Pathophysiology
Synovial fluid is in varying amounts in the joint space and consists of hyaluronic acid, glucose, proteins, lipids, electrolytes, enzymes, and cells. Its main functions are hydration and lubrication of the joint; it also provides a means for the passage of nutrients to the cartilage tissue. Synovial fluid is produced by ultrafiltration of peripheral blood through the synovium and the synthesis of hyaluronic acid by synovial cells.
Normal synovial fluid has the following characteristics: high viscosity, clarity and an opaque yellow color, low erythrocyte and leukocyte cellularity, with a predominance of lymphocytes and monocytes or macrophages; the neutrophil count is less than 10%. Normal synovial fluid is free of crystals and fibrinogen, and is sterile. Synovial fluid and its characteristics vary in different clinical conditions; its analysis can provide the clinician (orthopedist or internist) with helpful information to clarify the etiology of a joint pathology or its evolution.
Macroscopic Evaluation, Crystal Detection, and Cellular Analysis
Synovial fluid is collected through arthrocentesis in quantities of 3–5 mL.
Normal synovial fluid is generally light yellow, transparent, and viscous. In cases of rheumatic or infected effusions, it may be turbid; sometimes it may have a hemorrhagic appearance.
The search for crystals in synovial fluid is helpful in differential diagnostics; both the qualitative nature of the crystals and their semi-quantitative evaluation (rare, a few, or numerous) are of considerable clinical interest. The main constituents are monosodium urate (acute or chronic gout); calcium pyrophosphate (pseudogout or chondrocalcinosis); apatite (pre-articular calcification); and cholesterol crystals can also be found in joint effusions of subjects with chronic rheumatism.
The cell count in synovial fluid takes on different characteristics depending on the pathology involving the joint.
Bacterial Arthritis
Synovial fluid has a purulent appearance, and the cellular component consists predominantly of neutrophils, even in concentrations greater than 100,000 × 106/L cells. In Reiter’s syndrome (often associated with Chlamydia trachomatis infection), synovial fluid has a cellularity of approximately 40,000 × 106 cells/L, with 80% neutrophils. Occasionally, Reiter cells (macrophages with basophilic cytoplasmic inclusions with panoptic staining) are also present.
Rheumatoid Arthritis
The average cell count in this disease is 30,000 × 106/L cells, which varies according to the disease phase. During the acute phase, lymphocytes and macrophages prevail, which are not pathognomonic of rheumatoid arthritis because they can also be found in other joint diseases.
Acute Joint Rheumatism
Synovial fluid is rich in fibrin, with lymphocytes, histiocytes, and sometimes synoviocytes predominating. The average cell count is 10,000 × 106/L cells.
Systemic Lupus Erythematosus
Synovial fluid is straw-colored, and the predominant cells are lymphocytes, in variable numbers. The characteristic cell is Hargraves’ cell, or LE: a neutrophil twice or thrice the normal size with an eccentric nucleus surrounding an inclusion that appears red on panoptic staining. The average cell count is 12,000 × 106/L cells.
Gout
In the acute phase, the synovial fluid may appear cloudy to milky. Fresh urate crystals, with the appearance of needles or rods, can be observed either free or in the cytoplasm of neutrophils. The average cell count is 15,000 × 106/L cells, and neutrophils are the predominant cell population, followed by synoviocytes.
Pseudogout or Chondrocalcinosis
The synovial fluid is similar in cellular composition and appearance to that of gout, but the crystals are of calcium pyrophosphate, either in free form or phagocytosed. They are distinguishable by their rhomboidal shape and inhomogeneous size compared to urate crystals.
Traumatic Arthropathy
Synovial fluid is hemorrhagic or xanthochromic in color, with poor cellularity (average cell count <2000 × 106/L cells), predominantly neutrophils, sometimes also tissue cells such as chondrocytes or bone chips and connective tissue.
Villonodular Synovitis
It is a rare benign tumor of the synovial membrane, in which the synovial fluid is serohemorrhagic or brown, with few cellular elements ( <3000 × 106/L cells), mainly histiocytes with, within them, hemosiderin, and sometimes plurinucleated giant cells.
Primary or Secondary Neoplastic Arthritis
The fluid is serohemorrhagic with poor cellularity (mean cell count <2000 × 106/L), possible presence of “foreign” cellular elements typical of the histotype of the primary tumor.
Prosthetic Infections
In orthopedics, cytometric analysis of synovial fluid is essential for the differential diagnosis between periprosthetic infections and other non-infectious diseases.
Many studies propose different decision thresholds, both for the leukocyte count and for the relative value of neutrophils and/or polymorphonucleates; unfortunately, the decision cutoffs are often not concordant, and this limitation has repercussions in clinical practice.
Pathological synovial fluid can be divided into four categories, as shown in Table 1.
Table1. Main laboratory tests on the synovial fluid and related interpretative criteria
Biochemistry
Although not routinely measured on synovial fluid, some measurands, such as glucose, uric acid, lactic acid, lipids (cholesterol and triglycerides), proteins, and some enzymes may be helpful in selected cases. Table 2 shows the reference values of the main measurands in synovial fluid.
Table2. Reference values for the main biomarkers in the synovial fluid
Proteins are generally >3.0 g/dL in any type of inflammatory process, thus they have little diagnostic or prognostic usufulness.
Cholesterol and Triglycerides
The concentration of lipoproteins in synovial fluid is, on average, 40% lower than in plasma. In inflammatory processes and in crystal-induced arthritis (rheumatoid arthritis, SLE, gout), their levels increase significantly. Lipid effusions have been roughly divided into three groups: cholesterol- rich, lipid droplets, and chylous.
In synovial effusions, cholesterol can reach concentrations as high as 2600 mg/dL.
Chylous synovial effusions may be observed, rarely, in association with rheumatoid arthritis, SLE, trauma, filariasis, and pancreatitis (pancreatic-arthritic syndrome).
Glucose
The glucose level should be interpreted against the blood glucose level. Transient postprandial hyperglycemia is not reflected until several hours later in a physiologic increase in synovial fluid glucose. At equilibrium, normal synovial glucose is 10 mg/dL lower than plasma glucose, or even less. In general, in non-inflammatory or hemorrhagic joint diseases (osteoarthritis, villonodular synovitis pigmentosa, trauma, hemangioma, etc.), glucose may be, respectively, 10 and 20 mg/dL less than in plasma. In inflammatory diseases, instead, the distance between plasma glucose and joint glucose can vary from 0 to 40 mg/dL, while in infectious synovial forms, glucose can be 20–100 mg/dL less than in plasma; to a lesser extent (from 0 to 80 mg/dL), this is observed in crystal-induced forms.
Lactic Acid
The upper reference limit of the lactic acid is 25–30 mg/dL.
There is ample evidence that synovial fluid lactic acid is generally increased in monoarticular septic arthritis compared to non-septic forms.
In septic arthritis, lactic acid can reach concentrations of 1170 mg/dL, 40 times the value of the upper reference interval, contrary to what happens in degenerative forms. However, it has been observed that lactic acid does not always increase in bacterial forms; an example is Neisseria gonorrhoeae form. This bacterium does not induce an increase in synovial lactic acid. In general, a lactic acid >110 mg/dL indicates a septic form.
Uric Acid
The definitive diagnosis of gout is based on microscopic observation of monosodium urate crystals in synovial fluid.
Uric acid assay on synovial fluid proves to be a valuable aid in the definitive diagnosis of gout. The decision limits for the diagnosis are moderately controversial. For some authors, there is a substantial equivalence between the serum concentration of uric acid compared to the synovial fluid; for others, instead, its values in gout are higher than in the serum, thus constituting a situation without interpretative uncertainties. Probably both observations are true, due to a dynamic balance between the constitution and dissolution of crystals that would be reflected on the concentration of uric acid in this fluid.
Enzymes
Numerous enzymes have been studied in synovial fluid dis orders: LDH, aspartate aminotransferase (AST), ALP, γ-glutamyltransferase, ADA, neuraminidase (lysozyme), cytidine deaminase, and several others. Their presumed clinical utility has not always been confirmed in practice. Among the enzymes of proven diagnostic help, LDH certainly stands out. Values between 400 and 700 U/L suggest a moderate- medium inflammatory state, while values >700 U/L strongly indicates severe inflammatory state.
C-Reactive Protein (CRP)
When the inflammatory phenomenon is very circumscribed, in particular clinical pictures, assaying the CRP in a biological fluid can be of considerable diagnostic and prognostic help as in the case of joint infections following implantation of prostheses, representing a more powerful tool than the same imaging.
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