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Routine Measurement of Pleural Fluid Amylase Is Not Indicated
Paul Branca, MD;
R. Michael Rodriguez, MD;
Jeffrey T. Rogers, RRT;
Dereje S. Ayo, MD;
J. Phillip Moyers, MD;
Richard W. Light, MD
Arch Intern Med. 2001;161:228-232.
ABSTRACT
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Background The routine measurement of pleural fluid amylase is frequently recommended,
but the cost-effectiveness of this procedure is unknown.
Methods To assess the utility of routine measurement of pleural fluid amylase
in evaluating pleural effusions, we measured amylase, glucose, lactate dehydrogenase,
and protein levels and blood cell counts in 379 patients undergoing thoracentesis
during a 22-month period from 1997 to 1999. Of these, 199 had effusions after
cardiac surgery; 61, malignant; 48, transudative; 28, parapneumonic; 2, chylous;
2, rheumatoid; 1, tuberculous; and 1, from chronic pleuritis. There were 37
exudates of unknown origin.
Results Measurement of pleural fluid amylase levels did not assist in determining
the origin of the effusion in any of the patients. Amylase levels greater
than 100 U/L (normal serum level in our laboratory is 30-110 U/L) were found
in 5 (1.3%) of 379 patients: 1 patient with congestive heart failure (amylase,
173 U/L), 2 with post–cardiac surgery effusions (144 U/L and 130 U/L),
1 with pneumonia (109 U/L), and 1 with lung cancer (105 U/L).
Conclusions The routine measurement of pleural fluid amylase levels is neither clinically
indicated nor cost-effective. We suggest that pleural fluid serum amylase
levels be measured only if there is a pretest suspicion of acute pancreatitis,
chronic pancreatic disease, or esophageal rupture.
INTRODUCTION
WHEN a patient is diagnosed with a pleural effusion, a timely and systematic
evaluation is indicated. A transudative effusion has only a few likely causes.
An exudative effusion, however, has an extensive differential diagnosis. There
are many useful tests that have been recommended as part of the routine evaluation
of exudative effusion, including determining the level of amylase in the pleural
fluid.1, 2, 3, 4, 5
Although an elevated pleural fluid amylase level has been reported in many
diseases,2, 6, 7, 8, 9, 10
it is purported to be especially useful in establishing a diagnosis of malignancy,
pancreatitis, or esophageal rupture.1, 2, 3, 6
The purpose of this study was to assess the utility of pleural fluid
amylase measurement in the evaluation of pleural effusions. We hypothesized
that routine measurement of pleural fluid amylase levels would rarely provide
diagnostically useful information.
PATIENTS AND METHODS
PATIENT SELECTION
All patients undergoing thoracentesis in the Interventional Radiology
Department at St Thomas Hospital during the 22-month period from August 1997
through May 1999 were eligible for inclusion. We enrolled 416 patients, and
amylase levels were measured in pleural fluid samples from 379 patients. Amylase
levels were not measured in samples from 37 patients because of various technical
reasons and these patients were disqualified from the study. There were no
significant differences in the diagnoses of the disqualified patients compared
with those in whom pleural fluid amylase levels were measured (Table 1). This study was approved by the institutional review board
of St Thomas Hospital; all patients gave written informed consent.
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Table 1. Diagnoses of Pleural Effusion of the Patients Enrolled in
the Study
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PLEURAL FLUID ANALYSIS
At the time of thoracentesis, fluid was collected in a tube with EDTA
anticoagulant for white blood cell count and differential, and in a tube with
no additives for amylase, glucose, protein, and lactate dehydrogenase analysis.
The total white and red blood cell counts were obtained manually by microscopy.
The amylase, glucose, protein, and lactate dehyrogenase measurements were
made using an automated analyzer (Vitros model 950; Johnson & Johnson;
Rochester, NY). These studies were performed according to protocol for all
effusions for which consent was obtained, regardless of whether the clinician
formally ordered them. Results were provided and patients were billed only
for those studies actually ordered by the clinician. The normal range for
serum amylase levels in our laboratory is 30 to 110 U/L. Standard definitions
were used for identifying the cause of the pleural effusion.1
COST ANALYSIS
The clinical laboratories of the 4 largest hospitals in Nashville, Tenn
(where this study was conducted), were surveyed by telephone to obtain the
charge to the patient for measuring pleural fluid amylase levels for both
inpatients and outpatients.
STATISTICAL ANALYSIS
All values are given as mean ± SD unless otherwise noted.
RESULTS
Of the 379 patients who had pleural fluid amylase levels measured, 199
had effusions after cardiac surgery; 61, malignant; 48, transudative due to
congestive heart failure or cirrhosis; 28, parapneumonic; 2, chylous; 2, rheumatoid;
1, tuberculous; and 1, secondary to chronic pleuritis (Table 1). There were 37 exudates of unknown origin. No patient had
clinical pancreatitis.
Determining the pleural fluid amylase levels did not assist in making
the diagnosis in any of the patients. Of the 379 patients we studied, amylase
levels greater than 100 U/L (normal serum level at our hospital, 30-110 U/L)
were found in only 5 patients (Table 2).
None of these 5 patients had a simultaneous serum amylase level measured.
The highest pleural fluid amylase level occurred in patient 1, who was admitted
with an acute myocardial infarction. He had a bilateral (right greater than
left) transudative effusion, with an amylase level of 173 U/L on the left
side and 53 U/L on the right side. This effusion resolved with simple diuresis
and did not recur. Patient 2 had a loculated hemothorax with an amylase level
of 144 U/L that was drained 3 days after coronary artery bypass graft (CABG)
surgery. Although this effusion was initially thought to have resolved, he
was readmitted 3 months later with dyspnea, recurrent effusion, and weight
loss. His symptoms improved after an additional thoracentesis was performed.
The fluid from this second thoracentesis was a lymphocytic transudate with
an amylase level of less than 30 U/L. This patient underwent an extensive
evaluation for his weight loss, including computed tomographic scanning, bronchoscopy,
and thoracoscopy, with normal findings on pleural and lung biopsy, and negative
results of flow cytometry of the pleural fluid. The final diagnosis was severe
ischemic cardiomyopathy and cardiac cachexia. Patient 3 had a large-volume
bloody effusion 6 days following CABG surgery that had an amylase level of
130 U/L. His effusion completely resolved with thoracentesis and did not recur.
Patient 4 had a parapneumonic effusion with a borderline elevation of the
pleural fluid amylase level (109 U/L). No causative organism was found, and
the effusion resolved with antibiotics and a single thoracentesis. Patient
5 had a recurrent large-volume malignant effusion with an amylase level of
105 U/L. She had been receiving palliative chemotherapy for adenocarcinoma
of the lung previously diagnosed by bronchoscopy, and had undergone multiple
thoracenteses for symptomatic relief.
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Table 2. Patients With High Amylase Levels and Pleural Effusions*
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There were 17 patients who underwent bilateral thoracenteses and 26
patients who had repeated thoracenteses. None of the repeated measurements
of serum amylase levels was significantly elevated when the initial level
was normal.
A survey of the 4 largest hospitals in Nashville revealed that the average
laboratory charge for amylase measurement in pleural fluid was $36.01 for
an outpatient (range, $21.40-$50.00) and $58.76 for an inpatient (range, $53.95-$63.00).
The total charges for these 379 procedures at our hospital would have been
between $8110.60 and $20 447.05, respectively, and would have ranged
from $13 647.79 to $22 270.04 in our community.
COMMENT
In this study of 379 patients with pleural effusions of varying causes,
the measurement of pleural fluid amylase was not clinically useful in any
patient. Furthermore, the cost of performing all these amylase determinations
was substantial. The results of this study suggest that the common recommendation1, 2, 3, 4, 5
that amylase levels be measured routinely in exudative pleural effusion should
be reconsidered.
DIFFERENTIAL DIAGNOSIS
Elevated levels of pleural fluid amylase are commonly associated with
a diagnosis of pancreatitis, pulmonary malignancy, or esophageal rupture,
but have been reported in numerous other diseases.2, 6, 7, 8, 9, 10 Table 3 summarizes the 7 largest reported
series of pleural effusion in which amylase serum levels were measured. Of
the 1437 total effusions evaluated, only 89 (6.2%) had elevated amylase levels.
The most common causes in these series include malignancy (pulmonary or extrapulmonary)
(57.3%), pancreatitis (13.5%), pneumonia (11.2%), tuberculosis (6.7%), cirrhosis
(2.2%), and esophageal rupture (1.1%).
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Table 3. Summary of Reported Series of High Amylase Pleural Effusions
With High Amylase Levels*
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ISOENZYMES
There are at least 2 isoenzymes of amylase that separate with electrophoresis.
Pancreatic-type amylase originates in the pancreas, and its elevation in serum
or in other body fluids is specific for pancreatic inflammation.2, 11, 12
Salivary-type amylase is produced in the salivary glands, lungs, and fallopian
tubes and may be secreted ectopically by a variety of tumors.12, 13, 14, 15, 16, 17
In a prospective study of 200 patients with pleural effusions, Joseph et al2 performed isoenzyme analysis on 18 of 25 amylase-rich
effusions, confirming previous case reports that malignant, infectious, and
other nonpancreatic effusions have primarily salivary-type amylase.2, 11, 15, 16, 17, 18
Case reports and animal experiments have demonstrated consistently that pleural
effusions from esophageal ruptures contain high levels of salivary-type amylase,1, 19 presumably from the passage of amylase-rich
saliva through the tear and into the pleural space.
PANCREATITIS
In approximately 10% of patients with pancreatitis, a chest radiograph
will show a pleural effusion,20 and in as many
as 50%, computed tomography of the chest and abdomen will show a pleural effusion.21 The pleural fluid amylase level is often greater
than the serum amylase level.2, 4, 6, 20
When a pleural effusion complicates pancreatitis, regardless of its size or
location, it is a poor prognostic indicator and is associated with increased
mortality and increased frequency of pancreatic pseudocysts.21
Anatomically, the tail of the pancreas approaches the left hemidiaphragm;
when there is pancreatic inflammation, there can be local movement of fluid
across the diaphragm. Cases of amylase-rich pleural effusion in patients with
clinical pancreatitis but normal levels of serum amylase have been reported,4, 22 but it is unusual to make this diagnosis
on the basis of pleural fluid analysis alone.
Occasionally a pancreatic pseudocyst will decompress into the mediastinum
or into the pleural space, with relief of abdominal pain, but often with the
onset of pulmonary symptoms or symptoms of chronic illness.1, 23
When this occurs, the patient will frequently have an invasive evaluation
for an occult malignancy. Under these circumstances, demonstrating a markedly
elevated pancreatic isoamylase level in the pleural fluid can help establish
the diagnosis.1, 3, 4, 23
ESOPHAGEAL RUPTURE
Any patient with a pleural effusion who appears acutely ill should have
esophageal rupture included in the differential diagnosis.1
It is imperative that this diagnosis be made as quickly as possible, given
the rapidly progressive nature of esophageal ruptures and their potential
for surgical treatment if discovered early. Symptoms include severe chest
pain, dyspnea, and, occasionally, hematemesis, and they usually occur after
vomiting or an invasive esophageal procedure. Low pH, the presence of particulate
matter, and an elevated level of salivary amylase in the pleural fluid of
a patient with this constellation of symptoms constitute good evidence of
esophageal rupture.1, 19, 23
MALIGNANCY
Amylase-rich malignant effusions are not necessarily related to pancreatic
tumors. These effusions can occur with primary or metastatic lung cancer (often
adenocarcinoma) as well as other nonpancreatic tumors. In Table 3, there are data for 388 patients with cancer and malignant
effusions; of these, 38 (9.8%) had an increased amylase level. Previous reports
have demonstrated that approximately 50% of patients with amylase-rich malignant
effusions will also have an increased serum amylase level.1
When malignant effusions have elevated amylase levels the amylase is usually
of the salivary type2, 11, 12, 13, 15, 16, 17
and is produced ectopically by the tumor cells.12, 13, 14, 15, 16
It is also possible for amylase to accumulate in the pleural space due to
tumor obstruction of the pleural lymphatics.2
Malignancy is often unsuspected at the time of thoracentesis, and it
has been suggested that elevated pleural fluid amylase levels (especially
of the salivary type) in the absence of pancreatic disease or esophageal rupture
should prompt a search for occult malignancy.1, 2, 11
However, since only about 10% of patients with malignancy have an elevated
pleural fluid amylase level, this is certainly an inefficient means to screen
for this disease
AFTER CABG
Elevated pleural fluid amylase levels have been reported in association
with postoperative cardiac surgery.18 In our
series, 2 patients had an elevated pleural fluid amylase level following CABG.
In 1988, Kazmierczak et al18 reported that the serum amylase levels
were elevated in 49.5% of 101 patients following cardiac surgery and the amylase
was usually of the salivary type. They showed a significant correlation between
postoperative hyperamylasemia and the size of the pleural effusions and hypothesized
that saliva, with its high amylase level, was aspirated during anesthesia
and subsequently absorbed systemically. They did not measure pleural fluid
amylase levels. The present study documents that the vast majority of effusions
after CABG do not have a high amylase level.
ROUTINE MEASUREMENT
Several authors recommend routinely measuring pleural fluid amylase
levels in all exudative effusions.1, 2, 3, 4, 5
This study suggests problems with this diagnostic approach. Elevated pleural
fluid amylase levels are most common in, and therefore most potentially helpful
with, the diagnosis of pancreatitis, esophageal rupture, and malignant disease.
The history, physical examination, and serologic studies associated with acute
pancreatitis usually suggest this diagnosis without further confirmatory studies.
Pleural effusion complicating chronic pancreatitis can be more difficult to
identify, however, and the finding of elevated pancreatic amylase level in
this fluid can therefore be helpful. This test lacks the sensitivity to serve
as a screening study for malignancy. Therefore, apart from a pretest suspicion
of pancreatic disease or esophageal rupture, it is difficult to justify the
routine measurement of pleural fluid amylase levels.
LIMITATIONS OF THE STUDY
The current study is limited by several factors. The prevalence of amylase-rich
effusion is lower than in previous series, which may reflect either a selection
bias because our population had a disproportionate number of post-CABG pleural
effusions, or some systematic error in measurement of amylase levels. We did
not routinely measure serum amylase levels to determine pleural fluid to serum
amylase ratios, nor did we determine amylase isoenzymes levels in the samples
with elevated levels.
In conclusion, the present study, along with the previous studies on
the measurement of pleural fluid amylase levels, suggests that the routine
measurement of pleural fluid amylase levels is not indicated. Certainly, a
pleural fluid amylase level should be obtained for patients with pleural effusions
who are suspected of having esophageal rupture, because an elevated pleural
fluid amylase level is a sensitive test for this diagnosis. In like manner,
patients with chronic pleural effusions with high lactate dehydrogenase levels
or who appear to have a malignancy but who have negative pleural fluid cytologic
findings should have their pleural fluid amylase level measured to rule out
a chronic pancreatic pleural effusion before an invasive diagnostic procedure
such as thoracoscopy is undertaken.
AUTHOR INFORMATION
Accepted for publication July 20, 2000.
This study was supported in part by the St Thomas Foundation, Nashville,
Tenn, and by grant HL 07123 from the National Institutes of Health, Bethesda,
Md.
From the Division of Allergy, Pulmonary and Critical Care Medicine,
Department of Medicine, Vanderbilt University (Drs Branca and Light), and
Pulmonary Disease Program, Department of Medicine (Drs Rodriguez, Ayo, and
Light and Mr Rogers), and Department of Radiology (Dr Moyers), St Thomas Hospital,
Nashville, Tenn.
Corresponding author: Richard W. Light, MD, Director of Pulmonary
Disease Program, St Thomas Hospital, PO Box 380, 4220 Harding Rd, Nashville,
TN 37202 (e-mail: rlight98{at}yahoo.com).
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