Thyroid cancer in HCV-related mixed cryoglobulinemia patients

OBJECTIVE: The prevalence of thyroid cancer in a series of unselected HCV-related mixed cryoglobulinemic patients was investigated in comparison with a control group. METHODS: Among 107 consecutive patients with mixed cryoglobulinemia (MC), 94 were eligible for the study. A control group was obtained from a sample of the general population (2,401 subjects), age > 50 years, who had undergone thyroid ultrasonography (582 subjects); 5 sex-matched controls were randomly assigned to each MC patients (470 individuals). The mean age was similar in the MC patients and controls (64.2 +/- 10.0 vs. 63.4 +/- 7.0). RESULTS: The prevalence of thyroid nodules was higher, although not significantly so, in control subjects than in MC patients (65.3 vs. 54.8%). Two patients with papillary thyroid cancer were found in the MC series, while no case was observed among controls (p = 0.001, chi-square P value; p = 0.02, Fisher's exact test). In both MC patients with papillary thyroid cancer lymphocytic infiltration was observed in the thyroid tissue. CONCLUSION: The possible association between HCV-related MC and thyroid cancer indicates that a careful monitoring of the thyroid would be opportune during the clinical follow-up of HCV-associated MC patients, especially in those with signs of thyroid autoimmune disorders.     

Peripheral nervous system involvement in HCV-related mixed cryoglobulinemia

In HCV-related mixed cryoglobulinemia (MC) a peripheral neuropathy (PN) may occur. To evaluate the prevalence and the characteristics of PN, 133 consecutive patients with HCV-MC (117 type II, 16 type III) were studied. Neurologic evaluation was performed according to the guidelines of Italian Group for the Study of Cryoglobulinemias, using a neurological disability score and a neurological symptom score. In 52/133 patients an electrophysiologic study (ENG) of ulnar, peroneal and sural nerves was performed. For 27/52 patients ENG data registered at different times (interval 12-96 months) were available. In 11 patients a sural nerve biopsy was obtained. An overt PN, mostly as sensory asymmetrical or symmetrical nerve impairment, was found in 107/133 patients (80.4%). ENG abnormalities-reduction or absence of sensory and sometimes of motor action potential, normal or slightly impaired nerve conduction velocity, consistent with axonal damage- were detected in 48/52 patients (92.3%). In 26 out of the 27 patients observed at different times an evolution of PN was found. Nerve biopsies showed a prevalent axonal damage, swollen endothelial cells in epi- and perineurial vessels and scarce mononuclear perivascular infiltrates. No leukocytoclastic vasculitis was observed. Immunoglobulins and complement in sub-perineurial vessel wall were detected. CONCLUSIONS: In HCV-MC a PN is frequent. It is mostly a sensory and progressively worsening axonopathy. Different mechanisms may be involved in the pathogenesis of this disorder and a direct role of HCV cannot be excluded.     

Cerebral vasculitis in a patient with HCV-related type II mixed cryoglobulinemia.

The peripheral nervous system is often involved in patients with mixed cryoglobulinemia (MC), while there are few reports of central nervous system involvement. We describe a case of HCV-related type II MC with peripheral and central nervous system involvement. A 61-year-old woman, suffering from flaccid tetraparesis, was referred to our department because of an increasing disability. The presence of delirium prompted us to also investigate the central nervous system. MMSE, EEG, EMG, brain CT-scan, color-Doppler of neck vessels, retinal fluorangiography and brain MRI were performed. These investigations suggested a cerebral vasculitis. The finding of very low C4 serum levels, together with high rheumatoid factor serum levels, suggested the search for cryoglobulins. The laboratory findings showed a HCV-related type II (IgMk) MC. A marked improvement of symptoms and of laboratory data was obtained by treatment with methylprednisolone + cyclophosphamide.     

Improvement in liver cirrhosis after treatment of HCV-related mixed cryoglobulinemia with rituximab

Mixed cryoglobulinemia (MC) is the most strictly virus-related extrahepatic HCV disease. Antiviral therapy is considered the first therapeutic option; however, MC patients are frequently excluded from treatment due to contraindications. The effectiveness of B-cell depletion by anti-CD20 monoclonal antibody (rituximab) has recently been described, but the possibility of an immunodepression- related increase in viral replication and aminotransferase values limits its use in patients with advanced liver disease. Unfortunately, MC patients frequently also have cirrhosis. To our knowledge, no data are available regarding the effect of rituximab therapy in patients with decompensated cirrhosis.We report the successful treatment with rituximab (4 weekly infusions of 375 mg/m 2) of two patients (a 58-year-old man, and a 65-year-old woman) with HCV-related MC syndrome and decompensated liver cirrhosis. These patients underwent at least 6 months of post-treatment follow-up. In both cases a consistent improvement of MC syndrome was evident after treatment. In addition, improvement of liver protidosynthetic activity, increased prothrombin time, impressive reduction or disappearance of ascites and encephalopathy were also observed, in spite of some increase in viral titers or in ALT values. The Chil&Pugh score improved from B8 to A6 and from Cll to B7, respectively. Pre- and post-treatment transjugular liver biopsies were available in 1 patient, showing disappearance of lymphocytic infiltration after treatment.These case reports show the effectiveness and safety of rituximab in patients with HCV-related MC and advanced cirrhosis, and strongly suggest that the depletion of CD20 + B-cells induced by rituximab treatment may be responsible for liver function improvement. The mechanisms involved are uaaknown. Interesting working hypotheses may implicate a role played by B-cell infiltrates in conditioning liver damage. The improvement of Kupffer cell function due to the cryocrit value reduction might also play a role.     

Necrotizing acute pancreatitis following therapeutic plasmapheresis in HCV-related cryoglobulinemia

Mixed cryoglobulinemia and hepatitis C virus infection are strongly connected and the therapeutic approach is standardized according to the severity of the symptoms. We report the difficult management of 59 year old female HCV patient presenting cutaneous lesions and arthralgia due to mixed cryoglobulinemia. No therapy was able to achieve a complete remission and during the six years of active disease we observed several clinical recurrences. The intensive plasmapheresis regimen led to a complete remission of the symptoms but it was associated with severe complications. In this case report we describe an episode of acute necrotizing pancreatitis due to intravascular haemolysis following therapeutic plasmapheresis. To the best of our knowledge the association between plasmapheresis and acute pancreatitis has not been previously described.     

CD5/CD20 expression on circulating B cells in HCV-related chronic hepatitis and mixed cryoglobulinemia

The role of CD5⁺ B cells in patients with HCV infection and HCV-related disorders, including mixed cryoglobulinemia (MC), has been addressed in previous reports with conflicting results. We established a correlation between CD5/CD20 expression on circulating B lymphocytes, characterizing monoclonal B cell lymphocytosis (MBL), and clinical features in a cohort of 45 patients with chronic HCV hepatitis [without MC: 23 patients (MC- group); with MC: 22 patients (MC+ group)], and 45 HCV-negative healthy subjects as controls. By flow cytometry analysis, three B cells phenotypes were singled out: 1) CD5⁺CD20^dim (CLL-like phenotype); 2) CD5⁺CD20^bright (atypical phenotype); and 3) CD5^-CD20⁺ phenotype. CD5⁺CD20^bright cells were reduced in MC- patients (p=0.049). CD5⁺CD20^dim B cells were significantly higher in group B than in the control group (p=0.003). ROC curve analysis in MC+ patients showed the highest positive likelihood ratio at ≥7.35% (p=0.008) for CLL-like phenotype and at ≤63.6% (p=0.03) for the CD5^-CD20⁺ B cell phenotype. HCV infection was associated with a higher frequency of CLL-like (odds ratio=16, p=0.002) and a lower frequency of atypical (odds ratio: 3.1, p=0.02) and CD5^-CD20⁺ (odds ratio: 11, p=0.01) phenotypes. The association with higher levels of CLL-like phenotype progressively increased from group of MC- patients (odds ratio: 9.3, p=0.04) to the group of MC+ patients (odds ratio: 25.1, p=0.0003).ConclusionsThe occurrence of a CLL-like pattern may allow to identify HCV-infected patients at risk of developing MC and eventually non-Hodgkin lymphoma, who should require a closer surveillance and a longer follow-up.     

Essential mixed cryoglobulinemia type II

We report a rare case of essential mixed cryoglobulinemia type II with membrano-proliferative glomerulonephritis (MPGN) type I in which HCV was not found. Long-term history of palindromic rheumatism, skin leukocytoclastic vasculitis attacks and micro-normocytic anemia preceded the appearance of cryoglobulinemia. Cryoprecipitate consisted of monoclonal IgMk-RF and polyclonal IgG (essential mixed type II). The newly appreciated cryoglobulinemia was associated with Coombs positive hemolytic anemia. The MPGN in this case had a benign course and responded to complex simple therapies including prevention of exposure to cold, low antigen content diet, treatment of provoking factors such as UTI, and maximal dose of ACE inhibitor. Responsiveness of skin vasculitis to colchicine therapy was restored after a two-month colchicine withdrawal period and therefore corticosteroid and immunosuppressive therapy was postponed.     

Lymphocyte subpopulation in essential mixed cryoglobulinemia

Lymphocyte subpopulations were evaluated in 31 patients affected by essential mixed cryoglobulinemia, using OKT3, OKT4, and OKT8 monoclonal antibodies in a cytotoxic assay. The patients with essential mixed cryoglobulinemia had a normal number of OKT3+ and OKT4+ cells but significantly lower values of OKT8+ cells compared to healthy controls. When the OKT4+/OKT8+ ratio was considered, patients could be subdivided into 3 main subgroups: 6 patients had a low OKT4+/OKT8+ ratio, 10 patients had a normal ratio, and 15 had a high ratio. This ratio did not correlate with age, sex, disease duration, low corticosteroid therapy or serological hallmarks of the disease. In contrast, purpura and liver involvement were more prevalent in patients with a normal or high OKT4+/OKT8+ ratio, while lung involvement was more prevalent in patients with a low ratio.     

Hla antigens in essential mixed cryoglobulinemia

HLA antigens were studied in 36 patients with essential mixed cryoglobulinemia. The antigens that showed the largest percentage of deviations from the control group were DRw3 (40% versus 20%), DRw8 (32% versus 11.5%), and Cw6 (5.6% versus 20.7%). None of these changes, however, was significant when the P values were corrected for the number of specificities scored for each locus. These data indicate that essential mixed cryoglobulinemia is not strongly associated with any of the HLA antigens serologically determined, but there was a suggestion that certain manifestations, particularly renal involvement, are related to a specific haplotype.