What are the causes of raised plasma viscosity in adults, particularly older adults?

Causes of Raised Plasma Viscosity

Raised plasma viscosity is primarily caused by monoclonal gammopathies (particularly Waldenström macroglobulinemia and multiple myeloma) and less commonly by polyclonal hypergammaglobulinemia from chronic inflammation, liver disease, or autoimmune disorders.

Monoclonal Gammopathies (Primary Causes)

Waldenström Macroglobulinemia

• IgM monoclonal protein is the most common cause of clinically significant hyperviscosity, occurring in 10-30% of patients with Waldenström macroglobulinemia 1, 2, 3.
• IgM is a pentamer with large molecular size, making it particularly prone to causing hyperviscosity at lower concentrations than other immunoglobulins 1, 2.
• Symptomatic hyperviscosity typically occurs when serum IgM levels reach ≥3 g/dL, corresponding to plasma viscosity >4.0 centipoise 1, 2, 4.
• Many patients exhibit elevated serum viscosity >1.8 centipoise, though symptoms usually manifest at >4.0 centipoise 1.

Multiple Myeloma

• IgG and IgA myelomas cause hyperviscosity in only 2-6% of cases, making this a less common presentation than in Waldenström macroglobulinemia 1, 2, 4.
• IgG myeloma requires paraprotein levels >15 g/dL (or >4-5 g/dL for polymerized IgG3) to produce symptomatic hyperviscosity 4.
• IgA myeloma requires levels >10-11 g/dL (or >6-7 g/dL for polymerized IgA) to cause hyperviscosity 4.
• Less than 2% of multiple myeloma patients present with hyperviscosity at diagnosis 1.

IgM Monoclonal Gammopathy of Undetermined Significance (MGUS)

• IgM MGUS can produce elevated plasma viscosity when M-protein levels are elevated, though typically without the severe hyperviscosity seen in Waldenström macroglobulinemia 1.
• Defined by M-protein <30 g/L and bone marrow plasma cells <10% without end-organ damage 5.

Polyclonal Hypergammaglobulinemia (Secondary Causes)

Chronic Inflammatory and Infectious Conditions

• Chronic immune activation from persistent inflammation or infection stimulates multiple B-cell clones, producing polyclonal increases in immunoglobulins 5.
• Bronchiectasis commonly shows polyclonal rises in serum IgG and IgA reflecting ongoing infection and inflammation 5.
• A few cases of hyperviscosity syndrome have been reported with polyclonal hypergammaglobulinemia, though this is rare 6.

Liver Disease

• Chronic liver disease causes polyclonal hypergammaglobulinemia through impaired clearance and chronic immune stimulation 5.

Autoimmune Disorders and Vasculitis

• Autoimmune conditions produce chronic immune activation with polyclonal B-cell stimulation 5.
• These typically cause less severe viscosity elevation than monoclonal gammopathies 5.

Factors Contributing to Hyperviscosity Beyond Protein Concentration

Immunoglobulin Characteristics

• Molecular size, shape, and polymerization properties determine viscosity more than absolute concentration alone 6, 2, 4.
• Asymmetrical or cryosensitive paraproteins aggregate into hyperviscous macroaggregates 6.
• IgM's pentameric structure (molecular weight ~900 kDa) makes it 5-10 times more viscogenic than IgG 2, 4.

Cryoglobulins and Cold Agglutinins

• Up to 20% of Waldenström macroglobulinemia patients have monoclonal IgM behaving as type I cryoglobulin, though <5% are symptomatic 1.
• Fewer than 10% of Waldenström macroglobulinemia patients have cold agglutinin activity with titers >1:1,000 1.
• The presence of cryoglobulins or cold agglutinins may affect IgM level determination and contribute to viscosity 1.

Red Blood Cell Aggregation

• Intense red cell aggregation caused by paraproteins significantly contributes to whole blood viscosity beyond plasma viscosity alone 6, 4.
• This combined effect of plasma hyperviscosity and erythrocyte aggregation causes severe microcirculatory impairment 6.

Plasma Volume Expansion

• Significant plasma volume expansion accompanies paraproteinemia and contributes to the hyperviscosity syndrome 6, 4.

Clinical Threshold Values

• Normal plasma viscosity: 1.1-1.4 centipoise (or 1.4-1.8 centipoise by some references) 1, 7.
• Elevated but often asymptomatic: 1.8-4.0 centipoise 1.
• Symptomatic hyperviscosity typically begins at >4.0-5.0 centipoise 1, 2, 4.
• Some patients develop retinal changes and hemorrhages at lower viscosity levels, necessitating intervention 1.

Important Clinical Pitfalls

• Serum viscosity results should not be used as the sole criterion for intervention due to long turnaround time, potential technical issues, and poor correlation with individual symptom severity 1.
• Fundoscopic examination showing venous engorgement (sausaging) of retinal veins is more reliable than viscosity measurement for assessing clinically relevant hyperviscosity 1.
• The presence of cold agglutinins or cryoglobulins may falsely affect IgM level determination; samples should be maintained in a warm bath for accurate measurement 1.
• Rituximab can cause IgM flare, temporarily increasing viscosity; plasmapheresis should be considered before rituximab in patients with IgM ≥5,000 mg/dL 1.