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 Metintaş *, Ozkan ¨
Alataş , Fusun Alataş , Omer Çolak ,
a a
¨
Necla Ozdemir , Sinan Erginel
a
Department of Chest Diseases, Osmangazi University Medical Faculty, Eskişehir, Turkey
b
Department of Biochemistry, Osmangazi University Medical Faculty, Eskişehir, 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
150 M. Metintaş et al. / Clinica Chimica Acta 264 (1997) 149 – 162

Pleural / serum uric acid ratio was insignificant for the purpose of this study.  1997 Elsevier
Science B.V.
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, serum-
pleural 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 differentiat-
ing 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).
 M. Metintaş et al. / Clinica Chimica Acta 264 (1997) 149 – 162 151

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 No. of patients
Transudates 21
Congestive heart failure 18
Renal failure 2
Nephrotic syndrome 1
Exudates 72
Neoplastic conditions 41
Parapneumonic pleurisy 12
Tuberculous pleurisy 13
Benign asbestos pleurisy 2
Systemic lupus erythematosus 2
Pulmonary embolism 1
Dressler’s syndrome 1
152 M. Metintaş et al. / Clinica Chimica Acta 264 (1997) 149 – 162

(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
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
Criteria Transudates Neoplastic Tuberculous Other exudates
n 5 21 n 5 41 n 5 13 n 5 18
P/ S PROT x 0.328 0.655 0.642 0.614
SD 0.123 0.143 0.055 0.118
Range 0.03–0.54 0.46–1.1 0.58–0.77 0.39–0.77
P LDH x 63.429 436.073 415.769 484.389
SD 50.095 353.143 161.801 340.230
Range 10–189 124–1869 160–767 138–1316
P/ S LDH x 0.183 1.211 1.430 1.296
SD 0.169 1.016 0.825 1.059
Range 0.01–0.73 0.31–4.35 0.5–3.34 0.42–4.71
P CHOL x 35.667 87.902 93.692 65.444
SD 18.128 38.986 32.397 22.814
Range 7–80 28–218 63–89 32–114
P/ S CHOL x 0.201 0.480 0.523 0.433
SD 0.112 0.219 0.124 0.168
Range 0.02–0.4 0.1–1.1 0.3–0.8 0.2–0.8
S–F Alb x 1.981 1.080 1.085 1.311
SD 0.655 0.433 0.414 0.722
Range 0.9–3.2 0–2 0.5–2 0.4–3
M. Metintaş et al. / Clinica Chimica Acta 264 (1997) 149 – 162

P/ S BIL x 0.867 1.522 1.608 1.789

SD 0.463 1.623 1.658 1.392
Range 0.1–1.7 0.1–10 0.6–7 0.2–6
n 5 number of cases.
153
154 M. Metintaş et al. / Clinica Chimica Acta 264 (1997) 149 – 162

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 Transudates Neoplastic Tuberculous Other exudates
n 5 21 n 5 41 n 5 13 n 5 18
P AP x 35.048 96.073 138.538 89.778
SD 16.451 100.159 89.057 62.178
Range 8–69 27–440 53–346 27–227
P/ S AP x 0.177 0.409 0.749 0.34
SD 0.083 0.3 0.661 0.228
Range 0.04–0.37 0.12–1.8 0.38–2.7 0.05–0.95
P CK x 6.905 39.561 33.692 48.778
SD 7.210 47.989 21.735 59.554
Range 1–24 6–255 7–72 7–245
P/ S CK x 0.203 1.322 0.845 1.13
SD 0.250 1.501 0.583 1.256
Range 0.02–1 0.2–7.08 0.17–2.23 0.13–4.8
P UA x 7.190 5.522 4.546 4.039
SD 2.436 2.448 1.922 1.272
Range 3.3–11.8 1.7–15.9 1.8–7.2 1.7–5.9
P/ S UA x 1.181 1.001 0.992 0.972
SD 0.639 0.294 0.240 0.181
Range 0.1–3.2 0.3–2.0 0.3–1.3 0.5–1.3
n 5 number of cases.
 M. Metintaş et al. / Clinica Chimica Acta 264 (1997) 149 – 162 155

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 signifi-
cant 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.
156 M. Metintaş et al. / Clinica Chimica Acta 264 (1997) 149 – 162

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
 M. Metintaş et al. / Clinica Chimica Acta 264 (1997) 149 – 162 157

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.
158 M. Metintaş et al. / Clinica Chimica Acta 264 (1997) 149 – 162

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,
 M. Metintaş et al. / Clinica Chimica Acta 264 (1997) 149 – 162 159

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 differentiat-
ing 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
160 M. Metintaş et al. / Clinica Chimica Acta 264 (1997) 149 – 162

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 97 85 96 90 94
P LDH 81 100 100 60 85
P/ S LDH 86 95 98 67 88
LIGHT 100 81 95 100 96
P CHOL 75 86 95 50 77
P/ S CHOL 93 71 92 75 88
S–F Alb 63 81 92 39 67
P/ S BIL 90 38 83 53 78
P AP 82 76 92 55 81
P/ S AP 83 81 94 59 83
P CK 99 67 91 93 91
P/ S CK 82 86 95 58 83
P UA 71 70 42 90 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 serum-
albumin 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
 M. Metintaş et al. / Clinica Chimica Acta 264 (1997) 149 – 162 161

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.
162 M. Metintaş et al. / Clinica Chimica Acta 264 (1997) 149 – 162

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