**4. Diagnostic clues for exudates from transudates**

Light et al. in 1972 found a criteria to have sensitivity and specificity of 99% and 98%, respectively, for differentiating transudative and exudative PE (ratio of protein in pleural fluid and serum >0.5; ratio of LDH in pleural fluid and serum >0.6 and pleural fluid LDH > 2/3rd of upper limit of serum LDH) [21]. But the other investigators could only reproduce specificities of 70–86% using light's criteria. Also it is found that 25% of patients with transudates pleural effusion are mistakenly identified as having exudative effusion by Light's criteria.

Most transudates have absolute total protein concentrations below 3.0 g/dl (30 g/l), although acute diuresis in heart failure can elevate protein levels into the exudative range [22–24].

If one or more of the exudative criteria are met and the patient is clinically thought to have a condition producing a transudative effusion, the difference between the protein levels in the serum and the pleural fluid should be measured. If this gradient is >31 g/l (3.1 g/dl), the exudative categorization by these criteria can be ignored because almost all such patients have a transudative pleural effusion [25]. About only 75% of cases, the etiology of pleural effusion can be established with the clinical presentation, biochemical parameters and fluid cytology. Despite extensive diagnostic work up in about 20% of pleural effusion, the etiology remains unknown [26].

The second possible explanation is that pleural cholesterol derives from plasma; some 70% of plasma cholesterol is bound to low density, high molecular weight lipoproteins (LDL) and the rest to HDL or very low density lipoproteins (VLDL) and the increased permeability of pleural capillaries in pleural exudate patients would allow plasma cholesterol to enter the

Role of Pleural Fluid Cholesterol in Pleural Effusion http://dx.doi.org/10.5772/intechopen.76370 85

The cause of the increased cholesterol concentration is unknown, but two hypotheses are available [33, 34]: (A) cholesterol production by different cells has been recognized and it is possible that destruction of white and red blood cells in pleural effusion can cause an increase in the fluid cholesterol level. (B) Increased pleural permeability causes cholesterol concentra-

Measurement of pleural cholesterol >45 mg/dl has been used to improve the accuracy of dif-

Another study done in Catholic University hospital, Santiago, Chile [36] Marina Costa found sensitivity and specificity of following parameters for exudative pleural effusion as 98 and 82% (criteria by Light et al.), 90 and 100% (pCHOL >45 mg/dl) and 99 and 98% (by pCHOL+

A study done by Hamm et al., mean cholesterol level in malignant effusions was 94 mg/dl, 76 mg/dl in inflammatory effusions and 30 mg/dl in the transudates. Using a dividing line of 60 mg/dl to separate the exudates from transudates, only 5% were incorrectly classified.

Using pleural fluid, cholesterol levels at a cut-off point of greater than 60 mg/dl and/or total protein at a cut-off point of greater than 3 g/dl for distinguishing transudates and exudates, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value

Brett reviewing Eid et al. CHEST 2002 Nov, most but not all, exudative effusions in CHF patients have causes other than heart failure. The authors believe that, in some cases with no apparent cause other than CHF, transudates might be `converted' into exudates by traumatic taps (which lead to increased pleural fluid lactate dehydrogenase—itself a criterion for an exudate) or by aggressive dieresis (which might transiently increase protein and LDL cholesterol concentrations in pleural fluid). In patients with previous bypass surgery, persistent

Pleural fluid cholesterol is better than Light's criteria for the differentiation of transudates and exudates and is less cumbersome as it does not require a simultaneous blood sampling. Cutoff value of pleural fluid cholesterol for differentiating transudates and exudates should be 45 mg/dl [39]. In this study, the sensitivity, specificity, positive predictive value and negative predictive value of the pleural fluid cholesterol (cut-off >45 mg/dl) were 97.06, 94.74, 97.06 and

NT-proBNP has been shown to correctly diagnose congestive heart failure as a cause of most effusions that have been misclassified as exudates by Light's criteria. Use of this test may therefore avoid repeated invasive investigations in patients where there is a strong clinical

Elevated cholesterol levels in exudates seem to be independent of serum levels [34].

impairment of lymphatic clearance might predispose to exudative effusions [38].

(NPV), were 100% in a study done by Patel and Choudhury [37].

94.74%, respectively, for identifying exudates.

pleural cavity.

tions to increase.

pLDH >200 IU/l), respectively.

ferentiating transudative and exudative effusion [35].

From meta-analysis, Heffner et al. has identified pleural effusion of exudative type with at least one of the following condition [27]:


Roth et al. [28] found that despite the high sensitivity of Light's criteria (100%), these criteria had a low specificity (72%). Using an albumin gradient of 1.2 g/dl or less to indicate exudates and greater than 1.2 g/dl to indicate transudates, 57 of the 59 patients (41 exudates; 18 transudates) were correctly classified. Two patients with malignant effusions were misclassified as having transudates.

In 2003 National medical journal of India, one article published by Guleria R of AIIMS, New Delhi [29] found that for exudative pleural effusion, pleural fluid cholesterol ≥60 mg/dl has 92% accuracy, 88% sensitivity and 100% specificity; however, Light's criteria was 98% sensitive and 80% specific.

Evaluation through pleural fluid cholesterol only can avoid the financial burden and double pricks (serum and pleural fluid) in anxious patients to go through the series of tests to confirm the exudative pleural effusion.

In a study done in Nepal by Hamal et al. [30], pleural fluid cholesterol (pCHOL) is highly correlated than protein ratio (pleural fluid protein/serum protein) with clinical diagnosis for exudates. It is found that in transudates, parapneumonic, tubercular and neoplastic pleural effusion, pCHOL levels were 0.53 ± 0.28, 1.81 ± 0.59, 2.08 ± 0.58 and 1.58 ± 0.65 mmol/l, respectively. With a classifying threshold of 1.16 mmol/L, pCHOL has a sensitivity of 97.7% and specificity of 100% for diagnosis of exudates with accuracy of 98.3%.

Pleural cholesterol is thought to be derived from degenerating cells and vascular leakage from increased permeability. Though the cause of the rise in cholesterol levels in pleural exudates is unknown, two possible explanations have been put forward.

According to the first, the cholesterol is synthesized by pleural cells themselves for their own needs [31] (extrahepatic synthesis of cholesterol is now known to be much greater than was once thought, depends on the metabolic needs of cells, and is in dynamic equilibrium with cholesterol supply by LDL and cholesterol removal by HDL) [32] and the concentration of cholesterol in pleural cavity is increased by the degeneration of leukocytes and erythrocytes, which contain large quantities.

The second possible explanation is that pleural cholesterol derives from plasma; some 70% of plasma cholesterol is bound to low density, high molecular weight lipoproteins (LDL) and the rest to HDL or very low density lipoproteins (VLDL) and the increased permeability of pleural capillaries in pleural exudate patients would allow plasma cholesterol to enter the pleural cavity.

the serum and the pleural fluid should be measured. If this gradient is >31 g/l (3.1 g/dl), the exudative categorization by these criteria can be ignored because almost all such patients have a transudative pleural effusion [25]. About only 75% of cases, the etiology of pleural effusion can be established with the clinical presentation, biochemical parameters and fluid cytology. Despite extensive diagnostic work up in about 20% of pleural effusion, the etiology

From meta-analysis, Heffner et al. has identified pleural effusion of exudative type with at

Roth et al. [28] found that despite the high sensitivity of Light's criteria (100%), these criteria had a low specificity (72%). Using an albumin gradient of 1.2 g/dl or less to indicate exudates and greater than 1.2 g/dl to indicate transudates, 57 of the 59 patients (41 exudates; 18 transudates) were correctly classified. Two patients with malignant effusions were misclassified as

In 2003 National medical journal of India, one article published by Guleria R of AIIMS, New Delhi [29] found that for exudative pleural effusion, pleural fluid cholesterol ≥60 mg/dl has 92% accuracy, 88% sensitivity and 100% specificity; however, Light's criteria was 98% sensi-

Evaluation through pleural fluid cholesterol only can avoid the financial burden and double pricks (serum and pleural fluid) in anxious patients to go through the series of tests to confirm

In a study done in Nepal by Hamal et al. [30], pleural fluid cholesterol (pCHOL) is highly correlated than protein ratio (pleural fluid protein/serum protein) with clinical diagnosis for exudates. It is found that in transudates, parapneumonic, tubercular and neoplastic pleural effusion, pCHOL levels were 0.53 ± 0.28, 1.81 ± 0.59, 2.08 ± 0.58 and 1.58 ± 0.65 mmol/l, respectively. With a classifying threshold of 1.16 mmol/L, pCHOL has a sensitivity of 97.7% and

Pleural cholesterol is thought to be derived from degenerating cells and vascular leakage from increased permeability. Though the cause of the rise in cholesterol levels in pleural exudates

According to the first, the cholesterol is synthesized by pleural cells themselves for their own needs [31] (extrahepatic synthesis of cholesterol is now known to be much greater than was once thought, depends on the metabolic needs of cells, and is in dynamic equilibrium with cholesterol supply by LDL and cholesterol removal by HDL) [32] and the concentration of cholesterol in pleural cavity is increased by the degeneration of leukocytes and erythrocytes,

specificity of 100% for diagnosis of exudates with accuracy of 98.3%.

is unknown, two possible explanations have been put forward.

remains unknown [26].

84 Cholesterol - Good, Bad and the Heart

having transudates.

tive and 80% specific.

the exudative pleural effusion.

which contain large quantities.

least one of the following condition [27]:

• Pleural fluid cholesterol >45 mg/dl (1.16 mmol/l) • Pleural fluid LDH > 2/3rd of upper limit of serum

• Pleural fluid protein >2.9g/dl

The cause of the increased cholesterol concentration is unknown, but two hypotheses are available [33, 34]: (A) cholesterol production by different cells has been recognized and it is possible that destruction of white and red blood cells in pleural effusion can cause an increase in the fluid cholesterol level. (B) Increased pleural permeability causes cholesterol concentrations to increase.

Measurement of pleural cholesterol >45 mg/dl has been used to improve the accuracy of differentiating transudative and exudative effusion [35].

Another study done in Catholic University hospital, Santiago, Chile [36] Marina Costa found sensitivity and specificity of following parameters for exudative pleural effusion as 98 and 82% (criteria by Light et al.), 90 and 100% (pCHOL >45 mg/dl) and 99 and 98% (by pCHOL+ pLDH >200 IU/l), respectively.

A study done by Hamm et al., mean cholesterol level in malignant effusions was 94 mg/dl, 76 mg/dl in inflammatory effusions and 30 mg/dl in the transudates. Using a dividing line of 60 mg/dl to separate the exudates from transudates, only 5% were incorrectly classified. Elevated cholesterol levels in exudates seem to be independent of serum levels [34].

Using pleural fluid, cholesterol levels at a cut-off point of greater than 60 mg/dl and/or total protein at a cut-off point of greater than 3 g/dl for distinguishing transudates and exudates, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV), were 100% in a study done by Patel and Choudhury [37].

Brett reviewing Eid et al. CHEST 2002 Nov, most but not all, exudative effusions in CHF patients have causes other than heart failure. The authors believe that, in some cases with no apparent cause other than CHF, transudates might be `converted' into exudates by traumatic taps (which lead to increased pleural fluid lactate dehydrogenase—itself a criterion for an exudate) or by aggressive dieresis (which might transiently increase protein and LDL cholesterol concentrations in pleural fluid). In patients with previous bypass surgery, persistent impairment of lymphatic clearance might predispose to exudative effusions [38].

Pleural fluid cholesterol is better than Light's criteria for the differentiation of transudates and exudates and is less cumbersome as it does not require a simultaneous blood sampling. Cutoff value of pleural fluid cholesterol for differentiating transudates and exudates should be 45 mg/dl [39]. In this study, the sensitivity, specificity, positive predictive value and negative predictive value of the pleural fluid cholesterol (cut-off >45 mg/dl) were 97.06, 94.74, 97.06 and 94.74%, respectively, for identifying exudates.

NT-proBNP has been shown to correctly diagnose congestive heart failure as a cause of most effusions that have been misclassified as exudates by Light's criteria. Use of this test may therefore avoid repeated invasive investigations in patients where there is a strong clinical suspicion of cardiac failure. The cut-off value however, varied widely from 600 to 4000 pg/ml (with 1500 pg/ml being most commonly used), and most studies excluded patients with more than one possible etiology for their effusion [40].

absorbed at a similar rate by the parietal pleural lymphatic system [6]. Pleural fluid accumulates due to local factors, systemic factors or translocation of fluid. At normal circumstances, pleural fluid entering the pleural space from the capillaries in the parietal pleura is removed

Role of Pleural Fluid Cholesterol in Pleural Effusion http://dx.doi.org/10.5772/intechopen.76370 87

Pleural fluid accumulates in settings of increased hydrostatic pressure, increased vascular permeability, decreased oncotic pressure, increased intrapleural negative pressure and decreased lymphatic drainage. On the basis of pathophysiology, pleural effusion can be transudates or exudates. It is important to classify the pleural fluid for diagnosis and appropriate management. Transudates occur when the mechanical factors influencing the formation or reabsorption of pleural fluid are altered, like a decrease in plasma or elevated systemic or pulmonary hydrostatic pressure. Exudates results from inflammation or irritation or other

Light et al. found criteria to have sensitivity and specificity of 99 and 98%, respectively, for differentiating transudative and exudative PEs (ratio of protein in pleural fluid and serum >0.5; ratio of LDH in pleural fluid and serum >0.6 and pleural fluid LDH >2/3rd of upper limit of serum LDH) [20]. It is found that 25% of patients with transudates pleural effusion are mistakenly identified as having exudative effusion by Light's criteria. In cases of heart failure on diuretic therapy, the transudative pleural effusions have high protein. Pleural cholesterol is thought to be derived from degenerating cells and vascular leakage from increased permeability. The cause of the increased cholesterol concentration is unknown, but two hypotheses are available: one states that cholesterol production by different cells has been recognized and it is possible that destruction of white and red blood cells in pleural effusion can cause an increase in the fluid cholesterol level and second relates with increased pleural permeability

Pleural fluid cholesterol as proposed by Heffner's meta-analysis can diagnose exudative pleural effusion without need of serum values. This can avoid the financial burden and double pricks (serum and pleural fluid) in anxious patients to go through the series of tests to confirm the exudative pleural effusion. With a classifying threshold of 1.16 mmol/l, pCHOL has a sensitivity of 97.7% and specificity of 100% for diagnosis of exudates with accuracy of 98.3% compared to Light's criteria (98% sensitivity and 82% specificity). pCHOL is highly correlated than protein ratio with clinical diagnosis for exudates [29]. Moreover in pleural effusion with etiologies as transudates, parapneumonic, tubercular and neoplastic pleural effusion, pCHOL

Study done by Leers Mathie PG, it was found that pleural cholesterol and pleural LDH had accuracy of 98%, sensitivity of 98% and 95% specificity for diagnosing exudative pleural effusion compared that calculated by light's criteria being accuracy of 93%, sensitivity 100% and

It is concluded that pCHOL has a better sensitivity, specificity and accuracy in differentiating transudates and exudates than the parameters of Light's criteria. This also avoids the plasma protein and gradients, sLDH, pleural fluid protein and LDH. Therefore it is more efficient, easier and more cost effective method to differentiate exudates from transudates. This study also suggests that determination of pCHOL should be in routine practice in cases of pleural

levels were 0.53 ± 0.28, 1.81 ± 0.59, 2.08 ± 0.58 and 1.58 ± 0.65 mmol/L, respectively.

by the lymphatics which can absorb 20 times more fluid than is formed.

disease processes involving pleura resulting in increased permeability.

that causes cholesterol concentrations to increase.

specificity 73% [47].

effusion.

The findings in a study done by Mehdi Kashmiri showed taking a value of pleural cholesterol >55 mg/dl and pleural/serum cholesterol >0.3 to define exudative effusion resulted in less erroneous classification with a sensitivity of 93%, a specificity of 100%, a positive predictive value (PPV) of 100% and an accuracy of 95.2%. Using Light's criteria gave a sensitivity of 95%, a specificity of 95%, a PPV of 97.6% and an accuracy of 95.2%. Using cholesterol in differentiating exudate from transudate was especially useful in patients with congestive heart failure who received diuretics [41].

There are other biochemical parameters other than pleural fluid cholesterol to identify the exudative pleural effusions. The difficulties in classifying pleural fluid effusion are wiped away with few parameters other than cholesterol.

It has been observed that increase in uric acid level was present in pleural fluid of transudative pleural effusion than exudative pleural effusion. The optimum cut-off level for pleural fluid uric acid was 5.35 mg/dl with sensitivity of 89.32% and specificity of 92.60% [42]. Increase in uric acid in pleural fluid can be regarded to be a manifestation of tissue hypoxia [43]. Most of the patients with reasons to produce transudative effusion had oxidative stress or hypoxemia to explain the increased uric acid synthesis. The respiratory tract, indeed, remains a major target of oxidative damage caused by both endogenous and exogenous processes [44, 45]. The major causes of tissue damage associated with chronic inflammatory lung disease are the reactive species produced by phagocytes.

Metintas et al. [46] stated that the binding of uric acid is minimal to plasma protein and it is diffuse freely to different compartments. They suggested that the increase permeability, due to change in pleural-capillary pressure in formation of transudate, is the cause of the increase of uric acid levels in pleural fluid. So all these factors explains why uric acid level increases in transudative condition than exudative one.

In cases where no cause for an exudative effusion can be identified or CHF suspected, the sequential application of the fluid LDH, followed by the serum to pleural fluid protein (SF-P) and then the serum to pleural fluid albumin (SF-A) gradients, may assist in reclassifying pleural effusions as transudates [47].

Leers Mathie P.G. from Netherlands [48] found that combination of the parameters: pleural cholesterol and pleural LDH had accuracy of 98%, sensitivity of 98% and 95% specificity for diagnosing exudative pleural effusion compared that calculated by light's criteria being accuracy of 93%, sensitivity 100% and specificity 73%.
