Epidemiology
Physiology
- Cryoglobulins are immunoglobulins that precipitate in the cold and disolve on rewarming
Three Types of Cryoglobulins
- Type I Cryoglobulin: monoclonal antibody that does not have rheumatoid factor activity
- Associated with lymphoma, Waldenström’s macroglobulinemia, and multiple myeloma
- Because type I cryoglobulins do not easily activate complement, patients with type I are asymptomatic until the level of cryoglobulinemia is sufficiently high to cause hyperviscosity syndrome
- Type II Cryoglobulin: monoclonal rheumatoid factor (antibody that binds to the Fc fragment of IgG)
- Associated with lymphoproliferative diseases, rheumatic diseases, and chronic infections (HCV > HBV)
- Type III Cryoglobulin: polyclonal rheumatoid factor (antibody that binds to the Fc fragment of IgG)
- Associated with rheumatic diseases and chronic infections
Essential Cryoglobulinemia
- When disease occurs without an associated predisposing condition
Mixed Cryoglobulinemia
- Refers to type II and III cryoglobulinemia
- Mixed Cryoglobulinema frequently presents as hypersensitivity (leukocytoclastic) vasculitis
- Most patients diagnosed with type II or type III mixed essential cryoglobulinemia have the disease as an immune response to chronic hepatitis C infection (and less commonly, hepatitis B)
- The role of hepatitis C virus is suggested by finding that the cryoglobulins in these patients are enriched with anti–hepatitis C antibody and hepatitis C RNA
- Moreover, antviral therapy can remit the disease in some patients
Diagnosis
- PFT’s
- Increased DLCO: during active diffuse alveolar hemorrhage
- Open Lung Biopsy (OLB)
- Tissue Ab staining: granular pattern (IgG)
- CXR/Chest CT Patterns
- Interstitial infiltrates: may appear due to ILD or chronic/ recurrent DAH
- Diffuse or patchy focal alveolar infiltrates: seen in cases with DAH
- Serology
- ANA/RF: variable
- Anti-DNA/ANCA/Anti-GBM: negative
- C3/C4/CH50: decreased-normal
- Cryocrit (need to deliver warm to lab): positive
- HBsAg:
- ESR: usually elevated
- CBC: anemia (iron deficiency) is usually present/leukocytosis
- Urinalysis: abnormal
- Renal Bx: proliferative glomerulonephritis, crescents
- Immunofluorescence: positive, granular
Clinical Presentations (vary based on types of cryoglobulins)
Type I Cryoglobulinemia
Type II/III Cryoglobulinemia
- Arthritis (see Arthritis, [[Arthritis]])
- Dermal Hypersensitivity (Leukocytoclastic) Vasculitis (see Vasculitis, [[Vasculitis]])
- Diagnosis
- Pathology: dermal leukocytoclastic vasculitis -> perivascular polymorphonuclear infiltration with tissue extravasation and fragmentation in the dermis
- Clinical
- Splinter Hemorrhages
- Recurrent Lower Extremity Purpura (see Purpura, [[Purpura]])
- Interstitial Pulmonary Fibrosis (see Interstitial Lung Disease-Etiology, [[Interstitial Lung Disease-Etiology]])
- Epidemiology: most common pulmonary manifestation
- Physiology: likely due to immune complex-mediated systemic vasculitis
- Diagnosis:
- Pathology: inflammation and fibrosis of alveolar walls
- Clinical
- Diffuse Alveolar Hemorrhage (DAH) (see Diffuse Alveolar Hemorrhage, [[Diffuse Alveolar Hemorrhage]])
- Epidemiology: extremely rare (only a few reported cases)
- Diagnosis
- Pathology: pulmonary capillaritis
- Clinical: symptoms usually present for only days-weeks before presentation
- Chest Pain
- Cough
- Dyspnea
- Hemoptysis: may be absent initially in some cases even after significant bleed
- Glomerulonephritis (see Chronic Kidney Disease, [[Chronic Kidney Disease]])
- Neuropathy (see Peripheral Neuropathy, [[Peripheral Neuropathy]])
- Hepatitis
Treatment
Treatment of Type I Cryoglobulinemia-Related Hyperviscosity
- Plasmapheresis
- Chemotherapy (if associated with an underlying malignancy)
Treatment of Type II/III (Mixed) Cryoglobulinemia-Related Vasculitis
Treatment of Type II/III (Mixed) Cryoglobulinemia Associated with Hepatitis C
- Brief use of prednisone, followed by 6 mo of interferon alfa has produced clinical and liver function test improvement
- However, relapse of liver disease and vasculitis often occurs when interferon alfa is stopped
References