Amyloidosis

Seminars in

ARTHRITIS

AND RHEUMATISM OCTOBER

VOL 22, NO 2

1992

Amyloidosis By Gunnar Husby Amyloidosis is a heterogenous group of diseases characterized by deposition of a fibrillar, proteinaceous material, amyloid, in various tissues and organs. Increasing knowledge about the different proteins that constitute the amyloid fibrils has made it possible to classify amyloidosis by the fibril protein, which appears more rational than the traditional classification by its clinical expression. A serum protein is the precursor of the amyloid fibril protein in the various systemic forms of amyloidosis. Although the chemical composition of amyloid is pres-

T

HE TERM amyloidosis relates to a heterogeneous group of disorders characterized by extracellular deposition of a proteinaceous material, amyloid, in various tissues and organs.1-3 Based on its appearance in the light microscope, amyloid is traditionally described as a “homogeneous and eosinophilic substance.” However, electron microscopy shows that amyloid is by no means homogeneous but has a unique fibrillar ultrastructure. The unique amyloid fibril is the principal component of all amyloids, irrespective of the clinical expression, tissue, or animal species involved or whether it occurs spontaneously or is induced in experimental animals. Amyloid fibrils are rigid and nonbranching with a diameter of 10 to 15 nm, are of indefinite length, and consist of polypeptide chains arranged in a twisted B-pleated sheet conformation.2 This specific structure of the fibril proteins determines the tinctorial and optical properties of amyloid, ie, the affinity for Congo red and the typical green/yellow birefringence observed when amyloid stained with Congo red is viewed in a polarizing microscope.4 Low solubility and relative resistance to proteolytic digestion in physiological conditions contribute

ently well known, the pathogenetic processes that convert such proteins into a fibrillar form and lay them down in the tissues are far from clarified. This review describes the amyloid deposits, some putative pathogenetic mechanisms, and the clinical, therapeutic, and prognostic aspects of the most important forms of amyloid disease. Copyright o 1992 by W.B. Saunders Company INDEX WORDS: Amyloidosis; amyloid L; amyloid A; clinical amyloidosis syndromes.

to the irreversible and often progressive course of amyloidosis, in many cases leading to death within months or a few years of diagnosis.5 The deposition of amyloid results in a variety of clinical features. As a consequence of this clinical heterogeneity, Wilks proposed a classification of amyloidosis as early as 1856, when he divided a group of patients into five separate classes, one of which (class 2) was that “connected with syphilis, rheumatism etc.” Wilks also included idiopathic (primary) amyloidosis in his classification, and this is probably the first report of this clinical form of amyloidosis. Adams described amyloidosis with myelomatosis in 1872.

From the Department of Rheumatology, Universiry and Regional Hospital of Tromsa, Trams@, Norway. Supported by the Norwegian Council for Science and the Humanities, the Norwegian Women S Public Health Association, and Norsk Revmatiker-forbund. Gunnar Husby, MD: Professor of Rheumatology and Head, Depanment of Rheumatology, University and Regional Hospital of Tromsa. Address reprint requests to Gunnar Husby, MD, Department of Rheumatology, Universityand Regional Hospital of Tromsa, 9012 Tromsa, Norway. Copyright o 1992 by W.B. Saunders Company 0049-0172/9212202-0001$5.00

Seminars in Arthritis and Rheumatism, Vol22, No 2 (October), 1992: pp 67-82

67

GUNNAR HUSEY

68

At present, one and a half centuries later, many forms have become apparent, reflecting the pathophysiological consequences of different amounts, distribution, and composition of amyloid deposits. Using electron microscopy, Cohen and Calkin@ disclosed the fibrillar nature of amyloid and described the unique shape of the fibrils. In spite of their morphological similarity in different clinical settings, Benditt and Eriksen’ suggested for the first time that amyloidosis might also be heterogeneous with respect to the nature of amyloid fibrils. However, it was difficult to isolate them from affected tissues because of their very low solubility under physiological conditions. Important progress was made when Pras et al8 published their water-extraction method for the purification of amyloid fibrils. This method permitted chemical and immunological analysis of isolated amyloid fibrils that had been dissociated by treatment with agents such as sodium hydroxide, guanidine, or urea,3 leading to an understanding of the chemical composition of amyloid. During the last 20 to 30 years it has become clear that amyloid fibrils may be composed of completely different protein subunits.3 In addition to fibrils, an extrafibrillar protein traditionally called the amyloid P component or protein AP is invariably present regardless of the type of fibril protein.9 A carbohydrate moiety in the form of glycosaminoglycans or possibly proteoglycans has also been demonstrated in all amyloid deposits so far examined. Thus the notion by Virchow in 1854 of the carbohydrate nature of amyloid has at least in part been confirmed.lOJ1 AMYLOID

FIBRIL PROTEINS

Chemical analysis of solubilized amyloid fibrils obtained from different clinical and experimental types of amyloidosis in many instances has shown two main protein components.i2 One of these represents a material with very high molecular weight. A similar material is also present in corresponding extracts of normal tissues and appears to contain a variety of macromolecules, among them fibronectin and a protein related to reticulin.13 Their role in amyloid formation is not established, and recent studies14 suggest that at least part of these materials are not

integrated in the fibrils but rather coisolated with them; however, further studies are needed to confirm this. Materials from cell nuclei, namely different histones and the nucleic acids DNA and RNA, can also be coisolated with amyloid fibrils and appear in the high-molecularweight fraction after dissociation. Whether they are significant constituents of amyloid deposits is not clear. Disruption of the normal tissue architecture by amyloid may fascilitate the coextraction of such materials. The second and chief protein component is a distinct fibril subunit with much smaller molecular weight ranging from about 3,000 to 30,000 d in different amyloid preparations.2,3 The term amyloid protein in the following discussion relates to this low-molecular-weight fibril protein subunit. Several apparently nonrelated proteins can constitute the amyloid fibril subunit in different cases of amyloidosis,3 a common feature of such proteins being the ability to assume the B-pleated sheet structure typical of an amyloid.2 A steadily increasing number of such proteins (15 at the present time) are characterized by their amino acid sequence15 (Table l), and in many cases complementary DNA has also been established. The different amyloid proteins are often related to specific clinical forms of amyloidosis. Indeed, many types of amyloid disease can now be defined and classified by structural analysis of the fibril proteins (Table 1) and/or the genes coding for them.2v3J5J6 Certain serum proteins are precursors for the different fibril proteins in the various systemic forms of amyloidosis. 2,3Two important types of fibril protein related to systemic amyloidosis are the amyloid L (AL) and amyloid A (AA) proteins (Table 1). Protein AL, which consists of homogeneous (monoclonal) immunoglobulin light chains or their aminoterminal fragments, is seen in idiopathic and myeloma-associated amyloidosis (AL amyloidosis).2,17 The first AL protein was described in 1971. However, the first immunoglobulin heavy chain-derived amyloid (AH) constituted by a fragment of monoclonai y 1 heavy chains was described 19 years later.18 Protein AA, derived from the serum amyloid A (SAA) protein, is associated with reactive (secondary) amyloidosis, familial Mediterranean fever (FMF), familial nephropathic amyloi-

69

AMYLOIDOSIS

Table 1: Nomenclature

and Classification

of Human Amyloid and Amyloidosis

Amyloid

Protein

Protein Type

Protein

Precursor

or Variant

AA

Clinical Reactive (secondary); FMF; familial

SAA

amyloid nephropathy with urticaria and deafness (Muckle-Wells’syndrome) AL

K,h, eg, Klfl

AK, AA, eg, ArcIll

AH

lgG 1 (71) Transthyretin

A?1 eg, Met 30

Idiopathic (primary), myeloma- or macroglobulinemia-associated

Al-H7

Familial amyloid polyneuropathy,

Por-

tugal eg,Met

Familial amyloid cardiomyopathy,

111

Denmark TTR or Ile 122

Systemic senile amyloidosis

AApoAl

apoA1

Arg 26

Familial amyloid polyneuyropathy,

AGel

Gelsolin

Asn 18715

Familial amyloidosis, Finland

ACys

Cystatin C

Gln 68

Hereditary cerebral hemorrhage with

A6

P-protein precursor, eg,

Iowa

amyloidosis, Iceland Alzheimer’s disease; Down’s syn-

6PP 695

drome Gln 61822

Hereditary cerebral hemorrhage with amyloidosis, the Netherlands

AP2M AScr

Associated with chronic dialysis

62-microglobulin Scrapie protein precursor

Scrapie protein 27-30

Creutzfeldt-Jakob

disease, etc

eg, Leu 102

Gerstmann-Stratissler-Scheinker

33-35, cellular form syn-

drome ACal

(Pro)calcitonin

AANF

Atrial natriuretic factor

(Pro)calcitonin

In medullary carcinomas of the thyroid Isolated atrial amyloid

AIAPP

Islet amyloid polypeptide

In islets of Langerhans, diabetes type II; insulinoma

Abbreviations: FMF, familial Mediterranean fever; apoA1, apolipoprotein Al. Modified and reprinted with permission.15

dosis with febrile urticaria, the Muckle Well’s syndrome,19,20and spontaneous or experimental amyloidosis in animals. 2,3These forms of amyloidosis could therefore also be called AA amyloidoses. Different genetic variants of transthyretin (TI’R), previously termed prealbumin, are associated with the autosomal dominant familial amyloid polyneuropathies (FAP) and cardiomyopathies (FAC). 5,21-23 Normal ITR is associated with systemic senile amyloidosis.24 Two other serum proteins are also associated with FAP. A variant (Arg 26) of apolipoprotein AI represents the fibril protein in FAP originated in Iowa.25 Variant gelsolin (Asn 15), an actin-modulating protein, plays the same role in FAP of Finnish origin.26

A variant cystatin C (Gln68), an enzyme inhibitor, is the fibril protein precursor in inherited cerebral hemorrhage with amyloidosis, Icelandic type.27 Members of a Dutch family with a similar clinical picture are affected by amyloid made up of a variant form (Gln22) of the amyloid l3 protein, a 42-amino acid fragment of l3 protein precursor @PP), in their cerebral vessels.** Amyloid l3protein, derived from apparently normal PPP, makes up the amyloid in cerebral vessels, plaque cores, and helical filaments in Alzheimer’s disease and Down’s syndrome.29 The l3 protein is expressed in the central nervous system but also at extracerebral sites and may possess protease inhibitor properties. Normal p2-microglobulin makes up the fibrils

GUNNAR HUSBY

70

in amyloidosis associated with long-term dialysis treatment for renal failure.30231This amyloid affects mainly structures of the locomotor system such as the carpal tunnel, joints, and bone, but systemic distribution of Pz-microglobulinderived amyloid is also reported. Several hormones are known to form amyloid. The first to be demonstrated was a calcitoninlike molecule that formed amyloid fibrils locally in medullary carcinomas of the thyroid and their metastases.32 Atria1 natriuretic factor and islet amyloid polypeptide make up amyloids in isolated atria1 amyloidosis of the heart”” and islet (of Langerhans) amyloidosis associated with diabetes type II and insulinomas.24 Insulin also has been shown to make up amyloid fibrils, but so far only in the degu, a rodent.34 Finally, another rodent, the senescence-accelerated mouse, inherits amyloidosis by a genetic variant (Gln 5) of apolipoprotein AIIX5 Amyloidosis clearly is heterogeneous, not only with respect to clinical expression and protein composition but also to the functional aspect of the various protein precursors. However, there are exceptions to these clinicalchemical correlations. For example, AA protein from patients with “idiopathic” systemic amyloidosis3’j as well as from a patient with monoclonal gammopathy3’ has been shown by amino acid sequencing. Such cases illustrate the advantage of classifying amyloidosis by the fibril protein (Table l).‘”

PATHOGENESIS

The mechanisms by which the various soluble precursor proteins are converted to insoluble aggregates with the unique morphology of amyloid fibrils and deposited in the different target tissues are not clarified. Furthermore, the predilection of certain amyloid fibrils for particular tissues or organs, often distant from the cells actually producing the fibril protein precursor, also remains a mystery. Best studied are the pathogenetic mechanisms in reactive, AA type amyloidosis because this form of amyloid is readily induced in experimental animals, and spontaneous AA amyloidosis has been shown in a variety of warm-blooded animals, ranging from birds to humans.38 Inherited amyloidoses in humans as well as in animals has also pro-

vided opportunities to study genetic factors in amyloidosis. It is generally agreed that the following pathogenic factors are important in amyloidosis. Availability of Precursor Protein It is conceivable that amyloid is formed by amyloidogenic precursor protein that is present in excess amounts, as a consequence of either increased production or decreased catabolism. SAA is increased in those chronic inflammatory diseases (eg, rheumatoid arthritis [RA]) that stimulate the acute-phase response but not in those that do not (eg, scleroderma), and the former diseases are strikingly more often associated with reactive AA amyloidosis than the latter.“” In AL amyloidosis associated with monoclonal gammopathies and in &-microglobulin amyloidosis associated with chronic hemodialysis, excess precursors could be a predisposing factor. Structural Properties of Amyloid Precursor Protein

Normal TTR is associated with benign systemic senile amyloidosis occurring in old age and is capable of forming amyloidlike fibrils in vitro.4UPoint mutations of the TTR gene lead to production of TTR molecules with single amino acid substitution at different positions in the molecule.2’ A variety of such mutant TTR proteins are associated with the more severe, inherited amyloid polyneuropathies or cardiomyopathies with much earlier onset of disease. It is thus conceivable that certain amino acid substitutions in TTR enhance its capacity to form amyloid. AA amyloidosis affects only a minority of patients with chronic inflammatory disorders such as RA, although the majority of patients have chronically increased SAA levels.5,39Additional pathogenetic factors are required for amyloidosis to develop. SAA is polymorphic (Table 2), meaning that more than one gene codes for the protein.41l42 In the mouse, it has been shown that SAA2, one of two defined SAA protein variants in the circulation, forms amyloid whereas SAA1 does not,43 although SAA2 and SAA1 are expressed at the same magnitude in the acute-phase response.44 Furthermore, in a strain of mice resistant to induced amyloido-

71

AMYLOIDOSIS

Table 2: Partial Aminoterminal

Amino Acid Sequence of SAA and AA Proteins From Humans, Mice, Mink, and Horses 5

Human

SAA

Human

AA

Mouse

Phe

Phe

10

Arg

Ser

Ser

Phe

Leu

_

_

_

_

_

_

_

SAA1

Gly*

-

-

-

-

Val

Mouse

SAA2

Gly

-

-

-

-

Mouse

AA

Gly

-

-

-

-

Mink SAA1

PCA

Trp

Tyr

-

-

Phe

Mink SAA2

PCA

Trp

Tyr

-

-

Phe

Mink AA

PCA

Trp

Tyr

-

-

Phe

Horse SAA1

Leu

Leu

-

-

-

Horse SAA2

Leu

Leu

-

-

Horse AA

Leu

Leu

-

-

Reference

15

Gly

Glu

Ala

Gly

Ala

Arg

Asp

Met

Trp

_

_

_

Phe _

Asp _

_

_

_

_

_

_

109 110

His

-

-

-

Gln

-

-

Gly

-

-

-

111

k

Gly

-

-

-

Gln

-

-

Gly

-

-

-

111

E

-Gly -

-

-

-

Gln

-

-

Gly

-

-

-

-

-

Ile

Gln

-

-

Trp

-

-

Tyr

113,114

-

-

-

-

-

Trp

-

-

Tyr

113,114

-

-

-Val -Val

Gln

-

Gln

-

-

Trp

-

-

Tyr

115

-

-

-

Ala

Arg

-

Thr

Trp

-

-

Ile

116

-

-

-

-

Ala

Arg

-

Thr

Trp

-

-

&

116

-

-

-

-

Ala

Arg

-

Thr

Trp

-

-

&J

117

112

NOTE. Alignment is made to maximize homology. *Only the amino acid residues that differ from those of human SAA and AA are shown for mouse, mink, and horse

sis, the expression of the amyloidogenic SAA2 gene is defective. 45 Recent studies have similarly disclosed amyloidogenic and nonamyloidogenic molecular species of SAA in other experimental animals, including the mink, horse (Table 2), and rabbit, and possibly also in humans.39 A structural subgroup of immunoglobulin light chains, namely A VI, are associated with amyloidosis far more often than statistically expected.3,46 Furthermore, the Bence Jones proteins that are known to be associated with AL amyloidosis are more prone to form amyloid fibrils in vitro than those that are not.2,47 Defective Degradation of Precursor

Chemical analyses of purified amyloid proteins of different chemical composition have shown that in most instances they comprise a smaller or larger fragment of their precursors, pointing to incomplete degradation.2,48 It has been suggested that fragmentation of precursor protein makes it more prone to form fibrils. This suggestion is supported by in vitro studies in which limited proteolysis of both SAA and Bence Jones proteins resulted in the formation of Congo red-positive fibrils with an electron microscopic appearance similar to those deposited in vivo.2 A defective proteolysis resulting in incompletely degraded precursor proteins may therefore be implicated in amyloidosis.39 Of interest in this respect is the observation of a defective reticuloendothelial system in mice during induction of experimental amyloidosis.49

However, some amyloid fibril proteins (eg, TTR, B2-microglobulin, and in some cases AA) are identical in size to their precursors, showing that fragmentation is not an absolute prerequisite for fibrillogenesis. 39Furthermore, the degradation of SAA may be a postfibrillary event,5Oie, the protein precursor could be degraded after the fibrils have been formed. Amyloid-Enhancing Factor and Glycosaminoglycans

Amyloid-enhancing factor (AEF) is a poorly defined material that probably consists of both protein and carbohydrate; is induced in the spleen, liver, and kidney during persistent inflammation; and is probably synthesized and secreted by reticuloendothelial cells in these organs.10v51,52AEF consistently precedes the occurrence of amyloid induced in these organs in the mouselo and hamster.53 Intravenously administered AEF has been shown to shorten the induction time of experimental amyloidosis from weeks to 24 to 48 hours, possibly by altering the degradation of SAA and its processing to fibrils.54 AEF extracted from human organs laden with AA, AL, and TTR-related amyloid enhances experimental murine AA amyloidosis.55 Glycosaminoclycans and possibly proteoglycans consistently occur in the tissues in close temporal and morphological relation to amyloid deposition11,56,57and may account for the carbohydrate moiety in AEF.5h Glycosaminoglycans identified as chondroitin sulphate, dermatan

72

GUNNAR HUSBY

sulphate, and heparin/heparan sulphate are specifically copurified with amyloid fibrils,” in support of the theories of Niewold et aP3 and Snow et aIs that together with protein they constitute amyloid. The large negative charge of the glycosaminoglycans indicates an effect on precursor protein folding and incorporation into the fibrils.56 Protein AP-The

Amyloid P Component

Protein AP is an a-glycoprotein that is invariably present in amyloid deposits, regardless of the chemical nature of amyloid fibrils and the clinical type of amyloidosis.58-60AP is not part of the amyloid fibrils but is closely bound to them in a calcium-dependent fashion.58v59A normal plasma pentraxin protein, SAP, identical to protein AP in structure and binding properties, is its precursor.59,61,62Furthermore, an imaging technique using radiolabeled SAP is successfully used in the in vivo diagnosis of various types of human amyloidosis.60 Although the serum concentration of SAP is not increased in the acute phase or in patients with amyloidosis, the synthesis of the protein is increased in amyloidotic patients, indicating a specific role in amyloidogenesis. Purified human AP inhibits proteolytic activity of elastase in vitro.63 This may have implications in amyloidogenesis because AP could inhibit the enzymatic breakdown of amyloid precursor protein at the site of fibril deposition. A DNA polymorphic site 5’ to the SAP gene is significantly associated with AA amyloidosis in juvenile RA (JRA), further suggesting an active role of AP in amyloidogenesis.64 An animal model for AA amyloidosis, the Syrian hamster, clearly illustrates a role for SAP in amyloidosis. Female protein is a hamster pentraxin and an analog of human SAP.65,66The female protein gene is regulated by mediators of inflammation but also by sex steroid hormones, hence unstimulated female hamsters have high serum concentrations of female protein which decrease with inflammation (ie, negative acute-phase protein). In contrast, serum female protein levels are low in normal males but increase in the acute phase.65 Unstimulated female hamsters frequently develop amyloidosis, a significant cause of early death. Male hamsters are able to develop casein-induced

amyloidosis, but less readily than females, and indeed the female sex hormone diethylstilboestrol both increases serum FP and enhances experimental amyloidosis in males. CLINICAL AMYLOIDOSIS

SYNDROMES

Because deposition of amyloid may take place in practically any organ or tissue, a large number of partly overlapping clinical syndromes related to the systemic forms of amyloidosis have been described (Table 1) in addition to a variety of clinical features related to localized/ organ-limited amyloidoses. It is difficult to classify amyloidosis by its clinical expression, although it has been attempted many times during the last 150 years.1,2,3,9,67,68 The classification of amyloid and amyloidosis based on the fibril protein, when identified by its amino acid sequence (Table l), is therefore of great value in clinical practice as well as scientifically.‘5 A description of the most important amyloidosis syndromes in relation to their fibril protein correlates follows. Idiopathic and Myeloma-Associated AL Amyloidosis

The mean age at diagnosis of AL amyloidosis is approximately 60 years; idiopathic and myeloma-associated amyloidoses have similar organ distribution.67969The most severe clinical consequences of AL amyloidosis are caused by accumulation of amyloid in the heart and kidneys.67,69-71 Interstitial and vascular amyloidosis of the heart leads to congestive heart failure, conduction disturbances and angina pectoris, and eventually myocardial infarction and causes about half of the deaths (Table 3). Decreased voltage on electrocardiography (ECG) is common. Patients are hypersensitive to digitalis, which may cause fatal arrhythmias. Glomerular and vascular amyloidosis of the kidneys with consequent nephrosis and/or renal failure causes one third of the deaths.17,‘0 Pulmonary amyloidosis is common, causing cough and dyspnea. Amyloidosis of the skin with purpura, amyloid papules, or tumors is seen in nearly half of patients. Some patients develop peripheral neuropathy (10%) and carpal tunnel syndrome (20%) in addition to autonomic disturbances (eg, orthostatic hypotension). Characteristics of AL amyloidosis are

73

AMYLDIDOSIS

Table 3: Clinical Characteristics

of AL

Amyloidosis Heart Cause of death in = 50% of AL amyloidosis Restrictive cardiomyopathy Congestive heart failure Conduction disturbances Angina pectoris-myocardial

infarction

Low voltage on electrocardiogram Digitalis hypersensitivity

K-to-k

Lungs (90%)

ratio,

apprOXiInately

2: 1 in mydOmatOSiS,

is reversed (1:2) in AL amyloidosis, reflecting the more amyloidogenic nature of Alight chains. In particular, the variable subgroup VI of h light chains is strongly associated with amyloidosis.17

Cough Dyspnea Skin (40%) Purpura Papules

Reactive AA Amyloidosis

Tumors Peripheral neuropathy (10%) Carpal tunnel syndrome (20%) Autonomic disturbances orthostatic hypotension, etc Macroglossia

bone marrow, M components in serum, and Bence Jones proteinuria are frequent findings in idiopathic AL amyloidosis, indicating that this disorder belongs to the immunocyte dyscrasias resulting from the same basic pathogenetic mechanisms as myelomatosis. The major difference between them is the osteolytic lesions of myelomatosis, which are absent in idiopathic AL amyloidosis. Another difference is that the

(20%)

Bleeding due to vasculopathy and coagulation factor X deficiency Amyloid arthropathy Mainly large joints (eg, “shoulder pad

sign”)

macroglossia in 20% of patients and amyloid arthropathy affecting mainly large joints (5% or less). The “shoulder pad sign” caused by amyloid infiltration of the shoulder joint is an almost pathognomonic sign.72 Factor X deficiency in AL amyloidosis appears to be caused by the high affinity of AL-type amyloid fibrils for the coagulation factor X, which may therefore be trapped in the amyloid substance. 73 Together with increased fibrinolysis and amyloid infiltration of blood vessels, factor X deficiency may lead to severe hemorrhaging.67 Amyloidosis of the liver causes organ enlargement rather than functional disturbances. Gastrointestinal amyloidosis may be associated with malabsorption, malnutrition, obstruction, diarrhea (disturbed motility), and bleeding. Amyloid in the spleen and endocrine glands is often present, but severe symptoms are infrequent. Localized, so-called tumor-forming, AL amyloid has been found in various organs, of which the respiratory and genitourinary tracts and the skin are most frequent.*’ Increased numbers of plasma cells in the

Reactive (secondary) amyloidosis is associated mainly with long-standing infectious or noninfectious inflammation and less frequently with cancer, mainly renal cell carcinoma or Hodgkin’s disease. 5 In many countries where the incidence of chronic infections such as tuberculosis and leprosy has declined, reactive amyloidosis is mostly caused by chronic rheumatic diseases. Amyloidosis occurs in about 3% to 10% of living patients with RA, JRA, ankylosing spondylitis, and occasionally Reiter’s disease and psoriatic arthropathy. Interestingly, AA amyloidosis is extremely rare in systemic connective tissue diseases such as systemic lupus erythematosus, dermatomyositis, systemic sclerosis and Sjogren’s syndrome.74 The last three diseases are associated with lower serum concentrations of SAA than, for example, RA.39 Furthermore, amyloidosis is quite prevalent in Crohn’s disease, which stimulates acute-phase proteins, and is infrequent in ulcerative colitis, which does not stimulate such proteins.39 A marked geographic difference in the prevalence of AA amyloidosis in JRA, high (5% to 10%) in European countries and low (0.1%) in the United States, has been attributed to the more frequent occurrence of urinary tract infections caused by Escherichia coli in Europe.75 E coli endotoxin is a highly potent inducer of the acute-phase response as well as of experimental amyloidosis. Arthritic patients with prominent systemic disease activity are more prone to develop amyloidosis than those with milder disease, but

GUNNAR HUSBY

74

the development of amyloidosis in individual cases cannot be predictede5 HLA studies have failed to disclose markers for reactive amyloidosis. Some reports suggest that men with RA are more susceptible to AA amyloidosis than women.5 AA amyloid has a tendency to localize in small vessels and parenchymal organs (Table 4). Renal disease, often with the nephrotic syndrome and/or renal failure, is the chief manifestation and the major cause of death. In a series of 189 RA patients with AA amyloidosis reported by Wegelius et a1,76only 7 (4%) lacked demonstrable clinical signs of renal involvement, and all JRA patients in a series of 51 who developed amyloidosis had proteinuria at the time of diagnosis. ” Proteinuria in RA patients should always raise the diagnostic consideration of amyloidosis. Hematuria occurs, but less often. Hypertension is uncommon in adult-onset RA with amyloidosis but is found in about half of the patients with amyloidosis associated with JRA.” Renal vein thrombosis is frequently found postmortem. Infiltration of blood vessels by amyloid, particularly in the gastrointestinal tract, can result in severe, sometimes life-threatening, bleeding and malabsorption. AA amyloidosis of the liver is frequent and causes organ enlargement rather than functional disturbance. AA amyloid may also affect the spleen, endocrine glands, and heart without causing severe symptoms. Arthropathy and carpal tunnel syndrome are not features of AA amyloidosis but are characteristic of both AL and 13z-microglobulin-associated amyloidoses. No laboratory test (except biopsy) Table 4: Clinical Features Common to AL and AA Amyloidoses Weakness, fatigue and weight loss (most prominent in AL amyloidosis) Kidneys: Cause of death in the majority of AA amyloidosis and in l/3 of AL amyloidosis. Nephrosis and/or renal failure Gastrointestinal tract: Malabsorption,

malnutrition,

obstruction, diarrhea (disturbed motility), bleeding Liver: Mainly enlargement,

rarely functional distur-

bance Spleen, endocrine glands: Severe symptoms infrequent

can distinguish between arthritic patients with and without reactive amyloidosis.5 AA amyloidosis has been described in some patients without any underlying disorder, thus believed to have idiopathic amyloidosis.39 However, most reported patients had high erythrocyte sedimentation rates or other signs of acutephase response, and more studies are needed to prove the existence of idiopathic, AA amyloidosis. FMF With Amyloidosis

Amyloidosis associated with FMF is the only form of systemic amyloidosis known to be inherited as a recessive trait.‘s Like other forms of AA amyloidosis, nephropathy is the most important feature and a significant cause of deaths. FMF is characterized by attacks of fever, peritonitis, pleuritis and synovitis with onset during childhood, affecting mainly Sephardic Jews, Anatol Turks, and Armenians with origin in the Mediterranean area. The prevalence as well as the disease course of amyloidosis in FMF is highly heterogeneous in the different ethnic groups.78 It appears that the febrile attacks and amyloidosis are inherited independently, and marked heterogeneity with regard to the SAA genes has also been observed among FMF patients.79 A threonine for phenylalamine substitution at position 69 of protein AA involving all three bases of the codon has been observed in one case of FMF amyloidosiGO but not confirmed in others. Therefore, the molecular basis for FMF-associated amyloidosis is not clear, and environmental factors may also be important. Dominantly Inherited Amyloidoses

Point mutations causing single amino acid substitutions in various amyloid protein precursors are associated with a heterogeneous group of familial amyloidosis inherited dominantly (Fig 1).22,81The majority of cases are related to different genetic variants of TTR. Neuropathy, cardiopathy, nephropathy, and vitreous opacities are the most important clinical problems and occur in a variety of combinations but also as more or less single clinical entities. Amyloid made up by genetic variants of other proteins (Table 1) may show similar clinical characteristics in addition to causing cerebral amyloid

75

AMYLOIDOSIS

2. 3.

4.

Fig 1: Polarization microscopy of Congo redstained section from a rectal biopsy showing birefringent

vascular

(original magnification

and interstitial

amyloid

x 160).

angiopathy and lattice cornea1 dystrophy. Some examples of amyloidoses inherited dominantly, geographic origins, and protein correlates are listed in the following. The syndromes are described in more detail by Benson and Wallace22 and Glenner and Murphy.81 1. Familial amyloid polyneuropathy related to TTR methionine 30, Portugal (Table 1). This is the most widespread form of hereditary amyloidosis related to variant TTR and represents the most common features of hereditary amyloidosis, first reported in North Portugal by Andradees2 Other families have later been detected in many countries including Sweden and Japan, but all cases may be linked to one original mutation of codon 30 in the TTR gene resulting in a methionine-for-valine substitution in this position of TTR.22 The dominating clinical features are sensorimotor

8.

9.

neuropathy, particularly of the lower limbs, and autonomic disturbances severely affecting the gastrointestinal tract with diarrhea, weight loss, and sometimes death by malnutrition. Interestingly, there are significant interfamily variations in both clinical expression and age of onset which varies from approximately 20 to 90 years. Aged symptom-free gene carriers are reported, even among the very few persons known to be homozygous for the mutant TTR gene, showing that other genetic and possibly environmental factors are involved etiologically.83 Familial amyloid polyneuropathy related to TTR serine 84, Indiana/Switzerland.22 Familial amyloid polyneuropathy related to TI’R histidine 58, Maryland/Germany.84 Familial amyloid caridomyopathy and neuropathy related to TTR alanine 60, Appalachian Indians.22 Familial amyloid cardiomyopathy related to TTR methionine 111, Denmark.21q85 Familial amyloid polyneuropathy related to apolipoprotein AI arginine 26, Iowa.Z5 Familial amyloidosis with lattice cornea1 dystrophy related to gelsoline aspartic acid 187, Finland.26,86 Hereditary cerebral haemorrhage with amyloidosis related to cystatin C glutamic acid 58, Iceland,27 and to amyloid B-protein glutamic acid 618, the Netherlands.28 The Muckle Well’s syndrome (nephropathy, nerve deafness and urticaria) related to protein AA.r9a20

Alzheimer’s Disease and Down’s Syndrome

The presenile dementia described by Alzheimer is probably the most common form of amyloidosis.81 Cerebral amyloid is deposited extracellularly as Alzheimer’s plaques and in the wall of cerebral vessels. Even the intraneuronal neurofibrillary tangles are made up of paired helical filaments with the typical B-pleated sheet structure characteristic of amyloid. The amyloid l3 protein in Alzheimer’s disease derives from the BPP whose gene resides on chromosome 21. The same type of amyloid is occasionally seen in senile dementia.81 Similar manifestations of cerebral amyloid

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GUNNAR HUSBY

composed of the amyloid l3 protein is seen in Down’s syndrome patients who are over 40 years old.sl Down’s syndrome is associated with trisomy of chromosome 21, and it is conceivable that this leads to an overproduction of PPP. ORGAN MANIFESTATIONS

Heart

Cardiac amyloidosis manifest mainly as cardiomyopathy, but also with conduction disturbances and coronary heart disease (Table 3) is a particularly severe manifestation of AL17,67,s7 and of certain forms of inherited amyloidosis.22 Among the latter, the Danish TTR Met 1112’ and the Appalachian TTR Ala 6022 forms are the most important. Cardiac amyloidosis is also a major manifestation of senile systemic amyloidosis related to normal TTR40 and senile isolated atria1 amyloidosis related to the polypeptide hormone atria1 natriuretic factor.33 In general, the senile cardiac amyloidoses are benign. AA amyloidosis of the heart localizes mainly to the vasculature without causing major problems. The Respiratory Tract

Amyloid may be deposited in any part of the respiratory system, from the nasal cavity to the pulmonary parenchyma and hilar glands. The clinical consequences are most severe in AL amyloidosis.67 Localized (nodular) AL amyloidosis is quite frequent and has a much more favorable prognosis but sometimes requires surgical remova12J7 Kidney and Urinary Tract

The most severe manifestation is renal amyloidosis, the major cause of death in AA amyloidosis2J and in AL and hereditary amyloidoses related to variants of TTR and apolipoprotein AI.2,67,8oAtfected patients have proteinuria and/or nephrotic syndrome and frequently develop fatal renal failure. Renal biopsies show deposition of amyloid in glomeruli as well as peritubular, vascular, and interstitial localization. The Gastrointestinal Tract

The entire gastrointestinal tract is a common target of amyloid deposition, making it an accepted biopsy site for diagnosis (Fig 1). Intesti-

nal amyloid causes motility disturbances with diarrhea or constipation, malabsorption, bleeding, and perforation (Table 4).2,67Nutritional disturbance due to macroglossia in AL amyloidosis and altered intestinal motility in the inherited neuropathies are common causes of death. Fatal gastrointestinal bleeding due to AA amyloidosis has been observed in several patients with rheumatic disease.5 The Endocrine System

Fibrils made by hormone-related or -derived polypeptides are seen locally in some endocrine tumors. Calcitonin-related amyloid in medullary carcinoma of the thyroid and islet amyloid polypeptide in diabetes type II and insulinomas are best known. Endocrine glands are also affected by systemic AA and AL amyloidoses.5J7 Skin

Amyloid deposits are generally present in subcutaneous fat in both AL and AA, as well as inherited systemic amyloidoses, and thin-needle aspirates of abdominal fat (Fig 2) have become useful for histological diagnosis.88 In addition, cutaneous amyloid is a common feature of AL amyloidosis in the form of papules, nodules, or purpura.67 The skin is also the site of localized amyloid, eg, lichen amyloidosus.8y The Locomotor System

The deposition of amyloid in the locomotor system is perhaps most common in 132-microglobulin-related amyloidosis affecting patients on long-term renal dialysis. These patients develop carpal tunnel syndrome, arthropathy, and cystic bone lesions, sometimes with pathological fractures, particularly when on dialysis for more than 8 years. Ordinary hemodialysis is not able to remove 132-microglobulin from plasma. Although p2-microglobulin-related amyloidosis is undoubtedly of systemic nature, structures of the locomotor system show a marked predilection for amyloid deposition.9g26T90 Also characteristic of AL amyloidosis, although not as frequent, are the carpal tunnel syndrome (20%), peripheral neuropathy (10%) arthropathy, and myopathy ( < 5%).17,67 Another infrequent complaint is jaw claudication, which should be considered in the differential

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AMYLOIDOSIS

clinical significance of such amyloid deposits, possibly originating from local tissue proteins, is not clear.3

DIAGNOSIS

Fig 2:

Polarization

ous, abdominal red showing

microscopy of a subcutane-

fat smear stained with Congo

marked deposition

amyloid compatible Microphotograph Per Westermark,

of birefringent

with systemic amyloidosis.

kindly provided

by Professor

Linkiiping, Sweden.

diagnosis of temporal arthritis/polymyalgia rheumatica.91 Erosive arthritis occurs in some patients with hereditary amyloidosis, ie, of the Indiana and Iowa kindredsz2 Because amyloid arthropathy often has an inflammatory appearance, it may mistakenly be diagnosed as a rheumatic disorder. However, the joint fluid is generally noninflammatory, sometimes with amyloid-containing synovial debris.” Localized “microdeposits” of amyloid in structures of the locomotor system occur with increasing frequency in aged people, mostly in menisci of the knee, joint capsules, and intervertebral discs, sometimes associated with calcium pyrophosphate deposition or osteoarthrosis. The

The diagnosis of amyloidosis is based on the demonstration of tissue deposits of amyloid. Therefore, an absolute prerequisite for diagnosis is clinical suspicion in relevant situations. It is regrettable that the diagnosis of amyloidosis is often missed during life and is not evident until autopsy. The clinician should realize that AL amyloidosis may occur without an underlying predisposing disorder or in association with monoclonal gammopathies; that rheumatic disorders, long-standing or recurrent infections, and certain malignancies predispose to reactive, AA amyloidosis; and that a family history of amyloidosis may point to inherited disease. Unexplained manifestations that should alert the clinician to consider amyloidosis are loss of weight, fatigue, proteinuria with or without renal failure, restrictive cardiomyopathy, gastrointestinal or respiratory problems, hepatomegaly, cutaneous affections, including purpura, and neuropathy/carpal tunnel syndrome. Rectal tissue (Fig 1) which includes the submucosal vessels is a highly representative biopsy material in systemic amyloidosis.5 Bleeding may occur following this procedure, but severe blood loss is infrequent. In recent years, needle aspiration of abdominal subcutaneous fat (Fig 2) which is less invasive than rectal biopsy, is increasingly used for diagnosis.88 Other potential biopsy sites include the kidneys, liver, spleen, peripheral nerves, or skin, but the risk for complications must be considered. The carpal tunnel syndrome may be the initial finding in systemic amyloidosis. All tissues removed at surgery for this condition should therefore be examined for amyloid. Examination of alkaline Congo red-stained tissue sections or aspirated fat smears in a polarizing microscope shows the applegreen/ yellow birefringence characteristic of amyloid deposits; this is the histochemical method of choice (see Figs 1 and 2).2*67Immunohistochemical techniques using specific antisera to classify the various amyloid fibril proteins are increas-

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ingly used but are not available routinely. Electron microscopy may confirm the diagnosis. The strong calcium-dependent affinity of protein AP/SAP for amyloid fibrils of any protein type can be used diagnostically.““2 Radiolabeled SAP injected intravenously will rapidly and specifically localize to the amyloid deposits yielding high-resolution scintigraphic images. This experimental technique is highly promising. Other laboratory tests in the hereditary amyloidoses include analysis of DNA or its protein product to detect genetic variants of proteins known to make up amyloid.22 Restriction fragment length polymorphism combined with in vitro amplification of genes using the polymerase chain reaction technique is a sensitive tool to detect gene carriers and thereby individuals at risk, even before birth.93 Radionuclide imaging using calcium-seeking isotopes (eg, 99mT~), echocardiography, bone marrow examination, and demonstration of monoclonal immunoglobulins in serum or urine are used in the clinical work-up of patients with amyloidosis.

In general, amyloidosis is an incurable progressive disease. The etiology and pathogenesis are multifactorial, and prospective, controlled interventions are sparse. Prognostic heterogeneity among patients with hereditary amyloidoses makes genetic counselling difficult.94 The following therapeutic approaches are suggested: 1. Reduce availability of precursor protein to prevent or slow down amyloid formation. 2. Dissolve amyloid deposits in vivo. 3. Treat affected organs.

febrile attacks as well as AA amyloidosis and is effective in the treatment of established amyloidosis.98 In controlled trialsy9 melphalan in combination with corticosteroids improves the symptoms and signs and possibly survival of AL amyloidosis. Two studies using historical controls indicate that colchicine may exert some additional effect on AL amyloidosis when combined with melphalan and prednisolone.Y”~‘“” These treatments may work by reducing the number of cells producing the monoclonal immunoglobulin light-chain amyloid precursor or by hampering their protein production or secretion. A diet in which the only source of fat is fish oil high in o-3 polyunsaturated fatty acids has been shown to retard the progression of azocaseininduced AA amyloidoses in mice.101 Because fish oil diets may also suppress the activity of chronic inflammation, a prophylactic or retarding effect on human AA amyloidosis associated with arthritis is possible. Plasmapheresis has been tried in the amyloidoses related to genetic variants of TTR, but without documented benefit. Of more interest are the recently performed liver transplantations in such patients to remove the site of variant TTR production and replace it with a liver harboring only normal TTR genes (Drs G. Holmgren and L. Sten, Umel, Sweden, personal communication). Renal transplantation ameliorates articular complaints and retards the development of amyloid bone cysts in 132-microglobulin-associated amyloidosis.ioZ Restoration of the normal clearance of B,-microglobulin may explain the therapeutic effect.

Reduction of Amyloid Precursor

Dissolution of Amyloid Deposits In Vivo

In reactive, AA amyloidosis, the synthesis of amyloid precursor SAA can be reduced by turning down stimulated hepatic acute-phase protein production. 39This is achieved by effective treatment of the underlying inflammatory or neoplastic disorder. Facing the dubious prognosis of amyloidosis, drastic therapeutic intervention may be considered. Cytotoxic drugs improve the prognosis of amyloidosis associated with both adulty5~y6and juveniley7 RA but are associated with potentially hazardous adverse effects. Colchicine treatment of FMF prevents

Dimethyl sulfoxide (DMSO) partially dissolves amyloid fibrils in vitro, and treatment of amyloidotic mice with DMSO reduces the amount of amyloid.io3 DMSO has been tried in treatment of human AA, AL, and TTR-related amyloidoses. Some patients benefit,” but results of controlled studies are lacking.

THERAPEUTIC ASPECTS

Organ-Directed Therapy

Renal transplantation is increasingly used in amyloid nephropathy, particularly the AA type,“”

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with increased survival and improvement of quality of life.lo4 Heart transplantation has been reported in a few patients, mostly with AL amyloidosis.90 Five of six patients receiving cardiac transplants were alive 21 5 12 months after transplantation. Patients with cardiac amyloid have increased sensitivity to digitalis, and calcium channelblocking agents may aggravate heart failure. Amyloid appears to bind such agents in vitro and possibly in vivo,90 and they should be used with caution. PROGNOSIS

The prognosis of amyloidosis depends on the localization and progression of amyloid tissue deposition. Survival time is largely dependent on the time of diagnosis, which varies significantly among patients. Systemic amyloidosis is a serious condition with a high mortality rate. AA amyloidosis may cause up to 47% of deaths in European patients with JRA.lo5 A Finnish report concluded that amyloidosis was the cause of death in 8% of adult RA patients coming to autopsy.io6 On the other hand, reactive AA amyloidosis has a more favorable outcome than previously thought. Data from Finland and the United States indicate that survival time after

diagnosis of amyloidosis associated with RA is 4 to 5 years.67*76In JRA with amyloidosis, survival may be even better with cytotoxic treatment, namely 8 to 9 years77*105 or even longer.97 Individual variation in survival time of AA amyloidosis has been observed,lo7 ranging from a few weeks to 20 years. The prognosis of AL amyloidosis is less favorable. Survival rates are less than 2 years for idiopathic AL amyloidosis and 7 months or less for AL amyloidosis with myeloma.87,108Again, survival time of individual patients varies widely, from weeks to 5 years or more.69 Cardiac amyloid is the most common cause of death and the major determinant of prognosis among AL patients.lo8 In the hereditary amyloid polyneuropathies and cardiomyopathies related to variants of TTR, there are wide variations in course and prognosis among different affected families as well as between individual gene carriers in the same family. Some patients die of caxechsia before they are 40 years old, whereas others are in good health at 90 years.94 ACKNOWLEDGMENT The author thanks Marit Espejord for skillful secretarial assistance.

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