38 Arch Pathol Lab Med—Vol 125, January 2001 The Changing Concepts of Amyloid—Picken Historical Perspective The Changing Concepts of Amyloid Maria M. Picken, MD, PhD ● The first issue of the Archives of Pathology & Laboratory Medicine, published 75 years ago, contained an article by Richard Jaffe ´ on the experimental induction of amyloid- osis in mice. This publication was one of a series of mile- stones that have marked our ongoing and evolving con- cept of amyloidosis, beginning with the first description by Virchow more than a century ago. Since that time, sci- entific understanding of amyloidogenesis has expanded through the involvement of newly developed techniques, such as biochemical analysis, electron microscopy, and molecular genetics. As a result of these investigations, it is now known that amyloidoses comprise an entire family of sporadic, familial and/or inherited, degenerative, and infectious disease processes, linked by the common theme of abnormal protein folding and deposition. This article seeks to provide a synopsis of the present state of our knowledge with regard to these disorders, including cur- rent terminology, classification, major clinical syndromes, and diagnosis. (Arch Pathol Lab Med. 2001;125:38–43) A myloidosis in humans was first recognized in the mid- 19th century when Rudolf Virchow coined the term amyloid (for starch or cellulose) to describe abnormal ex- tracellular material seen in the liver at autopsy. 1 In fact, he was mistaken about the nature of the material, since all amyloid deposits characterized to date have been shown to consist predominantly of protein not carbohydrate. However, this first became apparent almost a century lat- er, with the advent of biochemical analysis. Nonetheless, Virchow’s erroneous term has endured. The first issue of Archives of Pathology & Laboratory Medicine contained an article by Richard Jaffe ´ 2 pertaining to studies of experi- mental amyloidosis induced in mice by repeated injections of casein. Before this, several articles (quoted by Jaffe ´) had been published at the beginning of the last century on experimental amyloidosis induced by repeated subcuta- neous injections of various proteins. Jaffe ´’s article expand- ed the results obtained earlier by others: his emphasis was on the twin issues of induction time and dose dependence in experimental amyloidosis. It is currently believed that this type of experimental amyloidosis is due to the abnormal production and deg- radation of serum amyloid A protein (SAA). 3 Although Accepted for publication August 16, 2000. From the Department of Pathology, Loyola University Medical Cen- ter, Maywood, Ill. Reprints: Maria M. Picken, MD, PhD, Department of Pathology,Loy- ola University Medical Center, 2160 S First Ave, Room 2242, Bldg 110, Maywood, IL 60153 (e-mail: mpicken@lumc.edu). SAA is a major acute phase reactant, its physiological role is unknown. Interestingly, SAA was first identified after the amyloid fibril protein was defined biochemically in 1971 by Benditt et al, 4 Levin et al, 5 and Husby and Natvig. 6 Jaffe ´ confirmed that the type of stimulus is not of primary importance in this particular model of amyloidosis, since similar results could be achieved with injections of differ- ent proteins (casein, serum, etc). As is currently known, in this experimental model, injections of various proteins ultimately lead to an increase in SAA, which subsequently undergoes partial degradation and is then deposited as amyloid fibrils. Thus, Jaffe ´ was correct in postulating an ‘‘abnormal toxic cleavage of body tissues’’ in experimental inflammatory amyloidosis. It took another quarter of a century before further meaningful progress in amyloid research was seen. In the late 1950s, with the introduction of electron microscopy, the fibrillar nature of amyloid became apparent. 7 In the electron microscope, amyloid was seen to consist of ran- domly dispersed, nonbranching fibrils that measured 8 to 10 nm in diameter. The characteristic -pleated sheet con- figuration was also discovered shortly thereafter. 8 The lat- ter is responsible for the Congo red staining properties of amyloid. Thus, the modern diagnostic criteria for amyloid were adopted. These criteria include the detection of am- yloid deposits in tissues that are Congo red positive, ap- pear birefringent when viewed under polarized light (Fig- ure 1), and display a characteristic fibrillar ultrastructure (Figure 2). In the early 1970s, the first 2 amyloid fibril proteins were extracted and chemically characterized. 4,9 Thereafter, it soon became apparent that amyloid is chemically het- erogeneous. Currently, 19 different proteins have been found to form amyloid fibrils in humans, and other pro- teins may soon be added to this group. 10–13 This diversity generated the need for a reliable nomenclature and clas- sification. Previously, several different classifications of amyloidosis were used that were essentially based on clin- ical features. However, the currently accepted classifica- tion, which was first proposed in 1990 and updated in 1998, is based on the chemical structure of the amyloid fibril protein. 10,11,14 According to the currently used no- menclature, the amyloid fibril protein is designated as protein A with a suffix that identifies the specific protein. Thus, amyloid derived from the immunoglobulin mono- clonal light chain is designated AL, whereas amyloid de- rived from protein A is designated AA. Although distinguishing between systemic and local- ized amyloidoses is of clinical importance, it is increas- ingly apparent that several amyloid proteins may be as- sociated with both systemic and localized forms. Thus,