Elevation of Angiotensin‐converting Enzyme in Granulomatous Lymph Nodes and Serum in Sarcoidosis: Clinical and Possible Pathogenic Significance*

Abstract

A statistically highly significant elevation of serum ACE was found in a group of 58 patients with sarcoidosis (serum ACE was elevated in 34% of patients), as compared with normal controls and patients with tuberculosis and various other common diseases. The results suggest that serum ACE is a useful aid for the diagnosis of sarcoidosis when elevated, but that a normal value does not rule out the condition and may occur in more than one-half of monitored patients. There is a trend to diminution of serum ACE with increasing duration of disease with or without steroid therapy, perhaps correlating with the total body mass of active granulomas, as indirectly suggested in preliminary data by correlation of serum ACE with serum globulin in 16 sarcoidosis patients. It is not yet clear whether there is any significant steroid effect on serum ACE, but a significant number of patients on steroid therapy for more than 2-4 yr have elevated serum ACE values, which in some instances are extremely high. There was a 12-fold elevation in ACE to specific activities generally exceeding those of normal lung in granulomatous lymph nodes of 14 patients with sarcoidosis, suggesting that sarcoid granulomas may be actively synthesizing ACE and resulting in elevation of serum ACE. Extensively fibrotic sarcoid lymph nodes had normal or slightly elevated ACE, suggesting that obliteration of granulomas in sarcoid lymph nodes diminishes their ACE content and that this obliteration may be related to the tendency to diminution of serum ACE with time. ACE was not elevated in one tuberculous lymph node or in experimental granulomas, suggesting that elevation of ACE may have some specificity for the granuloma of sarcoidosis rather than being a characteristic of all granulomas. The catalytic and physical properties of ACE in serum and lymph nodes in sarcoidosis were generally similar to normal ACE with respect to pH activity, modulators, polyacrylamide-gel electrophoresis, and Sephadex G-200 gel filtration. However, sarcoid lymph node ACE appeared to be more heat labile than normal lung or lymph node ACE, suggesting the possibility that an abnormal ACE may be present in sarcoidosis. If an abnormal enzyme is indeed present, it might be coded for by a host gene that is not normally expressed or a nonhost gene or it might be a normal ACE that has been altered. No ACE activity was found in circulating white blood cells in sarcoidosis or in control subjects, suggesting that circulating white blood cells may not contain the epithelioid cell precursor or that ACE synthesis (or less likely, uptake) may be turned on at a later stage in the transformation. Lysozyme activity was also elevated in sarcoid lymph nodes. Serum ACE and serum lysozyme were significantly positively correlated in 16 sarcoidosis patients, suggesting a relationship between the two...

Effect of SQ 14225, an inhibitor of angiotensin I-converting enzyme, on the granulomatous response to Schistosoma mansoni eggs in mice.

“…Many patients with sarcoidosis and leprosy are shown to have increased ACE activity in the circulation (4)(5)(6)(7)27). The nine-banded armadillo develops lepromatous type leprosy which is also associated with increased serum ACE activity (28).…”

Immunofluorescent localization of angiotensin converting enzyme in epithelioid and giant cells of sarcoidosis granulomas.

“…Knowledge of ACE levels appears to be useful in the diagnosis and management of these diseases (5-7, 9, 10). It is not elevated in granulomatous conditions generally, such as tuberculosis (3, 5, 7), rat Freund's adjuvant subcutaneous granulomas (11), chronic beryllium disease,"1 and Crohn's disease (unpublished observations), or in monocytes and macrophages generally in humans and experimental animals (4,7,11).…”

“…coidosis, a generalized disease of unknown etiology usually manifest as radiologically evident chest disease and associated with the presence of microscopic nonnecrotizing granulomas containing the mononuclear phagocytes, epithelioid and giant cells (3)(4)(5)(6)(7). ACE is also elevated in the serum and spleen in Gaucher's disease, an inherited disease characterized by the accumulation of glucocerebroside in Gaucher cells, large mononuclear phagocytes (8)(9)(10).…”

“…Because the characteristic feature of sarcoidosis is the presence of epithelioid and giant cells, and other types of granulomas do not generally contain abundant ACE, it was hypothesized that epithelioid cells in sarcoidosis granulomas may be specifically induced to synthesize ACE by a mechanism related to the pathogenesis of the sarcoidosis granuloma (7,12). We here report immunocytological evidence for the specific localization of ACE in epithelioid and giant cells of the sarcoidosis granuloma, which is consistent with the hypothesis that greatly increased ACE synthesis in these cells is responsible for the increased ACE in the circulation and in the sarcoidosis granuloma (7,12).…”

Increased angiotensin-converting enzyme in peripheral blood monocytes from patients with sarcoidosis.

“…A significant elevation of serum angiotensin-converting enzyme (ACE)' occurs in somewhere between 34 and 88% of patients with sarcoidosis (2)(3)(4)(5). The localization of ACE in epithelioid and giant cells of sarcoid granulomas, the marked increase in ACE activity in sarcoid granulomatous lymph nodes (6)(7)(8), and the biosynthetically active fine structural appearance of sarcoid epithelioid cells (9) strongly suggest that sarcoid granulomas may be responsible for the increased serum ACE activity.…”