CRYOGLOBULINEMIA and its pathophysiology

all about cryoglobulinemia

1. CRYOGLOBULINEMIA PRESENTER – Dr Gaurav DM Nephrology Resident

2. Outline INTRODUCTION CLASSIFICATION HEPATITIS C VS NON-HEPATITIS CRYOGLOBULINEMIA PATHOGENESIS CLINICAL FEATURES MICROSCOPY INVESTIGATIONS TREATMENT

3. INTRODUCTION Cryoglobulinemia is defined as the presence of cryoglobulins in the serum, which are immunoglobulins that reversibly precipitate at 4 °C and form a gel when the temperature is 37 °C Hepatitis C – 80 to 90% of cases Mixed Cryoglobulinemia represent 60–75% of all cryoglobulinemia's, and are found in connective tissue diseases, and infectious or lymphoproliferative disorders .

4. Bourets Classification

5. Etiology

6. Hepatitis C virus mixed cryoglobulinemia and kidney disease

7. Pathogenesis High concentrations of HCV envelope protein E2 in vitro stimulate B-cell expansion via interaction with CD81, a known HCV E2 entry factor IgG-bound HCV specifically drives T he clonal expansion of B cells secreting IgM RF M onoclonal 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

8. Extra Hepatic Manifestations

9. Clinical Features

10. CLINICAL FEATURES

11. PURPURIC LESIONS

12. Necrosis in patients with Cryoglobulinemia

13. Non-HCV mixed cryoglobulinaemic vasculitis P revalence reported as approximately 1:100,000 individuals Idiopathic cryoglobulinemia vasculitis is considered to be a rare disorder, but no recent study has evaluated the prevalence of the disease. Idiopathic cryoglobulinemia vasculitis appears more common aged 45–65 years, maximum incidence in women Worse prognostic factors were age (> 60 years) and renal involvement

14. 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 hematuria in all patients, nephrotic range proteinuria in 75% of patients, hypertension in 80% of patients, and renal failure in 85% Type I cryoglobulinemia develops in the setting of protein-secreting monoclonal gammopathies such as a monoclonal gammopathy of undetermined significance (MGUS) or a B-cell lineage malignancy ( eg , multiple myeloma, Waldenström macroglobulinemia, or chronic lymphocytic leukemia )

15. CRYOGLOBULINEMIA AND RENAL DISEASE 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

16. 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 Immune complexes containing 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 In large series was made by Roccatello et al. (2007), who included 146 patients with cryoglobulinemic nephritis, of whom 87% (N = 127) were HCV positive. Type II cryoglobulin (IgG/IgM κ) 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% crescents or Marked IFTA

18. Cryoglobulinemia PAS-positive findings in skin biopsy deposits can help differentiate type I cryoglobulinemia from other thrombotic vasculopathies Cryoglobulinemic glomerulonephritis PAS-positive cryo-plugs in capillary lumens are a key diagnostic feature. Other features include chunky, irregular capillary wall deposits, globular intracapillary deposits, and a double-contour appearance of the basement membrane on silver stain PAS-positive intracapillary deposits in the kidney glomeruli can help distinguish between vasculitis associated with infections, medications, or autoimmune diseases not involving cryoglobulins

19. Light Microscopy

20. A Double-contour Appearance Of The Basement Membrane On Silver Stain

21. Immunofluoresence

22. Electron Microscopy

23. Treatment Treatment of cryoglobulinemia depends upon the underlying disorder and upon the severity and nature of involvement Hepatitis C virus (HCV)-associated cryoglobulinemic vasculitis used to be a severe disease with an estimated five-year mortality rate of 25 percent Apart from liver fibrosis, the prognosis of HCV-associated cryoglobulinemic vasculitis is mainly dependent on vasculitic involvement of the kidney, central nervous system, heart, and gastrointestinal tract

24. Hepatitis C Diagnosis

25. Collection 10 to 20 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. 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 ryocrit 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. In type II, cryocrit is between 2 to 7 percent, while type III holds to around 1 to 3 percent P redictive measure for cryoglobulinemia is based on the measurement of cryoglobulin coupled with a low C4 complement level. This combination is typical of cryoglobulinemia syndromes

26. Indications for Renal Biopsy

27. Management

28. Anti Viral Agents

29. Anti Viral Agents

30. Therapy

31. Two RCTs have 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

32. Rituximab Rituximab interferes with 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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