Systemic amyloidosis

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Amyloidosis describes a heterogeneous group of diseases in which normally soluble plasma proteins are deposited in the extracellular space in an abnormal insoluble fibrillar form. These diseases can affect virtually any organ system and often present a major diagnostic and management challenge. Current therapies centre on reducing the supply of the respective amyloid fibril precursor protein, combined with supportive treatment. Better understanding of the mechanisms underlying amyloid formation has led to the development of novel treatment strategies aimed at inhibiting fibrillogenesis or destabilizing existing amyloid deposits. It is hoped that some of these developments might contribute to effective treatment not only of systemic amyloidosis, which is relatively rare, but also of the much more common type II diabetes and Alzheimer's disease, in which local amyloid formation is thought to play a role.

Introduction

Systemic amyloidosis can be either acquired or inherited, and at least 20 different proteins form amyloid fibrils in vivo [1] (Table 1). Despite the heterogeneity of these precursor proteins, the ultrastructural morphology and histochemical properties of all amyloid fibrils are remarkably similar, and diffraction studies have confirmed that they all share a common core structure of anti-parallel β-strands lying perpendicular to the long axis of the fibril [2]. This extremely abnormal, highly ordered conformation underlies the distinctive physicochemical properties of amyloid fibrils, including their relative stability and resistance to proteolysis, and their ability to bind molecules of the dye Congo red in a spatially organized manner, resulting in pathognomonic apple-green birefringence when viewed under cross polarised light [3] (Figure 1). Amyloid deposits also contain several common non-fibrillar constituents, including the normal plasma glycoprotein serum amyloid P component (SAP), gylcosaminoglycans (GAGs), apolipoprotein E, type IV collagen and laminin [4, 5]. The presence of SAP in amyloid deposits [4] reflects its specific binding to an as yet uncharacterised ligand common to all amyloid fibrils, and this is the basis for diagnostic scintigraphic imaging of amyloid with radiolablelled SAP [6].

Amyloid deposition is remarkably diverse in that it can be localized or systemic, rapidly lethal or merely an incidental finding [7]. Amyloid deposits cause disease when they accumulate in the extracellular space sufficiently to disrupt the structure, integrity and function of affected tissues and organs. The natural history of amyloidosis is usually of progressive accumulation, but amyloid deposition is not irreversible and clinical progression of amyloid disease merely reflects that fibrillar deposits are being laid down more rapidly than they are turning over. Although many of the conditions that underlie systemic amyloidosis are typically progressive and unremitting, there are numerous reports describing regression of amyloid when the underlying diseases have been successfully treated [8, 9, 10].

The focus of this article is to review the general principals and outcomes of existing therapeutic strategies, and to examine novel specific approaches, some of which are already being tested in patients.

Section snippets

General treatment principals

The prognosis of systemic amyloidosis is often grave but recent advances have greatly extended median survival. At present, the treatment of all types of amyloidosis centres on reducing the supply of the respective amyloid fibril precursor protein while supporting or replacing compromised organ function [10, 11]. Under favourable circumstances, this results in regression of existing amyloid deposits, preservation or recovery of the function of amyloidotic organs, and much improved patient

AL amyloidosis

AL is the commonest type of systemic amyloidosis diagnosed in the developed world; the reported incidence of ∼5–12 per million per year is almost certainly an underestimate and post mortem data suggest that it is the cause of death of ∼1 in 1500 people in the UK. AL amyloidosis can occur in association with any form of monoclonal B cell dyscrasia [13]. The fibrils are derived from monoclonal immunoglobulin light chains, generally consisting of the whole or part of the variable (VL) domain [14].

AA amyloidosis

Reactive systemic (AA) amyloidosis is a potential complication of any disorder that gives rise to a sustained acute-phase response, and the list of chronic inflammatory, infective or neoplastic disorders that can underlie it is almost without limit (Table 2). Biopsy and post mortem series suggest that the prevalence of AA amyloid deposition in patients with chronic inflammatory diseases is 3.6–5.8%, although a smaller proportion of patients have clinically significant amyloidosis [27, 28]. AA

Hereditary amyloidosis

The hereditary systemic amyloidoses are autosomal dominant conditions in which the amyloid fibrils are derived from genetic variants of transthyretin (TTR) [36], apolipoprotein AI, apolipoprotein AII, lysozyme, gelsolin or fibrinogen A α-chain [37]. In cases where synthesis of the variant amyloidogenic protein is solely or predominantly hepatic, liver transplantation can be an effective treatment. This form of ‘surgical gene therapy’ [38] has been successfully used in many patients with

Novel therapeutic strategies

Improved understanding of the mechanisms that underlie the formation and persistence of amyloid [43] has identified several novel therapeutic strategies [44, 45]. Small molecules that bind to and stabilize fibril precursor proteins can prevent their conversion into amyloid fibrils. Most progress has been made in TTR-type amyloidosis, where amyloidogenic mutations decrease stability of the tetrameric TTR protein structure. This facilitates monomer formation, from which the amyloid protofibrils

Conclusions

Current therapies for systemic amyloidosis require accurate identification of the amyloid fibril type so that production of the respective circulating precursors can be targeted. Chemotherapy in AL-type amyloidosis, vigorous anti-inflammatory treatment in AA-type amyloidosis, and liver transplantation in some types of hereditary amyloidosis have dramatically improved the outcome in these serious diseases. Nonetheless, treatment is limited by poor tolerability in often frail patients and by the

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

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