Pleural and peritoneal fluids

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Q: We are looking for information regarding reference ranges for Pleural Fluid for Total Protein, LD, Glucose, Amylase, pH, Cholesterol, and Triglyceride, Peritoneal Body Fluids for Albumin, Total Protein, and Amylase. Do you have any published reference ranges for these body fluids?

A: The standard format used in establishing reference ranges for all various serous body fluids has not been well established. And of those references published, the literature shows some variation in what is considered “normal.” Unlike taking a blood sample that is analyzed to see if there is some abnormality, the need to obtain other body fluids for diagnostic reasons generally implies that there is an existing medical problem.

Pleural effusions
Pleural Fluid (PF) is normally found in the space between the lung and the chest wall (normal amounts are estimated to be between 10 and 20mL) and is similar in biochemical composition to plasma.¹ However, excess PF can accumulate due to a number of different disorders resulting in a pleural effusion (PE) and is obtained through a procedure called thoracentesis. Approximately 1.3 million individuals in the United States are diagnosed with a PE each year.²

PEs may be classified as a transudative PE or as an exudative PE. A transudative PE may occur during systemic illnesses such as heart failure, cirrhosis (with ascites), or hypoalbuminemia (due to nephrotic syndrome), whereas exudative PE results from some abnormal local process, such as pneumonia, cancer, pulmonary embolism, and viral infection.^1,3

While a reference range for PF is not as clear-cut as that seen with other clinical laboratory tests, in general, normal PF may show the following:

• Appearance: Mostly clear, straw-colored, and odorless
• pH of 7.60 to 7.64
• Protein content of less than 1 to 2 g/dL
• Fewer than 1,000 WBC/µL
• Glucose level similar to that of plasma
• Lactate dehydrogenase (LD) of less than half that found in plasma.⁴

Light’s criteria is commonly used in evaluating abnormal PEs.^2,5 According to Light’s criteria, a PE exudate is present if one or more of the following exists:⁵

• PE protein: Serum protein ratio >0.5
• PE LD: Serum LD ratio >0.6
• PE LD: >2/3 of the upper limit of serum LD reference range

If none of these criteria are present, the PE is considered a transudate.¹ In general, Light’s criteria correctly identify exudates but may misclassify 20 percent to 25 percent of transudates as exudates.^1,3,4

Visual examination of exudative PEs may show turbidity and may be milky, hemorrhagic, or greenish in color. Evaluation of a PE exudative studies have shown:^3,4,6

• LD levels >0.45 of the upper limit of normal serum values
• Protein level >2.9 g/dL
• Cholesterol level >45 mg/dL
• Triglycerides >110 mg/dL
• Albumin gradient (serum albumin minus PE albumin) <12g/L for exudates and >12g/L for transudates
• WBC >500 /µL
• Hematocrit of PE is >50 percent of peripheral blood hematocrit, patient has hemothorax
  pH of 7.44 to 7.30
• PF Amylase: Serum amylase ratio >1
• PF Creatinine: Serum creatinine >1
• Transudate effusions: 6
• Appearance: Tends to be clear yellow in color
• Nucleated cells: Fewer than 500 nucleated cells/µL
• PE LD: Serum LD (upper normal limit): Ratio is <0.67
• Glucose: Level similar to serum glucose level
• Cholesterol: Less than 520mg/L
• pH of 7.45 to 7.55

Some additional analytes have also been noted to be of some value in evaluating pleural effusions. N-terminal pro-brain natriuretic peptide (NT-proBNP) has been shown to be elevated in heart failure (>1,300-4,000 ng/L). Effusions with elevated LD levels (>1,000IU/L) have been associated with empyema, malignancies, rheumatoid effusions, paragonimiasis (lung fluke), and Pneumocystis jiroveci (formally P carinii). Decreased glucose levels in PE have been seen in malignancies, tuberculosis, esophageal rupture, and lupus.⁴

The presence of biomarkers, such as carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), CA 125, CA 19-9, alpha-fetoprotein (AFP), CYFRA 21-1, and osteopontin, has been shown to differentiate between malignant and benign PE. Pancreatic disease may show elevated amylase level in PE and may reach levels of 100,000 IU/L.⁶

Lymphocytosis (>85 percent of nucleated cells) is seen in tuberculosis, lymphoma, sarcoidosis, and several other disorders. Eosinophilia (>10 percent of nucleated cells) may be encountered in cases of pulmonary embolism, benign asbestos PE, parasitic diseases, fungal infections, and with certain medications. Other testing that might be done may include cultures/Gram stains if infectious disease is involved or immunologic studies (such as ANA, RF) when autoimmune processes may be involved.⁴

Peritoneal fluids
The peritoneum consists of serous membranes that line the peritoneal cavity through a network of mesothelial cells and collagen.⁸ Pathologic accumulation of peritoneal fluid results in ascites fluid (obtained through peritoneocentesis) that is generally submitted to the laboratory for evaluation.⁹ The amount of peritoneal fluid normally present is 5mL to 20mL, but may be as much as 50mL, particularly in women during ovulation.^8,9

Similar to PF, reference ranges are generally not published as part of standard clinical laboratory guidelines. However, some cut-off values have been determined as to what one might find in normal fluids.^9-12

• Specific gravity: <1.016
• Protein: 3g/dL
• Glucose: similar to blood glucose
• Amylase: similar to blood amylase
• BUN: similar to blood BUN
• WBC: <500/µL
• pH of 7.5 to 8

Peritoneal fluid is often clear and/or slightly yellowish in color. A cloudy, turbid color suggests an infection, while a milky color suggests an inflammatory condition such as peritonitis, pancreatitis, or appendicitis. A red color is consistent with a traumatic tap (specimen has clots) or malignancy (non-traumatic tap has no clots). A greenish color has been associated with a ruptured gall bladder, pancreatitis, or intestinal perforation.^10,11

Peritoneal fluids may also be identified as an exudate or a transudate. Exudates are most often associated with infections, neoplasms, trauma, pancreatitis, or ruptured gall bladder. Transudates may be caused by congestive heart failure, hepatic cirrhosis, or hypoproteinemia (nephrotic syndrome). Peritoneal fluid resulting from an inflammatory condition generally contains an increased number of WBCs that are predominately neutrophils and reactive mesothelial cells. Transudates often will show more lymphocytes.^9,11

The serum-ascites albumin gradient (SAAG) is a reasonably reliable way to differentiate between transudate and exudate fluids (serum albumin minus the ascitic albumen level). Transudates, as found in portal hypertension, exhibit a SAAG level of 1.1 g/dL or greater, whereas, values less than 1.1 g/dL are seen in patients with normal portal pressure and with ascitic exudates.^7,9

Some additional tests to consider in the evaluation of ascites fluids: ^9,11,12

Tumor markers (CEA, CA 19-9, CA 15-3, PSA) may also be of some value when evaluating ascites fluid for the presence of certain malignant cells. CA-125 may be elevated in peritoneal fluid samples from patients with ovarian, fallopian, or endometrial carcinomas. It should be noted that it may also be positive in certain non-malignant disorders such as cardiovascular or chronic liver diseases.⁹

Each laboratory should carefully review the literature and make individual determinations in developing guidelines in assessing all body fluids. Collaboration with clinicians is often the best approach in establishing these guidelines so that appropriate diagnostic algorithms are developed to include laboratory testing, imaging studies, and the clinical presentation when diagnosing and managing patients with effusions.

REFERENCES

1. Kaplan JL, Porter RS, eds. Mediastinal and Pleural Disorders. In: Merck Manual of Diagnosis and Therapy, 19th ed. (2011) Whitehouse Station, NJ. Merck Sharp & Dohme Corp. Chapter 204.
2. Sahn SA, Huggins JT, San Jose E, et al. The art of pleural fluid analysis. Clin Pulmon Med. 2013; 20(2):77-96.
3. Light RW. Disorders of the Pleura. In:  Harrison’s Principles of Internal Medicine, 19th ed. (2015). Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J. eds. New York, NY: McGraw-Hill; Chap 316.
4. Rubins J. Pleural effusion work-up. Medscape. 2014. http://emedicine.medscape.com/article/299959-workup.
5. Lamberg JJ. Light’s criteria. Medscape. 2014. http://emedicine.medscape.com/article/2172232-overview. Accessed February 28,, 2016.
6. Sahn SA. Getting the most from pleural fluid analysis. Review. Respirol. 2012;17:270-277.
7. Kopcinovic LM, Culej J. Pleural, peritoneal, and pericardial effusions – a biochemical approach. Biochemia Medica. 2014;24(1):123-137. http://www.biochemia-medica.com/2014/24/123.
8. Brady M, Mahoney E. Peritoneal Cavity. In: Doherty GM. eds. CURRENT Diagnosis & Treatment: Surgery, 14 ed.(2015) New York, NY: McGraw-Hill; Chapter 22.
9. Karcher DS, McPherson RA. Cerebrospinal, synovial, serous body fluids, and alternative specimens. In: Henry’s Clinical Diagnosis and Management by Laboratory Methods, 22nd ed. (2011) Philidelphia:Elsevier/Saunders. Chapter 29.
10. Shah R. Ascites workup. Medscape. http://emedicine.medscape.com/article/170907-workup#c3.
11. Bhutta RA, Syed NA, Ahmad A. Peritoneal fluid analysis: Ascitic fluid analysis, Peritoneal tap or abdominal paracentesis, or abdominal tap, part 3. http://www.labpedia.net/test/227.
12. 2015-2016 Clinical Laboratory Reference. MLO. http://www.clr-online.com/.

Editor’s note: Anthony Kurec, MS, H(ASCP)DLM, is Clinical Associate Professor, Emeritus, at SUNY Upstate Medical University in Syracuse, NY. He is also a member of the MLO Editorial Advisory Board.