Primary amyloidosis

1. chron. Dis. 1966, Vol. 19, pp. 1145-l 156. Pergamon

PRIMARY THOMAS

Departments

Press Ltd. Printed in Great Britain

AMYLOIDOSIS

F. WHAYNE,JR., PETERM. BURKHOLDER and E. L~VELL BECKER

of Medicine and Pathology, The New York Hospital, Cornell Medical Center, New York (Received 18 May

1966)

INTRODUCTION

occurs without underlying chronic disease and reflects the deposition of an incompletely defined substance in several organs of the body. This report is concerned with a description of the signs, symptoms, classification, and possible etiology of this disease. It presents an unusual case of primary amyloidosis and reviews the literature as well as the experience at The New York Hospital. PRIMARY

amyloidosis

REPORT

OF

CASE

A 61-yr-old Caucasian man first entered The New York Hospital on December 4, 1964 complaining of shortness of breath, ankle swelling, and easy bruisability. He had been in good health until 13 months before admission when he noticed progressive weakness and ankle edema. During this period, marked dyspnea developed with anorexia and a 40-lb weight loss. He was treated with digoxin, low salt diet and diuretics, but heart failure, low pulse pressure and weak apical impulse persisted. Qccasionally, bright red blood was noted in his stools. Approximately ten months before admission, the patient complained of dysuria and hesitancy. At another hospital he was found to have a large prostate. Urethral dilatation and a biopsy o,f the prostate were performed. The histological changes were compatible with amyloid infiltration, presumably of a diffuse primary type. Ecchymoses under the left eye were first noted eight months before admission. Bence-Jones protein was found in the urine, and plasma cells were increased in the bone marrow. Amyloidosis associated with multiple myeloma could not be excluded. Sarcolysin, 6 mg per day, was given for 12 days in November, 1964, with 2 mg daily maintenance until admission to The New York Hospital on December 4, 1964. The patient stated that he had frequent pneumonias and possibly untreated tuberculosis. On admission,

the patient had a blood pressure of 90/ 70 mm Hg, respirations 25 per minute, coarse fingernails, decreased skin turgor, diffuse ecchymoses, especially around the eyes, with marked purpura even after minimal trauma, enlarged tongue (Fig. l), bilateral pleural effusions, gallop rhythm, 4+ ankle edema and impaired distal pain sensation in all extremities. b$ Grant No. AM 05009 from the National Institute of Arthritis and Metabolic Diseases and in part by Grant No. FR 47, Division of General Medical

This study was supported Sciences, National

Institutes

of Heilth. 1145

1146

THOMAS F.WHAYNE,JR.,PETER

M. BURKHOLDER and E. LOVELL BECKER

The hematocrit which was 43 per cent fell rapidly to 30 per cent. The white blood cell count was 6800 cells per cubic mm and decreased to 450 cells per cubic mm within a week. Platelet count on admission was 53,000 per cubic mm and then rose over a two week period to 223,000 per cubic mm. There was 4+ proteinuria and stool guaiacs were positive. Small diffuse bleeding points were seen on proctoscopy. Chest X-ray was interpreted as fibrosis in the right upper lung field, with streaky linear densities and small bilateral pleural elfusions, and cardiomegaly. Low amplitude QRS complexes with slight ST segment abnormalities were seen on the electrocardiogram. There was an increased number of plasma cells with plasmacytes of abnormal appearance in the bone marrow. Electromyogram con!%-med distal peripheral neuropathy. Thrombocytopenia with poor prothrombin consumption was present. Turberculin skin tests were negative. The basal metabolism rate was -23 per cent and urea clearance was 11 ml per minute. Urine protein excretion was 4.1 g per 24 hr and the selectivity pattern, as determined by an immunochemical diffusion pattern, gave a theta of 63.49”. This represents an intermediate type of glomerular selectivity in which there is moderate pathology of the kidney and little or no response to steroid therapy can be expected [l]. Blood urea nitrogen on admission was 51.6 mg per 100 ml and this increased to 91 mg per 100 ml. Serum haptoglobins were 209 mg per 100 ml (normal 70-150 mg per 100 ml). Cholesterol ranged from 275 to 330 mg per 100 ml. Albumin was 2.3 g per 100 ml and globulin 1.4 gm per 100 ml. Starch gel electrophoresis of the serum showed decreased albumin and gamma globulin with no evidence of myeloma protein. Starch gel electrophoresis of the urine proteins revealed a large amount of albumin with some excretion of all serum proteins, but no Benz-Jones protein. Twenty-four hour radioactive iodine uptake by the thyroid was 8 per cent of the administered dose and rose to 19 per cent following administration of thyroid hormone. Tubercle bacilli cultured from gastric washings were reported two weeks following the patient’s death. There was a progressive renal and cardiac decompensation during hospitalization. Granulocytopenia and thrombocytopenia were attributed to the sarcolysin therapy. Atria1 fibrillation developed on January 6th, and on January 7th there were gasping respirations, cyanosis and the patient died. PATHOLOGY At post-mortem examination, there was evidence of widespread systemic amyloidosis. The symmetrically enlarged heart weighed 410 g; the yellow-brown myocardium was firm and contained numerous small gray specks. Micro~scopically, the myofibers in many areas were surrounded by lamellae of hypereosinophilic material which interconnected with larger lamellae of similar material in the collagenous interstitium. In some myocardial bundles, myofibers were partially or completely replaced by this eosinophilic material. The adventitia, media, and sometimes the intima of many myocardial arteries, and the adventitia and media of some coronary sinuses contained moderate to extensive deposits of amorphous, hypereosinophilic material. The only deposits of amyloid in the liver were found in the adventitia and media of arteries in the portal triads (Fig. 2). The two kidneys weighed 270 g and were finely granular, very firm, and mottled. Microscopically, the cellular elements of most glomerular tufts were completely or partially replaced by pale eosinophilic material which had the appearance of

(Tofucep.

1146

.awaSu!qanq 3!o~yxp %u!]w)suowap aAlau 8 pw (qde.Boloqd 30 do]) aIo!.‘alle ue I#M alelsold aql u! ysodap P!O[KUIV ‘p .OIJ

~~ryalew y!qdou!soa alt?d Kq sn[nJaluo@ ay, 30 luaura3eldal Ik?!JnTds! alay ‘sa[o!.Ia$.Ie pmal KUTXII30 wpaw pue ~!l!lUaApz aql u! la!~alw_u z!I!qdou!soa-IadKq ‘snoqdlome 30 sl!sodap air! alaqL ‘Kaupg aql 30 u!e$s u!soa pue uqKxo]vwaH ‘E .OI~

FIG. 5.

Kidney

demonstrating

fluorescence of amyloid deposition.

immunoglobulins

at

sites

of

Primary Amyloidosis

1147

collagenous tissue rather than of amyloid. Sclerosed Bowman’s capsules were often adherent to the sclerosed glomeruli (Fig. 3). The adventitia and media of many renal arterioles and arteries contained deposits of hypereosinophilic, amorphous material. Eosinophilic, hyaline droplets were prominent in the cytoplasm of swollen epithelial cells of a few proximal convoluted tubules. The small, very firm spleen weighed only 100 g. Nodules of pale, eosinophilic, amorphous material were present in some Malpighian follicles and in the red pulp. A few penicilliary arterioles had medial deposits of hypereosinophilic material. Each adrenal gland contained several irregularly shaped cortical nodules of pale eosinophilic material, and the walls of many periadrenal arteries contained deposits of hypereosinophilic material. In the lungs, occasional alveolar trabeculae and the adventitia and media of arteries contained deposits of hypereosinophilic, amorphous material. Periarterial connective tissue and the media of arteries located in the prostate were also sites of extensive eosinophilic deposits. The hypereosinophilic deposits of amyloid in all the organs described above were generally stained by congo red and methyl violet with fair, but variable intensities, and were considered to represent amyloid deposits. Perimysial and interstitial eosinophilic deposits in the myocardium, and parenchymal deposits in the spleen, adrenal cortex, and submucosa of the bowel were stained with only minimal intensity or not at all by congo red, and not at all by methyl violet. Renal glomeruli and glomerular capsules which were sites of pale eosinophilic material did not take up either of these special stains. Under cross-polarized light, all of the sites of amyloid displayed dichroic birefringence, especially the sections of the prostate (Fig. 4). Immunohistologic studies were carried out in an effort to determine whether antibodyqglobulin was present in the deposits of amyloid in this case. Use of fluorescein-labeled rabbit antibodies reactive with the three major classes of human immunoglobulins (IgC, IgA, IgM) revealed apparently small amounts of immunoglobulins, as evidenced by traces of fluorescence, at sites of amyloid in some myocardial and renal arteries and in occasional glomeruli. In order to determine whether complement-fixing immune or immune-like aggregates were present in deposits of amyloid, an immunohistologic complement-fixation reaction with appropriate controls [2] was used in which unfixed frozen sections of tissue were first incubated with diluted fresh guinea pig serum as a source of complement and then in a second step were treated with fluorescein-labeled rabbit antibodies reactive with fixable components of complement (C’( and C9) to detect sites of fixation of the heterologous complement. This test disclosed that components of complement were fixed in vitro in a scanty, granular pattern of slightly greater intensity of fluorescence than that observed for localized the walls of some of the arteries and glomeruli (Fig. 5).

antibody-globulin

in

All of the above pathologic data, in particular the apparent pericollagenous distribution [3] and variable staining of deposits of amyloid with congo red and methyl violet, and the variable and minimally positive results of immunohistologic studies on localized antibody-globulin [4] suggest that the systemic amyloidosis in this case was of a so-called primary variety. Additional significant pathologic findings were plasmacytosis of the bone marrow,

1148

THOMAS F.WHAYNE,JR.,PFXIZRM.BURKHOLDER~~~ E.LOVELLBECKER

lymph nodes, and spleen; thromboembolism with thrombosis of the left atria1 appendage and multiple old pulmonary arterial emboli with organizing infarcts of the lungs; chronic and active tuberculosis of the right upper lobe of the lung; massive bilateral pleural effusions; multiple acute ulcers of the duodenum; and myelolipoma of the left adrenal gland. DISCUSSION

Classification

The classification and description of amyloidosis remains confused. This can be attributed to the unexplained pathogenesis and biochemistry. Nevertheless, in studying the disease, a working classification is necessary and the following outline has been found useful. 1. Primary amyloidosis: not associated with preexisting disease. 2. Amyloidosis associated with multiple myeloma. 3. Secondary amyloidosis: associated with chronic diseases such as rheumatoid arthritis, ulcerative colitis, regional ileitis, chronic pyelonephritis, empyema, osteomyelitis, tuberculosis [5]. 4. Familial systemic amyloidosis: familial incidence documented; no preexisting disease 161. 5. Experimental amyloidosis; induced in animals by injections of foreign substances [7]. There is considerable dispute as to whether primary systemic amyloido’sis represents a distinct entity. The major point of contention arises from the relationship and nature of primary systemic amyloidosis with respect to amyloidosis associated with multiple myeloma. Certainly, the similarities of these two forms appear significant. It has been estimated that 15 per cent of patients with multiple myeloma have amyloidosis. In a series of 81 patients with primary systemic amyloidosis, KYLE and BAYRD ,[8]showed a correlation with multiple myeloma in sex ratio and age distribution. Bone marrow examinations were done in 41 of their patients. Of these, 23 were diagnostic of multiple myeloma; in the remaining 18 the plasma cells were abnormal, but not diagnostic. While 17 of 58 patients had BencoJones proteinuria, only five of these were proven to have multiple myeloma. Serum electrophoresis performed on 22 patients showed abnormal results in 21, but myeloma was definitely diagnosed in only 11. They believed that a definite marrow diagnosis was necessary to distinguish the so-called paramyloidosis of multiple myeloma from primary amyloidosis, and that the two entities could not be definitely differentiated without more discriminating tests 181. Increased and/or abnormal plasma cells are usually found, even if not diagnostic in myeloma. Osserman suggests that most, if not all, cases of “primary amyloidosis” represent clinical and pathological variants of primary plasma cell proliferation [9]. MagnusLevy has pointed out that the amyloid deposits seen in multiple myeloma could precede the skeletal manifestations by years and cause death before the latter could appear. A unifying hypothesis for primary amyloidosis and multiple myeloma has not yet been clearly set forth. Gamma globulin products of plasma cells have been demonstrated and amyloid has been seen within plasma cells: however, no definite inter-relationship of one to the other has been proven [lo].

Primary Amyloidosis

1149

Clinical man ifestatims

The clinical manifestations of primary systemic amyloidosis are multiple. In decreasing order of involvements, a collected case series showed the following: congestive heart failure and generalized muscle weakness in 50 per cent; weight loss and macroglossia in 4Q per cent; skin and mucus membrane derangements in 33 per cent, with hemorrhage as the most common finding; lymphadenopathy and limb pains in 25 per cent; hypertension in 20 per cent. The following occurred in less than 20 per cent of cases: abdominal pain, hematuria, gastrointestinal hemorrhage, peripheral neuritis, and involvement of serous membranes, autonomic nerves, peripheral blood vessels and bone. Involvement is attributable to infiltration of amyloid between parenchymal cells and connective tissues [ll]. Other frequent conditions are congestive failure, arrhythmias, narrow pulse pressure, and pulsus paradoxus due to restriction during diastole. The nervous system is more frequently affected in the familial than in other forms of amyloidosis. The usual involvement is a symmetrical impairment of distal pain sensation and the patient may occasionally present with this as the initial complaint. Cerebral parenchymal involvement is almost unknown [ 121. Renal involvement with the nephrotic syndrome is considered extremely rare. In 1955, MUEHRCKE,PIRANI,POLLAKand KARK[ 131 reported finding only eight cases of primary amyloidosis with the nephrotic syndrome in the English literature. However, the incidence of renal involvement without the nephrotic syndrome is much higher, and in 1956 Rukavina reviewed 154 cases of primary amyloidosis and found evidence for renal involvement in 42 patients (27.2 per cent) with an age range from 15 to 78 years [ 141. Familial systemic amyloidosis is similar to the so-called primary type, but pedigrees and certain distinguishing features have been documented. No lesions associated with secondary amyloidosis can be found. Andrade, in 1952, described a peripheral neuropathy associated with amyloidosis as an endemic disease in a Portuguese fishing area, with 51 of 64 cases occurring in 12 families. KAUFMAN and THOMAS,in 1959, emphasized the presence of vitreous opacities as an important sign in separating familial from sporadic forms of primary amyloidosis. The lack of an increased serum hexosamine in 11 members of an affected family may help the differentiation from the non-hereditary form [ 151. Secondary amyloidosis is associated with an underlying chronic disease. The most frequently involved sites are the liver, spleen and kidney. Progression through the nephrotic syndrome to renal failure is frequent. There are actually many clinical and biochemical similarities to primary systemic amyloidosis. Pathogenesis The pathogenesis of amyloidosis remains unclear. Deposition of a proteinaceous material in the walls of small blood vessels appears to be the predominant lesion. While the actual mechanisms remain unclear, the possibilities include: (1) formation of amyloid by phagocytic cells, directly; (2) a form of proteinosis or storage disease; (3) direct antigen-antibody reaction; (4) diffusion of low molecular weight proteins (Bence-Jones protein) through capillary beds with the formation of ,insolubla complexes in conjunction with polysaccharides :[16]. An immune mechanism dependent upon gamma globulin elaborated by plasma cells may be an important

1150

THOMASF.WHAYNE,JR., PETER M. BURKH~LDER

and E. LOVELLBECKER

factor; (5) an alteration in the local cell synthesis of protein leading to amyloid formation [ 171. Amyloid appears to be a fibrillary structure measuring approximately 100 x 3600 A [18]. The amyloid fibril seems to appear earliest at the periphery of a histiocyte and is never within the cell membrane. This is consistent with the rarity of intracellular amyloid-staining deposits. Metachromatic staining and increased double refractility by congo red may be explained by the formation of an inclusion compound in an uncoiled helix [18]. A metabolic error instead of a hyperimmune phenomenon can be suggested by the absence of a fibrillar structure when the above is combined with gamma globulin [ 181. Studies in experimental amyloidosis induced in animals by injection of casein as a foreign protein suggest that amyloid is formed by an auto antigen-antibody reaction. In a study of 30 rabbits, a complement fixation reaction with organ proteins became progressively more positive as post-injection time increased in spleens, livers and kidneys containing newly deposited amyloid. Casein induces cell transformations in the reticuloendothelial system. The abnormal proteins thus produced probably act as auto-antigens. From this work, amyloid can be suggested as a precipitate of an auto-antigen and an autoantibody [19]. Histochemical studies of amyloid have been conflicting. The immunologic nature of the substance remains undetermined. CALKINS, COHEN and LARSEN [7] studied amyloid-infiltrated organs. They demonstrated a higher water and hexosamine content with glucosamine as the predominant amino sugar. Their data suggest that amyloid is a hydrophilic substance, predominantly protein (but not collagen) TABLET.

AUTOPSIEDCASES

~FAM~OIWSISATTHENEWYORKHOSPITAI

1932-1964 Primary amyloidosis* Male Female Proteinuria Nephrotic syndrome Blood pressure 9 Blood pressure & Cardiac involvement Diffuse small vessel involvement Renal involvement Thyroid involvement Underlying diseases RH arthritis Bronchiectasis Malig. lymphoma Ca colon TB Ca lung Bronchial adenoma Chronic pyelo. Ulc. colitis Chron. abscess Total

cases

*No underlying disease. tWith associated amyloidosis.

Multiple myelomat

Secondary amyloidosis 27 18 42 5 7 2 11 12 34 4

6 9 14 3 3 3 8 1: 5

4 7 8 2 10 5 1 6 1 1 15

7

45

Primary Amyloidosis

containing: glucosamine,

1151

galactosc, mannose, fucose and only minimal, if any, chondroitin sulfate and heparitin sulfate. It did not appear to be a mucopolysaccharide. Under electron microscopy, amyloid appeared finely filamentous, the filaments being much thinner than collagen and without its characteristic 640-angstroms periodicity. Studies by some workers on residues of normal and amyloidladen organs after incubation with rabbit anti-human gamma globulin were considered as lacking in proof for a pathogenetic role of immunoglobulins in amyloidosis since only small amounts of gamma globulin were present in extractible amyloid. Results of more recent analytical studies of this type have demonstrated that gamma globulin may be present in appreciable quantities in some amyloid laden tissues [20]. It was concluded in this latter report that gamma globulin was not the major component of amyloid and that the inconsistent presence of gamma globulin suggested a more complex pathogenesis for amyloid than precipitation of serum proteins in the tissues. VASQUEZ and DIXON [21] using the fluorescence technique, found that amyloid contains considerable concentration of gamma globulin. However, they interpreted this as either a metabolic deposition of globulin circulating in high concentrations in the plasma, or as a result of an antigen-antibody immunologic reaction. They did not feel that their data pointed to a definite mechanism. In a small study by CALKINS, COHEN and GITLIN [221, neither saline-washed liver homogenates containing much amyloid from two patients nor similarly heated liver homogenates from two normal subjects showed any binding elf anti-gamma globulin in inverse relation to the estimated amount of amyloid. The exact role of hexosamine in amyloid has not been defined. However, interesting observations have demonstrated an increase in serum hexosamine in both primary and secondary amyloidosis. Increase in serum levels is also accelerated after casein injections in animals for the production of experimental amyloidosis. On the other hand, it is interesting to note that serum hexosamine levels are notably normal in the familial form of amyloidosis [23]. OSSERMAN[24] introduced the term “gammaloid” in 1961 because he felt there was a definite similarity between amyloid and the immunoglobulins. Features considered similar were the source of production and the presence of conjugated carbohydrate and of antigenic determinants. He interpreted the immunohistochemical studies of Vasquez and Dixon as supporting the similarity. In these, they demonstrated a highly specific staining of secondary and experimental amyloid deposits with fluorescein-labeled anti-normal gamma globulin antibodies. Much evidence can be cited to show the propensity of normal and pathologic immunoglobulins to form protein : protein and protein : polysaccharide comp1exe.s. The so-called gammaloid appears to be 7s. Each myeloma serum globulin and each Bence-Jones protein has been shown to contain structural groupings in common with anti-serum to 7s gamma globulin. A chronic reticula-endothelial stimulus may give rise to an abnormal population of plasma cells. Abnormal gamma globulin products, especially of the Bence-Jones type (L-polypeptides), elaborated by abnormal plasma cells seem to be involved directly in amyloid infiltrates [25]. In regard to secondary amyloidosis, it has frequently been possible to demonstrate a plasma cell dyscrasia in many people long classified as having this type. Serum complement has been studied in patients with amyloidosis. WILLIAMS and LAW [26] used the 50 per cent hemolysis technique which estimates complement

1152

THOMAS F. WHAYNE, JR., PE-IERM. BURKHOLDERand E. LOV~LL BECKER

activity by hemolysis of sensitized sheep red cells. Twenty-four patients with various forms of amyloidosis were studied: 10 with lepromatous leprosy and amyloidosis, 7 with bone marrow plasmacytosis (most with multiple myeloma) and amyloidosis, and 7 with no plasmacytosis or amyloidosis. In patients with amyloidosis and plasmacytosis, there was a significant depression of serum complement which was not demonstrated in patients with marrow plasmacytosis alone, as shown in a control group of myeloma and lymphoma patients with associated plasmacytosis. No relation was demonstrated between depressed serum complement and elevations in gamma globulin. The serum complement depression suggests the following: a greater antigen-antibody reaction than in other forms of amyloidosis, a specific serum inhibitor, or a deficiency of complement production in associated amyloidosis and plasmacytosis [26]. Results of immunohistologic complement fixation tests for localized gamma globulin have indicated preliminarily that sites of amyloid in tissues of patients with secondary amyloidosis are immunochemically different from those in tissues of patients with so-called primary amyloidosis. Deposits of amyloid in patients with secondary amyloidosis associated with rheumatoid arthritis or chronic suppurative infection most frequently contain immunoglobulins :[21] in the form of aggregates which behave immunochemically like antigen-antibody complexes or aggregated gamma globulin on the basis of in vitro avidity for guinea pig complement [27, 281. In contrast to this finding, deposits of amyloid in patients with so-called primary amyloidosis infrequently contain immunoglobulins, and then apparently in less concentration than in secondary amyloidosis, and have little or no avidity for heterologous complement [4, 271. Findings of the latter type resulted from experimental immunohistologic analyses of the present case of probable primary type amyloidosis. Unusual manifestations

Amyloidosis can present with many unusual manifestations. The presence of amyloid in the prostate in our case was originally thought to be unusual, but search of the literature revealed that this is not uncommon. Although other organs are predominantly affected, the prostate may be among those showing involvement of the stroma or of the walls of blood vessels [29]. Cerebral parenchymal involvement in amyloidosis is rare. Haberland reports a case of primary amyloidosis with cerebral involvement and senile plaque formation. The amyloid was confined to the blood vessels, the lining of the subarachnoid space, and the ventricular walls. A relation to pre-senile dementia has been proposed because of the association of pre-senile and senile plaques with congophile angiopathy. Disturbed central nervous system protein metabolism has been proposed as a mechanism [30]. Some degree of amyloid infiltration of the thyroid occurs in 80 per cent of cases of secondary amyloidosis and 50 per cent of cases of primary amyloidosis. However, d&se clinical enlargement is rare. AREAN and KLEIN [31], in 1961, found only 29 cases in the literature acceptable as goiter due to amyloid. A striking feature is the occasional rapidity of development. A long history of suppurative tuberculosis is usually present. The interstitium becomes broadened and there can be nearly total replacement of thyroidal parenchyma. Presence of marked inflammatory cells,

Primary

Amyloidosis

1153

mostly the plasma cell type, may be noted. Confinement to the thyroid alone has never been proven. Amyloidosis, usually of the primary type, may rarely affect the lungs, sometimes without the involvement of other organs. Types of involvement include isolated nodular tumor-like deposits, deposits in bronchial branches with possible stenosis, and multiple deposits in trachea and bronchi. Involvement of the lower air passages is more uncommon. The amyloid may surround vessels and fill alveoli 1321. Cardiac involvement in generalized amyloidosis is not rare and has been found in 0.5 per cent of routine autopsies. Among the possible complications are a syndrome resembling chronic constrictive pericarditis, atrioventricular block and arrhythmias, especially atria1 fibrillation, and increased digitalis sensitivity [33]. Small bowel involvement is not uncommon with amyloidosis, but full-blown malabsorption is rare. BEDEOW and TILDEN ,[34] reported a case with associated lepromatous leprosy. Perforation of a duodenal ulcer, probably secondary to extensive infiltration of smooth muscle, has been reported. Medical and surgical emergencies may result from heavy amyloid infiltration of various organs, especially the liver and spleen ,[35]. Amyloid renal disease with associated renal vein thrombosis, although rare, is more common in the secondary than in the primary type of amyloidosis. BARCLAY, CAMERONand L~UGHRIEE 1[36], in 1960, reported a series of nine cases, all with secondary amyloidosis. They stated that only one example of renal vein thrombosis with primary amyloidosis had been reported despite the 3.5 per cent incidence of renal involvement in this type. Of the 45 cases of secondary amyloidosis autopsied at The New York Hospital, one was found to have bilateral renal vein thrombosis and rheumatoid arthritis. Theories of etiology include dehydration as a contributory factor, increased fibrinogen level during inflammation, and unexplained alteration of the thrombo-fibrinolytic system. Rare hematologic disorders have been documented with amyloidosis. REDLEAF er al., in 1963, reported a patient with an enlarged prostate who manifested melena while awaiting prostatic surgery ,[37]. Amyloid was demonstrated in the marrow. A persistently elevated acid phosphatase, similar in biochemical activity to that in Gaucher’s and Niemann-Pick diseases, was demonstrated. The prostate was not carcinomatous. A review of the literature provided no documentation for elevated acid phosphatase with amyloidosis. Decreased plasminogen and decreased plasminogen activator were demonstrated. Administration of ethylaminocaproic acid abolished the explained bleeding diathesis. Primary amyloidosis presenting with a pattern similar to scleroderma has been reported. The most important aspects were pallor, flattening of the facies, weight loss, symptoms and signs of vasospasm, stiff fingers and abdominal distention [38]. Amyloidosis may frequently be the only pathological manifestation of familial Mediterranean fever. It may appear at any age, but is most common in youth. The appearance of amyloidosis is independent of the clinical attacks. Characteristics documented for the amyloidosis associated with this disease are massive involvement of renal glomeruli, usually unaffected hepatic sinusoids, diffuse “lardaceous” infiltration of the spleen, and frequent involvement of pulmonary alveolar capillaries [39].

1154

THOMAS F. WHAYNE, JR., PETER M. BURKHOLDER and E. LOVELL BECKER

Diagnasis

The diagnosis of amyloidosis can be confirmed only by histological demonstration of the amyloid in involved tissues. Biopsy of any tissue suspected of involvement is satisfactory, depending on the safety of the necessary procedure. Rectal biopsy is rewarding and relatively safe in the general evaluation of a patient suspected of having amyloidosis. BLUM, in 1962, documented his data on this procedure and compared it to that of others ,[40]. In 62 cases of amyloidosis, rectal biopsy was positive in 75 per cent. Renal biopsy was positive in 87.5 per cent of 24 cases of amyloidosis. Gingival biopsy was positive in 19 per cent of 32 cases and liver biopsy positive in 48 per cent of 27 cases of amyloidosis. When amyloid material is present in a rectal biopsy specimen, it is usually found in the walls of small submucosal blood vessels, both arterioles and venules [41]. Treatment The treatment

of amyloidosis has been very unsuccessful. The literature deals mostly with regression of secondary amyloidosis, especially if the primary disease process is arrested ,[5]. Evidence of the benefit of corticosteroids is conflicting. Some observers believe that steroids actually enhance the disease process. In rabbits given casein injections and cortisone, less severe amyloid involvement has been demonstrated. In the same study, a slightly slower rise in serum hexosamine levels was noted in the cortisone-treated rabbits ,[42]. In a study of the effects of corticosteroid therapy with 60 mg of Prednisone per day on the nephrotic syndrome associated with amyloidosis, MAXWELL,ADAMS and GOLDMAN;[43] concluded that no beneficial or detrimental effect was obtained, but that such therapy was contraindicated owing to the secondary complications. In a review of 18 cases in the literature, he found that corticosteroids did not cause a biochemical reversal of agents such as the nephrotic syndrome in any patient. Chemotherapeutic sarcolysin are now used in treatment of patients with amyloidosis, particularly those with the primary variety. Part of the rationale for use of this type of cytotoxic agent is the postulated relationship of primary amyloidosis to multiple myeloma and the possible role of production of abnormal immunoglobulins and fragments of immunoglobulins. CONCLUSIONS

AND SUMMARY

Classification of individual cases of amyloidosis often remains extremely difficult, as is demonstrated by the present case report, the reviewed cases from The New York Hospital (Table 1) and the survey of the literature. The textbook description of primary amyloidosis emphasizes its skeletal, cardiac and smooth muscle involvement. Secondary amyloidosis is described as especially involving the spleen, kidney, liver and the cortex of the adrenal glands. However, when these classifications are studied closely and complete case descriptions are compared, considerable overlap is noted. The major site of amyloid infiltration is the perivascular smooth muscle of arterioles. In many of the cases reviewed at The New York Hospital and in the literature, there was extensive involvement of the abdominal and thoracic viscera. In addition, there was a marked overlap in the larger interstitial infiltrates. Both an immunologic mechanism and an error of metabolism have been con-

Primary

Amyloidosis

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sidered as possible etiologies of amyloidosis. Good evidence for both has been presented but the issue remains unresoSlved. However, recent immunologic and immunohistochemical studies favor some form of antigen-antibody reaction. The presence of gamma globulin has been demonstrated in amyloid deposits. Use of an immuno-histologic complement fixatioa test has demonstrated an ability of secondary type amyloid deposits to fix guinea pig complement and a general inability of primary type amyloid deposits to fix guinea pig complement. No good explanation for the difference has yet been made, although biochemical differences are demonstrable. The general presence or absence in weak amount of immunoglobulins in the deposits of amyloid and the generally negative or very weak in vitro fixation of complement at sites of amyloid, as well as the inconsistent staining of the deposits of amyloid with congo red and methyl violet, render this case similar to other cases of so-called primary amyloidosis. The rather extensive chronic and active pulmonary tuberculosis in this case is considered as an accessory disease with realization that its possible contribution to development of amyloid cannot be excluded. The relationship of primary amyloidosis to multiple myeloma remains unresolved. Features such as ESence-Jones prolteinuria and plasmacytosis which occur frequently in primary amyloidosis suggest a relationship to multiple myeloma. The possibility that all cases of primary amyloidosis represent a variant of myeloma that will eventually develop into the full-blown disease has been considered. REFERENCES JOACHIM,G. R., CAMERON,J. S., SCHWARTZ,M. and BECKER, E. L.: Selectivity of protein in patients with the nephrotic syndrome, J. clin. Invest. 43, 2332, 1964. 2. KLEIN, P. J. and BURKHOLDER,P. M.: Studies on the antigenic properties of complement. I. Demonstration of agglutinating antibodies against guinea pig complement fixed on sensitized sheep erythrocytes, J. enp. Med. 111,93, 1960. HJXLER, H., MISSMAHL, H. P., SOHAR,E. and GAFNI, J.: Amyloidosis: Its differentiation into peri-reticulin and peri-collagen types, J. Path. Butt. 88, 15, 1964. LEVINE, R. A., PAYNE, M. A. and BURKHOLDER,P. M.: Asymptomatic primary systemic amyloidosis, Ann. intern. Med. 56, 397, 1962. REIMANN, H. A., KOUCKY, R. F. and EKLUND, C. M.: Primary amyloidosis limited to tissue of mesodermal origin, Am. J. Path. 11, 977, 1935. RIJKAVINA,J. G., BLOCK, W. D., JACKSON,C. E., FILLLS, H. F., CAREY, J. H. and CURTIS, A. C. : Primary systemic amyloidosis : A review and an experimental, genetic and clinical study of 29 cases with particular emphasis on the familial form, Medicine, Bnltimore 35, 239, 1956. Preliminary clinical, chemical, 7. CALKINS, E., COHEN, A. S. and LARSEN, B. : Amyloidosis: and experimental observations, Ann. N.Y. Acad. Sci. 86, 1033, 1960. and myeloma, Arch. 8. KYLE, R. A. and BAYRD, E. D.: ‘Primary’ systemic amyloidosis intern. Med. 107, 344, 1961. 9. OSSERMAN,E. F. : Plasma-cell myeloma, New Engl. J. Med. 261,952 and 1006, 1959. 10. CLINIC~PA~OLOGIC CONFERENCE: Primary amyloidosis, Am. 1. Med. 33, 296, 1962. 11. EDITORIAL.:Primary systemic amyloidosis, Ann. intern. Med. 38, 620, 1953. Q. JI. Med. 12. CHAMBERS, R. A., MEDD, W. E. and SPENCER, H.: Primary amyloidosis, 27 (new series), 207, 1958. 13. MIJEHRCKE, R. C., PIRANI, C. L., POLLACK, V. E. and KARK, R. M.: Primary renal amvloidosis with the neohrotic svndrome studied bv serial bioosies of the kidnev.a7 Guv’s _ *~ Hosp. Rep. 104,295, 1953. . bv 14. SCHREINER.G. E.: The Neuhrotic Svndrome. in Diseases of the Kidnev.<_ D. I 335. (Ed. .~ _I STRAUSS,k. B. and WELT, c. G.) Little, Brown, Boston, 1965. 15. JACKSON,C. E., FALLS, H. F., BLOCK, W. D., RUKAVINA, J. K. and CAREY, J. H. : Inheritance of primary systemic amyloidosis, Am. J. hum. Genet. 12, 434, 1960. 16. BRIGGS, G. W. : Amyloidosis, Ann. intern. Med. 55, 943, 1961. 1.

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THOMASF. WHAYNE,JR., PETER M. BURKHOLDERand E. LOVELL BECKER TEILuM, G. : Pathogenesis of amyloidosis, Actu path. microbial. stand. 61,21, 1964. GUEFTS, B. and GHIDONI, J. I.: The site of formation and ultrastructure of amyloid, Am. J. Path. 43, 837, 1963. PAVL~KHINA,L. V. and SEROV, V. V. (Moscow): Pathogenesis of amyloidosis, Fedn. Proc. Fedn. Am. Sots. exp. Biol. 22, 531, 1963. Scrrr~~rz, R. T., CALKINS, E., MILGROM, F. and WITEBSKY, E.: Association of gammaglobulin with amyloid, Am. J. Path. 48, 1, 1966. analysis of amyloid by the VASQUEZ, J. J. and DIXON, F. J.: Immunohistochemical fluorescence technique, J. exp. Med. 104, 727, 1956. CALKINS, E., Corn&, A. S.-and Gm%, D.: Immunochemical determinations of gamma globulin content of amvloid. Fedn. Proc. Fedn. Am. Sots. exe. Biol. 17. 431. 1958. JACKSON, C. E., BLOC;, W.’ D. and RATLIFF, W. C.: Serum hexosamine content and urinary acid mucopolysaccharide excretion in hereditary primary amyloidosis, J. Lab. clin. Med. 56, 544, 1960. : Tissue proteinosis : Gammaloidosis, Ann. OSSERMAN, E. F.: Editorial-Amyloidosis intern. M>d. 55, 1033, 1961. OSSERMAN,E. F.. TAKATSUKI,K. and TALAL. N.: Multiule I. The _ uathoaenesis _ mveloma of ‘amyloidosis’, Semin. Hematol. 1, 3, 1964. WILLIAMS, R. C., Jr. and LAW, D. H., IV: Serum complement in amyloidosis, J. Lab. clin. Med. 56,629, 1960. BURKHOLDER,P. M. : Unpublished observations. Untersuchunaen mit fluoresceinVOGT. A. and KOCHEM, H. G.: Histo-seroloaische markiertem Antikomplement. Nachweis komplementbindender Subitanzen im Amyloid, Z. Zellforsch. mikrosk anat. 52,640, 1960. SYMMERS, W. ST. C.: Two cases of eosinophilic prostatitis due to metazoan infestation, J. Path. Bact. 73, 549, 1957. HABERLAND,C. : Primary systemic amyloidosis : Cerebral involvement and senile plaque formation, J. Neuropath. exp. Neurol. 23, 135, 1964. AREAN, V. M. and KLEIN, R. E. : Amyloid goiter: Review of the literature and report of a case, Am. .I. clin. Path. 36, 341, 1961. SORENSON,H. R.: Primary isolated nodular amyloidosis of the lung, Acta chir. stand. (Suppl.) 83, 162, 1961. CASSIDY, J. T. : Cardiac amyloidosis: Two cases with digitalis sensitivity, Ann. intern. Med. 55, 989, 1961. BEDWW, R. M. and TILDEN, I. L.: Malabsorption syndrome due to amyloidosis of the intestine secondary to lepromatous leprosy: Report of a case, Ann. intern. Med. 53, 1017, 1960. ARBARIAN, M. and FENTON, J.: Perforation of small bowel in amyloidosis, Archs. intern. Med. 114, 815, 1964. BARCLAY,G. P. T., CAMERON, H. MAcD. and LOUGHRIDGE,L. W.: Amyloid diseases of the kidney and renal vein thrombosis, Q. JI. Med. 29, 137, 1960. REDLEAF, P. D., DAVIS, R. B., KUCINSKI, C., HOILUND, L. and GANS, H.: Amyloidosis with an unusual bleeding diathesis. Observations on the use of epsilon amino caproic acid, Ann. intern. Med. 58, 347, 1963. LEACH, W. B., VASSAR, P. S. and CULLING, C. F. A.: Primary systemic amyloidosis presenting as scleroderma, Can. med. Ass. J. 83,263, 1960. BLUM, A., GAFNI, J., SCJHAR,E., SIIIBOLET, S. and HELLER, H.: Amyloidosis as the sole manifestation of familial Mediterranean fever (FMF). Ann. intern. Med. 57. 795. 1962. BLUM, A. and SOHAR, E.: The diagnosis of amyloidosis. Ancillary procedures, Lancei i, 721, 1962. FEN~EM, P. H., TURNBERG,L. A. and WORMSLEY,K. G.: Biopsy of the rectum as an aid to the diagnosis of amyloidosis, Bsr. med. J. 5275, 364, 1962. COHEN, A. S., CALKINS, E. and MULLINAX, P. F. : Studies in experimental amyloidosis. III. The effect of cortisone administration on the incidence of casein-induced amyloidosis in the rabbit, Archs. intern. Med. 110, 569, 1962. MAX~VELL,M. H., ADAMS, D. A. and GOLDMAN,R.: Corticosteroid treatment of amyloid nephrotic syndrome, Ann. intern. Med. 60, 539, 1964.