Serum angiotensin-converting enzyme activity as an indicator of prognosis in sarcoidosis

The relationship between the clinical course of sarcoidosis and serum angiotensin-converting enzyme (EC 3.4.15.1) activity was analyzed by observing 51 patients with sarcoidosis during a period of more than 1 yr. The patients were grouped into 3 categories irrespective of treatment: (1) sarcoid lesions in the chest disappeared within 1 yr, (2) sarcoid lesions remained for more than 1 yr with little improvement, (3) sarcoid lesions disappeared within 1 yr, but then relapsed. In group 1 (33 cases), the serum angiotensin-converting enzyme activity decreased from 35.9 +/- 2.0 to 22.0 +/- 1.3 nmol/ml/min after the chest roentgenogram cleared (P less than 0.005). In group 2 (12 cases), the mean serum angiotensin-converting enzyme activity after treatment was not significantly reduced, paralleling the lack of improvement. In group 3 (6 cases), a good correlation was observed between serum enzyme activity and clinical course. These findings indicate that serum angiotensin-converting enzyme activity is an indicator of the clinical course of sarcoidosis.     

Follow-up on angiotensin-converting enzyme in serum of patients with sarcoidosis

Fluorimetrically measured serum angiotensin-converting enzyme (ACE) activity was found to be significantly elevated (p less than 0.001) in 31 untreated patients with sarcoidosis in comparison to 38 healthy controls, 20 corticosteroid-treated patients with sarcoidosis, 15 subjects with resolved sarcoidosis and 100 patients with other lung diseases. ACE values more than 2 SD above the control mean value were seen in 68% of untreated patients with sarcoidosis, but only in 5% of healthy controls, 7% of patients with tuberculosis, 0% of patients with lung tumors, 9% of patients with bronchial asthma or chronic obstructive pulmonary disease and in 17% of patients with pulmonary fibrosis due to hypersensitivity pneumonitis or diffuse idiopathic fibrosis. Resolution of sarcoidosis, spontaneously or induced by corticosteroid therapy, was accompanied by normalization of serum ACE activity in 18 out of 19 cases. In 7 out of 9 patients without clear-cut clinical improvement, changes of serum activity of ACE were not substantiated. Relapse of sarcoidosis seen in 1 case qas associated with a significant increase in ACE levels. Our results suggest that longitudinal studies of serum ACE activity are valuable in assessing the current activity and the course of sarcoidosis. Furthermore, they may contribute to restriction of necessary operative diagnostic procedures.     

Clinical significance of serum KL-6 in pulmonary sarcoidosis]

We investigated whether the level of serum KL-6 could be an activity marker for pulmonary sarcoidosis. In 33 patients with pulmonary sarcoidosis, the relationships between serum KL-6 levels and diagnostic imaging, serum angiotensin-converting enzyme (ACE) levels, serum lysozyme levels, steroid therapy, and prognosis were evaluated. There were no significant differences in the level of serum KL-6 when the patients were divided on the basis of radiographic findings, but the level of serum KL-6 was markedly elevated in some patients with stage-II pulmonary sarcoidosis. There was a significant correlation between serum KL-6 levels and the following two parameters: serum ACE and lysozyme levels. Among patients with a high initial level of serum KL-6, pulmonary sarcoidosis tended to become exacerbated within one year. Steroid therapy significantly decreased the level of serum KL-6, suggesting that the level of serum KL-6 could be an activity indicator for pulmonary sarcoidosis. Immunohistochemical staining by anti-KL-6 antibody revealed that KL-6 was localized in proliferating type-II alveolar epithelial cells.     

Serum angiotensin-converting enzyme in leprosy and coccidioidomycosis.

Serum angiotensin-converting enzyme levels were found to be elevated in 71.4% of 42 leprosy patients, both treated and untreated, but in only one of 13 patients with disseminated coccidioidomycosis. The elevations with leprosy were present in association with each of the three major categories: lepromatous, borderline, or tuberculoid. Sulfone therapy had no immediate effect on the elevated serum levels, although long-term sulfone therapy appeared to result in lowering of the level. Corticosteroid therapy had a more immediate and dramatic effect on reducing the elevated angiotensin-converting enzyme level in leprosy. This assay cannot distinguish between sarcoidosis and leprosy or between the various categories of leprosy, but it can help differentiate sarcoidosis from fungal or tuberculous disease. Elevated levels of serum angiotensin-converting enzyme have now been associated with three diseases states: sarcoidosis, Gaucher's disease, and leprosy.     

Serum Lysozyme Levels and Clinical Features of Sarcoidosis

Serum lysozyme is used as a marker of sarcoidosis disease activity. In this study we examined the association between lysozyme levels and the clinical features of sarcoidosis and thus the clinical usability of this parameter in a large population. One hundred ten sarcoidosis patients from central Japan were examined for clinical features and serum lysozyme level at the first visit to our hospital and on a regular basis thereafter. The sensitivity of lysozyme for predicting sarcoidosis was 79.1%, whereas that of serum angiotensin-converting enzyme (ACE) was 59.0%. Even in the cases without an elevated serum ACE level, a value of 72.1% was obtained. The serum lysozyme level demonstrated a significant tendency to increase with the number of organs involved (p < 0.01). There were significant differences among the four radiographic stages (p < 0.05). The maximum serum lysozyme levels of patients without a disappearance of abnormal shadows on chest radiography within 5 years were significantly greater than those of individuals with a disappearance (p < 0.05). A positive correlation between serum lysozyme and serum ACE levels was observed. Because serum lysozyme is much less specific for sarcoidosis than serum ACE, its diagnostic value may be limited. However, the sensitivity was high even when serum ACE levels were within normal limits and correlated well with clinical features in sarcoidosis. Therefore, this parameter seems suitable for disease monitoring in proven cases. Accepted for publication: 19 November 1998     

Predictive value of gallium scan, angiotensin-converting enzyme level, and bronchoalveolar lavage in two-year follow-up of pulmonary sarcoidosis

Evaluation of patients with pulmonary sarcoidosis with serum angiotensin-converting enzyme (ACE), gallium scan, and bronchoalveolar lavage (BAL) has proved useful in demonstrating active disease, especially in the lungs. Long-term prognosis based on the results of pretreatment ACE, gallium scan, and BAL has not been previously clarified. We studied 44 patients with initially symptomatic pulmonary sarcoidosis who were begun on steroid therapy after initial evaluation. At 2 years, 21 of 44 (48%) patients still had worsening disease. Of 31 patients who had positive gallium scan pretreatment, 21 (68%) still had worsening disease at 2 years. None of the 13 patients with a negative gallium scan had worsening disease at 2 years (Chi square = 14.2, P less than 0.01). Similar analysis of the pretreatment serum ACE level, percentage of lymphocytes in the BAL fluid, and ratio of T-helper/inducer to T-suppressor/cytotoxic (T4/T8) in the BAL fluid also had some predictive value for worsening disease at 2 years; however, these tests were less sensitive than the gallium scan. In patients with pulmonary sarcoidosis, the finding of a negative gallium scan suggests a small likelihood that disease activity will worsen after 2 years.     

Serum concentration of soluble interleukin-2 receptor as a sensitive parameter of disease activity in sarcoidosis

We investigated the clinical value of measuring serum concentrations of soluble IL-2R in monitoring sarcoidosis. Serum concentrations of soluble IL-2R were measured in 70 patients with sarcoidosis. The mean value for active untreated sarcoidosis was 1,143 +/- 509 U/ml, while the normal range in 97 healthy control subjects was 80 to 300 U/ml. The mean value for active untreated sarcoidosis was significantly higher than that for dormant disease (353 +/- 183 U/ml) or that for corticosteroid-treated patients (380 +/- 151 U/ml). Serial changes in serum soluble IL-2R level were studied in cases of spontaneous remission or in corticosteroid-treated patients; a good correlation was noted between the changes in serum level of soluble IL-2R and clinical status. A positive correlation was noted between serum concentration of soluble IL-2R and serum ACE activity. These data confirmed that measurement of serum concentration of soluble IL-2R could be used in monitoring the disease activity in sarcoidosis.     

Bronchoalveolar lavage fluid angiotensin-converting enzyme in interstitial lung diseases

In this study we evaluated the disease specificity of bronchoalveolar lavage fluid angiotensin-converting enzyme (BALF-ACE), its correlation with cellular constituents of bronchoalveolar lavage fluid (BALF), and for sarcoidosis, with other proposed markers of disease activity. Furthermore, the question of the clinical value of BALF-ACE determinations in in interstitial lung diseases or any of its subgroups was addressed. The study population consisted of 222 patients, 69 with biopsy proven sarcoidosis, 3 with hypersensitivity pneumonitis, 4 with acute histoplasmosis, 27 with idiopathic pulmonary fibrosis (IPF), 4 with rheumatoid arthritis-related interstitial fibrosis, 9 with pulmonary drug toxicity, 16 with pulmonary malignancies, 26 with other parenchymal lung disease entities, and 30 in whom the final diagnosis remained indeterminate. Elevated BALF-ACE concentrations were seen in all diagnostic categories. In sarcoidosis BALF-ACE levels correlated well with lavage lymphocyte counts (r = 0.49; p less than 0.0001), in contrast to IPF where they correlated well with lavage neutrophil counts (r = 0.51; p less than 0.007). The correlation of BALF-ACE and serum-ACE was significant. In sarcoidosis the mean BALF-ACE level was lower for patients with Stage-I chest roentgenographic patterns (0.664 U/L), compared to those with Stage II (1.112 U/L) and Stage III (1.083 U/L). It was concluded that elevated BALF-ACE levels are not specific for sarcoidosis. The correlations of BALF-ACE levels with different cellular constituents of BALF suggest a different cellular origin of BALF-ACE. In sarcoidosis BALF-ACE levels correlate well with other proposed markers of disease activity and seem to reflect pulmonary activity better than serum ACE.(ABSTRACT TRUNCATED AT 250 WORDS)     

Serum angiotensin-converting enzyme activity in evaluating the clinical course of sarcoidosis

Thirty-five patients with sarcoidosis were serially monitored for serum angiotensin-converting enzyme activity by a simple radiochemical assay, and we analyzed the relation of such activity to the clinical status as judged from changes in chest roentgenograms, pulmonary function, or symptoms. Converting enzyme levels closely paralleled and occasionally antedated changes in clinical status in patients either undergoing spontaneous remission or being treated with prednisone. Converting enzyme activity seems to be a sensitive index for evaluating the clinical course of sarcoidosis. Converting enzyme determinations may be helpful in corroborating the diagnosis, assessing the likelihood of spontaneous remission, confirming the clinical status of the patient, and determining the adequacy of glucocorticoid therapy.     

Quantitative gallium scanning in pulmonary sarcoidosis

Pulmonary parenchymal involvement in sarcoidosis is due to noncaseating granuloma, fibrosis or both. To assess the granulomatous activity in pulmonary sarcoidosis, we performed gallium-67 citrate scans in 41 patients with sarcoidosis and in 13 non-sarcoid patients, who were free of pulmonary disease and served as controls. Gallium score, a measure of gallium accumulation in lung parenchyma, was obtained from the sum of activity indices (ratio of accumulated gallium activity over a chest quadrant and soft tissues of the mid-thigh) from each of the quadrants over the anterior and posterior aspects of the chest. The gallium score in patients with sarcoidosis was significantly higher than the gallium score in controls. The gallium scores in patients with sarcoidosis, with radiographically apparent pulmonary infiltrate were significantly higher than the scores in the patients with no radiographic evidence of pulmonary parenchymal involvement. The gallium scores in patients not receiving corticosteroids were significantly higher compared to patients who were receiving corticosteroids, and furthermore, the gallium scores fell significantly when corticosteroids were initiated. There was a significant correlation between serum angiotensin-converting enzyme (SACE) activity and gallium score. In 11 patients, 27 sequential gallium scans were performed and changes in gallium score correlated well with the changes in SACE activity and clinical assessment. These findings suggest that quantitative evaluation of gallium scans may be useful in assessing granulomatous activity of pulmonary sarcoidosis and following its response to therapy.     

Serum angiotensin-converting enzyme levels in sarcoid arthritis

The serum angiotensin-converting enzyme (SACE) level is elevated in 75% of patients with sarcoidosis and often is associated with disease activity. In an attempt to correlate the SACE level with sarcoid arthritis, we did a retrospective chart review of 116 patients with sarcoidosis. Of the 24 patients who complained of arthritis, five were excluded from the study because they were receiving corticosteroids, SACE levels were not determined, or another cause for their arthritis was found. The mean SACE levels were 65 units/mL for the patients with acute arthritis and 51 units/mL for the patients with chronic arthritis. Levels of SACE may be helpful in the differential diagnosis of patients with "seronegative polyarthritis."     

Predictive value of gallium scan,angiotensin-converting enzyme level,and bronchoalveolar lavage in two-year follow-up of pulmonary sarcoidosis

Evaluation of patients with pulmonary sarcoidosis with serum angiotensin-converting enzyme (ACE), gallium scan, and bronchoalveolar lavage (BAL) has proved useful in demonstrating active disease, especially in the lungs. Long-term prognosis based on the results of pretreatment ACE, gallium scan, and BAL has not been previously clarified. We studied 44 patients with initially symptomatic pulmonary sarcoidosis who were begun on steroid therapy after initial evaluation. At 2 years, 21 of 44 (48%) patients still had worsening disease. Of 31 patients who had positive gallium scan pretreatment, 21 (68%) still had worsening disease at 2 years. None of the 13 patients with a negative gallium scan had worsening disease at 2 years (Chi square =14.2,P <0.01). Similar analysis of the pretreatment serum ACE level, percentage of lymphocytes in the BAL fluid, and ratio of T-helper/inducer to T-suppressor/cytotoxic (T4/T8) in the BAL fluid also had some predictive value for worsening disease at 2 years; however, these tests were less sensitive than the gallium scan. In patients with pulmonary sarcoidosis, the finding of a negative gallium scan suggests a small likelihood that disease activity will worsen after 2 years. Presented in part to the national meeting of the american Thoracic Society, May 1986.     

Elevation of serum angiotensin-converting-enzyme (ACE) level in sarcoidosis.

The level of serum angiotensin-converting enzyme (ACE) was elevated in 15 of 17 patients with active sarcoidosis. Serum ACE was studied to determine the effect of chronic lung disease upon the blood level of an enzyme believed to originate from the lungs. The assay was performed in approximately 200 control subjects and 200 patients with chronic lung disease using hippuryl-L-histidyl-L-leucine as substrate. Enzyme activity greater in male control subjects than in female subjects of comparable age and greater in children than in adults. Serum ACE was significantly reduced in patients with chronic obstructive lung disease, lung cancer, tuberculosis and cystic fibrosis, as compared to control subjects, and was even lower in those receiving corticosteroids. Of greatest interest, however, was that levels in patients with active sarcoidosis not receiving steroids were greater than 2 standard deviations above the mean for the adult control subjects (greater than 11.6 units) whereas levels in patients with sarcoidosis receiving steroids and in those with resolved disease were normal. A survey of subjects with other granulomatous diseases failed to reveal any other condition that was significantly associated with a similar elevation of serum ACE levels. Elevation of ACE levels in sarcoidosis appears to be associated with the active disease process and does not appear to be a familial inherited enzyme abnormality. An assay of serum ACE is a useful tool for regulating therapy in sarcoidosis and for confirming the diagnosis, since it readily distinguishes these patients from others with tuberculosis, lung cancer or lymphoma.     

8-Isoprostane, a marker of oxidative stress, is increased in the expired breath condensate of patients with pulmonary sarcoidosis

STUDY OBJECTIVE: 8-Isoprostane is considered an index of oxidative stress. Measurement of 8-isoprostane in the expired breath condensate, a totally noninvasive method, has not been used to explore the level of inflammation in pulmonary sarcoidosis. Therefore, the aim of our study was to measure the levels of 8-isoprostane in the expired breath condensate of patients with sarcoidosis, and to investigate the relation of 8-isoprostane level to disease activity. PATIENTS: We investigated 30 patients with pulmonary sarcoidosis (active disease, n = 14; nonactive disease, n = 16) and 12 healthy subjects as control group. METHODS: 8-Isoprostane was measured in the expired breath condensate of all subjects, and its levels were compared between the control and sarcoidosis groups as well as between the subgroups of patients with active and nonactive disease. In the group with sarcoidosis, 8-isoprostane levels were further correlated with markers that may reflect disease activity, such as serum angiotensin-converting enzyme (sACE) level, serum calcium level, and pulmonary function test results. RESULTS: The concentration of 8-isoprostane was increased in patients with sarcoidosis compared to control subjects (mean, 64.23 pg/mL; 95% confidence interval [CI], 37.00 to 91.46 pg/mL; vs mean, 20.75 pg/mL; 95% CI, 16.06 to 25.44 pg/mL; p = 0.04). The difference was primarily due to the patients with active disease, who had significantly higher levels of 8-isoprostane (mean, 111.4 pg/mL; 95% CI, 62.56 to 160.30 pg/mL; p < 0.001) compared to patients with nonactive disease (mean, 22.94 pg/mL; 95% CI, 15.89 to 29.99 pg/mL) or healthy subjects. 8-Isoprostane levels in patients with nonactive disease did not differ from those in healthy subjects (p > 0.05). In the patients with sarcoidosis, 8-isoprostane levels were positively correlated with sACE level (p < 0.0001, r = 0.69), but was not correlated with serum calcium level or pulmonary function test values. CONCLUSIONS: Our data suggest that 8-isoprostane levels are increased in the expired breath condensate of patients with sarcoidosis and might serve as an index of disease activity.     

Angiotensin-converting enzyme in farmer's lung

Serum levels of angiotensin-converting enzyme were measured in a group of patients with farmer's lung and a group of precipitin-positive subjects with no history of farmer's lung. The levels did not differ significantly from control subjects matched for age and smoking history. The mean serum level of angiotensin-converting enzyme in a group of acutely ill patients with farmer's lung was significantly reduced. An acute challenge of three patients with Micropolyspora faeni did not produce an increase in serum levels of angiotensin-converting enzyme. These studies suggest that an increased serum level of angiotensin-converting enzyme can be a diagnostic aid in making a differential diagnosis between sarcoidosis and farmer's lung.     

Human chitotriosidase: a potential new marker of sarcoidosis severity

Sarcoidosis is a multisystemic granulomatous disorder of unknown etiology. The unpredictable clinical course of the disease has prompted research into biomarkers useful for predicting outcome. Among the potential markers of sarcoidosis, a recently proposed indicator was chitotriosidase, a chitinase produced by activated macrophages. Chitotriosidase is involved in the defense against pathogens containing chitin. Increased concentrations of chitotriosidase have been observed in a number of lysosomal storage diseases including Gaucher disease and more recently also in sarcoidosis. In 2004, significantly higher serum chitotriosidase activity was reported for the first time in sarcoidosis patients with respect to controls (p < 0.01); a similar increase was subsequently observed in bronchoalveolar lavage of these patients. In 2007, an increase in enzyme activity was described in juvenile sarcoidosis. Chitotriosidase activity was found to be correlated with angiotensin-converting enzyme levels in serum, radiological stages and quantitative high-resonance CT score for sarcoidosis, suggesting that this enzyme could be a potential marker of disease severity worthy of further study. To evaluate the sensitivity and specificity of this marker, further analysis was done in other granulomatous and diffuse lung diseases. Here, we review the principal literature and the recent evidence of chitotriosidase as a possible marker of sarcoidosis.     

Angiotensin converting enzyme. IV. Changes in serum activity and in lysozyme concentrations as indicators of the course of untreated sarcoidosis.

The mean values of serum angiotensin-converting enzyme (ACE) activities and lysozyme (LZM) concentrations measured during different phases of sarcoidosis coincided well with the clinical evaluation of the state of the disease. However, both enzymes, especially LZM, decreased before improvement was detected. Changes in these enzymes were in accord with the simultaneous clinical development in three fourths of cases. Incompatibility between clinical observations apnd LZM fluctuations was most frequently seen during active stable or inactive disease. LZM often decreased during the active stable phase and fluctuated irregularly during inactive disease. During the former phase LZM decrements possibly reflect decreasing activity of granulomatous macrophages and, in fact, precede detectable improvement. During inactive disease, on the other hand, cells were not connected with the disease process dominate LZM production. ACE changes paralleled the clinical development more often than corresponding LZM changes during stable sarcoidosis. This may have been misleading and due to a delayed reaction of serum ACE, compared with LZM, inreflecting the activity of granylomatous cells. This delayed reaction was also observed in connection with erythema nodosum. Stable ACE activity during inactive sarcoidosis indicated the usefulness of measurements when trying to predict a relapse. We conclude that ACE may be a secondary feature of sarcoidosis rather than a primary funtion of macrophage activity.     

Platelet-activating factor in bronchoalveolar lavage from patients with sarcoidosis.

Platelet-activating factor (PAF), a lipid mediator of inflammation and anaphylaxis, may play a role in several physiopathologic alterations of the lung. A lipid compound with physicochemical and biologic characteristics similar to synthetic PAF was extracted and purified from bronchoalveolar lavage (BAL) fluid of 15 of 34 patients with sarcoidosis. PAF was quantitated by a bioassay on washed rabbit platelets. The specificity of platelet aggregation was assessed by using two different PAF receptor antagonists. The incidence of detectable amounts of PAF in BAL fluid of sarcoid patients was statistically significant (chi 2 = 4.064, p = 0.044) when compared with the 14 normal control subjects. The results demonstrated an increased production of PAF in the lower respiratory tract of patients with sarcoidosis. The presence of PAF in BAL fluid, however, did not correlate with radiologic stage, intensity of alveolitis, gallium scanning positivity, angiotensin-converting enzyme serum level, or lung function tests. Therefore, a direct relationship between presence of PAF in BAL fluid and activity of lung disease in patients with sarcoidosis was not directly established.     

Angiotensin-converting enzyme. I. Activity and correlation with serum lysozyme in sarcoidosis, other chest or lymph node diseases and healthy persons.

Serum angiotensin-converting enzyme (ACE) activity was studied in healthy controls, in 57 untreated sarcoidosis patients, and in 164 patients with other chest or lymph node diseases. The serum ACE activity of healthy persons was independent of sex, intake of meals, and smoking habits. There were no diurnal variations. Healthy children had a significantly higher ACE mean value than adults, whose ACE activity was not affected by age. The sarcoidosis patients had the highest ACE mean values, but those of patients with silicosis and asbestosis were also significantly elevated. Pulmonary cancer patients had decreased serum ACE activity, which was probably due to antimitotic treatment. Serum lysozyme (LZM) concentrations did not correlate with normal ACE activity, but the correlation between elevated ACE and LZM was significant in sarcoidosis and silicosis, and the trend was clearly the same for asbestosis. This indicates separate sources for these enzymes when ACE activity is normal, and a common source, i.e. macrophages, when ACE activity is increased. ACE production in certain diseases involving macrophages may be due to the bradykinin inhibiting effect of this enzyme.     

Clinical analysis of sarcoidosis presenting with heterochronic cardiac involvement

BACKGROUND AND OBJECTIVES: A variety of markers, such as serum angiotensin-converting enzyme (sACE) and CXR have been used to evaluate the disease activity and progression of sarcoidosis. There are patients who have developed cardiac involvement several years after the initial diagnosis despite stable or decreased disease activity. This study clarified the clinical characteristics of those patients. METHODS: A total of 141 consecutive patients treated for sarcoidosis were studied. Heterochronic cardiac sarcoidosis was defined as the sudden onset of cardiac manifestations more than 2 years after the initial diagnosis despite stable lung disease and normal sACE levels. RESULTS: Of the patients studied four showed heterochronic cardiac involvement. These patients were all middle-aged women (mean age, 50.5 years) with multiple organ involvement. The time period from the initial diagnosis of sarcoidosis to the onset of cardiac involvement ranged from 3 to 8 years, with a mean duration of 5.2 years. All patients showed fatal conduction abnormalities. CONCLUSIONS: Middle-aged women with multiple organ involvement of sarcoidosis are at risk of developing cardiac sarcoidosis.