Severe hypertriglyceridaemia in idiopathic (non-HCV-related) mixed cryoglobulinaemia

We describe a 28-year-old male patient in whom the development of idiopathic mixed cryoglobulinaemia (MC) with typical clinical manifestations such as polyarthralgia, weakness, purpura, and Raynaud's phenomenon was associated with a remarkable increase in serum triglycerides (TG). Prednisone administration was effective in classical cryoglobulinaemia symptoms and also in dyslipidaemia. Infective, autoimmune, and haematological disorders are often related to cryoglobulinaemia and it has been analysed that some of them also show an increase in TG.     

Recovery from hepatitis C virus-positive cryoglobulinaemic glomerulonephritis after interferon therapy

The association between mixed cryoglobulinaemia and chronic hepatitis C virus infection has recently been described. Cryoglobulinaemic glomerulonephritis, a complication of mixed cryoglobulinaemia, is usually treated with immunosuppressive therapy, but, given the presence of viral infection, this therapy is no longer recommended. This report concerns a case of a 30-year-old patient with cryoglobulinaemic glomerulonephritis, refractory to steroid treatment, in whom recovery from hepatitis C virus infection was obtained as well as from cryoglobulinaemic glomerulonephritis after interferon therapy. The clinical symptoms and laboratory tests were normal after prolonged interferon therapy and, 3 years after the end of treatment, the patient is free from disease.     

Coexistence of B-cell non-Hodgkin lymphoma and cutaneous T-cell lymphoma in a patient with chronic hepatitis C and cryoglobulinaemia

The coexistence of chronic active hepatitis C with cryoglobulinemia and B-cell lymphoma has been presented in numerous case reports. However, the combination of these conditions with T-cell lymphoma has never been described before. We present the case of a patient who suffered chronic active hepatitis C, cryoglobulinaemia and B-cell lymphoma and was later complicated by cutaneous T-cell lymphoma (CTCL).     

Systemic lupus erythematosus preceded by long-term cryoglobulinaemia.

A patient with cryoglobulinaemia who developed systemic lupus erythematosus (SLE) 10 years later on is described. The relationship between these 2 conditions and the possibility that cryoglobulinaemia was the early presentation of SLE are discussed.     

Hepatitis C virus infection with peripheral neuropathy is not always associated with cryoglobulinaemia

OBJECTIVES: To describe cases of peripheral neuropathy associated with chronic hepatitis C virus infection without mixed cryoglobulinaemia. METHODS: Four cases of peripheral neuropathy associated with chronic hepatitis C virus infection with persistent negativity of mixed cryoglobulinaemia were found. RESULTS: All patients had small increases of transaminase levels and a positive viraemia. Liver biopsy showed chronic active hepatitis in all but one case (Knodell 4-9, Metavir A0F0-A3F3). Neuromuscular biopsy showed axonal neuropathy associated with lymphoid infiltrates around small vessels in two cases. Rheumatoid factor was always negative and C4 complement level was always normal. In three patients, neuropathy improved with interferon alpha, interferon alpha + ursodesoxycholic acid, or steroids + plasma exchange. CONCLUSION: Peripheral neuropathy may be associated with hepatitis C virus infection without mixed cryoglobulinaemia.     

Treatment of refractory antibody mediated autoimmune disorders with an anti-CD20 monoclonal antibody (rituximab)

BACKGROUND: Rituximab, a chimeric monoclonal anti-CD20 antibody, has recently been used for the treatment of refractory antibody mediated autoimmune diseases such as immune mediated thrombocytopenia and haemolytic anaemia. PATIENTS: Because of its novel mechanism of action, rituximab was used to treat three patients with refractory systemic antibody mediated autoimmune disorders. The first patient, a 71 year old woman with idiopathic type II mixed essential cryoglobulinaemia, had both dermatological and neurological manifestations with marked renal disease attributed to her cryoglobulinaemia. Patient 2, a 73 year old woman with Goodpasture's syndrome, was refractory to conventional treatment (cyclophosphamide, prednisone, plasmapheresis). She had persistent haemoptysis and haematuria and positive antiglomerular basement membrane antibodies. The third patient, a 75 year old man with primary biliary cirrhosis, myelodysplasia, and systemic immune complex vasculitis, had progressive renal insufficiency, a macular erythematous rash, and severe thrombocytopenia. RESULTS: Treatment with rituximab resolved all clinical and laboratory manifestations in the three patients. CONCLUSIONS: Rituximab may be an important therapeutic agent for the treatment of patients refractory or intolerant to corticosteroid or cytotoxic treatment, or both.     

Cryoglobulinaemia among maintenance haemodialysis patients and its relation to hepatitis C infection

It has been shown that hepatitis C virus (HCV) infection is closely associated with mixed type cryoglobulinaemia. It is also known that HCV infection is rampant among chronic haemodialysis patients. We studied 531 renal failure patients on maintenance dialysis including 170 with positive HCV antibodies for cryoglobulinaemia, and its incidence was compared with controls which consisted of 242 chronic hepatitis C patients without renal failure and 183 healthy adults. Cryoglobulinaemia was present in 30.6% of dialysis patients with HCV infection, 10.8% of dialysis patients without HCV infection, 29.8% of patients with chronic hepatitis C without renal failure, and 0% of healthy adults. Among the 30 new renal failure patients who were started on dialysis within 6 months, four were positive for HCV antibodies, and one of them had cryoglobulinaemia; of the 26 HCV-negative patients, four (15%) were cryoglobulinaemic. The cryocrit values among dialysis patients were much lower than those of the control cases and other reports on non-dialysis cases. Patients with cryoglobulinaemia were generally younger compared with patients negative for this condition. There was no correlation between cryoglobulinaemia and past blood transfusion, underlying disease or length of dialysis. Cryoglobulinaemic patients seem to develop renal failure at relatively young ages and a considerable proportion of cryoglobulinaemic dialysis patients may have already had cryoglobulinaemia at the time of the start of haemodialysis. There was no indication that the presence of cryoglobulin in serum adversely affects the liver disease nor increases serum virus load in HCV-infected dialysis patients. Thus, it was concluded that although HCV infection has a certain role in the development of cryoglobulinaemia in dialysis patients, they develop cryoglobulinaemia less frequently and produce cryoglobulin to a lesser degree in the presence of HCV infection as compared with non-dialysis patients.     

Clonal B-cell expansions in peripheral blood of HCV-infected patients

Summary. Clonal expansions of IgM-producing B cells were investigated in 38 patients with a chronic hepatitis C virus infection. Eight patients were affected with type II mixed cryoglobulinaemia (two of whom also had non-Hodgkin's lymphoma and one had Waldenstrom's disease), one with type III mixed cryoglobulinaemia, one with Waldenstrom's disease, and 28 with chronic liver disease. To detect the clonal B-cell expansions we used a RT/PCR procedure in which the CDR3/FW4 regions of the IgM heavy chain mRNAs were amplified and resolved in sequencing poly-acrylamide gels. Clonal Ig gene rearrangements were detected in all patients with type II mixed cryoglobulinaemia and also at a high frequency (24%) in the HCV-infected patients without cryoglobulinaemia. A polyclonal pattern was present in the patient with type III mixed cryoglobulinaemia and in the 15 normal individuals and 16 age-related patients with HCV-negative alcoholic liver disease which were investigated as controls. No association was found between the presence of a clonal B-cell expansion and age, sex, liver histology, or levels of serum aminotransferase. The serum levels of rheumatoid factor were increased in all patients with a clonal expansion, suggesting that the expanded B-cell clones belong to the rheumatoid factor producing B-cell subset.     

Cryoglobulinémie mixte symptomatique au cours de l’hépatite virale C

Cryoglobulins are immunoglobulins that reversibly precipitate in the cold. They may lead to an immune complex-mediated vasculitis, which may sometimes be severe. A wide range of conditions may be related to cryoglobulinaemia, and the most frequent of them is chronic hepatitis C. The purpose of this work was to emphasize the diagnostic and therapeutic characteristics of cryoglobulinaemia associated with hepatitis C. A 55-year-old woman, with a history of arterial hypertension, was admitted with transudative ascites. Clinical investigation revealed purpuric lesions and oedema of the lower limbs with Raynaud phenomenon. Proteinuria and haematuria were detected in the urine test strip. The patient had a positive serology for hepatitis C, but no signs of portal hypertension. Further investigations showed renal failure with nephrotic syndrome. Renal biopsy showed membranous proliferative glomerulonephritis with parietal and mesangial deposits of IgM and IgG antibodies. Skin biopsy showed leucocytoclastic vasculitis. Immunological investigations found type IIb mixed cryoglobulinaemia associated with hepatitis C. The patient was treated by pegylated interferon and ribavirin. She showed a satisfactory clinical and a sustained virological response for 1 year after the withdrawal of therapy. Mixed cryoglobulinaemia is the main extrahepatic manifestation of hepatitis C, but it is rarely symptomatic. The combination of peginterferon-α and ribavirin leads to virological and clinical responses of vasculitis in most patients.     

Triple antiviral therapy in hepatitis C virus infection with or without mixed cryoglobulinaemia: A prospective,controlled pilot study

BackgroundMixed cryoglobulinaemia is strongly related to hepatitis C virus infection. Treatment with peg-interferon and ribavirin has been indicated as first-line therapy for mild/moderate hepatitis C virus-related mixed cryoglobulinaemia.AimTo evaluate the safety and efficacy of triple boceprevir-based antiviral therapy in patients with or without mixed cryoglobulinaemia previously treated with peg-interferon and ribavirin, and with advanced liver disease.MethodsThirty-five hepatitis C virus-positive patients (17 with asymptomatic mixed cryoglobulinaemia, 5 with symptomatic mixed cryoglobulinaemia, and 11 without mixed cryoglobulinaemia) were treated with triple boceprevir-based antiviral therapy.ResultsIn 19/22 cryoglobulinaemic subjects (86%), the addition of boceprevir induced cryocrit disappearance. Cryocrit behaviour was related to virological response, with improvement of symptoms upon undetectable viraemia and reappearance after virological breakthrough. The rate of sustained virological response was lower in cryoglobulinaemic patients than in patients without mixed cryoglobulinaemia (23.8% vs 70% respectively, p = 0.01).ConclusionBoceprevir-based therapy was safe and effective in cryoglobulinaemic patients. The correlation between direct inhibition of hepatitis C virus replication and clinical improvement in mixed cryoglobulinaemic patients is definitive proof of the key pathogenetic role played by viral replication. Further studies are needed to confirm and clarify the reduced virological response in patients with mixed cryoglobulinaemia.     

Life-threatening acute pulmonary haemorrhage in primary Sjögren's syndrome with cryoglobulinaemia

We describe a woman with primary Sj?gren's syndrome who presented with an acute pulmonary-renal syndrome resulting from cryoglobulinaemic vasculitis. Pulmonary manifestations of Sj?gren's syndrome are relatively common, whereas overt pulmonary complications of cryoglobulinaemia are rare. Pulmonary haemorrhage is rare in either disorder. The combination of Sj?gren's syndrome, cryoglobulinaemia, and acute pulmonary haemorrhage has not been previously reported.     

SICKLEMIA WITH MULTI-ORGAN FAILURE SYNDROME AND THROMBOTIC THROMBOCYTOPENIC PURPURA

Acute multi-organ failure syndrome is a rare and life-threatening complication of patients with sickle cell disease. The syndrome appears to be reversed with prompt, aggressive exchange transfusion therapy. It has been attributed to widespread vascular occlusion due to micro-vascular red cell sickling. We present a case of severe multi-organ failure in a patient with sickle thalassemia and mild clinical course, who had clinical and laboratory features consistent with thrombotic thrombocytopenic purpura (TTP). The dramatic response to therapy with plasma exchange, a treatment often effective in TTP, suggests a similarity in pathophysiology of micro-vascular occlusion and multi-organ failure in sickle cell disease.     

The cryoglobulinaemias

Cryoglobulins are immunoglobulins that precipitate in vitro at temperatures less than 37°C and produce organ damage through two main pathways: vascular sludging (hyperviscosity syndrome, mainly in type I cryoglobulinaemia) and immune-mediated mechanisms (principally vasculitis, in mixed cryoglobulinaemia). Cryoglobulinaemia is associated with many illnesses, which can be broadly grouped into infections, autoimmune disorders, and malignancies; the most common cause is infection with hepatitis C virus. Mixed cryoglobulinaemic syndrome is diagnosed when a patient has typical organ involvement (mainly skin, kidney, or peripheral nerve) and circulating cryoglobulins. Cutaneous purpura is the most common manifestation of cryoglobulinaemic vasculitis. The most frequently affected internal organs are the peripheral nerves, kidneys, and joints. The course varies widely and prognosis is influenced by both cryoglobulinaemic damage to vital organs and by comorbidities associated with underlying diseases. More than 90% of cases of cryoglobulinaemia have a known underlying cause; therefore treatment is focused on the cause of the disorder rather than merely symptomatic relief. Studies suggest that both combined or sequential antiviral therapies and targeted biological treatments might be more effective than monotherapy.     

Coeliac disease, vasculitis, and cryoglobulinaemia

Four patients are described with the association of adult coeliac disease, vasculitis, and cryoglobulinaemia. In each patient the cryoglobulinaemia was of the mixed type consisting of more than one immunoglobulin class. It is suggested that the mixed cryoglobulins represent circulating immune complexes and that their deposition in small vessels causes the vasculitis. This is supported by immunofluorescent studies of skin biopsies from one of these patients. The significance of these findings in the four adult coeliac patients is discussed.     

Detection of cryoglobulins by Coulter Counter model S-Plus IV/D

Cryoglobulins may produce interference in results from electronic particle counters. Depending on their size, cold-precipitable globulin crystals can be counted as leucocytes and/or platelets. The Coulter Counter model S-Plus IV/D permits detection of this interference and its associated spurious counts by producing a characteristic WBC histogram accompanied by a leucocyte 'flag'. Using this instrument over a 1-year period, 10 cases of cryoglobulinaemia were detected, four from patients with lymphoproliferative disease and one from a patient with autoimmune disease. The remaining five were classified as essential mixed cryoglobulinaemia. The reproducibility of this instrument anomaly permits identification of the presence of cryoglobulins.     

Cryoglobulinaemia: clinical features and response to treatment

We report the clinical features and outcome of 16 patients with cryoglobulinaemia. Two patients with Type I cryoglobulinaemia both had IgG kappa monoclonal paraproteins. Nine of 10 with Type II disease had monoclonal IgM kappa and polyclonal IgG; one had monoclonal IgG kappa and polyclonal IgG in the cryoglobulin. Underlying disorders identified in 3 of the 4 Type III patients were Sjogren's syndrome, infective endocarditis, and non-A non-B hepatitis and HTLV III infection. The commonest presenting features were rash in 94 p. 100 (ulceration 25 p. 100), arthralgia in 63 p. 100 (erosive arthritis 32 p. 100), renal disease in 63 p. 100, neurological involvement in 56 p. 100, hepatomegaly in 32 p. 100 and splenomegaly in 32 p. 100. Major associated conditions were progressive bronchiectasis in one case, and severe peripheral vascular disease in another; underlying malignancy was found in 2 cases (lymphoma and malignant melanoma). Treatment was with plasma exchange (PE) and immunosuppressive drugs (ID) in 10, PE alone in 3, ID alone in 2 and antibiotics [corrected] in 1. Fourteen of 16 patients showed an initial clinical response and fall in cryoglobulin levels. Four patients have died, one each from gastro-intestinal haemorrhage, sepsis, pulmonary embolism and lymphoma. Of the remaining 12 patients, all are symptomatically controlled and 10 have persisting cryoglobulinaemia (3 on PE and ID, 2 on PE, 2 on ID and 3 on no treatment). Of the two cases in whom cryoglobulinaemia resolved, one (Type II) had received PE and ID and the other (Type III) had been treated with antibiotics and surgery for infective endocarditis.     

Clinical and virological findings in mixed cryoglobulinaemia

Abstract. Objectives . As a close relationship has been established between mixed cryoglobulinaemia and hepatitis C virus (HCV) infection, the clinical, histological and virological findings of patients affected by mixed cryoglobulinaemia were determined. Design . Hepatitis C virus infection was investigated by the presence of anti-HCV antibodies and PCR amplification of the 5′ untranslated region (5′ UTR), and the genotype of HCV was also determined according to Okamoto. A bone marrow biopsy was performed in all patients and liver and kidney biopsies when indicated. Subjects . Eighty-two subjects affected by mixed cryoglobulinaemia were enrolled in this study. Results . The prevalence of anti-HCV antibodies was high (83%); PCR amplification of the 5′UTR region was performed in 52 subjects and in 44 of them (85%) the results were positive. In the same subjects, the Core region amplification was positive in 46 cases (88%). A high prevalence of genotype II was found (54%). Chronic liver disease was present in 55 patients (67%). Bone marrow biopsies showed the presence of low-grade non-Hodgkin's lymphomas in 11 cases (13%). Membrano-proliferative glomerulonephritis was found in seven subjects (8%). Conclusions . Mixed cryoglobulinaemia is associated with HCV infection in the nearly all cases. Several HCV genotypes are involved in the pathogenesis of this disease. Mixed cryoglobulinaemia is associated with a high prevalence of chronic liver disease, low-grade non-Hodgkin's lymphomas and membranoproliferative glomerulonephritis.     

Sj?gren's syndrome,vasculitis, and cryoglobulinaemia associated with a monoclonal IgM (kappa) paraprotein with rheumatoid factor activity.

A patient is described with primary Sjögren's syndrome with an infrequently reported complication--vasculitis and cryoglobulinaemia due to a monoclonal IgM (kappa) paraprotein with rheumatoid factor activity. The clinical and theoretical implications are discussed.     

Autoimmunity and extrahepatic manifestations in hepatitis C virus infection

Hepatitis C virus (HCV) infection is associated with various extrahepatic manifestations: mixed cryoglobulinaemia, membranoproliferative glomerulonephritis and, in southern Europe, to some extent with porphyria cutanea tarda. The association of haplotype HLA B-8 and DR-3 mixed cryoglobulinaemia and HCV infection has recently been demonstrated. Interferon alpha therapy decreases hepatitis C viraemia and improves the clinical signs and biochemical abnormalities of cryoglobulinaemia. There seems to be a south-north gradient in the prevalence of HCV-associated cryoglobulinaemia. The rare combination of hepatitis C and panarteritis nodosa has still not been confirmed. The sicca syndrome also seems to be associated with hepatitis C virus, but this is not the typical Sj?gren syndrome. Existing studies have not answered the question of whether HCV plays a pathogenic role in the development of thyroid dysfunction and autoimmune thyroiditis. There seems to be a genetic predisposition for the manifestations of thyroid disease in the case of hepatitis C infection and interferon therapy. This predominantly affects women with haplotype HLA DR-3. Before beginning interferon therapy, these patients often show thyroid autoantibodies against the thyroid peroxidase and/or thyroglobulin. It is still unclear whether the rare combination of hepatitis C with aplastic anaemia and lymphoma has pathogenic aspects. These haematological manifestations are thought to be induced by the infection of haematopoietic cells with the hepatitis C virus. In rare cases, a stimulated HCV-induced interferon gamma synthesis by haematopoietic stem cells has been shown. Although an epidemiological association of hepatitis C with lichen planus, neuropathies and other diseases has been observed, the aetiological role and the pathogenic involvement of the hepatitis C infection remains unclear. Furthermore, the question of whether these extrahepatic diseases are autoimmune has not been clarified. On the other hand, a number of autoantibodies may be observed during the course of hepatitis C. Of particular interest are liver/kidney microsomal antibodies (LKM). Their occurrence in viral hepatitis may indicate an increased risk for treatment with interferons. In the clinical setting, the presence of these diseases should suggest hepatitis C infection and hepatitis C antibodies should be tested and, if positive, hepatitis C-RNA is indicated. If there is any evidence of an aetiological association of replicative hepatitis C infection and the above-mentioned extrahepatic diseases, antiviral treatment should be considered.     

Coulter S Plus STKR histograms detect spurious elevation of leucocyte and platelet counts associated with cryoglobulinaemia

Summary Abnormalities in the size frequency histogram generated by the Coulter S Plus STKR at room temperature raised the possibility of the presence of a cryoglobulinaemia in a man admitted to the hospital with pneumonia. The leucocyte and platelet counts generated by the Coulter S Plus STKR were higher when counts were done at room temperature than counts done at 37°C. Further investigation of the patient revealed the presence of Non-Hodgkin's Lymphoma which had not been suspected on clinical grounds. The importance of testing samples at 37°C, where an abnormality in the Coulter S Plus STKR histogram has been detected at room temperature, is emphasized.