Cryoglobulinemia

Epidemiology

Cryoglobulins are immunoglobulins that precipitate in the cold and disolve on rewarming

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

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

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

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
  - Dyspnea
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

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