**2. Pathophysiology**

The mechanism of pleural liquid formation is that the liquid originates from the systemic vessels of the pleural membranes, not from the pulmonary vessels [6]. It means that pleural liquid is interstitial fluid of the systemic pleural microvessels. There are three major considerations that support this hypothesis [7]:


#### **2.1. Increased fluid entry**

O).

O), but the pressure within the pleural cavity

pleura, mediastinal pleura, diaphragmatic pleura and cervical pleura. The pleural space lies between the lung and the chest wall and is bounded by the parietal and visceral membranes. It contains a thin layer of fluid that serves as a coupling system called pleural fluid. A pleural effusion (PE) is present when there is an excess fluid in the pleural space. It indicates an imbalance between pleural fluid formation and its removal. It is important to establish an accurate

The pleural space is a real, not potential, space that is approximately 10–20 μm wide and extends completely around the lung to the hilar root [1, 2]. When air or fluid collects between the two layers, the pleural cavity expands. The schematic diagram for pleural cavity and

Pleural fluid is formed from the systemic vessels of the pleural membranes at an approximate rate of 0.6 ml/h and is absorbed at a similar rate by the parietal pleural lymphatic system. Normally, the pleural spaces contain approximately 0.25 ml/kg of low protein liquid. Disturbances in

The volume of pleural fluid is small, approximately 0.1–0.2 ml/kg in different studies. From parietal pleural capillaries, there is constant movement of fluid into the pleural space at a rate of 0.01 ml/kg bodyweight/h. There is a balance of the formation (entry) and absorption (exit) of the pleural fluid. The resultant homeostasis leaves 5–15 ml of fluid in the normal pleural space [4]. For pleural effusion to be there must be an increase in entry rate or a reduction in

The parietal pleura has a hydrostatic pressure similar to that of the systemic circulation (30 cm

O), whereas that of the visceral pleura depends on the pulmonary circulation (10 cm H2

is affected by the gravity gradient. Thus, the pleural space is heterogeneous with a nondependent portion in which Starling forces favor outpouring of fluid into the cavity and the

The mechanism of pleural liquid formation is that the liquid originates from the systemic vessels of the pleural membranes, not from the pulmonary vessels [6]. It means that pleural

either formation or absorption result in the accumulation of excess pleural fluid [3].

etiological diagnosis so that the patient may be treated in a rational manner.

pleurae is in **Figure 1**.

76 Cholesterol - Good, Bad and the Heart

exit rate.

Oncotic pressure is similar in both (25 cm H2

**Figure 1.** Schematic diagram of pleura and pleural cavity.

parenchymal capillaries [5].

**2. Pathophysiology**

H2

Excess liquid filters out of microvessels based on a balance of hydrostatic and osmotic forces across a semi permeable membrane [1, 6]. These forces are well described in the Starling equation, in which the hydrostatic forces that filter water out of the vessel are balanced by osmotic forces that reabsorb water back into the vessel [10, 11].

$$\text{Flow} = \mathbf{k} \times [(\text{Pmv} - \text{Ppmv}) - \text{s} \ (\pi \text{mv} - \pi \text{pmv})].\tag{1}$$

In this equation, k is liquid conductance of the microvascular barrier, Pmv and Ppmv represent hydrostatic pressure in the microvascular and perimicrovascular compartments, respectively, is the reflection coefficient for total protein and ranges from 0 (completely permeable) to 1 (completely impermeable), and πmv and πpmv represent protein osmotic pressure in microvascular and perimicrovascular liquids, respectively and s is Staverman's reflection coefficient. In normal micro vessels, there is ongoing filtration of a small amount of low protein liquid. The flow can increase with changes in various parameters of the Starling equation.

**Increase in permeability:** An increase in flow can be due to increases in either liquid conductance (an increase in k) or protein permeability (a decrease in reflection coefficient). If the endothelial barrier becomes more permeable to liquid and protein, for example, there will be an increase in flow of a higher protein liquid. Because absorption does not alter the protein concentration of pleural liquid, pleural liquid with a high protein concentration indicates its origin from a circulation across an area of increased permeability.

(Ppmv) can enhance filtration across the microvascular barrier of a low protein liquid (with a

Role of Pleural Fluid Cholesterol in Pleural Effusion http://dx.doi.org/10.5772/intechopen.76370 79

**Decrease in plasma osmotic pressure:** Hypoproteinemia (due to hypoalbuminemia) will decrease the plasma oncotic pressure (πmv), thereby increasing the forces favoring filtration until the balance is restored. By itself, hypoproteinemia can probably induce small effusions with a low protein concentration. In addition, hypoproteinemia can lower the threshold for effusion formation when other Starling forces are changed. In a study of hospitalized patients with AIDS, for example, hypoproteinemia alone was the apparent cause of 19% of all pleural effusions [17]. Together with other factors, a lower plasma protein concentration may have contributed to effusion formation in many more patients, because, in general, all patients with effusions had a lower plasma albumin concentration than those without effu-

A decrease in exit rate reflects a reduction in lymphatic function. Because lymphatic function is poorly understood, much of this discussion is speculative. Unlike blood vessels, lymphatic vessels have one-way valves and propel lymph using both their own rhythmic contractions and the respiratory motions of the chest wall. In addition, flow is affected by lymphatic patency, availability of liquid, and the pressures influencing filling (pleural pressure) and

**Intrinsic factors:** A number of factors can interfere with or inhibit the ability of lymphatic's

**Extrinsic factors:** Multiple extrinsic factors can inhibit lymphatic function although the lym-

• Limitation of respiratory motion (e.g., diaphragm paralysis, lung collapse and pneumothorax)

• Blockage of lymphatic stomata (e.g., fibrin deposition on pleural surface and pleural

• Decreased intrapleural pressure (e.g., trapped lung caused by a fibrous rind on the visceral

• Extrinsic compression of lymphatics (e.g., pleural fibrosis and pleural granulomas)

pleural liquid-to-plasma protein ratio of less than 0.15).

emptying (systemic venous pressure) of lymphatics [18–20].

• Cytokines and products of inflammation (e.g., endotoxins)

• Injury due to radiation or drugs (e.g., chemotherapeutic agents)

• Endocrine abnormalities (e.g., hypothyroidism)

• Anatomic abnormalities (e.g., yellow nail syndrome)

phatics themselves are normal. These include:

• Infiltration of lymphatics by cancer

sion (2.5 versus 3.4 g/dl).

**2.2. Decreased fluid exit**

to contract, including:

malignancy)

pleura)

**Increase in microvascular pressure**: An elevation in venous outflow pressure induces the elevation of microvascular pressure (Pmv). Increases in arterial pressure are less likely to be transmitted to the microvessels because of the high precapillary resistance and autoregulation of arteriolar tone.

Elevations in either systemic venous pressure (affecting the parietal pleura) or pulmonary venous pressure (affecting the visceral pleura) can lead to an increase in pleural liquid formation and the development of a pleural effusion. As vascular permeability is unchanged in this setting, the increased flow is associated with a greater sieving of proteins, leading to a filtrate with a lower protein concentration than normal (with a pleural liquid-to-plasma protein ratio of less than 0.15). Of course, most effusions formed due to increased microvascular pressures, i.e., transudative effusions, have a pleural liquid-to-plasma protein ratio much higher than this, between 0.4 and 0.5. This fact demonstrates that most liquid must arise from a source other than the systemic circulation of the pleural membranes. The likely source is the large non-systemic circulation adjacent to the pleural space, namely the pulmonary circulation of the nearby lung. In the normal state, lung interstitial liquid, e.g., lymph, filtered from the lowpressure pulmonary circulation has a protein concentration ratio [12] (lung to plasma protein concentration ratio) of 0.7, but with increased flow due to increased pulmonary microvascular pressures, this ratio falls to 0.4–0.5. This lung interstitial oedema liquid then is the likely source of the majority of the hydrostatic pleural effusion [13].

The way lung liquid reach the pleural space is that when the rate of filtrate formation exceeds the absorptive capacity of the lung lymphatics, the filtrate accumulates in the peribronchovascular spaces ("cuffs") [14]. Once in these interstitial spaces, the liquid is not accessible to lung lymphatics [15].

Thus, although the lymphatics are undeniably important in removing liquid as it is filtered from the pulmonary circulation, they cannot account for the clearance of already established oedema from the lung [16]. This interstitial oedema probably leaves the lung by flowing down pressure gradients along the interstitial spaces (interlobular septae, peribronchovascular bundles and visceral pleura) of the lung toward either the mediastinum or the pleural space. The entry of large amounts of lung interstitial liquid into the pleural space will elevate the overall protein concentration of the pleural liquid, giving a ratio of 0.40–0.50, the expected range for a transudative effusion [16].

**Decrease in pleural pressure**: A decrease in pleural pressure, as seen with significant atelectasis, may alter the balance of forces described in the Starling equation by reducing the pressures surrounding the nearby micro vessels. This decrease in perimicrovascular pressures (Ppmv) can enhance filtration across the microvascular barrier of a low protein liquid (with a pleural liquid-to-plasma protein ratio of less than 0.15).

**Decrease in plasma osmotic pressure:** Hypoproteinemia (due to hypoalbuminemia) will decrease the plasma oncotic pressure (πmv), thereby increasing the forces favoring filtration until the balance is restored. By itself, hypoproteinemia can probably induce small effusions with a low protein concentration. In addition, hypoproteinemia can lower the threshold for effusion formation when other Starling forces are changed. In a study of hospitalized patients with AIDS, for example, hypoproteinemia alone was the apparent cause of 19% of all pleural effusions [17]. Together with other factors, a lower plasma protein concentration may have contributed to effusion formation in many more patients, because, in general, all patients with effusions had a lower plasma albumin concentration than those without effusion (2.5 versus 3.4 g/dl).

## **2.2. Decreased fluid exit**

**Increase in permeability:** An increase in flow can be due to increases in either liquid conductance (an increase in k) or protein permeability (a decrease in reflection coefficient). If the endothelial barrier becomes more permeable to liquid and protein, for example, there will be an increase in flow of a higher protein liquid. Because absorption does not alter the protein concentration of pleural liquid, pleural liquid with a high protein concentration indicates its

**Increase in microvascular pressure**: An elevation in venous outflow pressure induces the elevation of microvascular pressure (Pmv). Increases in arterial pressure are less likely to be transmitted to the microvessels because of the high precapillary resistance and autoregulation

Elevations in either systemic venous pressure (affecting the parietal pleura) or pulmonary venous pressure (affecting the visceral pleura) can lead to an increase in pleural liquid formation and the development of a pleural effusion. As vascular permeability is unchanged in this setting, the increased flow is associated with a greater sieving of proteins, leading to a filtrate with a lower protein concentration than normal (with a pleural liquid-to-plasma protein ratio of less than 0.15). Of course, most effusions formed due to increased microvascular pressures, i.e., transudative effusions, have a pleural liquid-to-plasma protein ratio much higher than this, between 0.4 and 0.5. This fact demonstrates that most liquid must arise from a source other than the systemic circulation of the pleural membranes. The likely source is the large non-systemic circulation adjacent to the pleural space, namely the pulmonary circulation of the nearby lung. In the normal state, lung interstitial liquid, e.g., lymph, filtered from the lowpressure pulmonary circulation has a protein concentration ratio [12] (lung to plasma protein concentration ratio) of 0.7, but with increased flow due to increased pulmonary microvascular pressures, this ratio falls to 0.4–0.5. This lung interstitial oedema liquid then is the likely

The way lung liquid reach the pleural space is that when the rate of filtrate formation exceeds the absorptive capacity of the lung lymphatics, the filtrate accumulates in the peribronchovascular spaces ("cuffs") [14]. Once in these interstitial spaces, the liquid is not accessible to

Thus, although the lymphatics are undeniably important in removing liquid as it is filtered from the pulmonary circulation, they cannot account for the clearance of already established oedema from the lung [16]. This interstitial oedema probably leaves the lung by flowing down pressure gradients along the interstitial spaces (interlobular septae, peribronchovascular bundles and visceral pleura) of the lung toward either the mediastinum or the pleural space. The entry of large amounts of lung interstitial liquid into the pleural space will elevate the overall protein concentration of the pleural liquid, giving a ratio of 0.40–0.50, the expected

**Decrease in pleural pressure**: A decrease in pleural pressure, as seen with significant atelectasis, may alter the balance of forces described in the Starling equation by reducing the pressures surrounding the nearby micro vessels. This decrease in perimicrovascular pressures

origin from a circulation across an area of increased permeability.

source of the majority of the hydrostatic pleural effusion [13].

of arteriolar tone.

78 Cholesterol - Good, Bad and the Heart

lung lymphatics [15].

range for a transudative effusion [16].

A decrease in exit rate reflects a reduction in lymphatic function. Because lymphatic function is poorly understood, much of this discussion is speculative. Unlike blood vessels, lymphatic vessels have one-way valves and propel lymph using both their own rhythmic contractions and the respiratory motions of the chest wall. In addition, flow is affected by lymphatic patency, availability of liquid, and the pressures influencing filling (pleural pressure) and emptying (systemic venous pressure) of lymphatics [18–20].

**Intrinsic factors:** A number of factors can interfere with or inhibit the ability of lymphatic's to contract, including:


**Extrinsic factors:** Multiple extrinsic factors can inhibit lymphatic function although the lymphatics themselves are normal. These include:


Normal pleural fluid resembles water in appearance and clarity, and is odorless [20]. Its chemical composition is summarized in **Table 1**.

The basis in which accumulation of pleural fluid occurs are: increased hydrostatic pressure, increased vascular permeability, decreased oncotic pressure, increased intrapleural negative

Pleural effusion may be of two types depending upon the underlying pathology, i.e., transudative and exudative. The causes of transudative and exudative pleural effusion are sum-

Transudate will be clear fluid with low protein while exudates will have cloudy fluid with high protein. Exudates have a 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. Protein in transudate is less than 2.5 g/dl while exudates have higher values [21].

Transudative pleural effusion is usually due to the increased hydrostatic pressure that is caused by congestion in the capillaries, e.g., in heart failure and there is formation of pleural fluid from the increased venous pressure of the pleural membranes. However in case of exudates, there is vascular leakage of fluid due to increased permeability as a result of inflammation.

Superior vena cava syndrome

Role of Pleural Fluid Cholesterol in Pleural Effusion http://dx.doi.org/10.5772/intechopen.76370 81

Constrictive cardiomyopathy Massive pulmonary embolism

Pericardial effusion

Nephrotic syndrome

Small Bowel disease

Peritoneal Dialysis

Myxoedema

Acute atelectasis Wet Beriberi Idiopathic

Protein losing enteropathy

Malnutrition

1. Increased hydrostatic pressure Congestive Heart Failure

2. Decreased capillary Oncotic pressure Cirrhosis of Liver

3. Transmission from Peritoneum Any cause of ascites

5. Miscellaneous Urinothorax

**Table 2.** Transudative pleural effusion.

4. Increased capillary permeability Small pulmonary emboli

pressure and decreased lymphatic drainage.

marized in **Tables 2** and **3**, respectively.

Pleural effusion is present when there is excess accumulation of pleural fluid due to its exceeding formation on pleural fluid absorption. At normal circumstances, pleural fluid entering the pleural space from the capillaries in the parietal pleura is removed by the lymphatics which can absorb 20 times more fluid than is formed.

Fluid can enter the pleural space from the interstitial spaces in the visceral pleura or through the diaphragmatic pores from the peritoneal cavity. So pleural effusion will develop in two circumstances:


**Local factors:** There is change in the pleural surface permeability due to which the exudative pleural effusion occurs.

**Systemic factors:** There is increase in pulmonary capillary wedge pressure (PCWP) or decrease in oncotic pressure that result in alteration of formation and absorption of pleural fluid as in transudative pleural effusion.

**Translocation of fluid:** Small pores in diaphragm act as pathways for peritoneal fluid to enter into the pleural cavity as in hepatic hydrothorax. It may be massive even without marked ascites.


**Table 1.** Normal composition of pleural fluid.

The basis in which accumulation of pleural fluid occurs are: increased hydrostatic pressure, increased vascular permeability, decreased oncotic pressure, increased intrapleural negative pressure and decreased lymphatic drainage.

Pleural effusion may be of two types depending upon the underlying pathology, i.e., transudative and exudative. The causes of transudative and exudative pleural effusion are summarized in **Tables 2** and **3**, respectively.

Transudate will be clear fluid with low protein while exudates will have cloudy fluid with high protein. Exudates have a 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. Protein in transudate is less than 2.5 g/dl while exudates have higher values [21].

Transudative pleural effusion is usually due to the increased hydrostatic pressure that is caused by congestion in the capillaries, e.g., in heart failure and there is formation of pleural fluid from the increased venous pressure of the pleural membranes. However in case of exudates, there is vascular leakage of fluid due to increased permeability as a result of inflammation.


**Table 2.** Transudative pleural effusion.

Normal pleural fluid resembles water in appearance and clarity, and is odorless [20]. Its

Pleural effusion is present when there is excess accumulation of pleural fluid due to its exceeding formation on pleural fluid absorption. At normal circumstances, pleural fluid entering the pleural space from the capillaries in the parietal pleura is removed by the lymphatics which

Fluid can enter the pleural space from the interstitial spaces in the visceral pleura or through the diaphragmatic pores from the peritoneal cavity. So pleural effusion will develop in two

**1.** When there is excess formation of pleural fluid from parietal pleura, interstitial spaces

**Local factors:** There is change in the pleural surface permeability due to which the exudative

**Systemic factors:** There is increase in pulmonary capillary wedge pressure (PCWP) or decrease in oncotic pressure that result in alteration of formation and absorption of pleural

**Translocation of fluid:** Small pores in diaphragm act as pathways for peritoneal fluid to enter into the pleural cavity as in hepatic hydrothorax. It may be massive even without marked

**2.** When there is inability of removal of pleural fluid by the lymphatics.

chemical composition is summarized in **Table 1**.

can absorb 20 times more fluid than is formed.

from the lung and peritoneal cavity.

fluid as in transudative pleural effusion.

**Table 1.** Normal composition of pleural fluid.

**Parameters Value** Volume 0.1-0.2ml/kg Cells 1000-5000/mm3

Mesothelial cells 3- 70% Monocytes 30-75% lymphocytes 2-30% Granulocytes 10% Protein 1-2gm/dl Albumin /protein 50-70% Glucose as in plasma Lactate Dehydrogenase < 50% of plasma

circumstances:

80 Cholesterol - Good, Bad and the Heart

pleural effusion occurs.

ascites.


**3. Clinical features**

**Table 3.** Exudative pleural effusion.

13. MISCELLANEOUS Amyloidosis

The clinical features of pleural effusion depend on the amount, the rate of accumulation of fluid and the underlying cause. In acute cases, the symptoms appear suddenly. Patients may present with shortness of breath, pleuritic pain, cough and constitutional symptoms. Dyspnea may result from compression of lung tissue and from mechanical alterations in the respiratory muscles as the fluid changes their length-tension relationship. There will be associated symptoms related to the etiology of the pleural effusion. So careful elicitation of history in cases of pleural effusion may streamline the physician toward the etiological aspect of pleural effusion. Physical examination reveals decreased respiratory movements on the affected side and displacement of mediastinum to the opposite side. If there is an associated collapse of lung or fibrosis, the trachea may be central or may even be pulled to the same side depending on the degree of collapse or fibrosis. Tactile fremitus may be decreased to absent but may also be increased toward the top of large effusion. Percussion reveals dull to flat note over the fluid. Auscultation reveals decreased to absent breath sounds but bronchial breath sounds may be heard near top of large effusion. Pleural rub can also be heard and sometimes crackles above the level of effusion. Frequently, there are E to A changes (egobronchophony) at the upper

Iatrogenic injury Radiation therapy Yellow nail syndrome Role of Pleural Fluid Cholesterol in Pleural Effusion http://dx.doi.org/10.5772/intechopen.76370 83

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

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

effusion are mistakenly identified as having exudative effusion by Light's criteria.

fluid border where underlying lung parenchyma is compressed.

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


**Table 3.** Exudative pleural effusion.
