Cryoglobulinemie

Cryoglobulinemie

Cryoglobulines: antilichamen die precipiteren in vitro bij <37°C en oplossen bij opwarming.

Type cryoglobulines:

  • Type I: monoklonaal, meestal IgG of IgM (zelden IgA of lichte keten)

    • 40% MGUS

    • 60% Lymfoproliferatieve malignitieit: MM, Waldenström macroglobulinemia [WM] of chronic lymphocytic leukemia [CLL]).


  • Type II: mix van monoklonaal IgM met reumfactor (RF) en polyklonaal IgG.

    • 90%: geassocieerd met HCV. Overig: HIV, HBV, connective tissue diseases (CTDs) en lymfoproliferatieve ziekte (WM or other B-cell lymphomas)

    • 10%: "essential mixed cryoglobulinemia", dat wil zeggen geen onderliggend lijden

  • Type III: mix van polyklonaal IgM met RF en polyklonaal IgG

    • CTDs of secundair aan infectie (mn HCV)r secondary to infection (mainly HCV).

NB. Overall, cryoglobulins in mixed cryoglobulinemia result from a B-cell lymphoproliferative process in the setting of persistent immune activation triggered by chronic infection, autoimmune disease, or an unknown cause.

Diagnostiek

Cryoprecipitatie

  • Type I: snelle precipitatie bij 1-4°C, meestal binnen uren

  • Type II/III: vertraagde precipitatie, soms 7dg

Cryocrit: the relative volume of the precipitate as a percentage of the total serum volume.

  • Type I: hoog (soms meer dan 50%)

  • Type II/III: laag (meestal <5%)

NB. Correlation between the cryocrit and disease manifestations is poor, although higher cryocrit has been reported to increase the likelihood of symptomatic disease. The cryocrit was prognostic in a few studies. Overall, cryocrit use should be reserved for diagnosis because there is a poor correlation between the cryocrit and the response to treatment.

Immunofixatie

After cryoprecipitation, the precipitate is washed in a cold buffer and dissolved in a warm solution; electrophoresis and immunofixation are then performed to type the cryoglobulins. Immunofixation may not be feasible if the concentration of cryoglobulins is low.

RF en complement (C3, C4, CH50)

  • Type II/III: RF verhoogd en complement verlaagd.

Pathogenesis

Cryoprecipitation

The process of cryoprecipitation is not entirely understood and probably differs between type I and type II/III.

  • Type I: monoclonal component undergoes crystallization and aggregation, which is dependent on temperature and concentration. Although the definition of cryoglobulins is precipitation at cold temperatures, this process can occur at room temperature at high cryoglobulin concentrations. This probably explains why distal extremities (lower temperatures) and kidneys (increase in concentration as a result of ultrafiltration) are major sites of pathology.

  • Type II/III: cryoprecipitation takes place in the setting of immune complex formation between polyclonal IgG and IgM with RF activity and complement fixation. Cryoprecipitation cannot be induced by the IgM or IgG components separately and requires specific antigen-avidity IgG molecules. This underscores the unique properties of cryoglobulins and explains the high incidence of HCV as a cause.

Tissue injury

The mechanism of cryoglobulin pathogenicity is best described for HCV-associated cryoglobulinemia. HCV drives a clonal B-cell expansion, which secretes a monoclonal IgM that binds to polyclonal IgG molecules, which defines a RF. The IgM interacts with anti-HCV IgG to form immune complexes. These immune complexes bind via a C1q to C1q receptors receptor on endothelial cells, which promotes inflammatory cell recruitment and produces vasculitis. In contrast, the underlying pathogenesis of cryoglobulins in type I is small blood vessel occlusion with minimal inflammatory response.

Kliniek

Asymptomatisch tot ernstige eind-orgaanschade a.g.v. precipitatie in kleine-middelgrote vaten.

Symptoom Type I Type II/III

Purpura 70% 90%

Ulcera 30% 15%

Glomerulonefritis 30% 30%

Neuropathie 30% 30%

Artralgie 30% 25-40%

Hyperviscositeit* soms zelden, nooit in type II

* Symptoms suggestive of hyperviscosity syndrome include oronasal bleeding, blurred vision, sudden deafness, headache, confusion, and heart failure as a result of plasma volume expansion

Type I cryoglobulinemie

Kliniek: met name huidmanifestaties; purpura, livedo reticularis, Raynaud's phenomenon, acrocyanosis, skin necrosis, ulcers and, infrequently, digital gangrene. Extracutaneous disease includes peripheral neuropathy, arthralgia and renal disease (renal biopsies show membranoproliferative glomerulonephritis (MPGN) with immune cell infiltration, glomerular thrombi, and microtubular deposits composed of the cryoglobulin aggregates).

Behandeling: indien symptomatisch, onderliggend lijden behandelen.

  • MM, treatment options follow MM consensus recommendations.

    • renal failure; bortezomib-based regimen

    • neuropathy; lenalidomide-based treatment

  • WM, bortezomib (cave IgM flare bij Rituximab, overweeg plasmaferese)

  • Indien hyperviscositeit; plasmaferese

Mixed cryoglobulinemie

Kliniek: vaker geassocieerd met B-symptomen (koorts, malaise, myalgie en anorexie). Meltzer's trias: purpura, arthralgia, and weakness (echter maar in 33%).

Behandeling: