Clinica Chimica Acta 343 (2004) 61 – 84

www.elsevier.com/locate/clinchim

Review
Biochemical analysis of pleural, peritoneal
and pericardial effusions
L.J. Burgess *
TREAD Research/Cardiology Unit, Stellenbosch University, P.O. Box 19174, Tygerberg 7505, Parow, South Africa
Received 18 August 2003; received in revised form 30 January 2004; accepted 2 February 2004

Abstract

Body fluids other than blood, urine and cerebrospinal fluid are often submitted for biochemical analysis. Of these, pleural,
peritoneal and pericardial fluids are the most common. Laboratory tests are a useful tool to assess the aetiology,
pathophysiology and subsequent treatment of effusions. A wide range of biochemical tests may be requested. This review
critically examines the various analytes that have been used to investigate these body fluids.
D 2004 Elsevier B.V. All rights reserved.

Keywords: Biochemical analysis; Pleural fluids; Peritoneal fluids; Pericardial effusions

1. Biochemical evaluation of pleural effusions
Pleural fluid is an ultrafiltrate of plasma and there
is usually less than 10 ml of fluid in each pleural
cavity [1]. The accumulation of clinically detectable
quantities of pleural fluid is distinctly abnormal [2].
Pleural effusions may indicate the presence of pleural,
pulmonary or extrapulmonary disease. In some cases,
the aetiology of the effusion is obvious from the
clinical picture (e.g. bilateral pleural effusions in
congestive cardiac failure) [3]. In other cases, the
cause and clinical significance is not apparent. In
approximately 70 – 80% of cases, a definitive or
presumptive identification of the cause can be deter-
mined through analysis of the pleural fluid obtained
by thoracentesis [4,5].
Diagnostic thoracentesis should be attempted
whenever the thickness of pleural fluid on the
decubitus radiograph is >10 mm or whenever locu-
lated pleural fluid is demonstrated with ultrasound,
unless the patient has typical congestive heart fail-
ure [2]. Thoracentesis may be associated with a
number of complications including pain, cough,
haematoma, pneumothorax, haemothorax, syncope,
splenic laceration, re-expansion pulmonary oedema
and pleural infection [6,7]. Performance of the
procedure by an experienced operator, especially
under ultrasound guidance, considerably reduces
the risk of complications [7].

1.1. General appearance of the pleural fluid

* Corresponding author. Tel.: +27-21-931-7825; fax: +27-21-
933-3597. The gross appearance and odour of the fluid may
E-mail address: lburgess@iafrica.com (L.J. Burgess). provide useful information regarding the aetiology of

0009-8981/$ - see front matter D 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.cccn.2004.02.002
62 L.J. Burgess / Clinica Chimica Acta 343 (2004) 61–84
the effusion [8]. Most transudates and many exudates
are clear, straw-coloured, odourless and non-viscous.
Frankly purulent fluid indicates an empyema [2]. In
the case of grossly bloody fluid, a haematocrit should
be performed. A pleural haematocrit >50% of the
peripheral haematocrit indicates a haemothorax which
often requires tube thoracostomy, a pleural haematoc-
rit of 1 – 20% is suggestive of cancer, pulmonary
embolism or trauma and a value < 1% is insignificant
[9,10].
A chylothorax is suspected when milky fluid is
obtained on thoracentesis [11]. Milky, turbid fluid can
also be caused by cells and debris or by a high lipid
level [2]. These two entities can be differentiated if the
supernatant is centrifuged and then examined. If tur-
bidity remains after centrifugation, it is probably due to
increased lipid content and the fluid should be sent for
lipid analysis. Alternatively, if the supernatant is clear,
the original turbidity was due to increased numbers of
cells or other debris [2]. Other causes of a milky
pleural effusion include total parenteral nutrition fluid
of lipid-containing solutions infused into the pleural
space and pseudochylous effusions (namely, an accu-
mulation of cholesterol and/or lecithin- or globulin-
rich fluid in long-standing pleural effusions) [12].
Pleural fluid that resembles anchovy paste or
chocolate sauce is suggestive of amoebiasis with a
hepatopleural fistula [13]. This is due to the presence
of blood, cytolyzed liver tissue and small solid par-
ticles of liver parenchyma that have resisted dissolu-
tion [2]. A clear or bloody viscous fluid suggests a
malignant mesothelioma; the high viscosity results
from an increased fluid hyaluronic acid concentration
[14]. A putrid odour may be indicative of an anaerobic
infection whereas an odour of urine suggests probable
urinothorax [2].
1.2. Distinguishing between transudates and exudates
Traditionally, pleural effusions are classified as
transudates and exudates [15]. A transudative pleural
effusion derives from ultrafiltration of the pleural fluid
across a membrane. Its presence implies a non-in-
flammatory process and occurs when pleural fluid
accumulates due to an imbalance between hydrostatic
and oncotic pressures. Common causes of transudates
include congestive cardiac failure, cirrhosis and pul-
monary embolism [2]. Pleural exudates imply in-
volvement of the pleura by an inflammatory or
malignant process causing increased capillary perme-
ability. Common causes include pneumonia, cancer,
pulmonary embolism and, especially in developing
countries, tuberculosis [16,17]. Some of the causes of
pleural effusions are shown in Table 1.
Separation of exudates from transudates is useful
in determining the cause of a pleural effusion and in
deciding whether further and often more invasive
investigations should be carried out on the patient
[18]. Historically, specific gravity was used to sepa-
rate these two entities [15]. Later a pleural fluid
protein level of 30 g/l was used [19,20]. Many
misclassifications were made resulting in patients
enduring unnecessary and often more invasive inves-
tigations. Chandresekhar et al. [20] thus proposed the
Table 1
Causes of pleural effusions
Transudative effusions
Congestive cardiac failure
Cirrhosis
Nephrotic syndrome
Hypoproteinaemic states
Pulmonary embolism
Peritoneal dialysis
Urinothorax
Acute atelectasis
Myxoedema
Post-thoracic and abdominal surgery
Post-partum effusion
Exudative effusions
Infections
e.g. parapneumonic effusions, tuberculosis, amoebiasis,
subphrenic abscess etc
Malignant disease
e.g. primary lung carcinoma, metastatic carcinoma, lymphoma,
leukaemia, mesothelioma, etc
Connective tissue disease
e.g. rheumatoid arthritis, systemic lupus erythematosus
Iatrogenic
. Drug-induced (including minoxidil, amiodarone, bromocrip-
tine, nitrofurantoin, methotrexate, dantrolene)
. Endoscopic oesophageal sclerotherapy
. Radiotherapy
Other inflammatory causes
e.g. pulmonary embolism, pancreatitis, uraemia, Dressler’s
syndrome, asbestos exposure
Diseases of the lymphatics
e.g. chylothorax (trauma, malignancy), lymphangiomyomatosis
Haemothorax (trauma, spontaneous)
 L.J. Burgess / Clinica Chimica Acta 343 (2004) 61–84
use of absolute values of pleural fluid lactate dehy-
drogenase (LDH) in making this distinction. Com-
bining these two entities resulted in the formulation
of the well-known ‘‘Light’s criteria’’ [21].
1.2.1. Light’s criteria
Light’s criteria [21] were retrospectively designed
to be close to 100% sensitive and 100% specific in
identifying pleural exudates. According to these cri-
teria exudative pleural effusions meet at least one of
the following criteria, whereas transudative pleural
effusions meet none:
 Pleural fluid/serum protein ratio >0.5.
 Pleural fluid/serum LDH ratio >0.6.
 Pleural fluid LDH activity >200 U/l (later modified
to 2/3 the upper limit of serum LDH).
In the original study by Light et al. [21], only two
effusions (out of 150 patients) were misclassified,
giving a diagnostic sensitivity of 99% and specificity
of 98% for an exudate. One patient (out of 47
transudates) with congestive cardiac failure met two
of the three criteria for an exudate and one out of 103
exudates contained malignant cells in the fluid, al-
though the effusion appeared to be due to congestive
cardiac failure. Several other prospective studies
using these criteria, while reproducing the sensitivity,
have reported much lower specificities (65 – 86%)
[18,22,23].
Several reasons for this lack of reproducibility have
been proposed [24,25]. Firstly, the original Light
report was a derivation sample. Diagnostic tests have
been shown to work better in derivation samples when
compared with subsequent validation samples [25].
Secondly, rigorous diagnostic criteria were used by
Light et al. in their retrospective study resulting in 33
of the original 183 patients being excluded. It has thus
been suggested that the low false-positive and false-
negative results obtained were the result of these
exclusions and that the diagnostic cut-offs could not,
therefore, be applied to unselected populations [18]. A
third reason proposed for the poorer diagnostic accu-
racy of later studies is the inappropriate use of an
absolute LDH cut-off value of 200 U/l [24]. This
value was originally proposed by Light et al. and later,
in order to account for different assay conditions,
modified by the same authors to two-thirds of normal
63
for serum [26]. Due to the fact that they share a
common test (namely pleural fluid LDH), the critical
pleural fluid LDH and pleural fluid/serum LDH ratio
are highly correlated and thus suffer from mathemat-
ical coupling. Diagnostic test rules do not perform as
well if they include highly correlated criteria. It has
thus been suggested that one of these parameters be
removed from Light’s criteria [25]. A further problem
with Light’s criteria arises from the combination of
multiple tests in parallel with an ‘‘either/or’’ rule,
namely the increase in sensitivity at the expense of
decreasing specificity. This would further explain the
misclassification of transudates as exudates [25]. In an
attempt to improve diagnostic specificity, numerous
investigators have attempted to modify Light’s criteria
[25,27,28] while others have proposed new tests to
differentiate between exudates and transudates.
1.2.2. Serum-effusion albumin gradient
The main disadvantage of Light’s criteria is the
misclassification of transudates as exudates [29]. This
appears to be due to the occurrence of an exudative
range of protein levels in many patients with conges-
tive cardiac failure following diuretic therapy. This
phenomenon was first reported by Pillay [30] who
demonstrated an increase in pleural protein concen-
tration from 15 to 29 g/l after diuretic therapy in
patients with heart failure. Chakko et al. [31] con-
firmed this phenomenon demonstrating a significant
increase in both protein concentration (from 22 to 32
g/l) and fluid/serum LDH ratio (from 0.39 to 0.64).
The origin of pleural exudates and transudates is
uncertain. The classic teaching has been that pleural
effusions arise from the pleural capillaries [32]. There
is a steady flux of fluid across the pleural space [33].
The pleural microvasculature endothelium is semiper-
meable resulting in the protein content of the pleural
fluid being lower than that of the serum [10,33]. The
pleural albumin and globulin components are believed
to originate from the serum via diffusion [34 –36] and
then cleared via the subpleural lymphatic vessels [33].
In the case of exudates, there is an increased leakage
of fluid out of the pleural microvasculature which has
a higher concentration of protein, resulting in a low
gradient between serum and fluid protein (and albu-
min). Exudates can also be formed by a decreased rate
of re-absorption of fluid from the pleural space. In the
case of transudates, the effusion results from an
64 L.J. Burgess / Clinica Chimica Acta 343 (2004) 61–84
imbalance of hydrostatic and osmotic forces and this
gradient is thus maintained [2,10,33].
Application of this principle resulted in the adop-
tion of the serum-effusion albumin gradient (SEAG)
as a means of distinguishing between exudates and
transudates. The SEAG, defined as serum albumin
concentration minus effusion albumin concentration,
was extrapolated by Roth et al. [23] from work done
on peritoneal fluid. Transudates were accordingly
described as having SEAG >12 g/l, while exudates
were described as having a SEAG V 12 g/l. Using
this cut-off point resulted in the correct classification
of all the transudates but incorrect classification of
two malignant effusions (sensitivity 95%, specificity
100%). Of particular note was the fact that fluids from
five patients (of whom four had received previous
diuretic therapy) were misclassified as exudates by
Light’s criteria.
In a subsequent study of 393 patients from South
Africa, poorer sensitivity and specificity (87% and
92%, respectively) were found when applying the
SEAG [29]. Nevertheless, use of the SEAG signifi-
cantly reduced the misclassification of transudative
effusions from patients receiving diuretic therapy.
Light [2] suggests that if, clinically, it is thought that
a patient has a transudative pleural effusion but
Light’s exudative criteria are not met, then it is
reasonable to measure the SEAG. This recommenda-
tion is based on deductive reasoning but has never
been validated in an independent sample. Further-
more, combination tests have enhanced sensitivity
but pay a price in lower specificity [25]. A further
argument against this recommendation is the obser-
vation that SEAG and each of the three elements of
Light’s criteria have the same diagnostic operating
characteristics [25]. According to Heffner et al. [37], a
better approach to managing the uncertainty that
arises from Light’s criteria, especially in the setting
of a patient with congestive heart failure treated with
diuretics, is to use a Bayesian approach.
1.2.3. Cholesterol
Hamm et al. [38] demonstrated that exudates tend
to have a higher pleural fluid cholesterol level than
transudates and proposed this as a means for distin-
guishing between transudates and exudates. The ra-
tionale for this mechanism is poorly understood,
although cholesterol release due to cellular degenera-
tion and serum leakage reflecting increased pleural
permeability have been postulated [24].
In the study by Hamm et al. [38] a cut-off point of
60 mg/dl (1.55 mmol/l) yielded the best results and
exudates were accordingly classified as having a
cholesterol concentration >60 mg/dl and transudates
< 60 mg/dl. Of the 70 effusions included in this study,
all 31 transudates had cholesterol levels < 60 mg/dl.
However, three of the 39 exudates were erroneously
classified as transudates (sensitivity 100%, specificity
95%). Use of Light’s criteria resulted in all the
exudates being correctly classified but with an overall
misclassification rate of 16%. These findings were
confirmed by Valdés et al. [39].
Subsequent studies have failed to reproduce these
results [27,29]. In an attempt to improve diagnostic
efficiency, a number of groups have studied the effect
of varying the cholesterol cut-off level [29,39], of
using fluid/serum cholesterol ratios [29] and of using
cholesterol in combination with LDH [40]. While
cholesterol reduces incorrect classification, it does so
at the expense of missing a significant number of
patients with exudates where further testing is often
warranted [24]. This apparent lower sensitivity may
be explained by the fact that a simple test is employed
as opposed to the three-test combination of Light’s
criteria [25].
1.2.4. Other biochemical analytes used to differen-
tiate between transudates and exudates
Meisel et al. [41] concluded that a serum/fluid
bilirubin ratio >0.6 was an alternative to Light’s
criteria for diagnosing pleural exudates. A total of
51 pleural fluids were evaluated and the diagnostic
sensitivity and specificity were calculated as 96% and
83%, respectively (compared with 90% and 82%,
respectively, for Light’s criteria). Subsequent studies
have failed to reproduce these results [29].
Pleural/serum cholinesterase ratios were shown to
have a similar accuracy to Light’s criteria in the
separation of pleural exudates from transudates [42].
A significant number of misclassified exudates by this
method were malignant, however, thus limiting its
clinical use [43]. Many of the parameters used for
identifying exudates are based on the fact that pleural
exudates more closely resemble plasma than transu-
dates. Pleural/serum ratios of various other parameters
(including aspartate transaminase, alanine transami-
 L.J. Burgess / Clinica Chimica Acta 343 (2004) 61–84
nase, alkaline phosphatase, creatinine kinase and g-
glutamyltransferase) have also been considered as
diagnostic tools [29,44] and all compared poorly with
Light’s criteria.
The use of urinary dipsticks as a side room test
was also evaluated as a rapid screening test for
pleural exudates [45]. Pleural fluid was diluted in
normal saline (1:10) and then tested for protein with
Combur9 reagent strips. The results of the study
demonstrated that a 1+ protein reading indicated a
transudate, as defined by Light’s criteria, with a
specificity of 97% and a 3+ reading indicated an
exudate with a specificity of 94%. A 2+ reading
provided too much overlap between transudates and
exudates to reach any conclusion. Using this method,
69% of pleural effusions could be correctly classi-
fied. Similar results were obtained when compared to
gold-standard diagnoses. The classification of pleural
effusions into transudates and exudates with urinary
reagent strips should not be regarded as a substitute
for laboratory investigations, but rather to add further
weight to the clinician’s initial assessment in order to
allow him/her to plan further investigations and
management with a greater degree of certainty. In
many cases, especially in rural areas far removed
from laboratories, time will also be saved by arriving
at an answer sooner with a resultant reduction in
costs [45].
1.2.5. Meta-analysis of tests used to distinguish
between transudates and exudates
A meta-analysis by Heffner et al. [46] examined
the accuracy of the various tests most frequently used
to distinguish exudates from transudates, either when
used alone or in combination. The authors used the
original criteria of Light et al. [25], as well as more
suitable cut-offs, by subjecting the meta-analysis data
to ROC analysis [47]. The area under the curve is
generally recognised as the most accurate method of
comparing discriminative properties. Accordingly,
single tests except for the bilirubin ratio all performed
reasonably well, although the protein ratio appeared
marginally the best. For tests used in combination, the
highest odd ratios were found for pairs or triplets that
included the albumin gradient. The combination of
three tests tended to give the highest sensitivity and
odds ratio, although the specificity was lower. Exten-
sive overlap of the confidence intervals, however,
65
meant that no clearly superior combination could be
selected.
1.3. Specialised biochemical tests for detecting causes
of pleural effusions
Apart from differentiating between exudates and
transudates, biochemical tests also serve as a guideline
when assessing the aetiology of the effusion.
1.3.1. Glucose
The measurement of glucose levels in pleural fluids
has been used in the differential diagnosis of exuda-
tive disorders. A pleural fluid glucose concentration
greater than 60 mg/dl (3.4 mmol/l) or a pleural/serum
glucose ratio >0.5 have widely been accepted as the
cut-off values [48]. There is dispute as to how the
specimen should be collected. Some investigators
believe that thoracentesis should be performed when
the patient is fasting and that both pleural and serum
glucose levels should be performed simultaneously. If
the fluid cannot be analysed immediately, it should be
frozen or collected in a sodium fluoride tube to
prevent in vitro glycolysis [49]. Light, however, is
of the opinion that it is not necessary to obtain a
fasting specimen, nor is it necessary to consider the
serum glucose level when evaluating the pleural
glucose level [2].
Low pleural fluid glucose levels ( < 60 mg/dl)
usually indicate the presence of one of the follow-
ing: complicated parapneumonic effusion [50], ma-
lignant disease [51 – 53], tuberculosis [54], or
rheumatoid disease [55]. Rare causes include para-
gonimiasis, haemothorax, the Churg-Strauss syn-
drome and lupus pleuritis. The low pleural fluid
glucose level appears to result from a combination
of increased glycolysis from pleural tissue, pleural
fluid inflammatory cells and bacteria in conjunction
with an impairment of glucose transport from blood
to pleural fluid [48].
1.3.2. pH
Measurement of the pleural fluid pH using a blood-
gas machine has also been used as a diagnostic tool. A
pH level < 7.20 suggests that the patient has one of
the following: complicated parapneumonic effusion,
oesophageal rupture, rheumatoid pleuritis, tuberculous
pleuritis, malignant pleural disease, haemothorax,
66 L.J. Burgess / Clinica Chimica Acta 343 (2004) 61–84
systemic acidosis, paragonimiasis, lupus pleuritis or
urinothorax [2].
Pleural fluid pH has traditionally been used to
determine whether or not a parapneumonic effusion
should be drained [56 –59]. Lower pH levels increase
the likelihood for pleural drainage, while higher levels
suggest that medical treatment is adequate. Primary
studies attempted to identify specific cut-off pH levels
for this purpose but these studies were small and
limited by poor study design. Of particular importance
is the fact that the investigators who determined the
outcome were not blinded to the pleural pH test results
[50,60].
Pleural fluid pH has also been implicated in ma-
lignant effusions, most notably in predicting survival.
Sahn and Good [61] demonstrated that patients with
pH levels < 7.30 had a shorter survival time. The low
pH in these effusions is probably due to the end
products of glycolysis in the pleural space caused by
extensive tumor deposits, signifying a late stage of
aggressive malignancy with a poor survival [62].
Lower pH levels were also noted with more extensive
pleural involvement, higher yield on cytological stud-
ies and decreased success of pleurodesis [61]. Rodri-
guez-Panadero et al. [63 –65] reported a correlation of
low pH with both survival of and the extent of
intrapleural tumor collections. These observations
have resulted in recommendations to utilise pleural
fluid pH in selecting patients for pleurodesis [66].
Other investigators have not observed an association
between pH and survival [67]. Heffner et al.
[37,60,68] performed meta-analyses of a number of
studies (both published and unpublished) that reported
pleural fluid pH values in malignant pleural effusions.
Accordingly, pleural fluid was found to have limited
clinical utility for predicting survival and only mar-
ginal value in predicting the outcome of pleurodesis.
Pleural fluid pH correlates closely with pleural
fluid glucose levels [69] and for parapneumonic
effusions, pleural fluid pH is more predictive of
complicated effusions than pleural fluid glucose
[50]. Pleural samples should, however, be handled
as carefully as arterial samples for pH measurements,
with fluid collected in heparanised syringes and trans-
ported on ice for measurement within 6 h [56]. Prob-
lems with measurement include failure to recognise
the importance of anaerobic collection, the need for
prompt analysis and the possibility of clot formation
in the blood gas analyser [70,71]. Litmus paper is not
a suitable alternative [72].
1.3.3. Lipids
A chylothorax is defined as the accumulation of
lymph or chyle in the thoracic cavity following a
leak from the thoracic duct [11]. Although this may
occur spontaneously, the most common cause is
malignancy [11,73], especially lymphoma; the rest
are secondary to metastatic carcinoma [73]. The next
most common cause is trauma, usually post-surgical
or secondary to blunt trauma. Less common causes
include tuberculosis, filariasis, cirrhosis, lymphangi-
tis of the thoracic duct and obstruction of the
superior vena cava [2].
Although a chylothorax may be suspected by its
milky appearance, the most reliable test is the dem-
onstration of chylomicrons by lipoprotein electropho-
resis [11]. Alternatively, the diagnosis can be made by
measuring triglyceride levels in the pleural fluid. If the
triglyceride level >110 mg/dl (1.24 mmol/l), the
patient has a 99% chance of having a chylothorax;
if the triglyceride level is < 50 mg/dl (0.50 mmol/l),
the patient has only a 5% chance of having a chylo-
thorax [73,74].
1.3.4. Adenosine deaminase and other biochemical
markers of tuberculosis
If tuberculous pleuritis is not treated, the effusion
usually resolves, however, pulmonary or extrapulmo-
nary tuberculosis subsequently develops in more than
50% of patients [75]. Tuberculous effusions are usu-
ally lymphocytic. Less than 40% of patients present-
ing with a tuberculous pleuritis have positive pleural
fluid cultures. Alternative tests, such as adenosine
deaminase (ADA) or interferon-g (IFN-g) are thus
required to establish the diagnosis [16].
Numerous studies have demonstrated the diagnos-
tic significance of increased levels of pleural ADA in
tuberculous pleurisy [76 –84] whereas other studies
have shown that ADA is of limited value [85,86] as
raised levels are also associated with a number of
other diseases including malignancies (especially
those of haematological origin), bacterial infections,
empyemas and collagen vascular diseases (including
systemic lupus erythematosus and rheumatoid arthri-
tis) [2]. Various cut-off levels ranging from 30 to 70
U/l have been used to make this diagnosis; corres-
 L.J. Burgess / Clinica Chimica Acta 343 (2004) 61–84
ponding diagnostic efficiencies range from 83% to
100% (sensitivity 75– 100%; specificity 79– 100%)
[76 – 86].
Initially, the presence of ADA in pleural fluids was
thought to reflect the cellular immune response, in
particular the activation of T-lymphocytes [78]. When
the lymphocytic/neutrophil ratio was considered to-
gether with ADA activity, the diagnostic efficiency
improved—most notably the specificity [87]. Howev-
er, numerous studies have failed to find a correlation
between number of lymphocytes or lymphocyte sub-
populations and ADA levels [78,88,89].
ADA is a polymorphic enzyme involved in purine
catabolism. Two molecular forms of ADA, each
having unique biochemical properties, have been
identified in humans: ADA1 and ADA2 [90]. ADA1
isoenzyme, while found in all cells, has the highest
activity in lymphocytes and monocytes, whereas
ADA2 isoenzyme originates from monocytes [91].
These results were confirmed by Valdés et al. [92].
In a subsequent study, Ungerer et al. [93] found that in
tuberculous effusions, the ADA2 isoenzyme was pri-
marily responsible for total ADA activity, while the
ADA1 isoenzyme contributed mainly to the ADA
activity in parainfective effusions. These results were
confirmed by Carstens et al. [94]. A few investigators
have now suggested a monocyte-macrophage origin
of ADA [95,96].
The IFN-g level is also useful in diagnosing
tuberculous pleuritis [87,97 –99]. IFN-g is produced
by the CD4+ lymphocytes from patients with tuber-
culous pleuritis [97]. In one report, 33 out of 35
patients with tuberculous pleuritis had IFN-g levels
>140 pg/ml, while only 9 of 110 other pleural fluids
had levels that exceeded this [87]. With the exception
of empyemas, there was only one non-tuberculous
pleural fluid that had an IFN-g level >200 pg/ml [87].
Comparable results have been reported in other series
[97 – 99] but comparison of the series is difficult
because different units are used. Pleural IFN-g levels
can be used in a similar manner to pleural ADA levels
to establish the diagnosis of tuberculous pleuritis with
reasonable certainty. The diagnosis of tuberculosis can
be made with a pleural fluid IFN-g level >200 pg/ml
and a clinical picture compatible with tuberculous
pleuritis [16].
The demonstration of tuberculous antigens or spe-
cific antibodies against tuberculous proteins in the
67
pleural fluid has been investigated in recent years as a
possible means for diagnosing tuberculous pleuritis. A
study by Baig et al. [100] demonstrated that the mean
level of tuberculous antigens was higher in the pleural
fluid of patients with tuberculous pleuritis. There was
considerable overlap, however, that limited the diag-
nostic utility. Similar results were demonstrated when
the level of tuberculostearic acid in pleural fluid was
analysed [101]. A number of reports have also dem-
onstrated that patients with tuberculous pleuritis tend
to have higher levels of specific anti-tuberculous
antibodies in their pleural fluid than patients with
effusions of other aetiologies [102 – 106]. Once again,
there is too much overlap for the test to be used
diagnostically. The anti-tuberculous antibody levels in
the pleural fluid appear to be due to passive diffusion
from the serum rather than local antibody production
in the pleural space [103].
Other biochemical markers of pleural fluid are of
limited value in establishing the diagnosis of tuber-
culous pleuritis. Although previous studies demon-
strated reduced pleural glucose levels in most cases of
tuberculous pleuritis, more recent studies show that
the majority of these patients have a pleural glucose
level >3.33 mmol/l [107,108]. A low pH was also
previously regarded as being suggestive of tubercu-
lous pleuritis, subsequent studies suggest that pH has
the same distribution in malignant as in tuberculous
pleural effusions [56,109]. Elevated levels of 1.25-
dihydroxyvitamin D has also been described in tuber-
culous pleurisy [110].
Lysozyme has been proposed as a diagnostic tool
for tuberculous pleurisy [82,83,111]. A pleural/serum
lysozyme ratio >1.2 has been proposed as a good test
for diagnosing tuberculous pleuritis [111]. When the
utility of this ratio is compared to that of the pleural
ADA or IFN-g level, the lysozyme ratio is distinctly
inferior [83]. However, Verea Hernando et al. [111]
have concluded that the use of lysozyme together with
ADA would give a sensitivity and specificity of 100%
in a population with a high prevalence of tuberculosis.
1.3.5. Malignant pleural markers
Various tumour markers and biochemical parame-
ters used in mainstream practice have been measured
in pleural fluid to help distinguish malignant from
benign effusions [112,113]. This includes: carcinoem-
bryonic antigen (CEA) [112 – 121], neuron-specific
68 L.J. Burgess / Clinica Chimica Acta 343 (2004) 61–84
enolase (NSE) [120,122,123], CA125 [120,121],
squamous cell carcinoma antigen [119,120], CA 19-
9 [112,121], tissue polypeptide antigen (TPA) [112,
119,121], a-foetoprotein [119] and CYFRA 21-1
[116,124].
Measurement of the levels of tumour markers in
the pleural fluid has proved disappointing in diagnos-
ing pleural malignancies [124]. Tumour markers are
highly suggestive of malignant effusions when pleural
antigen levels are very high, but because of low
sensitivity, they are not helpful if values are only
modestly increased [120,125].
The creatine kinase BB-isoenzyme has also been
suggested as being useful for differentiating between
malignant and benign effusions but it was shown to be
diagnostic in only 20% of cases [126]. LDH isoen-
zyme pattern was suggested as an aid to diagnosing
malignant pleural effusions [127] but subsequent
studies have demonstrated poor results [128]. Simi-
larly, pleural fluid zinc, copper and iron ratios have
also failed to show any significant diagnostic utility
[129,130].
1.3.6. Amylase
An elevated amylase level is found in patients with
pancreatitis (with or without pseudocyst formation)
[131 – 133] and oesophageal rupture [131]. Amylase
should thus only be measured if the patient’s history
and clinical picture are suggestive of one of these
diagnoses [131]. In addition, approximately 10% of
malignant effusions are associated with an elevated
pleural amylase levels (salivary isoform), with ex-
tremely high values being found in adenocarcinomata
of the lung and ovary [134].
1.3.7. Other biochemical analytes
A number of specific proteins have been studied in
pleural fluid, including haptoglobin [135], a1-anti-
trypsin [135], specific immunoglobulins [136,137],
pseudouridine [138], complement factors [135], oro-
somucoid [137] and a2-macroglobulin [137] yet little
clinical information has been gained from these stud-
ies. A number of disease associations with specific
proteins have, however, been demonstrated:
 Fibrin degradation products may be elevated in
patients with malignancy, pulmonary embolus and
infective effusions [139].
 Elevated h2-microglobulin levels have been asso-
ciated with tuberculosis, leukaemia, lymphoma
and, when expressed as a pleural fluid/serum ratio,
in some autoimmune disorders [140].
 Elevated levels of ferritin have been associated
with malignant effusions [117,141], however the
clinical utility thereof is questionable [113,142].
High lactic acid concentrations have been re-
ported in both bacterial and tuberculous effusions;
intermediate values have been associated with ma-
lignancy [143]. An increased pleural fluid urea or
creatinine may be specific for the diagnosis of
urinothorax [144].
2. Biochemical evaluation of peritoneal effusions
The peritoneal cavity normally contains less than
50 ml of fluid [145]. Ascites, the pathological accu-
mulation of fluid in the peritoneal cavity, are found in
a wide variety of conditions. In the USA and the
western world, ascites are the commonest cause of
liver cirrhosis accounting for approximately 75– 80%
of cases [146 – 150]. Ascites occur in about 50% of
these patients within ten years of diagnosis of com-
pensated cirrhosis [151] and its development heralds a
progressive deterioration in a patient’s clinical condi-
tion and only 50% of affected patients survive two
years after onset [152]. In many developing countries,
ascites secondary to tuberculous peritonitis are as
common as liver cirrhosis [153,154]. There are, how-
ever, a number of other causes including malignancy,
congestive cardiac failure, nephrotic syndrome, pan-
creatic disease and dialysis [155].
The pathogenesis of ascites formation is multifac-
torial as shown in Table 2. Initial evaluation of ascites
should include diagnostic paracentesis to ascertain the
cause. In most cases this procedure may be safely
performed despite the presence of coagulopathy and
thrombocytopaenia [156,157], provided the ascitic
fluid is accurately localised, abdominal surgical scars
avoided, aseptic technique followed and a small gauge
needle used [156]. Diagnostic paracentesis should be
routinely performed in patients presenting with new-
onset ascites, those requiring hospitalisation due to
ascites and those with ascites and unexplained clinical
deterioration [158].
 L.J. Burgess / Clinica Chimica Acta 343 (2004) 61–84
Table 2
Pathogenesis of ascites formation
Increased hydrostatic pressure
Cirrhosis
Budd-Chiari syndrome (Hepatic vein occlusion)
Inferior vena cava obstruction
Congestive cardiac failure
Constrictive pericarditis
Decreased colloid osmotic pressure
Chronic, end-stage liver disease with poor protein synthesis
Nephrotic syndrome with protein loss
Malnutrition
Protein losing enteropathy
Increased permeability of peritoneal capillaries
Infective peritonitis (bacterial, tuberculosis)
Malignant disease of the peritoneum
Leakage of fluid into the peritoneal cavity
Bile ascites
Chylous ascites
Pancreatic ascites (secondary to a leaking pseudocyst)
Urinary ascites
Other causes
Meigs’ syndrome (ovarian disease)
Myxoedema
Chronic haemodialysis
2.1. General appearance of the peritoneal fluid
The general appearance of the ascitic fluid may
provide diagnostic information. Usually ascitic fluid is
straw-coloured or yellow-tinged but in patients who
are deeply jaundiced, the fluid may have a deep
yellow colour (due to the presence of bilirubin) and
a ‘‘detergent’’ type of appearance [146].
If not related to a traumatic tap, bloody ascites are
most commonly due to malignancy. In one study,
approximately 20% of malignancy related ascitic
fluid samples and 10% of samples from patients
with peritoneal carcinomatosis were bloody [159].
It can also be caused by tuberculous peritonitis or
abdominal trauma [145]. Bloody ascites in a patient
with cirrhosis suggest complicating hepatocellular
carcinoma, although it can rarely occur in such
patients without an apparent cause [160]. If a trau-
matic tap is suspected, a separate needle immediately
inserted into the opposite flank will usually yield
clear ascitic fluid and quickly establish that the initial
69
tap was traumatic and not due to pre-existing hae-
moperitoneum [146]. Pink-coloured ascitic fluid con-
tains z 10,000 red cells/mm3 and blood-stained
ascites z 20,000 red cells/mm3. In a traumatic tap,
the fluid tends to clot when removed and left to
stand whereas non-traumatic bloody ascitic fluid
tends to be homogenously red and does not clot on
paracentesis [146].
Milky or turbid ascitic fluid results from the
presence of lymph and has a high fat concentration
(chylous ascites) [145]. The turbidity of these speci-
mens can be cleared by the addition of a few drops of
ether and microscopic examination shows large
numbers of fat globules [146]. Milk-like or chylous
ascites are generally due to the presence of a large
amount of triglycerides, usually in a concentration
>1000 mg/dl. Slightly less milky fluid tends to con-
tain between 100 and 500 mg/dl of triglycerides [150].
Chylous fluid may also be characterised by a lack of
odour, separation into a creamy layer (chylomicrons)
after refrigeration for 48 – 72 h and sterility [161].
Turbid fluid due to pseudochylous ascites may be
confused with chylous ascites but the turbidity is not
cleared by ether [146].
Sometimes the ascitic fluid may have a striking
appearance. A tea-coloured appearance is occasional-
ly seen in pancreatic ascites. This is due to degrading
ascitic fluid red cells [146]. This phenomenon can be
exaggerated in haemorrhagic pancreatitis, resulting in
a black-coloured fluid. Black ascites has also been
reported in malignant melanoma [146,162]. Ascitic
fluid secondary to perforation of the gut may have a
characteristic dark, molasses coloured appearance
[162]. Purulent ascitic fluid, usually characterised by
a polymorphonuclear leukocyte count z 50,000 mm3,
may be seen when there is gross intra-abdominal
infection [146]. Bile-stained fluid is green and may
be seen with perforation of the gallbladder or intes-
tine, with duodenal ulcer, in cholecystitis and acute
pancreatitis [49].
2.2. Distinguishing between transudates and exudates
2.2.1. Total protein
Traditionally, the exudate-transudate concept
based on ascitic fluid protein concentration has been
used to identify peritoneal exudates [163]. This
concept was based on the fact that fluid formed by
70 L.J. Burgess / Clinica Chimica Acta 343 (2004) 61–84
‘‘exudation’’ from an inflamed or tumour-laden
peritoneal surface (e.g. bacterial peritonitis, tubercu-
lous peritonitis, pancreatitis and peritoneal carcino-
matosis) was high in protein. Fluid that ‘‘transuded’’
from a normal peritoneal surface due to an imbal-
ance of Starling forces (as in cirrhosis, congestive
cardiac failure and nephrotic syndrome) was as-
sumed to be low in protein [164]. Different ascitic
protein levels have been suggested as cut-off levels
for identifying exudates, ranging from 25 to 30 g/l
[163 – 166].
Numerous problems and exceptions have been
noted with this approach. Many infective or malig-
nancy-related ascites have an ascitic protein level in
the transudative range, while those with cirrhosis and
congestive cardiac failure often have an ascitic protein
level in the exudative range [164,167]. Of particular
importance is the fact that this approach makes no
provision for patients having ascites of mixed origin
[164] and it has become customary to include these
patients in the exudates group [164,168,169]. In
addition, peritoneal fluid obtained from healthy wom-
en frequently has a total protein concentration >40 g/l,
well into the exudative range [164]. Other biochem-
ical parameters have thus been suggested to identify
exudates.
2.2.2. Boyer’s criteria
A variation of Light’s criteria [21] was suggested
for identifying ascitic exudates [170]. An exudative
peritoneal effusion was described as having at least
one of the following: ascitic fluid/serum protein
ratio z 0.5, ascitic fluid/serum LDH ratio z 0.6
and/or ascitic fluid LDH activity z 200 U/l. Boyer
et al. [171] modified these criteria. Using an ascitic
LDH level z 400 U/l, he demonstrated that at least
two of these criteria should be present in order to
exclude a transudate. Accordingly, an exudate was
diagnosed when two or more of the following were
present:
 Ascitic fluid/serum protein ratio z 0.5.
 Ascitic fluid/serum LDH ratio z 0.6.
 Ascitic fluid LDH activity z 400 U/l.
In an attempt to improve the diagnostic efficiency,
these criteria were also tested by various investigators
individually [168,172].
2.2.3. Other biochemical analytes used to identify
peritoneal exudates
According to Elis et al. [170], ascitic/serum biliru-
bin ratio is an additional marker for distinguishing
ascitic exudates from transudates. A ratio >0.6 was
found to be significantly associated with an exudate.
A number of researchers have also investigated the
use of ascitic cholesterol and ascitic/serum cholesterol
ratios in making a differential diagnosis of ascites
[163,173 –177]. Lack of reproducibility between stud-
ies has meant that these parameters have not been
routinely adopted in clinical practice.
Alexandrakis et al. [178] studied the value of many
different proteins in the serum and ascitic fluid and
assessed their potential in discriminating between
malignant and non-malignant ascites. A total of 57
different measurements (30 in serum and 27 in peri-
toneal fluid) were performed in 61 patients with
ascites (25 with malignant exudates, 13 with non-
malignant exudates and 23 with transudates). Using
correlation tests and one-way ANOVAs, discriminant
analyses were used to assess the significance of each
parameter in the differentiation process. Accordingly,
five ascitic fluid measurements—namely total protein,
LDH, TNF-a, complement factor C4 and haptoglo-
bin—were sufficient for a model to correctly classify
89% of cases. Cross-validation demonstrated that 70%
of unknown cases were correctly classified using this
model.
2.3. Tests for portal hypertension
The serum ascites albumin gradient (SAAG) has
been proposed as a physiologically based alternative
to the exudate-transudate concept in the classification
of ascites [164,166,168,169,172,173,179]. It is calcu-
lated by subtracting the albumin concentration of the
ascitic fluid from the albumin concentration of a
serum specimen obtained on the same day. This
concept is based on the fact that when portal hyper-
tension is the cause of ascites, the osmotic gradient
between serum and ascitic fluid has to be increased to
counterbalance the high hydrostatic pressure driving
fluid into the intraperitoneal cavity [166]. Since albu-
min is the single most important factor in osmotic
pressure generation, the difference between the serum
and ascites albumin concentration (i.e. the SAAG) can
be used to separate ascitic fluid into two main cate-
 L.J. Burgess / Clinica Chimica Acta 343 (2004) 61–84 71

gories: patients with ascites related to portal hyper- ascitic fluid, classically categorised as exudative, had
tension have a SAAG z 11 g/l, whilst those having a SAAG >11 g/l, indicating the possible role of portal
ascites associated with normal portal pressure have a hypertension in the development of the ascites.
SAAG < 11 g/l [167]. Hoefs reported a linear corre- The value of the SAAG in non-alcoholic chronic
lation between SAAG and portal pressure in 56 liver disease is controversial. Whilst no difference
patients with chronic liver disease, 52 of whom had could be found between alcoholic and non-alcoholic
an alcoholic liver disease (r = 0.73, p = 0.0001) [167]. groups by Akriviadis et al. [168], Kajani et al. [180]
Likewise, Rector and Reynolds reported an excellent demonstrated no correlation between measured portal
correlation in 18 patients with alcoholic liver disease venous pressure and SAAG in 24 patients with
(r = 0.81, p < 0.001) [179]. With a diagnostic accuracy chronic non-alcoholic liver disease (r = 0.398). A
of >90%, the SAAG is regarded as a reliable bio- subsequent study of 132 patients in Saudi Arabia
chemical marker to differentiate between patients with demonstrated that SAAG had a diagnostic efficiency
ascites due to normal and elevated portal pressure of 91% in separating ascites of liver disease (non-
(Table 3) [164,179]. alcoholic) from other causes of ascites [149].
There have been a number of studies demonstrat- The difference between these two groups of liver
ing the superiority of the SAAG compared to the disease may be due to an intrinsic difference in
exudate-transudate concept [164,169,173]. Mauer and portal shunting between patients with alcoholic and
Manzione [169] analysed ascitic fluid from 96 non-alcoholic liver disease [180]. The wedged he-
patients and confirmed the superior diagnostic utility patic venous pressure correlates closely with direct-
of the SAAG. This study also demonstrated that ly measured portal pressure in patients with
malignant ascites without liver metastases had fea- alcoholic cirrhosis whereas it tends to underestimate
tures of nonportal hypertensive ascites and this was portal pressure in non-alcoholic liver disease [171,
confirmed by the SAAG (SAAG < 11 g/l). The char- 181]. In addition, structural change of the hepatic
acteristics of malignant ascites associated with liver microcirculation, including sinusoidal hyalinisation
metastases, however, were shown to resemble those of and capillarisation, have been reported in alcoholic
portal hypertensive ascites complicating liver disease liver disease [182]. This may account for the close
(SAAG z 11 g/l). Of particular note, myxoedematous relationship between portal pressure measurements
obtained at presinusoidal (i.e. portal venous pres-
sure) and postsinusoidal (i.e. wedged hepatic venous
Table 3
Classification of ascites according to portal pressure
pressure) sites and the association between portal
pressure and the amount of hydrostatically filtered
Portal hypertension, Normal portal pressure,
Serum-ascites Serum-ascites
ascitic fluid. Specifically, the hepatic microvascula-
albumin gradient z 11 g/l albumin gradient < 11 g/l ture in alcoholic cirrhosis may be less permeable to
Cirrhosis Peritoneal carcinomatosis
albumin. As a result, higher portal pressures would
Alcoholic hepatitis Pancreatic ascites lead to increased water and not albumin filtration,
Congestive cardiac failure Biliary ascites thus lowering the ascitic albumin concentration and
Fulminant hepatic failure Tuberculous peritonitis thereby decreasing the SAAG [180]. No such
Massive lever metastases Nephrotic syndrome relationship would be expected in non-alcoholic
Portal vein thrombosis Serositis of collagen
vascular disease
hepatic injury where this microvascular pathology
Budd-Chiari syndrome Bowel obstruction is absent.
Veno-occlusive disease Bowel infarction The terms ‘‘high-albumin gradient’’ and ‘‘low-
Fatty liver of pregnancy Chlamydia/gonococcal albumin gradient’’ have replaced the terms ‘‘transu-
Myxoedema dative’’ and ‘‘exudative’’ in the description of ascites
Nephrogenous
‘‘Mixed’’ ascitesa
in many recent publications [147,148,166]. The ap-
a parent superiority of the SAAG over the traditional
Found in patients with portal hypertension and another cause
of ascites formation, e.g. cirrhosis with bacterial peritonitis. The exudate-transudate concept (as defined by an ascitic
portal pressure remains elevated in such cases, and the SAAG is total protein of z 30 g/l) in the classification of
thus high. ascites has largely been explained by factors influenc-
72 L.J. Burgess / Clinica Chimica Acta 343 (2004) 61–84
ing these parameters [167]. The SAAG correlates
directly with only one physiological factor (i.e. portal
venous pressure) whilst ascitic total protein concen-
tration is directly related to serum protein level and
indirectly related to portal pressure [167]. In patients
with cirrhosis, these two factors vary widely and
predictably lead to a highly variable ascitic total
protein concentration [164]. The SAAG has the added
advantage of providing a more rational approach to
the pathogenesis of ascitic fluid collection [168] and is
of particular importance when the patient is receiving
concurrent diuretic therapy or has complicated cirrho-
sis [164,168].
Certain caveats need to be recalled when apply-
ing the SAAG in the clinical setting [146]. Firstly, if
a patient with cirrhosis has a serum albumin value
< 11 g/l, the SAAG will be falsely low and if the
albumin assay is incorrect in the low range, errors
will occur. False values of the SAAG may likewise
occur if the serum and ascites samples are drawn at
different times or if the patient is unstable or in
shock. Secondly, lipid fractions tend to interfere
with the methodology for determining ascitic albu-
min. Patients with chylous ascites may have a
falsely high SAAG. A final pitfall is the presence
of hyperglobulinaemia (>50 g/l) which can falsely
lower or narrow the SAAG. This occurs in 1%
of ascites specimens and can be corrected by mul-
tiplying the uncorrected SAAG (in g/L) by
(2.1 + 0.208  serum globulin) [146, 183].
The SAAG may also be useful in predicting
therapeutic response. Patients with portal hypertensive
ascites (e.g. cirrhosis) usually respond to dietary
sodium restriction [184]. In contrast, patients with
ascites unrelated to portal hypertension (e.g. peritone-
al carcinomatosis) are refractory to diuretic therapy
[184].
2.4. Specialised biochemical tests for detecting causes
of ascites
The SAAG allows differentiation of ascites into
one of two broad categories but it does not replace
further evaluation such as histology to document liver
disease or cytology to diagnose malignant peritoneal
disease [146]. There are also a number of biochemical
tests that may serve as a useful guideline when
assessing the aetiology of the ascites.
2.4.1. Protein
In some circumstances, the ascitic total protein
concentration is of value other than for distinguishing
between exudates and transudates:
 A high ascitic total protein level may suggest the
possibility of heart failure as the cause of ascites in
a patient with a high SAAG [185].
 Patients with low ascitic fluid protein levels are
known to be at high risk for spontaneous peritonitis
[186].
 Prophylactic, poorly absorbed oral antibiotics have
been shown to selectively decontaminate the gut,
thus preventing bacterial infections in this sub-
group of patients who are identified by ascitic fluid
total protein concentration [187].
 Ascitic total protein concentration may also assist
in distinguishing between spontaneous and sec-
ondary bacterial peritonitis [186,188].
2.4.2. Lactate dehydrogenase
As a diagnostic test, LDH is of little value in
determining the cause of the ascites. The ascitic
fluid/serum LDH ratio is approximately 0.4 – 0.5 in
uncomplicated cirrhotic ascites and increases in spon-
taneous bacterial peritonitis, presumably due to re-
lease of this enzyme from polymorphonuclear
neutrophils [189]. If the LDH ratio is >1.0 it can be
assumed that LDH is being produced by the perito-
neum or by the cells within the ascitic fluid. LDH
elevation is more commonly observed in mixed cases
of tuberculous peritonitis [190].
2.4.3. Lipids
Chylous ascites are defined as the presence of
fluid in peritoneal cavity that has a triglyceride
concentration greater than that of plasma [191].
Although the mechanism of chylous ascites forma-
tion is not clear, it is believed to be related to
obstruction and damage of the intestinal lymphatic
drainage system and subsequent leakage of chylomi-
cron-rich fluid into the peritoneum [191]. Approxi-
mately 87% of chylous effusions are secondary to
malignancy, especially lymphomas and secondary
carcinomatosis [192]. Other causes include primary
lymphatic hypoplasia, inflammatory and infectious
causes (e.g. tuberculosis, pancreatitis, filariasis, radi-
ation therapy and sarcoidosis) and trauma (e.g.
 L.J. Burgess / Clinica Chimica Acta 343 (2004) 61–84
following abdominal surgery, stab wounds and gun-
shot wounds).
True chylous ascites must be distinguished from
chyliform and pseudochylous effusions, in which the
turbid, milky appearance is due to cellular degener-
ation caused by bacterial peritonitis or malignancy.
A low triglyceride level is characteristic of these
conditions.
2.4.4. Amylase
The ascitic fluid amylase concentration is useful in
detecting pancreatic ascites and perforation of the gut
into the peritoneal cavity [188,193]. Pancreatic ascites
may be missed without determination of ascitic amy-
lase. The values found in pancreatic ascites are
generally of the order of 2000 U/l, higher than that
found in gut perforation [188,193].
Clinically significant pancreatitis is caused by
extravasations of fluid from the pancreatic ductal
system, usually from a leaking pseudocyst or ruptured
pancreatic duct. On rare occasions, various non-
pancreatic tumours may cause an increase in the
serum and ascitic fluid amylase, which can cause
confusion with pancreatic ascites. However, if isoen-
zyme levels are measured, salivary type amylase will
be found [194]. Ascitic fluid amylase is usually within
normal limits in uncomplicated cirrhosis, with a mean
value of 42– 50 U/l (half serum values) [193].
2.4.5. Glucose
The measurement of ascitic fluid glucose is
relatively unimportant in elucidating the aetiology
of a peritoneal effusion [49]. Ascitic fluid glucose is
generally in the range of the serum glucose, as
glucose tends to enter ascites rapidly. The exception
to this is when glucose is being consumed in the
intraperitoneal ascitic fluid pool by white cells or by
bacteria. Despite this, ascitic fluid glucose levels do
not generally tend to decrease during intraperitoneal
ascitic fluid infections, such as spontaneous bacterial
peritonitis, tuberculous peritonitis and others [189].
However, when there is perforation of the gastroin-
testinal tract with high bacterial counts, there is a
significant consumption of glucose within the ascitic
fluid. This results in low ascitic glucose levels
compared to serum glucose levels and may be
useful in identifying or excluding secondary bacte-
rial peritonitis [195].
73
2.4.6. Malignant markers
In 1978, Lowenstein et al. reported that a CEA
level >10 ng/ml suggests malignancy, even if the fluid
is transudative [196]. However, others regard this test
as insensitive and of little clinical value [146].
Ascitic fluid cholesterol levels have also been
suggested as a diagnostic test to supplement cytolog-
ical examination in the prediction of malignancy.
Jungst et al. [174] demonstrated that an ascitic cho-
lesterol concentration of 1.2 mmol/l is useful in
predicting malignant disease (sensitivity 85%, speci-
ficity 88.9%). All patients with an ascitic cholesterol
concentration z 2.4 mmol/l turned out to have ma-
lignant diseases. In the fraction of patients with
malignant disease and a negative cytological exami-
nation, an ascitic cholesterol concentration >1.2
mmol/l detected 76.5% of patients with cancer cor-
rectly. These results were confirmed by Mortensen et
al. [175]. Another investigation of malignant ascites
proposed that the ascitic fluid fibronectin concentra-
tion discriminated between malignant and benign
ascites better than cytology [197].
A number of other ‘‘humoral tests of malignancy’’
(including cyclic AMP and a1-antitrypsin) have also
been proposed. These have since been found to be
unhelpful [198]. This is largely due to the fact that
appropriate control groups were not included and
patients were not stratified into subgroups of malig-
nancy-related ascites. Resultant analyses falsely im-
prove the results [159,199].
2.4.7. Adenosine deaminase (ADA) and other markers
of tuberculous peritonitis
Tuberculous peritonitis is a common cause of
ascites in undeveloped countries [153,154]. Early
diagnosis is important. Despite the availability of
effective treatment, the co-existence of malnutrition
and compromised immunity often has an adverse
effect on the outcome [200]. With a diagnostic effi-
ciency of >90%, ascitic ADA provides a rapid diag-
nostic test for tuberculous peritonitis [200 – 209],
especially in areas where there is a high prevalence
of tuberculosis. Varying cut-off levels for ADA have
been used, ranging from 30 to 40 U/l. No significant
differences in ascitic ADA activities have been dem-
onstrated between HIV-positive and HIV-negative
patients with tuberculous peritonitis [210]. Ascitic
ADA estimation allows empirical initiation of anti-
74 L.J. Burgess / Clinica Chimica Acta 343 (2004) 61–84
tuberculous therapy pending the confirmatory evi-
dence of ascitic fluid mycobacterial culture and re-
sponse to antituberculous therapy [201].
The low ascitic ADA activity found in the setting
of underlying, concomitant cirrhosis and other con-
ditions associated with portal hypertension has been
cited as a major shortcoming in its use as a diagnostic
aid [201,208]. Hillebrand et al. [201] demonstrated a
sensitivity of 59% in detecting tuberculous peritonitis,
primarily because of the low sensitivity (30%) in
detecting tuberculous peritonitis among cirrhotic
patients (specificity 95%). This has been attributable
to either a dilutional phenomenon and/or the concom-
itant immunosuppression associated with advanced
liver disease [200,201,208]. ADA activity is a marker
of immune response [205,211]. Cirrhotic patients
characteristically have poor reticulendothelial system
function [201]. In addition, they often have altered
humoral and cell-mediated immune responses result-
ing from abnormal T-lymphocyte activation and pro-
liferation [212].
Ribera et al. [207] examined ascitic fluid IFN-g
concentration in a prospective study of 86 patients
with ascites, including 16 patients with tuberculous
peritonitis. IFN-g concentration was significantly
higher in tuberculous peritonitis than in other causes
of ascites ( p < 0.0001) and a cut-off between 3 and 9
U/ml reached a sensitivity and specificity of 100%.
The mean F SD IFN-g level in tuberculous ascites
was 39.3 F 18.3 U/ml for HIV-negative patients and
14.2 F 4.7 U/ml for patients with AIDS. These find-
ings were demonstrated by Sathar et al. [213].
2.4.8. Other ascitic fluid tests
Although not useful in the routine identification of
ascitic exudates, the ascitic fluid bilirubin concentration
may be useful in cases where the ascites is brownish
or if there is a suspicion of a biliary leak or fistula
from either the intrahepatic tree or gallbladder. Gen-
erally this is elevated and greater than the serum biliru-
bin when there is bowel or biliary perforation [162].
Ascitic fluid pH has been proposed for differenti-
ating infection or malignancy related ascites. In gen-
eral, ascitic fluid pH is time-consuming, difficult to
determine accurately and has no impact on decision-
making [214,215]. Ascitic fluid pH is really an
indirect measure of the ascitic fluid neutrophil count
which is easier to perform.
Alkaline phosphatase (ALP) activity is high in the
intestinal tract. Various studies have demonstrated that
ascitic ALP levels may be helpful in evaluating the
condition of certain patients with abdominal disorders
[216,217]. Patients with obstruction, strangulation,
intestinal perforation or traumatic haemoperitoneum
may all have greatly elevated peritoneal ALP levels
[216,217], the corresponding serum ALP levels are
usually normal. Marx et al. [218] measured peritoneal
lavage ALP activity in 81 patients following blunt and
penetrating abdominal trauma and concluded that the
peritoneal lavage ALP is a sensitive marker for small
intestinal injury in the immediate posttraumatic peri-
od. Ascitic fluid ALP has also been noted to be a
sensitive marker for the presence of liver disease and
peritoneal carcinomatosis [159].
Various other analytes measured in ascitic fluid
have proven to be clinically useful in selected cases:
 Ascitic ammonia levels are increased over plasma
levels in cases of ruptured appendix, perforated
peptic ulcer, bowel strangulation with or without
perforation and ruptured urinary bladder with
extravasation of urine [219].
 The measurement of ascitic fluid lactic acid is
useful in diagnosing bacterial peritonitis, especially
in identifying spontaneous bacterial peritonitis in
patients with cirrhosis [220].
 An elevation in ascitic g-glutamyltransferase
(GGT) activity has been demonstrated in patients
with alcoholic cirrhosis; this is possibly a mere
reflection of the serum GGT levels [221].
 Elevated ascitic hyaluronic acid levels have been
associated with mesothelioma [49].
 Ascitic lysozyme levels have been suggested as a
diagnostic aid for tuberculous peritonitis in chil-
dren [222].
3. Biochemical evaluation of pericardial effusions
The pericardial space normally contains 15– 50 ml
of fluid, which serves as lubrication for the visceral and
parietal layers of the pericardium. This fluid is thought
to originate from the visceral pericardium and is
essentially an ultrafiltrate of plasma [223]. Pericardial
effusions, characterised by the accumulation of fluid in
the pericardial cavity, are present in a wide variety of
 L.J. Burgess / Clinica Chimica Acta 343 (2004) 61–84
pathological conditions. The cause of abnormal fluid
production depends on the underlying aetiology, but is
usually secondary to injury or insult to the pericardium
(i.e. pericarditis). Transudative fluids result from ob-
struction of fluid drainage; exudative fluids occur
secondary to inflammatory, infectious, malignant or
auto-immune processes within the pericardium [223].
The advent of echocardiography has provided an
accurate non-invasive method for diagnosing the
presence of such effusions [224]. However, the aeti-
ology of the effusion is often uncertain and cannot
always be clearly defined on the basis of clinical
assessment or even autopsy [225]. With very few
validated tests available, investigators have success-
fully made correct diagnoses on pericardial fluid
analysis in 24 – 93% of cases in reported series
[224,226]. Rapid diagnosis and treatment are, howev-
er, crucial in reducing morbidity and mortality from
pericardial disease [227].
Pericardiocentesis is used for both diagnostic and
therapeutic purposes. Indications include haemody-
namic compromise (cardiac tamponade), suspected
infectious aetiology and uncertain aetiology [228].
In contrast to the relatively well-documented ability
of tests on pleural and peritoneal fluids, very few
studies have reported the systematic evaluation and
utility of various diagnostic tests with pericardial
fluids [225,229].
3.1. General appearance
Normally only a small amount of clear, pale yellow
fluid is present in the pericardial cavity. If the peri-
cardial fluid is turbid, infection or malignancy must be
considered. Blood-streaked, cloudy fluid is frequently
associated with tumours and tuberculosis. A bloody
effusion is characteristic of cardiac rupture or punc-
ture. Uraemic renal failure is usually associated with a
clear-or straw-coloured fluid. Chylopericardium may
result in a milky effusion [49].
3.2. Distinguishing between transudates and exudates
Few studies have analysed the differentiation of
pericardial fluids into transudates and exudates. A
study by Meyers et al. [225] demonstrated that exu-
dates are best described by the following biochemical
parameters: specific gravity >1.015, pericardial fluid
75
protein level >30 g/l, pericardial/serum protein ratio
>0.5, pericardial fluid LDH >300 U/l and pericardial/
serum LDH ratio >0.6.
Another article reporting three ill-defined cases
with purported transudative pericardial fluid noted
specific gravities of 1.018 –1.022, protein levels of
44– 50 g/l and glucose levels of 70 – 90 mg/dl [230]. A
further case series noted that inflammatory pericardial
fluid had a mean F SD pH of 7.06 F 0.07 compared
with noninflammatory fluid (7.42 F 0.06) [231].
The biochemical characteristics of large pericardial
effusions in various disease states were determined in
110 consecutive patients presenting with pericardial
effusions in South Africa [229]. The biochemistry of
pericardial exudates differed significantly from peri-
cardial transudates. Light’s criteria [21] were applied
to pericardial fluids and shown to be the most reliable
diagnostic tool for identifying pericardial exudates
(sensitivity 98%, specificity 72%). As with pleural
effusions, the major disadvantage of this method was
the misclassification of transudates as exudates, espe-
cially in patients receiving concurrent diuretic therapy.
The occurrence of an exudative range of protein levels
in patients with transudates receiving diuretic therapy
has been described in both pleural [30,31] and ascitic
fluids [164,168]. It is probable that a similar mecha-
nism exists in the case of pericardial effusions.
The SEAG, which has been successfully used in
pleural fluids [23] and ascites [164,166,169] to dis-
criminate between exudates and transudates, was also
applied to this series of pericardial effusions [229].
Application of this concept resulted in a sensitivity of
90% and specificity of 89%, respectively, for the
identification of pericardial exudates. The major ad-
vantage of this biochemical test was the reduction in the
number of patients with transudates receiving concur-
rent diuretic therapy being misclassified as having
exudates. The use of effusion cholesterol levels, peri-
cardial/serum cholesterol ratios and pericardial/serum
bilirubin ratios was shown to be limited [229].
3.3. Specialised biochemical tests for detecting causes
of ascites
3.3.1. Adenosine deaminase (ADA) and other markers
for tuberculosis
Tuberculous pericarditis, which occurs in approx-
imately 1– 2% of pulmonary tuberculosis, remains a
76 L.J. Burgess / Clinica Chimica Acta 343 (2004) 61–84
major health problem in developing countries such as
Africa and Asia [232]. There is considerable urgency
in establishing the correct diagnosis so that appropri-
ate treatment can be started but it is often difficult and
time-consuming to establish a definitive bacteriologic
diagnosis of tuberculous pericarditis [233]. Pericardial
ADA levels provide a rapid and accurate means of
detecting tuberculous pericarditis, especially in high
prevalence areas, thereby expediting the initial deci-
sion-making process [234].
To date, relatively few studies regarding the use of
ADA in tuberculous pericarditis have been conducted
[233 – 239]. Varying cut-off levels for ADA activity
have been advocated and these range from 35 to 70 U/
l. Corresponding diagnostic efficiencies for the test
ranges from 83% to 100%, with sensitivities of 89 –
100% and specificities of 74 –100%.
Additional markers that have been suggested for
the diagnosis of pericardial tuberculosis include lyso-
zyme [238] and IFN-g [234]. Aggeli et al. [238]
assessed the value of pericardial lysozyme in a series
of 41 patients, including seven patients with tubercu-
lous pericarditis. Using a cut-off point of 6.5Ag/dl
yielded a sensitivity and specificity of 100% and 91%,
respectively. The utility of IFN-g as a diagnostic tool
for tuberculous pericarditis was assessed in a series of
35 patients, including 19 patients with pericardial
tuberculosis [234]. The concentration of IFN-g was
significantly higher in tuberculous pericardial effu-
sions than in other diagnostic classes ( p < 0.0005).
Using a cut-off level of 50 pg/l as being diagnostic for
tuberculous pericarditis, resulted in a 100% sensitivity
and 100% specificity. Technical and financial con-
straints, however, limit the diagnostic utility of this
test. Nested polymerase chain reaction from as little as
1 Al of pericardial fluid can also establish the diag-
nosis [240].
3.4. Malignant markers
CEA has been used to identify malignant pericar-
dial effusions [233,241 –243]. Koh et al. [233] have
shown that the pericardial CEA level in benign fluids
is significantly lower than in malignant pericarditis.
With a cut-off level of 5 ng/ml, sensitivity was 75%
and specificity 100% in the diagnosis of malignant
pericarditis. NSE has also been shown to be associat-
ed with malignant pericardial effusions [243]. Diag-
nostic utility of these tumour markers is limited by the
small series of patients in these studies.
3.4.1. Other pericardial fluid analytes
There are few validated tests available for pericar-
dial effusions. Case reports, however, have described
fluid characteristics in several specific diseases:
 Infective pericarditis [225,244]: Purulent pericar-
dial effusions are characterised by protein levels
ranging from 33 to 63 g/l and elevated LDH levels.
The pericardial fluid glucose levels vary; glucose
concentrations < 35 mg/dl have been described.
Significantly higher glucose levels have been
reported [225]; this is believed to be due to the
fact that infective pleuritis may produce a diffusion
block to glucose [245 –247].
 Rheumatoid arthritis [225,248 – 250]: The fluid is
always serosanguineous and sometimes viscous.
Pericardial total protein levels were 42 –64 g/l;
glucose levels varied widely. A notably elevated
interleukin-6 (IL6) concentration was described in
one case [248]. More specific tests include
immunoglobulin complexes [249] and decreased
fluid complement [250].
 Systemic lupus erythematosus and drug-induced
lupus [251 –255]: These effusions may be straw
coloured or serosanguineous [251 – 253]. The fluid
is an exudative effusion, having a specific gravity
of 1.028 [252], a protein concentration of 29 – 75 g/
l [253 – 256] and elevated LDH levels. The
pericardial glucose concentration varied from 20
to 100 mg/dl [252 –254]. Diminished levels of
pericardial fluid complement have also been
documented [255].
 Post myocardial infarction pericarditis [225,256]
and post-pericardiotomy syndrome [226,257]: The
fluid appears serous or serosanguinous with a mean
protein level of 61 g/l.
 Uraemic pericarditis [225,258,259]: These are
serosanguinous fluids with haematocrits ranging
from 1% to 24%. The mean fluid total protein
concentration is 40.8 g/l (80% that of serum
levels); the mean fluid cholesterol level is 94 mg/
dl (50% that of serum levels); and the mean F SD
pericardial fluid pH is 7.08 F 0.1.
 Myxoedema [225,260]: Davis and Jacob [260]
described the pericardial fluid secondary to myx-
 L.J. Burgess / Clinica Chimica Acta 343 (2004) 61–84
oedema as having an amber hue; the corresponding
total protein level was 60 g/l (similar to serum) and
cholesterol level 76 mg/dl. Meyers et al. [225]
studied two patients with myxoedematous effu-
sions; in both cases the protein levels were much
lower (35 F 17 g/l; 50% that of serum levels) and
the observed cholesterol levels higher (100 mg/dl;
similar to that of serum).
 Chylopericardium: Chylopericardium is a rare
entity that may be congenital in origin or secondary
to surgical trauma, malignancies (such as medias-
tinal lymphangiomas-hygromas) or radiation [261].
The effusion appears milky. Triglyceride analysis
is required to confirm the diagnosis.
4. Conclusion
Although many diseases are known to cause pleu-
ral, pericardial and peritoneal effusions, analysis of
the fluid, in conjunction with clinical acumen, pin-
points the aetiology in the majority of cases. The
following is a guide to the biochemical assessment of
an effusion:
1. Perform a diagnostic tap when indicated. A blood
sample, preferably taken at the same time as the
tap, should accompany the effusion sample to the
laboratory.
2. Distinguish transudative from exudative effusions;
in the case of ascitic effusions, the presence or
absence of portal hypertension must also be
confirmed.
3. Take note of the gross appearance of the fluid.
4. If the effusion is an exudate, more directed
biochemical testing should be requested based on
the following criteria:
. Gross appearance
. Clinical picture
. Geographic setting: Tuberculous effusions are an
important and common finding in developing
countries. Effusion ADA levels are important in
areas of high prevalence as this provides a rapid,
accurate means of diagnosis thereby expediting
the initial decision-making process; traditional
methods of diagnosing tuberculosis, such as
identification of Mycobacterium tuberculosis in
the effusion or biopsy specimen, are associated
77
with poor diagnostic efficiency and long culture
periods [262].
5. If the effusion is transudative, additional tests
provide no additional information and sometimes
produce misleading results [18]. The clinician must
establish or exclude common causes, such as
congestive cardiac failure, liver cirrhosis and
pulmonary embolism.
6. Biochemical results should be interpreted with
reference to clinical acumen and other laboratory
tests, including cytology, microbiology and
haematology.
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