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Comparative analysis of biochemical parameters for differentiation of pleural exudates from transudates
Clinica Chimica Acta 264 (1997) 149–162
Comparative analysis of biochemical parameters for differentiation of pleural exudates from transudates Light’s criteria, cholesterol, bilirubin, albumin gradient, alkaline phosphatase, creatine kinase, and uric acid a, b a ¨ b ¨ ¨ Muzaffer Metintas¸ *, Ozkan Alatas¸ , Fusun Alatas¸ , Omer C¸olak , a a ¨ Necla Ozdemir , Sinan Erginel a
Department of Chest Diseases, Osmangazi University Medical Faculty, Eskis¸ehir, Turkey b Department of Biochemistry, Osmangazi University Medical Faculty, Eskis¸ehir, Turkey
Received 26 November 1996; received in revised form 25 April 1997; accepted 29 April 1997
Abstract The differentiation of pleural effusions as being either transudate or exudate is the first step in the diagnosis of pleural effusions. The aim of this study was to compare the efficiency of the various biochemical parameters to the traditional criteria of Light et al., for differentiating exudates from transudates. Ninety-three pleural fluid and sera specimens were obtained and classified as transudates or exudates on the basis of their diagnosis. Of the 93 pleural fluids, 21 were transudates, 72 were exudates. The efficiencies of different parameters for detection of exudates were as follows: The criteria of Light 96%; effusion cholesterol concentration 77%; serum-fluid albumin gradient 67%, pleural / serum alkaline phosphatase ratio 83%; effusion creatine kinase levels 91%; pleural / serum creatine kinase ratio 83%, and effusion uric acid 71%.
*Corresponding author: Tel.: 1 90 222 2392979; Fax.: 1 90 222 2394714. Abbreviations: LDH, Lactate dehydrogenase; P/ S PROT, Pleural fluid / serum protein ratio; P LDH, Pleural fluid LDH concentration. P/ S LDH, Pleural fluid / serum LDH ratio; P CHOL, Pleural fluid cholesterol concentration; P/ S CHOL, Pleural fluid / serum cholesterol ratio; S–F Alb, Serum-pleural fluid albumin gradient; P/ S BIL, Pleural fluid / serum bilirubin ratio; P AP, Pleural fluid alkaline phosphatase concentration; P/ S AP, Pleural fluid / serum alkaline phosphatase ratio; P CK, Pleural fluid creatine kinase concentration; P/ S CK, Pleural fluid / serum creatine kinase; P UA, Pleural fluid uric acid concentration; P/ S UA, Pleural fluid / serum uric acid ratio; PPV, Positive predictive value; NPV, Negative predictive value; TP, True positive; TN, True negative; FP, False positive; FN, False negative 0009-8981 / 97 / $17.00 1997 Elsevier Science B.V. All rights reserved. PII S0009-8981( 97 )00091-0
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M. Metintas¸ et al. / Clinica Chimica Acta 264 (1997) 149 – 162
Pleural / serum uric acid ratio was insignificant for the purpose of this study. Science B.V.
1997 Elsevier
Keywords: Pleural fluid; Uric acid; Serum cholesterol
1. Introduction Although the pleural cavity contains a small amount of pleural fluid in normal conditions, the amount of fluid increases up to a few litres (an effusion) during pathological changes [1]. The differentiation of the pleural effusions as being either transudate or exudate is the first step in the diagnosis of pleural effusions. Defining an effusion as a transudate limits the differential diagnosis and the need for further diagnostic procedures, since a transudate is due to systemic factors, such as congestive heart failure and hypoproteinemia, that influence the formation and absorption of pleural fluid. In contrast, exudates more closely resemble plasma, as an exudate is the result of the increased permeability of the lung capillaries to protein, due to pleural inflammation or lymphatic obstruction. For this reason, to define an effusion as an exudate always requires more extensive and invasive diagnostic procedures [2,3]. The criteria established by Light et al., for differentiating exudates from transudates have been widely accepted [2,4]. However, in some prospective studies applying the criteria of Light et al., the sensitivity for exudates remained high but the specificity did not [5–7]. For this reason, several recent studies have evaluated alternative criteria, such as pleural fluid cholesterol level, serumpleural fluid albumin gradient, pleural fluid to serum cholesterol and bilirubin ratios, etc. [5–8]. In some of these studies authors have claimed that the parameters tested as alternative criteria showed higher sensitivity and specificity for the differentiation of transudate and exudate [5,6]. In others, however, the criteria of Light et al., had a higher sensitivity and specificity than the alternative criteria [9,10]. The purpose of this study was to evaluate the serum-pleural fluid albumin gradient, pleural fluid concentrations of cholesterol, alkaline phosphatase, creatine kinase and uric acid, as well as pleural fluid to serum ratios of cholesterol, bilirubin, alkaline phosphatase, creatine kinase and uric acid, for the purpose of differentiating exudates from transudates. We have found no information about uric acid, and only a little about creatine kinase in differentiating exudates from transudates. Thus, this is the first study of uric acid for this purpose. Also, the relative usefulness of these parameters was compared with the traditional criteria of Light et al. (pleural fluid lactate dehydrogenase [LDH] concentration, pleural fluid to serum LDH ratio, pleural fluid to serum protein ratio).
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2. Materials and methods One hundred and sixteen pleural fluid and sera specimens were obtained, respectively, from the same number of patients in our clinic, between February 1994 and August 1995. Twenty-three cases were excluded from the study, due to non-definitive diagnosis, obvious haemothorax secondary to trauma or diuretic treatment prior to thoracocentesis. The effusions of the remaining 93 cases were classified as transudates or exudates on the basis of their diagnosis. There were 64 men (69%) and 29 women (31%). The mean age of the patients was 55 years (range 17–82). Twenty-one effusions were defined as transudates and 72 as exudates. Of the 21 patients with transudates, 14 were men (67%) and 7 were women (33%), with a mean age of 58 years (range 42–72). Of the 72 patients with exudates, 50 were men (69%) and 22 were women (31%), with a mean age of 54 years (range 17–82). The causes of the pleural effusions of these 93 patients are shown in Table 1. The diagnoses of the patients were defined by the following predetermined criteria: (1) Congestive heart failure diagnosed as the cause of the pleural effusion had to meet the following four criteria: cardiomegaly, radiological evidence of congested lungs, peripheral edema, and response to treatment for congestive heart failure. (2) Renal failure was diagnosed when there were raised serum urea and creatinine levels together with the presence of clinical evidence of fluid overload. (3) Nephrotic syndrome was diagnosed if the patient had proteinuria, edema, and hypoalbuminemia. Table 1 Causes of pleural effusions Cause Transudates Congestive heart failure Renal failure Nephrotic syndrome Exudates Neoplastic conditions Parapneumonic pleurisy Tuberculous pleurisy Benign asbestos pleurisy Systemic lupus erythematosus Pulmonary embolism Dressler’s syndrome
No. of patients 21 18 2 1 72 41 12 13 2 2 1 1
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(4) Neoplastic effusions were diagnosed if one of the following criteria was met: detection of malignant cells at cytologic examination or in a biopsy specimen; histologically diagnosed primary malignancy with exclusion of any other cause known to be associated with pleural effusion. (5) Parapneumonic pleurisy was identified when there was an acute febrile illness with purulent sputum, pulmonary infiltrate and responsiveness to antibiotic treatment, or identification of the organism in the pleural effusion in the absence of any other cause associated with pleural effusions. (6) Tuberculous pleurisy was diagnosed if one of the following criteria was met: identifying bacillus in pleural fluid or biopsy specimen cultures; the presence of caseous granulomas in pleural biopsy tissue; radiological and clinical evidence of tuberculous pleurisy with acid-fast bacilli positive sputum, followed by response to antituberculous therapy. (7) Pulmonary embolism was diagnosed if there was a high-probability ventilation-perfusion scan and strong clinical suspicion. (8) Dressler’ s syndrome, systemic lupus erythematosus and benign asbestos pleurisy: these cases were definitively diagnosed and well documented by clinical and laboratory studies. The following studies were performed on all patients: pleural fluid cell count and differential cell count, the criteria of Light et al. (pleural fluid / serum protein ratio [P/ S PROT], pleural fluid LDH concentration [P LDH], pleural fluid / serum LDH ratio [P/ S LDH]), pleural fluid total cholesterol concentration [P CHOL], pleural fluid / serum cholesterol ratio [P/ S CHOL], serum-pleural fluid albumin gradient [S–F Alb], pleural fluid / serum bilirubin ratio [P/ S BIL], pleural fluid alkaline phosphatase concentration [P AP], pleural fluid / serum alkaline phosphatase ratio [P/ S AP], pleural fluid creatine kinase activity [P CK], pleural fluid / serum creatine kinase ratio [P/ S CK], pleural fluid uric acid concentration [P UA], and pleural fluid / serum uric acid ratio [P/ S UA]. Only the results of the first thoracocentesis were considered. A sample of serum, preferably simultaneous, but accepted within 24 h of thoracocentesis, was obtained to determined the above biochemical parameters. A sample of pleural fluid was also sent for routine microbiologic (Gram staining, acid-fast bacilli, bacterial culture) and cytologic examination. Further investigations, such as pleural biopsy, thoracoscopy or diagnostic thoracotomy were performed in the patients for whom the pleural effusion etiology had not been determined. A blood sample and an aliquot of pleural fluid were centrifuged at 3000 rpm for 10 min. The supernatant fluid and sera were stored at 2 208C until assayed. In both pleural effusions and sera the concentration of the above parameters were determined without any knowledge of the definitive diagnosis. The biochemical analyses were performed on BM-Hitachi 747-100 automated analyzer, using the original Boehringer Mannheim kits. The usefulness of each of the biochemical parameters for identifying exudates
n 5 number of cases.
P/ S BIL
S–F Alb
P/ S CHOL
P CHOL
P/ S LDH
P LDH
0.328 0.123 0.03–0.54 63.429 50.095 10–189 0.183 0.169 0.01–0.73 35.667 18.128 7–80 0.201 0.112 0.02–0.4 1.981 0.655 0.9–3.2 0.867 0.463 0.1–1.7
P/ S PROT
x SD Range x SD Range x SD Range x SD Range x SD Range x SD Range x SD Range
Transudates n 5 21
Criteria 0.655 0.143 0.46–1.1 436.073 353.143 124–1869 1.211 1.016 0.31–4.35 87.902 38.986 28–218 0.480 0.219 0.1–1.1 1.080 0.433 0–2 1.522 1.623 0.1–10
Neoplastic n 5 41 0.642 0.055 0.58–0.77 415.769 161.801 160–767 1.430 0.825 0.5–3.34 93.692 32.397 63–89 0.523 0.124 0.3–0.8 1.085 0.414 0.5–2 1.608 1.658 0.6–7
Tuberculous n 5 13 0.614 0.118 0.39–0.77 484.389 340.230 138–1316 1.296 1.059 0.42–4.71 65.444 22.814 32–114 0.433 0.168 0.2–0.8 1.311 0.722 0.4–3 1.789 1.392 0.2–6
Other exudates n 5 18
Table 2 Mean values (x), SDs and ranges of P/ S PROT, P LDH, P/ S LDH, P CHOL, P/ S CHOL, S–F Alb, and P/ S BIL in the groups of effusions
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was evaluated in terms of sensitivity (TP/ [TP 1 FN]), specificity (TN / [TN 1 FP]), positive predictive value (PPV ) 5 (TP/ [TP 1 FP]), negative predictive value (NPV ) 5 (TN / [TN 1 FN)], and efficiency ([TP 1 TN] / [TP 1 TN 1 FP 1 FN]). TP represents the number of true positive diagnoses, TN, the number of true negative diagnoses, FP, the number of false positive diagnoses and FN, the number of false negative diagnoses. Statistical analysis of data was done with Student’s t-test. p values less than 0.05 were considered statistically significant.
3. Results Of the 93 patients with pleural fluid, 21 were transudates and 72 were exudates. In order to evaluate the efficiency of the studied biochemical parameters in differential diagnosis of exudates, we divided the exudates into such subgroups as neoplastic, tuberculous and other exudates (parapneumonic pleurisy, benign asbestos pleurisy etc.), as their precise diagnosis. The means, standard deviations and ranges of P/ S PROT, P LDH, P/ S LDH, P CHOL, P/ S CHOL, S–F Alb and P/ S BIL for the different groups of patients are shown in Table 2, and the means, standard deviations and ranges of P AP, P/ S AP, P CK, P/ S CK, P UA, P/ S UA for the same groups are shown in Table 3. Table 3 Mean values (x), SDs and ranges P AP, P/ S AP, P CK, P/ S CK, P UA in the groups of patients Criteria P AP
P/ S AP
P CK
P/ S CK
P UA
P/ S UA
x SD Range x SD Range x SD Range x SD Range x SD Range x SD Range
n 5 number of cases.
Transudates n 5 21
Neoplastic n 5 41
Tuberculous n 5 13
Other exudates n 5 18
35.048 16.451 8–69 0.177 0.083 0.04–0.37 6.905 7.210 1–24 0.203 0.250 0.02–1 7.190 2.436 3.3–11.8 1.181 0.639 0.1–3.2
96.073 100.159 27–440 0.409 0.3 0.12–1.8 39.561 47.989 6–255 1.322 1.501 0.2–7.08 5.522 2.448 1.7–15.9 1.001 0.294 0.3–2.0
138.538 89.057 53–346 0.749 0.661 0.38–2.7 33.692 21.735 7–72 0.845 0.583 0.17–2.23 4.546 1.922 1.8–7.2 0.992 0.240 0.3–1.3
89.778 62.178 27–227 0.34 0.228 0.05–0.95 48.778 59.554 7–245 1.13 1.256 0.13–4.8 4.039 1.272 1.7–5.9 0.972 0.181 0.5–1.3
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Student’s t-test was used to examine whether there were any differences between the mean values of groups for each biochemical parameter. The mean P AP, P/ S AP, P CK, P/ S CK and P UA values in the exudate group were significantly different from those in the transudate group. There was no significant difference in P/ S UA (t 5 2 1.620, p 5 0.121). Moreover, a significant difference was observed for the P AP and P/ S AP values of tuberculous (n 5 13) and neoplastic groups (n 5 41), and the subgroups of exudates (t 5 3.152, p 5 0.008; t 5 2 3.983, p 5 0.001, respectively). We had expected a significant difference also between the tuberculous and other exudates (n 5 18). However, the difference was not significant (t 5 1.455, p 5 0.171; t 5 1.963, p 5 0.073, respectively) (Figs. 1 and 2). The P/ S CK level was significantly different in both the tuberculous and other exudates groups from that in the neoplastic group (t 5 2.341, p 5 0.037; t 5 2.092, p 5 0.052, respectively). However, we considered it more appropriate to discuss these only as transudates
Fig. 1. Pleural fluid alkaline phosphatase levels (P AP) (U l 21 ) in the different groups studied.
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Fig. 2. Ratios of pleural fluid alkaline phosphatase to serum. alkaline phosphatase levels (P/ S AP) in the different groups studied.
(n 5 21) and exudates (n 5 72), because of the small number of patients in the subgroups of exudates. Based on the previous studies, for differentiating exudate from transudate, we accepted the cut-off point as 200 U l 21 for LDH [4] and 60 mg dl 21 for cholesterol [5,6]. The dividing line was accepted as 0.5 for pleural fluid / serum protein ratio [4], 0.6 for pleural fluid / serum LDH ratio [4], 0.3 for pleural fluid / serum cholesterol ratio [5,6] and 0.6 for pleural fluid / serum bilirubin ratio [8]. In addition, based on the study by Roth et al. [7], a cut-off value of 1.2 g dl 21 was applied for the serum-fluid albumin gradient; an exudate having a gradient # 1.2 g dl 21 and a transudate having a gradient . 1.2 g dl 21 . There are a few studies about alkaline phosphatase concentration in pleural effusion and its significance in the diagnosis of the patients [11,12]. In accordance with previous
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findings and our own AP results, for differentiating transudates from exudates 45 U l 21 was accepted as the cut-off point (Fig. 1), and 0.25 as the dividing line (Fig. 2) in the present study. We accepted the cut-off levels of CK and UA as 7 U l 21 (Fig. 3) and 5.5 mg dl 21 (Fig. 4), respectively. Uric acid levels had a reverse relation with respect to other parameters; transudates had high concentrations of uric acid in effusions. We also accepted the dividing line as 0.4 for the pleural fluid / serum CK ratio (Fig. 5) for differentiating exudates from transudates. The pleural fluid / serum uric acid ratio was non-significant for any differentiation (Table 3). The sensitivity, specificity, positive predictive value, negative predictive value and efficiency of the investigated parameters, according to the different cut-off levels in the differentiation of exudates from transudates, are shown in Table 4.
Fig. 3. Pleural fluid creatine kinase levels (P CK) (U l 21 ) in the different groups studied.
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Fig. 4. Pleural fluid uric acid levels (P UA) (mg dl -1 ) in the different groups studied.
4. Discussion The initial step in determining the cause of a pleural effusion is to categorize effusions as transudates or exudates. Transudates develop when there is a change in systemic factors; thus, it does not require further diagnostic investigations. However, an exudative effusion always requires more extensive and invasive diagnostic investigations, since exudates are the result of pleural or other pulmonary pathologic conditions, of lymphatic obstruction [2,3,10,13,14]. In the literature there are few studies determining as many parameters as ours. We have found no information on uric acid and only a little on creatine kinase,
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Fig. 5. Ratios of pleural fluid creatine kinase to serum creatine kinase levels (P/ S CK) in the different groups studied.
in differentiating exudates from transudates. This is, therefore, the first study on uric acid for this purpose. The classic criteria given for differentiation of exudate from transudate was that of Light et al. [2]. In the initial study of Light et al., in 1972 [4], they used pleural and serum levels of protein and LDH to establish criteria for differentiating exudates from transudates. A pleural fluid is classified as an exudate if it meets one or more of the following criteria: 1) A pleural fluid to serum protein ratio greater than 0.5; 2) A pleural fluid LDH greater than 200 IU; 3) A pleural fluid to serum LDH ratio greater than 0.6. Light et al., have suggested that the sensitivity and specificity of these criteria are both near 100 percent, and that the cost, together with this high diagnostic accuracy, is relatively low. However, several recent articles have shown the criteria of Light et al., to have a low specificity for this aim [5–8]; consequently, the use of the Light criteria may
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Table 4 Sensitivity, specificity, positive predictive value (PPV ), negative predictive value (NPV ) and efficiency of each parameter studied Criteria
Sensitivity, %
Specificity, %
PPV, %
NPV, %
Efficiency, %
P/ S PROT P LDH P/ S LDH LIGHT P CHOL P/ S CHOL S–F Alb P/ S BIL P AP P/ S AP P CK P/ S CK P UA
97 81 86 100 75 93 63 90 82 83 99 82 71
85 100 95 81 86 71 81 38 76 81 67 86 70
96 100 98 95 95 92 92 83 92 94 91 95 42
90 60 67 100 50 75 39 53 55 59 93 58 90
94 85 88 96 77 88 67 78 81 83 91 83 71
lead to unwarranted invasive interventions in some patients with transudative effusions. In the light of these limitations, three further classifications have been suggested in the literature. These include use of the pleural fluid cholesterol concentration to pleural fluid / serum cholesterol ratio [5,6] and the serumalbumin gradient [7] to pleural fluid serum bilirubin ratio [8]. There are some recent studies investigating the usefulness of the pleural fluid cholesterol concentration for differentiating transudates from exudates. In two of them, the authors claim that both sensitivity and specificity of pleural fluid cholesterol concentration were found to be nearly 100 percent. They claim that pleural fluid cholesterol concentration and also pleural fluid serum cholesterol ratio were highly effective and superior to the criteria of Light et al. [5,6]. In addition, according to these authors the pleural fluid / serum cholesterol ratio ( $ 0.3) did not change the results determined by the pleural fluid cholesterol concentration. However, in two studies performed later by Romero et al. and Burgess et al. [9,10], pleural fluid cholesterol concentration had a lower sensitivity and specificity than Light’s criteria and was found to be a poor method for differentiating exudates from transudates. In the present study we have found that the sensitivity of pleural fluid cholesterol concentration ( $ 60 mg dl 21 ) to be 75% and the specificity 86%. These results suggest that the pleural fluid cholesterol concentration has a lower sensitivity and specificity than in the criteria of Light et al. In addition, the pleural fluid / serum cholesterol ratio is not a useful aid. In our series the criteria of Light et al., had a 100% sensitivity; however, this specificity was low, 81%, as in some other studies. Another criterion for differentiating exudates from transudates suggested to
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date is the serum-pleural fluid albumin gradient, which had a sensitivity and specificity of 95 and 100%, respectively, in the study of Roth et al. [7] and 87 and 92%, respectively, in the study of Burgess et al. [10]. In the present study this gradient had a 63% sensitivity and 81% specificity. These results indicate that the serum-fluid albumin gradient has no advantage over either the criteria of Light et al., or the pleural fluid cholesterol level. In their study, Meisel et al. [8] suggest that exudates having pleural fluid / serum bilirubin ratio had approximately 90% sensitivity and specificity, using a cut-off level of 0.6, for differentiating exudates from transudates. In another study, Burgess et al., claim that this parameter had a 81% sensitivity and 61% specificity for this aim [10]. In our study this parameter had a 90% sensitivity; however, its specificity was very low, 38%. Interestingly, the mean value of pleural fluid / serum bilirubin ratio in the transudates was higher than 0.6. In the present study of the criteria proposed to differentiate exudates from transudates to date, the criteria suggested by Light et al., had a 100% sensitivity, although its specificity was lower than other biochemical parameters studied, excluding pleural / serum bilirubin and cholesterol ratios. However, efficiency, PPV and NPV of Light’s criteria all had greater values than all of others. The use of pleural alkaline phosphatase and the ratio of pleural fluid to serum alkaline phosphatase for differentiating exudates from transudates is included in only a few studies involving a limited number of patients [11,12]; thus, satisfactory data have not yet been obtained concerning this parameter. In our series, both the pleural fluid alkaline phosphatase concentration and the pleural fluid / serum alkaline phosphatase ratio had limited sensitivities and specificities for differentiating exudates from transudates. Cytoplasmic enzymes, creatine kinase and uric acid have not been widely investigated for this purpose. We have found pleural fluid creatine kinase concentration to have a high sensitivity, 99%, but a low specificity, 67%. Pleural fluid / serum creatine kinase ratio had 82% sensitivity and 86% specificity; its usefulness, therefore, was lower than the criteria of Light et al. It was, however, more effective for differentiating exudates and transudates than cholesterol criteria previously suggested by some authors. Uric acid, the major product of purine metabolism in man, has a low molecular weight and its binding to plasma proteins is minimal. Thus, it is possible for uric acid to diffuse freely to different body compartments. We suggest that the increased permeability, due to changes in pleural-capillary pressures in the formation of transudates, is the cause of the increase of uric acid levels in pleural fluid. As a result, we conclude that the criteria of Light remain the best method for differentiating exudates and transudates among the criteria proposed to date, despite their low specificity. However, further studies, involving larger numbers of patients, to evaluate the parameters covered in our study are needed in order to draw any conclusion or to achieve higher sensitivity.
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References [1] Bartter T, Santarelli R, Akers SM, Pratter MR. The evaluation of pleural effusion. Chest 1994;106:1209–14. [2] Light RW, Pleural Disease. Baltimore: Williams and Wilkins, 1995:38–39. [3] Millard FJC, Pepper JR, Pleural disease. In: Brewis RAL, Gibson GJ, Geddes DM, editors. Respiratory Medicine. New York: Saunders, 1990:1407–1412. [4] Light RW, MacGregor MI, Luchsinger PC, Ball WC. Pleural effusions: the diagnostic separation of transudates and exudates. Ann Intern Med 1972;77:507–13. [5] Hamm H, Brohan U, Bohmer R, Missmahl HP. Cholesterol in pleural effusions: a diagnostic aid. Chest 1987;92:296–302. ´ L, Pose A, Suarez J, Gonzales-Juanatey JR, Sarandeses A, Jose´ ES, Dobana A, [6] Valdes Salgueiro M, Suarez JRR. Cholesterol: a useful parameter for distinguishing between pleural exudates and transudates. Chest 1991;99:1097–102. [7] Roth BJ, O’Meara TF, Cragun YM. The serum-effusion albumin gradient in the evaluation of pleural effusions. Chest 1990;98:546–9. [8] Meisel S, Shamis A, Thaler M, Nussinovicht N, Rosenthal T. Pleural fluid to serum bilirubin concentration ratio for the separation of transudates from exudates. Chest 1990;98:141–4. [9] Romero S, Candela A, Martin C, Hemandez L, Trigo C, Gil J. Evaluation of different criteria for the separation of pleural transudates from exudates. Chest 1993;104:399–404. [10] Burgess LJ, Maritz FJ, Taljaard JJF. Comparative analysis of the biochemical parameters used to distinguish between pleural transudates and exudates. Chest 1995;107:1604–9. ˇ [11] Tahaoglu K. Kizkin, O, El, R., Alkaline phosphatase: distinguishing between pleural exudates and transudates [letter]. Chest 1994;107:1912–3. [12] Syabbalo NC. Use of pleural alkaline phosphatase content to diagnose Tuberculous effusions [letter]. Chest 1991;99:522–3. [13] Broads VC, Light RW. What is the origin of pleural transudates and exudates? [editorial]. Chest 1992;102:658. [14] Sahn SA. The Pleura. Am Rev Respir Dis 1988;138:188–234.
Comparative analysis of biochemical parameters for differentiation of pleural exudates from transudates Light’s criteria, cholesterol, bilirubin, albumin gradient, alkaline phosphatase, creatine kinase, and uric acid a, b a ¨ b ¨ ¨ Muzaffer Metintas¸ *, Ozkan Alatas¸ , Fusun Alatas¸ , Omer C¸olak , a a ¨ Necla Ozdemir , Sinan Erginel a
Department of Chest Diseases, Osmangazi University Medical Faculty, Eskis¸ehir, Turkey b Department of Biochemistry, Osmangazi University Medical Faculty, Eskis¸ehir, Turkey
Received 26 November 1996; received in revised form 25 April 1997; accepted 29 April 1997
Abstract The differentiation of pleural effusions as being either transudate or exudate is the first step in the diagnosis of pleural effusions. The aim of this study was to compare the efficiency of the various biochemical parameters to the traditional criteria of Light et al., for differentiating exudates from transudates. Ninety-three pleural fluid and sera specimens were obtained and classified as transudates or exudates on the basis of their diagnosis. Of the 93 pleural fluids, 21 were transudates, 72 were exudates. The efficiencies of different parameters for detection of exudates were as follows: The criteria of Light 96%; effusion cholesterol concentration 77%; serum-fluid albumin gradient 67%, pleural / serum alkaline phosphatase ratio 83%; effusion creatine kinase levels 91%; pleural / serum creatine kinase ratio 83%, and effusion uric acid 71%.
*Corresponding author: Tel.: 1 90 222 2392979; Fax.: 1 90 222 2394714. Abbreviations: LDH, Lactate dehydrogenase; P/ S PROT, Pleural fluid / serum protein ratio; P LDH, Pleural fluid LDH concentration. P/ S LDH, Pleural fluid / serum LDH ratio; P CHOL, Pleural fluid cholesterol concentration; P/ S CHOL, Pleural fluid / serum cholesterol ratio; S–F Alb, Serum-pleural fluid albumin gradient; P/ S BIL, Pleural fluid / serum bilirubin ratio; P AP, Pleural fluid alkaline phosphatase concentration; P/ S AP, Pleural fluid / serum alkaline phosphatase ratio; P CK, Pleural fluid creatine kinase concentration; P/ S CK, Pleural fluid / serum creatine kinase; P UA, Pleural fluid uric acid concentration; P/ S UA, Pleural fluid / serum uric acid ratio; PPV, Positive predictive value; NPV, Negative predictive value; TP, True positive; TN, True negative; FP, False positive; FN, False negative 0009-8981 / 97 / $17.00 1997 Elsevier Science B.V. All rights reserved. PII S0009-8981( 97 )00091-0
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M. Metintas¸ et al. / Clinica Chimica Acta 264 (1997) 149 – 162
Pleural / serum uric acid ratio was insignificant for the purpose of this study. Science B.V.
1997 Elsevier
Keywords: Pleural fluid; Uric acid; Serum cholesterol
1. Introduction Although the pleural cavity contains a small amount of pleural fluid in normal conditions, the amount of fluid increases up to a few litres (an effusion) during pathological changes [1]. The differentiation of the pleural effusions as being either transudate or exudate is the first step in the diagnosis of pleural effusions. Defining an effusion as a transudate limits the differential diagnosis and the need for further diagnostic procedures, since a transudate is due to systemic factors, such as congestive heart failure and hypoproteinemia, that influence the formation and absorption of pleural fluid. In contrast, exudates more closely resemble plasma, as an exudate is the result of the increased permeability of the lung capillaries to protein, due to pleural inflammation or lymphatic obstruction. For this reason, to define an effusion as an exudate always requires more extensive and invasive diagnostic procedures [2,3]. The criteria established by Light et al., for differentiating exudates from transudates have been widely accepted [2,4]. However, in some prospective studies applying the criteria of Light et al., the sensitivity for exudates remained high but the specificity did not [5–7]. For this reason, several recent studies have evaluated alternative criteria, such as pleural fluid cholesterol level, serumpleural fluid albumin gradient, pleural fluid to serum cholesterol and bilirubin ratios, etc. [5–8]. In some of these studies authors have claimed that the parameters tested as alternative criteria showed higher sensitivity and specificity for the differentiation of transudate and exudate [5,6]. In others, however, the criteria of Light et al., had a higher sensitivity and specificity than the alternative criteria [9,10]. The purpose of this study was to evaluate the serum-pleural fluid albumin gradient, pleural fluid concentrations of cholesterol, alkaline phosphatase, creatine kinase and uric acid, as well as pleural fluid to serum ratios of cholesterol, bilirubin, alkaline phosphatase, creatine kinase and uric acid, for the purpose of differentiating exudates from transudates. We have found no information about uric acid, and only a little about creatine kinase in differentiating exudates from transudates. Thus, this is the first study of uric acid for this purpose. Also, the relative usefulness of these parameters was compared with the traditional criteria of Light et al. (pleural fluid lactate dehydrogenase [LDH] concentration, pleural fluid to serum LDH ratio, pleural fluid to serum protein ratio).
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2. Materials and methods One hundred and sixteen pleural fluid and sera specimens were obtained, respectively, from the same number of patients in our clinic, between February 1994 and August 1995. Twenty-three cases were excluded from the study, due to non-definitive diagnosis, obvious haemothorax secondary to trauma or diuretic treatment prior to thoracocentesis. The effusions of the remaining 93 cases were classified as transudates or exudates on the basis of their diagnosis. There were 64 men (69%) and 29 women (31%). The mean age of the patients was 55 years (range 17–82). Twenty-one effusions were defined as transudates and 72 as exudates. Of the 21 patients with transudates, 14 were men (67%) and 7 were women (33%), with a mean age of 58 years (range 42–72). Of the 72 patients with exudates, 50 were men (69%) and 22 were women (31%), with a mean age of 54 years (range 17–82). The causes of the pleural effusions of these 93 patients are shown in Table 1. The diagnoses of the patients were defined by the following predetermined criteria: (1) Congestive heart failure diagnosed as the cause of the pleural effusion had to meet the following four criteria: cardiomegaly, radiological evidence of congested lungs, peripheral edema, and response to treatment for congestive heart failure. (2) Renal failure was diagnosed when there were raised serum urea and creatinine levels together with the presence of clinical evidence of fluid overload. (3) Nephrotic syndrome was diagnosed if the patient had proteinuria, edema, and hypoalbuminemia. Table 1 Causes of pleural effusions Cause Transudates Congestive heart failure Renal failure Nephrotic syndrome Exudates Neoplastic conditions Parapneumonic pleurisy Tuberculous pleurisy Benign asbestos pleurisy Systemic lupus erythematosus Pulmonary embolism Dressler’s syndrome
No. of patients 21 18 2 1 72 41 12 13 2 2 1 1
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(4) Neoplastic effusions were diagnosed if one of the following criteria was met: detection of malignant cells at cytologic examination or in a biopsy specimen; histologically diagnosed primary malignancy with exclusion of any other cause known to be associated with pleural effusion. (5) Parapneumonic pleurisy was identified when there was an acute febrile illness with purulent sputum, pulmonary infiltrate and responsiveness to antibiotic treatment, or identification of the organism in the pleural effusion in the absence of any other cause associated with pleural effusions. (6) Tuberculous pleurisy was diagnosed if one of the following criteria was met: identifying bacillus in pleural fluid or biopsy specimen cultures; the presence of caseous granulomas in pleural biopsy tissue; radiological and clinical evidence of tuberculous pleurisy with acid-fast bacilli positive sputum, followed by response to antituberculous therapy. (7) Pulmonary embolism was diagnosed if there was a high-probability ventilation-perfusion scan and strong clinical suspicion. (8) Dressler’ s syndrome, systemic lupus erythematosus and benign asbestos pleurisy: these cases were definitively diagnosed and well documented by clinical and laboratory studies. The following studies were performed on all patients: pleural fluid cell count and differential cell count, the criteria of Light et al. (pleural fluid / serum protein ratio [P/ S PROT], pleural fluid LDH concentration [P LDH], pleural fluid / serum LDH ratio [P/ S LDH]), pleural fluid total cholesterol concentration [P CHOL], pleural fluid / serum cholesterol ratio [P/ S CHOL], serum-pleural fluid albumin gradient [S–F Alb], pleural fluid / serum bilirubin ratio [P/ S BIL], pleural fluid alkaline phosphatase concentration [P AP], pleural fluid / serum alkaline phosphatase ratio [P/ S AP], pleural fluid creatine kinase activity [P CK], pleural fluid / serum creatine kinase ratio [P/ S CK], pleural fluid uric acid concentration [P UA], and pleural fluid / serum uric acid ratio [P/ S UA]. Only the results of the first thoracocentesis were considered. A sample of serum, preferably simultaneous, but accepted within 24 h of thoracocentesis, was obtained to determined the above biochemical parameters. A sample of pleural fluid was also sent for routine microbiologic (Gram staining, acid-fast bacilli, bacterial culture) and cytologic examination. Further investigations, such as pleural biopsy, thoracoscopy or diagnostic thoracotomy were performed in the patients for whom the pleural effusion etiology had not been determined. A blood sample and an aliquot of pleural fluid were centrifuged at 3000 rpm for 10 min. The supernatant fluid and sera were stored at 2 208C until assayed. In both pleural effusions and sera the concentration of the above parameters were determined without any knowledge of the definitive diagnosis. The biochemical analyses were performed on BM-Hitachi 747-100 automated analyzer, using the original Boehringer Mannheim kits. The usefulness of each of the biochemical parameters for identifying exudates
n 5 number of cases.
P/ S BIL
S–F Alb
P/ S CHOL
P CHOL
P/ S LDH
P LDH
0.328 0.123 0.03–0.54 63.429 50.095 10–189 0.183 0.169 0.01–0.73 35.667 18.128 7–80 0.201 0.112 0.02–0.4 1.981 0.655 0.9–3.2 0.867 0.463 0.1–1.7
P/ S PROT
x SD Range x SD Range x SD Range x SD Range x SD Range x SD Range x SD Range
Transudates n 5 21
Criteria 0.655 0.143 0.46–1.1 436.073 353.143 124–1869 1.211 1.016 0.31–4.35 87.902 38.986 28–218 0.480 0.219 0.1–1.1 1.080 0.433 0–2 1.522 1.623 0.1–10
Neoplastic n 5 41 0.642 0.055 0.58–0.77 415.769 161.801 160–767 1.430 0.825 0.5–3.34 93.692 32.397 63–89 0.523 0.124 0.3–0.8 1.085 0.414 0.5–2 1.608 1.658 0.6–7
Tuberculous n 5 13 0.614 0.118 0.39–0.77 484.389 340.230 138–1316 1.296 1.059 0.42–4.71 65.444 22.814 32–114 0.433 0.168 0.2–0.8 1.311 0.722 0.4–3 1.789 1.392 0.2–6
Other exudates n 5 18
Table 2 Mean values (x), SDs and ranges of P/ S PROT, P LDH, P/ S LDH, P CHOL, P/ S CHOL, S–F Alb, and P/ S BIL in the groups of effusions
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was evaluated in terms of sensitivity (TP/ [TP 1 FN]), specificity (TN / [TN 1 FP]), positive predictive value (PPV ) 5 (TP/ [TP 1 FP]), negative predictive value (NPV ) 5 (TN / [TN 1 FN)], and efficiency ([TP 1 TN] / [TP 1 TN 1 FP 1 FN]). TP represents the number of true positive diagnoses, TN, the number of true negative diagnoses, FP, the number of false positive diagnoses and FN, the number of false negative diagnoses. Statistical analysis of data was done with Student’s t-test. p values less than 0.05 were considered statistically significant.
3. Results Of the 93 patients with pleural fluid, 21 were transudates and 72 were exudates. In order to evaluate the efficiency of the studied biochemical parameters in differential diagnosis of exudates, we divided the exudates into such subgroups as neoplastic, tuberculous and other exudates (parapneumonic pleurisy, benign asbestos pleurisy etc.), as their precise diagnosis. The means, standard deviations and ranges of P/ S PROT, P LDH, P/ S LDH, P CHOL, P/ S CHOL, S–F Alb and P/ S BIL for the different groups of patients are shown in Table 2, and the means, standard deviations and ranges of P AP, P/ S AP, P CK, P/ S CK, P UA, P/ S UA for the same groups are shown in Table 3. Table 3 Mean values (x), SDs and ranges P AP, P/ S AP, P CK, P/ S CK, P UA in the groups of patients Criteria P AP
P/ S AP
P CK
P/ S CK
P UA
P/ S UA
x SD Range x SD Range x SD Range x SD Range x SD Range x SD Range
n 5 number of cases.
Transudates n 5 21
Neoplastic n 5 41
Tuberculous n 5 13
Other exudates n 5 18
35.048 16.451 8–69 0.177 0.083 0.04–0.37 6.905 7.210 1–24 0.203 0.250 0.02–1 7.190 2.436 3.3–11.8 1.181 0.639 0.1–3.2
96.073 100.159 27–440 0.409 0.3 0.12–1.8 39.561 47.989 6–255 1.322 1.501 0.2–7.08 5.522 2.448 1.7–15.9 1.001 0.294 0.3–2.0
138.538 89.057 53–346 0.749 0.661 0.38–2.7 33.692 21.735 7–72 0.845 0.583 0.17–2.23 4.546 1.922 1.8–7.2 0.992 0.240 0.3–1.3
89.778 62.178 27–227 0.34 0.228 0.05–0.95 48.778 59.554 7–245 1.13 1.256 0.13–4.8 4.039 1.272 1.7–5.9 0.972 0.181 0.5–1.3
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Student’s t-test was used to examine whether there were any differences between the mean values of groups for each biochemical parameter. The mean P AP, P/ S AP, P CK, P/ S CK and P UA values in the exudate group were significantly different from those in the transudate group. There was no significant difference in P/ S UA (t 5 2 1.620, p 5 0.121). Moreover, a significant difference was observed for the P AP and P/ S AP values of tuberculous (n 5 13) and neoplastic groups (n 5 41), and the subgroups of exudates (t 5 3.152, p 5 0.008; t 5 2 3.983, p 5 0.001, respectively). We had expected a significant difference also between the tuberculous and other exudates (n 5 18). However, the difference was not significant (t 5 1.455, p 5 0.171; t 5 1.963, p 5 0.073, respectively) (Figs. 1 and 2). The P/ S CK level was significantly different in both the tuberculous and other exudates groups from that in the neoplastic group (t 5 2.341, p 5 0.037; t 5 2.092, p 5 0.052, respectively). However, we considered it more appropriate to discuss these only as transudates
Fig. 1. Pleural fluid alkaline phosphatase levels (P AP) (U l 21 ) in the different groups studied.
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Fig. 2. Ratios of pleural fluid alkaline phosphatase to serum. alkaline phosphatase levels (P/ S AP) in the different groups studied.
(n 5 21) and exudates (n 5 72), because of the small number of patients in the subgroups of exudates. Based on the previous studies, for differentiating exudate from transudate, we accepted the cut-off point as 200 U l 21 for LDH [4] and 60 mg dl 21 for cholesterol [5,6]. The dividing line was accepted as 0.5 for pleural fluid / serum protein ratio [4], 0.6 for pleural fluid / serum LDH ratio [4], 0.3 for pleural fluid / serum cholesterol ratio [5,6] and 0.6 for pleural fluid / serum bilirubin ratio [8]. In addition, based on the study by Roth et al. [7], a cut-off value of 1.2 g dl 21 was applied for the serum-fluid albumin gradient; an exudate having a gradient # 1.2 g dl 21 and a transudate having a gradient . 1.2 g dl 21 . There are a few studies about alkaline phosphatase concentration in pleural effusion and its significance in the diagnosis of the patients [11,12]. In accordance with previous
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findings and our own AP results, for differentiating transudates from exudates 45 U l 21 was accepted as the cut-off point (Fig. 1), and 0.25 as the dividing line (Fig. 2) in the present study. We accepted the cut-off levels of CK and UA as 7 U l 21 (Fig. 3) and 5.5 mg dl 21 (Fig. 4), respectively. Uric acid levels had a reverse relation with respect to other parameters; transudates had high concentrations of uric acid in effusions. We also accepted the dividing line as 0.4 for the pleural fluid / serum CK ratio (Fig. 5) for differentiating exudates from transudates. The pleural fluid / serum uric acid ratio was non-significant for any differentiation (Table 3). The sensitivity, specificity, positive predictive value, negative predictive value and efficiency of the investigated parameters, according to the different cut-off levels in the differentiation of exudates from transudates, are shown in Table 4.
Fig. 3. Pleural fluid creatine kinase levels (P CK) (U l 21 ) in the different groups studied.
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Fig. 4. Pleural fluid uric acid levels (P UA) (mg dl -1 ) in the different groups studied.
4. Discussion The initial step in determining the cause of a pleural effusion is to categorize effusions as transudates or exudates. Transudates develop when there is a change in systemic factors; thus, it does not require further diagnostic investigations. However, an exudative effusion always requires more extensive and invasive diagnostic investigations, since exudates are the result of pleural or other pulmonary pathologic conditions, of lymphatic obstruction [2,3,10,13,14]. In the literature there are few studies determining as many parameters as ours. We have found no information on uric acid and only a little on creatine kinase,
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Fig. 5. Ratios of pleural fluid creatine kinase to serum creatine kinase levels (P/ S CK) in the different groups studied.
in differentiating exudates from transudates. This is, therefore, the first study on uric acid for this purpose. The classic criteria given for differentiation of exudate from transudate was that of Light et al. [2]. In the initial study of Light et al., in 1972 [4], they used pleural and serum levels of protein and LDH to establish criteria for differentiating exudates from transudates. A pleural fluid is classified as an exudate if it meets one or more of the following criteria: 1) A pleural fluid to serum protein ratio greater than 0.5; 2) A pleural fluid LDH greater than 200 IU; 3) A pleural fluid to serum LDH ratio greater than 0.6. Light et al., have suggested that the sensitivity and specificity of these criteria are both near 100 percent, and that the cost, together with this high diagnostic accuracy, is relatively low. However, several recent articles have shown the criteria of Light et al., to have a low specificity for this aim [5–8]; consequently, the use of the Light criteria may
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Table 4 Sensitivity, specificity, positive predictive value (PPV ), negative predictive value (NPV ) and efficiency of each parameter studied Criteria
Sensitivity, %
Specificity, %
PPV, %
NPV, %
Efficiency, %
P/ S PROT P LDH P/ S LDH LIGHT P CHOL P/ S CHOL S–F Alb P/ S BIL P AP P/ S AP P CK P/ S CK P UA
97 81 86 100 75 93 63 90 82 83 99 82 71
85 100 95 81 86 71 81 38 76 81 67 86 70
96 100 98 95 95 92 92 83 92 94 91 95 42
90 60 67 100 50 75 39 53 55 59 93 58 90
94 85 88 96 77 88 67 78 81 83 91 83 71
lead to unwarranted invasive interventions in some patients with transudative effusions. In the light of these limitations, three further classifications have been suggested in the literature. These include use of the pleural fluid cholesterol concentration to pleural fluid / serum cholesterol ratio [5,6] and the serumalbumin gradient [7] to pleural fluid serum bilirubin ratio [8]. There are some recent studies investigating the usefulness of the pleural fluid cholesterol concentration for differentiating transudates from exudates. In two of them, the authors claim that both sensitivity and specificity of pleural fluid cholesterol concentration were found to be nearly 100 percent. They claim that pleural fluid cholesterol concentration and also pleural fluid serum cholesterol ratio were highly effective and superior to the criteria of Light et al. [5,6]. In addition, according to these authors the pleural fluid / serum cholesterol ratio ( $ 0.3) did not change the results determined by the pleural fluid cholesterol concentration. However, in two studies performed later by Romero et al. and Burgess et al. [9,10], pleural fluid cholesterol concentration had a lower sensitivity and specificity than Light’s criteria and was found to be a poor method for differentiating exudates from transudates. In the present study we have found that the sensitivity of pleural fluid cholesterol concentration ( $ 60 mg dl 21 ) to be 75% and the specificity 86%. These results suggest that the pleural fluid cholesterol concentration has a lower sensitivity and specificity than in the criteria of Light et al. In addition, the pleural fluid / serum cholesterol ratio is not a useful aid. In our series the criteria of Light et al., had a 100% sensitivity; however, this specificity was low, 81%, as in some other studies. Another criterion for differentiating exudates from transudates suggested to
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date is the serum-pleural fluid albumin gradient, which had a sensitivity and specificity of 95 and 100%, respectively, in the study of Roth et al. [7] and 87 and 92%, respectively, in the study of Burgess et al. [10]. In the present study this gradient had a 63% sensitivity and 81% specificity. These results indicate that the serum-fluid albumin gradient has no advantage over either the criteria of Light et al., or the pleural fluid cholesterol level. In their study, Meisel et al. [8] suggest that exudates having pleural fluid / serum bilirubin ratio had approximately 90% sensitivity and specificity, using a cut-off level of 0.6, for differentiating exudates from transudates. In another study, Burgess et al., claim that this parameter had a 81% sensitivity and 61% specificity for this aim [10]. In our study this parameter had a 90% sensitivity; however, its specificity was very low, 38%. Interestingly, the mean value of pleural fluid / serum bilirubin ratio in the transudates was higher than 0.6. In the present study of the criteria proposed to differentiate exudates from transudates to date, the criteria suggested by Light et al., had a 100% sensitivity, although its specificity was lower than other biochemical parameters studied, excluding pleural / serum bilirubin and cholesterol ratios. However, efficiency, PPV and NPV of Light’s criteria all had greater values than all of others. The use of pleural alkaline phosphatase and the ratio of pleural fluid to serum alkaline phosphatase for differentiating exudates from transudates is included in only a few studies involving a limited number of patients [11,12]; thus, satisfactory data have not yet been obtained concerning this parameter. In our series, both the pleural fluid alkaline phosphatase concentration and the pleural fluid / serum alkaline phosphatase ratio had limited sensitivities and specificities for differentiating exudates from transudates. Cytoplasmic enzymes, creatine kinase and uric acid have not been widely investigated for this purpose. We have found pleural fluid creatine kinase concentration to have a high sensitivity, 99%, but a low specificity, 67%. Pleural fluid / serum creatine kinase ratio had 82% sensitivity and 86% specificity; its usefulness, therefore, was lower than the criteria of Light et al. It was, however, more effective for differentiating exudates and transudates than cholesterol criteria previously suggested by some authors. Uric acid, the major product of purine metabolism in man, has a low molecular weight and its binding to plasma proteins is minimal. Thus, it is possible for uric acid to diffuse freely to different body compartments. We suggest that the increased permeability, due to changes in pleural-capillary pressures in the formation of transudates, is the cause of the increase of uric acid levels in pleural fluid. As a result, we conclude that the criteria of Light remain the best method for differentiating exudates and transudates among the criteria proposed to date, despite their low specificity. However, further studies, involving larger numbers of patients, to evaluate the parameters covered in our study are needed in order to draw any conclusion or to achieve higher sensitivity.
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