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CRYOGLOBULINEMIA and viral associations.pptx
- 1. CRYOGLOBULINEMIA PRESENTER – DRJAISH MODERATOR – DR YOUSUFF
- 2. Outline • INTRODUCTION • CLASSIFICATION •HEPATITIS C VS NON HEPATITIS CRYOGLOBULINEMIA • PATHOGENESIS • CLINICAL FEATURES • MICROSCOPY • INVESTIGATIONS • TREATMENT
- 3. INTRODUCTION • Cryoglobulinaemia isdefined as the presence of cryoglobulins in the serum, which are immunoglobulins that reversibly precipitate and form a gel when the temperature is 37 °C • Hepatitis C – 80 to 90% • MCs represent 60–75% of all cryoglobulinaemias, and are found in connective tissue diseases, and infectious or lymphoproliferative disorders, that is, secondary MC.
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- 7. Hepatitis C virusmixed cryoglobulinaemia and kidney disease
- 8. Non-HCV mixed cryoglobulinaemic vasculitis •Prevalence of the disease was reported as approximately 1:100,000 individuals • idiopathic cryoglobulinaemia vasculitis is considered to be a rare disorder, but no recent study has evaluated the prevalence of the disease. Idiopathic cryoglobulinaemia vasculitis appears more common in patients aged 45–65 years, with a maximum incidence in women • worse prognostic factors were age (> 60 years) and renal involvement • The rates of most clinical and immunological manifestations of MC vasculitis are quite similar in HCV-positive and -negative patients • renal manifestations are more frequently reported in HCV-negative patients, in 14–63 % of patients • Renal involvement was characterized by microscopic haematuria in all patients, nephrotic range proteinuria in 75% of patients, hypertension in 80% of patients, and renal failure in 85%
- 9. Pathogenesis High concentrations ofHCV envelope protein E2 in vitro stimulate B-cell expansion via interaction with CD81, a known HCV E2 entry factor IgG-bound HCV specifically drives the clonal expansion of B cells secreting IgM RF Monoclonal B-cell expansion leading to type II MC may evolve into frank B-cell non-Hodgkin lymphoma. (10%) Transformation from polyclonal B-cell proliferation (type III MC) to oligo/monoclonal B cell proliferation (type II MC) and to the overt malignant lymphoma is a multistep process probably requiring multiple mutagenic events
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- 13. Necrosis in patientswith Cryoglobulinemia
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- 15. CRYOGLOBULINEMIA AND RENALDISEASE • The first clinical manifestations of type II MC usually appear in the fourth to fifth decade of life. • More common in Women outnumber men • Cryoglobulins are deposited in the mesangium during their trafficking in the glomerulus. • They can also be seen as intense subendothelial IgM deposits by immunofluorescence. • Their nephrotoxicity is related to special affinity of the IgMκ RF for cellular fibronectin present in the mesangial matrix • Only the RF isolated from cryoprecipitable type II MC had specific affinity; all the other monoclonal RFs are not able to fix fibronectin • Cryoglobulins can also be deposited in the glomerular capillaries as eosinophilic thrombi and this is usually associated with vasculitis and fibrinoid necrosis of the glomeruli
- 16. • Immune complexescontaining HCV antigens have been observed in the mesangium of patients with cryoglobulinaemia leading to mesangial expansion • The presence of HCV-related proteins in the mesangium has been associated with higher proteinuria, possibly reflecting direct mesangialdamage by HCV . • An increased expression of toll-like receptors has been found in the mesangial cells target of HCV-related MPGN, but not non-HCV MPGN.
- 17. Case series • Inlarge series was made by Roccatello et al. (2007), who included 146 patients with cryoglobulinaemic nephritis, of whom 87% (N = 127) were HCV positive. • Type II cryoglobulin (IgG/IgMκ) occurred in 74.4% of cases. The remainder had type III cryoglobulins. • A diffuse MPGN was the most common histologic pattern (83%). • Survival at 10 years was about 30% and cardiovascular disease was the cause of death in > 60% of patients; additional causes of death included infections (10%), hepatic failure (19%), and neoplasia (3%). • Poor Prognosis – Elevated Creatinine (>1.5mg/dl) , Nephrotic range Proteinuria ,Severe Hypertension , >50% cresents or Marked IFTA
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- 25. Cryoprecipitate A. 10 to20 mL of blood is collected and prepared at 37°C without the addition of anticoagulants. The serum is then centrifuged and then refrigerated to allow precipitation of cryoglobulin. B. Type I cryoglobulinemia presents as a precipitate within 24 hours with a 3 to 5-day window. Type II/III present with precipitation approximately 5 to 7 days after initial refrigeration C. Cryocrit in individuals without cryoglobulinemia is close to zero, and a cryocrit greater than 0.5 to 1 percent or concentration over 50 mcg/mL is significant. D. In type II, cryocrit is between 2 to 7 percent, while type III holds to around 1 to 3 percent Predictive measure for cryoglobulinemia is based on the measurement of cryoglobulin coupled with a low C4 complement level. This combination is typical of cryoglobulinemia syndromes
- 27. Indications for RenalBiopsy
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- 34. • Two RCTshave demonstrated the superiority of rituximab monotherapy as compared with conventional immunosuppressive therapy (i.e., corticosteroids, azathioprine, cyclophosphamide, methotrexate, and plasma exchange) for the treatment of HCV- associated cryoglobulinemic vasculitis
- 35. Rituximab • Rituximab interfereswith synthesis of cryoglobulins, monoclonal IgM, and renal deposition of immune complexes. • An important pathogenetic feature of mixed cryoglobulinemia (including cryoglobulinemic GN) is chronic stimulation of B lymphocytes by HCV and widespread autoantibody synthesis related to HCV-induced lowering of the cell activation threshold. • Potential regimens include rituximab (375 mg/m2 weekly for 4 weeks, or 2 doses of 1 g given 14 days apart) with or without corticosteroids
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