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(Chest. 1999;115:1066-1069.)
© 1999 American College of Chest Physicians

Hypoalbuminemia as a Cause of Pleural Effusions*

Alain A. Eid, MD; Jean I. Keddissi, MD and Gary T. Kinasewitz, MD, FCCP

* From the Department of Pulmonary Disease and Critical Care Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK.


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Alterations in Starling forces that favor pleural fluid formation include an elevation in capillary hydrostatic pressure and a fall in plasma oncotic pressure. Although venous hypertension is a well-recognized cause of pleural effusion, the frequency with which hypoalbuminemia in the absence of volume expansion leads to pleural effusion is unclear.

Study Objective: We determined the frequency with which unexplained pleural effusions occur in patients with normal and low plasma oncotic pressures.

Design: A 2-month prospective screen of all admission patients to the University of Oklahoma Hospital and the Oklahoma City Veterans Administration (VA) Medical Center identified 152 patients who had chest radiographs and serum protein determinations on admission, but did not have an admission diagnosis that was a recognized cause of pleural effusion. In order to include more patients in the study with extremely low serum albumin levels, 20 additional study patients with serum albumin levels of < 2.0 g/dL were identified by a retrospective review of patients admitted during the previous 12 months. On the radiograph, pleural effusions were identified as a new blunting of the costophrenic angles. Study patients were divided into the following three groups: group 1 had serum albumin levels of > 3.5 g/dL; group 2 had serum albumin levels between 2.1 and 3.5 g/dL; and group 3 had serum albumin levels of <= 2.0 g/dL. Finally, the frequencies with which pleural effusions occurred were compared among the three groups.

Results: Seven of 104 patients in group 1, 2 of 45 patients in group 2, and 3 of 21 patients in group 3 had pleural effusions. Within each group, there were no significant differences in serum albumin concentration or plasma oncotic pressure between patients with and without pleural effusions. In all but two study patients, a careful review of records and a prospective follow-up of the patients' clinical course identified a potential cause for the effusions other than hypoalbuminemia. None of the 68 study patients with serum albumin levels of <= 3.5 g/dL had an unexplained pleural effusion.

Conclusion: We conclude that hypoalbuminemia, per se, is an uncommon cause of pleural effusion. The recognition of pleural effusions in patients with low serum albumin levels should prompt careful clinical evaluations to identify other potential causes for the effusions.

Key Words: albumin • oncotic pressure • pleural effusion • protein


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Alterations in the Starling forces that favor the filtration of pleural fluid include an elevation of the capillary hydrostatic pressure and a fall in the plasma oncotic pressure.1 ,2 High pulmonary capillary pressure and venous hypertension are well-recognized causes of pleural effusion.3 ,4 Hypoalbuminemia is characteristic of many other disorders that are associated with pleural effusion, such as hepatic cirrhosis and nephrotic syndromes.5 ,6 ,7 However, these conditions often have additional factors, such as an expanded plasma volume or ascites, that lead to pleural fluid formation. The frequency with which hypoalbuminemia and a low plasma oncotic pressure, in the absence of other confounding influences, lead to the accumulation of pleural fluid is unclear.

To address this question, we determined the frequency of radiographically apparent pleural effusions in patients who had normal and low serum albumin levels but did not have clinical diagnoses associated with their pleural effusions. Our findings suggest that hypoalbuminemia, per se, is an uncommon cause of pleural effusion.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
All patients admitted to the University of Oklahoma Hospital and the Oklahoma City Veterans Administration (VA) Medical Center between July and September 1996 were prospectively screened for inclusion in this study. Patients who fit the criteria for inclusion were those who obtained a chest radiograph, and serum albumin and total protein level determinations within 24 h of admission. Patients with clinical diagnoses associated with the development of pleural effusion were excluded from the analysis. These diagnoses included congestive heart failure (CHF; ie, determined by clinical diagnosis, an ejection fraction of < 40%, or cardiomegaly with congestion on the chest radiograph), pneumonia, undiagnosed pulmonary infiltrates, thoracic malignancy, abdominal diseases associated with pleural effusion (such as pancreatitis, ovarian cancer, and abdominal abscesses), nephrotic syndrome (ie, a proteinuria level of > 3.5 g/24 h or 3+ protein on the urine analysis), renal failure (ie, a creatinine level of > 3 mg/dL), liver failure (ie, determined by clinical signs of portal hypertension, ascites, a bilirubin level of > 2.0 mg/dL, or serum glutamic-pyruvate transaminase level of greater than five times the normal upper limit), thoracic trauma within 4 weeks, pulmonary embolism, and organ transplants.

Because only one patient with a serum albumin level of < 2.0 g/dL was found during the prospective screening, we also identified patients with hypoalbuminemia by reviewing laboratory records for the period from May 1996 to May 1997 at the VA medical center. Patients who had serum albumin levels of <= 2.0 g/dL at any time during their hospital stay and a chest radiograph within 24 h of the serum albumin measurement were included if they did not meet any of the exclusion criteria.

We also reviewed the VA medical center laboratory logs for the period from January 1994 to July 1998 and identified all patients who had transudative pleural fluid submitted for analysis. Fluid was considered a transudate if it met the criteria defined by Light et al.8 The etiology of the effusion was determined by reviewing the medical records.

All chest radiographs were reviewed by an investigator who was blind to patients' serum albumin levels, and pleural effusion was defined as a new blunting of the costophrenic angle on the posteroanterior or lateral chest radiograph. The plasma oncotic pressures were calculated from the serum albumin and globulin concentrations using the Landis and Pappenheimer equations.9

All data are expressed as mean (± SD). We divided our study patients into the following three groups: group 1 had serum albumin levels of > 3.5 g/dL; group 2 had serum albumin levels ranging from 2.1 to 3.5 g/dL; and group 3 had serum albumin levels of <= 2.0 g/dL. Significant differences between the three groups were determined by analysis of variance or the Fisher's exact test, and significance was accepted when the p value was < 0.05.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Prospective screening of 594 patients at admission identified 296 eligible patients with a chest radiograph, and serum albumin and total protein measurements within 24 h of admission. Of these 296 patients, 144 patients met one or more of the exclusion criteria, leaving 152 patients for analysis. Group 1 comprised 104 patients, group 2 comprised 47 patients, and group 3 comprised 1 patient with a serum albumin level of < 2.0 g/dL.

Twenty additional group 3 patients with serum albumin levels of <= 2.0 g/dL were identified by reviewing hospital laboratory logs and radiology records. A total of 217 patients had serum albumin levels of <= 2.0 g/dL and a chest radiograph within 24 h of the serum albumin measurement during their periods of hospitalization, but 197 of these patients met one or more of the exclusion criteria.

Clinical and demographic data describing the study patients are summarized in Table 1 . Study patients in group 1 were slightly younger (49 ± 16 years) than those in groups 2 and 3. The ratios of men to women were similar between groups 1 and 2. Group 3 comprised only men because study patients from that group were identified at the VA medical center. The indexes of renal and hepatic function were also similar among all three groups. By design, the serum albumin and total protein levels as well as the calculated plasma oncotic pressures were significantly different among all three groups.


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  		Table 1. Patient Characteristics*

 
Seven patients in group 1 (6.7%; 95% confidence interval [CI]), 2 to 12%), two patients in group 2 (4.3%; 95% CI, 0.5 to 15%), and three patients in group 3 (14.3%; 95% CI, 3 to 37%) had pleural effusions. The incidence of pleural effusions was not significantly different among the three groups. Within each group, the serum albumin levels and plasma oncotic pressures of patients with pleural effusions were similar to that of patients who did not have pleural effusions (Table 2 ). An etiology other than hypoalbuminemia was identified in 10 of the 12 patients with pleural effusions (Table 3 ) during their periods of hospitalization. A cause for the pleural effusions was not identified in two group 1 patients. Thus, none of the 68 patients with serum albumin levels of <= 3.5 g/dL had an unexplained pleural effusion.


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  		Table 2. Comparison of Patients With and Without Effusions

 

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  		Table 3. Etiology of Pleural Effusions*

 
A total of 104 patients with transudative pleural effusions was identified from the laboratory logs, but only 102 charts were available for review. CHF accounted for 76% of the transudates in the 29 patients with serum albumin levels of >= 3.5 g/dL and 74% of the effusions in the 73 patients with hypoalbuminemia. All study patients with low serum albumin levels had at least one other potential etiology for their transudate (eg, CHF or hepatic cirrhosis).


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The present study suggests that clinically significant pleural effusions are uncommon in patients who have low plasma albumin levels but no other causes for their pleural effusions. There were no apparent etiologies for the pleural effusions identified in two patients with normal serum albumin levels. We relied on posteroanterior and lateral chest radiography to identify their pleural effusions. It is possible that the incidence of pleural effusion was underestimated because up to 200 mL of fluid can be present without blunting of the costophrenic angle.10 Whereas decubitus radiograph and ultrasonography tests are more sensitive to the detection of pleural fluid,11 ,12 an asymptomatic effusion that can only be demonstrated by one of these techniques is unlikely to be clinically significant.

Because experimental studies have demonstrated that the distribution of hydrostatic and oncotic pressures across the pleural membranes are important determinants of pleural fluid flux,1 ,2 it may seem surprising that an increased incidence of pleural effusion was not found in study patients with low albumin levels. Certainly the clinical importance of elevated capillary hydrostatic pressures in the pathogenesis of pleural effusion has been well established.3 ,13 Indeed, CHF may be the most common cause of pleural effusion.14 ,15 CHF accounted for the vast majority of the transudative effusions found in the present study.

Pleural fluid accumulation is dependent on the rate of fluid filtration that exceeds its reabsorption from the pleural cavity. The contrast between the different effects of an increase in hydrostatic pressure and a reduction in oncotic pressure is easier to understand when we consider the effect of each condition on the relative rates of pleural fluid filtration and reabsorption. An elevation in hydrostatic pressure increases the rate of fluid filtration from the pleural capillaries and simultaneously decreases its reabsorption at the postcapillary venule. In addition, increases in systemic venous pressure reduce lymphatic flow from the pleural cavity by reducing flow at the level of the thoracic duct.16 ,17 A reduction in plasma oncotic pressure also increases the rate of fluid filtration at the pleural capillary membrane but, in the absence of volume expansion, lymphatic flow is unimpeded. Experimental studies have found that lymph flow is greater when capillary filtration is increased by lowering plasma protein concentrations than when a similar increase in capillary filtration is produced by raising the hydrostatic pressure.18 Assuming that the permeability of the pleural capillary is intact, a fall in the plasma albumin level of 3 g/dL will increase the filtration of fluid by three-fold. Because lymphatic flow can increase by more than 10-fold in the absence of venous outflow obstruction,18 this modest increase is well within the reabsorptive capacity of the pleural lymphatics.

We conclude that hypoalbuminemia, per se, is an uncommon cause of pleural effusion. The recognition of pleural effusions in patients with low serum albumin levels should prompt a careful clinical evaluation to identify other potential causes for the pleural effusion.


   Acknowledgements
 
ACKNOWLEDGMENT: The excellent secretarial assistance of Priscilla Peer is gratefully acknowledged.


   Footnotes
 
Correspondence to: Alain Eid, MD, Department of Pulmonary and Critical Care Medicine, 920 Stanton L. Young Blvd, WP 1310, Oklahoma City, OK 73104

Abbreviations: CHF = congestive heart failure; CI = confidence interval; VA = Veterans Administration

Received for publication April 29, 1998. Accepted for publication November 3, 1998.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Mellins, RB, Levine, OR, Fishman, AP (1970) Effect of systemic and pulmonary venous hypertension on pleural and pericardial fluid accumulation. J Appl Physiol 29,564-569[Free Full Text]
  2. Kinasewitz, GT, Fishman, AP (1981) Influence of alterations in Starling forces on visceral fluid movement. J Appl Physiol 51,671-677[Abstract/Free Full Text]
  3. Wiener-Kronish, JP, Matthay, MA, Callen, PW, et al (1985) Relationship of pleural effusions to pulmonary hemodynamics in patients with congestive heart failure. Am Rev Respir Dis 132,1253-1256[ISI][Medline]
  4. Race, GA, Scheifly, CH, Edwards, JE (1957) Hydrothorax in congestive heart failure. Am J Med 22,83-89
  5. Chen, A, Ho, YS, Tu, YC, et al (1988) Diaphragmatic defect as a cause of massive hydrothorax in cirrhosis of liver. J Clin Gastroenterol 10,663-666[ISI][Medline]
  6. Nakamura, T, Hara, H, Ijima, F, et al (1984) The effect of changing the contact surface area between pleural liquid and pleura on the turnover of pleural liquid. Am Rev Respir Dis 129,481-484[ISI][Medline]
  7. Pettersson, T, Riska, H, Sutinen, S, et al (1993) High concentrations of eosinophil cationic protein and eosinophil protein X in eosinophilic pleural effusions. Chest 103,475-478[Abstract/Free Full Text]
  8. Light, RW, MacGregor, IM, Luchsinger, PC, et al (1972) Pleural effusions: the diagnostic separation of transudates and exudates. Ann Intern Med 77,507-513
  9. Rehder, K, Schmid, ER, Knopp, TJ (1983) Long-term high-frequency ventilation in dogs. Am Rev Respir Dis 128,476-480[ISI][Medline]
  10. Colins, JD, Burwell, D, Furmanski, S, et al (1972) Minimal detectable pleural effusions: a roentgen pathology model. Radiology 105,51-53[ISI][Medline]
  11. McLoud, TC, Flower, CD (1991) Imaging the pleura: sonography, CT, MR imaging. Am J Roentgenol 156,1145-1153[Abstract/Free Full Text]
  12. Moskowitz, H, Platt, RT, Schachar, R (1973) Roentgen visualization of minute pleural effusion: an experimental study to determine the minimal amount of pleural fluid visible on a radiograph. Radiology 109,33-35[ISI][Medline]
  13. Wiener-Kronish, JP, Matthay, MA (1988) Pleural effusions associated with hydrostatic and increased permeability pulmonary edema. Chest 93,852-858[ISI][Medline]
  14. Sahn, SA (1988) The pleura. Am Rev Respir Dis 138,184-234[ISI][Medline]
  15. Marel, M, Zrustova, M, Stasny, B, et al (1993) The incidence of pleural effusion in a well-defined region: epidemiologic study in central Bohemia. Chest 104,1486-1489[Abstract/Free Full Text]
  16. Szabó, G, Magyar, Z (1967) Effect of increased systemic venous pressure on lymph pressure and flow. Am J Physiol 212,1469-1474[Free Full Text]
  17. Laine, GA, Allen, SJ, Katz, J, et al (1986) Effect of systemic venous pressure elevation on lymph flow and lung edema formation. J Appl Physiol 61,1634-1638[Abstract/Free Full Text]
  18. Aukland, K, Reed, RK (1996) Interstitial-lymphatic mechanisms in the control of extracellular fluid volume. Physiol Rev 73,1-78[Abstract/Free Full Text]



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