International Journal of Cardiologv. 32 (1991) 83-92 8: 1991 Elsevier Science Publishers B.V. 0167-5273/91/$03.50 ADONIS 0167527391001623
CARD10
83
01259
Senile systemic amyloidosis: a clinico-pathological study of twelve patients with massive amyloid infiltration Bjiirn Department
of Pathology,
Uniwrsrty
Hospital, (Received
Johansson
and Per Westermark
Uppsala. Sweden;
Department
10 May 1990; revision accepted
of Pathology. 24 January
Unicrersit_v Hospital. Linkiiping
Sweden
1991)
Johansson B. Westermark P. Senile systemic amyloidosis: a clinico-pathological with massive amyloid infiltration. Int J Cardiol 1991:32:83-92.
study
of twelve patients
Hearts from 12 patients, 82-92 years old, with immunohistochemically verified pronounced senile systemic amyloidosis, were studied postmortem. Sections from the left ventricle, atrioventricular and sinus nodes and atrioventricular bundle were studied using the light microscope. The weights of the hearts varied between 310 and 870 grams. In the studied parts of the conduction system, the amounts of amyloid were considerably smaller than in the surrounding myocardium. Clinical data were taken from available case records. Eight of the patients had a history of uncomplicated congestive heart failure, but only two had been in hospital with cardiac symptoms prior to their last admission. The electrocardiogram showed atrial fibrillation in nine cases, left bundle branch block in three, right bundle branch block in two and left anterior hemiblock in one. No evidence of atrioventrictdar dissociation was seen and, in no case, was death considered to be due to conduction disturbances. Amyloidosis was a contributing cause of death in 7 patients, while the remaining patients died of other diseases. Amyloidosis is rarely diagnosed before death and was not suspected during life in any of our patients. Key
words:
Amyloidosis;
Aging;
Heart disease;
Heart conduction
Introduction Senile systemic amyloidosis is a very common disease in older persons but is usually only detected at microscopical examination after autopsy. In most cases, there are only small deposits in the heart and in the vessels of many organs. Massive infiltration is sometimes seen in the heart but as a
Correspondence to: Dr B. Johansson, tion Medicine, Akademiska Sjukhuset. Sweden.
Dept. of RehabilitaS-751 85 Uppsala,
system;
Transthyretin
rule, only in very old persons [l-8]. The clinical significance of senile systemic amyloidosis is still a matter of discussion [1,3,5,7-lo]. Cardiac amyloidosis has been reported to be associated with congestive heart failure, angina pectoris, arrhythmia, conduction disturbances, digitalis sensitivity and low voltage electrocardiogram [ll]. In most previous studies, however, a detailed typing of the amyloid has not been performed. In this respect, it is significant that amyloid infiltration of the heart in familial amyloidosis with polyneuropathy of Japanese, Portuguese and Swedish type is known to cause severe arrhythmia and conges-
84
tive heart failure [12-151. In this setting, however, symptoms from other organs due to amyloid infiltration are generally found. Most prominent is a sensorimotor polyneuropathy [16]. Since senile systemic amyloidosis as well as familial amyloidosis with polyneuropathy are disorders of transthyretin (previously prealbumin) [17] one might have expected similar clinical cardiac manifestations. Indeed, there are some studies that support this expectation [5,7,9,18]. The chemical nature of the amyloid, nonetheless, was determined in only one of those studies [9], where, surprisingly, the ages of the patients were unusually low. Consequently, patients with other types of amyloid might have been included in those studies. We now describe the clinical and necropsy findings in 12 patients with verified senile systemic amyloidosis leading to massive cardiac involvement.
Materials and Methods Hearts Hearts from patients suspected at autopsy to have senile systemic amyloidosis were frozen at -20°C prior to further examination. Pieces from the wall of the left ventricle were fixed in 4% formaldehyde solution, embedded in paraffin, and sections stained with alkaline Congo red were examined in polarized light. Infiltration with amyloid was considered massive if 40% or more of the left ventricular sections were occupied by amyloid. Fourteen hearts with massive infiltration were originally included in the study. Clinical data and the result of the autopsy were obtained retrospectively from available case records. In one patient the record was not available and the data including information on cardiac insufficiency and atria1 fibrillation were taken from the referral to the pathology department. Amyloid typing A rabbit antiserum to the transthyretin-derived subunit protein of senile systemic amyloidosis has been previously characterized [4,19]. In immunohistochemistry, and in double immunodiffusion, this antiserum does not react with amyloid from
patients with systemic amyloidosis of primary or secondary type. In 8 of the 14 hearts, amyloid fibrils were extracted and degraded amyloid solution [20] was used for double immunodiffusion when typing [19]. Due to lack of material, the peroxidase-antiperoxidase method [21] was used for amyloid typing in the remaining 6 hearts. In two cases the amyloid did not react with the antiserum and these patients were consequently not included in the material. Thus, 12 patients, of whom 3 were women, remained for the study. In three of these patients (cases 34, 280 and 622), the transthyretin origin of the amyloid was further proven by sequence analysis of amino acids in the purified amyloid subunit protein [22, 23 and unpublished result]. Examination
of the conduction system
After the hearts had been thawed, the sinus node and the specialized atrioventricular junctional area were cut out en bloc [24]. After fixation in 4% formaldehyde solution and dehydration, the blocks were divided into 6-8 pieces which were embedded in paraffin and sectioned. Staining was performed according to van Gieson and with alkaline Congo red. The sections were examined in a microscope equipped with polarization filters.
Results Autopsy findings All patients were over 80 years old and six were over 90 (Table 1). The weights of the hearts varied between 310 and 870 g. All hearts were firm with a smooth cut surface and had thickened ventricular walls. In 9 patients, there was also a severe generalized atherosclerosis. In 7 patients, congestive heart failure due to senile systemic amyloidosis and atherosclerosis was considered to be the cause of death. Of the remaining 5 patients, one (case 250) died from adenocarcinoma of the large intestine, one (case 34) from uraemia due to chronic arteriosclerotic nephropathy, one (case 62) from pulmonary embolism, one (case 472) from
85 TABLE
1
Clinical and necropsy systemic amyloidosis. Mean age Mean heart weight No. of patients Heart failure Heart rhythm Sinus rhythm Atria1 fibrillation Cardiac death
findings
in patients
with severe senile
88 (range 82-92) 567 (range 310-870) 12 (males 9, females 3) 8
block in three cases, left anterior hemiblock in one and right bundle branch block in two. Three patients had sinus rhythm but no perfectly normal electrocardiogram was seen. Atrioventricular block was not seen in any electrocardiographic traces (Table 2). Histopathological
3 9 7
Cardiac death = death due to congestion. Heart failure = history of congestive heart failure before last admission to hospital.
pneumonia and one (case 272) from infarction of the brain. Clinical history
All patients died at hospital, 6 within one week and 5 within four weeks of admission. One died at a geriatric clinic where he had stayed for 8 months due to cirrhosis of the liver of unknown origin. In none of the patients was amyloidosis suspected before death, and no patient had any family history of arnyloidosis. Cardiac insufficiency varying from two months to several years had been seen in 8 of the patients. No patient suffered from severe cardiac insufficiency and all responded to the usual therapeutic measures. Only two patients had been admitted to hospital with cardiac symptoms before their last admission, One of these two had a history of varying arrhythmia with episodes of bradycardia where the electrocardiogram showed a nodal rhythm. Pace-maker treatment was discussed two years before death. He improved spontaneously when he stopped taking digitalis. Two days before death, his electrocardiogram showed atria1 fibrillation and left bundle branch block. The other patient had a period of ventricular tachycardia one month before death, but this was ascribed to an acute myocardial infarction. The day before death, the electrocardiogram showed atria1 fibrillation. In the entire material, atria1 fibrillation was noted in nine cases. Besides, the electrocardiogram showed left bundle branch
findings
Heavy amyloid deposits were seen in the myocardium of all patients (Fig. 1). The infiltration often was patchy with numerous small deposits which tended to coalesce in many areas. The deposits surrounded the individual, often atrophic muscle cells. The amount of amyloid in the sinus node was less than in the rest of the right atrium (Figs. 2, 3 and 4). The amyloid was largely restricted to the nodal vessels. Furthermore, in the area of the atrioventricular node and bundle, the amount of amyloid was considerably less than in the rest of the septum (Figs. 5 and 6). The amyloid was seen in the vessels and the adipose tissue but not, as a rule, in the conduction tissue. Atrophy of the sinus and atrioventricular nodes was frequently seen, with an increased amount of fat and TABLE 2 Histopathologic findings and rhythm and conduction disturbances as revealed by electrocardiogram in twelve patients with advanced senile systemic amyloidosis. Patient
Age
ECG
Sinus node
AV node
AV bundle
34 62 250 212 280 332 319 472 491 556 622 698
91 85 92 89 83 82 83 84 92 91 90 92
AF, LBBB LAH AF AF,RBBB LBBB AF AF AF AF AF AF, LBBB RBBB
A+ + N A4 A++,F A++,F A+,F A++,F A++ A+ A++ Not studied F
F A+ N A+,F N A+ A++,F A+, F A-t,F A+,F A+ A+,F
A+,F A++.F N A+ N A+ A+,F A++ F N N N
ECG = electrocardiogram; AV = atrioventricular; AF = atria1 fibrillation; LAH = left anterior hemiblock; RBBB = right bundle branch block; LBBB = left bundle branch block; A + = minor amounts of amyloid; A+ + = small amounts of amyloid; F = marked atrophy with fibrosis and fat; N = no amyloid or no marked atrophy.
86
connective tissue, consistent with what may expected in this age group [10,25] (Table 2).
be
Case Reports For illustration, four cases are reported. Case 250. This woman died when she was 92 years old. She had been healthy until three years before death when she was admitted to hospital with an abdominal tumour. She refused further investigations. She had not had any cardiac symptoms but a slight lower leg oedema, noticed one year before death. Eventually she was admitted to hospital due to nutritional problems. At examination, she was dehydrated, had minor lower leg oedema and a slight fever. The heart rhythm was irregular. An abdominal tumour could be palpated. Results of a chest X-ray examination were normal.
Fig. 1. Myocardial
tissue (M) of a patient
The electrocardiogram showed atria1 fibrillation and a flat T-wave. Her condition slowly deteriorated and she died after two weeks at hospital. Autopsy revealed a carcinoma of the large intestine with extensive necrosis but no metastases, pulmonary emphysema and a mild atherosclerosis. The heart was firm and weighed 310 g. The carcinoma was the immediate cause of death. The sections of the left ventricle contained about 40% amyloid but no amyloid occurred in the atrioventricular node or bundle. Minor amounts of amyloid were seen in the sinus node (Figs. 3 and 4). Case 280. This man, who died 83 years old, had previously been essentially healthy. He was admitted to hospital with one week’s history of increasing oedema of his lower legs. On examination, he had labial cyanosis and redness and
(case 62) with massive, patchy, infiltration of senile systemic trichrome stain, original magnification x 200.
amyloidosis
(A). Masson’s
87
oedema of the lower legs. He had no dyspnoea. The heart rhythm was even and a systolic murmur was heard. The electrocardiogram showed sinus rhythm and left bundle branch block. He became apathetic and died after 12 days. Autopsy showed a large and firm heart weighing 720 g, moderate generalized atherosclerosis, hydronephrosis, bronchopneumonia and acute and chronic venous congestion. The sections from the left ventricle contained more than 50% amyloid. Small amounts of amyloid were seen in the sinus node, but not in the atrioventricular node or bundle. The transthyretin origin of the amyloid was verified by sequence analysis of the ammo acids in this case. Case 62. This man was 86 years old when he died. He had suffered from uncharacteristic intermittent chest pain for a couple of years but did
not take any medicine. Otherwise, he had been essentially healthy but for a minor stroke two years earlier. He was admitted to hospital due to increasing chest pain that was most prominent the night before admission, when he also had bloodstreaked expectoration. When examined, he no longer had any pain and no apparent distress was noted. The heart rhythm was even, no murmurs were heard and the pulse rate was 90. Blood pressure was normal and he showed no signs of heart failure. The electrocardiogram showed sinus rhythm and left anterior hemiblock. A gastroscopy showed chronic atrophic gastritis. Routine laboratory examination was normal. After 5 days at hospital with no definite diagnosis, he suddenly died. Autopsy revealed massive pulmonary embolism, bronchitis, an old brain infarction and a
Fig. 2. Part of a sinus node (SN) of a patient (case 491) with senile systemic amyloidosis. No amyloid large amounts of amyloid in the surrounding atria1 tissue (arrows). Van Gieson stain, original
is seen in the node in spite of magnification X 80.
88
firm heart with thickened ventricular walls (heart weight 380 g). Pulmonary embolism was the cause of death. The sections from the left ventricle contained more than 50% amyloid (Fig. 1). No amyloid was seen in the sinus node. Small amounts of amyloid were seen in the atrioventricular node (Fig. 5) and bundle (Fig. 6), most prominent in some vessels in the bundle. Case 34. This man was 91 years old when he died. He had been essentially healthy until 6 months before death when mild cardiac and renal failure was diagnosed. He improved after treatment with digitalis and furosemide. He was admitted to hospital for the first time in his life because of an incipient gangrene of his right foot. On examination, he showed no signs of heart
failure and did not complain of dyspnoea. The heart rhythm was irregular and the frequency was 80. No murmurs were heard. The electrocardiogram showed atria1 fibrillation and left bundle branch block. A chest X-ray examination revealed a moderately enlarged heart. He died after one week at hospital. Autopsy revealed small arteriosclerotic kidneys, severe atherosclerosis, marked cardiac enlargement (heart weight 620 g) and bronchopneumonia. The cause of death was considered to be renal failure. The sections from the left ventricle contained about 50% amyloid. There were small amounts of amyloid in the sinus node and minor amounts in the atrioventricular bundle. No amyloid was seen in the atrioventricular node. In this case, the transthyretin origin of the amyloid
Fig. 3. Part of a sinus node (SN) of a patient (case 250) with senile systemic amyloidosis. No amyloid is seen in this section of the node. The surrounding atrial tissue is heavily infiltrated by amyloid (arrows). Van Gieson stain, original magnification X 80.
89
Fig. 4. Part of the same sinus node (SN) as in Fig. 3 in a higher magnification. Massive amyloid atrial tissue (arrows). Van Gieson stain. original magnification
was verified acids [23].
by sequence
analysis
of the amino
Discussion In this study, we found advanced senile systemic amyloidosis only in patients over 80, and more frequently in men. No patient seemed to have a history of severe congestive cardiac failure that was resistant to therapy. All but one died within four weeks of admission to hospital. An increased frequency of atria1 fibrillation [26-291 and, possibly, bundle branch blocks 1291 were seen. More complicated arrhythmias were rare, and could be explained by reasons other than infiltration of amyloid. Another striking finding in this material was the sparing of the conduction tissue from severe infiltration. Our findings are in
x
infiltration 200.
is seen in the surrounding
agreement with a previous study, probably mainly including patients with senile systemic amyloidosis, where only minor infiltration of the specialized conduction tissue was seen [lo]. Senile systemic amyloidosis, notwithstanding massive cardiac infiltration, is very seldom diagnosed before death. Thus, no patient in this study was suspected to have amyloidosis. One explanation of this could be that it more rarely gives severe symptoms, or that the symptoms do not differ from those of other age-related afflictions in this group of very old persons. In contrast, the conduction system of the heart in patients with familial amyloidosis with polyneuropathy of Japanese, Portuguese and Swedish type often is strongly infiltrated by amyloid [12-141. This could most certainly explain the frequent occurrence of severe arrhythmias in that form of
Fig. 5. Part of the atrioventricular whereas most of the surrounding
node (AV) from the same patient as in Fig. 1. Minor amounts cardiac muscle tissue to the right is replaced by amyloid (arrows). Van Gieson stain, original magnification x 80.
amyloidosis. Although it is difficult to differ between other age-related symptoms and those caused by amyloid, our study supports the suspicion that senile systemic amyloidosis is a relatively benign form of amyloidosis and, consequently, that there is an obvious difference in the cardiac manifestations in familial amyloidosis with polyneuropathy of Japanese, Portuguese and Swedish type and senile systemic amyloidosis. The reason for this is unknown, but it may be noted that most data indicate that transthyretin is normal in senile systemic amyloidosis [17,22,23] whereas familial amyloidosis with polyneuropathy has been shown to be related to a variant of transthyretin (methionine instead of valine in position 30 in the Japanese, Portuguese and Swedish type) [15-171.
of amyloid are seen in the node Central fibrous body to the left.
Recently, the occurrence of a variant of transthyretin in senile systemic amyloidosis (isoleucine instead of valine in position 122) has been reported [30-321. Compared to our findings, patients with this variant were much younger, they were black and they seemed to have had more severe cardiac symptoms. Furthermore, in one study, an unusually high frequency of senile systemic amyloidosis was reported in black male patients under the age of 80 [33]. Rather than senile systemic amyloidosis, they could represent a familial amyloidotic cardiomyopathy. Although most patients with familial amyloidosis hitherto described have other than cardiac manifestations, there is one type of familial amyloidosis which seems to affect mainly the heart. This Danish
Fig. 6. Penetrating atrioventricular bundle (AVB) from the same patient as in Fig. 1. Small amounts of amyloid are seen in some vessel walls (arrows). There is marked atrophy with increased amounts of fat. Van Gieson stain, original magnification x 80.
of familial amyloidotic cardiomyopathy has its onset in the fourth decade of life and leads to death in congestive heart failure within five years [34]. A variant of transthyretin (methionine instead of leucine in position 111) is also present in this Danish form of amyloidosis [35]. Consequently, the occurrence of variant instead of normal transthyretin could not be the only explanation of the different manifestations in transthyretin-related amyloidosis. Hypothetically, factors normally inhibiting the formation of fibrils from transthyretin could exist, which decreases with age and which is less efficient in inhibiting formation of fibrils from variants of transthyretin. A variation in activity in different tissues of this hypothetical factor could explain the wide range of
variant
affected tissues in variants lated to transthyretin.
forms
of amyloid
re-
Acknowledgements We thank Ylva Persson, Anna-Helena Forsberg and Christer Bergman for valuable technical assistance. We also thank Dr Hans Nordgren for supplying us with autopsy material, Nils Backer for help with the photographs and Nigel Rolhson for expert linguistic revision. This study was supported by the Swedish Medical Research Council (Project No. 5941), the Research Fund of Ring Gustaf V, the Foundation of Erik, Karin and Gbsta Selander, the Memorial Fund of Josef and Linnea Carlsson, and the Royal Scientific Society in Uppsala.
92
References 1 Buerger 2
3
4 5 6
7 8 9
10
11
12
13
14
15
16
17
L, Braunstein H. Senile Cardiac Amyloidosis. Am J Med 1960;28:357-367. Comwell GG III, Murdoch WL, Kyle RA, Westermark P, Pitkiinen P. Frequency and distribution of senile cardiovascular amyloid. A clinicopathologic correlation. Am J Med 1983;75:618-623. Hodkinson HM, Pomerance A. The clinical significance of senile cardiac amyloidosis: a prospective clinico-pathological study. Q J Med 1977;46:381-387. Pitkiien P, Westermark P, Cornwell GG III. Senile systemic amyloidosis. Am J Path01 1984;117:391-399. Pomerance A. The pathology of senile cardiac amyloidosis. J Path01 Bacterial 1966;91:357-367. Westermark P, Johansson B, Natvig JB. Senile cardiac amyloidosis: evidence of two different amyloid substances in the ageing heart. Stand J Imrnunol 1979;10:303-308. Wright JR, Calkins E. Amyloid in the aged heart: frequency and clinical significance. J Am Geriatr Sot 1975;23:97-103. Wright JR, Calkins E. Clinical-pathological differentiation of common amyloid syndromes. Medicine 1981;60:429-448. Olson LJ, Gertz MA, Edwards WD, Li C-Y, Pellikka PA, Holmes Jr DR, Tajik AJ, Kyle RA. Senile cardiac amyloidosis with myocardial dysfunction. Diagnosis by endomyocardial biopsy and immunohistochemistry. N Engl J Med 1987;317:738-742. Ridolfi RL, Bulkley BH, Hutchins GM. The conduction system in cardiac amyloidosis. Clinical and pathological features of 23 patients. Am J Med 1977;62:677-686. Falk RH. Cardiac involvement in amyloidosis. In: Marrink J, Van Rijswijk MH, eds. Amyloidosis. Dordrecht: Martinus Nijhoff Publishers, 1986;73-82. Eriksson A, Eriksson P, Olofsson B-O, Thomell LE. The sinoatrial node in familial amyloidosis with polyneuropathy. A clinico-pathological study of nine cases from Northem Sweden. Virchows Arch A 1984;402:239-246. Eriksson A, Eriksson P, Olofsson B-O, Thomell LE. The cardiac atrioventricular conduction system in familial amyloidosis with polyneuropathy. A clinico-pathologic study of six cases from Northern Sweden. Acta Path Microbiol Immunol Stand Sect A 1983;91:343-349. Takahashi K, Kimura Y, Yi S, A&i S. Cardiac pathology of familial amyloidotic polyneuropathy (FAP; Japanese type). In: Costa PP, Faldo de Freitas A, Saraiva MJM, eds. Proceedings of the First International Symposium on Familial Amyloidotic Polyneuropathy and other transthyretin related disorders. Porto: Arq Med Suppl 3, in press. Varga J, Wohlgethan JR. The clinical and biochemical spectrum of hereditary amyloidosis. Semin Arthritis Rheum 1988;18:14-28. Araki S. Familial amyloidotic polyneuropathies. In: Marrink J, Van Rijswijk MH, eds. Amyloidosis. Dordrecht: Martinus Nijhoff Publishers, 1986;195-218. Cornwell GG III, Sletten K, Olofsson B-O, Johansson B, Westermark P. Prealbumin: its association with amyloid. J Clin Path01 1987;40:226-231.
18 Liidholm PF, Wick MR. Isolated cardiac amyloidosis associated with sudden death. Arch Path01 Lab Med 1986;llO: 243-245. 19 Westermark P, Natvig JB, Johansson B. Characterization of an amyloid fibril protein from senile cardiac amyloidosis. J Exp Med 1977;146:631-636. 20 Pras M, Zucker-Franklin D, Rimon A, Franklin EC. Physical, chemical and ultrastructural studies of water-soluble human amyloid fibrils. Comparative analysis of nine amyloid preparations. J Exp Med 1969;130:777-795. 21 Stemberger LA. Immunocytochemistry, 2nd ed. New York: John Wiley and Sons, 1979. 22 Comwell GG III, Sletten K, Johansson 8, Westermark P. Evidence that the amyloid fibril protein in senile systemic amyloidosis is derived from normal prealbumin. Biochem Biophys Res Commun 1988;154:648-653. 23 Westermark P, Sletten K, Johansson B, Comwell GG III. The fibril in senile systemic amyloidosis is derived from normal transthyretin. Proc Nat1 Acad Sci USA 1990;87: 2843-2845. 24 Hudson REB. The human conducting-system and its examination. J Clin Path01 1963;16:492-498. 25 Lev M, Bharati S. Lesions of the conduction system and their functional significance. Path01 Ann 1974;9:157-207. 26 Carnm AJ, Evans KE, Ward DE, Martin A. The rhythm of the heart in active elderly subjects. Am Heart J 1980;99: 598-603. 27 Mihalick MJ, Fisch C. Electrocardiographic findings in the aged. Am Heart J 1974;87:117-128. 28 Pate1 KP. Electrocardiographic abnormalities in the sick elderly. Age Ageing 1977;6:163-167. 29 Cattin L, Melato M, Antonutto G, Mlaoc M, Da Co1 PG. ECG findings in elderly patients with and without senile cardiac amyloidosis. J Chron Dis 1981;34:503-509. 30 Gorevic PD. Prelli FC, Wright J, Pras M, Frangione B. Systemic senile amyloidosis. Identification of a new prealbumin (transthyretin) variant in cardiac tissue: immunologic and biochemical similarity to one form of familial amyloidotic polyneuropathy. J Clin Invest 1989;83:836843. 31 Nichols WC, Snyder EL, Liepnieks JJ, Benson MD. Senile cardiac amyloidosis is a hereditary disease. In: Costa PP, Falcb de Freitas A, Saraiva MJM, eds. Proceedings of the First International Symposium on Familial Amyloidotic Polyneuropathy and other transthyretin related disorders. Porto: Arq Med Suppl 3, in press. 32 Jacobson DR, Gorevic PD, Buxbaum JN. A homozygous transthyretin variant associated with senile systemic amyloidosis: evidence for a late-onset disease of genetic etiology. Am J Hum Genet 1990;47:127-136. 33 Wright JR, Calkins E. Clinical-pathologic differentiation of common amyloid syndromes. Medicine 1981;60:429-448. 34 Frederiksen T, Gotzsche H, Harboe N, Kiter W, Mellemgaard K. Familial primary amyloidosis with severe amyloid heart disease. Am J Med 1962;33:328-348. 35 Nordlie M, Sletten K, Husby G, Ranlav PJ. A new prealbumin variant in familial amyloid cardiomyopathy of Danish origin. Stand J Immunol 1988;27:119-122.
CARD10
83
01259
Senile systemic amyloidosis: a clinico-pathological study of twelve patients with massive amyloid infiltration Bjiirn Department
of Pathology,
Uniwrsrty
Hospital, (Received
Johansson
and Per Westermark
Uppsala. Sweden;
Department
10 May 1990; revision accepted
of Pathology. 24 January
Unicrersit_v Hospital. Linkiiping
Sweden
1991)
Johansson B. Westermark P. Senile systemic amyloidosis: a clinico-pathological with massive amyloid infiltration. Int J Cardiol 1991:32:83-92.
study
of twelve patients
Hearts from 12 patients, 82-92 years old, with immunohistochemically verified pronounced senile systemic amyloidosis, were studied postmortem. Sections from the left ventricle, atrioventricular and sinus nodes and atrioventricular bundle were studied using the light microscope. The weights of the hearts varied between 310 and 870 grams. In the studied parts of the conduction system, the amounts of amyloid were considerably smaller than in the surrounding myocardium. Clinical data were taken from available case records. Eight of the patients had a history of uncomplicated congestive heart failure, but only two had been in hospital with cardiac symptoms prior to their last admission. The electrocardiogram showed atrial fibrillation in nine cases, left bundle branch block in three, right bundle branch block in two and left anterior hemiblock in one. No evidence of atrioventrictdar dissociation was seen and, in no case, was death considered to be due to conduction disturbances. Amyloidosis was a contributing cause of death in 7 patients, while the remaining patients died of other diseases. Amyloidosis is rarely diagnosed before death and was not suspected during life in any of our patients. Key
words:
Amyloidosis;
Aging;
Heart disease;
Heart conduction
Introduction Senile systemic amyloidosis is a very common disease in older persons but is usually only detected at microscopical examination after autopsy. In most cases, there are only small deposits in the heart and in the vessels of many organs. Massive infiltration is sometimes seen in the heart but as a
Correspondence to: Dr B. Johansson, tion Medicine, Akademiska Sjukhuset. Sweden.
Dept. of RehabilitaS-751 85 Uppsala,
system;
Transthyretin
rule, only in very old persons [l-8]. The clinical significance of senile systemic amyloidosis is still a matter of discussion [1,3,5,7-lo]. Cardiac amyloidosis has been reported to be associated with congestive heart failure, angina pectoris, arrhythmia, conduction disturbances, digitalis sensitivity and low voltage electrocardiogram [ll]. In most previous studies, however, a detailed typing of the amyloid has not been performed. In this respect, it is significant that amyloid infiltration of the heart in familial amyloidosis with polyneuropathy of Japanese, Portuguese and Swedish type is known to cause severe arrhythmia and conges-
84
tive heart failure [12-151. In this setting, however, symptoms from other organs due to amyloid infiltration are generally found. Most prominent is a sensorimotor polyneuropathy [16]. Since senile systemic amyloidosis as well as familial amyloidosis with polyneuropathy are disorders of transthyretin (previously prealbumin) [17] one might have expected similar clinical cardiac manifestations. Indeed, there are some studies that support this expectation [5,7,9,18]. The chemical nature of the amyloid, nonetheless, was determined in only one of those studies [9], where, surprisingly, the ages of the patients were unusually low. Consequently, patients with other types of amyloid might have been included in those studies. We now describe the clinical and necropsy findings in 12 patients with verified senile systemic amyloidosis leading to massive cardiac involvement.
Materials and Methods Hearts Hearts from patients suspected at autopsy to have senile systemic amyloidosis were frozen at -20°C prior to further examination. Pieces from the wall of the left ventricle were fixed in 4% formaldehyde solution, embedded in paraffin, and sections stained with alkaline Congo red were examined in polarized light. Infiltration with amyloid was considered massive if 40% or more of the left ventricular sections were occupied by amyloid. Fourteen hearts with massive infiltration were originally included in the study. Clinical data and the result of the autopsy were obtained retrospectively from available case records. In one patient the record was not available and the data including information on cardiac insufficiency and atria1 fibrillation were taken from the referral to the pathology department. Amyloid typing A rabbit antiserum to the transthyretin-derived subunit protein of senile systemic amyloidosis has been previously characterized [4,19]. In immunohistochemistry, and in double immunodiffusion, this antiserum does not react with amyloid from
patients with systemic amyloidosis of primary or secondary type. In 8 of the 14 hearts, amyloid fibrils were extracted and degraded amyloid solution [20] was used for double immunodiffusion when typing [19]. Due to lack of material, the peroxidase-antiperoxidase method [21] was used for amyloid typing in the remaining 6 hearts. In two cases the amyloid did not react with the antiserum and these patients were consequently not included in the material. Thus, 12 patients, of whom 3 were women, remained for the study. In three of these patients (cases 34, 280 and 622), the transthyretin origin of the amyloid was further proven by sequence analysis of amino acids in the purified amyloid subunit protein [22, 23 and unpublished result]. Examination
of the conduction system
After the hearts had been thawed, the sinus node and the specialized atrioventricular junctional area were cut out en bloc [24]. After fixation in 4% formaldehyde solution and dehydration, the blocks were divided into 6-8 pieces which were embedded in paraffin and sectioned. Staining was performed according to van Gieson and with alkaline Congo red. The sections were examined in a microscope equipped with polarization filters.
Results Autopsy findings All patients were over 80 years old and six were over 90 (Table 1). The weights of the hearts varied between 310 and 870 g. All hearts were firm with a smooth cut surface and had thickened ventricular walls. In 9 patients, there was also a severe generalized atherosclerosis. In 7 patients, congestive heart failure due to senile systemic amyloidosis and atherosclerosis was considered to be the cause of death. Of the remaining 5 patients, one (case 250) died from adenocarcinoma of the large intestine, one (case 34) from uraemia due to chronic arteriosclerotic nephropathy, one (case 62) from pulmonary embolism, one (case 472) from
85 TABLE
1
Clinical and necropsy systemic amyloidosis. Mean age Mean heart weight No. of patients Heart failure Heart rhythm Sinus rhythm Atria1 fibrillation Cardiac death
findings
in patients
with severe senile
88 (range 82-92) 567 (range 310-870) 12 (males 9, females 3) 8
block in three cases, left anterior hemiblock in one and right bundle branch block in two. Three patients had sinus rhythm but no perfectly normal electrocardiogram was seen. Atrioventricular block was not seen in any electrocardiographic traces (Table 2). Histopathological
3 9 7
Cardiac death = death due to congestion. Heart failure = history of congestive heart failure before last admission to hospital.
pneumonia and one (case 272) from infarction of the brain. Clinical history
All patients died at hospital, 6 within one week and 5 within four weeks of admission. One died at a geriatric clinic where he had stayed for 8 months due to cirrhosis of the liver of unknown origin. In none of the patients was amyloidosis suspected before death, and no patient had any family history of arnyloidosis. Cardiac insufficiency varying from two months to several years had been seen in 8 of the patients. No patient suffered from severe cardiac insufficiency and all responded to the usual therapeutic measures. Only two patients had been admitted to hospital with cardiac symptoms before their last admission, One of these two had a history of varying arrhythmia with episodes of bradycardia where the electrocardiogram showed a nodal rhythm. Pace-maker treatment was discussed two years before death. He improved spontaneously when he stopped taking digitalis. Two days before death, his electrocardiogram showed atria1 fibrillation and left bundle branch block. The other patient had a period of ventricular tachycardia one month before death, but this was ascribed to an acute myocardial infarction. The day before death, the electrocardiogram showed atria1 fibrillation. In the entire material, atria1 fibrillation was noted in nine cases. Besides, the electrocardiogram showed left bundle branch
findings
Heavy amyloid deposits were seen in the myocardium of all patients (Fig. 1). The infiltration often was patchy with numerous small deposits which tended to coalesce in many areas. The deposits surrounded the individual, often atrophic muscle cells. The amount of amyloid in the sinus node was less than in the rest of the right atrium (Figs. 2, 3 and 4). The amyloid was largely restricted to the nodal vessels. Furthermore, in the area of the atrioventricular node and bundle, the amount of amyloid was considerably less than in the rest of the septum (Figs. 5 and 6). The amyloid was seen in the vessels and the adipose tissue but not, as a rule, in the conduction tissue. Atrophy of the sinus and atrioventricular nodes was frequently seen, with an increased amount of fat and TABLE 2 Histopathologic findings and rhythm and conduction disturbances as revealed by electrocardiogram in twelve patients with advanced senile systemic amyloidosis. Patient
Age
ECG
Sinus node
AV node
AV bundle
34 62 250 212 280 332 319 472 491 556 622 698
91 85 92 89 83 82 83 84 92 91 90 92
AF, LBBB LAH AF AF,RBBB LBBB AF AF AF AF AF AF, LBBB RBBB
A+ + N A4 A++,F A++,F A+,F A++,F A++ A+ A++ Not studied F
F A+ N A+,F N A+ A++,F A+, F A-t,F A+,F A+ A+,F
A+,F A++.F N A+ N A+ A+,F A++ F N N N
ECG = electrocardiogram; AV = atrioventricular; AF = atria1 fibrillation; LAH = left anterior hemiblock; RBBB = right bundle branch block; LBBB = left bundle branch block; A + = minor amounts of amyloid; A+ + = small amounts of amyloid; F = marked atrophy with fibrosis and fat; N = no amyloid or no marked atrophy.
86
connective tissue, consistent with what may expected in this age group [10,25] (Table 2).
be
Case Reports For illustration, four cases are reported. Case 250. This woman died when she was 92 years old. She had been healthy until three years before death when she was admitted to hospital with an abdominal tumour. She refused further investigations. She had not had any cardiac symptoms but a slight lower leg oedema, noticed one year before death. Eventually she was admitted to hospital due to nutritional problems. At examination, she was dehydrated, had minor lower leg oedema and a slight fever. The heart rhythm was irregular. An abdominal tumour could be palpated. Results of a chest X-ray examination were normal.
Fig. 1. Myocardial
tissue (M) of a patient
The electrocardiogram showed atria1 fibrillation and a flat T-wave. Her condition slowly deteriorated and she died after two weeks at hospital. Autopsy revealed a carcinoma of the large intestine with extensive necrosis but no metastases, pulmonary emphysema and a mild atherosclerosis. The heart was firm and weighed 310 g. The carcinoma was the immediate cause of death. The sections of the left ventricle contained about 40% amyloid but no amyloid occurred in the atrioventricular node or bundle. Minor amounts of amyloid were seen in the sinus node (Figs. 3 and 4). Case 280. This man, who died 83 years old, had previously been essentially healthy. He was admitted to hospital with one week’s history of increasing oedema of his lower legs. On examination, he had labial cyanosis and redness and
(case 62) with massive, patchy, infiltration of senile systemic trichrome stain, original magnification x 200.
amyloidosis
(A). Masson’s
87
oedema of the lower legs. He had no dyspnoea. The heart rhythm was even and a systolic murmur was heard. The electrocardiogram showed sinus rhythm and left bundle branch block. He became apathetic and died after 12 days. Autopsy showed a large and firm heart weighing 720 g, moderate generalized atherosclerosis, hydronephrosis, bronchopneumonia and acute and chronic venous congestion. The sections from the left ventricle contained more than 50% amyloid. Small amounts of amyloid were seen in the sinus node, but not in the atrioventricular node or bundle. The transthyretin origin of the amyloid was verified by sequence analysis of the ammo acids in this case. Case 62. This man was 86 years old when he died. He had suffered from uncharacteristic intermittent chest pain for a couple of years but did
not take any medicine. Otherwise, he had been essentially healthy but for a minor stroke two years earlier. He was admitted to hospital due to increasing chest pain that was most prominent the night before admission, when he also had bloodstreaked expectoration. When examined, he no longer had any pain and no apparent distress was noted. The heart rhythm was even, no murmurs were heard and the pulse rate was 90. Blood pressure was normal and he showed no signs of heart failure. The electrocardiogram showed sinus rhythm and left anterior hemiblock. A gastroscopy showed chronic atrophic gastritis. Routine laboratory examination was normal. After 5 days at hospital with no definite diagnosis, he suddenly died. Autopsy revealed massive pulmonary embolism, bronchitis, an old brain infarction and a
Fig. 2. Part of a sinus node (SN) of a patient (case 491) with senile systemic amyloidosis. No amyloid large amounts of amyloid in the surrounding atria1 tissue (arrows). Van Gieson stain, original
is seen in the node in spite of magnification X 80.
88
firm heart with thickened ventricular walls (heart weight 380 g). Pulmonary embolism was the cause of death. The sections from the left ventricle contained more than 50% amyloid (Fig. 1). No amyloid was seen in the sinus node. Small amounts of amyloid were seen in the atrioventricular node (Fig. 5) and bundle (Fig. 6), most prominent in some vessels in the bundle. Case 34. This man was 91 years old when he died. He had been essentially healthy until 6 months before death when mild cardiac and renal failure was diagnosed. He improved after treatment with digitalis and furosemide. He was admitted to hospital for the first time in his life because of an incipient gangrene of his right foot. On examination, he showed no signs of heart
failure and did not complain of dyspnoea. The heart rhythm was irregular and the frequency was 80. No murmurs were heard. The electrocardiogram showed atria1 fibrillation and left bundle branch block. A chest X-ray examination revealed a moderately enlarged heart. He died after one week at hospital. Autopsy revealed small arteriosclerotic kidneys, severe atherosclerosis, marked cardiac enlargement (heart weight 620 g) and bronchopneumonia. The cause of death was considered to be renal failure. The sections from the left ventricle contained about 50% amyloid. There were small amounts of amyloid in the sinus node and minor amounts in the atrioventricular bundle. No amyloid was seen in the atrioventricular node. In this case, the transthyretin origin of the amyloid
Fig. 3. Part of a sinus node (SN) of a patient (case 250) with senile systemic amyloidosis. No amyloid is seen in this section of the node. The surrounding atrial tissue is heavily infiltrated by amyloid (arrows). Van Gieson stain, original magnification X 80.
89
Fig. 4. Part of the same sinus node (SN) as in Fig. 3 in a higher magnification. Massive amyloid atrial tissue (arrows). Van Gieson stain. original magnification
was verified acids [23].
by sequence
analysis
of the amino
Discussion In this study, we found advanced senile systemic amyloidosis only in patients over 80, and more frequently in men. No patient seemed to have a history of severe congestive cardiac failure that was resistant to therapy. All but one died within four weeks of admission to hospital. An increased frequency of atria1 fibrillation [26-291 and, possibly, bundle branch blocks 1291 were seen. More complicated arrhythmias were rare, and could be explained by reasons other than infiltration of amyloid. Another striking finding in this material was the sparing of the conduction tissue from severe infiltration. Our findings are in
x
infiltration 200.
is seen in the surrounding
agreement with a previous study, probably mainly including patients with senile systemic amyloidosis, where only minor infiltration of the specialized conduction tissue was seen [lo]. Senile systemic amyloidosis, notwithstanding massive cardiac infiltration, is very seldom diagnosed before death. Thus, no patient in this study was suspected to have amyloidosis. One explanation of this could be that it more rarely gives severe symptoms, or that the symptoms do not differ from those of other age-related afflictions in this group of very old persons. In contrast, the conduction system of the heart in patients with familial amyloidosis with polyneuropathy of Japanese, Portuguese and Swedish type often is strongly infiltrated by amyloid [12-141. This could most certainly explain the frequent occurrence of severe arrhythmias in that form of
Fig. 5. Part of the atrioventricular whereas most of the surrounding
node (AV) from the same patient as in Fig. 1. Minor amounts cardiac muscle tissue to the right is replaced by amyloid (arrows). Van Gieson stain, original magnification x 80.
amyloidosis. Although it is difficult to differ between other age-related symptoms and those caused by amyloid, our study supports the suspicion that senile systemic amyloidosis is a relatively benign form of amyloidosis and, consequently, that there is an obvious difference in the cardiac manifestations in familial amyloidosis with polyneuropathy of Japanese, Portuguese and Swedish type and senile systemic amyloidosis. The reason for this is unknown, but it may be noted that most data indicate that transthyretin is normal in senile systemic amyloidosis [17,22,23] whereas familial amyloidosis with polyneuropathy has been shown to be related to a variant of transthyretin (methionine instead of valine in position 30 in the Japanese, Portuguese and Swedish type) [15-171.
of amyloid are seen in the node Central fibrous body to the left.
Recently, the occurrence of a variant of transthyretin in senile systemic amyloidosis (isoleucine instead of valine in position 122) has been reported [30-321. Compared to our findings, patients with this variant were much younger, they were black and they seemed to have had more severe cardiac symptoms. Furthermore, in one study, an unusually high frequency of senile systemic amyloidosis was reported in black male patients under the age of 80 [33]. Rather than senile systemic amyloidosis, they could represent a familial amyloidotic cardiomyopathy. Although most patients with familial amyloidosis hitherto described have other than cardiac manifestations, there is one type of familial amyloidosis which seems to affect mainly the heart. This Danish
Fig. 6. Penetrating atrioventricular bundle (AVB) from the same patient as in Fig. 1. Small amounts of amyloid are seen in some vessel walls (arrows). There is marked atrophy with increased amounts of fat. Van Gieson stain, original magnification x 80.
of familial amyloidotic cardiomyopathy has its onset in the fourth decade of life and leads to death in congestive heart failure within five years [34]. A variant of transthyretin (methionine instead of leucine in position 111) is also present in this Danish form of amyloidosis [35]. Consequently, the occurrence of variant instead of normal transthyretin could not be the only explanation of the different manifestations in transthyretin-related amyloidosis. Hypothetically, factors normally inhibiting the formation of fibrils from transthyretin could exist, which decreases with age and which is less efficient in inhibiting formation of fibrils from variants of transthyretin. A variation in activity in different tissues of this hypothetical factor could explain the wide range of
variant
affected tissues in variants lated to transthyretin.
forms
of amyloid
re-
Acknowledgements We thank Ylva Persson, Anna-Helena Forsberg and Christer Bergman for valuable technical assistance. We also thank Dr Hans Nordgren for supplying us with autopsy material, Nils Backer for help with the photographs and Nigel Rolhson for expert linguistic revision. This study was supported by the Swedish Medical Research Council (Project No. 5941), the Research Fund of Ring Gustaf V, the Foundation of Erik, Karin and Gbsta Selander, the Memorial Fund of Josef and Linnea Carlsson, and the Royal Scientific Society in Uppsala.
92
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