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Skeletal muscle amyloid deposition in AL- (primary or myeloma-associated), AA- (secondary), and prealbumin-type amyloidosis
Journal of the Neurological Sciences, 1988, 85:223-232
223
Elsevier JNS 03006
Skeletal muscle amyloid deposition in AL- (primary or myeloma-associated), AA- (secondary), and prealbumin-type amyloidosis Masahito Y a m a d a ~, Hiroshi TsukagoshP and Shigeru H a t a k e y a m a 2 lDept, of Neurology, and 2Dept. of Pathology, Faculty of Medicine, Tokyo Medical and Dental University, Tokyo 113 (Japan)
(Received24 November, 1987) (Revised,received 8 February, 1988) (Accepted 10 February, 1988)
SUMMARY Amyloid deposition in the quadriceps femoris muscle was investigated in 12 cases of systemic amyloidosis including 6 of AL-(primary or myeloma-associated) type, 2 of AA- (secondary) type, and 4 of prealbumin- (familial or sporadic) types. Clinically, muscle weakness was found in 7 patients. Among the 7 patients, one of the AL-type suffered from systemic myopathy showing progressive muscular stiffness, pseudohypertrophy, and weakness. The other 6 presented with polyneuropathy. Pathologically, no amyloid was found to be deposited in the AA-type. In all of the ALand prealbumin-types, amyloid deposition was found in the blood vessels and peri- and endomysium. The degrees of amyloid deposition were marked in one case of the AL-type, which was considered to be suffering from amyloid myopathy, moderate in one of the AL-type, and slight in the rest of the AL-type and all of the prealbumin-type. Our observations and descriptions in the literature indicate that the presence and degrees of amyloid deposition in the skeletal muscles would be related to the types of amyloid proteins in amyloidosis. It seems likely that the alTmity of amyloid to the skeletal muscles is variable in AL-type, probably depending on the molecular heterogeneity of AL protein, is low in prealbumin-type, and is almost absent in AA-type.
Key words: Systemic amyloidosis; Amyloid proteins; AL amyloid; AA amyloid; Prealbumin-related amyloid; Skeletal muscle; Amyloid myopathy
Correspondence to: Masahito Yamada, MD, Dept. of Neurology, Faculty of Medicine, Tokyo Medical and Dental University, 1-5-45,Yushima, Bunkyo-ku,Tokyo 113,Japan.
0022-510X/88/$03.50 © 1988Elsevier SciencePublishers B.V. (BiomedicalDivision)
224 INTRODUCTION
Amyloid deposition in the skeletal muscles is commonly found in systemic amyloidosis, although it is usually clinically silent (Engel and Banker 1986). Some cases with systemic amyloidosis show exceptionally massive deposition of amyloid in the skeletal muscles with myopathic manifestations (Lange 1970; Martin et ai. 1970; Miyazaki et al. 1973; Terashima et al. 1977; Whitaker et al. 1977; Miyasald et al. 1979; Ringel and Claman 1982; Ii et al. 1984; Doriguzzi et al. 1987). Recently, considerable advancements have been made in the biochemical characterization of amyloid proteins, and proposals have been made for the chemical categorization of amyloid disease (Glenner 1980; Husby and Sletten 1986; Cohen and Connors 1987). The major amyloid fibril protein is known to be AA in secondary amyloidosis and familial Mediterranean fever, and AL (A-kappa or A-lambda) in primary and myeloma-associated amyloidosis. Prealbumin-type amyloid (Comwell et al. 1987) has been known to be found in 2 forms of systemic amyloidosis, type I familial amyloidotic polyneuropathy (FAP) (Tawara 1983; Saraiva 1984) and senile systemic amyloidosis (SSA) (Pitkanen 1984). The relationships between the type of amyloid proteins and involvement of the skeletal muscles have not yet been elucidated. In this report, we investigate amyloid deposition in the skeletal muscles in 12 cases of systemic amyloidosis which were classified to AL-, AA-, and prealbumin-types. The relationships between the type of amyloid and deposition in the skeletal muscles are discussed.
MATERIALS AND METHODS
Twelve cases of systemic amyloidosis were studied (Table I). Six cases (cases I-6) were classifiedas AL- (primary or myeloma-associated) type amyloidosis. These 6 cases had no positivefamily history.Plasma celldyscrasias (PCD) with monoclonal immunoglobulins and/or Bence-Jones proteins (BJP) were found in all 6 of these cases (Table i). One of them (case I) suffered from multiple myeloma. The other 5 cases (cases 2-6) had small quantitiesof serum M-components and mild proliferationof the bone marrow plasma cells (up to 7 ~), but no overt myeloma. In these cases, amyloid was resistantto potassium permanganate treatment before Congo red staining (Wright et al. 1977) and did not stain with anti-human AA-antisera (Kyowa Medex) or anti-human prealbumin-antisera(Hoechst-Behring) by the peroxidase-antiperoxidase(PAP) technique (Fujihara et al. 1981). Two cases (cases 7 and 8) were classified as AA- (secondary) type. The amyloidosis in both of the 2 cases was associatedwith chronic rheumatoid arthritis.In these cases, amyloid was sensitiveto potassium permanganate treatment, and stained with anti-human AA-antisera by the P A P technique. The 4 remaining cases (cases 9-12) were classifiedas prealbumin-type. All of these 4 cases presented with polyneuropathy, and the amyloid was resistant to potassium permanganate treatment and stained with anti-human prealbumin-antisera
70/F 60/F
34/M 40/M 70/M 76/M
7 8
9 10 11 12
Prealbumin Prealbumin Prealbumin Prealbumin
AA
AL AL AL AL AL AL
amyloidosis
Type of
-
BJP-lambda BJP-lambda IgA-lambda IgG-lambda IgG-lambda IgG-lambda
M-protein
+ + + +
+
+ + +
+ + + + + +
+ + +++ +
+
++
+
Conduction
block
Heart failure
Cardiac disorders
Clinical features
WITH SYSTEMIC A M Y L O I D O S I S
- , absent; + , slight, + +, moderate; + + + ; marked. a Case 1 showed progressive muscular stiffness, pseudohypertrophy, and weakness.
57/M 52/M 79/F 46/F 71/M 67/M
Age/Sex (yrs)
1 2 3 4 5 6
Case No.
CLINICAL FEATURES O F 1 2 P A T I E N T S
TABLE I
+++ +++
++-i+ + + ++ +++
Renal disorders
+ +
+++ +++
Macroglossia
+++ +++ +++ +++
+++ +++
Neuropathy
-I-++ +++ +++ +++
+++ +++
+++a
Muscle weakness
L~
226 by the PAP technique. Two (cases 9 and 10) were hereditary and diagnosed as type I FAP. The other two (cases 11 and 12) had no positive family history or PCD. Details of the two sporadic cases were previously reported (Yamada et al. 1987). One (case 11) of the 2 cases was considered to be atypical FAP because an abnormal serum prealbumin and prealbumin gene, which were found in type I FAP (Nakazato et al. 1984; Sasaki et al. 1984), were detected. The exact origin of amyloid protein in the other case (case 12) remains unclear. Clinical data are shown in Table 1. Concerning neuromuscular disorders, polyneuropathies were found in 6 cases, consisting of 2 of the AL-type (cases 3 and 4) and 4 of the prealbumin-type (cases 9-12). The polyneuropathies were of the sensorimotor type. All of these 6 cases presented with distal-dominant muscular atrophy and weakness of marked degree. One case of the AL-type without polyneuropathy (case 1) showed progressive muscular stiffness and weakness with hypertrophic appearances of the muscles in the entire extremities, and was considered to be suffering from systemic amyloid myopathy. Macroglossia was noted in 6 of our cases, and it was especially prominent in 2 cases (cases 1 and 2). Cardiac and renal disorders were commonly found, although no cardiac disorder was found in AA-type. Biopsied (in cases 11 and 12) and autopsied (in cases 1-10 and 12) muscle tissues obtained from the quadriceps femoris were examined pathologically. In all of the cases, formalin-f'Lxed, paraff'm-embedded sections were stained with Congo red and examined under polarized light for the presence of green birefringence. In one case of the AL-type which showed a large amount of amyloid deposition in the quadriceps femoris (case 1), muscle tissue was fixed in 2.5~ glutaraldehyde, and examined in an electron microTABLE 2 H I S T O P A T H O L O G I C A L F I N D I N G S ON A M Y L O I D D E P O S I T I O N A N D M U S C U L A R A T R O P H Y IN T H E Q U A D R I C E P S F E M O R I S M U S C L E S F R O M 12 PATIENTS WITH SYSTEMIC AMYLOIDOSIS
Case No.
Type of amyloidosis
Amyloid deposition
Muscular atrophy (type of change)
1
AL
+ + +
+ + + (M)
2 3 4 5 6
AL AL AL AL AL
+ + + + + +
+ (M) + + (N) + + + (N) -
7 8
AA AA + + + +
+ + + +
9 10 11 12
Prealbumin Prealbumin Prealbumin Prealbumin
+ + (N) + + (N) + (N) + (N)
- ; absent; + , slight; + +, moderate; + + + , marked. M; myopathic change; N, neurogenic change.
227 scope. Amyloid deposits in other organs were also evaluated histologically for the purpose of elucidating the relationships in amyloid deposition between skeletal muscle and other organs.
RESULTS
Degrees of amyloid deposition and muscle fiberatrophy in the quadriceps fcmoris muscle are shown in Table 2. All cases of the AL- and prealbumin-types presented amyloid deposition in the quadriceps femoris muscles, although the degrees of amyloid deposition varied. Amyloid was deposited in and around intramuscular small blood vessels and in pcriand endomysium. In the AL-type, a case with progressive muscular stiffnessand weakness (case I) showed massive amyloid deposition in the quadriceps femoris (Fig. I).Amyloid infiltration of blood vessel walls was marked. Vessels of all sizes, some of which wcrc identifiableas arteryor vein, had amyloid deposition showing thickening of theirwalls with or without luminal stenosis.Vascular amyloid deposits massively extended to the perivascular areas. Interstitialamyloid infiltrationwas also found in the pcri- and endomysium. The amyloid was associated with atrophy and distortion of adjacent muscle fibers, but was not observed beneath the sarcolemma. N o necrosis or
Fig. 1. Quadriceps femoris muscle from case 1. Massive amyloid deposits, showing green birefringence under polarized fight, are found in the blood vessels and interstitium (a). There is endomysial amyloid deposition with atrophy ofthe muscle fibers (b). (a: Congo red, polarized light, x 52; b:Congo red, polarized light, x 130.)
228
Fig. 2. Electron micrographs of the quadriceps fcmoris muscle from case 1. Amyloidfibrils (AF) are depositedaroundmusclefibers( x 4300).Inset; ~-power magnificationof straightnon.branchingamyloid fibrils ( x 32400). phagocytosis of muscle fibers were found. Inflammation was absent. Electron microscopically, amyloid fibrils, which appeared as straight and nonbranching fibrils, were densely deposited around the muscle fibers and blood vessels (Fig. 2). No amyloid fibrils were observed within the muscle fiber. Sarcolemmal membranes appeared intact. The quadriceps femoris of the other cases of the AL-type showed moderate or mild amyloid deposition which was vascular and interstitial. Muscle fibers surrounded by endomysial amyloid deposition were focally found, and these fibers showed atrophic
changes of various degrees. In the prealbumin-type, amyloid deposition in the quadriceps was mild and almost confined to the blood vessels. The 6 cases with polyneuropathy including both the A L (cases 3 and 4) and prealbumin typos (eases 9-12) showed marked or moderate neurog~aic atrophy of the quadriceps femoris muscles, such as group atrophy and small angulated fibers. In the AA-type, amy!old depositionwas absent in the quadriceps fcmoris muscle. Muscle fibers were well preserved. Marked macroglossia was found in the 2 cases which showed marked or moderate amyloid deposition in the quadriceps femoris muscle (cases 1 and 2; Tables 1 and 2). Amyloid deposits in organs other than the quadriceps femoris muscle are shown in Table 3. Amyloid deposits in the quadriceps femoris muscle did not appear
229 TABLE 3 AMYLOID DEPOSITION
I N T H E O R G A N S O T H E R T H A N S K E L E T A L M U S C L E S I N T H E 12
CASES WITH SYSTEMIC AMYLOIDOSIS
C a s e No.
Type of amyloidosis
Heart
Kidney
Spleen
Gastrointenstinal tract
Peripheral nerve
++ ++ ++ +++ ++ +++
+
+
+++
-
3 4 5 6
AL AL AL AL AL AL
+++ +++ + + ++
+ +++ + + +
++ ++ ++ +++ ++
+++ +++ -
7 8
AA AA
+ +
+++ +++
++ +
++ ++
Prealbumin Prealbumin Prealbumin Prealbumin
+ + + + n.e. + + +
n.e. + + n.e. +
+ + n.e. n.e. +
n.e. + +a + + +
1 2
9 10 11 12
+ + + +
+ + + + a + +
- , a b s e n t ; + , slight; + + , m o d e r a t e ; + + + , m a r k e d ; n.e., not e x a m i n e d . a Biopsied material.
to be significantly correlated with those in the heart, kidneys, spleen, gastrointestinal tract, and peripheral nerve.
DISCUSSION
Our series included AL-, AA-, and prealbumin-type amyloidosis. The presence and degrees of amyloid deposition in the skeletal muscles appeared to be related to the types of amyloidosis as discussed below. In the 2 cases of the AA- (secondary) type, no amyloid deposit was found in the skeletal muscles. Darlin (1949) reported no involvement of the striated muscle in 30 patients with secondary amyloidosis. Adams (1975) described that skeletal muscles might be rarely involved in secondary amyloidosis. The affinity of AA amyloid to skeletal muscles would be almost absent. In the 4 cases of the prealbumin-type, amyloid deposition in the skeletal muscles was uniformly mild and almost confined to the blood vessels. Prealbumin-type amyloid (Comwell et al. 1987) has been known to be found in type I FAP (Tawara et al. 1983; Saraiva et al. 1984) and SSA (Pitkanen et al. 1984). All of the 4 cases had polyneuropathy as found in type I FAP. As mentioned above, 3 of the 4 cases (cases 9, 10, ll) were classified as FAP, whereas the origin of amyloid protein in the rest (case 12) remains unclear. Skeletal muscle amyloid deposition in type I FAP has been reported to be slight or absent (Andrade 1952; Shirabe et al. 1969). Skeletal muscle amyloid deposition was not described in SSA, although amyloid deposits were reported in the
230 striated muscle of the tongue (Pitkanen et al. 1984). The affinity of prealbumin-type amyloid to skeletal muscles appears low. Degrees of amyloid deposition in the skeletal muscles in 6 cases of AL type varied. Amyloid deposition, which was vascular and interstitial, was marked in one (case 1), moderate in one (case 2), and mild in the others (cases 3-6). In the case of amyloid myopathy (case 1), amyloid deposition in the quadriceps was massive in blood vessels and peri- and endomysium. Amyloid deposition in the endo- and perimysium appeared to cause compression atrophy of the muscle fibers, and massive vascular amyloid deposition might cause ischemic changes of the muscle fibers. It is very rare that massive amyloid deposition in the skeletal muscles causes progressive muscular weakness, stiffness, and pseudohypertrophy as found in case 1. Amyloid myopathies due to massive amyloid deposition have been reported to be often associated with the presence of PCD, suggesting that the major amyloid was AL (Miyazaki et al. 1973; Terashima et al. 1977; Whitaker et al. 1977; Ringel and Claman 1982; Ii et al. 1984; Doriguzzi et al. 1987). Ii (1984) postulated that kappa-type BJP was found in most cases of amyloid myopathy, although the presence of lambda chains has also been reported including our case 1 (Whitaker et al. 1977; Ringel and Claman 1982). Because the 6 cases of AL type which we examined all had lambda-type light chain as M-protein, we cannot comment on the difference in skeletal muscle involvement between A-kappa and A-lambda types. Variable regions of light chains have been known to be "amyloidogenic" in the AL-type, and "amyloidogenic" light chains vary and do not have uniform peculiarity (Glenner 1980). Such a molecular variety of "amyloidogenic" light chains might be related to a variety in degrees of amyloid deposition in skeletal muscles. In other words, a variety of affinity of AL amyloids to the skeletal muscles might depend on heterogeneity of "amyloidogenic" light chains. Isobe and Osserman (1974) postulated that the binding affinities of amyloids to certain tissue might be due to immunologic interaction between certain tissue constituents (i.e., autoantigens) and light chains of autoantibodies. To elucidate the peculiarity of AL amyloid or "amyloidogenic" light chains causing amyloid myopathy, further studies are necessary. Furthermore, it is noteworthy that all of the reported cases of amyloid myopathy including our cases have presented with macrogiossia, although this was not necessarily associated with amyloid myopathy. The affinity ofAL amyloid to skeletal muscle would be generally lower than that to the lingual muscle which is also a striated muscle. Amyloid deposition in skeletal muscle was not correlated with that in the heart, kidneys, spleen, gastrointestinal tract, and peripheral nerve. Interstitial connective tissue in each organ is a major site of amyloid deposition. In skeletal muscle, it was reported that the collagens mainly consisted of type IV and III in the endomysium and of type III in the perimysium (Duance et al. 1977). The differences in collagen types exist among various tissues and organs (Bornstein and Sage 1980), and may be important for tissue distribution of amyloid deposits.
231 ACKNOWLEDGEMENTS
This work was supported in part by Research Committee on Primary Amyloidosis, Ministry of Health and Welfare, Japan. The authors are grateful to all of the members of the Departments of Neurology and Pathology, Tokyo Medical and Dental University, for their help.
REFERENCES Adams, R.D. (1975) Diseases of muscle. A Study in Pathology, Harper and Row, Hagerstown, MD. Andrade, C. (1952) A peculiar form of peripberal neuropathy. Familiar atypical generalized amyloidosis with special involvement of the peripheral nerves, Brain, 75: 408-427. Bomstein, P. and H. Sage (1980) Structurally distinct collagen types, Annu. Rev. Biochem., 49: 957-1003. Cohen, A. S. and L.H. Connors (1987) The pathogenesis and biochemistry of amyioidosis, J. Pathol., 151" 1-10. Cornwell, III, G.G., K. Sletten, B.O. Olofsson, B. Johansson and P. Westermark (1987) Prealbumin: its association with amyloid, J. Cfin. Pathol., 40" 226-231. Dahlin, D.C. (1949) Secondary amyloidosis, Ann. Intern. Med., 31: 105-119. Doriguzzi, C., T. Mongini, W. Treni and G. Monga (1987) Early sarcolemmal dysfunction in skeletal muscle amyloidosis, J. NeuroL, 234: 52-54. Duance, V.C., D.J. Restall, H. Beard, F.J. Bourne and A.J. Bailey (1977) The location of three collagen types in skeletal muscle, FEBS Lett., 79: 248-252. Engel, A.G. and B. Q. Banker (1986) Myology, Basic and Cfinical, McGraw-Hill Book Company, New York, NY. Fujihara, S., J.E. Balow, J.C. Costa and G.G. Glenner (1980) Identification and classification of amyloid in formalin-fixed, paraffin-embedded tissue sections by the unlabeled immunoperoxidase method, Lab. Invest., 43: 358-365. Glenuer, G.G. (1980) Amyloid deposits and amyloidosis, N. Engl. J. Med., 502: 1283-1292, 1333-1343. Husby, G. and K. Sletten (1986) Chemical and clinical classification of amyloidosis 1985, Scand. J. ImmunoL 23: 253-265. Ii, K., K. Hizawa, S. Nunomura and H. Morizumi (1984) Systemic amyloid myopathy - light-microscopic and fine-structural study of the skeletal muscles with histochemical and immanohistocbemical study of amyloid, Acta Neuropathol. (Bed.), 64:114-121. Isobe, T. and E.F. Osserman (1974) Patterns of amyloidosis and their association with plasma-cell dyscrasia, monoclonal immtmoglobulins and Bence-Jones proteins, N. Engl. J. Med., 290: 473-477. Lange, R.K. (1970) Primary amyloidosis of muscle, South. Med. J., 63: 321-323. Martin, J.J., L. Van Bogaert, J. Van Damme and J. Peremans (1970) Sur une pseudo-myopathie ligueuse g6n6ralis,~e par amyloYdoseprimaire endomysio-vasculalre, J. NeuroL Sci., 11: 147-166. Miyasaki, K., S. Murao, S. Tstmetoshi, N. Koizumi, T. Isobe, N. Nakamura, H. Nakano, T. Ogino and S. Hosokawa (1979) Primary systemic amyloidosis. A case permitting pathological and biochemical investigations, Acta PathoL Jpn., 29: 157-169. Miyazaki, T., I. Chin, S. Inoue, K. Ozeki, T. Koide and M. Iio (1973) An autopsy case of muscle amyloidosis, Saishin lgaku (Jpn. ), 28: 801-809. Nakazato, M., K. Kangawa, N. Minamino, S. Tawara, H. Matsuo and S. Araki (1984) Radioimmunoassay for detecting abnormal prealbumin in the serum for diagnosis of familial amyloidotic polyneuropathy (Japanese type), Biochem. Biophys. Res. Commun., 122: 719-725. PitkSnen, P., P. Westermark and G. G. Cornwell, III (1984) Senile systemic amyloidosis,Am. J. Pathol., 117: 391-399. Ringel, S.P. and H.N. Claman (1982) Amyloid-associated muscle pseudohypertrophy, Arch. NeuroL, 39: 413-417. Saraiva, M.J.M., S. Birken, P.P. Costa and D.S. Goodman (1984) Amyloid fibril protein in familial amyloidostic polyneuropathy, Portuguese type. Definition of molecular abnormality in transthyretin (prealbumin), J. Clin. Invest., 74: 104-119. Sasaki, H., Y. Sakaki, H. Matsuo, I. Goto, Y. Kuroiwa, I. Sahashi, A. Takahashi, T. Shinoda, T. Isobe and
232 Y. Takagi (1984) Diagnosis of familial amyloidotic polyneuropathy by recombinant DNA techniques, Biochem. Biophys. Res. Commun., 125: 636-642. Shirabe, T., M. Hashimoto, S. Araki, S. Mawatari and Y. Kuroiwa (1969) Two autopsy cases of familial polyneuritic amyloidosis, Adv. Neurol. Sci. (Jpn.), 13: 206-215. Tawara, S., M. Nakazato, K. Kangawa, H. Matsuo and S. Araki (1983) Identification of amyloid prealbumin variant in familial amyloidotic polyneuropathy (Japanese type), Biochem. Biophys. Res. Commun., 116: 880-888. Terashima, K., A. Matsuda, M. Matsuda, H. Yamagata, Y. Imai and M. Kojima (1977) An autopsy case of skeletal muscle amyloidosis with IgA-kappa type myeloma, J. Jpn. Soc. R. E. S. (Jpn.), 17:169-185. Whitaker, J.N,, K. Hashimoto and M. Quinones (1977) Skeletal muscle pseudohypertrophy in primary amyloidosis, Neurology, 27: 47-54. Wright, J.R., E. Calkins and R.L. Humphrey (1977) Potassium permanganate reaction in amyloidosis. A histologic method to assist in differentiating forms of this disease, Lab. Invest., 36: 274-281. Yamada, M., H. Tsukagoshi, J. Satoh, S. Ishiai, M. Nakazato, H. Furuya, H. Sasaki, Y. Sakaki and T. Yokota (1987) "Sporadic" prealbtmain-related amyloid polyneuropathy: report of two cases, J. Neurol., in press.
223
Elsevier JNS 03006
Skeletal muscle amyloid deposition in AL- (primary or myeloma-associated), AA- (secondary), and prealbumin-type amyloidosis Masahito Y a m a d a ~, Hiroshi TsukagoshP and Shigeru H a t a k e y a m a 2 lDept, of Neurology, and 2Dept. of Pathology, Faculty of Medicine, Tokyo Medical and Dental University, Tokyo 113 (Japan)
(Received24 November, 1987) (Revised,received 8 February, 1988) (Accepted 10 February, 1988)
SUMMARY Amyloid deposition in the quadriceps femoris muscle was investigated in 12 cases of systemic amyloidosis including 6 of AL-(primary or myeloma-associated) type, 2 of AA- (secondary) type, and 4 of prealbumin- (familial or sporadic) types. Clinically, muscle weakness was found in 7 patients. Among the 7 patients, one of the AL-type suffered from systemic myopathy showing progressive muscular stiffness, pseudohypertrophy, and weakness. The other 6 presented with polyneuropathy. Pathologically, no amyloid was found to be deposited in the AA-type. In all of the ALand prealbumin-types, amyloid deposition was found in the blood vessels and peri- and endomysium. The degrees of amyloid deposition were marked in one case of the AL-type, which was considered to be suffering from amyloid myopathy, moderate in one of the AL-type, and slight in the rest of the AL-type and all of the prealbumin-type. Our observations and descriptions in the literature indicate that the presence and degrees of amyloid deposition in the skeletal muscles would be related to the types of amyloid proteins in amyloidosis. It seems likely that the alTmity of amyloid to the skeletal muscles is variable in AL-type, probably depending on the molecular heterogeneity of AL protein, is low in prealbumin-type, and is almost absent in AA-type.
Key words: Systemic amyloidosis; Amyloid proteins; AL amyloid; AA amyloid; Prealbumin-related amyloid; Skeletal muscle; Amyloid myopathy
Correspondence to: Masahito Yamada, MD, Dept. of Neurology, Faculty of Medicine, Tokyo Medical and Dental University, 1-5-45,Yushima, Bunkyo-ku,Tokyo 113,Japan.
0022-510X/88/$03.50 © 1988Elsevier SciencePublishers B.V. (BiomedicalDivision)
224 INTRODUCTION
Amyloid deposition in the skeletal muscles is commonly found in systemic amyloidosis, although it is usually clinically silent (Engel and Banker 1986). Some cases with systemic amyloidosis show exceptionally massive deposition of amyloid in the skeletal muscles with myopathic manifestations (Lange 1970; Martin et ai. 1970; Miyazaki et al. 1973; Terashima et al. 1977; Whitaker et al. 1977; Miyasald et al. 1979; Ringel and Claman 1982; Ii et al. 1984; Doriguzzi et al. 1987). Recently, considerable advancements have been made in the biochemical characterization of amyloid proteins, and proposals have been made for the chemical categorization of amyloid disease (Glenner 1980; Husby and Sletten 1986; Cohen and Connors 1987). The major amyloid fibril protein is known to be AA in secondary amyloidosis and familial Mediterranean fever, and AL (A-kappa or A-lambda) in primary and myeloma-associated amyloidosis. Prealbumin-type amyloid (Comwell et al. 1987) has been known to be found in 2 forms of systemic amyloidosis, type I familial amyloidotic polyneuropathy (FAP) (Tawara 1983; Saraiva 1984) and senile systemic amyloidosis (SSA) (Pitkanen 1984). The relationships between the type of amyloid proteins and involvement of the skeletal muscles have not yet been elucidated. In this report, we investigate amyloid deposition in the skeletal muscles in 12 cases of systemic amyloidosis which were classified to AL-, AA-, and prealbumin-types. The relationships between the type of amyloid and deposition in the skeletal muscles are discussed.
MATERIALS AND METHODS
Twelve cases of systemic amyloidosis were studied (Table I). Six cases (cases I-6) were classifiedas AL- (primary or myeloma-associated) type amyloidosis. These 6 cases had no positivefamily history.Plasma celldyscrasias (PCD) with monoclonal immunoglobulins and/or Bence-Jones proteins (BJP) were found in all 6 of these cases (Table i). One of them (case I) suffered from multiple myeloma. The other 5 cases (cases 2-6) had small quantitiesof serum M-components and mild proliferationof the bone marrow plasma cells (up to 7 ~), but no overt myeloma. In these cases, amyloid was resistantto potassium permanganate treatment before Congo red staining (Wright et al. 1977) and did not stain with anti-human AA-antisera (Kyowa Medex) or anti-human prealbumin-antisera(Hoechst-Behring) by the peroxidase-antiperoxidase(PAP) technique (Fujihara et al. 1981). Two cases (cases 7 and 8) were classified as AA- (secondary) type. The amyloidosis in both of the 2 cases was associatedwith chronic rheumatoid arthritis.In these cases, amyloid was sensitiveto potassium permanganate treatment, and stained with anti-human AA-antisera by the P A P technique. The 4 remaining cases (cases 9-12) were classifiedas prealbumin-type. All of these 4 cases presented with polyneuropathy, and the amyloid was resistant to potassium permanganate treatment and stained with anti-human prealbumin-antisera
70/F 60/F
34/M 40/M 70/M 76/M
7 8
9 10 11 12
Prealbumin Prealbumin Prealbumin Prealbumin
AA
AL AL AL AL AL AL
amyloidosis
Type of
-
BJP-lambda BJP-lambda IgA-lambda IgG-lambda IgG-lambda IgG-lambda
M-protein
+ + + +
+
+ + +
+ + + + + +
+ + +++ +
+
++
+
Conduction
block
Heart failure
Cardiac disorders
Clinical features
WITH SYSTEMIC A M Y L O I D O S I S
- , absent; + , slight, + +, moderate; + + + ; marked. a Case 1 showed progressive muscular stiffness, pseudohypertrophy, and weakness.
57/M 52/M 79/F 46/F 71/M 67/M
Age/Sex (yrs)
1 2 3 4 5 6
Case No.
CLINICAL FEATURES O F 1 2 P A T I E N T S
TABLE I
+++ +++
++-i+ + + ++ +++
Renal disorders
+ +
+++ +++
Macroglossia
+++ +++ +++ +++
+++ +++
Neuropathy
-I-++ +++ +++ +++
+++ +++
+++a
Muscle weakness
L~
226 by the PAP technique. Two (cases 9 and 10) were hereditary and diagnosed as type I FAP. The other two (cases 11 and 12) had no positive family history or PCD. Details of the two sporadic cases were previously reported (Yamada et al. 1987). One (case 11) of the 2 cases was considered to be atypical FAP because an abnormal serum prealbumin and prealbumin gene, which were found in type I FAP (Nakazato et al. 1984; Sasaki et al. 1984), were detected. The exact origin of amyloid protein in the other case (case 12) remains unclear. Clinical data are shown in Table 1. Concerning neuromuscular disorders, polyneuropathies were found in 6 cases, consisting of 2 of the AL-type (cases 3 and 4) and 4 of the prealbumin-type (cases 9-12). The polyneuropathies were of the sensorimotor type. All of these 6 cases presented with distal-dominant muscular atrophy and weakness of marked degree. One case of the AL-type without polyneuropathy (case 1) showed progressive muscular stiffness and weakness with hypertrophic appearances of the muscles in the entire extremities, and was considered to be suffering from systemic amyloid myopathy. Macroglossia was noted in 6 of our cases, and it was especially prominent in 2 cases (cases 1 and 2). Cardiac and renal disorders were commonly found, although no cardiac disorder was found in AA-type. Biopsied (in cases 11 and 12) and autopsied (in cases 1-10 and 12) muscle tissues obtained from the quadriceps femoris were examined pathologically. In all of the cases, formalin-f'Lxed, paraff'm-embedded sections were stained with Congo red and examined under polarized light for the presence of green birefringence. In one case of the AL-type which showed a large amount of amyloid deposition in the quadriceps femoris (case 1), muscle tissue was fixed in 2.5~ glutaraldehyde, and examined in an electron microTABLE 2 H I S T O P A T H O L O G I C A L F I N D I N G S ON A M Y L O I D D E P O S I T I O N A N D M U S C U L A R A T R O P H Y IN T H E Q U A D R I C E P S F E M O R I S M U S C L E S F R O M 12 PATIENTS WITH SYSTEMIC AMYLOIDOSIS
Case No.
Type of amyloidosis
Amyloid deposition
Muscular atrophy (type of change)
1
AL
+ + +
+ + + (M)
2 3 4 5 6
AL AL AL AL AL
+ + + + + +
+ (M) + + (N) + + + (N) -
7 8
AA AA + + + +
+ + + +
9 10 11 12
Prealbumin Prealbumin Prealbumin Prealbumin
+ + (N) + + (N) + (N) + (N)
- ; absent; + , slight; + +, moderate; + + + , marked. M; myopathic change; N, neurogenic change.
227 scope. Amyloid deposits in other organs were also evaluated histologically for the purpose of elucidating the relationships in amyloid deposition between skeletal muscle and other organs.
RESULTS
Degrees of amyloid deposition and muscle fiberatrophy in the quadriceps fcmoris muscle are shown in Table 2. All cases of the AL- and prealbumin-types presented amyloid deposition in the quadriceps femoris muscles, although the degrees of amyloid deposition varied. Amyloid was deposited in and around intramuscular small blood vessels and in pcriand endomysium. In the AL-type, a case with progressive muscular stiffnessand weakness (case I) showed massive amyloid deposition in the quadriceps femoris (Fig. I).Amyloid infiltration of blood vessel walls was marked. Vessels of all sizes, some of which wcrc identifiableas arteryor vein, had amyloid deposition showing thickening of theirwalls with or without luminal stenosis.Vascular amyloid deposits massively extended to the perivascular areas. Interstitialamyloid infiltrationwas also found in the pcri- and endomysium. The amyloid was associated with atrophy and distortion of adjacent muscle fibers, but was not observed beneath the sarcolemma. N o necrosis or
Fig. 1. Quadriceps femoris muscle from case 1. Massive amyloid deposits, showing green birefringence under polarized fight, are found in the blood vessels and interstitium (a). There is endomysial amyloid deposition with atrophy ofthe muscle fibers (b). (a: Congo red, polarized light, x 52; b:Congo red, polarized light, x 130.)
228
Fig. 2. Electron micrographs of the quadriceps fcmoris muscle from case 1. Amyloidfibrils (AF) are depositedaroundmusclefibers( x 4300).Inset; ~-power magnificationof straightnon.branchingamyloid fibrils ( x 32400). phagocytosis of muscle fibers were found. Inflammation was absent. Electron microscopically, amyloid fibrils, which appeared as straight and nonbranching fibrils, were densely deposited around the muscle fibers and blood vessels (Fig. 2). No amyloid fibrils were observed within the muscle fiber. Sarcolemmal membranes appeared intact. The quadriceps femoris of the other cases of the AL-type showed moderate or mild amyloid deposition which was vascular and interstitial. Muscle fibers surrounded by endomysial amyloid deposition were focally found, and these fibers showed atrophic
changes of various degrees. In the prealbumin-type, amyloid deposition in the quadriceps was mild and almost confined to the blood vessels. The 6 cases with polyneuropathy including both the A L (cases 3 and 4) and prealbumin typos (eases 9-12) showed marked or moderate neurog~aic atrophy of the quadriceps femoris muscles, such as group atrophy and small angulated fibers. In the AA-type, amy!old depositionwas absent in the quadriceps fcmoris muscle. Muscle fibers were well preserved. Marked macroglossia was found in the 2 cases which showed marked or moderate amyloid deposition in the quadriceps femoris muscle (cases 1 and 2; Tables 1 and 2). Amyloid deposits in organs other than the quadriceps femoris muscle are shown in Table 3. Amyloid deposits in the quadriceps femoris muscle did not appear
229 TABLE 3 AMYLOID DEPOSITION
I N T H E O R G A N S O T H E R T H A N S K E L E T A L M U S C L E S I N T H E 12
CASES WITH SYSTEMIC AMYLOIDOSIS
C a s e No.
Type of amyloidosis
Heart
Kidney
Spleen
Gastrointenstinal tract
Peripheral nerve
++ ++ ++ +++ ++ +++
+
+
+++
-
3 4 5 6
AL AL AL AL AL AL
+++ +++ + + ++
+ +++ + + +
++ ++ ++ +++ ++
+++ +++ -
7 8
AA AA
+ +
+++ +++
++ +
++ ++
Prealbumin Prealbumin Prealbumin Prealbumin
+ + + + n.e. + + +
n.e. + + n.e. +
+ + n.e. n.e. +
n.e. + +a + + +
1 2
9 10 11 12
+ + + +
+ + + + a + +
- , a b s e n t ; + , slight; + + , m o d e r a t e ; + + + , m a r k e d ; n.e., not e x a m i n e d . a Biopsied material.
to be significantly correlated with those in the heart, kidneys, spleen, gastrointestinal tract, and peripheral nerve.
DISCUSSION
Our series included AL-, AA-, and prealbumin-type amyloidosis. The presence and degrees of amyloid deposition in the skeletal muscles appeared to be related to the types of amyloidosis as discussed below. In the 2 cases of the AA- (secondary) type, no amyloid deposit was found in the skeletal muscles. Darlin (1949) reported no involvement of the striated muscle in 30 patients with secondary amyloidosis. Adams (1975) described that skeletal muscles might be rarely involved in secondary amyloidosis. The affinity of AA amyloid to skeletal muscles would be almost absent. In the 4 cases of the prealbumin-type, amyloid deposition in the skeletal muscles was uniformly mild and almost confined to the blood vessels. Prealbumin-type amyloid (Comwell et al. 1987) has been known to be found in type I FAP (Tawara et al. 1983; Saraiva et al. 1984) and SSA (Pitkanen et al. 1984). All of the 4 cases had polyneuropathy as found in type I FAP. As mentioned above, 3 of the 4 cases (cases 9, 10, ll) were classified as FAP, whereas the origin of amyloid protein in the rest (case 12) remains unclear. Skeletal muscle amyloid deposition in type I FAP has been reported to be slight or absent (Andrade 1952; Shirabe et al. 1969). Skeletal muscle amyloid deposition was not described in SSA, although amyloid deposits were reported in the
230 striated muscle of the tongue (Pitkanen et al. 1984). The affinity of prealbumin-type amyloid to skeletal muscles appears low. Degrees of amyloid deposition in the skeletal muscles in 6 cases of AL type varied. Amyloid deposition, which was vascular and interstitial, was marked in one (case 1), moderate in one (case 2), and mild in the others (cases 3-6). In the case of amyloid myopathy (case 1), amyloid deposition in the quadriceps was massive in blood vessels and peri- and endomysium. Amyloid deposition in the endo- and perimysium appeared to cause compression atrophy of the muscle fibers, and massive vascular amyloid deposition might cause ischemic changes of the muscle fibers. It is very rare that massive amyloid deposition in the skeletal muscles causes progressive muscular weakness, stiffness, and pseudohypertrophy as found in case 1. Amyloid myopathies due to massive amyloid deposition have been reported to be often associated with the presence of PCD, suggesting that the major amyloid was AL (Miyazaki et al. 1973; Terashima et al. 1977; Whitaker et al. 1977; Ringel and Claman 1982; Ii et al. 1984; Doriguzzi et al. 1987). Ii (1984) postulated that kappa-type BJP was found in most cases of amyloid myopathy, although the presence of lambda chains has also been reported including our case 1 (Whitaker et al. 1977; Ringel and Claman 1982). Because the 6 cases of AL type which we examined all had lambda-type light chain as M-protein, we cannot comment on the difference in skeletal muscle involvement between A-kappa and A-lambda types. Variable regions of light chains have been known to be "amyloidogenic" in the AL-type, and "amyloidogenic" light chains vary and do not have uniform peculiarity (Glenner 1980). Such a molecular variety of "amyloidogenic" light chains might be related to a variety in degrees of amyloid deposition in skeletal muscles. In other words, a variety of affinity of AL amyloids to the skeletal muscles might depend on heterogeneity of "amyloidogenic" light chains. Isobe and Osserman (1974) postulated that the binding affinities of amyloids to certain tissue might be due to immunologic interaction between certain tissue constituents (i.e., autoantigens) and light chains of autoantibodies. To elucidate the peculiarity of AL amyloid or "amyloidogenic" light chains causing amyloid myopathy, further studies are necessary. Furthermore, it is noteworthy that all of the reported cases of amyloid myopathy including our cases have presented with macrogiossia, although this was not necessarily associated with amyloid myopathy. The affinity ofAL amyloid to skeletal muscle would be generally lower than that to the lingual muscle which is also a striated muscle. Amyloid deposition in skeletal muscle was not correlated with that in the heart, kidneys, spleen, gastrointestinal tract, and peripheral nerve. Interstitial connective tissue in each organ is a major site of amyloid deposition. In skeletal muscle, it was reported that the collagens mainly consisted of type IV and III in the endomysium and of type III in the perimysium (Duance et al. 1977). The differences in collagen types exist among various tissues and organs (Bornstein and Sage 1980), and may be important for tissue distribution of amyloid deposits.
231 ACKNOWLEDGEMENTS
This work was supported in part by Research Committee on Primary Amyloidosis, Ministry of Health and Welfare, Japan. The authors are grateful to all of the members of the Departments of Neurology and Pathology, Tokyo Medical and Dental University, for their help.
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