTR) Cardiac Amyloidosis

(2003). Tabulation of human transthyretin (TTR) variants, 2003. Amyloid: Vol. 10, No. 3, pp. 160-184.

Tabulation of human transthyretin (TTR) variants, 2003.

Cutaneous lesions are present in up to 40% of patients with primary and myeloma-associated systemic amyloidosis and occur as a result of tissue deposition of immunoglobulin light chain material derived from a circulating paraprotein. The occurrence of waxy, purpuric mucocutaneous lesions provides a crucial early pointer to underlying occult plasma cell dyscrasia; the combination of the symptoms of the carpal tunnel syndrome, macroglossia, and specific mucocutaneous lesions is highly characteristic. Although secondary systemic (reactive) amyloidosis rarely gives rise to clinically evident cutaneous lesions, it may be etiologically related to a number of chronic dermatoses. Lesions of nodular primary localized cutaneous amyloidosis are indistinguishable from those of primary and myeloma-associated systemic amyloidosis, and they result from local plasma cell infiltration. Macular and papular (lichen amyloidosus) variants of primary localized cutaneous amyloidosis may have a familial or racial basis and are characterized by a tendency for keratinocytes to undergo filamentous degeneration and apoptosis. The prognosis of patients with plasma cell dyscrasia-related systemic amyloidosis remains poor, since there is little response to therapy with cytotoxic agents, colchicine, or dimethylsulfoxide. Colchicine is the drug of choice in the prevention and treatment of the renal amyloidosis associated with familial Mediterranean fever, and dimethylsulfoxide may be useful in the management of patients with secondary systemic amyloidosis. Macular amyloid and lichen amyloidosus generally follow a chronic course with intractable pruritus; there have been isolated reports of the beneficial effect of dermabrasion, topical dimethylsulfoxide, and therapy with the aromatic retinoid, etretinate.

Amyloid and amyloidosis.

https://www.amjmed.com/article/0002-9343(83)90443-6/pdf

Frequency and distribution of senile cardiovascular amyloid: A clinicopathologic correlation

Localized laryngeal amyloidosis: partial characterization of an amyloid fibril protein AL.

The main amyloid fibril (AL) proteins extracted from the spleen of Patient So 124 with systemic amyloidosis and from a skin nodule of Patient KSA with localized amyloidosis were studied by partial amino acid sequence analysis and proved to be of kappa III immunoglobulin light-chain origin. The sequences were similar to that of Bence Jones protein V and, which has been reported to have a unique kappa III subset sequence. Thus, except for position 9 in protein AL(KSA), the amino acid sequences were identical to position 25 in AL(So 124) and in AL(KSA). The question is being raised whether this kappa III subset might contain amyloidogenic sequences.

Amino acid sequences in amyloid proteins of kappa III immunoglobulin light-chain origin.

Amyloid fibrils have been extracted from seminal vesicles, and a dominant 14 kD amyloid fibril protein has been identified. An antiserum to this protein reacted both with amyloid and with epithelial cells in some normal seminal vesicles. These reactions were blocked with seminal vesicle secretion and seminal vesicle amyloid fibril protein, but not by degraded amyloid fibrils or fibril protein from other types of amyloid. It is concluded that seminal vesicle amyloid is derived from secretory proteins of the seminal vesicles. As such, it is the first amyloid described which appears to be the product of an exocrine secretory cell.

Seminal vesicle amyloid: the first example of exocrine cell origin of an amyloid fibril precursor.

A middle-aged woman without any symptoms of ectopic hormone production underwent a right-sided mastectomy for infiltrating ductal carcinoma. She later developed axillary lymph node metastases which were somewhat carcinoid-like. This prompted further investigation, when scattered argyrophilic endocrine cells were found in both the primary tumour and its metastases. The endocrine cells reacted immunocytochemically with antisera against ACTH and HCG. Despite the endocrine activity of the tumour, it was still regarded as a ductal carcinoma since the endocrine cells constituted the minority cell population. The present study indicates strongly that ectopic hormone production in association with carcinoma of the breast is a result of hormone synthesis and release by the tumour cells.

Peter Pitkänen

Papers

Frequency and distribution of senile cardiovascular amyloid: A clinicopathologic correlation

Localized laryngeal amyloidosis: partial characterization of an amyloid fibril protein AL.

Amino acid sequences in amyloid proteins of kappa III immunoglobulin light-chain origin.

Seminal vesicle amyloid: the first example of exocrine cell origin of an amyloid fibril precursor.

Argyrophil endocrine cells with ACTH and HCG immunoreactivity in a carcinoma of the breast.