A. Classification

1. Type I
   1. Monoclonal Protein (25-40%), usually IgM or IgG
   2. Mycoplasma infection, Myeloma, Macroglobulinemia
   3. Myelodysplastic / Lymphoproliferative Syndromes
   4. Angioimmunoblastic Lymphadenopathy
2. Type II
   1. Mixed Cryoglobulinemia
   2. IgM usually monoclonal, with Rheumatoid Factor (RF, anti-IgG) activity
   3. Polyclonal immunoglobulins (Igs) also present
   4. ~90% of cases associated with Hepatitis C Virus (HCV), most often genotype 2a/3 [3]
3. Type III
   1. Mixed Cryoglobulinemia
   2. Both IgM and IgG are polyclonal
   3. IgM component has RF (anti-IgG) activity

B. Etiology of Mixed Cryoglobulinemia

1. Infections [1,3]
   1. Viral: HCV in ~90% of cases; Hepatitis B Virus (HBV) > Hepatitis A virus (HAV), EBV, CMV
   2. Hepatitis GB Virus frequently found, but unlikely to play etiologic role [4]
   3. Bacterial: endocarditis, post-streptococcal nephritis, leprosy, syphilis, Lyme Disease
   4. Parasitic: toxoplasmosis, echinococcus
2. Lymphoproliferative Disease
   1. Macroglobulinemia
   2. Chronic Lymphocytic Leukemia
   3. Non-Hodgkin's Lymphoma (NHL) usually associated with HCV infection
3. HCV Associated Lymphoproliferation [2]
   1. 76% of HCV+ patients with mixed cryoglobulinemia had bcl-2 rearrangements
   2. Rearranged Bcl-2 genes t(14;18) most common finding in human lymphomas
   3. Bcl-2 rearrangements more common in Type II (85%) than Type III (65%) disease (all HCV+)
   4. High ratio of bcl-2 to Bax in patients with bcl-2 rearrangement
   5. Bcl-2 rearrangement disappeared after therapy
4. Collagen Vascular Disease
   1. Systemic Lupus Erythematosus (SLE)
   2. Polyarteritis Nodosa (PAN)
   3. Rheumatoid Arthritis
   4. Sjogren's Syndrome
   5. Progressive Systemic Sclerosis
   6. Overlap Syndromes
5. Miscellaneous
   1. Chronic Liver Disease
   2. Sarcoidosis
   3. Proliferative Glomerulonephritis
6. Intestinal Bypass

C. Symptoms [5,6]

1. Present in only ~50% of patients
   1. Usually due to immune complex deposition
   2. Hyperviscosity and occlusive symptoms also occur
2. Recurrent purpura > petechiae (vaso-occlusive)
3. Weakness and arthralgias (polyarthritis) common
4. Digital Ischemia
   1. Raynaud's phenomenon
   2. Ulcers
   3. May progress to gangrene
5. B Cell Lymphoproliferation
   1. Lymphadenopathy
   2. Splenomegaly
   3. Hepatomegaly
6. Renal Dysfunction
   1. Pathology shows membranoproliferative glomerulonephritis
   2. Rapid renal deterioration may occur with emergent plasmapheresis required
7. Hemolytic Anemia
8. Peripheral neuropathy, mononeuritis multiplex
9. Cold-induced urticaria
10. Clotting of blood below body temperature
11. Diffuse vasculitis

D. Treatment of Mixed Cryoglobulinemia [1]

1. Cases associated with HCV [5,6]
   1. Treatment of HCV appears to improve symptoms of cryoglobulinemia [7]
   2. Combination of Peg-Interferon alpha with ribavirin is standard of care
   3. Antiviral therapy can lead to disappearance of cryoglobulins
2. Emergent Plasmapheresis [5]
   1. For hyperviscosity syndrome and/or progressive renal failure
   2. Hyperviscosity often with retinal "box-car" findings ± ocular symptoms
   3. Removes Ig temporarily
   4. Must be followed by immunosuppressive agent (unless HCV involved)
3. Immunosuppressive Treatment
   1. Alkylating agents such as cyclophosphamide or melphalan used for further treatment
   2. Combination with glucocorticoids often used
   3. Mycophenolate mofitel (Cellcept®) 1gm po bid may be used in moderate caess
   4. Rituximab (Rituxan®), an anti-B cell monoclonal antibody, has also been used

E. Treatment of Idiopathic Cryoglobulinemia

1. Plasmapheresis is mainstay of therapy for hyperviscosity syndrome
2. Prednisone in low doses is effective in some patients with this disease
3. In general, a bone marrow biopsy should be considered to assess for neoplastic cells
4. Alkylating agents (melphalan, busulfan, cyclophosphamide) may be added
5. Treatment for lymphoma may be beneficial, including rituximab

References

1. Kay J and McCluskey RT. 2005. NEJM. 353(15):1605 (Case Record)
2. Zignego AL, Ferri C, Giannelli F, et al. 2002. Ann Intern Med. 137(7):571
3. Zignego AL, Ferri C, Giannini C, et al. 1996. Ann Intern Med. 124(1):31
4. Misiani R, Mantero G, Bellavita P, et al. 1997. Ann Intern Med. 127(10):891
5. Prasad M, Buller GK, Mena CI, Sofair AN. 2006. NEJM. 355(23):2468 (Case Discussion)
6. Menkes DL, Palmer-Toy DE, Hedley-Whyte ET. 1999. NEJM. 340(4):300 (Case Record)
7. Guillevin L, Lhote F, Gherardi R. 1997. Curr Opin Rheumatol. 9(1):31