Heart Vessels (1992) Suppl. 7:11-17

Heart

andVesselS

© Springer-Verlag1992

Pathological studies on Takayasu arteritis Masao Hotchi Department of Pathology, Shinshu University School of Medicine, Asahi 3-1-1, Matsumotõ, 390 Japan

S u m m a r y . Takayasu arteritis is a primary inflammatory disease of elastic arteries such as the aorta, its larger branches and the pulmonary artery trunk. According to our recent statistical survey of autopsy cases in Japan, the frequency of the disease in all autopsy cases was approximately 0.033% and the sex ratio was 1 : 4.5. The most frequent ages of the onset were 20-30 years, those of the death were 40-50 years. The latter was delayed about 20 years in comparison with a previous report. In the recent cases, the vascular lesions widely expanded. Luminal dilatation and aneurysm formation also increased in frequency, their ratio being approximately 57%. In the autopsy cases, the following active lesions were observed: (1) acute exudative inflammation (including suppuration), (2) chronic non-specific productive inflammatiorl and (3) various types of granulomatous inflammation. These findings suggest that many triggers may play a role in the morphogenesis of Takayasu arteritis. The inflammatory lesions are produced in the media and adventitia through the vasa vasorum, and terminate in a diffuse or nodular fibrosis. New active lesions are often observed near the old fibrotic ones. This suggests that Takayasu arteritis may be a progressive disease. Intimal thickening of the peripheral branches from the affected arteries is very often observed. In consequence, secondary ischemic lesions are formed in various organs, especially the heart, brain and kidneys.

Key words: Takayasu arteritis - Pulseless disease Aortitis syndrome - Elastic arteries

Introduction The first description concerning Takayasu arteritis dates back to 1908, when Takayasu, a Japanese ophthalmologist, reported a case of a peculiar arteriovenous anastomosis of the retina [1], which was considered as advanced chronic ischemic retinopathy, at the Twelfth Congress of the Japanese Ophthalmological Society. In the field of ophthalmology this retinal change had been called Takayasu's disease. Although he did not point out any vascular abnormalities, in the discussion that followed Takayasu's report, Ohnishi [2] and Kagoshima [3] mentioned the absence of the radial pulse in their patients who had ocular findings similar to those of Takayasu's patient. In 1940, Oota reported that the lesions were present mainly in the arterial trunk in the first autopsy case of Takayasu arteritis [4]. In 1948, Shimizu and Sano called it the "pulseless disease", defining it in terms of the following three points: (1) absent or diminished radial pulse (pulseless symptom), (2) specific findings in the retina, (3) accelerated carotid sinus reflex [5]. These studies have gradually clarified the fact that this disease primarily consists of vascular lesions. In 1963, Nasu reviewed 21 autopsy cases and clarified that the main lesions of this disease exist in cardinal arteries, meaning the aorta, its major branches and pulmonary artery trunk [6]. In 1985, Koide statistically investigated clinical cases to study the recent tendency of the disease [7]. According to this survey, in Japan, approximately 100 new cases are found yearly.

Incidence and distribution of lesions in autopsy cases

Address correspondence to: M. Hotchi

In 1975, Nasu performed a statistical survey of 76 autopsy cases during the 16 year period from 1958 to 1973 by using the Annual Reports of the Pathological Autopsy Cases in Japan published by the Japanese

M. Hotchi: Pathological studies on Takayasu arteritis

12 5 [

10 [

15 i

20 I

cases

Table 1. Distribution of vascular lesion [8-10] Arteries

0~9

10~19 20~29

30~39

40~49

50~59

60~69 age

Fig. 1. Age distribution upon disease onset [9, 10]

Society of Pathology [8]. This annual includes about 90% of the autopsy cases performed in Japan. In 1987, we reported again a similar statistical survey of 115 autopsy cases during the 10-year period from 1975 to 1984 in Japan [9, 10]. The ratio of 115 autopsy cases to all autopsy cases performed in this period was 0.033%. This ratio was similar to that of Nasu's report (0.036%). Eighty-two of these cases were available for investigation of autopsy records with the sex ratio of male to female being 1:4.5. This was also the same as that of Nasu's report. The age distribution for disease onset was from 1 - 6 0 years of age, with two peaks in the 20-30 and 30-40 year ranges (Fig. 1). Death occurred from 2 to 86 years of age, with a peak in the 40's. This was a shift from the third decade of life in Nasu's report (Fig. 2), which may indicate an increase in long-term survival cases due to improvement of therapies against this disease. The inflammatory vascular lesions are present in the aorta, its direct branches and the pulmonary artery trunk. Recently there has been a tendency for the lesions to extend over a broad part of such elastic

o

5

10

15

20

1958-1973

1975-1984

Ascending aorta Coronary artery Aortic arch Brachiocephalic artery Right subclavian artery Right common carotid artery Left common carotid artery Left subclavian artery Thoracic aorta Abdominal aorta Celiac artery Superior mesenteric artery Renal artery Inferior mesenteric artery Common iliac artery

78 11 86 82 75 82 87 88 71 59 13 15 24 8 3

73 45a 74 57 45 50 62 57 81 67 9 5 40a 2 27a

Pulmonary artery trunk Intrapulmonary branches

45 28

35 17

a

(%)

(%)

Artery increasing in frequency of lesions

arteries. Furthermore, involvement of the coronary, renal and common iliac arteries increases with the prolongation of the course of this disease (Table 1). Nasu classified the distributions of vascular lesions as follows: type I (cranial branches), type I1 (ascending aorta to aortic arch), type III (abdominal aorta and its main branches), and type IV (a broad portion of the arteries) [11]. According to this classification, type IV was the most frequent in the cases investigated in our survey.

Main vascular lesions in autopsy cases The affected areas of the arteries reveal uneven inner surfaces corresponding to the medial lesions. However, intact areas are usually present between the affected ones which are called "skip lesions" (Fig. 3). Recently gradual decrease of the intact area and

25

cases

1

0~ 9 L

10~19t~y//////////////.N 20~29 "////////////////////////////////N 30~39 L~ / / / / / / / / / / / / / / / / / / / . d 40--49~ 50~59 t 60~69

~///////////////////A

7 o ~ 7 9 L~///////////A 80~891 age

I It958~1973 g///////A 1 9 7 5 ~ t o 8 4

NN Fig. 2. Age distribution upon patient's death [8-10]

M. Hotchi: Pathological studies on Takayasu arteritis

13

Fig. 3. Inner surface of the aorta of Takayasu arteritis. Note skip lesions Table 2. Frequency of aneurysm, dilatation and dissection in 82 autopsy cases of Takayasu arteritis [9, 10] Lesions

Frequency (%)

Aneurysm Dilatation Aneurysm + dilatation Dissection

11/82 (13.4) 26/82 (31.7) 6/82 (7.3) 4/82 (4.9)

Total

47/82 (57.3)

Multiple aneurysm

14/82 (17.1)

frequent complication of atherosclerosis have been noted in elderly patients. Luminal närrowing by fibrous thickening of the intima had been emphasized before. However, the incidence of dilated lesions is increasing in recent prolonged cases (Table 2). In autopsy cases, perivascular fibrous thickening is also prominent as a result of an inflammatory reaction from the outer part of the media to the adventitia. Histologically, Nasu classified Takayasu arteritis into the following three types: granulomatous inflammation, diffuse productive inflammation and fibrotic types [11]. These types are the most frequent lesions found in autopsy with the fibrotic type being major and showing further tendency to increase. However, active lesions are offen observed near old cicatricial lesions even in the cases of fibrotic type (Fig. 4). Although it is quite difficult to determine the initial changes of the arterial lesions in autopsy cases, we investigated the following three different inflammatory lesions: acute exudative (including suppurative) (Fig. 5), chronic non-specific productive (Fig. 6), and

Fig. 4. Old cicatricial lesion of the subclavian artery. Segmental destruction of the media, reactive fibrous thickening of the intima, and perivascular fibrosis. Elastica van Gieson

granulomatous ones in different autopsy cases [12]. This suggests that many triggers affecting the arterial wall may exist in Takayasu arteritis. The granulomatous inflammation is also variable from epithelioid cell type to foreign body type (Figs. 7,8). However, elasticophagia may be an important feature, being frequently observed in various active lesions, even in productive inflammatory ones (Fig. 10). These inflammatory lesions originate in the outer area of the media and a part of the adventitia through the vasa vasorum, and rarely spread to the intima (Fig. 9). However, these lesions are not limited only to the media. Reactive fibrocellular thickening of the intima occurs in correspondence to the continuous destruction of the media and adventitia. On the other hand, the inflammatory lesions gradually progress to scar stage and result in fibrosis. Consequently, the lumen of the affected arteries is narrowed segmentally at the affected sites. On the contrary, when fibrosis is delayed and insufficient due to rapid progression of the lesion, the wall is thinned and orten results in aneurysm. In

14

M. Hotchi: Pathological studies on Takayasu arteritis

Fig. 5. Exudative inflammatory lesion of the left common carotid artery. (H&E, x 100 original magnification)

Fig. 6. Diffuse productive inflammatory lesion of the thoracic aorta. (H&E, x 100 original magnification)

addition the intact wall is orten dilated at the portion proximal to the constricted fibrotic area of the affected arteries. Furthermore, new active lesions are orten observed adjacent to old fibrous lesions, and result in gradual enlargement of the affected area. Hence, prolongation of the disease produces a large area of distortion and fibrosis of the wall. Lesions at the trunk of the pulmonary artery are essentially the same as those of the aorta. Occlusive lesions are observed at the peripheral branches, which are eventually recanalized by bronchial arteries. Saito reported that these lesions are found in nearly all autopsies [13].

the central nervous system, infarction is the most frequent, followed by hemorrhage and edema. In the heart, the frequency of hypertrophy is almost 100%, and associated aortic regurgitation has recently been increasing in prolonged cases. In the lung, edema, congestion and hemorrhage are common, but pulmonary hypertension is not so frequent. Contracted kidney, infarction, congestion and tubular necrosis are relatively frequent associated lesions of the kidney.

Lesion sites besides the elastic arteries Inflammatory lesions characteristic to this disease occur in the elastic arteries and orten spread to the origin of muscular arteries which branch oft directly from the aorta. Luminal narrowing or occlusion at the origin of the branching arteries leads to intimal thickening in their peripheral branches with no associated medial and adventitial changes. This finding has been observed in many cases [14]. Ischemic changes are common in various organs. In

Complications When the duration of the disease is prolonged, complications which are not directly related to the disease, such as cancer or infectious diseases (especially pneumonia) may occur. In elderly patients, the complication of atherosclerosis in the aorta or other arteries may also occur. In addition, a number of the following complications considered to possibly be related to the disease have been reported: necrotizing vasculitis [15], SLE [16], rheumatoid arthritis [17], ankylosing spondylitis [18], ulcerative colitis [19], Crohn's disease [20], and glomerulonephritis [21]. Immunological dysfunction is regarded as a factor common to these complications and Takayasu arteritis. Pyoderma

Fig. 7. Epithelioid cell granuloma of the thoracic aorta. (H&E, × 100 original magnification)

Fig. 8. Foreign-body type granuloma of the aortic arch. (H&E, ×100 original magnification)

Fig. 9. Destruction of the media, in which elastic fibers are cut oft from the adventitia side, and extensive fibrosis of the adventitia and intima. (Elastica van Gieson)

Fig. 10. Elasticophagia in the lesion in Fig. 9. (Elastica van Gieson, × 100 original magnification)

16 gangrenosum is also an important complication, especially in Japan [22] with elasticophagia being reported in the skin and arterial lesions of this complication [23]. This likely reßects with the fact that the main lesions of Takayasu arteritis occur in the elastic arteries. Furthermore, generalized amyloidosis has been also reported as a complication, which is believed to appear at the late stages of the disease [24].

Differential diagnosis So far, the following disorders have been discussed for differential diagnosis of Takayasu arteritis: mesaortitis syphilitica, tuberculous aortitis, giant cell arteritis (temporal arteritis), rheumatic aortitis, Beh~et disease (especially vasculo-Beh~et disease) and Buerger disease [6]. Since cicatricial lesions formed in elastic arteries are a common feature in these arteritides, it is difficult to histologically differentiate all the disorders in which the cardinal arteries have been affected. Moreover, as mentioned above, the active lesions of this disease are not specific. Therefore, at present, diagnosis is made by summation of various factors, such as clinical background, distribution of lesions and so on. There was even a time when syphilis and tuberculosis were thought to be its etiologic factors, but in spite of decreased incidence of these diseases, Takayasu arteritis still persists. Therefore, at present, if the findings of syphilis or tuberculosis are present, such cases with arteritis should be rather excluded from Takayasu arteritis. Giant cell arteritis occurs within the media and generally does not affect the outer border of the media which is the most frequent site of the lesion of Takayasu arteritis. Clinical findings are also important in the diagnosis of rheumatic aortitis and Beh~et's disease in which characteristic histological findings are not present. Recently, since there has been an increase of luminal dilatation and aneurysm in Takayasu arteritis, the disease should be differentiated from various inflammatory aneurysms. The so-called inflammatory aneurysm of the abdominal aorta reported by Walker et al. in 1982 is also included [25]. This aneurysm occurs in relatively elderly patients, and forms a spindle shaped lesion in the abdominal aorta below the renal arteries. CT shows the characteristic mantle sign. Histology reveals extensive atherosclerosis in the intima to the media and perivascular dense fibrosis with chronic inflammation. The media is usually unaffected from the adventitia side, which is the feature distinguishing inflammatory aneurysm from Takayasu arteritis [26]. Moreover, although the structure of the adventitia is only slightly affected, in the continuous area surrounding the aorta, extensive fibrosis and chronic inflammation are pre-

M. Hotchi: Pathological studies on Takayasu arteritis seht. Histologically, this feature has some similarity rather with idiopathic retroperitoneal fibrosis.

References 1. Takayasu M (1908) A case of peculiar changes in the central retinal vessels (in Japanese). Acta Soc Ophth Jpn 12:554-555 2. Oonishi K (1908) Discussion on Takayasu's presentation (in Japanese). Acta Soc Opth Jpn 12:555 3. Kagoshima S (1908) Discussion on Takayasu's presentation (in Japanese). Acta Soc Opth Jpn 12:555 4. Oota K (1940) Ein seltener Fall von beiderseitigem Carotis-Subclaviaverschluss. Ein Beitrag zur Pathologie der Anastomosis peripapillaris des Auges mit fehlendem Radialpuls. Trans Soc Path Jpn 30:680-690 5. Shimizu K, Sano K (1951) Pulseless disease. J Neuropathol Clin Neurol 1:37-47 6. Nasu T (1963) Pathology of pulseless disease. A systematic study and critical review of twenty-one autopsy cases reported in Japan. Angiology 14:225-242 7. Koide K (1986) Aortitis syndrome. The second statistical survey (in Japanese). Report of the Research Committee on Systemic Vascular Disorders of the Ministry of Health and Welfare, Japan. pp 33-35 8. Nasu T (1975) Takayasu's truncoarteritis in Japan: A statistical observation of 76 autopsy cases. Pathol Microbiol 43:140-146 9. Nagata S (1990) Present state of autopsy cases of Takayasu's arteritis (aortitis syndrome) in Japan (in Japanese). J Jpn Coll Angiol 30:1303-1308 10. Hotchi M (1991) Recent state of autopsy cases of Takayasu arteritis (in Japanese). J Jpn Coll Angiol 31: 1213-1216 11. Nasu T (1982) Takayasu's truncoarteritis. Pulseless disease or aortitis syndrome. Acta Pathol Jpn 32 (Suppl 1):117-131 12. Hotchi M (1987) Pathology of aortitis syndrome (in Japanese). Geka 44:691-698 13. Saito K (1988) Pulmonary arteritis in Takayasu's arteritis (in Japanese). Nihon Kyoubu Rinshou 47:655665 14. Hotchi M, Fujiwara M (1982) Aortitis syndrome (in Japanese). Rinshou Men-eki 14:350-358 15. Hosoda Y, Iri H, Hata J, Wakasugi A (1973) Granulomatous aortitis associated with necrotizing angiitis and glomerulonephritis. Acta Pathol Jpn 23:129-138 16. Takase S, Sato E, Oimomi M, Baba S, Maeda S, Miyazaki K, Sugiyama T (1981) A case of aortitis syndrome in systemic lupus erythematosus (in Japanese). J Jpn Coll Angiol 21:51-54 17. Rush PJ, Inman R, Reynolds WJ (1986) Rheumatoid arthritis after Takayasu's arteritis. J Rheumatol 13:427430 18. Graham DC, Smythe HA (1958) The carditis and aortitis of ankylosing spondylitis. BuU Rheum Dis 9: 171-174 19. Achar KN, AI-Nakib B (1986) Takayasu's arteritis and ulcerative colitis. Am J Gastroenterol 81:1215-1217 20. Yassinger S, Adelman R, Cantor D (1976) Association of inflammatory bowel disease and large vascular lesions. Gastroenterology 71:844-846 21. Zilleruelo GE, Ferrer P, Garcia OL, Moore M, Pardo V, Strauss J (1978) Takayasu's arteritis associated with

M. Hotchi: Pathological studies on Takayasu arteritis glomerulonephritis. A case report. Am J Dis Child 132:1009-1013 22. Nagashima M, Nishikawa T (1967) Pyoderma gangrenosum associated with aortitis syndrome (in Japanese). Rinshou Hifuka 21:591-598 23. Yoshii K, Oohata Y, Tashiro M (1978) Pyoderma gangrenosum associated with aortitis syndrome (in Japanese). Nishinihon Hifuka 40:64-71 24. Vinogradova OM, Nevaera EG (1981) Aortic arch syndrome in a patient with primary generalized amyloidosis.

17 Terapenicheskii Arkhiv 53:26-28 25. Walker DI, Bloor K, Williams G, Gillie I (1972) Inflammatory aneurysms of the abdominal aorta. Br J Surg 59:609-614 26. Nakamura T, Ito M, Shiozawa N, Hotchi M (1991) A histopathological study on so-called inflammatory aneurysm of the abdominal aorta. Report of the Research Committee on Intractable Angiitis of the Ministry of Health and Welfare, Japan (in Japanese) pp 31-35

Pathological studies on Takayasu arteritis.

Takayasu arteritis is a primary inflammatory disease of elastic arteries such as the aorta, its larger branches and the pulmonary artery trunk. Accord...
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