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Pseudochylothorax Without Pleural Thickening: Time to Reconsider Pathogenesis? FREE TO VIEW

John M. Wrightson, MA; Andrew E. Stanton, MD; Nicholas A. Maskell, DM; Robert J. O. Davies, DM; Y. C. Gary Lee, PhD
Author and Funding Information

Affiliations: From the Oxford Pleural Unit (Drs. Wrightson, Stanton, Davies, and Lee), Oxford Centre for Respiratory Medicine, Churchill Hospital, Oxford, UK; the North Bristol Lung Centre (Dr. Maskell), Southmead Hospital, Bristol, UK; the NIHR Oxford Biomedical Research Centre (Dr. Davies), University of Oxford, Oxford, UK; and the Centre for Respiratory Research (Dr. Lee), University College London, UK.

Correspondence to: Y. C. Gary Lee, PhD, University Department of Medicine and Lung Institute of Western Australia, University of Western Australia, Perth, WA 6009, Australia; e-mail: gary.lee@uwa.edu.au


This research was supported by the NIHR Oxford Biomedical Research Centre, UK (Dr. Davies), Medical Research Council, UK, and National Health & Medical Research Council, Australia (Dr. Lee), Department of Health & Higher Education Funding Council for England (HEFCE), Senior Clinical Lecturer awards (Drs. Maskell and Lee), and NIHR Academic Clinic Fellow programme, UK (Dr. Wrightson).

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/misc/reprints.xhtml).


© 2009 American College of Chest Physicians


Chest. 2009;136(4):1144-1147. doi:10.1378/chest.09-0445
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Pseudochylothorax (cholesterol pleurisy or chyliform effusion) is a cholesterol-rich pleural effusion that is commonly associated with chronic inflammatory disorders such as tuberculosis or rheumatoid arthritis. Until now, there were only 15 published cases of arthritis-associated pseudochylothorax in the English language literature. Previous literature has suggested that pleural fluid cholesterol enrichment occurs in the context of grossly thickened (fibrotic) pleura over a prolonged period, usually > 5 years. We present six well-characterized cases of arthritis-associated pseudochylothorax, each notable due to their minimal pleural thickening. The median duration of symptoms (or arthritis, in the case of asymptomatic effusions) was 15 months. Such findings cast significant doubt on the conventional concepts of the pathogenesis of rheumatoid-associated pseudochylothorax. Clinicians should consider pseudochylothorax even in short-duration nonfibrotic pleural effusions.

Figures in this Article

A pseudochylothorax is a pleural effusion characterized by high cholesterol content and milky pleural fluid,1 often with cholesterol crystals seen on microscopy. The majority of pseudochylothoraces are associated with tuberculous or rheumatoid pleuritis,2,3 or rarely pleural paragonimiasis4 or trauma. Such effusions are rare. To our knowledge, there are only 15 cases of rheumatoid-associated pseudochylothorax that have been reported in the English language literature. Pseudochylothorax may enlarge with time and cause dyspnea. The pathogenesis of pseudochylothorax has never been systematically investigated, and consequently its optimal management is unclear.

Since Weem's description in 1918, the medical literature1,5,6 has always emphasized that a hallmark of pseudochylothoraces is the presence of a grossly thickened (fibrotic) pleura, resulting from chronic intense pleuritis. Authors5,7 have suggested that a pleural inflammatory process of at least 5 years is required for the development of a pseudochylothorax. Such chronicity and thickening is often considered to be a prerequisite for a diagnosis of pseudochylothorax to be considered, although one case of rapid-onset pseudochylothorax associated with tuberculous pleurisy has been reported.8 It has been postulated that the lysis of erythrocytes and neutrophils in the pleural fluid releases cholesterol and lecithin-globulin complexes; these are “trapped” in the pleural cavity as the fibrotic pleural thickening blocks the drainage of fluid and particulates via parietal lymphatics. The eventual concentration of these lipids gives the pleural fluid a milky appearance.

We present six cases of pseudochylothorax diagnosed in tertiary pleural referral units, all in the absence of a thickened pleura. The patients had a short duration of symptoms, and three of the patients had a relatively short history of rheumatoid arthritis. The collection of these cases disputes the necessity of chronic pleuritis and significant pleural thickening in the etiology and diagnosis of pseudochylothorax; doubt is therefore cast on the conventionally accepted disease mechanism.

Patient A

A 67-year-old man was found to have an asymptomatic unilateral effusion seen on chest radiography. He had a 2-year history of rheumatoid arthritis that was treated with methotrexate, nonsteroidal antiinflammatory therapy, and tramadol. There was no pleural thickening on a CT scan with pleural phase contrast enhancement (Fig 1). Thoracoscopy confirmed a lack of gross thickening on direct visual inspection. A postthoracoscopy chest radiograph (Fig 2) demonstrated the lack of thickening. The pleural fluid was milky, and contained cholesterol crystals and a high cholesterol concentration (182 mg/dL [4.7 mmol/L]) [Table 1], confirming pseudochylothorax. Pleural biopsy specimens showed fibrous tissue with chronic inflammatory cells including histiocytes with epithelioid granuloma formation without caseation, which is consistent with rheumatoid pleuritis. Over subsequent months, the effusion increased in size; a subsequent increase in the methotrexate dose and the addition of prednisone to therapy brought about a marked reduction in fluid volume.

Figure Jump LinkFigure 1 CT scan of the pleural effusion without pleural enhancement in patient A.Grahic Jump Location
Figure Jump LinkFigure 2 x: patient A, radiograph postthoracoscopy showing pleural drain and lack of pleural thickening. y: patient C, radiograph 5 months prior to presentation showing neither effusion nor thickening. z: patient C, radiograph at presentation showing bilateral effusions without thickening.Grahic Jump Location
Table Graphic Jump Location
Table 1 Pleural Fluid Characteristics

NA = not applicable; LDH = lactate dehydrogenase.

*Upper limit of normal serum LDH = 250 international units/L.

Patient B

Rheumatoid arthritis was diagnosed in a 62-year-old man following a 3-year history of arthralgia, joint stiffness, and a raised rheumatoid factor of 68 international units/mL (normal level, < 10 international units/mL). A chest radiograph and CT scan at the time of diagnosis revealed a right-sided pleural effusion without pleural thickening. Pleural fluid analyses confirmed a pseudochylothorax with a milky-yellow appearance, an elevated cholesterol concentration (452 mg/dL [11.7 mmol/L]), and the presence of cholesterol crystals. Again, the pleura was not thickened but looked macroscopically inflamed during thoracoscopy. Multiple biopsy specimens were obtained and yielded no evidence of tuberculosis or alternative etiology for the pseudochylothorax. Hydroxychloroquine provided good control of both his palindromic rheumatoid arthritis and the pseudochylothorax.

Patient C

A 58-year-old woman presented with dyspnea and arthralgia. Five months earlier, the findings of a chest radiograph were normal and showed no pleural effusion. A chest radiograph at the time of presentation and a subsequent CT scan found moderate-sized bilateral pleural effusions with no evidence of pleural thickening (Fig 2). Laboratory investigations showed raised levels of rheumatoid factor (148 international units/mL; normal level, < 10 international units/mL) and anti-cyclic citrullinated peptide antibody (55 units/mL; normal level, < 7 units/mL), a peripheral eosinophilia, and a raised erythrocyte sedimentation rate (31 mm/h). The pleural fluid appeared milky with a raised cholesterol concentration (460 mg/dL [11.9 mmol/L]). The results of laboratory investigation for chylomicrons were negative. Thoracoscopy of the right pleural cavity showed no gross pleural thickening, and biopsy revealed chronic inflammatory cell infiltrates including lymphocytes, eosinophils, and plasma cells. Therapy with prednisone and methotrexate were started for the treatment of rheumatoid arthritis, and the pseudochylothorax was stable at the 6-month follow-up.

Patient D

An incidental, moderate, left pleural effusion was detected on the chest radiograph of a 60-year-old man with rheumatoid arthritis (rheumatoid factor titer, 1:160) prior to starting therapy with methotrexate. The pleural fluid was turbid and odorless, with biochemical features of a pseudochylothorax (Table 1). A CT scan confirmed the effusion but showed no evidence of pleural thickening. The patient was asymptomatic from his effusion for > 18 months; radiographic follow-up showed no change in effusion size.

Patient E

A 61-year-old man with rheumatoid arthritis presented with 6 months of progressive breathlessness and bilateral pleural effusions seen on chest radiographs. Pleural aspiration showed milky yellow fluid with elevated cholesterol and triglyceride concentrations (Table 1), without the presence of chylomicrons. A CT scan confirmed bilateral pleural effusions with no pleural thickening. Over a 2-year follow-up period while receiving therapy with methotrexate, the patient had no increase in the size of his effusion with no further pleural intervention.

Patient F

Dyspnea developed over 3 months in a 50-year-old man with seronegative arthritis, while receiving therapy with methotrexate and low-dose prednisone. Pleural aspiration of a right-sided pleural effusion confirmed a pseudochylothorax (Table 1), despite a CT scan confirming pleural fluid with only a minimal amount of pleural thickening. His effusion was controlled by increasing the dosages of methotrexate and prednisone.

This case series described six patients with arthritis-related pseudochylothorax of modestly rapid onset and in the absence of a typical thick pleural peel; five patients had seropositive rheumatoid disease, and one patient had seronegative arthritis. Pseudochylothorax is an uncommon and underrecognized condition. Although rheumatoid arthritis is stated to be the second most common underlying cause, to our knowledge, there are only 15 published cases of such association in the English language literature.5,7,914Table 2 summarizes the published literature on rheumatoid arthritis and pseudochylothorax. This series therefore adds significantly to the total number of published cases of arthritis-related pseudochylothorax and expands the understanding of the clinical phenotype of this syndrome. Rheumatoid pleural disease is likely to account for a greater proportion of cases in years to come as chronic tuberculosis, the current leading cause, becomes less common with improving treatment.

Table Graphic Jump Location
Table 2 Published Cases of Rheumatoid-Associated Pseudochylothorax in English Literature

Our patients had biochemical confirmation of pseudochylothorax, but minimal (or no) pleural thickening seen even on CT scans. In three cases, this was further confirmed on direct inspection at thoracoscopy. This observation disproves the current standard published view1,5 that pseudochylothorax can only develop when chronically inflamed pleura become grossly thickened, “trapping” and concentrating cholesterol within the pleural space.

These cases show that the notion that pseudochylothoraces can only develop in effusions of > 5 years' duration is incorrect.5,7 Of our patients, one had a normal chest radiograph 5 months before the diagnosis of pseudochylothorax. The median duration of symptoms (or arthritis, if asymptomatic) was 15 months. Our patients are unlikely to have had a longer duration of pleurisy.

The source of cholesterol in pseudochylothorax remains intriguing. The conventional belief is that the high concentration of cholesterol in the pleural fluid originates from degraded erythrocytes and neutrophils. A previous theory proposed by Desbordes15 in 1938 was that alteration of the pleural fluid albumin/globulin ratio caused cholesterol precipitation in pseudochylothorax. This has subsequently been discounted.5 There is no evidence that raised serum cholesterol causes pseudochylothorax.13 When it was measured, the serum cholesterol concentration was actually lower than the pleural fluid cholesterol concentration in two of our patients (patient C: serum cholesterol concentration, 240 mg/dL [6.2 mmol/L]; patient F: serum cholesterol concentration, 232 mg/dL [6.0 mmol/L]). The authors of a small study16 hypothesized that low-density lipoprotein-bound cholesterol accumulates in the pleural space in acute inflammatory effusions. They found that chronic effusions, however, had a predominance of high-density lipoproteins, possibly suggesting that local metabolic processes cause the cholesterol concentration. The lack of pleural thickening in our patients suggests that an active acute or subacute process produces the intrapleural accumulation of cholesterol, rather than the previously suggested cellular breakdown and cholesterol release within an entrapped pleural space. The exact pathogenesis of pseudochylothorax remains a topic for further research.

The treatment of pseudochylothoraces remains challenging. In most of the patients we reported, aggressive treatment for rheumatoid arthritis coincided with control or resolution of the pseudochylothorax, although a causal relationship cannot be determined without a randomized trial. Pleural fluid volume was controlled or improved by increasing the steroid dose or by the addition of a disease-modifying antirheumatic drug.

This report adds six further cases of arthritis-related pseudochylothorax to the literature. All of the patients had a relatively short clinical history and an absence of significantly thickened pleura, challenging the generally held opinion that the mechanism of cholesterol enrichment in the effusion is due to a very long period of inflammation encased within severely thickened pleura. It is important for clinicians to consider pseudochylothorax as a differential diagnosis in patients with unexplained pleural effusions, even in the absence of a prolonged history and the absence of marked pleural thickening.

Financial/nonfinancial disclosures: The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions: The authors are grateful to Mrs. Nicky Richards for secretarial assistance in case file retrieval.

Hillerdal G. Chylothorax and pseudochylothorax. Eur Respir J. 1997;10:1157-1162. [PubMed] [CrossRef]
 
Light RW, Lee YCG. Textbook of pleural diseases. 2008;2212nd edition London, UK Hodder Arnold:243-244:389-395
 
Light RW, Lee YCG.Mason RJ, Broaddus VC, Murray JF, et al. Pneumothorax, chylothorax, hemothorax, and fibrothorax. Murray and Nadel's textbook of respiratory medicine. 2005;4th edition Philadelphia, PA Elsevier Saunders:1978
 
Thewjitcharoen Y, Poopitaya S. Paragonimiasis presenting with unilateral pseudochylothorax: case report and literature review. Scand J Infect Dis. 2006;38:386-388. [PubMed]
 
Ferguson GC. Cholesterol pleural effusion in rheumatoid lung disease. Thorax. 1966;21:577-582. [PubMed]
 
Weems BF. Cholesterohydrothorax. Am J Med Sci. 1918;156:20
 
Garcia-Zamalloa A, Ruiz-Irastorza G, Aguayo FJ, et al. Pseudochylothorax: report of 2 cases and review of the literature. Medicine (Baltimore). 1999;78:200-207. [PubMed]
 
Nogueras C, Monteagudo M, Vila M, et al. Recent-onset tuberculous pleurisy presenting as pseudochylothorax. Am J Med. 2002;113:166-168. [PubMed]
 
Bower GC. Chyliform pleural effusion in rheumatoid arthritis. Am Rev Respir Dis. 1968;97:455-459. [PubMed]
 
Dodson WH, Hollingsworth JW. Pleural effusion in rheumatoid arthritis: impaired transport of glucose. N Engl J Med. 1966;275:1337-1342. [PubMed]
 
Engel U, Aru A, Francis D. Rheumatoid pleurisy: specificity of cytological findings. Acta Pathol Microbiol Immunol Scand A. 1986;94:53-56. [PubMed]
 
Lee SS, Trimble RB. Rheumatoid arthritis with bloody and cholesterol pleural effusion. Arch Pathol Lab Med. 1985;109:769-771. [PubMed]
 
Shen PU, Blair JL. Cholesterol crystals causing falsely elevated automated cell count. Am J Clin Pathol. 2006;125:358-363. [PubMed]
 
Stengel BF, Watson RR, Darling RJ. Pulmonary rheumatoid nodule with cavitation and chronic lipid effusion. JAMA. 1966;198:1263-1266. [PubMed]
 
Desbordes J. Sur le mécanisme de solubilisation ou de précipitation du cholestérol dans sérum ou les liquides pathologiques. C R Soc Biol (Paris). 1938;127:869-872
 
Hamm H, Pfalzer B, Fabel H. Lipoprotein analysis in a chyliform pleural effusion: implications for pathogenesis and diagnosis. Respiration. 1991;58:294-300. [PubMed]
 

Figures

Figure Jump LinkFigure 1 CT scan of the pleural effusion without pleural enhancement in patient A.Grahic Jump Location
Figure Jump LinkFigure 2 x: patient A, radiograph postthoracoscopy showing pleural drain and lack of pleural thickening. y: patient C, radiograph 5 months prior to presentation showing neither effusion nor thickening. z: patient C, radiograph at presentation showing bilateral effusions without thickening.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 Pleural Fluid Characteristics

NA = not applicable; LDH = lactate dehydrogenase.

*Upper limit of normal serum LDH = 250 international units/L.

Table Graphic Jump Location
Table 2 Published Cases of Rheumatoid-Associated Pseudochylothorax in English Literature

References

Hillerdal G. Chylothorax and pseudochylothorax. Eur Respir J. 1997;10:1157-1162. [PubMed] [CrossRef]
 
Light RW, Lee YCG. Textbook of pleural diseases. 2008;2212nd edition London, UK Hodder Arnold:243-244:389-395
 
Light RW, Lee YCG.Mason RJ, Broaddus VC, Murray JF, et al. Pneumothorax, chylothorax, hemothorax, and fibrothorax. Murray and Nadel's textbook of respiratory medicine. 2005;4th edition Philadelphia, PA Elsevier Saunders:1978
 
Thewjitcharoen Y, Poopitaya S. Paragonimiasis presenting with unilateral pseudochylothorax: case report and literature review. Scand J Infect Dis. 2006;38:386-388. [PubMed]
 
Ferguson GC. Cholesterol pleural effusion in rheumatoid lung disease. Thorax. 1966;21:577-582. [PubMed]
 
Weems BF. Cholesterohydrothorax. Am J Med Sci. 1918;156:20
 
Garcia-Zamalloa A, Ruiz-Irastorza G, Aguayo FJ, et al. Pseudochylothorax: report of 2 cases and review of the literature. Medicine (Baltimore). 1999;78:200-207. [PubMed]
 
Nogueras C, Monteagudo M, Vila M, et al. Recent-onset tuberculous pleurisy presenting as pseudochylothorax. Am J Med. 2002;113:166-168. [PubMed]
 
Bower GC. Chyliform pleural effusion in rheumatoid arthritis. Am Rev Respir Dis. 1968;97:455-459. [PubMed]
 
Dodson WH, Hollingsworth JW. Pleural effusion in rheumatoid arthritis: impaired transport of glucose. N Engl J Med. 1966;275:1337-1342. [PubMed]
 
Engel U, Aru A, Francis D. Rheumatoid pleurisy: specificity of cytological findings. Acta Pathol Microbiol Immunol Scand A. 1986;94:53-56. [PubMed]
 
Lee SS, Trimble RB. Rheumatoid arthritis with bloody and cholesterol pleural effusion. Arch Pathol Lab Med. 1985;109:769-771. [PubMed]
 
Shen PU, Blair JL. Cholesterol crystals causing falsely elevated automated cell count. Am J Clin Pathol. 2006;125:358-363. [PubMed]
 
Stengel BF, Watson RR, Darling RJ. Pulmonary rheumatoid nodule with cavitation and chronic lipid effusion. JAMA. 1966;198:1263-1266. [PubMed]
 
Desbordes J. Sur le mécanisme de solubilisation ou de précipitation du cholestérol dans sérum ou les liquides pathologiques. C R Soc Biol (Paris). 1938;127:869-872
 
Hamm H, Pfalzer B, Fabel H. Lipoprotein analysis in a chyliform pleural effusion: implications for pathogenesis and diagnosis. Respiration. 1991;58:294-300. [PubMed]
 
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