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type 2 (mixed) cryoglobulinemia
Disease characterized by recurrent episodes of purpura, arthralgias, weakness & multiorgan involvement. Similar to type 3 (mixed) cryoglobulinemia.
Etiology:
1) frequently associated with:
a) chronic infection
b) hepatitis B
c) hepatitis C (> 80-90%)
d) HIV1 [3]
e) autoimmune disorders
1] systemic lupus erythematosus
2] vasculitis
3] Sjogren's syndrome
f) lymphoproliferative disorders
1] Waldenstrom's macroglobulinemia
2] B-cell non_Hodkins's lymphoma, chronic lymphocytic leukemia
2) essential or idiopathic cryoglobulinemia is generally due to hepatitis C [3]
Pathology:
1) deposition of immune complexes
a) polyclonal immunoglobulins + monoclonal IgM or IgA [3]
b) generally IgM kappa with anti-immunoglobulin specificity (rheumatoid factor)
c) rheumatoid factor is monoclonal*
d) other components:
1] hepatitis C antigen
2] other infectious agents
3] cellular & nuclear antigens
4] complement
2) present in smaller quantities than type 1 globulins (50-500 mg/dL)
3) cryoglobulins disappear when infection resolves
4) non-systemic, small vessel vasculitis
- occurs secondary to immune complex deposition & complement fixation on surface of endothelial cells
5) histopathology of vascular structures similar to leukocytoclastic vasculitis
* Distinguishes type 2 from type 3
Clinical manifestations:
1) recurrent symptoms
2) common
a) local & systemic small vessel vasculitis
- lower extremity palpable purpura 60%
- urticaria
- cutaneous ulceration NOT a feature
- skin ulcers & necrosis [3]
- CNS vasculitis [3]
- gastrointestinal vasculitis
b) arthralgias & arthritis (15-20%)
c) peripheral neuropathy 5%
d) Raynaud's phenomenon 40%
5) acrocyanosis [3]
e) digital ischemia [3]
3) less common manifestations
a) focal segmental sclerosing glomerulonephritis
b) membranoproliferative glomerulonephritis
c) hepatomegaly
d) pulmonary manifestations (uncommon)
- diffuse pulmonary vasculitis
- alveolar hemorrhage
- bronchiolitis obliterans (BOOP)
- bronchiectasis
- pneumonitis
- pulmonary hemorrhage
e) serositis: pleurisy, pericarditis
f) thyroiditis
Laboratory:
1) blood collection & specimen processing
a) blood collected in pre-warmed tubes
b) kept at 37 degrees during clotting to keep cryoglobulins from precipitating with clot
c) serum separated from clot at 37 degrees
d) incubation at 4 degrees C for 72 hours
2) cryoglobulins in serum/plasma
- trace amounts of cryoglobulins may be found in normal individuals
3) serum protein electrophoresis & immunofixation elecrophoresis
- polyclonal IgG, monoclonal IgM rheumatoid factor [3]
4) serum complement levels (C1q-C4, CH50) are generally decreased
5) erythrocyte sedimentation rate is generally increased
6) rheumatoid factor is generally positive (monoclonal IgM)
7) hepatitis serology
a) frequently positive for hepatitis C
b) may be positive for hepatitis B
8) biopsy of vascular structures
Complications:
1) glomerulonephritis secondary to deposition of immune complexes (most common)
a) focal segmental glomerulonephritis
b) membranoproliferative glomerulonephritis [3,5]
2) hepatosplenomegaly
3) hepatic cirrhosis
4) pneumonitis
5) pulmonary hemorrhage
6) serositis
a) pleurisy
b) pericarditis
7) thyroiditis
8) lymphoproliferative disorder
Management:
1) therapy directed at underlying disease
- ledipasvir & sofosbuvir for treatment of hepatitis C [3]
2) idiopathic or essential cryoglobulinemia
a) prednisone
b) other immunosuppressive agents
Related
cryoglobulin
General
cryoglobulinemia (cryoglobulinemic vasculitis)
References
- Manual of Medical Therapeutics, 28th ed, Ewald &
McKenzie (eds), Little, Brown & Co, Boston, 1995, pg 527
- Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed)
Lippincott-Raven, Philadelphia, 1998, pg 610, 784, 849
- Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 15,
16, 17, 18. American College of Physicians, Philadelphia 1998, 2006,
2009, 2012, 2015, 2018.
- Brahn E, Scoville CD
Biochemical markers of disease activity.
Baillieres Clin Rheumatol 1988 2:153
PMID: 2458192
- Roccatello D, Fornasieri A, Giachino O et al
Multicenter study on hepatitis C virus-related cryoglobulinemic
glomerulonephritis.
Am J Kidney Dis. 2007 Jan;49(1):69-82.
PMID: 17185147
- Dammacco F, Sansonno D.
Therapy for hepatitis C virus-related cryoglobulinemic vasculitis.
N Engl J Med. 2013 Sep 12;369(11):1035-45.
PMID: 24024840