INTRODUCTION

Although case descriptions dating back to the early 1600s probably recorded what we now recognize as amyloidosis, it was Rudolph Virchow in 1854 who adopted the term “amyloid,” first introduced by Schleiden in 1838 to describe plant starch, to refer to tissue deposits of material that stained in a similar manner to cellulose when exposed to iodine. In these original descriptions, amyloid deposits were noted by Rokitansky to have a “waxy” or “lardaceous” appearance grossly and by Virchow to be amorphous and hyaline on light microscopy. Congo red staining (later shown to confer typical apple-green birefringence with polarized microscopy) for the better demonstration of amyloid was introduced in the 1920s by Bennhold, and the use of thioflavine T (producing an intense yellow-green fluorescence) was popularized in the 1950s (picture 1A-D) [1].

Electron microscopic examination of amyloid deposits, first performed in 1959, generally demonstrates straight and unbranching fibrils 8 to 10 nm in width, which may be composed of protofilaments at higher resolution [2,3]. Transmission electron and atomic force microscopy have had a role in elucidating the three dimensional structure of these macromolecular aggregates and in defining folding intermediates [4]. In many instances, the type of amyloid fibril unit can be further defined by immunohistology (immunofluorescence or immunoenzymatic techniques) or by immunoelectron microscopy [5].

A general overview of the pathogenesis, clinical manifestations, diagnosis, and treatment of the different amyloid disorders is presented here. More complete discussions of the individual disorders are presented elsewhere on the appropriate topic reviews.

PATHOGENESIS

Amyloidosis is a generic term that refers to the extracellular tissue deposition of fibrils composed of low molecular weight subunits (most of which are in the molecular weight range of 5 to 25 kD) of a variety of proteins, many of which circulate as constituents of plasma. At least 27 different human and nine different animal protein precursors of amyloid fibrils are now known. Listings of these molecules, nomenclature for subunit proteins [6], and corresponding amyloid diseases are presented in the tables (table 1A-B). (See "Genetic factors in the amyloid diseases".)

As is apparent from these tables, several types of amyloidosis are clearly hereditary, and, in most familial forms, clinical disease has been linked to missense mutations of the precursor proteins. In some instances, deletions or premature stop codon mutations have also been described [7,8]. Virtually all of the heredofamilial amyloidoses associated with nephropathic, neuropathic, or cardiopathic disease are dominantly inherited heterozygous disorders, and both the wild-type and mutant molecules can be identified in the amyloid deposits. In some instances (eg, transthyretin [TTR], apolipoprotein A-I [ApoAI], Alzheimer amyloid precursor protein [APP], prion protein [PRP]), both the wild-type and mutant molecules may separately form amyloid fibrils under different circumstances (eg, wild type TTR, ApoA1, and Ab deposits in association with organ-specific aging pathology in the heart, aorta, and brain, respectively) [8-10]. (See "Genetic factors in the amyloid diseases".)