Elsevier

The Lancet

Volume 387, Issue 10038, 25 June–1 July 2016, Pages 2641-2654
The Lancet

Seminar
Systemic amyloidosis

https://doi.org/10.1016/S0140-6736(15)01274-XGet rights and content

Summary

Tissue deposition of protein fibrils causes a group of rare diseases called systemic amyloidoses. This Seminar focuses on changes in their epidemiology, the current approach to diagnosis, and advances in treatment. Systemic light chain (AL) amyloidosis is the most common of these conditions, but wild-type transthyretin cardiac amyloidosis (ATTRwt) is increasingly being diagnosed. Typing of amyloid fibrils, a critical determinant of therapy, has improved with the wide availability of laser capture and mass spectrometry from fixed histological tissue sections. Specific and accurate evaluation of cardiac amyloidosis is now possible using cardiac magnetic resonance imaging and cardiac repurposing of bone scintigraphy tracers. Survival in AL amyloidosis has improved markedly as novel chemotherapy agents have become available, but challenges remain in advanced disease. Early diagnosis, a key to better outcomes, still remains elusive. Broadening the amyloid-specific therapeutic landscape to include RNA inhibitors, fibril formation stabilisers and inhibitors, and immunotherapeutic targeting of amyloid deposits holds promise to transform outcomes in systemic amyloidoses.

Introduction

The amyloidoses are a rare group of diseases that result from extracellular deposition of amyloid, a fibrillar material derived from various precursor proteins that self-assemble with highly ordered abnormal cross β-sheet conformation.1, 2 Deposition of amyloid can occur in the presence of an abnormal protein (eg, hereditary amyloidosis and acquired systemic immunoglobulin light chain [AL] amyloidosis), in association with prolonged excess abundance of a normal protein (eg, reactive systemic [AA] amyloidosis and β2-microglobulin [β2M] dialysis-related amyloidosis), and, for reasons unknown, accompanying the ageing process (eg, wild-type transthyretin amyloidosis [ATTRwt; or senile systemic amyloidosis] and atrial natriuretic peptide amyloidosis).

More than 30 proteins have been identified to form amyloid in man,3 but recent use of mass spectrometry to identify amyloid suggests that many more proteins might be amyloidogenic.4 The most frequent type of amyloidosis in high-income countries is AL amyloidosis. The availability of new technologies has improved diagnosis and enabled accurate fibril typing and better risk stratification. Outcomes have improved, at least in AL amyloidosis, and several novel therapies are on the horizon for various types of amyloidosis, including antibody-based therapy and RNA inhibition strategies. However, management of patients with advanced organ involvement at diagnosis remains a major challenge, with nearly a third of all patients with AL amyloidosis still dying within a few months of diagnosis. Early diagnosis of amyloidosis remains an elusive goal that requires education of both physicians and patients. This Seminar reviews progress in the field over the past decade.

Section snippets

Epidemiology of amyloidosis

Few epidemiological data have been published for amyloidosis. The first population-based study of AL amyloidosis was done in Olmsted County, MN, USA, and was published in 1992. It reported the incidence of AL amyloidosis as three to five cases per million population.5 Death certificates from the UK indicate that amyloidosis has an incidence of about one per 100 000 population and is the cause of death in 0·58 per 1000 individuals.6 Analysis of Swedish hospital discharge and outpatient registers

Amyloid fibrils

All amyloid deposits are composed of protein fibrils that have a remarkably similar structure, with a diameter of 7–13 nm and a common core structure consisting of anti-parallel β-strands (less commonly, parallel β-strands) that form sheets.20, 21, 22, 23 All amyloid deposits also contain several minor non-fibrillary constituents, including glycosaminoglycans (GAGs) and serum amyloid P component (SAP).24, 25 The specific, highly ordered ultrastructure of amyloid fibrils accounts for their

Clinical features of amyloidosis

The potential for amyloid deposits to affect almost any organ system means that the clinical features of systemic amyloidosis are diverse, and they are rarely specific to one type of amyloidosis, which leads to difficulties and delays in diagnosis. Table 1 details features of the common types of amyloidosis. Clinical features that are virtually pathognomonic of AL amyloidosis include a combination of macroglossia and periorbital purpura (figure 1), but these occur in less than a third of all

Diagnosis

A stepwise approach to diagnosis and staging of amyloidosis is critical and involves confirmation of amyloid deposition, identification of fibril type, assessment of the underlying amyloidogenic disorder, and evaluation of the extent and severity of amyloidotic organ involvement. Serum cardiac biomarkers are an important validated method for risk stratification and staging in AL amyloidosis.39

Advanced and irreversible organ dysfunction has often ensued by the time a clinical diagnosis of

Principles of treatment

A reduction in the supply of precursor proteins for amyloid fibril underpins all current treatment for amyloidosis, although this is not yet possible for some types. Various drugs can be very effective in AL and AA amyloidoses but are often poorly tolerated because of impaired organ function. Orthotropic liver transplantation to remove or diminish the hepatic source of genetically variant amyloidogenic proteins has a role in selected patients with hereditary ATTR, AApoAI, and AFib amyloidoses.

Enhancing regression by immunotherapeutic targeting

Interest is growing in developing therapeutic antibodies to target amyloid deposits directly. A chimeric antibody, Mu11–1F4, reacts with many AL fibrils;143, 144 its localisation has been studied in patients with PET imaging145 and it is now in phase 1 clinical trials. Another monoclonal antibody, mAb2A4, binds AL/AA fibrils and human AL amyloid extracts,146 leading to regression of amyloid in mouse models of AA and AL amyloidosis. This antibody has been further developed as NEOD001 and has

Search strategy and selection criteria

A literature search was performed between 1990 and 2014 using PubMed and Web of Science with the search terms “amyloidosis” or “amyloid*” and each of “systemic amyloidosis”, “AL”, “AA”, “ATTR”, “AFib”, “AApoA1”, “ALys”, “Aβ2M”, “ALect2”, “epidemiology”, “imaging”, “diagnosis”, “treatment”, “chemotherapy”, “stem cell transplantation”, and “outcome”. We also reviewed conference abstracts of the international amyloidosis workshops in Rome 2010 and Groningen 2012, the Annual Meeting of the American

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