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Clinical presentation, diagnosis, and management of cholesterol pleural effusions

Clinical presentation, diagnosis, and management of cholesterol pleural effusions
Literature review current through: Jan 2024.
This topic last updated: Jun 12, 2023.

INTRODUCTION — The presence of high amounts of cholesterol in a pleural effusion is termed a cholesterol pleural effusion (also called chyliform effusion or pseudochylothorax). Cholesterol pleural effusions are rare and primarily need to be distinguished from chylothorax (the presence of chyle in a pleural effusion).

The etiology, clinical presentation, diagnosis, and management of cholesterol pleural effusions will be reviewed here. The etiology, clinical presentation, diagnosis, and management of chylothorax and general issues regarding the evaluation and management of pleural effusions are discussed separately. (See "Etiology, clinical presentation, and diagnosis of chylothorax" and "Mechanisms of pleural liquid accumulation in disease" and "Pleural fluid analysis in adults with a pleural effusion" and "Imaging of pleural effusions in adults".)

EPIDEMIOLOGY — Cholesterol pleural effusions are rare. Epidemiologic studies are limited to case reports and case series with only a few hundred cases reported internationally [1,2]. However, the incidence may be higher in those at risk (eg, patients with Mycobacterium tuberculosis and rheumatoid arthritis) (table 1) and in areas endemic for paragonimiasis (eg, Far East, West Africa, and Central and South America). In one large series, three-quarters were men [2].

PATHOGENESIS — While chronic inflammation in the pleural membrane may be a risk factor for the development of a cholesterol effusion, the pathogenesis of cholesterol effusions is unknown. Most likely, different mechanisms of pathogenesis exist in different clinical settings.

It has been postulated that lysis of erythrocytes and neutrophils in pleural fluid releases cholesterol and other lipid constituents from degenerating cell membranes; these compounds may be "trapped" in the pleural space by thickened pleural membranes. Eventually, these lipid constituents become concentrated and impart a milky quality to the pleural fluid [1].

An alternate theory is that the pleural cholesterol is derived from serum lipids bound to low density lipoproteins (LDLs) that accumulate in the pleural space during acute inflammation [3]. Over time, lipoprotein binding of cholesterol shifts from LDLs to high density lipoproteins (HDLs). The mechanism for this shift in lipoprotein binding is not known.

ETIOLOGIES — Any condition associated with a chronic pleural effusion with or without thickened or calcified pleural membranes can result in a cholesterol pleural effusion (table 1).

The two most common etiologies of cholesterol pleural effusion are tuberculous and chronic rheumatoid pleuritis, which, in the largest series to date, were responsible for 89 percent of reported cases [2]. Worldwide, paragonimiasis is a common etiology in endemic areas (eg, Far East, West Africa, and Central and South America). Rare causes of cholesterol pleural effusions include hepatopulmonary echinococcosis, chronic hemothorax, chronic pneumothorax (including that induced for the treatment of tuberculosis), syphilis, lung cancer, and pleural metastases [4-11]. Rarely, cholesterol effusions have also been associated with alcoholism, traumatic pulmonary cysts, heart failure, nephrotic syndrome, and Hodgkin disease [4,12].

In a systematic review of 62 studies of 104 reported cases in which underlying causes of cholesterol effusions were diagnosed in 87 cases, 51 percent (44 cases) were due to tuberculosis, 38 percent (33 cases) rheumatoid arthritis, and the remainder attributed to other diagnoses that included paragonimiasis (3 cases), yellow nail syndrome (2 cases), iatrogenic (2 cases), hydatidosis (1 case), Demons-Meigs syndrome (1 case), malignant pleural effusion (1 case), and uncertain etiology (17 cases) [2]. Seventeen additional cases had unknown or unreported underlying diagnoses. A cholesterol pleural effusion can develop in the setting of pleural scarring from tuberculosis, despite successful treatment of the infection. In a series of 11 patients with cholesterol pleural effusions who had previously undergone pneumothorax therapy for tuberculous, progressive pleural thickening developed over the subsequent 5 to 40 years [13].

CLINICAL FEATURES — The clinical findings are nonspecific and are more likely to represent those of a moderate to large pleural effusion. In many cases, because the findings are nonspecific and the condition is rare, a cholesterol effusion is often not suspected until pleural fluid returns as milky on thoracentesis. (See 'Diagnostic evaluation' below.)

Signs and symptoms — Cholesterol pleural effusion usually presents in patients with a known or suspected chronic pleural effusion. Although one series reported a median age at presentation of 58 years, the range was wide (20 to 88 years); three-quarters were men [2]. While some patients may be asymptomatic, many patients present with progressive or slow-onset dyspnea induced by the mechanical effects of the pleural effusion [1,4,14]. Less commonly, patients may complain of chest pain [4]. On physical examination, findings of decreased breath sounds and dullness on percussion may be present, depending on the size and location of the effusion. (See "Overview of pleuropulmonary diseases associated with rheumatoid arthritis", section on 'Pleural disease'.)

The time course of onset of symptoms due to a cholesterol pleural effusion varies. Typically, patients have a history of pleural disease dating back five years or longer [1]. However, in one case series of six patients with rheumatoid arthritis, the duration of symptoms associated with the cholesterol effusions was relatively brief (median 15 months) and the pleura was normal or only minimally thickened [14]. Rapid onset of a cholesterol effusion has also been reported in two patients with tuberculous pleurisy [15] and one patient with hepatothoracic echinococcus [16].

Signs and symptoms of an underlying disease are sometimes present [4,14]. For example, weight loss, fever, night sweats, arthralgias, joint stiffness, or rheumatoid nodules on the skin may be seen in patients with rheumatoid arthritis. Patients with paragonimiasis are typically from an endemic area (eg, Asia, Africa, and South America) and report consuming raw shellfish [6,7,17]; symptoms may be more rapid in onset, migratory nodules on the lower abdominal wall, inguinal region, and thighs may be present, and effusions may be bilateral [18]. (See "Clinical manifestations of rheumatoid arthritis" and "Paragonimiasis" and "Tuberculous pleural effusion", section on 'Clinical manifestations' and "Paragonimiasis", section on 'Clinical manifestations' and "Pulmonary tuberculosis: Clinical manifestations and complications".)

Laboratory studies — There are no specific laboratory findings associated with a cholesterol pleural effusion and serum cholesterol is not typically elevated. Peripheral blood eosinophilia may be found in patients with paragonimiasis [6,7].

Chest radiography — Plain chest radiography shows evidence of a pleural effusion. The effusion is unilateral in the majority (88 percent), and is often right-sided; pleural thickening maybe present in 60 percent [2]. Bilateral effusion is unusual (12 percent) but can be found in those with paragonimiasis. Loculations may be present. Occasionally, signs of the underlying disorder may be evident. (See "Imaging of pleural effusions in adults", section on 'Loculated pleural effusions'.)

DIAGNOSTIC EVALUATION — A cholesterol pleural effusion should be suspected in a patient with progressive dyspnea from a chronic pleural effusion in the setting of conditions known to be associated with its development (table 1). It should also be suspected when milky fluid returns on thoracentesis or when no obvious cause for an exudative effusion is found.

Pleural fluid analysis — The initial diagnostic test for patients suspected to have a cholesterol pleural effusion is analysis of the pleural fluid collected by thoracentesis or from a pre-existing chest tube (algorithm 1). Samples of pleural fluid should be assessed for triglyceride and cholesterol levels in addition to the tests typically sent in all patients undergoing thoracentesis, which include white blood cell count and differential, glucose, lactic dehydrogenase (LDH), total protein, cytology, and microbiologic smear, Gram stain, and culture. Specifically, when a cholesterol pleural effusion is suspected, fluid should also be examined under polarized light for the presence of cholesterol crystals, which, when found, is diagnostic. When the diagnosis remains unclear after testing, pleural fluid lipoprotein analysis to demonstrate the absence of chylomicrons is obtained. (See "Pleural fluid analysis in adults with a pleural effusion", section on 'Routine pleural fluid biomarkers' and "Ultrasound-guided thoracentesis", section on 'Technique'.)

General findings — The appearance of pleural fluid in patients with a cholesterol effusion is classically milky white, turbid, or opaque (table 2 and picture 1). In a systematic review of 83 cases of cholesterol pleural effusion in which the gross appearance of the fluid was described, fluid appeared milky in 46 percent, turbid/cloudy in 40 percent; opaque in 8 percent; oily yellow in 2 percent; and bloody, bloody-chylous, or serous in the remainder (1 percent each) [2]. The pleural fluid is exudative in nature in all reported cases. Pleural fluid typically has a lymphocyte predominance (61 percent of patients) and a low number of nucleated cells (<5000 cells/microL) predominance. Automatic cell counters can misinterpret the presence of a large number of cholesterol crystals, typical of cholesterol pleural effusions as high white and red cell counts, which is corrected by performing a manual cell count [19].

Features typical of rheumatoid or tuberculosis pleurisy or of parasitic infection (eg, pleural fluid eosinophilia (table 3)) may also be present and are discussed below. (See 'Identifying the cause' below.)

Cholesterol and triglyceride level — The pleural fluid cholesterol level is greater than 200 mg/dL (5.17 mmol/L) in 74 percent of patients and the cholesterol to triglyceride ratio is >1 in 98 percent [1,2,20]. The triglyceride level is typically below 110 mg/dL (1.24 mmol/L), but can be higher in 25 percent of patients [2,21]. The detection of chylomicrons by lipoprotein electrophoresis, which is characteristic of chylothoraces, is absent; lipoprotein electrophoresis, however, is not routinely performed because it is laborious, not widely available, and costly. We recommend its use only when pleural fluid analysis is inconclusive and the diagnosis of chylothorax needs to be ruled out or confirmed (the presence of chylomicrons are diagnostic of chylothorax). (See "Etiology, clinical presentation, and diagnosis of chylothorax", section on 'Lipoprotein electrophoresis'.)

Cholesterol crystals — When a cholesterol pleural effusion is suspected based upon the above general findings and chemistries and the diagnosis requires additional confirmation, pleural fluid should be examined under polarized light for the presence of cholesterol crystals. Cholesterol crystals appear as rectangular plates with notched edges (image 1) [19,22]. Cholesterol crystals are virtually diagnostic of a cholesterol effusion but are absent in 10 percent of cases [2]. Thus, their absence does not rule out the diagnosis. Of note, a repeat thoracentesis may be required to obtain additional fluid for crystal analysis.

Other — Other tests including computed tomography (CT) of the chest and pulmonary function testing (PFTs) are also nonspecific but may provide some clues to the underlying cause. (See 'Chest computed tomography' below and 'Pulmonary function tests' below and 'Identifying the cause' below.)

Chest computed tomography — Contrast-enhanced chest CT will often reveal thickening of the parietal and visceral pleura in 80 percent of cases [2,23]. Nodular or linear calcifications of the pleura may be noted. Fat-fluid and fat-calcium levels in the pleural effusion have been reported on CT views of cholesterol effusions caused by tuberculosis, rheumatoid pleurisy, and paragonimiasis [23]. CT is also helpful in evaluating the effusion size, the presence of trapped lung, and the presence of a possible underlying cause (rheumatoid nodules, apical scarring suggesting old tuberculosis, or masses and ring shadow lesions with linear streaks suggesting paragonimiasis). Signs of nonexpandable lung (eg, thickened or calcified pleura, loculations) may also be seen on chest CT and help predict a poor response to initial drainage. (See "Imaging of pleural effusions in adults", section on 'Computed tomography' and "Overview of pleuropulmonary diseases associated with rheumatoid arthritis" and "Pulmonary tuberculosis: Clinical manifestations and complications" and "Paragonimiasis", section on 'Pulmonary paragonimiasis'.)

Pulmonary function tests — PFT findings are also nonspecific and are typically normal or show restriction (eg, reduced forced vital capacity, total lung capacity, and diffusing capacity for carbon monoxide). Findings may be reflective of the presence of a moderate or large pleural effusion but may also be due to old tuberculosis or interstitial lung disease from rheumatoid arthritis. (See "Overview of pulmonary function testing in adults".)

Differential diagnosis — For patients who present with pleural fluid that is turbid or milky in appearance, the major differential includes chylothorax and empyema. Rarely, tube feed leaks due to a misplaced catheter can cause milky-appearing fluid. For the patients who do not have pleural fluid with a milky appearance, the differential diagnosis is broader considering that cholesterol effusions are exudative (table 4). In most cases, triglyceride and cholesterol analysis and the demonstration of cholesterol crystals will distinguish a cholesterol pleural effusion from all other causes of an exudative, milky, or non-milky effusion. Further details on how to distinguish these from one another are provided separately. (See "Etiology, clinical presentation, and diagnosis of chylothorax", section on 'Milky fluid'.)

DIAGNOSIS — There are no strict diagnostic criteria. Nonetheless, we suggest the following (table 2 and algorithm 2):

Typical chemical parameters – In the correct clinical setting (eg, patients with rheumatoid arthritis with a longstanding pleural effusion), an elevated cholesterol concentration greater than or equal to 200 mg/dL (≥5.18 mmol/L) [1], a triglyceride concentration below 110 mg/dL (1.24 mmol/L) [20], and a cholesterol/triglyceride ratio >1 together are typically sufficient to make the diagnosis of a cholesterol pleural effusion [1,20]. Among these chemical parameters, the cholesterol/triglyceride ratio >1 appears to be most sensitive (98 percent) since cholesterol and triglyceride concentrations are not always above and below the specified parameters, respectively.

Cholesterol crystals – In most cases, it is appropriate that fluid be additionally analyzed for the presence of cholesterol crystals, the demonstration of which is virtually diagnostic. However, the absence of this finding does not exclude the diagnosis since crystals are not found in 10 percent of patients [2,13].

When the findings are inconclusive and chylothorax remains in the differential, demonstrating the absence of chylomicrons by lipoprotein electrophoresis further supports the diagnosis of a cholesterol pleural effusion while the presence of chylomicrons supports the diagnosis of a chylothorax. (See "Etiology, clinical presentation, and diagnosis of chylothorax", section on 'Diagnosis'.)

IDENTIFYING THE CAUSE — Once a cholesterol pleural effusion has been diagnosed by pleural fluid analysis, investigations should be undertaken to discover the underlying etiology, if not already known (table 1). This typically involves additional clinical and laboratory testing as well as computed tomography (CT) of the chest (if not already performed). In rare cases, a cause is not found.

Testing for tuberculosis — Patients with cholesterol pleural effusions of unknown or obscure etiology (eg, heart failure) should be thoroughly evaluated for tuberculosis (TB) [4]. This may involve tuberculin skin testing (which is likely to be positive in patients with a chronic tuberculous effusion), demonstrating a pleural fluid level of adenosine deaminase ≥45 IU/L [2], and the demonstration of mycobacterial tuberculosis in pleural fluid (which has a low sensitivity for pleural TB) or on pleural biopsy (culture and/or histology). The general features of tuberculous pleuritis may be present (eg, exudative, elevated lactic dehydrogenase [LDH], low pH, normal or low glucose). Previous chest CT may show findings suggestive of old granulomatous disease due to TB. The characteristics and diagnosis of tuberculous effusions are discussed separately. (See "Tuberculous pleural effusion", section on 'Diagnosis' and "Diagnostic evaluation of the hemodynamically stable adult with a pleural effusion", section on 'Pleural biopsy'.)

Testing for paragonimiasis — In endemic areas, investigations for Paragonimus should be performed. Clues include peripheral blood eosinophilia (typically in the range of 10 to 30 percent) and pleural fluid eosinophilia [6,7]. The presence of pleural eosinophilia in a patient with a cholesterol effusion suggests parasitic infection, but several other processes are also associated with pleural fluid eosinophilia including rheumatoid pleurisy, hemothorax, and malignancy (table 3). (See "Pleural fluid eosinophilia".)

Serology for Paragonimus should be sent since enzyme-linked immunoassay (ELISA) testing for Paragonimus antibodies in serum has a high sensitivity and specificity (92 and >90 percent, respectively) for the diagnosis [6,7,17]. Pleural fluid should be examined under the microscope for ova, although this is negative in approximately 50 percent [6,7,24-26]. Sputum and stool tests for helminth ova may be performed but are rarely positive in patients with a cholesterol pleural effusion due to paragonimiasis. (See "Paragonimiasis", section on 'Diagnosis'.)

Testing for rheumatoid arthritis — When a cholesterol effusion is suspected and the patient does not have a known diagnosis of rheumatoid arthritis, the pleural fluid analysis may provide some clues as to whether rheumatoid arthritis (RA) is likely. Chronic rheumatoid effusions are typically exudative, the pleural fluid glucose is usually low (<29 mg/dL, or 1.6mmol/L), and the LDH very high (eg, >1000 IU/L) (table 5) [20]. Pleural fluid rheumatoid factor should be measured and a level >240 IU/mL (>1:320) is supportive of RA. Previous chest CT may show findings suggestive of pulmonary fibrosis consistent with rheumatoid lung. The laboratory evaluation of rheumatoid effusions and RA are presented separately. (See "Overview of pleuropulmonary diseases associated with rheumatoid arthritis", section on 'Thoracentesis' and "Diagnosis and differential diagnosis of rheumatoid arthritis".)

Others — The diagnosis of other rare conditions associated with cholesterol effusion may be pursued when suspected. Further details are provided separately:

Echinococcus (see "Echinococcosis: Clinical manifestations and diagnosis")

Chronic hemothorax (see "Initial evaluation and management of blunt thoracic trauma in adults")

Syphilis (see "Syphilis: Screening and diagnostic testing")

Lung cancer (see "Selection of modality for diagnosis and staging of patients with suspected non-small cell lung cancer", section on 'Pleural (T2, T3, M1a)')

Yellow nail syndrome (see "Onychomycosis: Epidemiology, clinical features, and diagnosis")

Demon-Meigs syndrome (see "Sex cord-stromal tumors of the ovary: Epidemiology, clinical features, and diagnosis in adults", section on 'Granulosa cell tumors')

Tumor embolism (see "Pulmonary tumor embolism and lymphangitic carcinomatosis in adults: Diagnostic evaluation and management")

Heart failure (see "Heart failure: Clinical manifestations and diagnosis in adults", section on 'Natriuretic peptide')

MANAGEMENT — The initial step in the management of a cholesterol pleural effusion is treatment of the underlying disease process, whether it is tuberculosis, paragonimiasis, rheumatoid pleurisy, or another treatable disease (table 1). In parallel, a drainage procedure, typically thoracentesis, is performed for symptomatic effusions [2]. Patients with a cholesterol effusion are at increased risk of having nonexpandable lung and such cases additionally typically need a more-aggressive approach that involves surgical decortication/pleurectomy. Similarly, recurrence is often treated surgically. The natural history without therapy is unknown. (See "Diagnosis and management of pleural causes of nonexpandable lung".)

Initial management

Treating the underlying disease process — Based upon analysis of case reports and case series, treatment of the underlying disease process is often successful in resolving or stabilizing cholesterol pleural effusions due to active infection or rheumatoid pleurisy, although data on the exact success rate are limited [1]. In most cases the response is slow and it may take weeks to months for a clinical and radiographic response to be appreciated. Data to support this approach include the following:

Data that support the treatment of cholesterol effusions due to chronic tuberculous infection with antituberculous medications are provided separately. (See "Tuberculous pleural effusion", section on 'Management' and "Tuberculous pleural effusion".)

Cholesterol effusions due to rheumatoid pleurisy may be reduced or stabilized with disease modifying antirheumatic drugs (eg, prednisone and methotrexate, hydroxychloroquine) [14]. (See "Overview of pleuropulmonary diseases associated with rheumatoid arthritis", section on 'Treatment of rheumatoid pleural effusion'.)

Successful treatment of cholesterol effusions due to paragonimiasis has been reported with praziquantel 75 mg/kg per day (in divided doses) for two to three days [7,17,18,27]. Triclabendazole is not as widely available, but is generally better tolerated; the dose is 10 mg/kg given once or twice a day. Screening of family members of index cases with a chest radiograph may reveal additional cases. (See "Paragonimiasis", section on 'Treatment'.)

Symptomatic treatment of the effusion (therapeutic thoracentesis) — In general, we suggest that patients with symptomatic cholesterol pleural effusions undergo a drainage procedure (therapeutic thoracentesis or chest tube/catheter drainage). In contrast, most patients who are asymptomatic can be observed clinically and drainage performed, only if symptoms develop. Although therapeutic thoracentesis is typically our first-choice, choosing between thoracentesis and chest tube/catheter drainage is often institution- or operator-specific. Assessment of the contribution of the effusion to dyspnea may be challenging especially in patients with underlying lung disease. In general, patients with resting or progressive dyspnea, patients with chest pain, and patients with moderate to large-sized effusions are drained. Ultimately, symptoms related to the effusion are best appreciated when the patient reports improvement after drainage.

Due to the longstanding nature of many cholesterol pleural effusions, the underlying pleura may be thickened and fibrotic such that patients with cholesterol pleural effusions are at increased risk of nonexpandable lung (ie, poor re-expansion of the underlying lung following thoracentesis). If nonexpandable lung is suspected clinically before therapeutic thoracentesis (usually by the demonstration of thickened pleura on chest computed tomography), measuring pleural pressures during the procedure may confirm the presence of nonexpandable lung and guide the volume of drainage. Nonexpandable lung after thoracentesis/drainage may be suggested by poor lung re-expansion, development of chest discomfort during the procedure, the presence of pneumothorax ex vacuo, air bubbles during drainage, or rapid reaccumulation of pleural fluid (days). (See "Diagnosis and management of pleural causes of nonexpandable lung" and "Large volume (therapeutic) thoracentesis: Procedure and complications".)

Data to support thoracentesis in patients with cholesterol pleural effusions are limited to case reports and case series. As examples:

In a review of 53 patients, therapeutic thoracentesis was performed in 47 (88 percent) [4]. Recurrence of pleural fluid was reported in 64 percent, some of whom responded to repeat thoracentesis. Complications of pneumothorax and empyema were reported in a small number of patients. It is unknown whether the pneumothoraces resulted from failure of the lung to re-expand to the chest wall after removal of fluid (pneumothorax ex-vacuo due to nonexpandable lung) or were trauma-related.

A systematic review of 104 patients reported a favorable response to therapeutic thoracentesis in only 48 percent [2].

Recurrent pleural effusion — Although estimates are limited to case series, up to two-thirds of patients with a cholesterol pleural effusion may fail initial therapy and the effusion may reaccumulate, typically over a period of several weeks to months. Rapid recurrence may suggest paragonimiasis or nonexpandable lung. Symptomatic patients with expandable lung should undergo repeat thoracentesis or a more definitive treatment (eg, pleurodesis) while those with nonexpandable lung may benefit from surgical decortication or indwelling pleural catheter (IPC) in the nonsurgical candidate.

Expandable lung (repeat thoracentesis) — In patients with recurrent symptoms due to a cholesterol pleural effusion who have expandable lung, we suggest repeat thoracentesis. The rationale for this approach is that a second or third intervention may be sufficient, allowing time for the underlying disease to be treated.

For the rare patients with expandable lung who have recurrent cholesterol effusions despite two or three attempts at therapeutic thoracentesis (ie, failed repeat thoracentesis), we suggest pleurodesis. Choosing among the options of chemical (medical or surgical) or mechanical (surgical) pleurodesis is operator-dependent and may also depend upon patient candidacy for surgery. In the largest case series of 104 patients with cholesterol pleural effusions, only three cases underwent pleurodesis with talc, Povidine, or tetracycline, and only two of those were successful [2]. Refractory cases may require surgical pleurectomy.

In this population there are limited data to support use of indwelling pleural catheter (IPC) drainage devices while medical therapy is ongoing [2]. Nonetheless, IPC may be appropriate in patients who decline repeat thoracentesis or pleurodesis. Limited data in other patients with recurrent nonmalignant pleural effusion (NMPE) have also reported some success with IPC use; however, the risk of infections may be increased in some patients with NMPE (eg, patients with rheumatoid arthritis on immunosuppressive agents). IPC use and management of refractory NMPE are provided separately. (See "Management of malignant pleural effusions", section on 'Indwelling pleural catheter (IPC)' and "Management of nonmalignant pleural effusions in adults", section on 'Indwelling pleural catheter'.)

Nonexpandable lung (decortication) — For patients with persistent dyspnea after initial therapeutic thoracentesis in whom dyspnea is thought to be due to nonexpandable lung, we suggest surgical decortication (removal of a restrictive layer of fibrous tissue overlying the lung) with or without visceral pleurectomy (procedure to increase adherence of visceral and parietal pleural membranes). Rarely, a total or partial pleurectomy (removal of pleura) may be performed. The main purpose of surgical procedures is the improvement in symptoms and lung function and the avoidance of the risks of empyema and pleurocutaneous fistula due to repetitive thoracentesis [1,22,28]. (See "Diagnosis and management of pleural causes of nonexpandable lung", section on 'Management of trapped lung'.)

Decortication is a major surgical procedure with significant morbidity. Selection of an appropriate surgical approach requires careful individualization of care based upon the underlying etiology of the effusion, operability of the patient, response to initial thoracentesis, extent of the pleural fluid loculation, degree of pleural thickening, and institutional surgical skills and resources. Alternatively, some surgeons combine decortication with pleurodesis. Combining decortication with pleurodesis results in adequate lung re-expansion and also minimizes the risk of a recurrent cholesterol pleural effusion. (See "Chemical pleurodesis for the prevention of recurrent pleural effusion" and "Management of nonmalignant pleural effusions in adults", section on 'Pleurodesis'.)

Decortication has been reported to reduce dyspnea when performed in patients with cholesterol pleural effusions, although the number of reported cases is small [2,13,29]. A systematic review of 104 patients with cholesterol pleural effusion reported favorable outcomes in the 13 out of 15 patients who underwent decortication/pleurectomy [2]. However, outcome data are limited since multiple treatments were commonly used, follow-up was short-term, and many patients were lost to follow-up.

For patients who decline surgery or patients who are not surgical candidates and have an expandable lung, options include bedside chemical pleurodesis via a chest tube or thoracoscopic talc insufflation. On the other hand, for patients with a nonexpandable lung an IPC can be considered although to date there are no publications available supporting this practice [2].

PROGNOSIS — The prognosis of patients with a cholesterol pleural effusion varies and likely depends upon the nature of the underlying etiology and clinical factors such as age, severity of associated lung disease, and the degree of expandable or nonexpandable lung.

No studies compare outcomes between the various available treatments. Nevertheless, a systematic review of 62 studies totaling 104 patients with cholesterol effusions reported favorable outcomes in 79 percent of patients managed with drug therapy, 48 percent managed with therapeutic thoracentesis, and 87 percent managed with surgical decortication/pleurectomy [2]. However, the interpretation of these data is complicated by the small number of patients and use of combination therapies.

SUMMARY AND RECOMMENDATIONS

The presence of high amounts of cholesterol in a pleural effusion is termed a cholesterol pleural effusion (also called chyliform effusion or pseudochylothorax). (See 'Introduction' above.)

Cholesterol pleural effusions are rare. However, the incidence may be higher in those with chronic pleural inflammation including patients with tuberculous and rheumatoid pleurisy and in areas endemic for paragonimiasis (table 1). The exact pathogenesis of cholesterol effusions is uncertain, but it is likely that different mechanisms exist in different clinical settings. (See 'Pathogenesis' above and 'Etiologies' above.)

The clinical findings of a cholesterol pleural effusion are nonspecific and are more likely to represent those of a moderate to large pleural effusion. In many cases, because the findings are nonspecific and the condition is rare, it is often not suspected until pleural fluid returns as milky on thoracentesis. The effusion is typically unilateral and frequently associated with pleural thickening. (See 'Clinical features' above.)

For patients suspected to have a cholesterol pleural effusion, the initial diagnostic test is analysis of the pleural fluid for its appearance/color and for white blood cell count and differential (algorithm 1). Pleural fluid should also be analyzed for glucose, lactic dehydrogenase (LDH), and total protein levels, as well as for cytology, microbiologic smear, Gram stain, and culture. Specifically, pleural fluid levels of triglyceride and cholesterol should also be measured. (See 'Diagnostic evaluation' above and 'Pleural fluid analysis' above and 'Diagnosis' above.)

A cholesterol pleural effusion is classically milky white/turbid, has exudative characteristics, and may have additional features on chemistry that are suggestive of the underlying pathology (eg, eosinophilia to suggest paragonimiasis, low pH, high LDH, low glucose to suggest rheumatoid arthritis, tuberculosis, or malignancy). (See 'General findings' above.)

The diagnosis of a cholesterol effusion is supported by an elevated cholesterol concentration greater than or equal to 200 mg/dL (5.18 mmol/L) and a triglyceride concentration below 110 mg/dL (1.24 mmol/L) together with a cholesterol/triglyceride ratio >1. The cholesterol/triglyceride ratio >1 appears to be more sensitive for the diagnosis (98 percent). In the appropriate clinical context, these findings are typically sufficient for the diagnosis. However, the cholesterol level may be less than 200 mg/dL in a quarter of patients and the triglyceride concentration above 110 mg/dL (1.24 mmol/L) in another quarter. (See 'Cholesterol and triglyceride level' above.)

When diagnostic confirmation is needed, we suggest that pleural fluid also be examined under polarized light for the presence of cholesterol crystals (image 1), the presence of which is diagnostic (table 2); however, 10 percent of patients do not have cholesterol crystals such that their absence does not rule out the diagnosis. (See 'Cholesterol crystals' above.)

For patients who present with pleural fluid that is turbid or milky in appearance, the major differential includes chylothorax and empyema, and rarely, tube feed leaks due to a misplaced catheter. For the patients who do not have pleural fluid with a milky appearance, the differential diagnosis is broader considering that cholesterol effusions are exudative (table 4). In most cases, triglyceride and cholesterol analysis and the demonstration of cholesterol crystals will distinguish a cholesterol pleural effusion from all other causes of an exudative effusion, regardless of its appearance. When the diagnosis remains in doubt, we suggest pleural fluid lipoprotein analysis, to demonstrate the absence of chylomicrons (which is diagnostic of chylothorax). (See 'Differential diagnosis' above.)

For patients diagnosed with a cholesterol pleural effusion, the causative underlying disease, if not already known, should be sought based upon history (eg, tuberculous exposure, arthritis, helminth endemic area) and physical examination. Testing may include tuberculin skin testing, laboratory testing (eg, peripheral eosinophilia, rheumatoid factor), microbiologic cultures of pleural fluid, and pleural fluid cytology or biopsy. (See 'Identifying the cause' above.)

The initial step in the management of cholesterol effusions is treatment of the underlying disease process, whether it is tuberculosis, paragonimiasis, rheumatoid pleurisy, or other treatable disease. In parallel, patients who are assessed to be symptomatic from their cholesterol pleural effusion (eg, resting or progressive dyspnea, chest pain), should undergo a drainage procedure; therapeutic thoracentesis or chest tube or catheter drainage is appropriate. For patients without symptoms referable to the cholesterol effusion, we typically avoid a drainage procedure and wait for a clinical and radiologic response to treatment of the underlying disease (eg, weeks to months). (See 'Initial management' above.)

Although data are limited, up to two-thirds of patients with a cholesterol pleural effusion may fail initial therapy over a period of several weeks to months. Managing such patients is challenging and options may depend upon whether the lung is expandable or nonexpandable. (See 'Recurrent pleural effusion' above.)

For patients who have recurrent cholesterol effusion and expandable lung, we suggest repeat thoracentesis rather than pleurodesis (Grade 2C). The rationale for this approach is that a second or third intervention may be sufficient, allowing time for the underlying disease to be treated. For patients who fail repeated attempts of therapeutic thoracentesis, medical or surgical pleurodesis is typically indicated. An indwelling catheter (IPC) may be appropriate in patients who decline repeat thoracentesis or pleurodesis. (See 'Expandable lung (repeat thoracentesis)' above.)

For patients who have recurrent cholesterol effusion and symptoms thought to be due to nonexpandable lung, curative options are limited. In this population, we suggest surgical decortication with or without visceral pleurectomy (Grade 2C). The rationale for this approach is the avoidance of empyema and pleurocutaneous fistula associated with repetitive thoracentesis. Alternatives, for patients who decline or are not candidates for surgery, include continued intermittent thoracentesis or placement of an IPC. (See 'Recurrent pleural effusion' above.)

The prognosis of patients with cholesterol pleural effusions is poorly studied. Outcome varies and likely depends upon the nature of the underlying etiology and clinical factors such as age, severity of associated lung disease, and the degree of expandable or nonexpandable lung. (See 'Prognosis' above.)

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Topic 16317 Version 27.0

References

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